BR112018000080B1 - BICYCLIC LACTAMS AND METHODS OF USE THEREOF - Google Patents

Abstract

BICYCLIC LACTAMS AND METHODS OF USE THEREOF. The invention provides new compounds having the general formula I, wherein R1, X, Z1, L, n, ring A, ring B, and ring C are as described in this context, pharmaceutical compositions that include the compounds and methods of using the compounds.

Description

Remission to Related Requests

[0001] The present application claims priority under 35 U.S.C. 119(e) for U.S. provisional patent applications Nos. 62/188,153, filed on July 2, 2015, and 62/387,295, filed on December 23, 2015, The entire content of the aforementioned patent applications is included in this context by reference.

Technical Field

[0002] The present invention relates to organic compounds of use for therapy and/or prophylaxis in a mammal, and in particular to RIP1 kinase inhibitors of use for the treatment of diseases and disorders associated with inflammation, cell death and others. .

Background of the Invention

[0003] Receptor-interacting protein kinase-1 ("RIP1") is a serine/threonine protein kinase. RIP1 is a cell signaling regulator that is involved, among other things, in mediating programmed cell death pathways, e.g. necroptosis. The best-studied form of necroptotic cell death is initiated by TNFα (tumor necrosis factor), but necroptosis can also be induced by other members of the TNFα death ligand family (Fas and TRAIL/Apo2L), interferons, Toll (TLRs) signaling and viral infection through the DNA sensor DAI (DNA-dependent activator of interferon regulatory factor) [1-3]. The binding of TNFa to TNFR1 (TNF receptor 1) induces the trimerization of TNFR1 and the formation of an intracellular complex, Complex-I. TRADD (TNF receptor-associated death domain protein) binds to the intracellular death domain of TNFR1 and recruits the protein kinase RIP1 (receptor-interacting protein 1) through the death domain present in both proteins [ 4]. After initial recruitment into the TNFR1-associated signaling complex, RIP1 transfers to a secondary cytoplasmic complex, Complex-I [5-7]. Complex I is formed by the death domain that contains the protein FADD (Fas-associated protein), RIP1, caspase-8 and cFLIP. If caspase-8 is not fully activated or its activity is blocked, the protein kinase RIP3 is recruited to the complex, forming a necrosome, which will lead to the initiation of necroptotic cell death [8-10]. Once the necrosome is formed, RIP1 and RIP3 engage in a series of auto- and cross-phosphorylation events that are essential for necroptotic cell death. Necroptosis can be completely blocked by kinase-inactivating mutation in either of the two kinases, or chemically by RIP1 kinase inhibitors (necrostatins) or RIP3 kinase inhibitors [11-13]. Phosphorylation of RIP3 allows the binding and phosphorylation of the pseudokinase MLKL (lymphatic-type related kinase domain), a key component of necroptotic cell death [14, 15].

[0004] Necroptosis has crucial pathophysiological relevance in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel diseases, retinal degeneration and a series of other common clinical disorders [16]. For this reason, selective inhibitors of RIP1 kinase activity are therefore desired as a potential treatment of diseases mediated by this pathway and associated with inflammation and/or necroptotic cell death.

[0005] RIP1 kinase inhibitors have been previously described. The first published inhibitor of RIP1 kinase activity was necrostatin 1 (Nec-1) [17]. This initial discovery was followed by modified versions of Nec-1 with various abilities to block RIP1 kinase activity [11, 18]. Recently, other RIP1 kinase inhibitors have been described that differ structurally from the necrostatin class of compounds [19, 20, 21].

[0006] References cited herein above, each of which is included in this context by reference in its entirety: 1) Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. and Vandenabeele, P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nature reviews. Molecular cell biology. 15, 135-147, 2) Newton, K. (2015) RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends in cell biology. 25, 347-353, 3) de Almagro, M. C. and Vucic, D. (2015) Necroptosis: Pathway diversity and characteristics. Semin Cell Dev Biol. 39, 56-62, 4) Chen, Z. J. (2012) Ubiquitination in signaling to and activation of IKK. Immunological reviews. 246, 95-106, 5) O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C. and Ting, A. T. (2007) Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol. 17, 418-424, 6) Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D. P., Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G . and Leverkus, M. (2011) cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Molecular cell. 43, 449-463, 7) Bertrand, M. J., Milutinovic, S., Dickson, K. M., Ho, W. C., Boudreault, A., Durkin, J., Gillard, J. W., Jaquith, J. B., Morris, S. J. and Barker, P. A. (2008) cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 30, 689-700, 8) Wang, L., Du, F. and Wang, X. (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 133, 693703, 9) He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L. and Wang, X. (2009) Receptor interacting protein kinase-3 determinations cellular necrotic response to TNF-alpha. Cell. 137, 1100-1111, 10) Cho, Y. S., Challa, S., Moquin, D., Genga, R., Ray, T. D., Guildford, M. and Chan, F. K. (2009) Phosphorylation-driven assembly of the RIP1- RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 137, 11121123, 11) Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina, O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C. , Wagner, G., Hedrick, S. M., Gerber, S. A., Lugovskoy, A. and Yuan, J. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 4, 313-321, 12) Newton, K., Dugger, D. L., Wickliffe, K. E., Kapoor, N., de Almagro, M. C., Vucic, D., Komuves, L., Ferrando, R. E., French, D. M., Webster , J., Roose-Girma, M., Warming, S. and Dixit, V. M. (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 343, 1357-1360, 13) Kaiser, W. J., Sridharan, H., Huang, C., Mandal, P., Upton, J. W., Gough, P. J., Sehon, C. A., Marquis, R. W., Bertin, J. and Mocarski, E. S. (2013) Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. The Journal of biological chemistry. 288, 31268-31279, 14) Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J. and Liu, Z. G. (2012) Mixed lineage kinase domainlike is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proceedings of the National Academy of Sciences of the United States of America. 109, 5322-5327, 15) Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X. and Wang, X. (2012) Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase. Cell. 148, 213-227, 16) Linkermann, A. and Green, D. R. (2014) Necroptosis. The New England journal of medicine. 370, 455-465, 17) Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A. and Yuan, J. (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 1, 112-119, 18) Takahashi, N., Duprez, L., Grootjans, S., Cauwels, A., Nerinckx, W., DuHadaway, J. B., Goossens, V., Roelandt, R., Van Hauwermeiren, F., Libert, C., Declercq, W., Callewaert, N., Prendergast, G. C., Degterev, A., Yuan, J. and Vandenabeele, P. (2012) Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437, 19) Harris, P. A., Bandyopadhyay, D., Berger, S. B., Campobasso, N., Capriotti, C. A., Cox, J. A., Dare, L., Finger, J. N., Hoffman, S. J., Kahler, K. M., Lehr , R., Lich, J. D., Nagilla, R., Nolte, R. T., Ouellette, M. T., Pao, C. S., Schaeffer, M. C., Smallwood, A., Sun, H. H., Swift, B. A., Totoritis, R. D., Ward, P. , Marquis, R. W., Bertin, J. and Gough, P. J. (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243, 20) Najjar, M., Suebsuwong, C., Ray, S. S., Thapa, R. J., Maki, J. L., Nogusa, S., Shah, S., Saleh, D., Gough, P. J., Bertin , J., Yuan, J., Balachandran, S., Cuny, G. D. and Degterev, A. (2015) Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1, Cell Rep. 21) International Patent Publication N °. WO 2014/125444,

Summary of the Invention

[0007] In this context, compounds of formula I are provided: (I) or pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl; ring A is selected from the group consisting of cyclopropyl, 6-element aryl, and 5- to 6-element heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein ring A is optionally substituted by: (a) 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thio alkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in ring A is substituted, the substituent is not comprised of halogen, cyano, or a C1-C6 alkoxy, C1-C6 halo alkoxy, or C1-C6 thio alkyl endowed with an attached oxygen or sulfur atom directly to the nitrogen atom; (b) 1 substituent selected from the group consisting of C4-C6 heterocyclyl, C5-C6 heteroaryl, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), CH2CH2CH2-(C4-C6 heterocyclyl), CH2- (C5-C6 heteroaryl), CH2CH2-(C5-C6 heteroaryl); CH2CH2CH2-(C5-C6 heteroaryl); and optionally a second substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; or (c) two adjacent substituents that together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl; ring B is comprised of tetrazolyl or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein ring B is optionally substituted by 1 to 2 substituents selected from the group consisting of halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano ; and wherein if a nitrogen atom in ring B is substituted, the substituent is not comprised of halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thio alkyl which is endowed with an oxygen atom or sulfur linked directly to the nitrogen atom; ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, 4 to 7-membered cycloalkyl, and 4 to 7-membered heterocyclyl; wherein the C ring is optionally substituted by: (a) 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thio alkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in the C ring is substituted, the substituent is not comprised of halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thio alkyl endowed with a directly bonded oxygen or sulfur atom to the nitrogen atom; (b) 1 to 2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), and C5C6 unsubstituted heteroaryl; or (c) Two adjacent substituents that together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl; L is selected from the group consisting of a bond, O, S, NH, NCH3, (CH2)m, CH(CH3), C(CH3)2, CF2, CH2O, CH2S, CH(OH), CH2NH, and CH2N(CH3), or L is absent such that ring B and ring C are fused; X is selected from the group consisting of O, S, SO, SO2, CH2, C(CH3)2, CF2 and CHCF3; Z1 is selected from the group consisting of: (i) C and N when ring A is comprised of a 5- or 6-membered heteroaryl, (ii) C when ring A is comprised of a 6-membered aryl, and (iii) CH when ring A is comprised of cyclopropyl; m is comprised of 1 or 4; en is comprised of 1 or 2; from the moment that if ring A is comprised of 6-membered aryl or 6-membered heteroaryl, L is absent such that ring B and ring C are fused; Furthermore, if ring A is a heteroaryl of 5 to 6 elements with 3 heteroatoms, two of said heteroatoms must be nitrogen; further from the moment that if ring A is comprised of unsubstituted 6-element aryl and L is absent, the fused B and C rings are not unsubstituted indolyl or indolyl substituted by one or two halogen atoms; and from the moment even if ring B is comprised of tetrazolyl, L is selected from the group consisting of CH2, CH(CH3), C(CH3)2, CF2; and the C ring is comprised of phenyl.

[008] In the following description, all references to formula I also include sub-embodiments of formula I (i.e., formulas 1a, 1b, and so on).

[009] Also provided in this context are pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for intravenous or oral administration.

[0010] Also provided in this context are oral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral administration.

[0011] Also provided in this context are parenteral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for parenteral administration.

[0012] According to certain embodiments, the uses of a compound of the formula, or a pharmaceutically acceptable salt thereof, for the treatment of illnesses and disorders are provided in this context. According to certain embodiments, the illnesses and disorders that are to be treated are selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemic-reperfusion injury of the kidneys, liver and lungs, cisplatin-induced kidney injury, septicemia, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, diseases chronic kidney disease, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD).

[0013] According to certain embodiments, the disease or disorder that is to be treated is selected from the group consisting of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, degeneration macular, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyl arthrosis, gout, systemic-onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti - phospholipid (APS), vasculitis, liver damage/diseases (non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney injury/injury (nephritis, renal transplantation, surgery, administration of nephrotoxic drugs, e.g., cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia, solid organ reperfusion injury, septicemia, systemic inflammatory response (SIRS), cerebrovascular accident (CVA, cerebrovascular accident), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy ( SMA), allergic illnesses (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) fever syndrome associated, chronic obstructive pulmonary disease (COPD), tumor necrosis factor, receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO deficiency syndrome (F-kappa-B essential modulation syndrome (also known as NEMO deficiency syndrome) IKK gamma or IKKG), HOIL-1 deficiency ((also known as RBCKl) heme-oxidized IRP2 ubipitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological malignancies and solid organs, bacterial infections and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (in particular, Gaucher disease, including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, cholesteryl ester storage disease, deficiency chronic Hexosaminidase A, cystinosis, Danon disease, Fabry disease, Farber disease, Fucosidosis, galactosialidosis, GM1 gangliosidosis, Mucolipidosis, infantile free sialic acid storage disease, juvenile Hexosaminidase A deficiency, Krabbe disease, lipase deficiency lysosomal acid deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay disease -Sachs and Wolman).

[0014] According to certain embodiments, the illnesses and disorders that are to be treated are selected from the group consisting of irritable bowel diseases (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, heart attack myocardial injury, stroke, traumatic brain injury, atherosclerosis, ischemic-reperfusion injury of kidneys, liver and lungs, cisplatin-induced renal injury, septicemia, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa and retinal degeneration .

[0015] According to certain embodiments, provided in this context are methods for treating or preventing a disease or disorder with a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and/or necroptosis. According to certain embodiments said illness or disorder is selected from the specific illnesses or disorders described in this context.

[0016] According to certain embodiments, methods are provided in this context for inhibiting RIP1 kinase activity by contacting a cell with a compound of formula I or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention Definitions

[0017] As provided in this context, all chemical formulas and generic chemical structures should be interpreted to provide appropriate valence and chemically stable bonds between atoms as understood by the person normally skilled in the art. Where appropriate, substituents may be attached to more than one adjacent atom (e.g., alkyl includes methylene where two bonds are present).

[0018] In the chemical formulas provided in this context, “halogen” or “halo” refers to fluorine, chlorine, and bromine (i.e., F, Cl, Br).

[0019] Alkyl, unless otherwise specifically defined, refers to a C1-C12 alkyl group, normal or branched chain, optionally substituted. In certain embodiments, alkyl refers to a C1-C6 alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-oxyl. The substituted alkyl groups provided in this context are substituted by one or more substituents selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, OH, CO2H, CO2(C1 -C4 alkyl), NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C =O)N(C1-C4 alkyl)2, S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl )2, and NHSO2(C1-C4 alkyl). According to certain embodiments, the substituted alkyl group is provided with 1 or 2 substituents. In certain embodiments, the alkyl group is unsubstituted.

[0020] Cycloalkyl, unless otherwise specifically defined, refers to an optionally substituted C3-C12 cycloalkyl group and includes fused bicyclic, espirocyclic and bridged groups, in which the substituents are selected from the group which consists of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, OH, CO2H, CO2(C1-C4 alkyl), NH2, NH(C1-C4 alkyl), N(C1- C4 alkyl)2, NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl)2, S(C1-C4 alkyl) , SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)2, and NHSO2(C1-C4 alkyl). According to certain embodiments, cycloalkyl refers to a C3-C6 cycloalkyl group. According to certain embodiments, the C3-C6 cycloalkyl group is optionally substituted by 1 to three halogen atoms. According to certain embodiments, the C3-C6 cycloalkyl group is optionally substituted by 1 to three fluorine atoms. Exemplary C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary C3-C12 cycloalkyl groups further include bicyclo[3,1,0] hexyl, bicyclo[2,1,1] hexyl, cycloheptyl, bicyclo[4,1,0] heptyl, espiro[4,2] heptyl, cyclooctyl, espiro [4,3] octyl, espiro [5,2] octyl, bicyclo [2,2,1] heptanyl, bicyclo [2,2,2] octanyl, adamantanyl, decalinyl, and espiro [5,4] decanyl. Where appropriate, cycloalkyl groups may be fused to other groups such that there is more than one chemical bond between the cycloalkyl group and another ring system (for example, ring C of formula I). In certain embodiments, the cycloalkyl group is unsubstituted.

[0021] Haloalkyl, unless otherwise specifically defined, refers to a normal or branched chain C1-C12 alkyl group, in which one or more hydrogen atoms are replaced by a halogen. According to certain embodiments, haloalkyl refers to a C1-C6 haloalkyl group. According to certain embodiments, 1 to 3 hydrogen atoms of the haloalkyl group are replaced by a halogen. According to certain embodiments, each hydrogen atom of the haloalkyl group is replaced by a halogen (e.g., trifluoromethyl). According to certain embodiments, haloalkyl is as defined in this context wherein the halogen in each case is comprised of fluorine. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluromethyl, trifluoroethyl, and pentafluoroethyl.

[0022] Alkoxy, unless otherwise specifically defined, refers to a C1-C12 alkyl group of normal or branched chain, in which one or more oxygen atoms are present, in each case between two carbon atoms °. In certain embodiments, alkoxy refers to a C1-C6 alkoxy group. According to certain embodiments, the C1-C6 alkoxy groups provided in this context are provided with an oxygen atom. Exemplary alkoxy groups include methoxy, ethoxy, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2CH2OCH2CH3, CH2OCH2CH2CH3, CH2CH2CH2OCH3, CH2OCH(CH3)2, CH2OC(CH3)3, CH(CH3)OCH3, CH2CH(CH3)OCH3, CH(CH3)OCH2CH3, CH2OCH2OCH3, CH2CH2OCH2CH2OCH3, and CH2OCH2OCH2OCH3,

[0023] Unless otherwise specifically defined, cycloalkoxy refers to a C4-C10 group or a C4-C6 alkoxy group as previously defined in which the group is cyclic and contains an oxygen atom. Exemplary cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0024] Unless otherwise specifically defined, haloalkoxy refers to a C1-C6 haloalkyl group as previously defined, in which one or two oxygen atoms are present, in each case between two carbon atoms. . According to certain embodiments, the C1-C6 haloalkoxy groups provided in this context are provided with an oxygen atom. Exemplary haloalkoxy groups include OCF3, OCHF2 and CH2OCF3,

[0025] Thio alkyl, unless otherwise specifically defined, refers to a C1-C12 or C1-C6 alkoxy group as previously defined in which the oxygen atom is replaced by a sulfur atom. According to certain embodiments, thioalkyl groups may include sulfur atoms substituted by one or two oxygen atoms (i.e., alkylsulfones and alkylsulfoxides). Exemplary thio alkyl groups are those exemplified previously in the definition of alkoxy, in which each oxygen atom is replaced by a sulfur atom in each case.

[0026] Thiocycloalkyl, unless otherwise specifically defined, refers to a C4-C10 group or a C4-C6 thio alkyl group as previously defined wherein the group is cyclic and contains a sulfur atom. According to certain embodiments, the sulfur atom of the thiocycloalkyl group is replaced by one or two oxygen atoms (i.e., a cyclic sulfone or sulfoxide). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiolanyl, and 1,1-dioxothianyl.

[0027] Heterocyclyl, unless otherwise specifically defined, refers to a ring of 4 to 8 simple saturated or partially unsaturated elements that is endowed with at least one atom other than the carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that are provided with at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are provided with 7 to 12 atoms and are further described below. Thus, the term includes simple saturated or partially unsaturated rings (e.g., rings of 3, 4, 5, 6, 7, or 8 elements) from about 1 to 7 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be C-branched (i.e. substituted by C1-C4 alkyl). The ring may be replaced by one or more (e.g. 1, 2 or 3) oxo groups and sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl and piperidinyl. The rings of the condensed multiple ring system may be connected to each other via fused, spiral and bridge bonds when permitted by valence requirements. It should be understood that the individual rings of the multiple condensed ring system can be connected in any order relative to each other. It should also be understood that the connection point of a multiple condensed ring system (as defined for a heterocycle) can be at any position in the multiple condensed ring system. It should also be understood that the attachment point for a heterocyclic or heterocyclic multiple condensed ring system may be at any appropriate atom of the heterocyclic group, including a carbon atom and a nitrogen atom. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, didrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, didrooxazolyl, cromanyl, 1,2-dihydropyridinyl, 2,3-didrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, espiro [cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1 -one, 2-oxa-6- azaespiro [3,3] heptanyl, imidazolidin-2-one N- methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolan, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3- pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro [3,3] heptane, (1R,5S)- 3-azabicyclo [3,2,1] octane, (1s,4s)-2-azabicyclo [2,2,2] octane, (1R,4R)-2-oxa-5-azabicyclo [2,2,2] octane and pyrrolidin -2-one.

[0028] According to certain embodiments, the heterocyclyl is comprised of a C4-C10 heterocyclyl that is provided with 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. According to certain embodiments, the heterocyclyl group is neither bicyclic nor espirocyclic. According to certain embodiments, the heterocyclyl is comprised of a C5-C6 heterocyclyl that is endowed with 1 to 3 heteroatoms, at least 2 of which are nitrogen if 3 heteroatoms are present.

[0029] Unless otherwise specifically defined, aryl refers to a single full-carbon aromatic ring or a multiple fully condensed carbon ring system in which at least one of the rings is aromatic and in which the aryl group is endowed with 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes the phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) that are endowed with about 9 to 20 carbon atoms in which at least one ring is aromatic and in which the others rings can be aromatic or non-aromatic (i.e. carbocycle). Such multiple condensed ring systems are optionally substituted by one or more (e.g., 1, 2, or 3) oxo groups on any carbocycle part of the multiple condensed ring system. The rings of the multiple condensed ring system may be connected to each other via fused, espiro or bridge bonds when permitted by valence requirements. It should be understood that the attachment point of a multiple condensed ring system, as defined above, can be located at any position of the ring system including an aromatic part or a carbocycle of the ring. Exemplary aryl groups include phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

[0030] Unless otherwise specifically defined heteroaryl refers to an aromatic ring of 5 to 6 elements that is endowed with at least one non-carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple condensed ring systems that are endowed with 8 to 16 atoms that are endowed with at least one such aromatic ring, which multiple condensed ring systems are described in more detail below. Thus, "heteroaryl" includes single aromatic rings with from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Sulfur and nitrogen atoms can also be present in an oxidized form, as long as the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems comprising 2 or 3 rings) in which a heteroaryl group, as previously defined, is condensed with one or more rings selected from heteroaryls (for form, for example, a naphthyridinyl, such as 1,8-naphthyridinyl), heterocycles, (to form, for example, a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro- 1,8-naphthyridinyl), carbocycles (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example, indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or a multiple condensed ring system) is endowed with 1 to 15 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensing ring systems may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensation ring system may be connected to each other through bridged, fused and spiral connections and when permitted by valence requirements. It should be understood that the individual rings of the multiple condensed ring system can be connected in any order relative to each other. It should also be understood that the point of attachment of a multiple condensed ring system (as defined for a heteroaryl) may be situated at any position of the multiple condensed ring system, including a heteroaryl, heterocycle, aryl or carbocycle part of the system. of multiple condensed ring. It should also be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system may be situated at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, tianafthenyl, pyrrole [2,3-b] pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6 ,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole.

[0031] As used in this context, the term "chiral" refers to molecules that are endowed with the property of non-superposition of the reflection partner, while the term "achiral" refers to molecules which are susceptible to superimposition on their reflex image partner.

[0032] As used in this context, the term "stereoisomers" refers to compounds that have an identical chemical constitution, but differ with respect to the arrangement of the atoms or groups in space.

[0033] As used in this context, a wavy line "™~ ” that intercepts a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intercepts in the chemical structure to the rest of a molecule.

[0034] As used in this context, the term “C-linked” means that the group that the term describes is attached to the rest of the molecule through a ring carbon atom.

[0035] As used in this context, the term “N-linked” means that the group that the term describes is attached to the rest of the molecule through a ring nitrogen atom.

[0036] "Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are non-reflective images of each other. Diastereomers are endowed with different physical properties, for example, melting points, boiling points, spectral properties, and reactivities.Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0037] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable reflection images of each other.

[0038] The stereochemical definitions and conventions used in this context generally follow the publications of S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994, Compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms . It is intended that all stereo isomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, that is, they are endowed with the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to signify the absolute configuration of the molecule in relation to the chiral center(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning the compound is a levo rotator. A compound prefixed with (+) or d is right-handed. For a given chemical structure, these stereoisomers are identical except that they are reflection images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereo selection or stereo specificity in a chemical process or reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0039] When a bond in a compound formula in this context is drawn in a non-stereochemical manner (e.g., flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula in this context is drawn in a defined stereochemical manner (e.g., in bold, in bold, dashed wedge, or dashed wedge), it should be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer illustrated unless otherwise stated. According to one embodiment, the compound may be at least 51% of the illustrated absolute stereoisomer. According to another embodiment, the compound may be at least 80% of the absolute stereoisomer illustrated. According to another embodiment, the compound may be at least 90% of the absolute stereoisomer illustrated. embodiment, the compound may be at least 95% of the absolute stereoisomer illustrated. According to another embodiment, the compound may be at least 97% of the absolute stereoisomer illustrated. According to another embodiment, the compound may be at least 98% of the absolute stereoisomer illustrated. According to another embodiment, the compound may be at least 99% of the absolute stereoisomer illustrated.

[0040] As used in this context, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by rearranging some of the bonding electrons.

[0041] As used in this context, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is comprised of water.

[0042] As used in this context, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group in a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenyl methyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a hydroxy group that blocks or protects the hydroxy functionality. Protecting groups that are suitable include acetyl and silyl. A "carboxy protecting group" refers to a substituent on the carboxy group that blocks or protects the carboxy functionality. Common carbohydrate protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphine)-ethyl , nitroethyl and the like. For a general description of protection groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006,

[0043] As used in this context, the term "mammal" includes, but is not limited to, human beings, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs and sheep.

[0044] As used in this context, the term "pharmaceutically acceptable salts" is understood to include salts of active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described in this context. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganic, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of secondary and tertiary primary amines, including substituted amines, cyclic amines, naturally occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzyl ethylenediamine, diethylamine, 2- diethylamino ethanol, 2-dimethylamino ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, whether pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogen phosphoric, didrogenophosphoric, sulfuric, monohydrogen sulfuric, hydrodic or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetate, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, sulfonic benzene, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactonoric acids and the like (see, for example, Berge, S. M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted to either base or acid addition salts.

[0045] The neutral forms of the compound can be regenerated by contacting the salt with a base or acid and isolating the original compound in the conventional manner. The original form of the compound differs from the various salt forms in some of the physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the original form of the compound for the purposes of the present invention.

[0046] In addition to salt forms, the present invention provides compounds that are in a prodrug form. "Prodrug" refers to compounds that readily undergo chemical changes under physiological conditions to provide the compound of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention via chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted into the compound of the present invention when placed in a transdermal reservoir with a suitable enzyme or chemical reagent.

[0047] The prodrugs of the invention include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently linked through an amide bond or ester to a free amino, hydroxy or carboxylic acid group of a compound of the present invention. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids generally designated by three-letter symbols and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methyl histidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargyl glycine, sarcosine, methionine sulfone and tert-butylglycine.

[0048] Other types of prodrugs are also covered. For example, a free carboxyl group of a compound of the invention may be derived in the form of an amide or alkyl ester. As another example, compounds of this invention comprising free hydroxy groups can be derived as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylamino acetate or oxymethyl oxycarbonyl phosphoryl group, as described in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19: 115, The carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. The derivatization of hydroxy groups such as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester optionally substituted by groups including, but not limited to, ether, amine and carboxylic acid, or where the acyl group is an amino acid ester as described previously, are also covered. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include the replacement of the hydrogen atom of the alcohol group with a group such as alkanoyloxymethyl (C1-6), 1 - (C1-6 alkanoyloxy) ethyl, 1- methyl-1 - ((C1-6) alkanoyloxy) ethyl, oxymethyl (C1-6) alkoxycarbonyl, N- (C1-6) alkoxycarbonyl aminomethyl, succinoyl, (C1-)alkanoyl 6), alpha-amino (C1-4) alkanoyl, arylacyl and alpha-aminoacyl or alpha-aminoacyl-alpha - aminoacyl, wherein each alpha-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O ) (OH) 2, -P (O) (O (C1-6) alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0049] For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Farm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0050] Furthermore, the present invention provides metabolites of compounds of the invention. As used in this context, a "metabolite" refers to a product produced through metabolism in the body of a specified compound or salt thereof. These products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

[0051] Metabolite products are typically identified by preparing a radiolabeled isotope (e.g., 14C or 3H) of a compound of the invention, administering it parenterally at a detectable dose (e.g., greater than about 0 .5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey or man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated once they are labeled (others are isolated by using antibodies capable of binding epitopes that survive in the metabolite). Metabolite structures are determined conventionally, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is carried out in the same way as conventional studies of drug metabolism, widely known to those skilled in the art. Metabolic products, provided they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

[0052] Some compounds of the present invention may exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple amorphous or crystalline forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0053] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; Racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to fall within the scope of the present invention.

[0054] As used in this context, the term "composition" is intended to encompass a product that comprises the specified ingredients in the specified quantities, as well as any product that results, directly or indirectly, from the combination of the ingredients specified in the specified quantities. By "pharmaceutically acceptable" it is understood that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to the recipient.

[0055] The terms "treat" and "treatment" refer to therapeutic treatment and/or prophylactic treatment or preventive measures, where the object is intended to prevent or delay (lessen) a physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, relief of symptoms, lessening of the extent of the illness or disorder, stabilized (i.e., not worsening) disease state or disorder, delay or slowing down the progression of the disease, improvement or palliation of the state of the disease or disorder, remission (partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment. Those in need of treatment include those who already have the illness or disorder, as well as those likely to have the illness or disorder or those in whom the illness or disorder must be prevented.

[0056] The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular illness, condition or disorder, (i) attenuates, improves, eliminates one or more symptoms of the specific illness, condition or disorder, ii) prevents or delays the appearance of one or more symptoms of the specific illness, condition or disorder described in this context. For cancer therapy, efficacy can, for example, be measured by assessing time to disease progression (TTP) and/or determining response rate (RR).

[0057] The term "bioavailability" refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates the measure of both the time (rate) and the total amount (extent) of the drug reaching the general circulation from an administered dosage form.

RIP1 Kinase Inhibitors

[0058] The present invention provides new compounds that have the general formula I: wherein R1, X, Z1, L, n, ring A, ring B, and ring C are as described in this context.

[0059] According to certain embodiments of formula (I), ring A is selected from the group consisting of cyclopropyl, aryl of 6 elements, and heteroaryl of 5 to 6 elements which is endowed with 1 to 3 heteroatoms selected from from the group consisting of nitrogen, oxygen and sulfur; wherein ring A is optionally substituted by: (a) 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thio alkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in ring A is substituted, the substituent is not halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thio alkyl that is endowed with a directly bonded oxygen or sulfur atom to the nitrogen atom; (b) 1 substituent selected from the group consisting of C4-C6 heterocyclyl, C5-C6 heteroaryl, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), CH2-(C5-C6 heteroaryl), CH2CH2-(C5-C6 heteroaryl); and optionally a second substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; or (c) two adjacent substituents which together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl; and ring C is selected from the group consisting of phenyl, 5- to 6-member heteroaryl, 5- to 7-member cycloalkyl, and 5- to 7-member heterocyclyl; wherein the C ring is optionally substituted by: (d) 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thio alkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in ring C is substituted, the substituent is not comprised of halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thio alkyl endowed with an attached oxygen or sulfur atom directly to the nitrogen atom; (e) 1 to 2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), and C5C6 unsubstituted heteroaryl; or (f) Two adjacent substituents that together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl.

[0060] According to certain embodiments, R1 is selected from the group consisting of H, methyl, ethyl and isopropyl. According to certain embodiments, R1 is comprised of H. According to other embodiments, R1 is comprised of methyl.

[0061] According to certain embodiments, X is comprised of CH2, According to certain embodiments, X is comprised of CF2, According to certain embodiments, X is comprised of S and Z1 is comprised of C.

[0062] According to certain embodiments, X is comprised of O, Z1 is comprised of CH and ring A is comprised of cyclopropyl.

[0063] According to certain embodiments, L is comprised of (CH2)m and m is comprised of 1 or 2, According to certain embodiments, L is comprised of (CH2)m and m is comprised of 1, According to other embodiments, L is absent such that ring B and ring C are fused.

[0064] According to certain embodiments, n is comprised of 1,

[0065] According to certain embodiments, ring A is comprised of cyclopropyl. According to certain embodiments, ring A is comprised of unsubstituted cyclopropyl. According to certain embodiments, ring A is comprised of cyclopropyl substituted by 1 to 2 C1-C4 alkyl groups. According to certain embodiments, ring A is comprised of cyclopropyl substituted by a substituent selected from the group consisting of C1-C4 alkyl, phenyl or benzyl. According to certain embodiments, ring A is comprised of cyclopropyl substituted by one or two halogens. According to certain embodiments, ring A is as defined in this paragraph and n is comprised of 1. According to certain embodiments, ring A is as defined in this paragraph, and X is selected from the group consisting of CH2, C(CH3)2, CF2 and CHCF3,

[0066] According to certain embodiments, ring A is comprised of a 5-element heteroaryl that is endowed with 1 to 2 nitrogen atoms and 0 to 1 oxygen or sulfur atoms as the only heteroatoms. According to certain embodiments, ring A is comprised of a 5-element heteroaryl which is endowed with 1 to 2 nitrogen atoms and 0 to 1 oxygen or sulfur atom as the only heteroatoms, wherein the 5-element heteroaryl is unsubstituted. or is substituted by C1-C4 alkyl. According to certain embodiments, ring A is comprised of a 5-element heteroaryl which is provided with 2 nitrogen atoms as the only heteroatoms, wherein the 5-element heteroaryl is unsubstituted or is substituted by C1-C4 alkyl. According to certain embodiments in which ring A is as defined in this paragraph, X is comprised of CH2 or O.

[0067] According to certain embodiments, ring A is comprised of an unsubstituted 6-membered aryl. According to certain embodiments, ring A is comprised of a 6-membered aryl substituted with one or two substituents selected from the group consisting of halogen and C1-C4 alkyl. According to certain embodiments, ring A is comprised of a 6-membered aryl substituted by one or two substituents selected from the group consisting of halogen and methyl. According to certain embodiments, ring A is comprised of a 6-membered aryl substituted by one or two substituents selected from the group consisting of fluorine and methyl.

[0068] According to certain embodiments, ring B is comprised of a heteroaryl of 5 or 6 elements that is endowed with 1 to 3 nitrogen atoms in the ring. According to other embodiments, ring B is comprised of a 5- or 6-element heteroaryl that is endowed with 1 to 2 nitrogen atoms and 0 to 1 oxygen or sulfur atoms in the ring. According to certain embodiments, ring B is selected from the group consisting of furanyl, pyrroyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and triazolyl. According to certain embodiments, ring B is comprised of pyrazolyl. According to certain embodiments, ring B is comprised of imidazolyl. According to certain embodiments, ring B is comprised of oxazolyl. According to certain embodiments, ring B is comprised of thiazolyl. According to certain embodiments, ring B is comprised of triazolyl. According to certain embodiments, ring B is comprised of oxadiazolyl. According to certain embodiments, ring B is comprised of pyridinyl or pyrimidinyl. According to certain embodiments of this paragraph, ring B is unsubstituted.

[0069] According to certain embodiments in which L is absent such that rings B and C are fused, ring C is comprised of a 5- to 7-membered heterocyclyl containing 1 to 2 heteroatoms selected from the group which consists of nitrogen, oxygen and sulfur. According to an embodiment in which L is such that rings B and C are fused, ring C is comprised of a 5- to 7-element heterocyclyl containing 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. . According to other embodiments in which L is absent such that rings B and C are fused, ring C is comprised of a 5- to 7-membered cycloalkyl. According to other embodiments in which L is absent such that rings B and C are fused, ring C is comprised of phenyl. According to certain embodiments of this paragraph, ring C is unsubstituted.

[0070] According to certain embodiments in which L is present, the C ring is comprised of phenyl substituted by 1 or 2 substituents selected from the group consisting of halogen, C1-C4 alkyl, and C1-C4 alkoxy. According to other embodiments in which L is present, ring C is comprised of unsubstituted phenyl.

[0071] According to certain embodiments, a compound of formula I(a) is provided in this context: or a pharmaceutically acceptable salt thereof, wherein R1, from the group consisting of CRZ and NR8; Each RZ is independently selected from the group consisting of H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, CH2(C3-C6 cycloalkyl), C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thio alkyl, CH2 (C4-C6 cycloalkoxy), CH2(C4-C6 thio cycloalkyl), phenyl, benzyl, 4- to 6-membered heterocyclyl; and heteroaryl of 5 to 6 elements; each R8 is either absent if the nitrogen atom to which it is attached is endowed with three bonds to the other atoms, or R8 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, CH2(C3- C6 cycloalkyl), C1-C6 haloalkyl, CH2(C4-C6 cycloalkoxy), CH2(C4-C6 thio cycloalkyl), phenyl, and benzyl; where Z1 is comprised of N only if X is CH2, CF2, CH(CH3), CH(CF3), C(CH3)2, or CH(OH); wherein if Z1 is comprised of N, at least one of Z2, Z3 or Z4 is comprised of CRZ; wherein, when Z2 and Z3 are each independently selected from CRZ and NR8, Z2 and Z3 together with their respective substituents RZ and R8 can form a 6-membered aryl, 6-membered heteroaryl, 5-to-6 cycloalkyl group elements or heterocyclyl of 5 to 6 elements; wherein, when Z3 and Z4 are each independently selected from CRZ and NR8, Z3 and Z4 together with their respective substituents RZ and R8 can form a 6-membered aryl, 6-membered heteroaryl, 5-membered cycloalkyl group. to 6 elements or heterocyclyl of 5 to 6 elements.

[0072] According to certain embodiments of the formula, R1 is selected from H and CH3, According to certain embodiments, R1 is comprised of H. According to other embodiments, R1 is comprised of CH3,

[0073] According to certain embodiments of formula I(b), X is CH2 or O; Z1 is comprised of C; and Z2, Z3, and Z4 are each independently selected from the group consisting of CRZ, NH, NCH3. According to certain embodiments of formula I(a), X is comprised of CH2 or O; Z1 is comprised of C; and Z2, Z3, and Z4 each being independently selected from the group consisting of CH and NH.

[0074] According to certain embodiments of the formula (a), X is comprised of CH2; Z1 is comprised of N; and Z2, Z3, and Z4 are each independently selected from the group consisting of CRZ, NH, NCH3, wherein at least one of Z2, Z3, and Z4 is comprised by CRZ. According to certain embodiments of formula (a), X is comprised of CH2; Z1 is comprised of N; and Z2, Z3, and Z4 are each independently selected from the group consisting of CH and NH, wherein at least one of Z2, Z3, and Z4 is comprised of CH.

[0075] According to certain embodiments of formula I(a), n is comprised of 1,

[0076] According to certain embodiments of formula I(a), the selected compound a is from a formula from the group consisting of: wherein each R9 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy) -C1-C2 alkyl, phenyl, benzyl, C4-C6 heterocyclyl, CH2-(C3-C6 cycloalkyl), CH2-(C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms), and CH2-(C4-C6 heterocyclyl ).

[0077] According to certain embodiments, each R9 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, CH2CH2OCH3, C3-C4 cycloalkyl, C3-C4 cycloalkyl substituted by 1 to 2 atoms of fluorine, CH2-(C3-C4 cycloalkyl), CH2-(C3-C4 cycloalkyl substituted by 1 to 2 fluorine atoms), and CH2-(C4 heterocyclyl).

[0078] According to certain embodiments of formula I(a), the compound is of a formula selected from the group consisting of:

[0079] According to some of the aforementioned embodiments of formula I(a), R1 is comprised of H or methyl.

[0080] According to certain embodiments, a compound of formula I(b) is provided in this context: or a pharmaceutically acceptable salt thereof, wherein R1, X, L, n, ring A, ring B, and ring C are as described herein, wherein Z1 is comprised of CH; and R2 and R3 are each independently selected from the group consisting of H, halo, C1-C6 alkyl, C3C6 cycloalkyl, CO2(C1-C6 alkyl), phenyl, benzyl, heterocyclyl of 5 to 6 elements, heteroaryl of 5 to 6 elements, -CH2(C3-C6 cycloalkyl), and -CH2(C4-C6 heterocyclyl); from the moment that when each of R2 and R3 are different from H or halo, one of them must be C1-C4 alkyl.

[0081] According to certain embodiments of formula I(b), R2 and R3 are each independently selected from the group consisting of H, fluorine, C1-C6 alkyl, C3-C6 cycloalkyl, CO2(C1-C6 alkyl ), phenyl, benzyl, 5- to 6-member heterocyclyl, 5- to 6-member heteroaryl, -CH2(C3-C6 cycloalkyl), and -CH2(C4-C6 heterocyclyl); from the moment that when each of R2 and R3 are different from H or fluorine, one of them must be C1-C4 alkyl.

[0082] According to certain embodiments of formula I(b), R2 and R3 are each independently H or C1-C6 alkyl.

[0083] According to certain embodiments of formula I(b), R1 is comprised of H or methyl.

[0084] According to certain embodiments, there is provided in this context a compound of formula I, I(a) and I(b) in which what Y is selected from the group consisting of wherein 1 or 2 of X1, X2 and X3 is comprised of N; X4 and X5 are each independently comprised of N or CH; R5a and R5b, are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, benzyl, - CH2(C3-C6 cycloalkyl); and heteroaryl of 5 to 6 elements; wherein R5a and R5b together with the carbon atom to which they are linked can form a cycloalkyl of 3 to 5 elements optionally substituted by one or two fluorines, or a cycloalkoxy of 4 to 5 elements; R6a and R6b are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, mono- or di-fluorophenyl , benzyl, - CH2 (C3-C6 cycloalkyl), and heteroaryl of 5 to 6 elements; wherein R6a and R6b together with the carbon atom to which they are attached can form a cycloalkyl of 3 to 5 elements optionally substituted by one or two fluorines, or a cycloalkoxy of 4 to 5 elements; wherein when R5a and R6a are each comprised of H, R5b and R6b can together form a 3- or 4-element cycloalkyl; and in which only two of R5a, R5b, R6a and R6b can be different from H in each case; R7 is selected from the group consisting of H, unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkoxy; R10 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl, and benzyl; and R11 is selected from the group consisting of H, halogen, cyano, C1-C4 alkyl, and C1-C4 haloalkyl.

[0085] According to certain embodiments, Y is comprised of O.

[0086] According to certain embodiments, R5a and R5b are each comprised of H.

[0087] According to certain embodiments, R5a and R5b are each comprised of H; and R6a and R6b are each independently C1-C4 alkyl. According to certain embodiments, R5a and R5b are each H; R6a is comprised of H; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl. According to certain embodiments, R5a and R5b are each H; R6a is H; and R6b is C1-C4 alkyl or C1-C4 haloalkyl. According to certain embodiments, R5a and R5b are each H; R6a is comprised of methyl; and R6 is comprised of C1-C4 alkyl or C3-C4 cycloalkyl. According to certain embodiments, R5a and R5b are each H; R6a is comprised of methyl; and R6bé comprised of phenyl.

[0088] According to certain embodiments, R5a and R6a are each comprised of H, and R5b and R6b together form cyclopropyl or cyclobutyl; and Y is comprised of O.

[0089] According to certain embodiments, R7 is comprised of H or methyl.

[0090] According to certain embodiments, R10 is selected from the group consisting of H, C1-C4 alkyl, C3-C4 cycloalkyl, phenyl, and benzyl.

[0091] According to certain embodiments, R11 is selected from the group consisting of H, halogen, methyl, and trifluromethyl.

[0092] According to certain embodiments, there is provided in this context a compound of formula I, I(a) and I(b) in which is selected from the group consisting of: wherein R5b, R5b, R6a, R6b, R7, R10 and R11 are as defined above; and Y is comprised of O.

[0093] According to certain embodiments, there is provided in this context a compound of formula I, I(a) and I(b) in which is selected from the group consisting of: wherein R6a and R11 are as defined above. According to certain embodiments, R6a is comprised of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl or phenyl. According to certain embodiments, R11 is comprised of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl or phenyl.

[0094] According to certain embodiments, a compound is provided in this context wherein R6a and R6b are as defined above. According to certain embodiments, R6a and R6b are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl or phenyl; since if one of R6a and R6b is phenyl, the other is comprised of H. According to certain embodiments, R6a and R6b together form C3-C6 cycloalkyl.

[0095] According to certain embodiments, there is provided in this context a compound of formula I, I(a) or I(b) in which where R6a is as defined previously. According to certain embodiments, R6a is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl or phenyl. According to certain embodiments, R6a is comprised of phenyl.

[0096] According to certain embodiments, a compound of formula I(a) or I(b) is provided in this context, wherein o is selected from the group consisting of: wherein R12 is selected from the group consisting of halogen and methyl; et is comprised of 0, 1 or 2,

[0097] According to certain embodiments, R12 is comprised of fluorine and t is comprised of 1 or 2, According to certain embodiments, t is comprised of 0, formula I

[0098] According to certain embodiments, a compound of formula I(a) or I(b) is provided, wherein ; where R12 et are as defined above. According to certain embodiments, each R12 is selected from fluoro and chloro. According to certain embodiments, each R12 is F et is 1 or 2,

[099] According to certain embodiments, a compound of formula I(a) or I(b) is provided, wherein ; wherein R12 and t are as defined above. According to certain embodiments, each R12 is selected from fluorine and chlorine. According to certain embodiments, each R12 is comprised of F and t is comprised of 1 or 2,

[0100] Also provided in this context are the specific stereoisomers of the compounds of each of the previously exposed embodiments of formulas I, I(a) and I(b): and each of the substituents is as defined above.

[0101] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein each of the substituents is as defined above.

[0102] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein R1 is comprised of H, methyl or ethyl; R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy)-C1-C2 alkyl, phenyl and benzyl; R12 is comprised of F or Cl; et is comprised of 0, 1, 2 or 3. According to certain embodiments, R1 is comprised of methyl; R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms; R12 is comprised of F; et is comprised of 0, 1 or 2,

[0103] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein each of the substituents are as defined above.

[0104] According to certain embodiments, a compound of formula I(i) of the formula is provided: wherein R1 is comprised of H, methyl or ethyl; R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy)-C1-C2 alkyl, phenyl and benzyl; R12 is comprised of F or Cl; et is comprised of 0, 1, 2 or 3. According to certain embodiments, R1 is comprised of methyl; R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms; R12 is comprised of F; et is comprised of 0, 1 or 2,

[0105] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein R1, ring A, Z1, X, and R6b are as previously defined in this context. According to certain embodiments, R1 is comprised of H, methyl or ethyl. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6bé as defined in this context. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl.

[0106] According to certain criteria, a compound of formula I(a) of the formula is provided: wherein R1, ring A, Z1, X, and R6b are as defined. According to certain embodiments, R1 is comprised of H, methyl or ethyl. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6bé as defined in this context. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl.

[0107] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein R1, ring A, Z1, X, and R6b are as defined herein, and Y is comprised of NH or O. According to certain embodiments, R1 is comprised of H, methyl or ethyl. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6bé as defined in this context. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl.

[0108] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein each R13 is comprised of halo or C1-C4 alkyl, v is comprised of 0 to 2; and R1, X, and R6b are as defined in this context. According to certain embodiments, R1 is comprised of H, methyl or ethyl. According to certain embodiments, R1 is comprised of H or methyl; X is comprised of CH2 or O; and R6bé as defined in this context. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl. According to certain embodiments, each R13 is comprised of F or methyl.

[0109] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein each R13 is comprised of halo or C1-C4 alkyl, v is comprised of 0 to 2; and R1, X, and R6b are as defined in this context. According to certain embodiments, R1 is comprised of H, methyl or ethyl. According to certain embodiments, R1 is comprised of H or methyl; X is comprised of CH2 or O; and R6bé as defined in this context. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl. According to certain embodiments, each R13 is comprised of F or methyl.

[0110] According to certain embodiments, a compound of formula I(a) of the formula is provided: or wherein each R13 is comprised of halo or C1-C4 alkyl, v is comprised of 0 to 2; Y is comprised of NH or O; and R1, X, and R6b are as defined in this context. According to certain embodiments, R1 is comprised of H, methyl or ethyl. According to certain embodiments, R1 is comprised of H or methyl; X is comprised of CH2 or O; and R6bé as defined in this context. According to certain embodiments, R1 is comprised of H or methyl; ring A is comprised of 6-membered aryl or 5-membered heteroaryl; Z1 is comprised of C or N; X is comprised of CH2 or O; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl. According to certain embodiments, each R13 is comprised of F or methyl.

[0111] According to certain embodiments, a compound of formula I(a) of the formula is provided: wherein R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy)-C1 -C2 alkyl, phenyl and benzyl; and R6bé as defined in this context. According to certain embodiments, R9 is comprised of H, C1-C4 alkyl, or C3-C6 cycloalkyl; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl). According to certain embodiments, R9 is comprised of H, C1-C4 alkyl, C3-C6 cycloalkyl; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl, phenyl, fluorophenyl or difluorophenyl.

[0112] According to certain embodiments, a compound of formula I(a) of the formula is provided: or wherein R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy)- C1-C2 alkyl, phenyl and benzyl; and R6bé as defined in this context. According to certain embodiments, R9 is comprised of H, C1-C4 alkyl, or C3-C6 cycloalkyl; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl). According to certain embodiments, R9 is comprised of H, C1-C4 alkyl, C3-C6 cycloalkyl; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl, phenyl, fluorophenyl or difluorophenyl.

[0113] According to certain embodiments, a compound of formula I(a) of the formula is provided: where Y is comprised of NH or O; R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy)-C1-C2 alkyl, phenyl and benzyl; and R6bé as defined in this context. According to certain embodiments, R9 is comprised of H, C1-C4 alkyl, or C3-C6 cycloalkyl; and R6 is comprised of C1-C4 alkyl, C1-C4 haloalkyl or phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3C6 cycloalkyl, C1-C6 alkoxy , C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl). According to certain embodiments, R9 is comprised of H, C1-C4 alkyl, C3C6 cycloalkyl; and R6 is comprised of C1-C4 alkyl, C1C4 haloalkyl, phenyl, fluorophenyl or difluorophenyl.

[0114] Also provided in this context are embodiments corresponding to each of those described above, in which each substituent is unsubstituted unless otherwise specified in the embodiment.

[0115] Particular compounds of the formulas I, I(a), I(b) and II (hereinafter collectively referred to as “formula I”) include the following, wherein each compound is the result of a condensation between an amine on the “side left” (Amine LHS) of Table A, and a carboxylic acid on the “right side” (Acid RHS) of Table A to form an amide of formula I. For reasons of simplicity, hydrogens are not illustrated. All possible combinations of an LHS Amine with an RHS Acid are considered and within the scope of the invention.

[0116] Table A

[0117] According to one embodiment, there is provided in this context a compound of formula I which is selected from the group consisting of: 5a -methyl -N -((S) -5 -methyl -4 -oxo -2 ,3,4,5-tetrahydrobenzo-[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1',4',5', 7'-tetrahydrospiro [cyclopropane -1,6'-indazole]-3'-carboxamide; 5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -4 ,5,6,7 - tetrahydro -1H -indazole -3 -carboxamide; N -((S) -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,4,4a,5,5a,6 -hexa hydrocyclopropa [f] indazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -5 -(2,2,2 - trifluoroethyl) - 4,5,6,7 -tetrahydro -1H -pyrazolo [4,3 -c] pyridine -3 - carboxamide; N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -5 -phenyl -4,6,7,8 -tetrahydropyrazole [1,5 -a][1,4] diazepine -2 -carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl) -1,4,5,7 -tetrahydropyrano[3,4 -c] pyrazole -3 -carboxamide; 5,5 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -4,7 -dihydro -1H -pyrano[3, 4 -c] pyrazole -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl) -5 -phenyl -1,4,5,7 -tetrahydropyrano[3,4 -c] pyrazole -3 -carboxamide; 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl) -6,8 -dihydro -5H -imidazo[5,1 - c][1,4]oxazine -3 -carboxamide; 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl) -5,6,7,8 -tetrahydroimidazo[1,5 -a] pyridine -3 -carboxamide; (R) -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (S) -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (S) -2 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -2H -indazole -3 - carboxamide; 5,5 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -1,4,6,7 -tetrahydroindazole -3 - carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,7 ,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-carboxamide; 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,8-tetrahydro-1H-oxepino[3,4-c]pyrazol-3-carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(1H -pyrazole -1 - il) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 ,3 - dihydrofuro[3,4 -c] pyridine -4 -carboxamide; 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 ,3 - dihydrofuro[3,4 -c] pyridine -6 -carboxamide; (S) -1,1 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,3 -dihydrofuro[3,4 -c] pyridine -6 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5,6,7,8 -tetra hydro isoquinoline -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -phenyl -4,5,6 ,7-tetrahydro-1H-indazole-3-carboxamide; (S) -5,5 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5 ,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-carboxamide; (S) -6,6 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5 ,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazol-3-carboxamide; 5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) -4H - 1,2,4 - triazole -3 -carboxamide; (S) -5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -4H - 1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) - 4H - 1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl ) -4H -1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(4 -methyl -5 -oxo -2 -(trifluoromethyl) - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(3,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) - 4H - 1,2,4 -triazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydro -1H - indazole -3 -carboxamide; (S) -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5 ,6,7 - tetrahydro -1H -indazole -3 -carboxamide; (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (S) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) imidazo[1, 5 -a] pyridine -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) -5,6 ,7,8 - tetrahydroimidazo[1,5-a] pyridine -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -7 -(trifluoromethyl)imidazo[1, 5 - a] pyridine -1 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -7 -(trifluoromethyl) -5,6 ,7,8 - tetrahydroimidazo[1,5-a] pyridine -1 -carboxamide; (S) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (R) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,4,5,6,7 ,8 - hexahydrocyclohepta[c] pyrazole-3-carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydro-2H-indazole-3-carboxamide; N -((S) -7 -chloro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo- [b] azepin -3 -yl) -5 -methyl -4,5,6, 7-tetrahydro-2H-indazole-3-carboxamide; 5 -(tert -butyl) -N -((S) -7 -chloro -2 -oxo -2,3,4,5 - tetrahydro -1H -benzo- [b] azepin -3 -yl) -4, 5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,4,5,6 -tetra hydrocyclopenta[c]pyrazole-3-carboxamide; (S) -N -(7 -chloro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo- [b]azepin -3 -yl) -1,4,5,6 -tetrahydro cyclopenta[c] pyrazole -3 -carboxamide; N -((S) -7 -chloro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo- [b] azepin -3 -yl) -5a -methyl -1,4,4a, 5,5a,6 - hexahydro cyclopropa [f] indazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5,6,7,8 -tetra hydro quinoline - 2 -carboxamide; (S) -6 -chloro -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -[1,2, 4]triazolo [4,3 -b] pyridazine -3 -carboxamide; (S) -N -(7 -chloro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo- [b] azepin -3 -yl) -6,6 -dimethyl -4,5, 6,7-tetrahydro-1H-indazole-3-carboxamide; N -((S) -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -3,4,5,5a,6,6a - hexahydrocycloprope [e]indazole -1 -carboxamide; (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,4,4a,5,5a ,6-hexahydro cyclopropa[f] indazole-3-carboxamide; 5 -methyl -N -((S) -4 -oxo -2,3,4,5 -tetra hydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydro -1H - indazole -3 -carboxamide; (S) -5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 - il) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -3,4,5,5a,6 ,6a - hexahydrocyclopropa[e]indazole -1-carboxamide; (R) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -4 ,5,6,7 - tetrahydro -1H -indazole -3 -carboxamide; (R) -5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4] oxazepin -3 - il) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; 5 -methyl -N -((S) -4 -oxo -2,3,4,5 -tetra hydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydrobenzo[c]isoxazole-3-carboxamide; 5 -methyl -N -((S) -4 -oxo -2,3,4,5 -tetra hydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydrobenzo[d]isoxazole-3-carboxamide; 5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -4 ,5,6,7 - tetrahydrobenzo [d] isoxazole -3 -carboxamide; 5 -(tert -butyl) -N -((S) -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; (R) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; (R) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7 -tetrahydro benzo[c]isoxazole -3 -carboxamide: 1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; (S) -1 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1H - 1,2,4 -triazole -3 -carboxamide; 5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydro-2H-indazole-3-carboxamide; (S) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3]diazepin -6 -yl) -7 - (trifluoromethyl) imidazo[1,5-a] pyridine-1-carboxamide; N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazolo [1,5 -a][1,3]diazepin -6 -yl) -7 -(trifluoromethyl ) imidazo[1,5 -a] pyridine -1 -carboxamide; (S) -5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -5 -chloro -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 - carboxamide; (S) -5 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -5 -benzyl -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ]diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) - [1, 2,4]triazolo [4,3 -b] pyridazine -3 -carboxamide; and (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) - [1 ,2,4]triazolo [4,3 -a] pyridine -3 -carboxamide.

[0118] According to one embodiment, there is provided a compound of formula I selected from the group consisting of: 5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo -2 ,3,4,5 -tetrahydrobenzo-[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -5 -phenyl -4,6,7,8 -tetrahydropyrazole [1,5 -a][1,4]diazepine -2 -carboxamide; 5,5 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -4,7 -dihydro -1H -pyrano[3, 4 -c] pyrazole -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl) -5 -phenyl -1,4,5,7 -tetrahydropyrano[3,4 -c] pyrazole -3 -carboxamide; 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl) -5,6,7,8 -tetrahydroimidazo[1, 5 -a] pyridine -3 -carboxamide; (R) -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (S) -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; 5,5 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -1,4,6,7 -tetrahydroindazole -3 - carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(1H -pyrazole -1 - il) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 ,3 - dihydrofuro[3,4 -c] pyridine -6 -carboxamide; (S) -1,1 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,3 -dihydrofuro[3,4 -c] pyridine -6 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -phenyl -4,5,6 ,7-tetrahydro-1H-indazole-3-carboxamide; 5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) -4H - 1,2,4 - triazole -3 -carboxamide; (S) -5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -4H - 1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) - 4H - 1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl ) -4H -1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(4 -methyl -5 -oxo -2 -(trifluoromethyl) - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; 5 -benzyl -N -(3,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) - 4H - 1,2,4 -triazole -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5 ,6,7 - tetrahydro -1H -indazole -3 -carboxamide; (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (S) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl)imidazo[1, 5 - a] pyridine -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) -5,6 ,7,8 - tetrahydroimidazo[1,5-a] pyridine -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -7 -(trifluoromethyl)imidazo[1, 5 - a] pyridine -1 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -7 -(trifluoromethyl) -5,6 ,7,8 - tetrahydroimidazo[1,5-a] pyridine -1 -carboxamide; (R) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydro-2H-indazole-3-carboxamide; N -((S) -7 -chloro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo- [b] azepin -3 -yl) -5 -methyl -4,5,6, 7-tetrahydro-2H-indazole-3-carboxamide; 5 -(tert -butyl) -N -((S) -7 -chloro -2 -oxo -2,3,4,5 - tetrahydro -1H -benzo- [b] azepin -3 -yl) -4, 5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1,4,4a,5,5a ,6 - hexahydrocyclopropa [f] indazole -3 -carboxamide; 5 -methyl -N -((S) -4 -oxo -2,3,4,5 -tetra hydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydro -1H - indazole -3 -carboxamide; (S) -5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 - il) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; (R) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (R) -5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 - il) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide; 5 -methyl -N -((S) -4 -oxo -2,3,4,5 -tetra hydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydrobenzo[c]isoxazole -3-carboxamide; 5 -methyl -N -((S) -4 -oxo -2,3,4,5 -tetra hydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydrobenzo[d]isoxazole -3-carboxamide; 5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; 5 -(tert -butyl) -N -((S) -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; (R) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; (R) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; 1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) - 1H - 1,2,4 -triazole -3 -carboxamide; (S) -1 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1H - 1,2,4 -triazole -3 -carboxamide; 5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydro-2H-indazole-3-carboxamide; (S) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3]diazepin -6 -yl) -7 - (trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide; N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazolo [1,5 -a][1,3]diazepin -6 -yl) -7 - (trifluoromethyl )imidazo[1,5 -a] pyridine -1 -carboxamide; (S) -5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -5 -chloro -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 - carboxamide; (S) -5 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -5 -benzyl -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ]diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) - [1, 2,4]triazolo [4,3 -b] pyridazine -3 -carboxamide; and (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) - [1 ,2,4]triazolo [4,3 -a] pyridine -3 -carboxamide.

[0119] According to another embodiment, a compound selected from the compounds of Tables 1, 2, 3, 4 and 5 below is provided. According to one embodiment, the compound is comprised of a compound of Table 1, According to another embodiment, the compound is comprised of a compound of Table 2,

[0120] According to another embodiment, there is provided a compound selected from the group consisting of: (S) -1 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; (S) -1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; 5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5,6 ,7-tetrahydro-2H-indazole-3-carboxamide; (S) -5 -chloro -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 - carboxamide; (S) -5 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -5 -benzyl -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide; (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -( trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S) -N -((S) -6 -fluoro -8 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (R) -N -((S) -6 -fluoro -8 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide; (S) -5 -methyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl)benzo[d]isothiazol - 3 -carboxamide; (S) -1 -benzyl -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; (S) -5 -cyclopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 -carboxamide; (S) -5 -(4 -fluorobenzyl) -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -5 -(2,3 -difluorobenzyl) -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3 ]diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; 1 -benzyl -N -(3,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) - 1H - 1,2,4 -triazole -3 -carboxamide; 1-benzyl -N -(1-methyl -2 -oxo -2,3,4,5 -tetrahydro - 1H -[1,3]diazepine[1,2 -b]indazol -3 -yl) -1H - 1,2,4 - triazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -6 -(perfluoroethyl) - [1, 2,4]triazolo [4,3 -b] pyridazine -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -1H -indazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(perfluoroethyl) -1H -pyrazole [3,4 -b] pyridine -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4'H,6'H -spiro [cyclopentane - 1,5'-pyrrolo[1,2-c][1,2,3]triazole]-3'-carboxamide; (S) -1 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -pyrazole [3 ,4 - d] pyrimidine -6 -carboxamide; (S) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -5 -phenyl -6,7 - dihydro -5H -pyrrolo[1,2-b][1,2,4]triazole -2 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 -(tetrahydrofuran -3 -yl ) -1H -pyrazolo [4,3 -c] pyridine -6 -carboxamide; (S) -5 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -pyrazole [4 ,3 - b] pyridine -3 -carboxamide; 1-benzyl -N -(1-methyl -2 -oxo -1,2,3,4,5,10 - hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a ][1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -5 -chloro -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -1H -pyrazole [4 ,3 - b] pyridine -3 -carboxamide; 1-benzyl -N -((S) -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 -a][1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; 1-benzyl -N -((S) -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 -a][1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -[1,2,3]triazolo [1,5 -a] Upiridine - 3 -carboxamide; (S) -1 -benzyl -N -(9 -methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo[1,2 -a][1,3]diazepin -7 -yl ) -1H -1,2,4 -triazole -3 -carboxamide; N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 -((R) -tetrahydrofuran -3 -yl ) - 1H -pyrazolo [4,3 -c] pyridine -6 -carboxamide; (S) -1 -benzyl -N -(4 -methyl -5 -oxo -4,5,6,7,8,9 - hexahydropyrazole [1,5 -a][1,3]diazocin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -benzyl -N -(1 -methyl -2 -oxo -1,2,3,4,5,6 - hexahydroimidazo[1,5 -a][1,3]diazocin -3 -yl) -1H -1,2,4 - triazole -3 -carboxamide; (S) -1 -(cyclopentylmethyl) -N -(2 -cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; (R) -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 -(2,2,2 - trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide; (S) -1 -(cyclopentylmethyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepine -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -(cyclohexylmethyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepine -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) - 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) - 1 -((S) -1 - phenylethyl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -benzyl -N -(3,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -4,5 -dihydro -2H,3'H -eespiro[furan -3,1' -furo[3,4 -c] pyridine] -6' - carboxamide; (S) -1 -(4 -chlorobenzyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3 ]diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; 6 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5,6,7 ,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) - [1, 2,3]triazolo [1,5 -a] pyridine -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -2 -(trifluoromethyl) imidazo [1, 5 -a] pyrimidine -8 -carboxamide; (S) -1 -ethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -1H -pyrazole [4 ,3 - c] pyridine -6 -carboxamide; 5 -(2,4 -difluorophenyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyrano[3,4-c]pyrazol-3-carboxamide; 5 -(2,4-difluorophenyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyrano[3,4-c]pyrazol-3-carboxamide; (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5,7 -dihydrofuro[3,4 -d] pyrimidine -2 -carboxamide; (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5,7 -dihydrothieno[3,4 -d] pyrimidine -2 -carboxamide; (S) -1 -(2,3 -difluorobenzyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3]diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -(3,4-difluorobenzyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3]diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -(2,4-difluorobenzyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3]diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) - 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl )-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl ) -1 -(2,4-difluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl )-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; (S) -5 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4] oxazepin -3 -yl) -1H -indazole -3 - carboxamide; 1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 -(2, 2,2 - trifluoroethyl) -1,3 -dihydrofuro[3,4 -c] pyridine -6 - carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -7 -(trifluoromethyl)imidazo[1, 5 - c] pyrimidine -1 -carboxamide; (S) -5 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1H -pyrazole [3 ,4 - b] pyridine -3 -carboxamide; (S) -5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 -ethyl -1 -methyl - 1,3 -dihydrofuro[3,4 -c] pyridine -6 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(1,1,1 - trifluoropropan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide; 1 -cyclopropyl -1 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -1 ,3 - dihydrofuro[3,4 -c] pyridine -6 -carboxamide; N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl) - 1 -(1 -(4 - fluorophenyl)ethyl) -1H -1,2,4 -triazole -3 -carboxamide; (S)-1-(2,3-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1,5-a] [1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; (S)-1-(3,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1,5-a] [1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; (S) -1 -benzyl -N -(2,3,4 -trimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(perfluoroethyl) -4,5 ,6,7 - tetrahydro -[1,2,3]triazolo [1,5 -a] pyridine -3 - carboxamide; (S)-1-(2,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1,5-a] [1,3]diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; (S) -1 -(4-fluorobenzyl) -N -(2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3]diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; 1 -(4-chlorobenzyl) -N -(2 -cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3]diazepine -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide; N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 -(1,1,1 - trifluoropropan -2 - yl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxamide; (S) -1 -benzyl -N -(1 -methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo[1,5 -a][1,3]diazepin -3 -yl ) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -2',3',5', 6' -tetrahydro -3H - spiro[furo[3,4 -c] pyridine -1,4' -pyran] -6 -carboxamide; (S) -5 -benzyl -N -(2,3,4 -trimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepine -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1 -(2,6-difluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl )-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1 -(2,5-difluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -1 -(2,5-difluorobenzyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3]diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1 -(2,3-dichlorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1 -(2,4-dichlorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide; 7 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -7 -propyl -5 ,7 - dihydrofuro[3,4 -d] pyrimidine -2 -carboxamide; 7 -ethyl -7 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo- [b] [1,4]oxazepin -3 -yl) -5 ,7 - dihydrofuro[3,4 -d] pyrimidine -2 -carboxamide; 1 -(2,3-difluorobenzyl) -N -((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5-a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; 1 -(2,4-difluorobenzyl) -N -((S) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5-a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; 1 -(2,4-difluorobenzyl) -N -((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5-a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; (S) -N -((S) -2 -((R) -2,2 -difluorocyclopropyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 - a][1,3]diazepin -6 -yl) -1 -ethyl -1 -methyl -1,3 - dihydrofuro[3,4 -c] pyridine -6 -carboxamide; 1 -(2,3-difluorobenzyl) -N -((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5-a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; 1 -(3,4-difluorobenzyl) -N -((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5-a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; 1 -(2,4-difluorobenzyl) -N -((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5-a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 -carboxamide; N -((S) -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3]diazepin -6 -yl) -1 -(4-fluorobenzyl) -1H -1,2,4 - triazole -3 -carboxamide; (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3]diazepin -6 -yl ) -1 -(2,3-difluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide; and (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3]diazepin -6 - yl)-5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxamide. Synthesis

[0121] The compounds of formula I can be prepared by means of the processes illustrated in the schemes presented below or by means of methods that are known to those normally skilled in the art. Scheme 1 below is an example of a method of preparing a compound of formula I, wherein "R" represents the "right side" of the building block derived from the carboxylic acid intermediates of exemplary Schemes 2-14 and 26-35. (when L of formula I is absent) or is prepared according to the procedures described in WO 2014/125444 (when L is present). Schemes 15-25 show illustrative methods for preparing the “left-hand” lactam building blocks of compounds of formulas I, I(a) and I(b).

[0122] Isothiazoles are prepared in the same way as illustrated in Scheme 11 NH2-OH.

Pharmaceutical Compositions and Administration

[0123] In this context, pharmaceutical compositions or medicines are provided that contain the compounds of the invention (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof), a carrier, diluent or therapeutic excipient inert, as well as methods for using the compounds of the invention to prepare such compositions and medicaments. According to one example, the compounds of formula I can be formulated by mixing at room temperature under the appropriate pH, and with the desired degree of purity, with physiologically acceptable carriers, that is, carriers that are not toxic to humans. receptors in the doses and concentrations used in a form of galenic administration. The pH of the formulation depends primarily on the particular use and concentration of the compound, but preferably varies in any circumstance from about 3 to about 8. According to one example, a compound of formula I is formulated in an acetate buffer under pH 5, According to another embodiment, the compounds of formula I are sterile. The compound can be stored, for example, in the form of a solid or amorphous composition, in the form of a lyophilized formulation or as an aqueous solution.

[0124] The compositions are formulated, dosed and administered in a manner compatible with good medical practice. Factors to be considered in this context include the particular disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of application of the agent, the method of administration, the scheduling of administration and other factors of medical knowledge. According to certain embodiments, the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit RIP1 kinase activity in order to provide a therapeutic effect in the mammal to be treated. Furthermore, such an effective amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

[0125] According to one example, the pharmaceutically effective amount of the compound of the invention administered intravenously or parenterally will be in the dose range of about 0.1 to 100 mg/kg, alternatively about 0. 1 to 20 mg/kg of the patient's body weight per day, or alternatively about 0.3 to 15 mg/kg/day.

[0126] According to another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg) of the compound of the invention . The daily dose, according to certain embodiments, is given as a single daily dose or in divided doses of two to six times a day, or in sustained-release form. In the case of a 70 kg adult human, the total daily dose will generally vary from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds can be administered in a regimen of 1 to 4 times per day, preferably once or twice per day.

[0127] According to certain embodiments, a low dose of the compound of the invention is administered in order to provide therapeutic benefit while minimizing or preventing adverse effects.

[0128] The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration and , if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. In specific embodiments, the compound of formula I is administered orally. In other specific embodiments, the compound of formula I is administered intravenously

[0129] The compounds of the present invention can be administered in any convenient administrative form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, plasters, and the like. Such compositions may contain conventional components in pharmaceutical preparations, for example, diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents.

[0130] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are widely known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005, Formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, gliding agents, processing aids , dyes, sweeteners, perfuming agents, flavoring agents, diluents and other known additives that are used to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or assist in the manufacture of the pharmaceutical product (i.e. is, medicine).

[0131] Suitable carriers, diluents and excipients are widely known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents , water and the like. The particular carrier, diluent or excipient used will depend on the means and purposes for which a compound of the present invention is intended to be applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) to be administered to a mammal. Generally speaking, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, sliding agents, processing agents, colorants, sweeteners, perfuming agents. , flavoring agents and other additives that are known to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or assist in the manufacture of the pharmaceutical product (i.e., medicament).

[0132] Acceptable diluents, carriers, excipients and stabilizers are not toxic to receptors at the doses and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants that include ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethylene chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl paraben, such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m- cresol); low molecular weight polypeptides (less than about 10 residues); proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g. Zn protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). An active pharmaceutical ingredient of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin and poly(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems. (e.g. liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. These techniques are set out in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA.

[0133] Sustained release preparations of a compound of the invention (for example, the compound of formula I or an embodiment thereof) can be prepared. Suitable examples of sustained release preparations include semipermeable matrices and solid hydrophobic polymers containing a compound of formula I or an embodiment thereof, which matrices are in the form of molded articles, for example films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (US Patent No. 3,773,919), copolymers of L-glutamic acid and gamma- ethyl-L-glutamate (Sidman et al., Biopolymers 22: 547, 1983), non-degradable ethylene vinyl acetate (Langer et al., J. Biomed, Mater. Res. 15: 167, 1981), degradable lactic acid - glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D - (-) - 3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposomally entrapped compounds, which can be prepared by known methods (Epstein et al., Proc. Natl. Acad. Sci. USA 82: 3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77: 4030, 1980; US Patent Nos. 4,485,045 and 4,544,545 and EP 102, 314A). Typically, liposomes are of the small unilamellar type (about 200-800 Angstroms) in which the lipid content is greater than about 30% by % cholesterol, with the selected proportion being adjusted for optimal therapy.

[0134] According to one example, compounds of formula I or an embodiment thereof can be formulated by mixing at room temperature and at an appropriate pH, and under the desired degree of purity, with physiologically acceptable carriers, that is, carriers that They are non-toxic to receptors under the dosages and concentrations used in a galenic form of administration. The pH of the formulation depends primarily on the specific use and concentration of the compound, and preferably ranges anywhere from about 3 to about 8. According to one example, a compound of formula I (or an embodiment of the same) is formulated in an acceptable buffer under pH 5. According to another embodiment, the compounds of formula I, or an embodiment thereof, are sterile. The compound may be stored, for example, in the form of a solid or amorphous composition, such as a lyophilized formulation or in the form of an aqueous solution.

[0135] An example of a suitable oral dosage form provided in this context is a tablet containing about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg) of the compound of the invention with appropriate amounts of anhydrous lactose, croscarmellose sodium, polyvinyl pyrrolidone (PVP) K30 and magnesium stearate. The powdered ingredients are first mixed and then mixed with a PVP solution. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.

[0136] Formulations of a compound of the invention (for example, the compound of formula I or an embodiment thereof) may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated in accordance with the known art using suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be comprised of a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles, the solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils can be used conventionally as a solvent or suspending medium. For this purpose, any fixed blend oil can be used, including synthetic mono- or diglycerides. Furthermore, fatty acids, such as oleic acid, can be used in the preparation of injectable forms.

[0137] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will be variable depending on the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with a convenient appropriate amount of carrier material which may range from about 5 to about 95% of the compositions. totals (weight : weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution, so that a suitable volume can be infused at a rate of about 30 mL/h.

[0138] Formulations suitable for parenteral administration include aqueous, non-aqueous, aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatics and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous, non-aqueous, and aqueous sterile suspensions which may include suspending agents and thickening agents.

[0139] The formulations may be packaged in single-dose or multi-dose containers, e.g., ampoules and vials, and may be stored in a frozen-dry (lyophilized) condition that requires only the addition of the sterile liquid carrier, e.g., water, for injection immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile tablets, granules and the type described above.

[0140] For this reason, an embodiment includes a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof. According to a further embodiment, it includes a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or excipient.

[0141] When the binding target is located in the brain, certain embodiments of the invention provide a compound of formula I (or an embodiment thereof) to cross the blood-brain barrier. In these embodiments, the compounds provided in this context exhibit sufficient brain penetration as potential therapeutics in neurological diseases. In certain embodiments, brain penetration is assessed by assessing the free brain/plasma ratio (Bu/Pu) such as in vivo pharmacokinetic studies measured in rodents or by other methods known to those skilled in the art (see , e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008).

[0142] Certain neurological diseases are associated with an increased permeability of the blood-brain barrier, so that a compound of formula I (or an embodiment thereof) can be easily introduced into the brain. When the blood-brain barrier remains intact, there are several approaches known in the art for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods. Physical methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, completely bypassing the blood-brain barrier or creating openings in the blood-brain barrier.

[0143] Circumvention methods include, but are not limited to, direct injection into the brain (see, for example, Papanastassiou et al., Gene Therapi 9: 398-406, 2002), interstitial infusion / enhanced distribution by convection (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implanting a delivery device in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

[0144] Methods of creating openings in the barrier include, but are not limited to, ultrasound (see, for example, U.S. patent publication No. 2002/0038086), osmotic pressure (e.g., by means of administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, for example, bradykinin or A-7 permeabilizer (see, for example, U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0145] Lipid-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating the compound of formula I or II (or one embodiment) in liposomes that are coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier (see, for example, U.S. patent publication No. 2002/0025313), and coating a compound of formula I (or an embodiment thereof) in low-density lipoprotein particles (see, for example, U.S. patent publication No. 2004/0204354) or apolipoprotein E (see, for example, U.S. patent publication No. 2004/0131692).

[0146] Methods for transporting a receptor and channel-based compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, the use of glucocorticoid blockers to increase barrier permeability. hematocerebral (see, for example, U.S. patent publications Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activation of potassium channels (see, for example, U.S. patent publication No. 2005/0089473), inhibition of ABC drug transporters (see, for example, U.S. patent publication No. 2003/0073713); coating a compound of formula I or I-I (or an embodiment thereof) with a transferrin and modulating activity of one or more transferrin receptors (see, e.g., U.S. patent publication No. 2003/0129186), and cationization of antibodies (see, for example, U.S. Patent No. 5,004,697).

[0147] For intracerebral use, according to certain embodiments, the compounds can be administered continuously by infusion into the CNS fluid reservoirs, although bolus injection may be acceptable. Inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration may be accomplished by means of an indwelling catheter and a continuous administration means such as a pump, or may be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, inhibitors can be injected through chronically implanted cannulas or chronically infused with the aid of osmotic minipumps. There are subcutaneous pumps that deliver proteins through a small tube to the brain ventricles. Highly sophisticated pumps can be recharged through the skin and their supply rate can be adjusted without surgical intervention. Examples of suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebroventricular infusion through a fully implanted drug delivery system are those used for the administration of dopamine, dopamine agonists, agonists and cholinergics to patients with disease. of Alzheimer's disease and animal models of Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987,

Indications and Treatment Methods

[0148] The compounds of the invention inhibit the activity of the RIP1 kinase. Consequently, the compounds of the invention are useful for the treatment of diseases and disorders mediated by this pathway and associated with inflammation and/or necroptotic cell death. For this reason, the compounds of the invention are useful for treating or preventing an illness or disorder selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis. , myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs and cisplatin-induced renal injury, septicemia, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa , retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0149] According to another embodiment, the compounds of the invention are of use for treating one or more symptoms of the diseases and disorders mentioned above in this context. According to certain embodiments, the disease or disorder is comprised of an irritable bowel disorder. In certain embodiments, the illness or disorder is comprised of irritable bowel syndrome (IBS), Crohn's disease, or ulcerative colitis. According to certain embodiments, the disease or disorder is comprised of an ischemic-reperfusion injury of the kidneys, liver and lungs. According to certain embodiments, the disease or disorder is comprised of a chronic kidney disease. According to certain embodiments, the illness or disorder is comprised of acute respiratory failure syndrome (ARDS). According to certain embodiments, the illness or disorder is comprised of chronic obstructive pulmonary disease (COPD).

[0150] According to certain embodiments, the disease or disorder that is to be treated is selected from the group consisting of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration , pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthrosis, gout, systemic-onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS) renal, surgery, administration of nephrotoxic drugs, e.g., cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, septicemia, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atropia (SMA), diseases allergic (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, lung disease chronic obstructive disease (COPD), tumor necrosis factor, receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO deficiency syndrome (F-kappa-B essential modulation syndrome (also known as IKK gamma deficiency syndrome or IKKG ), HOIL-1 deficiency ((also known as RBCKl) heme-oxidized ubipitin ligase-1 deficiency IRP2), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, infections bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (particularly, Gaucher disease, including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, cholesteryl ester storage disease, chronic Hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile Hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, disorders of Mucopolysaccharidoses, Multiple sulfatase deficiency, Niemann-Pick disease, Neuronal Ceroid Lipofuscinoses, Pompe disease, picododostostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs and Wolman disease).

[0151] Equally proportionate in this context is the use of a compound of the invention in therapy. According to certain embodiments, the use of a compound of the invention for the treatment or prevention of the aforementioned diseases and disorders is provided in this context. It is also provided in this context the use of a compound of the invention in the manufacture of a medicine for the treatment or prevention of the diseases and disorders mentioned above.

[0152] Also provided in this context is a method of treating a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD), irritable bowel (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemic-reperfusion injury of kidneys, liver and lungs, cateplatin-induced renal injury, septicemia, inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to said mammal an amount therapeutically effectiveness of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0153] Also provided in this context is a method of treating a symptom of a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD). , irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemic-reperfusion injury of kidneys, liver and lungs, cateplatin-induced renal injury, septicemia, syndrome of systemic inflammatory response (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0154] Also provided in this context is a method of treating a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD), irritable bowel (IBS), Crohn's disease, ulcerative colitis, wherein the method comprises orally administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, such as an orally acceptable pharmaceutical compound.

Combination Therapy

[0155] The compounds of the invention can be combined with one or more other compounds of the invention or one or more other therapeutic agents as any combination thereof, in the treatment of the diseases and disorders mentioned above in this context. For example, a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents known to be useful for treating a disease or disorder selected from those cited above.

[0156] According to certain embodiments, a compound provided in this context can be combined with another therapeutically active agent as described in document WO 2016/027253, the contents of which are included in this context by reference in its entirety. In such embodiments, the compound that inhibits RIP1 kinase in the combinations cited in WO 2016/027253 is replaced by a compound of formula I of the present description.

[0157] As used in this context, "combination" refers to any mixture or exchange of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agents. Unless the context makes it clear, "combination" may include simultaneous or sequential delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes it clear, "combination" may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes it clear, "combination" may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes it clear, "combination" may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described in this context.

EXAMPLES

[0158] The invention will be more fully understood by reference to the examples set out below. However, they should not be understood as limiting the scope of the invention.

[0159] These examples serve to provide guidance to a person skilled in the art to prepare and use the compounds, compositions and methods of the invention. Although a particular embodiment of the present invention is described, the person skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the inventions.

[0160] The chemical reactions in the examples described can be easily adapted to prepare a series of other compounds of the invention, and alternative methods for preparing the compounds of this invention are considered within the scope of this invention. For example, the synthesis of compounds according to the invention not exemplified can be carried out successfully by means of modifications that will be evident to those skilled in the art, for example, by adequately protecting the interfering group, using other known suitable reagents. in the art, for example, by adequately shielding interfering groups using other suitable reagents known in the art other than those described and/or by making routine modifications of the reaction conditions.

[0161] In the examples set out below, unless otherwise indicated, all temperatures are indicated in degrees Celsius. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and were used without further purification unless otherwise noted. The reactions presented below were generally carried out under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise noted) in anhydrous solvents, and the reaction flasks were typically equipped with rubber septa for the introduction of substrates and reagents through the syringe. The glass products were oven dried and/or heat dried. 1H NMR spectra were obtained in deuterated CDC13, d6-DMSO, CH3OD, or d6-acetone solvent solutions (reported in ppm) using trimethylsilane (TMS) or residual non-deuterated solvent peaks as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, br (enlarged), dd (doublet of doublets), dt (doublet of triplets) Coupling constants, when administered, are reported in Hz (Hertz).

[0162] In the following examples, the LCMS methods were run for 10 or 30 minutes according to the following conditions:

[0163] Agilent LCMS Method 10 min.: Experiments performed on an Agilent 1290 UHPLC coupled to the Agilent MSD mass spectrometer (6140) using ESI as an ionization source. LC separation was performed using a Phenomenex XB-C18, 1.7 mm, 50 x 2.1 mm column with a flow rate of 0.4 ml/minute. Solvent A is comprised of water with 0.1% FA and solvent B is comprised of acetonitrile with 0.1% FA. The gradient consisted of 2 - 98% solvent B over 7 min. and maintaining 98% B for 1.5 min. following equilibrium for 1.5 min. The temperature of the LC column is 40°C. UV absorbance was collected at 220 nm and 254 nm and full mass scanning was applied throughout the experiment.

[0164] Agilent 30 min. LCMS Method: Experiments performed on an Agilent 1100 HPLC coupled with the Agilent MSD mass spectrometer using ESI as the ionization source. LC separation was performed using an Agilent Eclipse XDB-C18, 3.5 mm, 100 x 3.0 mm column with a flow rate of 0.7 ml/minute. Solvent A is comprised of water with 0.1% FA and solvent B is comprised of acetonitrile with 0.1% FA. The gradient consisted of 2 - 98% solvent B over 25.5 min. and maintaining 98% B for 2.5 min. then equilibration for 1.5 min. UV absorbances were collected under 220 nm and 254 nm and mass-specific full scanning was applied in all experiments.

[0165] All abbreviations used to describe reagents, reaction conditions or equipment must be consistent with the definitions presented in the list of abbreviations set out below. The chemical names of distinct compounds of the invention were typically obtained using the structure naming function of the ChemDraw naming program. Abbreviations ACN Acetonitrile Boc tert-Butoxycarbonyl DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide HPLC High pressure liquid chromatography LCMS Liquid chromatography mass spectrometry RP Reverse Phase RT or RT Retention time SEM 2-(Trimethylsilyl)ethoxymethyl THF Tetra hydrofuran Examples of Preparation Example 1: Synthetic method A

[0166] According to synthetic method A, 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa [f] indazole-3-carboxylic acid and similar carboxylic acid systems are prepared in accordance with paragraph forward or from the procedures described in the documents J. Med. Chem. (2014), 57(13), 5714-5727; J. Med. Chem. (2015), 58(9), 3806-3816; and WO 2014023258 A1. Step 1: 5a-Methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid

[0167] A stirred solution of ethyl 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa [f] indazole-3-carboxylate (200 mg, 0.907 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL), a 2M LiOH solution (0.69 mL, 1.36 mmol) was added, and stirred at room temperature for 16 h. The reaction mixture was concentrated to drying in vacuo, redissolved in water, and neutralized with 1N HCl. The resulting crushed solid was filtered, washed with water and dried to provide 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-carboxylic acid (120 mg, 69% yield) used in the next step without any further purification. Step 2: 5a -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 1, 4,4a,5,5a,6 -hexa hydrocyclopropa [f] indazol -3 - carboxamide

[0168] To a screw cap vial was added 5a-methyl-4,4a,5,6-tetrahydro-1H-cyclopropa [f] indazole-3-carboxylic acid (20 mg, 0.104 mmol), 1-[ bis(dimethylamino) methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxid hexafluoro phosphate (51 mg, 0.1357), (3S)-3-amino-5- hydrochloride methyl-2,3-dihydro-1,5-benzoxazepin-4-one (26 mg, 0.115 mmol) and dissolved in N,N-dimethylformamide (3 mL). Trimethylamine (0.101 mL, 0.728 mmol) was added to the reaction mixture, the vial was capped and shaken at RT for 16 h. The mixture was concentrated to drying in vacuo and the residue was purified by RP-HPLC to provide 5a-methyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo - [b] [1,4] oxazepin-3-yl)-1,4,4a,5,5a,6-hexa hydrocycloprop [f] indazol-3-carboxamide (12 mg, 31%): 1H NMR (400 MHz, DMSO- d6) δ 12.88 (s, 1H), 7.96 - 7.87 (m, 1H), 7.52 - 7.44 (m, 1H), 7.35 - 7.26 ( m, 2H), 7.25 - 7.21 (m, 1H), 4.88 - 4.75 (m, 1H), 4.53 - 4.44 (m, 1H), 4.43 - 4, 36 (m, 1H), 3.11 - 3.02 (m, 1H), 2.98 - 2.90 (m, 1H), 2.79 - 2.70 (m, 1H), 2.70 - 2.60 (m, 1H), 1.19 (s, 3H), 1.03 - 0.93 (m, 1H), 0.35 - 0.26 (m, 1H), 0.09 - 0, 00 (m, 1H). LC-MS RT = 4.98 min., m/z = 367.2 (M+H) +. Example 2: Method A' Step 1: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -1',4', 5',7' -tetra hydrospiro [cyclopropane -1,6' -indazole] -3' - carboxamide

[0169] To a solution of 1'-((2- (trimethylsilyl) ethoxy) methyl)-1',4',5',7'-tetra hydrospiro acid [cyclopropane-1,6'-indazole]-3' -carboxylic acid (68 mg, 0.21 mmol) in N,N-dimethylformamide (0.350 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (40 mg, 0.21 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (86 mg, 1.3527 mmol) and triethylamine (0.171 mL, 0.0012 mmol) and stirred at RT for 16 h. The residue was dissolved in methanol (2 ml) and a 4M solution of HCl in dioxane (0.135 ml, 3.66 mmol). The reaction mixture was stirred at RT for 16 h, concentrated to drying in vacuo and the residue was purified by RP-HPLC to provide (S)-N-(5-methyl-4-oxo-2, 3,4,5- tetrahydrobenzo- [b] [1,4] oxazepin-3-yl)-1',4',5',7'- tetrahydrospiro [cyclopropane-1,6'-indazole]-3 '-carboxamide (9 mg, 12% yield): 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7 .52 - 7.45 (m, 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.21 (m, 1H), 4.90 - 4.76 (m, 1H) , 4.56 - 4.32 (m, 2H), 2.68 - 2.55 (m, 2H), 2.48 - 2.42 (m, 2H), 1.53 - 1.37 (m, 2H), 0.42 - 0.33 (m, 4H). LC-MS RT = 4.64 min., m/z = 367.2 (M+H) +. Example 3: Method B

[0170] According to synthetic method B, 5-(tert-butyl)-4,5,6,7-tetrahydro-1H-indazol-3-carboxylic acid and similar carboxylic acid systems are prepared according to the following paragraph or from procedures described in J. Med. Chem. (2014), 57(13), 5714-5727; J. Med. Chem. (2015), 58(9), 3806-3816; and WO 2014023258 A1. 5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4 ,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide

[0171] To a screw cap bottle (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one hydrochloride (30 mg, 0.131 mmol), 1- [ bis(dimethylamino) methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxid hexafluorophosphate (75 mg, 0.197 mmol), 5-(tert-butyl)-4,5,6 acid ,7-tetrahydro-1H-indazole-3-carboxylic acid (35 mg, 0.157 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). Trimethylamine (0.127 mL, 0.918 mmol) was added to the reaction mixture, the flask was capped and shaken at RT for 16 h. The mixture was concentrated to drying in vacuo and the residue was purified by RP-HPLC to provide 5-(tert-butyl)-N-((S)-5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide (9 mg, 14%): 1H NMR ( 400 MHz, DMSO-d6) δ 12.88 - 12.77 (m, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.35 - 7.26 (m, 2H), 7.27 - 7.19 (m, 1H), 4.88 - 4.77 (m, 1H), 4.55 - 4.35 (m, 2H) ), 2.86 - 2.65 (m, 2H), 2.19 - 2.05 (m, 1H), 2.01 - 1.91 (m, 1H), 1.37 - 1.17 (m , 2H), 0.89 (s, 9H). LCMS RT = 5.52 min., m/z = 397.2 [M + H]+. Example 4: Method B' Step 1: N -((S) -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -1,4,4a,5,5a, 6 - hexahydrocyclopropa [f] indazole -3 -carboxamide

[0172] To a bottle with screw cap 1,4,4a,5,5a,6-hexahydrocyclopropa [f] indazol-3-carboxylic acid (44 mg, 0.247 mmol), 3-[bis(dimethylamino) methyliumyl]- 3H-benzotriazol-1-oxide hexafluorophosphate (127 mg, 0.3367 mmol), 3S)-3-amino-3,5-dihydro-2H-1,5-benzoxazepin-4-one (40 mg, 0.225 mmol) was added and dissolved in N,N-dimethylformamide (3 mL). Trimethylamine (0.094 mL, 0.673 mmol) was added to the reaction mixture, the vial was capped and shaken at RT for 16 h. The mixture was concentrated to drying in vacuo and the residue was purified by RP-HPLC to provide N-((S)-4-oxo-2,3,4,5-tetrahydrobenzo-[b][1, 4] oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa [f] indazol-3-carboxamide (10.4 mg, 14%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.12 (s, 1H), 8.02 - 7.87 (m, 1H), 7.22 - 7.05 (m, 4H), 4.87 - 4.66 (m, 1H), 4.55 - 4.32 (m, 2H), 3.23 - 3.09 (m, 1H), 3.00 - 2.62 ( m, 4H), 2.15 - 2.01 (m, 1H), 1.32 - 1.09 (m, 2H), 0.62 - 0.40 (m, 1H), -0.05 - - 0.14 (m, 1H). LCMS RT = 4.21 min., m/z = 339.1 [M + H]+. Example 5: Method C

[0173] According to synthetic method C, 5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazole [4,3-c] pyridine-3-carboxylic acid and acid systems Similar carboxylic acids are prepared according to the paragraph below or from procedures described in J. Med. Chem. (2014), 57(13), 5714-5727; J. Med. Chem. (2015), 58(9), 3806-3816; and WO 2014023258 A1. Step 1: tert-butyl (S)-3-((5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo- [b] [1,4] oxazepin-3-yl)carbamoyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0174] To a solution of 5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-3-carboxylic acid (455 mg, 1.15 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (200 mg, 1.0405 mmol) , 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (524.83 mg, 1.3527 mmol) and N,N-diisopropylethylamine ( 1.27 mL, 7.2837 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to drying in vacuo and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to provide tert-butyl (S)-3 - ((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo-[b] [1,4] oxazepin-3-yl)carbamoyl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (523 mg, 88%) as a colorless oil: LCMS RT = 1.62 min ., m/z = 572.1 [M + H]+. Step 2: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo-[b][1,4] oxazepin-3-yl)-4,5 hydrochloride, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

[0175] A stirred solution of tert-butyl 3-[[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]carbamoyl]-1- (2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (523 mg, 0.915 mmol) in methanol was added a 4M solution of HCl in dioxane (0.915 mL, 3 .66 mmol). The reaction mixture was stirred at RT for 16 h and concentrated to drying in vacuo to provide (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo-[ hydrochloride b] [1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine-3-carboxamide as crude product (317 mg, 92%) used in the next step without any further purification: LCMS RT = 0.77 min., m/z = 342.1 [M + H]+. Step 3: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo-[b][1,4]oxazepin-3-yl)-5-(2,2 ,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

[0176] To a stirred solution of N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5,6 hydrochloride, 7-tetrahydro-1H-pyrazole[4,3-c]pyridine-3-carboxamide (30 mg, 0.07941 mmol) in dichloromethane was added N,N-diisopropyl ethylamine (0.0416 mL, 0.2382 mmol ). To the reaction mixture, 2,2,2-trifluoroethyl trifluoromethane sulfonate (24.70 mg, 0.1032 mmol) was added and stirred at 35 ° C for 16 h. The reaction mixture was concentrated to drying in vacuo and the residue was purified by RP-HPLC to provide (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo- [b] [1,4] oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine- 3-carboxamide (13 mg, 38%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.23 (dd, J = 7.7, 1.8 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.58 - 4.47 (m, 1H), 4.44 - 4.35 (m, 1H), 3.74 (s, 2H), 2.89 (t, J = 5.7 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H). Example 6: Method D N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -5 -phenyl -4,6,7,8 -tetrahydropyrazole [1,5 -a][1,4] diazepine -2 -carboxamide Step 1: tert -butyl 2 -[[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]carbamoyl] -4,6,7,8 -tetra hydropyrazole [1,5 -a][1,4] diazepine -5 - carboxylate

[0177] To a solution of 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazole [1,5-a][1,4] diazepine-2-carboxylic acid (500 mg, 1.78 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (376 mg, 1.96 mmol) 1- hydroxybenzotriazole (288 mg, 2.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (409 mg, 2.13 mmol). The reaction mixture was stirred at RT for 2 h and then diluted with ethyl acetate (15 ml). The solution was washed with water (3 x 15 mL), saline solution (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated for drying in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide tert-butyl 2-[[(3S)-5-methyl - 4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] carbamoyl]-4,6,7,8-tetrahydropyrazole [1,5-a][1,4] diazepine-5-carboxylate (800 mg, 99% yield) as a light yellow oil: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.72 min. , ESI+ found [M+H] = 456. Step 2: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5,6,7,8 -tetrahydro -4H - pyrazole [ 1,5 -a][1,4] diazepine -2 -carboxamide 2,2,2 - trifluoroacetate

[0178] To a solution of tert-butyl 2-[[(3S)- 5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] carbamoyl]- 4,6,7 ,8-tetrahydropyrazole [1,5-a][1,4] diazepine-5-carboxylate (780 mg, 1.71 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at RT for 2 h and then concentrated to drying in vacuo to provide N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin- 3-yl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 2,2,2-trifluoroacetate (802 mg, 100% yield) as a yellow solid used as is in the next step: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.29 min., ESI+ found [M+H] = 356. Step 3: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5 -phenyl -4,6,7,8 -tetrahydropyrazole [ 1,5 -a][1,4] diazepine -2 -carboxamide

[0179] A mixture of N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6,7,8-tetrahydro - 4H-pyrazole [1,5-a][1,4] diazepine-2-carboxamide 2,2,2-trifluoroacetate (197 mg, 0.42 mmol) in toluene (5 mL) was added copper (II) acetate (8 mg, 0.04 mmol), tetradecanoic acid (19 mg, 0.08 mmol), 2,6-lutidine (45 mg, 0.42 mmol) and phenylboronic acid (77 mg, 0.63 mmol) under oxygen (15 Psi). The reaction mixture was stirred at 25°C for 12 h and concentrated to drying in vacuo. The residue was purified using RP-HPLC (0.40% acetonitrile in water and 0.1% ammonium hydroxide) to provide N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1 ,5- benzoxazepin-3-yl]-5-phenyl-4,6,7,8-tetrahydropyrazole [1,5-a][1,4] diazepine -2-carboxamide (2.5 mg, 1.4 % yield) as a white solid: 1H NMR (400MHz, DMSO-d6) δ 7.93 (d, J = 8.0 Hz, 1H), 7.51 - 7.44 (m, 1H ), 7.35 - 7.18 (m, 3H), 7.10 (t, J = 8.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.73 (s, 1H), 6.58 (t, J = 7.2 Hz, 1H), 4.83 - 4.64 (m, 3H), 4.54 - 4.40 (m, 3H), 4, 37 - 434 (m, 1H), 3.93 - 3.79 (m, 2H), 3.29 (s, 3H), 1.84 - 1.82 (m, 2H). LCMS RT = 2.45 min., m/z = 432.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 2.45 min., ESI+ found [M+H] = 432.2. Example 7: Method E 5 -methyl -4 -oxo -2,3,4,5 - oxazepin -3 -yl) -1,4,5,7 - tetrahydropyrano[3,4 -c] pyrazole -3 -carboxamide and 7 -methyl - N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -2,4,5,7 - tetra hydropyrano[3,4-c] pyrazole -3 -carboxamide Step 1: Ethyl 2-diazo-2-(4-hydroxy-2-methyltetrahydro-2H-pyran-4-yl) acetate

[0180] To a solution of ethyl 2-diazoacetate (8.0 g, 70.1 mmol) and 2-methyldihydro-2H-pyran-4(3H)-one (5.0 g, 43.8 mmol) in tetra hydrofuran (100 mL) lithium diisopropylamide (2 M in tetrahydrofuran, 39.5 mL, 79.0 mmol) was added at -78oC under nitrogen. After addition, the reaction mixture was stirred at -78°C for 1 h and then terminated by addition of saturated aqueous ammonium chloride (60 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide ethyl 2-diazo-2-(4-hydroxy-2-methyl- tetrahydropyran-4-yl) acetate (4.0 g, 40% yield). Step 2: Ethyl 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c] pyrazol-3-carboxylate and ethyl 7-methyl-1,4,5,7-tetrahydropyrano[3,4 -c] pyrazol-3-carboxylate [0181] A solution of ethyl 2-diazo-2-(4-hydroxy-2-methyl-tetrahydropyran-4-yl) acetate (3.0 g, 13.1 mmol) in pyridine (20 mL) phosphorus oxychloride (8.06 g, 52.6 mmol) was added. The resulting mixture was stirred at 15°C for 3 h and then poured into water (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated for drying in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 in 25% ethyl acetate in petroleum ether) to provide a mixture of regioisomer, which was further purified by RP- HPLC (15-45% acetonitrile in water and 0.05% ammonia) to provide ethyl 5-methyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylate (300 mg, 10.9% yield) and ethyl 7-methyl-1,4,5,7-tetrahydropyran [3,4-c] pyrazol-3-carboxylate (300 mg, 1.427 mmol, 10.9% yield) in form a white solid. Step 3: 5-Methyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0182] To a solution of ethyl 5-methyl-2,4,5,7-tetrahydropyran [3,4-c]pyrazol-3-carboxylate (100 mg, 0.48 mmol) in tetrahydrofuran (3 mL) and water (3 mL) lithium hydroxide monohydrate (320 mg, 7.61 mmol) was added. The reaction mixture was stirred at 15°C for 15 h and then concentrated to drying in vacuo. The residue was diluted with water (5 mL) and then adjusted to pH = 3 by addition of 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 15 mL). The combined layers were dried over anhydrous sodium sulfate and concentrated to provide 5-methyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (80 mg, 92. 3% yield) in the form of a white solid, which was used in the next step without any further purification. Step 4: 5-methyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo-[b][1,4] oxazepin-3-yl)-1, 4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxamide

[0183] To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (60 mg, 0.31 mmol) in N,N-dimethylformamide ( 5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (50 mg, 0.37 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane hydrochloride 1,3-diamine (72 mg, 0.37 mmol) and 5-methyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (63 mg, 0.34 mmol ). The reaction mixture was stirred at 15°C for 1 h and then concentrated to drying in vacuo. The residue was purified by RP-HPLC (28-58% acetonitrile in water and 0.05% hydrochloric acid) to provide 5-methyl-N-[(3S)-5-methyl-4-oxo-2, 3-dihydro-1,5-benzoxazepin-3-yl]-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-carboxamide (55.7 mg, 49% yield) in the form of a white solid: 1H NMR (400MHz, Methanol-d4) δ 7.44 - 7.40 (m, 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.20 (m, 1H), 5.01 - 4.97 (m, 1H), 4.82 - 4.77 (m, 1H), 4.72 - 4.70 (m, 1H), 4.61 - 4 .57 (m, 1H), 4.41 - 4.33 (m, 1H), 3.70 - 3.66 (m, 1H), 3.41 (s, 3H), 2.87 - 2.82 (m, 1H), 2.50 - 2.44 (m, 1H), 1.32 (d, J = 6.0 Hz, 3H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.77 min., ESI+ found [M+H] =357.0. Step 5: 7-Methyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0184] To a solution of ethyl 7-methyl-1,4,5,7-tetrahydropyrano[3,4-c]hpyrazol-3-carboxylate (100 mg, 0.48 mmol) in tetrahydrofuran (3 mL) and water (3 mL) lithium hydroxide monohydrate (320 mg, 7.61 mmol) was added. The reaction mixture was stirred at 15°C for 15 h and then concentrated to drying in vacuo. The residue was diluted with water (5 mL) and then adjusted to pH = 3 by addition of 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 15 mL). The combined layers were dried over anhydrous sodium sulfate and concentrated to provide 7-methyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (~80 mg, 92 .3% yield) as a white solid used in the next step without any further purification. Step 6: 7-methyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo-[b][1,4] oxazepin-3-yl)-2, 4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxamide

[0185] To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (60 mg, 0.31 mmol) in N,N-dimethylformamide ( 5 mL) was added 1H-benzo[d][1,2,3] triazol-1-ol (50 mg, 0.37 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1, 3-diamine hydrochloride (72 mg, 0.37 mmol) and 7-methyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-carboxylic acid (63 mg, 0.34 mmol) . The reaction mixture was stirred at 15°C for 1 h and concentrated for drying in vacuo. The residue was purified by RP-HPLC (25-48% acetonitrile in water and 0.05% hydrochloric acid) to provide 7-methyl-N-[(3S)-5-methyl-4-oxo-2, 3-dihydro -1,5- pyrazole-3-carboxamide (39.8 mg, 35% yield) as a white solid: 1H NMR (400MHz, Methanol- d4) δ 7.44 - 7.40 (m, 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.20 (m, 1H), 4.99 - 4.91 (m, 1H), 4.77 - 4 .75 (m, 1H), 4.62 - 4.56 (m, 1H), 4.41 - 4.33 (m, 1H), 4.19 - 4.12 (m, 1H), 3.62 - 3.60 (m, 1H), 3.41 (s, 3H), 2.80 - 2.73 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.76 min., ESI+ found [M+H] =357.0. Example 8: Method F (S) -5,5 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -1,4 ,5,7 - tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -2,4,5,7 - tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide Step 1: Ethyl 2 -diazo -2 -(4 -hydroxy -2,2 dimethyltetrahydro -2H -pyran -4 -yl) acetate

[0187] A solution of 2,2-dimethyl tetrahydropyran-4-one (5.0 g, 39.0 mmol) and ethyl diazoacetate (7.1 g, 62.4 mmol) in tetrahydrofuran (100 mL) was Added lithium diisopropylamide (2M in tetrahydrofuran, 35.1 mL, 70.2 mmol) at -78oC under nitrogen. After addition, the reaction mixture was stirred at -78°C for 1 h and then terminated by addition of saturated aqueous ammonium chloride (60 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide ethyl 2-diazo-2-(4-hydroxy-2, 2- dimethyl-tetrahydropyran-4-yl) acetate (6.0 g, 63.5% yield) in the form of a yellow-colored oil that was used in the next step as it was. Step 2: ethyl 5,5-dimethyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylate and ethyl 7,7-dimethyl-1,4,5,7-tetrahydropyran [3,4 -c] pyrazole -3 - carboxylate

[0188] To a solution of ethyl 2-diazo-2-(4-hydroxy-2, 2-dimethyl-tetrahydropyran-4-yl) acetate (3.0 g, 12.38 mmol) in pyridine (60 mL) Phosphorus oxychloride (7.6 g, 49.53 mmol) was added. The reaction mixture was stirred at 15°C for 3 h and then poured into water (30 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 25% ethyl acetate in petroleum ether) to provide a mixture of ethyl 7,7-dimethyl-4,5-dihydro- 1H -pyran [3,4 -c] pyrazol -3 - carboxylate and ethyl 7,7 -dimethyl -4,5 -dihydro -1H -pyran [3,4 -c] pyrazol -3 -carboxylate (1.0 g, 36% yield, 1:1 mixture) in the form of a light yellow oil that was used in the next step as it was: LCMS RT = 0.62 min., m/z = 224.8 [M +H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.615 min., ESI+ found [M+H] = 224.8. Step 3: 5,5-Dimethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-carboxylic acid and 4,4-dimethyl-1,4,6,7-tetra acid hydropyrano[4,3 -c] pyrazole -3 -carboxylic acid

[0189] To a solution of ethyl 5,5-dimethyl - 4,7 -dihydro -2H -pyran [3,4 -c] pyrazol -3 -carboxylate and ethyl 7,7 -dimethyl -4,5 -dihydro -1H -pyran[3,4-c]pyrazole-3-carboxylate (200 mg, 0.9 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (299 mg, 7.1 mmol). The reaction mixture was stirred at 15oC for 15 h and concentrated for drying in vacuum. The residue was diluted with water (5 mL) and adjusted to pH = 3 with 1M hydrochloric acid. The resulting mixture was extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum to provide a crude product mixture of 5,5-dimethyl-4,7-dihydro-1H-pyrano[3,4- c] pyrazole -3 -carboxylic acid and 7,7 -dimethyl -4,5 -dihydro -1H -pyrano[3,4 -c] pyrazole -3 -carboxylic acid (120 mg, 68.6% yield) in the form of a yellow colored oil used in the next step without any further purification. Step 4: (S) -5,5 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide

[0190] To a solution of (3S) -3 -amino -5 - methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (100 mg, 0.52 mmol) in N,N -dimethylformamide ( 5 mL) a mixture of 5,5-dimethyl-4,7-dihydro-1H-pyran[3,4-c]pyrazol-3-carboxylic acid and 7,7-dimethyl-4,5-dihydro-acid was added. 2H - pyrano[3,4 -c] pyrazole -3 -carboxylic (118 mg, 0.60 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (83 mg, 0.62 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (99 mg, 0.52 mmol). The reaction mixture was stirred at 15oC for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (17 -37% acetonitrile in water and 0.05% ammonium hydroxide) to provide: 5,5 -dimethyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -4,7 -dihydro -1H -pyrano[3,4 -c] pyrazole -3 -carboxamide (59 mg, 30.7% yield ) in the form of a white solid: 1H NMR (400MHz, Methanol - d4) δ 7.44 - 7.40 (m, 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.20 (m, 1H), 5.01 - 4.97 (m, 1H), 4.71 (s, 2H), 4.62 - 4.57 (m, 1H), 4.39 - 4, 36 (m, 1H), 3.42 (s, 3H), 2.68 (s, 2H), 1.25 (s, 6H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.79 min., ESI+ found [M+H] = 371.0. 7,7 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -4,5 -dihydro -2H -pyran [3, 4 -c] pyrazole -3 -carboxamide (20 mg, 10.4% yield) as a white solid: 1H NMR (400MHz, METHANOL -d4) δ 13.10 (s, 1H), 7, 99 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.34 - 7.22 (m, 3H), 4.87 - 4.80 (m, 1H), 4.55 - 4.49 (m, 1H), 4.42 - 4.37 (m, 1H), 3.73 (s, 2H), 3.31 (s, 3H), 2.58 -2.20 (m, 2H), 1.39 (s, 6H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.78 min., ESI+ found [M+H] = 371.0. Example 9: Method G N -((S) -5 -methyl -4 -oxo -2,3,4,5 –tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 -phenyl -1,4,5 ,7-tetrahydropyran[3,4-c] pyrazole -3 –carboxamide Step 1: Ethyl 5-phenyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylate

[0191] To a solution of 2-phenyltetrahydropyran-4-one (1.00 g, 5.68 mmol) in dimethyl sulfoxide (10 mL) was added ethyl diazoacetate (0.32 g, 2.84 mmol) and pyrrolidine (40.3 mg, 0.57 mmol) under nitrogen protection. The reaction mixture was stirred at RT for 12 h and diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (3 x 50 mL), saline solution (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give ethyl 5-phenyl-1,4,5,7-tetrahydropyran [3,4-c] pyrazole -3 - carboxylate (180 mg, 12% yield) as a light yellow oil: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1. 5 min.) retention time 0.70 min., ESI+ found [M+H] = 273. Step 2: 5-Phenyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0192] To a solution of ethyl 5-phenyl - 1,4,5,7 -tetrahydropyran [3,4-c] pyrazole -3-carboxylate (100 mg, 0.37 mmol) in ethanol (4 mL) and water (4 mL) lithium hydroxide monohydrate (154 mg, 3.67 mmol) was added. The reaction mixture was stirred at RT for 12 h and concentrated to drying in vacuum. The residue was diluted with water (5 mL) and adjusted to pH = 5 with 1M hydrochloric acid. The mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum to provide 5-phenyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid ( 89 mg, 99% yield) in the form of a yellow oil used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) holding time retention 0.62 min., ESI+ found [M+H] = 245. Step 3: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 -phenyl - 1, 4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide

[0193] To a solution of 5-phenyl - 1,4,5,7 -tetrahydropyran [3,4-c] pyrazole -3-carboxylic acid (88.0 mg, 0.36 mmol) in N,N - dimethylformamide (5 mL) was added 1H -benzo [d][1,2,3] triazol -1 -ol (58 mg, 0.43 mmol), N1 -((ethylimino) methylene hydrochloride) -N3,N3 - dimethylpropane -1,3 -diamine (83 mg, 0.43 mmol) and (3S) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (76 mg, 0.43 mmol) 40 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to drying in vacuum. The residue was purified using RP-HPLC (0 - 40% acetonitrile in water and 0.1% ammonium hydroxide) to provide N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -5 -phenyl -1,4,5,7 -tetrahydropyrano[3,4 -c] pyrazole -3 -carboxamide (24 mg, 16% yield) in the form of a white solid: 1H NMR (400MHz, DMSO -d6) δ 13.10 (br. s, 1H), 8.04 (br. s, 1H), 7.47 - 7.23 (m, 9H) , 4.97 - 4.92 (m, 1H), 4.85 - 4.82 (m, 2H), 4.60 - 4.54 (m, 2H), 4.46 - 4.35 (m, 1H), 3.33 (s, 3H), 3.05 - 3.01 (m, 1H), 2.68 - 2.56 (m, 1H). LCMS RT = 1.88 min., m/z = 419 [M + H]+.

[0194] LCMS (10 - 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.88/min., ESI+ found [M+H] = 419. Example 10: Method H 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -6,8 -dihydro -5H -imidazo [5,1 -c][1,4] oxazine -3 -carboxamide Step 1: (1-trityl-1H-imidazol-4-yl)methanol

[0195] To a solution of (1H-imidazol-4-yl) methanol (5.0 g, 51.0 mmol) and triethylamine (15.5 g, 152.9 mmol) in N,N-dimethylformamide (100 mL ) tribenzene (15.6 g, 56.1 mmol) was slowly added. After addition, the reaction mixture was stirred at RT for 3 h and then poured into water (300 ml). The resulting solid was collected by filtration, washed with water (2 x 100 mL) and recrystallized with dioxane (300 mL) to provide (1-trityl-1H-imidazol-4-yl)methanol (9.8 g, 56% yield) as a white solid: 1H NMR (400 MHz, DMSO - d6): δ 7.43 - 7.39 (m, 9H), 7.29 (s, 1H), 7, 10 - 7.08 (m, 6H), 6.72 (s, 1H), 4.89 - 4.86 (m, 1H), 4.33 - 4.32 (d, J = 5.6 Hz, 2H). Step 2: ethyl 2 -((1 -trityl -1H -imidazol -4 -yl) methoxy) propanoate

[0196] To a solution of (1-trityl -1H - imidazol -4 -yl) methanol (6.0 g, 17.6 mmol) in N,N - dimethylformamide (400 mL) was added sodium hydride (60% , 1.4 g, 35.2 mmol) per parts. After addition, the reaction mixture was stirred at RT for 2 h and ethyl 2-bromopropanoate (6.4 g, 35.2 mmol) was added. The resulting mixture was stirred at RT for another 15 h and finalized by addition of aqueous saturated ammonium chloride (300 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide ethyl 2 -((1-trityl -1H -imidazol -4 -yl )methoxy)propanoate (2.0 g, 26% yield) as an orange oil: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) RT = 0 .81 min., m/z = 449.1 [M -C2H5+CH3+ Na]+. Step 3: 2 -((1 -trityl -1H -imidazol -4 -yl)methoxy) propan -1 -ol

[0197] To a solution of ethyl 2 -((1-trityl - 1H -imidazol-4-yl)methoxy) propanoate (2.00 g, 4.54 mmol) in methanol (40 mL) was added sodium borohydride ( 0.86 g, 22.70 mmol) in small portions. After addition, the reaction mixture was stirred at 25°C for 16 h and then terminated by addition of saturated aqueous ammonium chloride (40 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 2-((1-trityl-1H-imidazol-4-yl)methoxy)propan-1-ol as the crude product (1. 30 g, 72% yield) in the form of a colorless oil used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0 .80 min., ESI+ found [M+Na] = 421.1. Step 4: 2-((1-trityl-1H-imidazol-4-yl)methoxy)propyl 4-methylbenzene sulfonate

[0198] To a solution of 2 -((1-trityl -1H - imidazol -4 -yl)methoxy) propan -1 -ol (1.3 g, 3.26 mmol) and triethylamine (1.0 g, 9 .79 mmol) in dichloromethane (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (0.8 g, 3.91 mmol) in small portions. After addition, the mixture was stirred at RT for 15 h. The reaction was washed with saturated sodium bicarbonate (2 x 15 mL), dried over sodium sulfate and concentrated for drying in vacuum to provide 2 - ((1-trityl -1H -imidazol -4 -yl)methoxy) crude propyl 4 - methylbenzene sulfonate (1.8 g, 99% yield) in the form of a colorless oil used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid during 1.5 min.) retention time 0.86 min., ESI+ found [M+H] = 553.1. Step 5: 2-((1H-imidazol-4-yl)methoxy)propyl 4-methylbenzene sulfonate 2,2,2-trifluoroacetate

[0199] A mixture of 2 -((1-trityl -1H - imidazol -4 -yl) methoxy) propyl 4 -methylbenzene sulfonate (1.8 g, 3.26 mmol) in 2,2,2 -trifluoroacetic acid (20 mL) was stirred at RT for 3 h and concentrated to drying in vacuum to provide 2-((1H-imidazol-4-yl)methoxy)propyl 4-methylbenzene sulfonate as crude product (1.0 g , 99% yield) in the form of a red oil used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.64 min., ESI+ found [M+H] = 310.9. Step 6: 6 -methyl -6,8 -dihydro -5H -imidazo[5,1 - c][1,4]oxazine

[0200] A mixture of 2-((1H-imidazol-4-yl)methoxy) propyl 4-methylbenzene sulfonate (1.0 g, 3.22 mmol) and cesium carbonate (3.2 g, 9.67 mmol ) in N,N-dimethylformamide (20 mL) was heated at 80oC for 15 h. After cooling, the mixture was poured into water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 6-methyl -6,8 - dihydro -5H -imidazo[5, 1-c][1,4] oxazine (0.2 g, 46% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min .) retention time 1.19 min., ESI+ found [M+H] = 139.1. Step 7: ethyl 6 -methyl -6,8 -dihydro -5H -imidazo [5,1 -c][1,4] oxazine -3 –carboxylate

[0201] To a solution of 6 -methyl -6,8 -dihydro -5H -imidazo[5,1 -c][1,4] oxazine (0.20 g, 1.45 mmol) and N - ethyl -N -isopropylpropan-2-amine (0.70 g, 5.79 mmol) in acetonitrile (2 mL) at -40°C was added ethyl chloroformate (0.24 g, 2.17 mmol). After addition, the reaction mixture was stirred at RT for 15 h and then concentrated to drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide ethyl 6-methyl-6,8-dihydro-5H-imidazo[ 5,1-c][1,4] oxazine -3 -carboxylate (0.09 g, 30% yield) as a colorless oil: LCMS RT = 1.52 min., m/z = 211.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.52 min., ESI+ found [M+H] = 211.2. Step 8: lithium 6 -methyl -6,8 -dihydro -5H - imidazo[5,1 -c][1,4] oxazine -3 -carboxylate

[0202] To a solution of ethyl 6 -methyl -6,8 - dihydro -5H -imidazo [5,1 -c][1,4] oxazine -3 -carboxylate (90 mg, 0.43 mmol) in ethanol ( 8 mL) and water (4 mL) were added lithium lithium hydroxide hydrate (180 mg, 4.28 mmol). The mixture was stirred at RT for 1 h and concentrated to drying in vacuum to provide lithium 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3- carboxylate (71 mg, 90.7% yield) as a white solid used in the next step without further purification. Step 9: 6 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6, 8 -dihydro -5H -imidazo [5,1 -c][1,4] oxazine -3 -carboxamide

[0203] To a solution of lithium 6 -methyl -6,8 - dihydro -5H -imidazo [5,1 -c][1,4] oxazine -3 -carboxylate (71 mg, 0.39 mmol) in N, N -dimethylformamide (5 mL) was added 1H -benzo[d][1,2,3]triazol-1-ol (53 mg, 0.39 mmol), (3S)-3-amino-5-methyl-2 ,3-dihydro -1,5 - benzoxazepine -4 -one (50 mg, 0.26 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 - diamine hydrochloride (75 mg, 0.39 mmol). The mixture was stirred at 20°C for 2 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (30 - 60% acetonitrile in water and 0.05% ammonium hydroxide) to provide 6 -methyl -N -((S) -5 -methyl -4 -oxo - 2 ,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -6,8 -dihydro -5H -imidazo [5,1 -c] [1,4] oxazine -3 - carboxamide (37 mg, 39% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6): δ 8.39 - 8.36 (m, 1H), 7.50 - 7, 48 (m, 1H), 7.32 - 7.30 (m, 2H), 7.29 - 7.24 (m, 1H), 6.89 (s, 1H), 4.99 - 4.95 ( m, 1H), 4.78 - 4.73 (m, 2H), 4.60 - 4.56 (m, 2H), 4.52 - 4.39 (m, 1H), 3.84 - 3, 83 (m, 1H), 3.65 - 3.62 (m, 1H), 3.31 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H). LCMS RT = 1.21 min., m/z = 357.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid 2 min.) retention time 1.21 min., ESI+ found [M+H] = 357.2, Example 11: Method I 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5,6,7 ,8 - tetrahydroimidazo [1,5 -a] pyridine -3 -carboxamide 0 Step1: ethyl 2 -(((5 -methylpyridin -2 - yl)methyl)amino) -2 -oxoacetate

[0204] To a solution of (5-methylpyridin-2-yl) methanamine (1.00 g, 8.19 mmol) and triethylamine (1.24 g, 12.28 mmol) in tetrahydrofuran (10 mL) was added ethyl oxalyl chloride (1.23 g, 9.00 mmol) under 0oC. After addition, the reaction mixture was stirred at 20°C for 10 h and then quenched with saturated aqueous sodium carbonate (20 mL). The solution was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide ethyl 2 - [(5 -methyl -2 -pyridyl)methylamino] - 2-oxo-acetate (1.20 mg, 66% yield) as a brown-colored oil: 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.19 (br., s, 1H), 7.46 - 7.44 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.56 (d, J = 5.2 Hz, 2H), 4.35 (q, J =7.2 Hz, 2H), 2.30 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). Step 2: ethyl 6-methylimidazo[1,5-a]pyridine-3-carboxylate

[0205] A mixture of ethyl 2 -[(5-methyl -2 - pyridyl) methylamino] -2 -oxo -acetate (1.0 g, 4.5 mmol) and phosphorus oxychloride (28.0 g, 182. 6 mmol) was heated at 100oC for 10 h and concentrated for drying in vacuum. The residue was poured into water (20 mL) and adjusted to pH = 8 by adding aqueous saturated sodium bicarbonate (20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 70% ethyl acetate in petroleum ether) to provide ethyl 6-methylimidazo[1,5a]pyridine-3-carboxylate ( 250 mg, 27.2% yield) as a brown solid: LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 1.5 min.) retention time: 0.74 min., ESI+ found [M+H] = 204.8, Step 3: ethyl 6-methyl -5,6,7,8 -tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

[0206] A solution of ethyl 6-methylimidazo [1,5-a] pyridine-3-carboxylate (200 mg, 0.98 mmol) in methanol (5 mL) was treated with 10% palladium on carbon (200 mg, 0.19 mmol). The mixture was hydrogenated [4.46 bar (50 psi)] at 20°C for 24 h and then filtered through Celite. The filtrate was concentrated for drying in vacuum to provide crude ethyl 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (200 mg, 98.1% yield) in the form of a colorless oil that was used in the next step without any further purification: 1H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 4.75 - 4.70 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 3.68 - 3.62 (m, 1H), 2.99 - 2.94 (m, 1H), 2.77 - 2.75 ( m, 1H), 1.96 - 1.93 (m, 2H), 1.47 - 1.40 (m, 4H), 1.13 (d, J = 6.8Hz, 3H). Step 4: 6 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5, 6,7,8 - tetrahydroimidazo [1,5 -a] pyridine -3 -carboxamide

[0207] A stirred solution of ethyl 6-methyl-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine-3-carboxylate (300 mg, 1.4 mmol) in ethanol (10 mL) and water (5 mL) lithium hydroxide (345 mg, 14.4 mmol) was added. The mixture was stirred at 20°C for 1 h and concentrated to drying under pressure in vacuum to provide lithium 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate raw.

[0208] To a solution of crude lithium 6-methyl - 5,6,7,8 -tetra hydroimidazo [1,5 -a] pyridine -3 - carboxylate (70 mg, 0.39 mmol) in N,N - dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 1H-benzo[d] [1,2,3] triazol -1 -ol (53 mg, 0.39 mmol) and N -1 -((ethylamine) ethylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (75 mg, 0.39 mmol). The mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (49% acetonitrile in water and 0.05% ammonium hydroxide) to provide 6-methyl -N -((S) -5 -methyl -4 -oxo -2,3 ,4,5 -tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) -5,6,7,8 -tetra hydroimidazo[1,5 -a] pyridine -3 - carboxamide (29 mg, 31 .4% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.28 - 8.25 (m, 1H), 7.50 - 7.47 (m, 1H ), 7.34 - 7.29 (m, 2H), 7.24 - 7.23 (m, 1H), 6.82 (s, 1H), 4.82 - 4.75 (m, 1H), 4.58 - 4.51 (m, 2H), 4.42 - 4.40 (m, 1H), 3.55 - 3.49 (m, 1H), 3.31 (s, 3H), 2, 86 - 2.85 (m, 1H), 2.72 - 2.64 (m, 1H), 2.53 - 2.51 (m, 1H), 1.83 - 1.80 (m, 1H) , 1.38 - 1.32 (m, 1 H), 0.99 (d, J = 6.4 Hz, 3 H). LCMS (10 to 80% acetonitrile in water + 0.1% NH4OH for 3 min.) retention time 1.90 min., ESI+ found [M+H] = 355.2. N -(5 -methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -6 -phenyl -4,5,6,7 -tetra hydro -1H -indazole -3 -carboxamide Step 1: ethyl 6 -phenyl -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate

[0209] To a solution of 4-phenyl cyclohexanone (2.0 g, 11.48 mmol) in dimethyl sulfoxide (20 mL) was added pyrrolidine (40.8 mg, 0.57 mmol). The mixture was stirred at 20°C for 15 min, and ethyl 2-diazoacetate (654.8 mg, 5.74 mmol) was added. The resulting mixture was stirred at 20°C for 15 h and then diluted with water (20 ml). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 25% ethyl acetate in petroleum ether) to provide ethyl 6-phenyl - 4,5,6,7 -tetrahydro -1H - indazol -3 - carboxylate (830 mg, 53% yield) as a brown colored oil: 1H NMR (400 MHz, CDCl3)δ 7.35 - 7.32 (m, 2H), 7.27 - 7 .22 (m, 3H), 4.39 - 4.33 (m, 2H), 3.08 - 2.97 (m, 3H), 2.81 - 2.72 (m, 2H), 2.15 - 2.12 (m, 1H), 1.95 - 1.89 (m, 1H), 1.38 - 1.34 (m, 3H). LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.99 min., ESI+ found [M+H] = 271.2. Step 2: 6-Phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

[0210] To a solution of ethyl 6-phenyl - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate (400 mg, 1.5 mmol) in tetrahydrofuran (8 mL) and water (8 mL) lithium hydroxide monohydrate (354 mg, 14.8 mmol) was added. The mixture was stirred at 20°C for 22 h and concentrated for drying in vacuum. The residue was diluted with water (10 mL) and adjusted to pH = 3 with 1M hydrochloric acid. The resulting solid was collected by filtration to provide crude 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (320 mg, 89.3% yield) in the form of a yellow solid that was used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.67 min., ESI+ found [M+H] = 242.9, Step 3: N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -6 -phenyl -4,5,6, 7 -tetrahydro -1H -indazole -3 -carboxamide

[0211] A solution of 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (189 mg, 0.78 mmol) in N,N-dimethylformamide (5 mL) was added 1H -benzo [d] [1,2,3] triazol -1 -ol (105 mg, 0.78 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (100 mg, 0.52 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (150 mg, 0.78 mmol). The mixture was stirred at 20°C for 1 h and then concentrated for drying in vacuum. The residue was purified by RP-HPLC (40 - 70% acetonitrile in water and 0.05% ammonium hydrate) to provide N -(5-methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) - 6 -phenyl -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide (77 mg, 34% yield as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 12.94 (s, 1H), 7.96 (d, J = 8.0, 1H), 7.49 (d, J = 7 .6 Hz, 1H), 7.34 - 7.27 (m, 6H), 7.25 - 7.22 (m, 2H), 4.88 - 4.83 (m, 1H), 4.52 - 4.48 (m, 1H), 4.44 - 4.41 (m, 1H), 3.32 (s, 3H), 2.93 - 2.69 (m, 4H), 2.58 - 2, 55 (m, 1H), 1.93 - 1.90 (m, 1H), 1.81 - 1.78 (m, 1H). LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 2.03 min., ESI+ found [M+H] = 417.2. Example 13: Method K Step 1: Ethyl 2 -oxo -2 -[2 -oxo -5 - (trifluoromethyl) cyclohexyl] acetate

[0212] To a solution of 4-(trifluoromethyl) cyclohexanone (15.0 g, 90.3 mmol) in ethanol (45 mL) was added a solution of sodium ethoxide (6.8 g, 100.0 mmol) in ethanol (36 mL), followed by diethyl oxalate (13.19 g, 90.29 mmol) under 0oC. After addition, the mixture was allowed to warm to 25°C and stirred for 15 h. The reaction mixture was concentrated to drying in vacuum to provide crude ethyl 2-oxo-2-[2-oxo-5-(trifluoromethyl)cyclohexyl] acetate (33.0 g, 138% yield) as a yellow solid for use in the next step without any further purification: LCMS (5 to 95% acetonitrile in water + 0.04% formic acid for 1.5 min.) retention time 0.861 min., ESI+ found [M+ H] = 266.9. Step 2: (R)-ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate and (S)-ethyl 5-(trifluoromethyl)-4,5,6, 7 -tetrahydro -1H -indazole -3 - carboxylate

[0213] To a solution of ethyl 2-oxo-2-[2-oxo-5-(trifluoromethyl) cyclohexyl] acetate (33.0 g, 90.3 mmol) in glacial acetic acid (33 mL) was added hydrate of hydrazine (6.2 g, 124.0 mmol) under 0oC. The mixture was stirred for 1 h at 25°C, and then adjusted to pH=8 with aqueous sodium bicarbonate. The resulting mixture was extracted with methanol and dichloromethane (3 x 300 mL, methanol/dichloromethane = 5:95). The combined organic extracts were washed with water (20 mL), saline solution (20 mL), dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide ethyl 5-(trifluoromethyl)-4,5,6,7-tetra racemic hydro -1H -indazole -3 -carboxylate (5.0 g, 21% yield) as a white solid. In a 500 mg load, the enantiomers were separated by means of SFC to provide arbitrarily assigned enantiomers: Peak 1 (Retention time: 3.36 min): (R)-ethyl 5-(trifluoromethyl)-4.5 ,6,7-tetrahydro-1H-indazole-3-carboxylate (180 mg, 36% yield); Peak 2 (Retention time 3.66 min): (S)-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (132 mg, 26% yield) SFC Condition: Column: Lux Cellulose -2 150x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5, 5 min. and 40% retention for 3 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/ min. Column temperature: 40oC. Example 14: Method L

[0214] (5R) -1 -methyl -N - [(3S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl ] -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide and (5R) -2 -methyl -N -[(3S) - 5 -methyl -4 -oxo - 2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide Step 3: (R)-ethyl 1-methyl-5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate and (R) -ethyl 2 - methyl -5 -(trifluoromethyl) -4, 5, 6, 7 -tetrahydro - 2H - indazole -3 -carboxylate

[0215] To an arbitrarily assigned solution of ethyl (R) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylate (180 mg, 0.69 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (104 mg, 0.76 mmol). After stirring for 30 min, methyl iodide (86 mg, 0.60 mmol) was added and stirring was continued for 15 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (50 mL), saline solution (50 mL), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by prep TLC (30% ethyl acetate in petroleum ether) to give (R)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H - indazole -3 -carboxylate (Rf = 0.2, 72 mg, 37% yield) and (R) -ethyl 2-methyl -5 -(trifluoromethyl) - 4,5,6,7 -tetrahydro -2H -indazole -3 -carboxylate (Rf = 0.5, 53 mg, 28% yield): 1H NMR (400MHz, CDCl3) δ 4.40 - 4.35 (m, 2H), 3.80 (s, 3H ), 3.22 - 3.15 (m, 1H), 2.81 - 2.50 (m, 3H), 2.38 - 2.40 (m, 1H), 2.31 - 2.19 (m , 1H), 1.82 - 1.67 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H). LCMS RT = 0.835 min., m/z = 276.9 [M + H]+ ; 1H NMR (400MHz, CDCl3) δ 4.37 - 4.32 (m, 2H), 4.10 (s, 3H), 3.15 - 3.09 (m, 1H), 2.88 - 2.83 (m, 1H), 2.72 - 2.63 (m, 2H), 2.49 - 2.30 (m, 1H), 2.27 - 2.13 (m, 1H), 1.76 - 1 .61 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.835 min., ESI+ found [M+H] = 276.9 and retention time 0.895 min., ESI+ found [M+H] = 276.9. Step 4: (R)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid

[0216] To a solution of ethyl (R) -1 -methyl -5 -(trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 - carboxylate arbitrarily assigned (72 mg, 0.26 mmol) in ethanol ( 5 mL) and water (2 mL) potassium hydroxide (73 mg, 1.3 mmol) was added. The mixture was stirred at 25°C for 15 h and concentrated for drying in vacuum. The residue was dissolved in water (5 mL) and adjusted to pH = 3 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to provide (R)-1-methyl-5-(trifluoromethyl)-4 acid, 5,6,7-tetrahydroindazole -3 - carboxylic acid (52 mg, 80% yield) in the form of a white solid used without any further purification in the following step: LCMS (0 to 60% acetonitrile in water + 0. 04% formic acid for 2 min.) retention time 1.10 min., ESI+ found [M+H] = 249.0, Step 5: (5R)-1-methyl -N -[(3S)-5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl ] -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide

[0217] To a solution of (R) -1 -methyl - 5 - (trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 - carboxylic acid (52 mg, 0.20 mmol) in N,N - dimethylformamide (4 mL) was added 1-1H-benzo[d][1,2,3]triazol-1-ol (62 mg, 0.46 mmol), (3S)-3-amino-5-methyl-2 ,3-dihydro-1,5-benzoxazepin-4-one (88 mg, 0.46 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (88 mg , 0.46 mmol). The reaction mixture was stirred at 25oC for 12 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (25 -55% acetonitrile in water and 0.225% formic acid) to provide (5R) -1 -methyl -N -[(3S) -5 - methyl -4 -oxo - 2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (21 mg, 25% yield) in the form of a white solid: 1H NMR (400MHz, Methanol -d4) δ 7.44 - 7.41 (m, 1H), 7.33 - 7.22 (m, 3H), 4.97 - 4.94 (m , 1H), 4.60 - 4.56 (m, 1H), 4.37 - 4.31 (m, 1H), 3.77(s, 3H), 3.42 (s, 3H), 3, 12 - 3.07 (m, 1H), 2.85 - 2.81 (m, 1H), 2.68 - 2.45 (m, 3H), 2.26 - 2.21 (m, 1H), 1.76 - 1.63 (m, 1H). LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.64 min., ESI+ found [M+H] = 423.2. Step 6: (R)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid

[0218] To a solution of ethyl (R) -2 -methyl -5 -(trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 - carboxylate (53 mg, 0.19 mmol) in ethanol (5 mL ) and water (2 mL) potassium hydroxide (62 mg, 1.1 mmol) was added. The mixture was stirred at 25°C for 15 h and concentrated for drying in vacuum. The residue was dissolved in water (5 mL) and adjusted to pH = 3 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, and concentrated for drying in vacuum to provide (R)-2-methyl-5-(trifluoromethyl) acid )-4,5,6,7-tetrahydroindazole-3-carboxylic acid (53 mg, 99% yield) as a white solid used without further purification in the following step: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2min.) retention time 1.16 min., ESI+ found [M+H] = 249.0. Step 7: (5R)-2-methyl -N -[(3S)-5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5 - (trifluoromethyl) -4 ,5,6,7 -tetrahydroindazole -3 -carboxamide

[0219] To a solution of (5R) -2 -methyl -5 - (trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 - carboxylic acid (53 mg, 0.21 mmol) in N,N - dimethylformamide (4 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (121 mg, 0.64 mmol), 1-1H-benzo [d][1,2,3] triazol -1 -ol (86 mg, 0.64 mmol) and N1 -((ethylimino)methylene) - N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (122 mg , 0.64 mmol). The reaction mixture was stirred at 25oC for 12 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (25 -55% acetonitrile in water and 0.225% formic acid) to provide (5R) -1 - methyl -N -[(3S) -5 -methyl -4 -oxo - 2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (33 mg, 37% yield) in the form of a white solid: 1H NMR (400MHz, CD3OD) δ7.45 - 7.41 (m, 1H), 7.35 - 7.18 (m, 3H), 5.03 - 4.97 (m, 1H) , 4.60 - 4.55 (m, 1H), 4.43 - 4.37 (m, 1H), 3.91 (s, 3H), 3.42 (s, 3H), 3.12 - 3 .05 (m, 1H), 2.87 - 2.30 (m, 4H), 2.26 - 2.22 (m, 1H), 1.77 -1.71(m, 1H). LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 7 min.) retention time 6.00min., ESI+ found [M+H] = 423.1. Example 15: Method M

[0220] (5S) -1 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl ] -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide and (5S) -2 -methyl -N -[(3S) - 5 -methyl -4 -oxo Step 1: (S) -ethyl 1 -methyl -5 -tetrahydro -1H -indazole -3 -carboxylate and (S) -ethyl 2 -methyl -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro - 2H -indazole -3 -carboxylate

[0221] To a solution of ethyl (S) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylate (132 mg, 0.50 mmol) in N,N - dimethylformamide (10 mL) was added potassium carbonate (104 mg, 0.76 mmol). After stirring for 30 min, methyl iodide (86 mg, 0.60 mmol) was added and stirring was continued for 15 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by prep TLC (30% ethyl acetate in petroleum ether) to give (S)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H -indazole -3 -carboxylate (Rf = 0.2, 38 mg, 27.5% yield) and (S) -ethyl 2 -methyl -5 -(trifluoromethyl) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate (Rf = 0.5, 86 mg, 62.3% yield) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5min.) retention time 0.83min., ESI+ found [M+H] = 276.9 and RT = 0.89 min., m/z = 276.9 [M + H]+. Step 2: (S)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid

[0222] To a solution of (S) -ethyl 1 -methyl -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro - 1H -indazole -3 - carboxylate (38 mg, 0.14 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (38 mg, 0.69 mmol). The mixture was stirred at 25°C for 15 h and concentrated for drying in vacuum. The residue was dissolved in water (5 mL) and adjusted to pH = 3 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated for drying in vacuum to provide the acidic product (R)-1-methyl-5-( trifluoromethyl) - 4,5,6,7 -tetrahydroindazole -3-carboxylic acid (38 mg, 100% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.12 min., ESI+ found [M+H] = 249.0. Step 3: (5S)-1-methyl -N -[(3S)-5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5 - (trifluoromethyl) -4 ,5,6,7 -tetrahydroindazole -3 -carboxamide

[0223] To a solution of (S) -1 -methyl - 5 - (trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 - carboxylic acid (38 mg, 0.14 mmol) in N,N - dimethylformamide (4 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (88 mg, 0.46 mmol), 1-1H-benzo [d][1,2,3] triazol -1 -ol (62 mg, 0.46 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (88 mg, 0.46 mmol). The reaction mixture was stirred at 25oC for 12 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (25 -55% acetonitrile in water and 0.225% formic acid) to provide (5S) -1 - methyl -N -[(3S) -5 -methyl -4 -oxo - 2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (31 mg, 52% yield) in the form of a white solid: 1H NMR (400MHz, Methanol - d4) δ 7.46 - 7.40 (m, 1H), 7.36 - 7.20 (m, 3H), 4.99 - 4.94 (m , 1H), 4.60 - 4.56 (m, 1H), 4.38 -4.33 (m, 1H), 3.79 (s, 3H), 3.41 (s, 3H), 3, 11 - 3.06 (m, 1H), 2.85 - 2.81 (m, 1H), 2.67 - 2.46 (m, 3H), 2.25 - 2.21 (m, 1H), 1.75 - 1.67 (m, 1H). LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 7 min.) retention time 6.20 min., ESI+ found [M+H] = 423.2. Step 4: (S)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid

[0224] To a solution of (S) -ethyl 2 -methyl -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro - 1H -indazole -3 - carboxylate (86 mg, 0.31 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (91 mg, 1.60 mmol). The mixture was stirred at 25°C for 15 h and concentrated for drying in vacuum. The residue was dissolved in water (5 mL) and adjusted to pH = 3 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated for drying in vacuum to provide (R)-2-methyl-5-(trifluoromethyl) acid - 4,5,6,7-tetrahydroindazole-3-carboxylic acid (74 mg, 92% yield) as a white solid. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.17 min., ESI+ found [M+H] = 249.0. Step 5: (5S)-2 -methyl -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl ) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -2H -indazole -3 -carboxamide

[0225] To a solution of (S) -2 -methyl - 5 - (trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 - carboxylic acid (74 mg, 0.30 mmol) in N,N - dimethylformamide (4 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (121 mg, 0.64 mmol), 1-1H-benzo [d][1,2,3] triazol -1 -ol (86 mg, 0.64 mmol) and N1 -((ethylimino)methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (122 mg, 0.64 mmol). The reaction mixture was stirred at 25oC for 12 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (25 -55% acetonitrile in water and 0.225% formic acid) to provide (5S) - 2 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -5 -(trifluoromethyl) -4,5,6,7 -tetrahydroindazole -3 -carboxamide (33 mg, 26% yield) in the form of a white solid: 1H NMR (400MHz, Methanol - d4) δ 7.45 - 7.41 (m, 1H), 7.36 - 7.17(m, 3H), 4.98 - 4.94 ( m, 1H), 4.60 - 4.55(m, 1H), 4.44 - 4.37 (m, 1H), 3.90 (s, 3H), 3.42 (s, 3H), 3 .09 - 3.04 (m, 1H), 2.83 - 2.60 (m, 4H), 2.28 - 2.19 (m, 1H), 1.75 - 1.65 (m, 1H) . LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 7 min.) retention time 6.00 min., ESI+ found [M+H] = 423.2. Example 16: Method N (S) -1 -(3, 4 -difluorobenzyl) -N -(5 -oxo - 4,5,6,7 -tetrahydro -1H -pyrazole [3, 4 -b][1,4]oxazepin - 6 -yl) -1H -pyrazole -3 -carboxamide Step 1: 4 -nitro -1 -((2 -(trimethylsilyl) ethoxy) methyl) -1H -pyrazole

[0226] To a solution of 4-nitro-1H-pyrazole (30.0 g, 265 mmol) in tetrahydrofuran (400 mL) was added sodium hydride (60%, 15.9 g, 398 mmol) under 0°C . The reaction mixture was stirred for 30 min, and (2-(chloromethoxy)ethyl)trimethylsilane (66.3 g, 398 mmol) was added at 0°C. After addition, the mixture was stirred at 25°C for 2 h and then finalized by adding water (100 ml). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 4 -nitro -1 -((2 -(trimethylsilyl) ethoxy) methyl )-1H-pyrazole (60.0 g, 93% yield) used in the next step without any further purification. Step 2: 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0227] To a solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (20.0 g, 82.2 mmol) in tetrahydrofuran (300 mL) was added with lithium bis(trimethylsilyl) azanide (1M in tetrahydrofuran, 89.0 mL, 89.0 mmol) at -78oC. The mixture was stirred for 30 min, and hexachloroethane (21.3 g, 90.1 mmol) was added dropwise. After addition, the mixture was allowed to warm to RT and stir for 16 h. The reaction mixture was terminated by adding saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 5 -chloro -4 -nitro - 1 -((2 -( trimethylsilyl) ethoxy) methyl) -1H -pyrazole (15.0 g, 66% yield) in the form of a colorless oil: 1H NMR (400 MHz, DMSO -d6) δ 8.53 (s, 1H), 5, 56 (s, 2H), 3.61 (t, J = 8.2 Hz, 2H), 0.86 (t, J = 8.2 Hz, 2H), 0.05 (s, 9H). Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy acid ) propanoic

[0228] A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (1.77 g, 8.64 mmol) in N,N-dimethylformamide (50 mL) was Sodium hydride (60%, 691 mg, 17.28 mmol) was added under 0oC. The mixture was subjected to stirring at 0°C for 1 h, and then 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.40 g, 8.64 mmol) was added. The resulting mixture was stirred at 20°C for 3 h and finalized by the addition of 1M hydrochloric acid (30 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide (S)-2-((tert-butoxycarbonyl)amino acid)- 3 -((4 -nitro -1 -((2 - (trimethylsilyl) ethoxy) methyl) -1H -pyrazol -5 -yl) oxy) propanoic acid (1.00 g, 26% yield) in the form of an oil of yellow color. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.99 min., ESI+ found [M+H] = 469.1. Step 4: (S) -3 -((4 -amino -1 -((2 - (trimethylsilyl) ethoxy) methyl) -1H -pyrazol -5 -yl) oxy) -2 -((tert -butoxycarbonyl) amino acid ) propanoic

[0229] To a solution of acid (S) -2 -((tert -butoxycarbonyl) amino) -3 -((4 -nitro -1 -((2 - (trimethylsilyl) ethoxy)methyl) -1H -pyrazole -5 -yl)oxy)propanoic acid (600 mg, 1.34 mmol) in methanol (50 mL) was added 10% palladium on carbon (212 mg, 2.00 mmol). The resulting mixture was hydrogenated [46.6 bar (50 psi)] under 20°C for 2 h and then filtered through Celite. The filtrate was concentrated for drying in vacuum to provide (S)-3-((4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy)-2 acid -((tert-butoxycarbonyl)amino) crude propanoic acid (500 mg, 89% yield) as a yellow oil: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.831 min., ESI+ found [M+H] = 417.2. Step 5: (S)-tert-butyl(5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazole[3,4-b] [1,4]oxazepin -6 -yl) carbamate

[0230] To a solution of acid (S) -3 -((4 - amino -1 -((2 -(trimethylsilyl) ethoxy) methyl) -1H -pyrazol - 5 -yl) oxy) -2 -((terc -butoxycarbonyl)amino)propanoic acid (500 mg, 1.20 mmol) in N,N-dimethylformamide (10 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride ( 275 mg, 1.44 mmol). The reaction mixture was stirred at 20°C for 2 h and then concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether) to provide (S) -tert -butyl (5 -oxo -1 -(( 2 -(trimethylsilyl) ethoxy) methyl) -4,5,6,7 -tetrahydro - 1H -pyrazole [3,4 -b][1,4] oxazepin -6 -yl) carbamate (300 mg, 63% yield) as a yellow colored oil: 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.22 (s, 1H), 5.79 (s, 1H), 5.35 (d, J = 11.2 Hz, 1H), 5.22 (d, J = 11.2 Hz, 1H), 4.63 (d, J = 11.2 Hz, 1H), 4.53 (s , 1H), 4.24 -4.20 (m, 1H), 3.62 (t, J = 8.2 Hz, 2H), 1.48(s, 9H), 0.93 (t, J = 8.2Hz, 2H), 0.01 (s, 9H). Step 6: (S) -6 -amino -6,7 -dihydro -1H -pyrazole [3,4 -b][1,4] oxazepin -5(4H) -one 2,2,2 -trifluoroacetate

[0231] To a solution of (S) - tert -butyl (5 - oxo -1 - ((2 - (trimethylsilyl) ethoxy) methyl) -4,5,6,7 -tetrahydro -1H -pyrazole [3, 4-b][1,4] oxazepin-6-yl) carbamate (100 mg, 0.25 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (565 mg, 5.00 mmol) . The reaction mixture was stirred at 20°C for 2 h and concentrated to drying in vacuum to provide (S)-6-amino-6,7-dihydro-1H-pyrazole [3,4-b][1,4] oxazepin -5(4H)-one 2,2,2-trifluoroacetate (70 mg, 99% yield) as a yellow solid used without any further purification in the next step. Step 7: ethyl 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylate

[0232] A mixture of ethyl 1H -pyrazole -3 - carboxylate (1.4 g, 9.66 mmol), 4 -(bromomethyl) -1,2 - difluorobenzene (1.0 g, 4.83 mmol) and hydroxide of potassium (0.27 g, 4.83 mmol) in tetrahydrofuran (100 mL) was stirred at 70oC for 12 h. After cooling to RT, the mixture was filtered and the filtrate was concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide ethyl 1-(3,4-difluorobenzyl)-1H-imidazole -4-carboxylate (1.2 g, 93% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time1.25 min., ESI+ found [M+H] = 266.9. Step 8: 1-(3,4-difluorobenzyl)-1H-pyrazol-3-carboxylic acid

[0233] A mixture of ethyl methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (1.2 g, 4.51 mmol) in ethanol (40 mL) and water (5 mL) and hydroxide of potassium (2.5 g, 45.07 mmol) was stirred at 25oC for 13 h and concentrated for drying in vacuum. The residue was dissolved with water (5 mL) and adjusted to pH = 3 by adding 1M hydrochloric acid. The resulting solid was collected by filtration and dried under reduced pressure to provide 1-(3,4-difluorobenzyl)-1H-pyrazol-3-carboxylic acid (0.73 g, 68% yield) in the form of a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.07 min., ESI+ found [M+H] = 238.9. Step 9: (S) -1 -(3,4 -difluorobenzyl) -N -(5 - oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3, 4 -b][1,4] oxazepin -6 -yl) -1H -pyrazole -3 -carboxamide

[0234] To a solution of (S) -6 -amino -6,7 - dihydro -1H -pyrazole [3,4 -b][1,4] oxazepin -5(4H) -one 2,2,2 - trifluoroacetate (70.0 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3,4-difluorobenzyl)-1H-pyrazol-3-carboxylic acid (71.4 mg, 0. 30 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (40.5 mg, 0.30 mmol) and N1 -((ethylimino) methylene hydrochloride) -N3,N3 - dimethylpropane -1,3 -diamine (57.3 mg, 0.30 mmol). The reaction mixture was heated to 50°C for 16 h and concentrated to drying in vacuum. The residue was purified by RP-HPLC (18 -48% acetonitrile in water and 0.05% ammonium hydroxide) to provide (S) -1 -(3,4 -difluorobenzyl) -N -(5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b][1,4] oxazepin -6 -yl) -1H -pyrazole - 3 -carboxamide (5.9 mg, 6.1 % yield) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.78 (d, J = 2.4 Hz, 1H), 7.36 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.14 - 7.10 (m, 1H), 6.80 (d, J = 2.0 Hz, 1H), 5.41 (s, 2H), 4.89 - 4.85 (m, 1H), 4.53 - 4.50 (m, 1H), 4.33 - 4.28 (m, 1H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.74 min., ESI+ found [M+H] = 389.0. Example 17: Method O 1 -[(3,4-difluorophenyl) methyl] -N -[(6S) -5 -oxo -1,4,6,7 -tetrahydropyrazole [3,4 -b][1,4] oxazepin -6 - il] imidazole -4 -carboxamide Step 1: methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate

[0235] A mixture of 4 -(bromomethyl) -1,2 - difluorobenzene (10.0 g, 48.3 mmol), 1H -imidazole -4 - carboxylate (12.2 g, 96.6 mmol) and carbon hydroxide potassium (5.4 g, 96.6 mmol) in tetrahydrofuran (100 mL) was heated at 70°C for 12 h. After cooling, the mixture was filtered and the filtrate was concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 1 -(3,4-difluorobenzyl)-1H -imidazole - 4 -carboxylate (5.0 g, 41% yield) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0 .70 min., ESI+ found [M+H] = 252.8. Step 2: 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylic acid

[0236] To a mixture of methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (5.0 g, 19.07 mmol) in ethanol (50 mL) and water (5 mL) was added potassium hydroxide (5.4 g, 95.34 mmol). The mixture was stirred at 25°C for 13 h and concentrated for drying in vacuum. The residue was diluted with water (5 mL) and adjusted to pH = 3 by adding 1M hydrochloric acid. The resulting solid was collected by filtration and subjected to drying under reduced pressure to yield 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylic acid (4.5 g, 99.1% yield) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.22 min., ESI+ found [M+H] = 238.8. Step 3: 1 -[(3,4-difluorophenyl) methyl] -N - [(6S) -5 -oxo -1,4,6,7 -tetrahydropyrazole [3,4 -b][1,4] oxazepine -6 -yl] imidazole -4 -carboxamide

[0237] To a solution of (S) -6 -amino -6,7 - dihydro -1H-pyrazole [3,4-b][1,4] oxazepin-5(4H) -one 2,2,2 - trifluoroacetate (70 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylic acid (71 mg, 0.30 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (41 mg, 0.30 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (57 mg, 0.30 mmol). The mixture was heated at 50°C for 16 h and concentrated to drying in vacuum. The residue was purified by RP-HPLC (17 -47% acetonitrile in water and 0.05% ammonium hydroxide) to provide (S) -1 -(3,4 -difluorobenzyl) -N -(5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 - b][1,4] oxazepin -6 -yl) -1H -imidazole -4 -carboxamide (4.9 mg, 5.1 % yield) as a white solid: 1H NMR (400 MHz, CD3OD) δ7.79 (s, 1H), 7.74 (s, 1H), 7.36 (s, 1H), 7, 32 - 7.24 (m, 2H), 7.14 - 7.05 (m, 1H), 5.26 (s, 2H), 4.82 - 4.50 (m, 1H), 4.51 - 4.48 (m, 1H), 4.31 - 4.26 (m, 1H). LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.36 min. ESI+ found [M+H] = 389.1. Example 18: Method P 5,5 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -1,4,6,7 -tetrahydroindazole -3 -carboxamide Step 1: ethyl 2 -(5,5 -dimethyl -2 -oxocyclohexyl) -2 -oxo acetate

[0238] To a solution of 4,4-dimethyl cyclohexanone (2.5 g, 19.8 mmol) in ethanol (30 mL) was added a solution of sodium ethoxide (1.5 g, 21.8 mmol) in ethanol (30 mL), followed by diethyl oxalate (2.9 g, 19.8 mmol) under 0oC. After addition, the mixture was stirred at 25°C for 15 h and concentrated to drying in vacuum to provide crude ethyl 2-(5,5-dimethyl-2-oxo cyclohexyl)-2-oxo acetate (4.5 g , 100% yield) in the form of a yellow solid used in the next step without any further purification. Step 2: 5,5-Dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

[0239] To a solution of ethyl 2-(5,5-dimethyl-2-oxocyclohexyl)-2-oxo acetate (4.47 g, 21.8 mmol) in glacial acetic acid (5 mL) was added hydrazine hydrate (0.18 g, 21.8 mmol) under 0oC. The mixture was stirred at 25°C for 1 h and then adjusted to pH = 8 by addition of aqueous sodium bicarbonate. The resulting mixture was extracted with methanol and dichloromethane (3 x 300 mL, methanol/dichloromethane = 5:95). The combined organic extracts were washed with water (50 mL), saline solution (50 mL), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give ethyl 5,5-dimethyl-4,5,6,7-tetra hydro - 1H -indazole -3 -carboxylate (700 mg). The aforementioned material was dissolved in THF (10 mL) and water (2 mL), and lithium hydroxide monohydrate (500 mg, 11.9 mmol) was added. The mixture was stirred at 25°C for 12 h and concentrated for drying in vacuum. The residue was diluted with water (10 mL) and washed with ethyl acetate (2 x 20 mL). The aqueous layer was then adjusted to pH = 3 by adding 1M HCl. The solution was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated for drying in vacuum to provide 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (100 mg , 2.5% yield during 2 steps) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.04% formic acid for 1.5min.) retention time 0.66 min., ESI+ found [M+H] = 195.1. Step 3: 5,5 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1,4,6,7 -tetra hydroindazole -3 -carboxamide

[0240] To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (100 mg, 0.51 mmol) in N,N-dimethylformamide (5 mL ) 1H -benzo [d][1,2,3] triazol -1 -ol (76 mg, 0.56 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro -1 was added ,5-benzoxazepin -4 -one (108 mg, 0.56 mmol) and N -1 - ((ethylamine)ethylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (108 mg, 0.56 mmol ). The mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (45-75% acetonitrile in water and 0.05% hydrochloric acid) to give 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo -2,3-dihydro -1,5 -benzoxazepin -3 -yl] -1,4,6,7 -tetrahydroindazole -3 -carboxamide (30 mg, 15.8% yield) as a colored solid white: 1H NMR (400 MHz, DMSO -d6) δ 7.90 (d, J = 8.0 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.31 - 7.19 ( m, 3H), 4.82 - 4.77 (m, 1H), 4.51 - 4.34 (m, 2H), 3.29 (s, 3H), 2.57 - 2.52 (m, 2H), 2.32 (s, 2H), 1.45 (t, J = 6.4 Hz, 2H), 0.88 (s, 6H). LCMS (5 to 95% acetonitrile in water + 0.04% formic acid for 1.5min.) retention time 0.86 min., ESI+ found [M+H] = 369.0. Example 19: Q Method

[0241] 5 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 4, 5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazole -3 - carboxamide

[0242] 8 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4, 5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide

[0243] 7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4, 5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide

[0244] 6 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4, 5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide Step 1: 7 -methyloxepan -4 -one and 2 -methyloxepan -4 -one

[0245] To a solution of 2-methyldihydro -2H - pyran -4(3H) -one (3.0 g, 26.68 mmol) in dichloromethane (60 mL) and boron trifluoride ethyl ether (8.1 mL , 48% ethyl ether) trimethylsilyl diazomethane (14.5 mL, 28.91 mmol, 2 M in hexane) was added dropwise under -30°C. After addition, the resulting solution was stirred for 1 h at -30°C and finalized by addition of saturated sodium bicarbonate (30 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide a mixture of 7-methyloxepan-4-one and 2-methyloxepan- 4-one (1.2 g, 35.1% yield) in the form of a colored oil in the next step without any further Step 2: ethyl 5-methyl -4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 -carboxylate; ethyl 7-methyl -4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 -carboxylate; ethyl 8 -methyl -4,5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 -carboxylate and ethyl 6 -methyl -4,5,6,8 -tetrahydro -1H - oxepin [3,4 -c] pyrazole -3 -carboxylate

[0246] To a solution of 7-methyloxepan-4-one and 2-methyl oxepan-4-one (1.00 g, 7.8 mmol) in dimethyl sulfoxide (30 mL) was added ethyl diazo acetate (1. 07 g, 9.4 mmol), pyrrolidine (0.11 g, 1.56 mmol). The mixture was stirred at 20oC for 16 h and diluted with water (20 mL). The solution was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water (3 x 25 mL), dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide:

[0247] ethyl 5 -methyl -4,5,7,8 -tetrahydro - 1H - oxepino[4,5 -c] pyrazole -3 -carboxylate (120 mg, 6.9% yield) in the form of a solid yellow in color: 1H NMR (400MHz, CDCl3) δ 4.38 (q, J = 6.8 Hz, 2H), 4.24 - 4.20 (m, 1H), 3.63 - 3.55 (m , 2H), 3.45 - 3.41 (m, 1H), 3.06 - 3.05 (m, 1H), 2.97 - 2.89 (m, 1H), 2.70 - 2.63 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H);

[0248] ethyl 7-methyl -4,5,7,8 -tetrahydro - 1H -oxepino[4,5 -c] pyrazole -3 -carboxylate (120 mg, 6.9% yield) in the form of a solid yellow in color: 1H NMR (400MHz, CDCl3) δ 4.38 (q, J = 7.2 Hz, 2H), 4.26 - 4.22 (m, 1H), 3.67 - 3.56 (m , 1H), 3.54 - 3.49 (m, 1H), 3.37 - 3.32 (m, 1H), 3.04 - 2.90 (m, 1H), 2.90 - 2.83 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.0 Hz, 3H);

[0249] ethyl 8 -methyl -4,5,6,8 -tetrahydro - 1H -oxepino [3,4 -c] pyrazole -3 -carboxylate (250 mg, 14.3% yield) as a solid yellow in color: 1H NMR (400MHz, CDCl3) δ 4.60 - 4.55 (m, 1H), 4.44 - 4.35 (m, 2H), 4.33 - 4.28 (m, 1H) , 3.86 - 3.79 (m, 1H), 3.39 - 3.34 (m, 1H), 2.80 - 2.76 (m, 1H), 1.90 - 1.83 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H) and

[0250] ethyl 6 -methyl -4,5,6,8 -tetrahydro - 1H -oxepino[3,4 -c] pyrazole -3 -carboxylate (250 mg, 14.3% yield) in the form of a solid yellow in color: 1H NMR (400MHz, CDCl3) δ 4.92 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 4.41 - 4, 35 (m, 2H), 3.86 - 3.82 (m, 1H), 3.43 - 3.37 (m, 1H), 2.70 - 2.65 (m, 1H), 2.00 - 1.92 (m, 1H), 1.64 - 1.61 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.29 (d, J = 6.4 Hz , 3H). Step 3: 5-Methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-carboxylic acid

[0251] To a solution of ethyl 5 -methyl - 4,5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazole -3 - carboxylate (110 mg, 0.49 mmol) in tetrahydrofuran (5 mL) and water (1 mL) lithium hydroxide (118 mg, 4.91 mmol) was added. The mixture was stirred at 20°C for 20 h and then concentrated for drying in vacuum. The residue was diluted with water (30 mL) and adjusted to pH = 3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole acid. Crude 3-carboxylic acid (100 mg, 100% yield) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.86 min., ESI+ found [M+H] =196.9, Step 4: 5 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 4 ,5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazole -3 - carboxamide

[0252] To a solution of 5-methyl - 4,5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazol -3 - carboxylic acid (50.0 mg, 0.25 mmol) in N,N -dimethylformamide (5 mL) was added 1H -benzo [d][1,2,3] triazol -1 -ol (41.3 mg, 0.31 mmol), N1 -((ethylimino)methylene) hydrochloride of -N3,N3 -dimethylpropane -1,3 -diamine (58.6 mg, 0.31 mmol) and (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 - benzoxazepine -4 -one (53.9 mg, 0.28 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (50 -80% methanol in water and 0.05% ammonia) to provide 5 -methyl -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] - 4,5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazole -3 - carboxamide (30.0 mg, 32% yield ) in the form of a white solid: 1H NMR (400MHz, DMSO -d6) δ 12.94 (s, 1H), 8.01 - 7.99 (m, 1H), 7.49 - 7.47 ( m, 1H), 7.32 - 7.28 (m, 2H), 7.24 - 7.21 (m, 1H), 4.82 - 4.79 (m, 1H), 4.42 - 4, 39 (m, 1H), 4.37 - 4.35 (m, 1H), 4.07 - 4.04 (m, 1H), 3.49 - 3.45 (m, 3H), 3.31 ( s, 3H), 2.87 - 2.80 (m, 2H), 2.49 - 2.35 (m, 1H), 1.13 (d, J = 6.0 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.78 min., ESI+ found [M+H] =371.0.

[0253] 7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4, 5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide Step 5: 7-Methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-carboxylic acid

[0254] To a solution of ethyl 7-methyl - 4,5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazole -3 - carboxylate (120 mg, 0.54 mmol) in tetrahydrofuran (5 mL) and water (1 mL) lithium hydroxide (128 mg, 5.35 mmol) was added. The mixture was stirred at 20°C for 20 h and then concentrated for drying in vacuum. The residue was diluted with water (30 mL) and adjusted to pH = 3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3 acid -crude carboxylic acid (100 mg, 95% yield) as a white solid used without further purification in the following step: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.85 min., ESI+ found [M+H] =197.0. Step 6: 7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4 ,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide

[0255] To a solution of 7-methyl - 4,5,7,8 -tetrahydro -1H -oxepino[4,5 -c] pyrazole -3 -carboxylic acid (50.0 mg, 0.25 mmol) in N,N -dimethylformamide (5 mL) was added 1H -benzo[d][1,2,3]triazol-1-ol (41.3 mg, 0.31 mmol), N1 -((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (58.6 mg, 0.31 mmol) and (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 - benzoxazepine - 4-one (53.9 mg, 0.28 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (50 -80% methanol in water and 0.05% ammonia) to provide 7 -methyl -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide (20 mg, 21% yield) in form a white solid: 1H NMR (400MHz, DMSO -d6) δ 12.92 (s, 1H), 8.00 - 7.97 (m, 1H), 7.49 - 7.47 (m, 1H), 7.32 - 7.28 (m, 2H), 7.24 - 7.23 (m, 1H), 4.84 - 4.79 (m, 1H), 4.50 - 4.44 ( m, 1H), 4.42 - 4.39 (m, 1H), 4.05 - 4.01 (m, 1H), 3.61 - 3.58 (m, 1H), 3.38 - 3, 36 (m, 1H), 3.31 (s, 3H), 3.30 - 3.26 (m, 1H), 2.87 - 2.83 (m, 1H), 2.71 - 2.65 ( m, 1H), 2.61 - 2.50 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.78 min., ESI+ found [M+H] =371.0.

[0256] 8 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4, 5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide Step 7: 8-Methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazol-3-carboxylic acid

[0257] To a solution of ethyl 8 -methyl - 4,5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxylate (250 mg, 1.11 mmol) in tetrahydrofuran (5 mL) and water (1 mL) lithium hydroxide (267 mg, 11.15 mmol) was added. The mixture was stirred at 20°C for 20 h and concentrated for drying in vacuum. The residue was diluted with water (30 mL) and adjusted to pH = 3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 8-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazol-3 acid -crude carboxylic acid (200 mg, 91% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1 .26 min., ESI+ found [M+H] =197.2. Step 8: 8 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 4, 5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide

[0258] To a solution of 8-methyl - 4,5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxylic acid (70.0 mg, 0.35 mol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (57.9 mg, 0.43 mmol), N1-((ethylimino)methylene hydrochloride ) -N3,N3 -dimethyl propane -1,3 -diamine (82.1 mg, 0.43 mmol), and (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 - benzoxazepine -4 -one (75.4 mg, 0.39 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (21 -51% acetonitrile in water and 0.05% ammonia) to provide 8 -methyl -N -((S) -5 -methyl -4 -oxo -2,3 ,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -4,5,6,8 - tetrahydro -1H -oxepino [3,4 - c] pyrazole -3 -carboxamide ( 65 mg, 49% yield) as a white solid: 1H NMR (400MHz, DMSO -d6) δ 12.90 (s, 1H), 8.00 (br. s, 1H), 7.50 - 7.47 (m, 1H), 7.33 - 7.28 (m, 2H), 7.26 - 7.24 (m, 1H), 4.84 - 4.81 (m, 1H), 4 .63 - 4.60 (m, 1H), 4.48 - 4.39 (m, 2H), 4.09 - 4.07 (m, 1H), 3.73 - 3.70 (m, 1H) , 3.32 (s, 3H), 3.20 - 3.17 (m, 1H), 2.70 - 2.65 (m, 1H), 1.78 - 1.70 (m, 1H), 1 .62 - 1.59 (m, 1H), 1.48 (d, J = 6.8 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.78 min., ESI+ found [M+H] =371.0.

[0259] 6 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4, 5,6,8 -tetrahydro -1H -oxepino[3,4 -c] pyrazole -3 - carboxamide Step 9: 6-Methyl -4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazol-3-carboxylic acid

[0260] To a solution of ethyl 6 -methyl - 4,5,6,8 -tetrahydro -1H -oxepino[3,4 -c] pyrazole -3 - carboxylate (250 mg, 1.11 mmol) in tetrahydrofuran ( 5 mL) and water (1 mL) lithium hydroxide (267 mg, 11.15 mmol) was added. The mixture was stirred at 20°C for 20 h and concentrated for drying in vacuum. The residue was diluted with water (30 mL) and adjusted to pH = 3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 6-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole acid. Crude 3-carboxylic acid (200 mg, 91% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.27 min., ESI+ found [M+H] =197.2. Step 10: 6 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 4, 5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide

[0261] To a solution of 6-methyl - 4,5,6,8 -tetrahydro -1H -oxepino[3,4-c] pyrazole -3 -carboxylic acid (70.0 mg, 0.35 mmol) in N,N -dimethylformamide (5 mL) was added 1H -benzo[d][1,2,3]triazol-1-ol (57.9 mg, 0.43 mmol), N1-((ethylimino) hydrochloride methylene) -N3,N3 -dimethylpropane -1,3 -diamine (82.1 mg, 0.43 mmol) and (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 - benzoxazepine - 4-one (75.4 mg, 0.39 mmol), The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (23 -53% acetonitrile in water and 0.05% ammonia) to provide 6 -methyl -N - ((S) -5 -methyl -4 -oxo -2, 3,4,5 -tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) -4,5,6,8 - tetrahydro -1H - oxepino[3,4 -c] pyrazole -3 -carboxamide (62 mg, 47% yield) as a white solid: 1H NMR (400MHz, DMSO -d6) δ 8.05 - 8.03 (m, 1H), 7.50 - 7.47 (m , 1H), 7.33 - 7.23 (m, 3H), 4.84 - 4.80 (m, 1H), 4.70 (d, J = 14.8 Hz, 1H), 4.49 - 4.40 (m, 3H), 3.78 - 3.74 (m, 1H), 3.31 (s, 3H), 3.30 - 3.24 (m, 1H), 2.49 - 2, 47 (m, 1H), 1.83 - 1.78 (m, 1H), 1.41 - 1.32 (m, 1H), 1.15 (d, J = 6.0 Hz, 3H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79 min., ESI+ found [M+H] =371.1. Example 20: R Method

[0262] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 - (1H - pyrazole -1 -yl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide Step 1: 1,4 -dioxaspiro [4,5] decan -8 -ol

[0263] To a solution of 1,4-dioxaspiro [4,5] decan-8 -one (10.0 g, 64.0 mmol) in methanol (150 mL) was added sodium borohydride (2.5 g, 66.1 mmol) under 0oC. The mixture was heated to 20°C for 3 h and then poured into water (150 mL). The resulting mixture was extracted with dichloromethane (3 x 200 mL). The combined organic phases were filtered through a cotton pad, and the filtrate was concentrated for drying in vacuum to provide 1,4-dioxa spiro[4.5]decan-8-ol (7.0 g, 69% yield) used without any further purification in the following step: 1H NMR (400 MHz, CDCl3) δ 3.95 - 3.91 (m, 4H), 3.80 - 3.77 (m, 1H), 1.87 - 1.80 (m, 4H), 1.69 - 1.56 (m, 5H). Step 2: 1,4-dioxaspiro[4,5]decan-8-yl 4-methylbenzene sulfonate

[0264] A solution of 1,4-dioxaspiro [4,5]decan-8-oI (7.0 g, 44.25 mmol) in pyridine (70 mL) was treated with 4-methylbenzensulfonyl chloride (10. 1 g, 53.1 mmol). The reaction mixture was stirred at 20oC for 16 h and then terminated by adding saline solution (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with 0.5 M HCl (100 mL), saturated aqueous sodium bicarbonate (100 mL), saline solution (100 mL), dried over sodium sulfate and concentrated for drying in vacuum to provide 1,4-dioxa spiro[4,5]decan-8-yl 4-methylbenzene sulfonate (10.0 g, 72.3% yield) in the form of a clear liquid which was used without any further purification in the next step: 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.63 - 4.60 (m , 1H), 3.93 - 3.86 (m, 4H), 2.42 (s, 3H), 1.84 - 1.76 (m, 6H), 1.54 - 1.50 (m, 2H ). Step 3: 1 -(1,4 -dioxa spiro [4,5] decan -8 - yl) -1H -pyrazole

[0265] To a mixture of sodium hydride (60%, 0.97 g, 24.24 mmol) in N,N-dimethylformamide (5 mL) was slowly added 1H-pyrazole (1.65 g, 24.24 mmol ) under 0°C. The reaction mixture was stirred for 30 min. el,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzene sulfonate (6.26 g, 20.03 mmol) was added. After addition, the reaction mixture was subjected to stirring at 0°C for 10 min. and under 60°C for 5 h. The reaction mixture was cooled and finished by adding water (30 mL). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide l -(1,4-dioxaspiro [4,5] dec - 8 -yl) -1H - pyrazole (2.0 g, 48% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 7.73 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 6.20 (t, J = 2.0 Hz, 1H), 4.29 - 4.21 (m, 1H), 3.87 - 3.90 (m, 4H), 1.98 - 1.93 (m, 4H), 1.75 - 1.65 (m, 4H). Step 4: 4 -(1H -pyrazol -1 -yl)cyclohexanone

[0266] A solution of l -(1,4-dioxaspiro [4,5] decan-8 -yl) -1H -pyrazole (2.0 g, 9.60 mmol) and 36% HCl (4.9 g, 48.02 mmol) in THF (20 ml) was stirred at room temperature for 20 h. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide crude 4-(1H-pyrazol-1-yl)cyclohexanone (1.5 g, 95% yield) as a white solid: 1H NMR (400 MHz, DMSO - d6) δ 7.81 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 6, 26 (t, J = 1.8 Hz, 1H), 4.74 - 4.67 (m, 1H), 2.59 - 2.52 (m, 2H), 2.33 - 2.17 (m, 6H). Step 5: ethyl 2 -oxo -2 -(2 -oxo -5 -(1H -pyrazol -1 -yl) cyclohexyl) acetate

[0267] To a solution of 4-pyrazole-1-ylcyclohexanone (1.2 g, 7.31 mmol) in ethanol (15 mL) was added a solution of sodium ethanoxide in ethanol (10 mL) under 0°C. The reaction mixture was stirred for an additional 10 min. and diethyl oxalate (1.1 g, 7.31 mmol) was added. The resulting mixture was stirred at RT for 20 h and concentrated for drying in vacuum to provide ethyl 2-oxo-2-(2-oxo-5-pyrazol-1-yl-cyclohexyl)acetate (2.0 g, over 100% yield) in the form of a yellow solid for use in the next step without any further purification. Step 6: ethyl 5 -(1H -pyrazol -1 -yl) -4,5,6,7 - tetrahydro -1H -indazole -3 -carboxylate

[0268] To a solution of ethyl 2-oxo-2-(2-oxo-5-pyrazol-1-yl-cyclohexyl) acetate (1.90 g, 7.19 mmol) in acetic acid (10 mL) was added 50% hydrazine in water (0.52 g, 8.04 mmol) under 0°C. The mixture was stirred at 25°C for 1 h and then finalized by addition of saturated aqueous sodium bicarbonate. The mixture was extracted with methanol/dichloromethane (3 x 50 mL, 1:10). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide ethyl 5-pyrazol-1-yl-4,5,6, 7-tetrahydro-1H-indazole-3-carboxylate (1.0 g, 53% yield) as a yellow solid: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1 .5 min.) retention time 0.61 min., ESI+ found [M+H] = 260.9. Step 7: 5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

[0269] To a solution of ethyl 5 -(1H -pyrazol -1 -yl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate (200 mg, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL) lithium hydroxide (92 mg, 3.83 mmol) was added. The mixture was stirred at RT for 20 h and concentrated for drying in vacuum. The residue was diluted with water (10 mL) and then adjusted to pH = 3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3 acid -carboxylic acid (100 mg, 56% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.36 min., ESI+ found [M+H] =233.2, Step 8: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 -(1H - pyrazole -1 -yl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0270] To a solution of 1H -benzo [d][1,2,3] triazol -1 -ol (49 mg, 0.36 mmol) in N,N -dimethylformamide (5 mL) was added N1 hydrochloride - ((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine (69 mg, 0.36 mmol), 6,6 -dimethyl acid -1,4,5,8 -tetrahydrooxepino [3,4 - c] pyrazole -3 -carboxylic acid (63 mg, 0.30 mmol) and (3S) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (64 mg, 0.30 mmol) 33 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to drying in vacuum. The residue was purified by RP-HPLC (28 - 58% acetonitrile in water and 0.05% ammonia) to provide N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 - (1H -pyrazol - 1 -yl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide ( 60 mg, 49% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 13.00 (br. s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.35 - 7.19 (m, 3H), 6.26 - 6.18 (m, 1H), 4.87 - 4.77 (m, 1H), 4.62 - 4.46 (m, 2H), 4.44 - 4.36 (m, 1H), 3 .31 (s, 3H), 3.20 - 3.10 (m, 1H), 2.98 - 2.65 (m, 3H), 2.25 - 2.09 (m, 2H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.78 min., ESI+ found [M+H] =407.1. Example 21: Method S

[0271] 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 - il ) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide and 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -4 -carboxamide Step 1: 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one

[0272] n -BuLi (2.5 M in hexane, 16 mL, 40 mmol) was added dropwise to a solution of diisopropyl amine (4.7 g, 46.5 mmol) under -78oC. The mixture was stirred at -78oC for 40 min. and a solution of 2,6-dichloronicotinic acid (3 g, 15.6 mmol) in tercahydrofurano (30 mL) was added dropwise to the reaction mixture under -78°C and the resulting mixture was subjected to stirring under -78°C for 3 H. Butanone (10 g, 139 mmol) was added dropwise to the reaction mixture under -78°C and the reaction mixture was slowly heated to RT and stirred for 16 h. The reaction mixture was cooled to 0oC, quenched with saturated ammonium chloride to pH 7 and acidified with 3N HCl to pH 4. The mixture was extracted with ethyl acetate (30 mL x 4). The organic layers were combined, dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 8 : 1 to 6 : 1 to 4 : 1 ethyl acetate : petroleum ether) to give 4,6-dichloro-1-ethyl -1-methylfuro[3,4-c]pyridin-3(1H)-one as a brown solid (1.3 g, 34% yield). LCMS: m/z = 246.0 / 248.1 [M+1]. Column: MERCK RP18 (50 -3). Mobile phase: H2O (0.01%TFA) (A) / ACN(0.01% TFA)(B) Elution program. Gradient from 10 to 95% B in 1.8 min. under 2.0 ml/min. Temperature: 45°C. gradient 3 min. Step 2: 4,6 -dichloro -1 -ethyl -1 -methyl -1,3 — dihydrofuro [3,4 -c] pyridin -3 -ol

[0273] To a stirred suspension of 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (1.3 g, 5.28 mmol) in Toluene (30 mL) was added diisobutyl aluminum hydride (1 M in toluene, 12 mL, 12 mmol) under -78°C. The reaction mixture was stirred at -78oC for 1.5 h and finished with saturated ammonium chloride (50 ml) dropwise at -78oC. The mixture was slowly heated to RT and stirred for 30 min. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 4:1 to 2:1 ethyl acetate:petroleum ether) to provide 4,6-dichloro-1-ethyl-1-methyl -1,3 - dihydrofuro [3,4 -c] pyridin -3 -ol (1 g, 76% yield) as a colorless oil: LCMS: m/z = 248.0/ 250.1 [M+ 1]. Column: MERCK RP18 (50 -3). Mobile phase: H2O(0.01%TFA) (A) / ACN(0.01% TFA)(B) Elution program: Gradient from 10 to 95% B in 1.8 min. under 2.0 ml/min. Temperature: 45°C. gradient 3 min. CL Step 3: 4,6 -dichloro -1 -ethyl -1 -methyl -1,3 — dihydrofuro [3,4 -c] pyridine

[0274] A stirred solution of 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (1 g, 4.06 mmol) in dichloromethane (10 ml) trifluoroacetic acid (1.5 ml, 20.1 mmol) was added dropwise under 0°C and the mixture was stirred under 0°C for 30 min. Triethylsilane (2 mL, 12.55 mmol) was added dropwise to the reaction mixture under 0 ° C and the reaction mixture was slowly heated to RT and stirred under RT for 2 h. The reaction mixture was concentrated for drying in vacuum. The residue was dissolved in ethyl acetate (50 mL) and adjusted to pH = 7 by addition of saturated sodium bicarbonate. The ethyl acetate layer was separated, dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 8:1 ethyl acetate : petroleum ether) to provide 4,6-dichloro-1-ethyl-1-methyl-1,3 -dihydrofuro 3 [3,4 -c] pyridine (0.83 g, 88% yield) was obtained as a white solid. LCMS: m/z = 232.1/ 234.1 [M+1]. Column: MERCK RP18 (50 -3). Mobile phase: H2O(0.01%TFA) (A) / ACN(0.01% TFA)(B) Elution program: Gradient from 10 to 95% B in 1.8 min. under 2.0 ml/min. Temperature: 45°C. Gradient 3 min. Step 1: methyl 4-chloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate and methyl 6-chloro-1-ethyl-1-methyl-1,3 -dihydrofuro [3,4 -c] pyridine -4 -carboxylate

[0275] A solution of 4,6-dichloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine (0.50 g, 2.15 mmol) in methanol (10 mL) was [1,1'-Bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.16 g, 0.22 mmol) and triethylamine (2.18 g, 21.54 mmol) were added. The reaction mixture was subjected to stirring at 80oC for 15 h under carbon monoxide (25 psi). After cooling to room temperature, the reaction mixture was concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide methyl 4-chloro-1-ethyl-1-methyl-3H-furo [3,4 -c] pyridine -6 -carboxylate and methyl 6 -chloro -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -4 -carboxylate (140 mg (3:1 mixture) , 0.55 mmol, 25.5% mixing yield) in the form of a light yellow oil used as it was in the next step without any further purification. Step 2: methyl 1-ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxylate and methyl 1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c ] pyridine -4 -carboxylate

[0276] To a solution of methyl 4 -chloro -1 - ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -6 -carboxylate and methyl 6 -chloro -1 -ethyl -1 -methyl -3H -furo[3,4-c]pyridine-4-carboxylate (140 mg, 0.55 mmol) in methanol (10 mL) was added 10% palladium (437 mg, 0.41 mmol) on carbon. The reaction mixture was hydrogenated [2.05 bar (15 psi)] under 20°C for 1 h and then filtered through Celite. The filtrate was concentrated for drying in vacuum to provide methyl 1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate and methyl 1-ethyl-1-methyl-3H-furo[3 ,4 -c] pyridine - 6 -carboxylate (100 mg, 82.6% yield) as a yellow oil: LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1. 5 min.) retention time 0.65 min., ESI+ found [M+H] = 222. Step 3: 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid and 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c] acid ] pyridine -4 -carboxylic acid

[0277] To a solution of methyl 1-ethyl -1 - methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxylate and methyl 1 -ethyl -1 -methyl -1,3 -dihydrofuro [3 ,4-c]pyridine-4-carboxylate (100 mg, 0.46 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (202 mg, 4.81 mmol). The reaction mixture was stirred at 15oC for 15 h and concentrated for drying in vacuum. The residue was diluted with water (5 mL) and adjusted to pH = 3 by addition of 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid and 1 -ethyl -1 -methyl - 1,3 -dihydrofuro [3,4 -c] pyridine -4 -carboxylic acid (50 mg, 50.5% yield) in the form of a yellow oil used in the next step without any further purification. Step 4: 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 - yl ) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide and 1 -ethyl -1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -1,3 - dihydrofuro [3,4 -c] pyridine -4 -carboxamide

[0278] To a solution of 1-ethyl -1 - methyl -3H -furo [3,4 -c] pyridine -6 -carboxylic acid and 1 -ethyl - 1 -methyl -3H -furo [3,4 -c ] pyridine -4 - carboxylic acid (3:1 mixture, 41 mg, 0.20 mmol) in N,N - dimethylformamide (5 mL) was added N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride -1 ,3-diamine (59 mg, 0.31 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro - 1,5 -benzoxazepin -4 -one (50 mg, 0.26 mmol) and 1H -benzo [d][1,2,3] triazol -1 -ol (35 mg, 0.26 mmol). The reaction mixture was stirred at 15oC for 1 h and concentrated for drying in vacuum. The residue was purified using RP-HPLC (40 -70% acetonitrile in water and 0.05% ammonium hydroxide) to provide:

[0279] 1-ethyl -1 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -3H -furo [3,4 -c] pyridine-6-carboxamide (15 mg, 20.7% yield) as a white solid and 1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -3H -furo [3,4 -c] pyridine -4 - carboxamide (7 mg, 9.6% yield) as a solid white color: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.86 (s, 1H), 7.45 - 7.43 (m, 1H), 7.39 - 7.29 (m, 2H), 7.26 - 7.25 (m, 1H), 5.16 (d, J = 3.6 Hz, 2H), 5.05 - 5.00 (m, 1H), 4, 67 - 4.62 (m, 1H), 4.41 (t, J = 9.6, 1H), 3.43 (s, 3H), 1.88 - 1.82 (m, 2H), 1, 46 (s, 3H), 0.77 (t, J = 7.2, 3H); LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) RT = 0.87 min., m/z =382.0 [M + H]+e 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J = 5.6 Hz, 1H), 7.45 - 7.42 (m, 2H), 7.34 - 7.24 (m, 3H), 5.33 - 5.28 (m, 2H), 5.02 - 4.97 (m, 1H), 5.16 (d, J = 3.6 Hz, 2H), 5.05 - 5.00 (m, 1H ), 4.63 (t, J = 10.0 Hz, 1H), 4.41 (t, J = 9.6 Hz, 1H), 3.43 (s, 3H), 1.87 - 1.81 (m, 2H), 1.45 (s, 3H), 0.75 (t, J = 7.6 Hz, 3H); LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) RT = 1.17 min., m/z =382.3 [M + H]+. Example 22: T Method (S) -1,1 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -1,3 — dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[0280] 6-Chloro -1,1 -dimethylfuro [3,4 -c] pyridin -3(1H) -one and similar starting materials for Method T are found commercially available or prepared according to exemplary procedures illustrated in the documents : WO 2005080342 A1; WO 2005074939 A1; and WO 2004029026 A1. Step 1: 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol

[0281] To a stirred solution of 6-chloro-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-one (18.5 g, 0.09362 mol) in anhydrous toluene (300 mL) under RT under nitrogen which was cooled to -700C, diisobutyl aluminum hydride (197.24 mL, 0.18724 mol, 1M in Toluene) was added dropwise and the reaction mixture was allowed to stir under -700C for 3h. The reaction mixture was finished with filtered saturated ammonium chloride solution. The filtrate was extracted with ethyl acetate (2x 200 mL) and the combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate:petroleum ether) to provide 6-chloro-1,1-dimethyl-1,3-dihydrofuro [ 3,4 -c] pyridin -3 -ol (17.5 g, 94%): 1H NMR (400 MHz, DMSO -d6) δ 8.4 (s, 1H), 7.65 (s, 1H), 7.2 - 6.40 br., s, 1H), 6.35 (s, 1H), 1.35 (s, 3H), 1.23 (s, 3H). Step 2: 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine

[0282] 6-Chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (17.5 g, 0.0877 mol) was dissolved in anhydrous dichloromethane and cooled to 0°C under nitrogen. To the stirred solution, trifluoroacetic acid (32.66 ml 0.438 mol.) was added dropwise and stirred for 30 min. under 0°C. Triethyl silane (42.47 ml, 0.263 mol) was added to the reaction mixture under 0°C and stirred at RT for 3h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2 x 200 mL). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate:petroleum ether) to provide 6-chloro-1,1-dimethyl-1,3-dihydrofuro [ 3,4 -c] pyridine (15.2 g, 94%): LCMS RT = 1.55 min., m/z = 184.04 [M + H]+. Column: Aquidade UPLC BEH C -18 (2.1X50 mm) 1.7u; MP :A: 0.05%FA in Water, B: 0.05%FA in Acetonitrile; T/%B : 0/10,0.5/10, 1/35, 1.5/45, 2.3/90, 3.2/90, 3.6/10, 4/10; Flow: 0.55 mL; Diluent: ACN+WATER (70:30); Column Temperature :35°C. Step 3: 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-6-amine

[0283] To a stirred solution of 6-chloro-1,1-dimethyl-1,3-dihydrofuro [3,4-c] pyridine (15.0 g, 0.082 mol) in anhydrous tetrahydrofuran was added benzophenone imine (15.39 g, 0.085 mol.) and cesium carbonate (39.92 g, 0.12254) under a nitrogen atmosphere. The resulting solution was degassed with nitrogen for 10 min. and 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (1.88g, 0.003 mol) and palladium (II) acetate (0.440 g, 0.002 mol.) were added under a nitrogen atmosphere. The reaction mixture was heated under reflux for 11 h. the reaction was cooled to RT, filtered through Celite and washed with ethyl acetate. The filtrate was washed with water, saline solution, dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was dissolved in tetrahydrofuran, cooled to 0°C and 2N HCl (30 mL) was added to the reaction mixture and stirred at RT for 3 h. The reaction mixture was poured into water, extracted with ether and the aqueous layer was adjusted to pH = 8 by adding sodium bicarbonate. The mixture was extracted with ethyl acetate (2 x 200 mL), dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 5% methanol in dichloromethane) to provide 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin- 6-amine (3g, 29%) as a white solid: LCMS RT = 1.09 min., m/z = 165.11 [M + H]+. Step 4: 6-bromo-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine

[0284] To a solution of 1,1-dimethyl -3H - fur [3,4 -c] pyridin -6 -amine (200 mg, 1.22 mmol) in hydrobromic acid (0.06 mL, 1.22 mmol ) sodium nitrite (210 mg, 3.05 mmol) in water (0.2 mL) and bromine (0.12 mL, 2.44 mmol) were added under -25oC. The reaction was stirred at -25oC for 1 h and heated to 15oC for 30 min. The solution was diluted with 5M sodium hydroxide (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-bromo-1,1-dimethyl-3H-furo [3 ,4-c] pyridine (150 mg, 54% yield) in the form of a colorless oil for use in the next step without any further purification. Step 5: methyl 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate

[0285] To a solution of 6-bromo-1,1-dimethyl-3H-furo[3,4-c]pyridine (150 mg, 0.66 mmol) in methanol (10 mL) was added [1, 1' - bis(diphenylphosphine) ferrocene] palladium (II) (48 mg, 0.07 mmol) and triethylamine (665 mg, 6.58 mmol). The reaction mixture was subjected to stirring at 80oC for 15 h under carbon monoxide [2.74 bar (25 psi)]. The reaction mixture was concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide methyl 1,1-dimethyl-3H-furo[3,4-c ] pyridine-6-carboxylate (100 mg, 73.4% yield) as a light yellow oil: LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min. ) retention time 0.97 min., ESI+ found [M+H] = 208.2. Step 6: 1,1-Dimethyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

[0286] To a solution of methyl 1,1 -dimethyl - 3H -furo [3,4 -c] pyridine -6 -carboxylate (100 mg, 0.48 mmol) in tetrahydrofuran (5 mL) and water (5 mL ) lithium hydroxide monohydrate (202 mg, 4.83 mmol) was added. The reaction mixture was stirred at 15°C for 15 h and then concentrated for drying in vacuum. The residue was diluted with water (5 mL) and then adjusted to pH = 3 by addition of 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 15 mL). The combined layers were dried over sodium sulfate and concentrated to provide crude 1,1-dimethyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (50 mg, 53.9% yield ) in the form of a yellow oil used in the next step without any further purification. Step 7: S) -1,1 -dimethyl -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -1 ,3-dihydrofuro [3,4-c] pyridine -6 -carboxamide

[0287] To a solution of (3S) -3 -amino -5 - methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (50 mg, 0.26 mmol) in N,N -dimethylformamide ( 5 mL) 1,1-dimethyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (56 mg, 0.29 mmol) was added, N1-((ethylimino)methylene)-N3 hydrochloride, N3 -dimethyl propane -1,3 -diamine (60 mg, 0.31 mmol) and 1H -benzo [d][1,2,3] triazol -1 -ol (42 mg, 0.31 mmol). The reaction mixture was stirred at 15oC for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (35 - 65% acetonitrile in water and 0.05% ammonium hydroxide) to provide 1,1 -dimethyl -N -[(3S) -5 -methyl -4 -oxo -2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide (18 mg, 18.8% yield) as a solid white color: 1H NMR (400MHz, CD3OD) δ 8.57 (s, 1H), 7.91 (s, 1H), 7.44 - 7.43 (m, 1H), 7.34 - 7.31 ( m, 2H), 7.26 - 7.25 (m, 1H), 5.15 (s, 2H), 5.05 - 5.00 (m, 1H), 4.65 - 4.62 (m 1H ), 4.43 - 3.98 (m, 1H), 3.43 (s, 3H), 1.49 (s, 6H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.84 min., ESI+ found [M+H] =368.0. Example 23: Method U

[0288] (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5,6,7, 8 - tetrahydro isoquinoline -3 -carboxamide Step 1: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5,6,7, 8 - tetrahydro isoquinoline -3 -carboxamide

[0289] To a solution of 5,6,7,8-tetrahydroisoquinoline-3-carboxylic acid (80 mg, 0.45 mmol) in N,N-dimethylformamide (5 mL) was added (3S) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (96 mg, 0.50 mmol), N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1 hydrochloride, 3-diamine (104 mg, 0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol). The reaction mixture was stirred at RT for 12 h and concentrated to drying in vacuum. The residue was purified by RP-HPLC (0 -40% acetonitrile in water and 0.1% ammonium hydroxide) to provide (S) - N -(5 -methyl -4 -oxo -2,3,4 ,5-tetrahydrobenzo-[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide (26 mg, 16.5% yield) in the form of a white solid: 1H NMR (400MHz, CD3OD) δ 8.32 (s, 1H), 7.71 (s, 1H), 7.43 (d, J = 6.0 Hz, 1H), 7, 37 - 7.19 (m, 3H), 5.02 - 4.97 (m, 1H), 4.64 - 4.60 (m, 1H), 4.37 (t, J = 10.8 Hz, 1H), 3.42 (s, 3H), 2.83 - 2.81 (m, 4H), 1.87 - 1.82 (m, 4H). LCMS (10 - 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.15 min., ESI+ found [M+H] = 352.2. Example 24: Method V

[0290] N -((S) -5 -methyl -4 -oxo -2,3,4,5 tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 -phenyl - 4.5 ,6,7 -tetrahydro -1H -indazole -3 -carboxamide Step 1: ethyl 2 -oxo -2 -(2 -oxo -5 phenylcyclohexyl) acetate

[0291] To a solution of 4,4-dimethylcyclohexanone (2.50 g, 19.8 mmol) in ethanol (30 mL) was added a solution of sodium ethoxide (1.48 g, 21.8 mmol) in ethanol (30 mL), followed by diethyl oxalate (2.9 g, 19.8 mmol) under 0oC. After addition, the mixture was stirred at 25°C for 15 h and concentrated to drying in vacuum to provide crude ethyl 2-oxo-2-(2-oxo-5-phenylcyclohexyl) acetate (5.4 g, 99. 4% yield) as a yellow solid used in the next step without any further purification. Step 2: ethyl 5 -phenyl -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate

[0292] To a solution of ethyl 2-oxo-2-(2-oxo-5-phenylcyclohexyl) acetate (5.4 g, 19.7 mmol) in glacial acetic acid (5 mL) was added hydrazine hydrate (1 .09 g, 21.8 mmol) under 0oC. The mixture was stirred at 25°C for 1 h and then adjusted to pH = 8 by addition of aqueous sodium bicarbonate. The resulting solid was collected by filtration and dried to provide crude ethyl 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.5 g, 28% yield) for use in the next step without any further purification. Step 3: 5-Phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

[0293] To a solution of ethyl 5-phenyl - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate (405 mg, 1.5 mmol) in tetrahydrofuran (8 mL) and water (4 mL) hydrated lithium hydroxide (621 mg, 14.8 mmol) was added. The mixture was stirred at 25°C for 25 h and concentrated for drying in vacuum. The residue was diluted with water (5 mL) and adjusted to pH = 3 by adding 1 N hydrochloric acid. The resulting solid was collected by filtration and dried to provide crude 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (330 mg, 90.9% yield) as a white solid: LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.77 min., ESI+ found [M+H] = 242.9. Step 4: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 -phenyl - 4, 5,6,7 -tetrahydro -1H -indazole -3 -carboxamide

[0294] To a stirred solution of 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (94 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 1-hydroxy benzotriazole (53 mg, 0 .39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol). The mixture was stirred at 20°C for 1 h and then concentrated for drying in vacuum. The residue was purified by RP-HPLC (42 -72% acetonitrile in water and 0.05% ammonium hydroxide) to provide N -((S) -5 -methyl -4 -oxo -2,3,4 ,5-tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 -phenyl -4,5,6,7 -tetrahydro -1H - indazole -3 -carboxamide (73 mg, 67.6 % yield) as a white solid: 1H NMR (400 MHz, DMSO - d6) δ12.95 (s, 1H), 7.97 - 7.95 (m, 1H), 7.48 - 7 .45 (m, 1H), 7.33 - 7.25 (m, 6H), 7.23 - 7.17 (m, 2H), 4.85 - 4.78 (m, 1H), 4.54 - 4.47 (m, 1H), 4.42 - 4.37 (m, 1H), 3.31 (s, 3H), 2.98 - 2.92 (m,1H), 2.88 - 2 .83 (m, 1H), 2.72 - 2.67 (m, 2H), 2.56 - 2.53 (m, 1H), 1.98 - 1.89 (m, 2H). LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.19 min., ESI+ found [M+H] = 417.3. Example 25: W Method 5 -methyl -N -((S) -5 -oxo -4,5,6,7 -tetrahydro 1H -pyrazolo [3,4 -b][1,4] oxazepin -6 -yl) -1,4 ,5,7-tetrahydropyran [3,4-c] pyrazole -3 –carboxamide

[0295] To a solution of (S) -6 -amino -6,7 dihydro -1H -pyrazole [3,4 -b][1,4] oxazepin -5(4H) -one 2,2,2 -trifluoroacetate (70 mg, 0.25 mmol) in N,N - dimethylformamide (5 mL) was added 1H -benzo[d][1,2,3]triazol-1-ol (41 mg, 0.30 mmol), acid 5-methyl -1,4,5,7 -tetrahydropyran [3,4-c] pyrazole -3 -carboxylic acid (55 mg, 0.30 mmol), and N1 -((ethylimino) methylene hydrochloride) - N3, N3 - dimethylpropane -1,3 -diamine (57 mg, 0.30 mmol). The reaction mixture was heated at 50°C for 16 h and concentrated to drying in vacuum. The residue was purified by RP-HPLC (0 to 27% acetonitrile in water and 0.05% hydrochloric acid) to provide 5-methyl-N-((S)-5-oxo-4,5,6, 7 -tetrahydro -1H -pyrazolo [3,4 -b][1,4]oxazepin -6 -yl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide ( 3.3 mg, 4%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.52 (s, 1 H), 4.91 - 4.74 (m, 3 H), 4.58 - 4.54 (m, 1 H), 4.39 - 4.35 (m, 1 H), 3.75 - 3.71 (m, 1 H), 3.00 - 2.88 ( m, 1 H), 2.55 - 2.51 (m, 1 H), 1.36 (d, J = 3.2 Hz, 3 H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.35 min., ESI+ found [M+H] =333.0. Example 26: Method

[0296] (S) -5,5 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide

[0297] (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide

[0298] (S) -6,6 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4,5,6,8 -tetrahydro -1H -oxepino[3,4 -c] pyrazole -3 - carboxamide Step 1: 7, 7 -dimethyloxepan -4 -one and 2, 2 - dimethyloxepan -4 -one

[0299] To a solution of 2,2-dimethyltetrahydropyran-4-one (10.4 g, 81.14 mmol) in dichloromethane (40 mL) and boron fluoride ethyl ether (11.2 mL, 48% ether ethyl) (diazomethyl) trimethylsilane (48.0 mL, 96.0 mmol, 2 M in hexane) was added dropwise under -30oC. After addition, the resulting solution was stirred for 1 h at -30°C and then finalized by addition of saturated sodium bicarbonate (30 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 18% ethyl acetate in petroleum ether) to provide a mixture of 7,7-dimethyl oxepan-4-one and 2, 2-dimethyloxepan-4-one (2.6 g, 22.5% yield, ratio1:1) as a light yellow oil. Step 2: ethyl 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate; ethyl 7,7 -dimethyl -4,5,7,8 -tetrahydro -1H - oxepin [4,5 -c] pyrazole -3 -carboxylate; ethyl 6,6 -dimethyl -4,5,6,8 -tetrahydro -1H - oxepin [3,4 -c] pyrazole -3 -carboxylate

[0300] To a solution of 7,7-dimethyl oxepan - 4 -one and 2,2 -dimethyl oxepan -4 -one (2.6 g, 18.3 mmol) and pyrrolidine (85 mg, 1.2 mmol) in dimethyl sulfoxide (20 mL) ethyl diazo acetate (1.39 g, 12.2 mmol) was slowly added. After addition, the reaction was stirred at 22oC for 16 h and poured into water (30 mL). The mixture was then extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with water (2 x 30 mL) and brine (30 mL), dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 18% ethyl acetate in petroleum ether) to provide a mixture of three regioisomers (900 mg, 20.6% yield) in the form of a yellow oil. The regioisomers were separated using SFC to provide:

[0301] Peak 1 (Retention time 3.31 min.), ethyl 5,5 -dimethyl -4,5,7,8 -tetrahydro -1H -oxepino [4,5 - c] pyrazole -3 -carboxylate ( 200 mg): 1H NMR (400 MHz, CDCl3) δ 4.38 - 4.33 (m, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.11 (s, 2H) , 2.97 (t, J = 6.00 Hz, 2H), 1.37 (t, J = 6.00 Hz, 2H), 1.21 (s, 6H)

[0302] Peak 2 (Retention time 3.37 min.), ethyl 7,7 -dimethyl -4,5,7,8 -tetrahydro -1H -oxepino [4,5 - c] pyrazole -3 -carboxylate ( 150 mg) in the form of a yellow colored oil: 1H NMR (400 MHz, CDCl3) δ 4.39 - 4.34 (m, 2H), 3.92 - 3.87 (m, 2H), 3.08 - 3.03 (m, 2H), 2.98 (s, 2H), 1.38 (t, J = 6.0 Hz, 3H), 1.23 (s, 6H)

[0303] Peak 3 (Retention time 6.30 min.), ethyl 6,6 -dimethyl -4,5,6,8 -tetrahydro -1H -oxepino [3,4 - c] pyrazole -3 -carboxylate ( 150 mg) in the form of a yellow colored oil: 1H NMR (400 MHz, CDCl3) δ 4.68 (s, 2H), 4.40 - 4.35 (m, 2H), 3.00 - 2.92 (m, 2H), 1.95 - 1.88 (m, 2H), 1.39 (t, J = 6.0 Hz, 3H), 1.33 (s, 6H).

SFC Conditions:

[0304] Column: Chiralpak AD -3 150x4.6 mm ID, 3um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 35% to 40% B in 5 min. and maintain 40% for 2.5 min., then 5% B for 2.5 min., Flow rate: 2.5mL/min. Column temp.: 35OC Column: Chiralpak AY 150x4.6 mm ID, 3 μ m Mobile phase: A: CO2 B: iso-propanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and hold at 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Temp column 35℃ Step 3: 5,5-Dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-carboxylic acid

[0304] To a solution of ethyl 5,5 -dimethyl - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxylate (200 mg, 0.84 mmol) in tetrahydrofuran (5 mL) and water (1 mL) were added to lithium hydroxide (100 mg, 4.20 mmol). The mixture was stirred at 20°C for 20 h and concentrated for drying in vacuum. The residue was diluted with water (30 mL) and adjusted to pH = 3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole acid -3-carboxylic acid (160 mg, 90.7% yield) as a white solid: LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1 .76 min., ESI+ found [M+H] =211.2. Step 4: (S) -5,5 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide

[0305] To a solution of 1-hydroxybenzotriazole (54 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol), 5,5-dimethyl-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazol-3-carboxylic acid (70 mg, 0.33 mmol) and (3S)-3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one (70 mg, 0.37 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (26 -56% acetonitrile in water and 0.05% ammonia) to provide (S) -5,5 - dimethyl -N -(5 -methyl -4 -oxo -2 ,3,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -4,5,7,8 -tetrahydro -1H - oxepin [4,5 -c] pyrazole -3 - carboxamide (95 mg, 74.9% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 12.93 (s, 1H), 8.00 (d, J = 8 .0 Hz, 1H), 7.49 - 7.47 (m, 1H), 7.35 - 7.19 (m, 3H), 4.85 - 4.78 (m, 1H), 4.52 - 4.46 (m, 1H), 4.41 - 4.37 (m, 1H), 3.77 - 3.75 (m, 2H), 3.31 (s, 3H), 3.01 (s, 2H), 2.82 - 2.79 (m, 2H), 1.04 (s, 6H). LCMS RT = 0.80 min., m/z = 385.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.80 min., ESI+ found [M+H] =385.1. Step 5: 7,7-Dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-carboxylic acid

[0306] To a solution of ethyl 7,7 -dimethyl - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxylate (150 mg, 0.63 mmol) in tetrahydrofuran (5 mL) and water (1 mL) were added lithium hydroxide (75 mg, 3.15 mmol). The mixture was stirred at 20°C for 20 h and concentrated for drying in vacuum. The residue was diluted with water (20 mL) and adjusted to pH = 3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 7,7-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole acid -3-carboxylic acid (95 mg, 71.8% yield) as a white solid: LCMS RT = 1.80 min., m/z = 211.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.80 min., ESI+ found [M+H] =211.2, Step 6: (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - 4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide

[0307] To a solution of 1-hydroxybenzotriazole (39.2 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (55. 6 mg, 0.29 mmol), 7,7-dimethyl-1,4,5,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxylic acid (50.0 mg, 0.24 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50.3 mg, 0.26 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (26 -56% acetonitrile in water and 0.05% ammonia) to provide (S) -7,7 -dimethyl -N -(5 -methyl -4 - oxo -2 ,3,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -4,5,7,8 -tetrahydro -1H -oxepino [4,5 -c] pyrazole -3 - carboxamide (65 mg, 70.5% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 12.91 (s, 1H), 7.98 (d, J = 8 .0 Hz, 1H), 7.50 - 7.48 (m, 1H), 7.36 - 7.19 (m, 3H), 4.85 - 4.78 (m, 1H), 4.54 - 4.37 (m, 2H), 3.73 - 3.71 (m, 2H), 3.31 (s, 3H), 2.89 - 2.79 (m, 4H), 1.12 (s, 3H), 1.11 (s, 3H). LCMS RT = 0.79 min., m/z = 385.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79 min., ESI+ found [M+H] =385.1, Step 7: 6,6-Dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazol-3-carboxylic acid

[0308] To a solution of ethyl 6,6 -dimethyl - 4,5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxylate (100 mg, 0.42 mmol) in tetrahydrofuran (5 mL) and water (1 mL) were added to lithium hydroxide (50 mg, 2.10 mmol). The mixture was stirred at 23°C for 20 h and concentrated for drying in vacuum. The residue was diluted with water (20 mL) and adjusted to pH = 3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuum to provide 6,6-dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole acid Crude -3-carboxylic acid (70 mg, 79.3% yield) as a white solid: LCMS RT = 1.86 min., m/z = 211.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.86 min., ESI+ found [M+H] =211.2. Step 8: (S)-6,6-dimethyl -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) - 4,5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide

[0309] To a solution of 1-hydroxybenzotriazole (54 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (77 mg , 0.40 mmol), 6,6 -dimethyl - 1,4,5,8 -tetrahydrooxepino [3,4 -c] pyrazole -3 - carboxylic acid (70 mg, 0.33 mmol) and (3S) - 3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (70 mg, 0.37 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated for drying in vacuum. The residue was purified by RP-HPLC (55 -85% methanol in water and 0.05% ammonia) to provide (S) -6,6 -dimethyl -N -(5 -methyl -4 -oxo -2 ,3,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -4,5,6,8 -tetrahydro -1H -oxepino [3,4 -c] pyrazole -3 - carboxamide (95 mg, 74.9% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 12.93 (br. s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.39 - 7.16 (m, 3H), 4.83 - 4.81 (m, 1H) , 4.61 - 4.33 (m, 4H), 3.31 (s, 3H), 2.80 - 2.70 (m, 2H), 1.85 - 1.70 (m, 2H), 1 .20 (s, 6H). LCMS RT = 0.81 min., m/z = 385.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.81 min., ESI+ found [M+H] =385.1. Example 27: Method Y

[0310] (S) -5 -benzyl -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -4H -1,2,4 -triazol -3 -carboxamide and (R) -5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide Step 1: N -(1H -pyrazol -3 -yl)formamide

[0311] A solution of 1H-pyrazole-3-amine (2.5 g, 30.09 mmol) in formic acid (10 mL) was heated at 110°C for 2 h in a sealed vessel. After this period, the reaction mixture was concentrated in vacuum and purified column chromatography (silica gel, 100 -200 mesh, 0 to 100% 3:1 isopropyl acetate:methanol in heptane) to provide N -(1H -pyrazole -3 -yl)formamide (2.75 g, 82%) as a white solid used as it was in the following step: LCMS RT = 0.25 min., m/z = 112 [M +H]+. Step 2: N -methyl -1H -pyrazole -3 -amine

[0312] To a solution of N -(1H -pyrazol -3 - yl)formamide (2.75 g, 24.8 mmol) in anhydrous tetrahydrofuran (100 mL) cooled to 0 ° C under nitrogen was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 37.1 mL, 74.3 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 16 h. After this period, the reaction was terminated with solid sodium sulfate decahydrate and stirred at RT for 30 min. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuum to provide N-methyl-1H-pyrazol-3-amine (1.97 g, 82% yield) as an oil of orange color used in the next step without any further purification. Step 3: 4-chloro-N-(1-(4-chlorobutanoyl)-1H-pyrazol-5-yl)-N-methylbutanamide

[0313] To a stirred solution of N -methyl -1H -pyrazole -5 -amine (200 mg, 2.06 mmol) in anhydrous dichloromethane (10 mL) cooled to 0°C was added N, N -diisopropyl ethylamine (1.08 mL, 6.18 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (0.697 g, 4.94 mmol) under nitrogen. To the resulting mixture was added 4-dimethylamino pyridine (0.025 g, 0.21 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% isopropyl acetate in heptane) to provide 4 -chloro -N -(1 -(4 - chlorobutanoyl) -1H - pyrazol -5 -yl) -N -methylbutanamide in the form of a colorless oil (0.450 g, 71%) used as it was in the following step: LCMS RT 306 [M + H]+. Step 4: 4-chloro-N-methyl-N-(1H-pyrazol-5-yl)butanamide

[0314] To a stirred solution of 4-chloro-N-(1-(4-chlorobutanoyl)-1H-pyrazol-5-yl)-N-methyl butanamide (0.338 g, 1.10 mmol) in ethanol ( 2 mL) sodium hydroxide (1 mol/L) in water (1.10 mL, 1.10 mmol) was added and the mixture was allowed to sit at RT for 3 5 min. The reaction mixture was concentrated to drying in vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4-chloro-N-methyl-N-(1H - pyrazol-5-yl) butanamide as a white solid (0.185 g, 83%) used in the next step without any further purification: LCMS RT = 0.86 min., m/z = 202 [M + H ]+. Step 5: 4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[0315] To a solution of 4-chloro-N-methyl-N-(1H-pyrazol-5-yl) butanamide (0.185 g, 0.92 mmol) in N,N-dimethylformamide (4 mL) was added carbonate cesium (0.597 g, 1.83 mmol) and stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4-methyl -7,8 - dihydro -4H -pyrazole [1.5 -a][1,3] diazepin -5(6H) -one in the form of a colorless viscous oil (0.123 g, 81%) used as it was in the following step: LCMS RT = 0.76 min., m/z = 166 [M + H]+. Step 6: 6 -bromo -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one

[0316] To a solution of 4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (0.123 g, 0.745 mmol) cooled to - 78OC in anhydrous tetrahydrofuran (5 mL) was added dropwise a solution of lithium bis(trimethylsilyl) amide (1 mol/L) in anhydrous tetrahydrofuran (2.23 mL, 2.23 mmol) under nitrogen. The resulting solution was stirred under -78°C for 30 min. and N-bromo succinimide (0.265, 1.49 mmol) was added and then stirred under -78°C for 2 h. The reaction mixture was finished with saturated sodium bisulfite (50 mL) and extracted with isopropyl acetate (3 x 50 mL), dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-bromo-4-methyl-7,8-dihydro-4H- pyrazole [1,5 -a][1,3] diazepin - 5(6H) -one in the form of a light yellow oil (0.083g, 46%) used in the next step as it was: LCMS RT = 0.83 min., m/z = 244 [M + H]+. Step 7: 6 -azide -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one

[0317] To a solution of 6-bromo-4-methyl - 7,8 -dihydro -4H -pyrazole [1,5-a][1,3] diazepin -5(6H) -one (0.083 g, 0. 30 mmol) in N,N-dimethylformamide (1 mL) sodium azide (0.026 g, 0.41 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-azide-4-methyl-7,8-dihydro-4H-pyrazole [1,5 -a][1,3] diazepin -5(6H) -one in the form of a light orange oil (0.067 g, 96%) which was used in the next step in the condition it was in: LCMS RT = 0.93 min., m/z = 207 [M + H]+. Step 8: 6 -amino -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one

[0318] To a solution of 6-azide -4 -methyl - 7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (0.067 g, 0. 32 mmol) in methanol (2 mL) was added 10% Pd/C (0.069 g, 0.065 mmol), a hydrogen balloon, and the mixture was subjected to stirring at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to drying in vacuum to provide 6-amino-4-methyl-7,8-dihydro-4H-pyrazole [1,5-a][1,3] diazepin -5 (6H)-one in the form of a viscous oil (0.055 g, 94%) which was used in the next step without any further purification: LCMS RT = 0.25 min., m/z = 181 [M + H]+. Step 9: 5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 4H -1,2,4 -triazole -3 -carboxamide

[0319] To a stirred solution of 6-amino-4-methyl-7,8-dihydro-4H-pyrazolo [1,5-a][1,3] diazepin -5(6H)-one (0.055 g , 0.31 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.074 g, 0.37 mmol), hexafluorophosphate ( (3H -[1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl) phosphonium (V) (0.182 g, 0.34 mmol) and N, N -diisopropyl ethylamine (0.160 mL, 0.92 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by RP-HPLC (0 to 35% acetonitrile in water and 0.1% formic acid) to give 5-benzyl-N- (4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 - triazole -3 -carboxamide as a white solid (0.029 mg, 26%): 1H NMR (400 MHz, DMSO -d6) δ 14.42 (s, 1H), 8.56 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.38 - 7.16 (m, 5H), 6.34 (d, J = 2.0 Hz, 1H), 4.42 - 4 .13 (m, 3H), 4.11 (s, 2H), 3.24 (s, 3H), 2.69 - 2.53 (m, 1H), 2.47 - 2.32 (m, 1H ). LCMS RT = 3.35 min., m/z = 366.2 [M + H]+. Step 10: (S) -5 -benzyl -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -4H -1,2,4 -triazol -3 -carboxamide and (R) -5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide

[0320] 5-Benzyl -N -(4-methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -4H -1,2,4 -triazole -3 -carboxamide was further purified via chiral SFC (ID column, 30% methanol + 0.1% ammonium hydroxide isocratic elution) to afford the arbitrarily assigned enantiomers (S) - 5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -4H - 1,2,4 - triazol -3 -carboxamide (0.012 g, 11%) and (R) -5 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide (0.012 g, 11%) as white solids:

[0321] Analytical data for the first elution enantiomer (arbitrarily assigned S configuration): SFC RT (ID column, 30% methanol + + 0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.545 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 14.44 (s, 1H), 8.54 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.35 - 7.20 (m, 5H), 6.34 (d, J = 2.0 Hz, 1H), 4.42 - 4.13 (m, 3H), 4.10 (s , 2H), 3.24 (s, 3H), 2.65 - 2.53 (m, 1H), 2.44 - 2.30 (m, 1H). LCMS RT = 3.35 min., m/z = 366.1 [M + H]+.

[0322] Analytical data for the second elution enantiomer (arbitrarily assigned R configuration): SFC RT: 0.908 min., 99% ee: 1H NMR (400 MHz, DMSO -d6) δ 14.43 (s, 1H), 8 .54 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.43 - 7.13 (m, 5H), 6.34 (d, J = 2.0 Hz, 1H), 4.42 - 4.13 (m, 3H), 4.10 (s, 2H), 2.67 - 2.52 (m, 1H), 2.46 - 2.29 (m, 1H) . LCMS RT = 3.35 min., m/z = 366.2 [M + H]+. Example 28: Method Z

[0323] 5 -benzyl -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 - il) -4H -1,2,4 -triazole -3 -carboxamide Step 1: N -(5 -methyl -1H -pyrazol -3 -yl)formamide

[0324] A solution of 5-methyl -1H -pyrazole - 3 -amine (1.8 g, 18.5 mmol) in formic acid (10 mL) was heated at 110 ° C for 3 h in a sealed vessel. After this period, the reaction mixture was concentrated in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide N -(5-methyl -1H -pyrazole -3 - il)formamide (1.96 g, 85%) in the form of an off-white solid that was used in the next step as it was: LCMS RT = 0.50 min., m/z = 126 [M + H] +. Step 2: N,5-dimethyl-1H-pyrazol-3-amine

[0325] A solution of N -(5-methyl -1H - pyrazol -3 -yl)formamide (1.96 g, 15.7 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0 ° C under nitrogen was Slowly add a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 23.5 mL, 47.0 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 16 h. After this period, the reaction was terminated with solid sodium sulfate decahydrate and stirred at RT for 30 min. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuum to provide N,5-dimethyl-1H-pyrazol-3-amine (1.79 g, 103% yield) as a yellow colored oil used in the next step without any further purification. Step 3: 4-chloro-N-[1-(4-chlorobutanoyl)-5-methyl-pyrazol-3-yl]-N-methyl-butanamide

[0326] To a stirred solution of N,5-dimethyl-1H-pyrazol-3-amine (1.74 g, 15.7 mmol) in anhydrous dichloromethane (50 mL) cooled to 0°C was added N, N -diisopropylethylamine (8.19 mL, 47.0 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (5.3 g, 37.6 mmol) under nitrogen. To the resulting mixture was added 4-dimethylamino pyridine (0.191 g, 1.57 mmol), and the reaction mixture was stirred at RT for 6 h. The reaction mixture was partially concentrated in vacuum and purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% isopropyl acetate in heptane) to provide 4 -chloro -N -[1 -(4 - chlorobutanoyl)-5-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.37 g, 47%) in the form of an orange oil used in the next step as it was: LCMS RT = 1.43 min., m/z = 320 [M + H]+. Step 4: 4-chloro-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)butanamide

[0327] To a stirred solution of 4-chloro-N-[1-(4-chlorobutanoyl)-5-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.37 g, 7.4 mmol) in ethanol (20 mL) sodium hydroxide (1 mol/L) in water (7.4 mL, 7.4 mmol) was added and the mixture was allowed to sit at RT for 3 5 min. The reaction mixture was concentrated to drying in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4-chloro-N-methyl-N- (5-methyl-1H-pyrazol-3-yl)butanamide (1.4 g, 88%) as a yellow colored oil used in the next step without any further purification: LCMS RT = 0.99 min., m /z = 216 [M + H]+. Step 5: 2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0328] To a solution of 4-chloro-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)butanamide (1.4 g, 6.5 mmol) in acetonitrile (10 mL) was added cesium carbonate (3.2 g, 13.0 mmol), and the resulting suspension was subjected to stirring at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 2,4-dimethyl-7,8-dihydro-6H-pyrazole [ 1,5 - a][1,3] diazepin -5 -one (0.655 g, 56%) in the form of a colorless viscous oil used as it was in the following step: LCMS RT = 0.91 min., m/z = 180 [M + H]+. Step 6: 6 -iodine -2,4 -dimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one

[0329] To a solution of 2,4 -dimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (0.655 g, 3.65 mmol) in dichloromethane anhydrous (20 mL) under nitrogen cooled to -10°C in a salt/ice bath was added N,N,N',N'-tetramethyl ethylenediamine (2.55g, 22 mmol) followed by iodotrimethylsilane (4.4 g , 22 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time iodine (2.8 g, 11 mmol) was added. The mixture continued under stirring in the salt/ice bath for another 2 h, after which time the reaction mixture was quenched with saturated sodium bisulfite (50 mL). The layers were separated, and the aqueous extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-iodo-2,4-dimethyl-7,8-dihydro-6H - pyrazole [1,5 -a][1,3] diazepin -5 -one in the form of a brown solid (0.874 g, 78%) which was used in the next step in the condition it was in: LCMS RT = 1.03 min., m/z = 306 [M + H]+. Step 7: 6 -azide -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0330] To a solution of 6 -iodo -2,4 -dimethyl -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one (0.874 g, 2.86 mmol) in N,N-dimethylformamide (2 mL) sodium azide (0.223 g, 3.44 mmol) was added, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-azide-2,4-dimethyl-7,8-dihydro- 4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one in the form of a light orange oil (0.606 g, 96%) that was used as it was in the step following: LCMS RT = 0.99 min., m/z = 221 [M + H]+. Step 8: 6 -amino -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0331] To a solution of 6-azide -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (0.606 g, 2.75 mmol) in tetrahydrofuran (5 mL) was added water (1 mL) followed by polymer-bound triphenylphosphine (2.75 g, ~3 mmol/g loading). The mixture was stirred at RT for 16 h, filtered through Celite and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% methanol in dichloromethane) to provide 6-amino -2,4 - dimethyl -7,8 - dihydro -6H - pyrazole [1,5 -a][1,3] diazepin - 5 -one in the form of a colorless oil (0.500 g, 94%) that was used in the next step in the condition it was in: LCMS RT = 0.54 min., m/z = 195 [M + H]+. Step 9: 5 -benzyl -N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -4H - 1,2,4 -triazole -3 -carboxamide

[0332] To a stirred solution of 6-amino -2,4-dimethyl -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -5 -one (0.029 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H -[ 1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl)phosphonium hexafluorophosphate(V) (0.095 g, 0.18 mmol) and N,N -diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) to provide 6-amino-2,4-dimethyl - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one as a white solid (0.029 g, 51%): 1H NMR (400 MHz, DMSO -d6) δ 14.39 (s, 1H), 8.53 (s, 1H), 7.36 - 7.21 (m, 6H), 6.13 (s, 1H), 4.39 - 4, 21 (m, 2H), 4.18 - 4.01 (m, 4H), 3.22 (s, 3H), 2.57 (ddd, J = 12.8, 8.0, 4.9 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.17 (s, 3H). LCMS RT = 3.58 min., m/z = 380.2 [M + H]+.

[0333] 5-Benzyl -N -(2-cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) - 4H -1,2,4 -triazole -3 -carboxamide Step 1: N -(5-cyclopropyl-1H-pyrazol-3-yl)formamide

[0334] A solution of 5-cyclopropyl -1H - pyrazole -3 -amine (2.0 g, 16.2 mmol) in formic acid (10 mL) was heated at 110 ° C for 3 h in a sealed vessel. After this period, the reaction mixture was concentrated in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide N -(5-cyclopropyl -1H - pyrazol -3 -yl)formamide (1.74 g, 71%) as an off-white solid used in the next step as it was: LCMS RT = 0.86 min., m/z = 152 [M + H]+. Step 2: 5-cyclopropyl-N-methyl-1H-pyrazol-3-amine

[0335] To a solution of N -(5-cyclopropyl - 1H -pyrazol-3-yl)formamide (1.74 g, 11.5 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0 ° C was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 17.3 mL, 34.5 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 16 h. After this period, the reaction was terminated with solid sodium sulfate decahydrate and stirred at RT for 30 min. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuum to provide 5 - cyclopropyl -N -methyl -1H -pyrazole -3 -amine (1.70 g, 110% yield) in the form of an orange oil used in the next step without any further purification. Step 3: 4-chloro-N-[1-(4-chlorobutanoyl)-5-cyclopropyl-pyrazol-3-yl]-N-methyl-butanamide

[0336] To a stirred solution of 5-cyclopropyl-N-methyl-1H-pyrazol-3-amine (0.760 g, 5.5 mmol) in anhydrous dichloromethane (50 mL) cooled to 0°C was added N, N -diisopropyl ethylamine (2.90 mL, 16.6 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (1.87 g, 13.3 mmol) under nitrogen. To the resulting mixture was added 4-dimethyl aminopyridine (0.068 g, 0.55 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) to provide 4-chloro-N-[1-( 4-chlorobutanoyl)-5-cyclopropyl-pyrazol-3-yl]-N-methyl-butanamide (1.18 g, 62%) in the form of an orange oil used as it was in the following step: LCMS RT = 1.50 min., m/z = 346 [M + H]+. Step 4: 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-methyl-butanamide

[0337] To a stirred solution of 4-chloro-N-[1-(4-chlorobutanoyl)-5-cyclopropyl-pyrazol-3-yl]-N-methyl-butanamide (1.18 g, 3.4 mmol) in ethanol (5 mL) sodium hydroxide (1 mol/L) in water (3.4 mL, 3.4 mmol) was added and the mixture was allowed to sit at RT for 5 min. The reaction mixture was concentrated to drying in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4 -chloro -N -(5 - cyclopropyl -1H -pyrazol -3 -yl) -N -methyl -butanamide (0.540 g, 66%) in the form of a colorless oil that was used in the next step in the condition it was in: LCMS RT = 1.08 min. , m/z = 242 [M + H]+. Step 5: 2 -cyclopropyl -4 -methyl -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0338] To a solution of 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-methyl-butanamide (0.540 g, 2.2 mmol) in acetonitrile (10 mL) was added carbonate of cesium (1.46 g, 4.5 mmol), and the resulting suspension was subjected to stirring at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 2-cyclopropyl-4-methyl-7,8-dihydro-6H- pyrazole [1,5 -a][1,3] diazepin -5 -one (0.332 g, 72%) in the form of a pink oil that was used in the next step as it was: LCMS RT = 0 .98 min., m/z = 206 [M + H]+. Step 6: 6 -bromo -2 -cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one

[0339] To a solution of 2-cyclopropyl -4 - methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (0.332 g, 1.6 mmol) cooled to -78OC in anhydrous tetrahydrofuran (8 mL), a solution of lithium bis(trimethylsilyl) amide (1 mol/L) in anhydrous tetrahydrofuran (3.23 mL, 3.23 mmol) was added dropwise under nitrogen. The resulting solution was stirred at -78°C for 30 min. and N-bromo succinimide (0.432, 2.42 mmol) was added and stirred at -78°C for 2 h. The reaction mixture was finished with saturated sodium bisulfite (50 mL) and extracted with isopropyl acetate (3 x 50 mL), dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 4% methanol in dichloromethane) to provide 6-bromo-2-cyclopropyl-4-methyl-7,8-dihydro-6H -pyrazole [1,5 - a][1,3] diazepin -5 -one in the form of a light yellow oil (0.210 g, 46%) used as it was in the following step: LCMS RT = 1 .06 min., m/z = 284 [M + H]+. Step 7: 6 -azide -2 -cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0340] To a solution of 6-bromo-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazole [1,5-a] [1,3] diazepin -5-one (0.210 g, 0 .74 mmol) in N,N-dimethylformamide (1.5 mL) sodium azide (0.058 g, 0.89 mmol) was added, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-azide -2 - cyclopropyl -4 -methyl -7,8 - dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one in the form of a yellow oil (0.109 g, 60%) that was used in the next step in the condition in which it was: LCMS RT = 1.05 min., m/z = 247 [M + H]+. Step 8: 6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one

[0341] To a solution of 6-azide -2 - cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (0.109 g, 0 .44 mmol) in tetrahydrofuran (2 mL) was added water (0.4 mL) followed by polymer-bound triphenylphosphine (0.44 g, ~3 mmol/g loading). The mixture was stirred at RT for 16 h, filtered through Celite and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% methanol in dichloromethane) to provide 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro- 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one in the form of a colorless oil (0.096 g, 99%) which was used in the next step in the condition it was in: LCMS RT = 0 .73 min., m/z = 221 [M + H]+. Step 9: 5 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) - 4H -1,2,4 -triazole -3 -carboxamide

[0342] To a stirred solution of 6-amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (0.033 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H -[1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl) phosphonium hexafluorophosphate (V) (0.095 g, 0.18 mmol) and N,N -diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) to provide 5-benzyl-N- (2-cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 - triazole -3 -carboxamide as a white solid (0.038 g, 62%): 1H NMR (400 MHz, DMSO -d6) δ 8.51 (d, J = 7.8 Hz, 1H), 7.36 - 7.19 (m, 5H), 6.06 (s, 1H), 4.37 - 4.20 (m, 2H), 4.16 - 4.02 (m, 3H), 3.20 (s , 3H), 2.65 - 2.53 (m, 1H), 2.40 - 2.27 (m, 1H), 1.91 - 1.80 (m, 1H), 0.92 - 0.81 (m, 2H), 0.73 - 0.60 (m, 2H). LCMS RT = 3.95 min., m/z = 406.2 [M + H]+. Example 30: BB Method 5 -benzyl -N -[4 -methyl -5 -oxo -2 (trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -4H - 1,2,4 -triazole -3 -carboxamide Step 1: N -[5 -(trifluoromethyl) -1H -pyrazol -3 -yl]formamide

[0343] A solution of 5-(trifluoromethyl)-1H-pyrazole-3-amine (2.3 g, 15.2 mmol) in formic acid (10 mL) was heated at 110°C for 3 h in a sealed vessel . After this period, the reaction mixture was concentrated in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide N -[5-(trifluoromethyl)-1H -pyrazol -3 -yl]formamide (2.15 g, 79%) as an off-white solid that was used in the next step as it was: LCMS RT = 0.85 min., m/z = 180 [M + H]+. Step 2: N -methyl -5 -(trifluoromethyl) -1H - pyrazol -3 -amine

[0344] To a solution of N -[5-(trifluoromethyl)-1H-pyrazol-3-yl]formamide (2.15 g, 12.0 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0°C under nitrogen was slowly added to a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 18.0 mL, 36.0 mmol) under nitrogen. The reaction mixture was allowed to warm to RT gradually and stirred for 16 h. After this period, the reaction was terminated with solid sodium sulfate decahydrate and stirred at RT for 30 min. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuum to provide N-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (2.3 g, 120% yield). in the form of an orange-colored oil that was used in the next step without any further purification. Step 3: 4-chloro-N-methyl-N-[5(trifluoromethyl)-1H-pyrazol-3-yl]butanamide

[0345] To a stirred solution of N -methyl -5 -(trifluoromethyl) -1H -pyrazol -3 -amine (2.3 g, 14 mmol) in anhydrous dichloromethane (50 mL) cooled to 0 ° C was added N,N-diisopropyl ethylamine (7.3 mL, 42.0 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (4.7 g, 33 mmol) under nitrogen. To the resulting mixture was added 4-dimethylamino pyridine (0.170 g, 1.4 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4-chloro-N-methyl-N- [5-(trifluoromethyl)-1H-pyrazol-3-yl]butanamide (1.03 g, 27%) as an orange solid that was used in the next step as it was: LCMS RT = 1 .18 min., m/z = 270 [M + H]+. Step 4: 4 -methyl -2 -(trifluoromethyl) -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0346] To a solution of 4-chloro-N-methyl-N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]butanamide (1.0 g, 3.8 mmol) in acetonitrile (10 mL) Cesium carbonate (2.5 g, 7.7 mmol) was added, and the resulting suspension was stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% isopropyl acetate in heptane) to provide 4-methyl-2-(trifluoromethyl)-7,8-dihydro- 6H -pyrazole [1,5-a][1,3] diazepin -5 -one (0.420 g, 47%) in the form of a yellow solid that was used in the next step as it was: LCMS RT = 1.05 min., m/z = 234 [M + H]+. Step 5: 6 -iodo -4 -methyl -2 -(trifluoromethyl) - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0347] To a solution of 4-methyl -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (0.420 g, 1.80 mmol) in anhydrous dichloromethane (20 mL) under nitrogen cooled to ~-10OC in a salt/ice bath was added N,N,N',N'-tetramethyl ethylenediamine (1.26 g, 10.8 mmol) followed by iodine trimethyl silane (2.2 g, 10.8 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time iodine (1.4 g, 5.4 mmol) was added. The mixture continued stirring in the salt/ice bath for another 2 h, after which time the reaction mixture was quenched with saturated sodium bisulfite (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% isopropyl acetate in heptane) to provide 6-iodo-4-methyl-2-(trifluoromethyl)-7, 8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one in the form of a white solid (0.470 g, 73%) which was used in the next step under the condition that found: LCMS RT = 1.25 min., m/z = 360 [M + H]+. Step 6: 6 -azide -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0348] To a solution of 6 -iodo -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (0.470 g , 1.3 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (0.102 g, 1.57 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 70% isopropyl acetate in heptane) 6-azide-4-methyl-2-(trifluoromethyl)-7,8-dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one in the form of a white solid (0.330 g, 92%) which was used in the next step in the condition it was in: LCMS RT = 1.21 min., m/z = 275 [M + H]+. Step 7: 6 -amino -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one

[0349] To a solution of 6-azide -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (0.330 g , 1.2 mmol) in tetrahydrofuran (5 mL) was added water (1 mL) followed by polymer-bound triphenylphosphine (1.2 g, ~3 mmol/g loading). The mixture was stirred at RT for 16 h, filtered through Celite and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% methanol in dichloromethane) to provide 6-amino-4-methyl-2-(trifluoromethyl)-7,8- dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one in the form of a colorless oil (0.260 g, 87%) which was used in the next step as it was: LCMS RT 249 [M + H]+. Step 8: 5 -benzyl -N -[4 -methyl -5 -oxo -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ] -4H -1,2,4 -triazole -3 -carboxamide

[0350] To a stirred solution of 6-amino -2,4-dimethyl -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -5 -one (0.037 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H -[ 1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl) phosphonium hexafluoro phosphate (V) (0.095 g, 0.18 mmol) and N,N - diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) to provide 5-benzyl-N-[4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -4H -1,2,4 - triazole -3 -carboxamide as a white solid (0.039 g, 60%): 1H NMR (400 MHz, DMSO -d6) δ 14.42 (s, 1H), 8.64 (s, 1H), 7 .47 - 7.13 (m, 5H), 6.93 (s, 1H), 4.53 - 4.41 (m, 1H), 4.41 - 4.26 (m, 2H), 4.11 (s, 2H), 3.27 (s, 3H), 2.74 - 2.57 (m, 1H). LCMS RT = 4.33 min., m/z = 434.1 [M + H]+. Example 31: CC Method 5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - 4H -1,2,4 -triazole -3 -carboxamide Step 1: N -(4 -methyl -1H -pyrazol -3 -yl)formamide

[0351] A solution of 4-methyl -1H -pyrazole - 3 -amine (1.3 g, 13.4 mmol) in formic acid (10 mL) was heated at 110 ° C for 3 h in a sealed case. After this period, the reaction mixture was concentrated in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide N -(4-methyl -1H - pyrazol-3-yl)formamide (1.44 g, 86%) as an off-white solid that was used in the next step as it was: LCMS RT = 0.37 min., m/z = 126 [ M + H]+. Step 2: N,4-dimethyl-1H-pyrazol-3-amine

[0352] A solution of N -(4-methyl -1H - pyrazol -3 -yl)formamide (1.44 g, 11.5 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0 ° C under nitrogen was Slowly add a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 17.3 mL, 34.5 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 16 h. After this period, the reaction was terminated with solid sodium sulfate decahydrate and stirred at RT for 30 min. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuum to provide N ,4-dimethyl-1H-pyrazol-3-amine (1.29 g, 101% yield) in the form of a yellow oil which was used in the next step without any further purification. Step 3: 4-chloro-N-[1-(4-chlorobutanoyl)-4-methyl-pyrazol-3-yl]-N-methyl-butanamide

[0353] To a stirred solution of N,4-dimethyl-1H-pyrazol-3-amine (1.28 g, 11.5 mmol) in anhydrous dichloromethane (50 mL) cooled to 0°C was added N, N -diisopropyl ethylamine (6.03 mL, 34.6 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (3.9 g, 27.6 mmol) under nitrogen. To the resulting mixture was added 4-dimethylamino pyridine (0.141 g, 1.15 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4-chloro-N-[1-( 4-chlorobutanoyl)-4-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.2 g, 60%) in the form of an orange-colored oil which was used in the next step in the condition in which it was found : LCMS RT = 1.32 min., m/z = 320 [M + H]+. Step 4: 4-chloro-N-methyl-N-(4-methyl-1H-pyrazol-3-yl)butanamide

[0354] To a stirred solution of 4-chloro-N-[1-(4-chlorobutanoyl)-4-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.2 g, 6.9 mmol) in ethanol (20 mL) sodium hydroxide (1 mol/L) in water (6.9 mL, 6.9 mmol) was added and the mixture was allowed to sit at RT for 5 min. The reaction mixture was concentrated to drying in vacuum and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 4-chloro-N-methyl-N -(4-methyl -1H -pyrazol -3 -yl) butanamide (1.18 g, 80%) in the form of a yellow oil that was used in the next step in the condition it was in: LCMS RT = 0, 99 min., m/z = 216 [M + H]+. Step 5: 3,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0355] To a solution of 4-chloro-N-methyl-N-(4-methyl-1H-pyrazol-3-yl) butanamide (1.47 g, 6.8 mmol) in acetonitrile (20 mL) was added cesium carbonate (8.9 g, 27.2 mmol), and the resulting suspension was subjected to stirring at RT for 48 h. The reaction mixture was filtered through Celite and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 3,4-dimethyl-7,8-dihydro-6H-pyrazole [ 1,5 -a][1,3] diazepin -5 -one (0.510 g, 42%) in the form of a white viscous solid that was used in the next step in the condition it was in: LCMS RT = 0, 86 min., m/z = 180 [M + H]+. Step 6: 6 -iodine -3,4 -dimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one

[0356] To a solution of 3,4 -dimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (0.450 g, 2.51 mmol) in dichloromethane (20 mL) under nitrogen cooled to ~-10°C in a salt/ice bath was added N,N,N',N'-tetramethylethylene diamine (1.75 g, 15.1 mmol) followed by iodotrimethylsilane ( 3.0 g, 15.1 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time iodine (1.91 g, 7.5 mmol) was added. The mixture continued to be stirred in the salt/ice bath for another 2 h, after which time the reaction mixture was quenched with saturated sodium bisulfite (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-iodo-3,4-dimethyl-7,8-dihydro- 6H -pyrazole [1,5-a][1,3] diazepin -5 -one in the form of a brown solid (0.420 g, 55%) which was used in the next step as it was: LCMS RT = 0.99 min., m/z = 306 [M + H]+. Step 7: 6 -azide -3,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0357] To a solution of 6 -iodo -3,4 -dimethyl -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one (0.420 g, 1.4 mmol) in N,N-dimethylformamide (2 mL) sodium azide (0.107 g, 1.65 mmol) was added, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 6-azide-3,4-methyl-7,8-dihydro- 4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one in the form of a light orange oil (0.289 g, 95%) which was used in the next step under the condition that found: LCMS RT = 0.80 min., m/z = 221 [M + H]+. Step 8: 6 -amino -3,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0358] To a solution of 6-azide -3,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (0.289g, 1.31 mmol) in tetrahydrofuran (5 mL) was added water (1 mL) followed by polymer-bound triphenylphosphine (1.31 g, ~3 mmol/g loading). The mixture was stirred at RT for 16 h, filtered through Celite and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% methanol in dichloromethane) to provide 6-amino -3,4 - dimethyl -7,8 - dihydro -6H - pyrazole [1,5 -a][1,3] diazepin - 5 -one in the form of a colorless oil (0.146 g, 57%) that was used in the next step in the condition it was in: LCMS RT = 0.65 min., m/z = 195 [M + H]+. Step 9: 5 -benzyl -N -(3,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -4H - 1,2,4 -triazole -3 -carboxamide

[0359] To a stirred solution of 6-amino -3,4-dimethyl -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -5 -one (0.029 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H -[ 1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl) phosphonium hexafluoro phosphate(V) (0.095 g, 0.18 mmol) and N,N - diisopropyl ethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) to provide 5-benzyl-N- (3,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 -triazole -3 - carboxamide in the form of a white solid (0.036 g, 63%): 1H NMR (400 MHz, DMSO -d6) δ 14.41 (s, 1H), 8.45 (d, J = 7.6 Hz , 1H), 7.39 - 7.12 (m, 6H), 4.40 - 3.99 (m, 5H), 3.21 (s, 3H), 2.62 - 2.51 (m, 1H) ), 2.36 - 2.21 (m, 1H), 2.01 (s, 3H). LCMS RT = 3.61 min., m/z = 380.2 [M + H]+. Example 32: DD Method Step 1: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -4,5,6, 7 - tetrahydro -1H -indazole -3 -carboxamide

[0360] A stirred solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (0.025 g, 0.13 mmol) in N,N -dimethylformamide (1 mL) was added 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.026 g, 0.16 mmol), ((3H-[1,2,3] triazole [ 4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl) phosphonium hexafluoro phosphate (V) (0.078 g, 0.14 mmol) and N,N -diisopropyl ethylamine (0.045 mL, 0. 26 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by RP-HPLC (5 to 60% acetonitrile in water and 0.1% formic acid) to provide (S)-N-( 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide as a white solid (0.017 g, 38%): 1H NMR (400 MHz, DMSO -d6) δ 12.83 (s, 1H), 7.90 (d, J = 8.0 Hz , 1H), 7.52 - 7.46 (m, 1H), 7.37 - 7.20 (m, 3H), 4.82 (dt, J = 11.3, 7.8 Hz, 1H), 4.49 (dd, J = 11.4, 9.8 Hz, 1H), 4.40 (dd, J = 9.8, 7.7 Hz, 1H), 3.31 (s, 3H), 2 .62 - 2.53 (m, 4H), 1.75 - 1.57 (m, 4H). LCMS RT = 4.21 min., m/z = 341.2 [M + H]+. Example 33: EE Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 - carboxamide

[0361] A stirred solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (0.025 g, 0.13 mmol) in N,N -dimethylformamide (1 mL) was added 1H -indazole -3 -carboxylic acid (0.026 g, 0.16 mmol), ((3H -[1,2,3] triazolo [4,5 -b] pyridin -3 - il) oxy) tri(pyrrolidin -1 -yl) phosphonium hexafluoro phosphate (V) (0.078 g, 0.14 mmol) and N,N -diisopropyl ethylamine (0.045 mL, 0.26 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (5 to 60% acetonitrile in water and 0.1% formic acid) to provide (S) - N - (5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -1H -indazole -3 -carboxamide in the form of a white solid (0.015 g, 34%): 1H NMR (400 MHz, DMSO -d6) δ 13.71 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.06 (dt, J = 8.2, 1.0 Hz, 1H), 7.63 (dt, J = 8.5, 0.9 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.42 (ddd, J = 8.4, 6.9, 1.1 Hz, 1H), 7.38 - 7.19 (m, 4H), 4.95 (dt, J = 11.6, 7.9 Hz , 1H), 4.63 (dd, J = 11.6, 9.9 Hz, 1H), 4.47 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LCMS RT = 4.32 min., m/z = 337.1 [M + H]+. Example 34: FF Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5 ,6,7 -tetrahydro -1H -indazole -3 -carboxamide Step 1: ethyl 2 -oxo -2 -(2 -oxo -5 - (trifluoromethyl)cyclohexyl)acetate

[0362] To a stirred solution of sodium ethoxide (2.68 mol/L) in ethanol (2.7 mL, 7.2 mmol) cooled to 0°C, a solution of 4 -( trifluoromethyl) cyclohexanone (1 g, 6 mmol) in diethyl oxalate (1 g, 7.2 mmol). The reaction mixture was heated to RT and stirred for 4 h. The reaction was then terminated with a 5% aqueous solution of citric acid (75 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% isopropyl acetate in heptane) to provide ethyl 2-oxo-2-(2-oxo-5-(trifluoromethyl ) cyclohexyl) acetate in the form of a yellow oil (0.623 g, 39%) that was used in the next step as it was: LCMS RT = 1.34 min., m/z = 267 [M + H ]+. Step 2: ethyl 5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate

[0363] To a solution of ethyl 2-oxo-2-(2-oxo-5-(trifluoromethyl) cyclohexyl) acetate (0.623 g, 2.34 mmol) in acetic acid (5 mL) was added hydrazine hydrate (300 mg, 4.68 mmol). The reaction mixture was heated at 80°C for 16 h. The reaction mixture was concentrated to drying in vacuum and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to provide ethyl 5-(trifluoromethyl)-4, 5,6,7-tetrahydro-1H-indazole-3-carboxylate (0.425 g, 69%) as a white solid that was used in the next step as it was: LCMS RT = 1.23 min., m/z = 263 [M + H]+. Step 3: 5-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

[0364] To a solution of ethyl 5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylate (0.425 g, 1.62 mmol) in methanol (4 mL) was added hydroxide of sodium (1 mol/L) in water (4.05 mL, 4.05 mmol). The reaction mixture was subjected to stirring at RT for 16 h. After this period, the mixture was concentrated in vacuum to remove methanol. The remaining solution was added to hydrochloric acid (1 mol/L) in water (50 mL). The resulting precipitate was collected, washed with 1N hydrochloric acid, and dried entirely to yield 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.164 g, 42% yield) as a white solid which was used in the next step without further purification: LCMS RT = 1.03 min., m/z = 235 [M + H]+. Step 4: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) - 4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0365] A stirred solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (0.035 g, 0.18 mmol) in N,N -dimethylformamide (2 mL) was added 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.051 g, 0.22 mmol), ((3H -[1 ,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl)phosphonium hexafluorophosphate (V) (0.109 g, 0.2 mmol) and N,N -diisopropylethylamine ( 0.095 mL, 0.55 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (20 to 60% acetonitrile in water and 0.1% formic acid) to provide N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetra hydro -1H -indazole -3 -carboxamide (0.037 g, 50%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 13.01 (s, 1H), 8.00 (d , J = 8.0 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.37 - 7.20 (m, 3H), 4.83 (dt, J = 11.5, 8 .1 Hz, 1H), 4.52 (ddd, J = 11.3, 10.7, 3.9 Hz, 1H), 4.40 (ddd, J = 10.0, 7.7, 2.5 Hz, 1H), 3.31 (s, 3H), 2.98 (dt, J = 16.0, 4.4 Hz, 1H), 2.85 - 2.54 (m, 3H), 2.49 - 2.38 (m, 1H), 2.15 - 2.01 (m, 1H), 1.71 - 1.53 (m, 1H). LCMS RT = 4.95 min., m/z = 409.1 [M + H]+. Step 5: (5S)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6 ,7-tetrahydro -1H -indazole -3 -carboxamide and (5R) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] - 5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H - indazole -3 -carboxamide

[0366] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) - 4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide was further purified via chiral SFC (SFC conditions: Column: Regis Whelk O -1 (s,s) 50x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 25% B in 2.5 min Flow rate: 4mL / min Column temperature: 40°C, BPR: 120 bar) to se provide arbitrarily assigned diastereomers (5S) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5 -(trifluoromethyl) -4,5, 6,7 -tetrahydro -1H - indazole -3 -carboxamide (0.015 g, 20 %) and (5R) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide (0.013 g, 17%) as a white solid:

[0367] Analytical data for the first elution diastereomer (arbitrarily assigned S,S configuration): SFC RT (Whelk O -1 (S,S) column, 25% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.): 1.01 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 12.97 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.68 - 7.41 (m, 1H), 7.41 - 7.06 (m, 3H), 4.83 (dt, J = 11.4, 7.7 Hz, 1H), 4 .51 (dd, J = 11.5, 9.8 Hz, 1H), 4.40 (dd, J = 9.8, 7.7 Hz, 1H), 3.31 (s, 3H), 2, 98 (dd, J = 16.0, 5.1 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.74 - 2.57 (m, 2H), 2.47 - 2, 37 (m, 1H), 2.16 - 2.02 (m, 1H), 1.72 - 1.51 (m, 1H). LCMS RT = 4.95 min., m/z = 409.1 [M + H]+.

[0368] Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC RT 1.13 min., 98% ee: 1H NMR (400 MHz, DMSO -d6) δ 13.00 (s, 1H ), 8.01 (d, J = 8.0 Hz, 1H), 7.63 - 7.39 (m, 1H), 7.43 - 7.11 (m, 3H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.52 (dd, J = 11.5, 9.8 Hz, 1H), 4.41 (dd, J = 9.9, 7.7 Hz , 1H), 3.31 (s, 3H), 2.99 (dd, J = 16.0, 5.1 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.74 - 2.58 (m, 2H), 2.48 - 2.38 (m, 1H), 2.16 - 2.03 (m, 1H), 1.71 - 1.53 (m, 1H). LCMS RT = 4.95 min., m/z = 409.1 [M + H]+. Example 35: GG Method

[0370] N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -6 -(trifluoromethyl) imidazo [1,5 -a] pyridine - 3-carboxamide Step 1: ethyl 2 -oxo -2 -[[5 -(trifluoromethyl) -2 -pyridyl] methylamino] acetate

[0371] To a solution of [5-(trifluoromethyl)-2-pyridyl] methanamine (1.0 g, 5.7 mmol) in anhydrous tetrahydrofuran cooled to 0°C under nitrogen was added triethylamine (1.19 mL, 8.5 mmol) followed by ethyl 2-chloro-2-oxo-acetate (0.85 g, 6.25 mmol). The reaction mixture was warmed to RT slowly and stirred for 16 h. The reaction mixture was concentrated to drying in vacuum and partitioned between isopropyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated for drying in vacuum to provide ethyl 2-oxo-2-[[5-(trifluoromethyl)-2-pyridyl]methylamino] acetate (1.2 g, 77%) as an orange solid used in the next step without further purification: LCMS RT = 1.05 min., m/z = 277 [M + H]+. Step 2: ethyl 6 -(trifluoromethyl)imidazo[1,5 -a] pyridine -3 -carboxylate

[0372] A suspension of ethyl 2 -oxo -2 -[[5 - (trifluoromethyl) -2 -pyridyl]methylamino]acetate (1.2 g, 4.3 mmol) in phosphoryl chloride (12 mL, 129 mmol) was heated to 100 °C for 16 h. The reaction mixture was concentrated to drying in vacuum, diluted with dichloromethane/methanol/trimethylamine (85:5:10) and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide ethyl 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate as a brown solid (0.460 g, 32%) which was used in the next step under the condition that found: LCMS RT = 1.26 min., m/z = 259 [M + H]+. Step 3: sodium 6 -(trifluoromethyl) imidazo[1,5 - a] pyridine -3 -carboxylate

[0373] To a solution of ethyl 6 - (trifluoromethyl)imidazo[1,5 -a] pyridine -3 -carboxylate (0.100 g, 0.39 mmol) in tetrahydrofuran (2 mL) was added sodium hydroxide (1 mol /L) in water (0.47 mL. 0.47 mmol). The reaction mixture was stirred at RT for 16 h, concentrated for drying in vacuum to provide sodium 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate as a brown solid used in next step without any further purification: LCMS RT = 0.93 min., m/z = 231 [M + H]+. Step 4: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6 -(trifluoromethyl)imidazo[1,5 -a] pyridine - 3-carboxamide

[0374] To a stirred solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] ammonium chloride (0.074 g, 0.32 mmol ) in N,N - dimethylformamide (1.5 ml) was added sodium 6 - (trifluoromethyl)imidazo[1,5 -a] pyridine -3 -carboxylate (0.097 g, 0.39 mmol), ((3H -[1 ,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl)phosphonium hexafluorophosphate(V) (0.210 g, 0.39 mmol) and N,N - diisopropylethylamine ( 0.17 mL, 0.97 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by column chromatography (silica gel, 100 - 200 mesh, 0 to 70% isopropyl acetate in heptane) to provide N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6 - (trifluoromethyl) imidazo[1,5 -a] pyridine -3 -carboxamide in the form of a solid yellow color (0.118 g, 91%): 1H NMR (400 MHz, DMSO -d6) δ 9.66 (p, J = 1.2 Hz, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.03 (dt, J = 9.6, 0.9 Hz, 1H), 7.81 (d, J = 0.8 Hz, 1H), 7.58 - 7.46 (m, 1H ), 7.41 - 7.19 (m, 4H), 4.91 (dt, J = 11.6, 7.8 Hz, 1H), 4.69 (dd, J = 11.6, 9.9 Hz, 1H), 4.46 (dd, J = 9.9, 7.7 Hz, 1H), 3.33 (s, 3H). LCMS RT = 5.64 min., m/z = 405.1 [M + H]+. Example 36: HH Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) -5,6 ,7,8 -tetra hydroimidazo[1,5 -a] pyridine -3 - carboxamide

[0375] To a solution of N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6 - (trifluoromethyl)imidazo[1,5 - a] pyridine-3-carboxamide (0.034 g, 0.084 mmol) in methanol (2 mL) was added palladium hydroxide (10%, by weight, loading, 0.020 g) followed by a balloon of hydrogen. The reaction mixture was stirred at RT for 16 h, filtered through Celite and concentrated to drying in vacuum to provide N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) -5,6,7,8 -tetra hydroimidazo[1,5 -a] pyridine -3 - carboxamide (34 mg, 99%) in the form of a yellow colored oil: 1H NMR (400 MHz, DMSO -d6) δ 8.35 (d, J = 8.0 Hz, 1H), 7.54 — 7.45 (m, 1H ), 7.37 — 7.19 (m, 3H), 6.89 (d, J = 0.8 Hz, 1H), 4.91 - 4.69 (m, 2H), 4.57 (ddd, J = 11.6, 9.8, 3.6 Hz, 1H), 4.40 (ddd, J = 9.8, 7.6, 2.0 Hz, 1H), 4.12 - 4.01 ( m, 2H), 3.31 (s, 3H), 3.04 - 2.92 (m, 1H), 2.84 - 2.69 (m, 1H), 2.15 - 2.04 (m, 1H), 1.83 - 1.67 (m, 1H). LCMS RT = 5.07 min., m/z = 409.1 [M + H]+. Example 37: Method II N -[(3S) -5-methyl -4 -oxo -2,3 -dihydro -1,5 -7 -(trifluoromethyl)imidazo[1,5 -a] pyridine -1 –carboxamide Step 1: ethyl 2 -amino -2 - [4 -(trifluoromethyl) - 2 -pyridyl]acetate

[0376] To a stirred suspension of sodium hydride (95%, 0.631 g, 25 mmol) in N,N-dimethylformamide (50 mL) cooled to 0°C was added ethyl acetate 2-(benzhydrylidene amino) (5.35 g, 20 mmol). After stirring the reaction for 30 min. under 0°C, 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22 mmol) was added. The reaction mixture was heated to RT and stirred for 4 h. Hydrochloric acid (1 mol/L) in water (50 mL) was added, and the resulting mixture was stirred at RT for 3 h. The mixture was diluted with isopropyl acetate (100 mL) and neutralized with saturated aqueous sodium bicarbonate (50 mL). The layers were separated, and the aqueous layer was extracted with isopropyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated for drying in vacuum, and purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide ethyl 2 - amino -2 -[4 -(trifluoromethyl) -2 - pyridyl] acetate (0.630 g, 13%) which was used in the next step as it was: LCMS RT = 0.93 min., m/z = 249 [M + H]+. Step 2: ethyl 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate

[0377] To a solution of ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate (0.630 g, 0.254 mmol) in toluene (5 mL) was added N,N-dimethylformamide dimethyl acetal (0 .44 mL, 3.3 mmol), and the resulting mixture was heated to 80 °C in a sealed vessel for 16 h. The reaction mixture was then concentrated to drying in vacuum and purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide ethyl 7-(trifluoromethyl)imidazo[1, 5 -a] pyridine -1 -carboxylate (0.147 g, 22%) as a white solid that was used in the next step as it was: LCMS RT = 1.19 min., m/z = 259 [M + H]+. Step 3: sodium 7 -(trifluoromethyl)imidazo[1,5 -a] pyridine -1 -carboxylate

[0378] To a stirred solution of ethyl 7-(trifluoromethyl)imidazo[1,5-a] pyridine-1-carboxylate (0.147 g, 0.57 mmol) in tetrahydrofuran (2 mL) was added sodium hydroxide (1 mol/L) in water (1.4 mL, 1.4 mmol). The resulting mixture was heated at 50°C for 6 h, concentrated to drying in vacuum to provide sodium 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate as a white solid which was used in the next step in the condition it was in: LCMS RT = 0.95 min., m/z = 231 [M + H]+. Step 4: N -[(3S)-5-methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -7 -(trifluoromethyl) imidazo [1,5 -a] pyridine - 1 -carboxamide

[0379] To a stirred solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] ammonium chloride (0.052 g, 0.23 mmol ) in N,N-dimethylformamide (1.5 mL) was added sodium 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate (0.069 g, 0.27 mmol), ((3H-[ 1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl)phosphonium hexafluorophosphate (V) (0.148 g, 0.27 mmol) and N,N - diisopropylethylamine (0.12 mL, 0.68 mmol). After stirring at RT for 16 h, the reaction mixture was charged directly for purification by means of RP-HPLC (30 to 70% acetonitrile in water and 0.1% formic acid) to provide N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -7 -(trifluoromethyl) imidazo [1,5 -a] pyridine -1 -carboxamide (0.067 g, 73%) in form a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.71 - 8.66 (m, 2H), 8.36 - 8.25 (m, 2H), 7.55 - 7 .47 (m, 1H), 7.39 - 7.21 (m, 3H), 7.12 (dd, J = 7.4, 1.9 Hz, 1H), 4.92 (dt, J = 11 .5, 7.8 Hz, 1H), 4.60 (dd, J = 11.5, 9.8 Hz, 1H), 4.47 (dd, J = 9.8, 7.7 Hz, 1H) , 3.33 (s, 3H). LCMS RT = 5.03 min., m/z = 405.1 [M + H]+. Example 38: JJ Method N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -7 -(trifluoromethyl) imidazo[1,5 -a] pyridine -1 -carboxamide

[0380] To a solution of N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -7 - (trifluoromethyl) imidazo[1,5 - a] pyridine-1-carboxamide (0.050 g, 0.12 mmol) in methanol (2 mL) palladium hydroxide (10%, by weight, charge, 0.030 g) was added followed by a hydrogen balloon. The reaction mixture was stirred at RT for 16 h, filtered through Celite and concentrated to drying in vacuum to provide N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro - 1 ,5-benzoxazepin -3-yl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (31 mg, 61%) in the form of an oil yellow in color: 1H NMR (400 MHz, DMSO -d6) δ 7.88 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.53 - 7.45 (m, 1H), 7.36 - 7.20 (m, 3H), 4.81 (dt, J = 11.2, 7.9 Hz, 1H), 4.54 - 4.36 (m, 2H), 4 .33 - 4.23 (m, 1H), 3.95 (tt, J = 12.4, 4.4 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.31 (s , 3H), 3.05 - 2.86 (m, 1H), 2.80 - 2.64 (m, 1H), 2.26 - 2.12 (m, 1H), 1.95 - 1.78 (m, 1H). LCMS RT = 4.46 min., m/z = 409.1 [M + H]+.

[0381] (5S) -N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide and (5R) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide Step 1: (6S) -6 -amino -4 -methyl -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one and (6R) -6 - amino - 4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[0382] To a solution of 6-azide -4 -methyl - 7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (0.500 g, 2, 42 mmol) in methanol (10 mL) was added 10% Pd/C (0.258 g, 0.242 mmol), a hydrogen balloon, and the mixture was subjected to stirring at RT for 16 h. The reaction mixture was filtered through Celite, concentrated to drying in vacuum, and purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% methanol in dichloromethane) to provide 6-amino-4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (0.210 g, 48%) in the form of a viscous oil. The resulting compound was further purified using chiral SFC (Chiralpak AD 150x21.2 mm I.D column, 5 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic 25% B for 6.0 min. Rate flow rate: 70 mL/min. Column temperature: 40°C. BPR: 100 bar) to provide the arbitrarily assigned diastereomers (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazole [1 ,5 -a][1,3] diazepin -5 -one (0.074 g, 17 %) and (6R) -6 -amino -4 -methyl -7,8 - dihydro -6H -pyrazole [1,5 -a ][1.3] diazepin -5 -one (0.074 g, 17%) in the form of viscous oils used in the condition in which they were in the next step.

[0383] Analytical data for the first elution enantiomer (arbitrarily assigned S configuration): SFC RT (AD column, 25% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.): 0.42 min., 98% ee; Analytical data for the second elution enantiomer (arbitrarily assigned R configuration): SFC RT = 0.69 min., 97% ee. (5S) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -5 -( trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide and (5R) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0384] A stirred solution of (6S) -6 -amino -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (0.022 g, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.034 g, 0. 15 mmol), ((3H -[1,2,3] triazolo [4,5 -b] pyridin -3 -yl) oxy) tri(pyrrolidin -1 -yl) phosphonium hexafluorophosphate (V) (0.080 g, 0. 15 mmol) and N,N - diisopropylethylamine (0.064 mL, 0.37 mmol). After stirring at RT for 16 h the reaction mixture was charged directly for purification by means of RP-HPLC (20 to 60% acetonitrile in water and 0.1% formic acid) to provide N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide (0.040 g, 83%) as a white solid.

[0385] The resulting compound was further purified using chiral SFC (SFC conditions: Column: Lux Cellulose -1 50x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 20% B in 2.5 min. Flow rate: 4mL/min. Column temperature: 40OC, BPR: 120 bar) to provide the arbitrarily assigned diastereomers (5R) -N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H - indazol -3 - carboxamide (0.019 g, 38 %) and (5S) -N -[(6S) -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 - yl] -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide (0.019 g, 38%) as white solids:

[0386] Analytical data for the first elution diastereomer (arbitrarily assigned R,S configuration): SFC RT (Lux Cellulose -1 column, 25% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min. ): 1.23 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 12.97 (s, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7, 49 (d, J = 2.1 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 4.42 - 4.24 (m, 2H), 4.23 - 4.12 (m, 1H), 3.25 (s, 3H), 3.05 - 2.93 (m, 2H), 2.84 - 2.74 (m, 1H), 2.74 - 2.54 (m , 3H), 2.39 - 2.25 (m, 1H), 2.15 - 2.04 (m, 1H), 1.72 - 1.55 (m, 1H). LCMS RT = 3.97 min., m/z = 397.1 [M + H]+.

[0387] Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC RT 1.59 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 12.98 (s, 1H ), 8.08 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 4.45 - 4.09 (m, 3H), 3.25 (s, 3H), 3.01 (dd, J = 16.0, 5.1 Hz, 1H), 2.87 - 2.56 ( m, 4H), 2.47 - 2.25 (m, 2H), 2.18 - 2.02 (m, 1H), 1.74 - 1.52 (m, 1H). LCMS RT = 3.95 min., m/z = 397.1 [M + H]+. Examples 40 -43: Chiral Separation of Compounds

[0388] Supercritical fluid chromatography (SFC) was performed on selected compounds of the invention in order to obtain chiral separation of stereoisomers. The chiral conditions of SFC are as follows. All peaks were assigned arbitrarily. Example 40: (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -4 ,5,6,7 - tetrahydro -1H -indazole -3 -carboxamide and R) -5 -methyl - N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -4,5,6,7 -tetrahydro -1H -indazole - 3 –carboxamide

Prep:

[0389] SFC Condition: Column: Chiralcel OX 150 x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 45% B in 6 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 2: 4.5 min.) and SFC condition: Column: Chiralcel OX 150 x 21.2mm I.D., 5 μm Mobile phase: A: CO2 B: Methanol ( 0.1% NH4OH) Isocratic: 45% B in 6 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 1: 4.0 min.).

Analytical:

[0390] SFC condition: Column: Chiralcel OX 50x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 40% B in 2.5 min. Flow rate: 4 mL/min. Column temperature: 40°C, BPR: 120 bar (Peak 2: 1,200 min.) and SFC condition: Column: Chiralcel OX 50x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.1 % NH4OH) Isocratic: 40% B in 2.5 min. Flow rate: 4 mL/min. Column temperature: 40°C, BPR: 120 bar (Peak 1: 1.031 min.). Example 41: (S) -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -4 ,5,6,7 - tetrahydrobenzo [c] isoxazole -3 -carboxamide and (R) -5 - methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetra hydrobenzo [c] isoxazole -3 –carboxamide

Prep:

[0391] SFC Condition: Column: Chiralpak AD 150 x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 25% B in 6.0 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 1: 2.6 min.) and SFC condition: Column: Chiralpak AD 150 x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 25% B in 6.0 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 2: 3.0 min.).

Analytical:

[0392] SFC Condition: Column: Chiralpak AD 50x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 20% B in 2.5 min. Flow rate: 4 mL/min. Column Temperature: 40°C, BPR: 120 bar (Peak1: 0.862 min.) and SFC Condition: Column: Chiralpak AD 50x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 20% B in 2.5 min. Flow rate: 4 mL/min. Column temperature: 40°C, BPR: 120 bar (Peak 2: 0.957 min.). Example 42: (S) -5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 - il) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxamide and (R) -5 -(tert -butyl) -N -((S) -5 -methyl -4 -oxo -2 ,3,4,5 -tetra hydrobenzo - [b] [1,4]oxazepin -3 -yl) -4,5,6,7 -tetrahydro -1H -indazole -3 –carboxamide

Prep:

[0393] SFC Condition: Column: Lux Cellulose -3 150x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 15% B in 6 min. Flow rate: 70 mL/min. Column Temperature: 40°C, BPR: 100 bar (Peak 2: 2.5 min.) and SFC Condition: Column: Lux Cellulose -3 150x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 15% B in 6 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 1: 2.0 min.).

Analytical:

[0394] SFC Condition: Column: Lux Cellulose -3 50x4.6mm ID, 3μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 15% B in 2.5 min. Flow rate: 4 mL/min. Column Temperature: 40°C, BPR: 120 bar (Peak 2: 0.551 min.) and SFC Condition: Column: Lux Cellulose -3 50x4.6mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0. 1% NH4OH) Isocratic: 15% B in 2.5 min. Flow rate: 4 mL/min. Column temperature: 40°C, BPR: 120 bar (Peak 1: 0.0.470 min.). Example 43:

Prep:

[0395] SFC Condition: Column: Chiralpak ID 150 x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 40% B in 6 min. Flow rate: 70 mL/min. Column Temperature: 40°C, BPR: 100 bar (Peak 1: 2.0 min.) and SFC Condition: Column: Chiralpak ID 150 x 21.2 mm I.D., 5 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 40% B in 6 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 2: 3.25 min.).

Analytical:

[0396] SFC Condition: Column: Chiralpak ID 50x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B: Ethanol (0.1% NH4OH) Isocratic: 30% B in 2.5 min. Flow rate: 4 mL/min. Column Temperature: 40°C, BPR: 120 bar (Peak 1: 0.888 min.) and SFC Condition: Column: Chiralpak ID 50x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B: Ethanol (0.1 % NH4OH) Isocratic: 30% B in 2.5 min. Flow rate: 4 mL/min. Column temperature: 40°C, BPR: 120 bar (Peak 2: 1.424 min.).

[0397] Examples 44 -82 were prepared according to the above procedures and synthetic schemes as illustrated in Table I below. Example 83 (S) -5 -cyano -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -1H -indazole - 3 -carboxamide Method B

[0398] (33 mg, 59% yield) 1H NMR (400 MHz, DMSO -d6) δ 14.23 (s, 1H), 8.68 - 8.59 (m, 1H), 8.52 - 8 .43 (m, 1H), 7.87 - 7.74 (m, 2H), 7.58 - 7.48 (m, 1H), 7.42 - 7.18 (m, 3H), 5.00 - 4.88 (m, 1H), 4.73 - 4.60 (m, 1H), 4.53 - 4.41 (m, 1H), 3.33 (s, 3H). LC -MS RT = 4.57 min., m/z = 362.1 (M+H) +.

[0399] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.57 min., ESI+ found [M+H] = 362.1. Step 1: 6-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid

[0400] In a vial with a screw cap, ethyl 6-bromo-[1,2,4] triazole [4,3-a] pyridine-3-carboxylate (70 mg, 0.259 mmol) was dissolved in tetrahydrofuran ( 1 mL) and methanol (0.2 mL). Lithium hydroxide (0.20 mL, 0.388 mmol) was then added to the reaction and stirred at RT for 18 h. On completion, the reaction was concentrated to drying in vacuum to provide crude 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid (62 mg, 98% yield). which was used in the next stage in the condition in which it was found. Step 2: (S) -6 -bromo -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) - [1 ,2,4] triazolo [4,3 -a] pyridine -3 –carboxamide

[0401] To a screw-capped vial was added (S)-3-amino-5-methyl-2,3-dihydrobenzo-[b] [1,4]oxazepin-4(5H)-one hydrochloride (58 mg, 0.255 mmol), 1 -[bis(dimethylamino) methylene] -1H -1,2,3 -triazolo [4,5 -b] pyridinium 3-oxide hexafluorophosphate (120 mg, 0.316 mmol), and 6 -bromo acid -[1,2,4] triazolo [4,3 -a] pyridine -3 -carboxylic acid (62 mg, 0.243 mmol) and dissolved in N,N -dimethylformamide (5 mL). Trimethylamine (0.136 mL, 0.973 mmol) was added to the reaction mixture, the vial was capped and shaken at RT for 16 h. The mixture was concentrated to drying in vacuum and the residue was purified by RP-HPLC to provide (S)-6-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -[1,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide (92 mg, 90% yield), which was used in next stage in the condition in which it was found. Example 84 Step 3: (S) -6 -cyclopropyl -N -(5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -[1 ,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide

[0402] In a microwave flask were added (S) -6 -bromo -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin - 3 -yl) -[1,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide (92 mg, 0.221 mmol), potassium cyclopropyl trifluoroborate (68.9 mg, 0.442 mmol), palladium acetate (II) (4.96 mg, 0.022 mmol), di(adamantan -1-yl)(butyl) phosphine (12.51 mg, 0.0332 mmol), and cesium carbonate (288.1 mg, 0.884 mmol) and purged N2 for 2 min. Toluene (4.42 ml, 41.8 mmol) and water (0.442 ml, 24.54 mmol) were then added to the flask and the reaction was allowed to stir at 110°C for 18 h. The mixture was concentrated to drying in vacuum and the residue was purified by RP-HPLC to provide (S)-6-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide (18 mg, 21% yield): 1H NMR ( 400 MHz, DMSO -d6) δ 9.31 (d, J = 8.0 Hz, 1H), 9.25 - 9.20 (m, 1H), 7.99 (dd, J = 9.7, 1 .0 Hz, 1H), 7.72 (dd, J = 9.7, 1.8 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.42 - 7.22 (m, 3H), 5.02 - 4.87 (m, 1H), 4.81 - 4.67 (m, 1H), 4.54 — 4.41 (m, 1H), 1.79 — 1.69 ( m, 1H), 1.03 — 0.93 (m, 2H), 0.80 - 0.69 (m, 2H). LC -MS RT = 4.66 min., m/z = 378.1 (M+H) +.

[0403] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.66 min., ESI+ found [M+H] = 378.1. Example 85 Step 1: 1 -benzyl -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide Method B

[0404] To a screw cap vial was added 6-amino -4 -methyl -2 -(trifluoromethyl) -7,8 - dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5 (6H)-one (74 mg, 0.298 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (158 mg, 0.417 mmol), 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (76mg, 0.358 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). Trimethylamine (0.166 mL, 1.19 mmol) was added to the reaction mixture, the flask was capped and shaken at RT for 16 h. The mixture was concentrated to drying in vacuum and the residue was purified by RP-HPLC to provide 1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide (77 mg, 59% yield): 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 7.49 - 7.19 (m, 5H), 6, 93 (s, 1H), 5.49 (s, 2H), 4.51 - 4.42 (m, 1H), 4.39 - 4.27 (m, 2H), 3.27 (s, 3H) , 2.72 - 2.59 (m, 1H), 2.48 - 2.42 (m, 1H). LC -MS RT = 4.34 min., m/z = 434.1 (M+H) +.

[0405] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.34 min., ESI+ found [M+H] = 434.1. Example 86 (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 - ( trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0406] Method B (20 mg, 29% yield) 1H NMR (400 MHz, DMSO -d6) δ 13.02 (s, 1H), 10.03 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.31 - 7.16 (m, 1H), 7.12 - 6.96 (m, 1H), 4.95 - 4.81 (m, 1H), 4, 69 - 4.56 (m, 1H), 4.56 - 4.44 (m, 1H), 3.10 - 2.95 (m, 1H), 2.87 - 2.58 (m, 3H), 2.17 - 2.03 (m, 1H), 1.72 - 1.55 (m, 1H). LC -MS RT = 5.03 min., m/z = 434.1 (M+H) +.

[0407] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.03 min., ESI+ found [M+H] = 434.1. Example 87 (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 - ( trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0408] Method B (12 mg, 17% yield) 1H NMR (400 MHz, DMSO -d6) δ 13.02 (s, 1H), 10.03 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.49 - 7.12 (m, 1H), 7.12 - 6.87 (m, 1H), 5.06 - 4.81 (m, 1H), 4, 67 - 4.55 (m, 1H), 4.55 - 4.45 (m, 1H), 3.08 - 2.95 (m, 1H), 2.87 - 2.59 (m, 3H), 2.20 - 2.02 (m, 1H), 1.76 - 1.56 (m, 1H). LC -MS RT = 5.01 min., m/z = 434.1 (M+H) +.

[0409] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.01 min., ESI+ found [M+H] = 434.1. Example 88 (S) -N -((S) -6 -fluoro -8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0410] Method B (29 mg, 42% yield) 1H NMR (400 MHz, DMSO -d6) δ 13.01 (s, 1H), 9.95 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.05 - 6.93 (m, 1H), 6.93 - 6.83 (m, 1H), 4.90 - 4.77 (m, 1H), 4, 60 - 4.51 (m, 1H), 4.49 - 4.41 (m, 1H), 3.06 - 2.95 (m, 1H), 2.85 - 2.74 (m, 1H), 2.74 - 2.58 (m, 2H), 2.47 - 2.42 (m, 1H), 2.30 (s, 3H), 2.14 - 2.09 (m, 1H), 1, 70 - 1.56 (m, 1H). LC -MS RT = 5.20 min., m/z = 427.1 (M+H) +.

[0411] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.20 min., ESI+ found [M+H] = 427.1. Example 89 (R) -N -((S) -6 -fluoro -8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0412] Method B (19mg, 27% yield) 1H NMR (400 MHz, DMSO -d6) δ 13.01 (s, 1H), 9.95 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.07 - 6.92 (m, 1H), 6.92 - 6.80 (m, 1H), 4.97 - 4.74 (m, 1H), 4.63 - 4.49 (m, 1H), 4.49 — 4.37 (m, 1H), 3.07 — 2.94 (m, 1H), 2.87 — 2.74 (m, 1H), 2 .74 - 2.59 (m, 2H), 2.48 - 2.42 (m, 1H), 2.30 (s, 3H), 2.18 - 2.02 (m, 1H), 1.72 - 1.55 (m, 1H). LC -MS RT = 5.19 min., m/z = 427.1 (M+H) +.

[0413] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.19 min., ESI+ found [M+H] = 427.1. Example 90 (S) -5 -methyl -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) benzo [d] isothiazole - 3-carboxamide

[0414] Method B (24 mg, 24% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.89 (d, J = 8.0 Hz, 1H), 8.48 - 8.40 (m , 1H), 8.23 - 8.14 (m, 1H), 7.59 - 7.46 (m, 2H), 7.40 - 7.20 (m, 3H), 4.99 - 4.86 (m, 1H), 4.72 - 4.62 (m, 1H), 4.54 - 4.42 (m, 1H), 3.34 (s, 3H), 2.46 (s, 3H). LC -MS RT = 5.97 min., m/z = 368.1 (M+H) +.

[0415] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.97 min., ESI+ found [M+H] = 368.1. Example 91 (S) -1 -benzyl -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[0416] Method B (35 mg, 27% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 7.46 - 7.17 (m, 5H), 6.93 (s, 1H), 5.49 (s, 2H), 4.52 - 4.43 (m, 1H), 4.39 - 4, 27 (m, 2H), 3.27 (s, 3H), 2.70 - 2.58 (m, 1H), 2.47 - 2.42 (m, 1H). LC -MS RT = 4.63 min., m/z = 434.1(M+H) +.

[0417] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.63 min., ESI+ found [M+H] = 434.1. Example 92 (5) -5 -cyclopropyl -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -1H -indazole -3 -carboxamide

[0418] Method B (13.8 mg, 25% yield) 1H NMR (400 MHz, DMSO -d6) δ 13.58 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H ), 7.78 - 7.70 (m, 1H), 7.58 - 7.46 (m, 2H), 7.39 - 7.22 (m, 3H), 7.16 (dd, J = 8 .7, 1.7 Hz, 1H), 5.03 - 4.83 (m, 1H), 4.67 - 4.57 (m, 1H), 4.52 - 4.42 (m, 1H), 2.10 - 1.96 (m, 1H), 1.00 - 0.91 (m, 2H), 0.68 - 0.59 (m, 2H). LC -MS RT = 5.36 min., m/z = 377.1 (M+H) +.

[0419] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.36 min., ESI+ found [M+H] = 377.1. Example 93 (general for all 8-element lactams) 5 -benzyl -N -(4 -methyl-5 -oxo -4,5,6,7,8,9 - hexahydropyrazole [1,5 -a][1,3] diazocin -6 -yl) -4H -1 ,2,4-triazole-3-carboxamide

[0420] All NMR spectra were recorded in DMSO -d6/ CD3OD/ CDCl3 solution in tubes with an external diameter of 5 mm [Wilmad NMR tubes (Sigma - 5 mm Thin wall, 7” Length] under 300.0 K and were collected on Bruker Avance NMRS -400 under 400 MHz for 1H. The chemical shifts (ô) are relative to CDCl3 (CDCl3 = 7.26 ppm), d6 -DMSO (d6 -DMSO = 2.5 ppm), CD3OD ( CD3OD = 3.3 ppm) and expressed in ppm. The chemical shifts in CDCl3, d6 - DMSO and CD3OD are relative to tetramethylsilane (TMS, = 0.00 ppm) and expressed in ppm.

[0421] All LC-MS were performed using the following methods;

[0422] Column - ZORBAX EXT (4.6X50 mm, 5u), (mobile phase: from 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30 % [CH3CN] in 1.5 min., still at 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min., maintaining this mobile phase until 4.0 min. and finally back to initial condition in 5.0 min.). Flow =1.2 ml/min.

[0423] Column - Restek Ultra AQ C18 (30 x 2.1 mm, 3u), (mobile phase: 98% [0.05% HCOOH in water] and 2% [CH3CN] maintained for 0.75 min., then to 90% [0.05% HCOOH in water] and 10% [CH3CN] in 1.0 min., further to 2% [0.05% HCOOH in water] and 98% [CH3CN] in 2.0 min. , maintaining this mobile phase composition until 2.25 min and finally back to the initial condition in 3.0 min.). Flow =1.5 ml/min. Step 1: 5-chloro-N-(1-(5-chloropentanoyl)-1H-pyrazol-5-yl)-N-methylpentanamide

[0424] To a stirred solution of N,5-dimethyl-1H-pyrazol-3-amine (0.500 g, 5.15 mmol) in anhydrous dichloromethane (25 mL) cooled to 0°C was added N,N - diisopropylethylamine (2.0 mL, 15.4 mmol) followed by dropwise addition of 5-chloropentanoyl chloride (1.65 mL, 12.9 mmol) under nitrogen. To the resulting mixture was added 4-dimethyl aminopyridine (33.0 mg, 0.515 mmol), and the reaction mixture was stirred at RT for 6 h. The mixture was diluted with dichloromethane (2 x 125 mL), and washed with saturated sodium bicarbonate (1 x 100 mL), water (1 x 100 mL), saline solution (1 x 100 mL), dried over sodium sulfate. sodium and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 20 to 30% ethyl acetate in hexane) to provide 5-chloro-N-(1-(5-chloropentanoyl)-1H-pyrazole -5-yl)-N-methylpentanamide (1.3 g, 76%) as a yellow oil: 1H NMR (400 MHz, DMSO -d6) 8.36 (s, 1H); 6.8 (br. s, 1H); 3.69 -3.64 (m, 5H); 3.31 (s, 3H); 3.10 -3.07 (m, 2H); 2.55 (br. s, 1H); 1.80 -1.62 (m, 8H).LCMS RT = 3.46 min., m/z = 334 (M+H)+. Step 2: 5-chloro-N-methyl-N-(1H-pyrazol-5-yl)pentanamide

[0425] To a stirred solution of 5-chloro-N-(1-(5-chloropentanoyl)-1H-pyrazol-5-yl)-N-methylpentanamide (12.5 g, 37.4 mmol) in ethanol (70 mL) sodium hydroxide (1.5 g, 37.4 mmol) in water (37 mL) was added and the mixture was allowed to sit at RT for 5 min. The reaction mixture was concentrated to drying in vacuum, diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The filtrate was washed with water, saline solution, dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 50 to 60% ethyl acetate in hexane) to provide 5-chloro-N-methyl-N-(1H-pyrazol-5-yl ) pentanamide (6 g, 74%) in the form of a sticky yellow solid: 1H NMR (400 MHz, DMSO -d6) δ 12.76 (br. s, 1H); 7.75 (s, 1H); 6.22 (s, 1H); 3.55 (br. s, 2H); 3.09 (s, 3H); 2.17 (br. s, 2H); 1.60 (br. s, 4H). LCMS RT = 2.45 min., m/z = 216.3 (M + H)+. Step 3: 4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one

[0426] To a solution of 5-chloro-N-methyl-N-(1H-pyrazol-5-yl)pentanamide (5.0 g, 23.2 mmol) in anhydrous acetonitrile (200 mL) was added cesium carbonate (15.11 g, 46.4 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated for drying in vacuum and the residue was diluted with ethyl acetate (200 mL) and washed with water (2 x 200 mL), saline solution (1 x 100 mL), dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 40 to 50% ethyl acetate in hexane) to provide 4-methyl -6,7,8,9 -tetrahydropyrazole [1,5 -a][1.3] diazocin -5(4H) -one (3.4g, 82%) as a yellow solid: 1H NMR (400 MHz, DMSO -d6) 7.49 (s, 1H ); 6.28 (s, 1H); 4.33 -4.28 (m, 1H); 3.78 -3.71 (m, 1H); 3.15 (s, 3H); 2.30 -2.24 (m, 1H); 1.93 -1.88 (m, 2H); 1.67 -1.57 (m, 2H); 1.38 -1.42 (m, 1H). LCMS RT = 1.64 min., m/z = 180 (M + H)+. Step 4: 6 -iodo -4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3]diazocin -5(4H) -one

[0427] To a solution of 5-chloro-N-methyl-N-(1H-pyrazol-5-yl) pentanamide (3.4 g, 19.0 mmol) in anhydrous dichloromethane (100 mL) under nitrogen cooled to ~ -10°C in a salt/ice bath was added N,N,N',N'-tetramethylethylene diamine (17.1 mL, 113.8 mmol) followed by iodotrimethylsilane (15.8 mL, 113.8 mmol) . The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time iodine (14.44 g, 56.9 mmol) was added. The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with sodium bisulfite (1 x 150 mL), water (1 x 100 mL), saline solution (1 x 100 mL) and dried over anhydrous sodium sulfate and concentrated for drying in vacuum to obtain provide 6 -iodo -4 -methyl -6,7,8,9 - tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one (5.5 g, 95%) in the form of a light yellow oil, used in the next step in the condition it was in: 1H NMR (400 MHz, DMSO -d6) 7.54 (s, 1H); 6.39 (s, 1H); 4.33 - 4.26 (m, 1H); 4.04 -4.00 (m, 1H); 3.78 -3.71 (m, 1H); 3.17 (s, 3H); 2.32 -2.27 (m, 2H); 1.93 -1.61 (m, 2H). LCMS RT = 2.63 min., m/z = 306 (M + H)+. Step 5: 6 -azide -4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one

[0428] To a solution of 6 -iodo -4 -methyl - 6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one (1.3 g , 4.26 mmol) in N,N-dimethylformamide (15 mL) was added sodium azide (1.10 g, 17.0 mmol), and the reaction mixture was stirred at RT for 17 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 100 mL), saline solution (1 x 100 mL), dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 30 to 50% ethyl acetate in heptane) to provide azide -6 -azide -4 -methyl -6,7,8,9 - tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one (0.500 g, 53%) as a yellow solid (0.606 g, 96%): 1H NMR (400 MHz, DMSO -d6) δ 7.53 (s, 1H); 6.37 (s, 1H); 4.34 -4.29 (m, 1H); 3.87 -3.80 (m, 1H); 3.18 (s, 3H); 3.17 -3.15 (m, 1H); 2.05 -1.95 (m, 3H); 1.68 -1.57 (m, 1H). LCMS RT = 2.72 min., m/z = 221.2 (M + H)+. Step 6: 6 -amino -4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3]diazocin -5(4H) -one

[0429] To a solution of 6-azide -4-methyl - 6,7,8,9 -tetrahydropyrazole [1,5-a][1,3] diazocin -5(4H)-onaone (2.2 g , 9.98 mmol) in methanol (50 mL) was added 10% palladium on carbon (1.0 g) under argon. The reaction mixture was subjected to stirring under hydrogen (flask pressure) under RT for 17 h. The reaction mixture was filtered through Celite, the cake washed with 5% methanol in dichloromethane and the combined filtrate was concentrated for drying in vacuum to provide 6-amino-4-methyl-6,7,8,9-tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one (1.65 g, 85%) in the form of a brown viscous liquid that was used in the next step in the condition in which it was found : 1H NMR (400 MHz, DMSO -d6) 7.51 (s, 1H); 6.29 (s, 1H); 4.29 -4.24 (m, 1H); 3.78 -3.71 (m, 1H); 3.17 (s, 3H); 2.74 -2.70 (m, 1H); 1.96 -1.88 (m, 3H); 1.66 -1.60 (m, 3H). LCMS RT = 1.42 min., m/z = 195.2 (M + H)+. 5 -benzyl -N -(4 -methyl -5 -oxo -4,5,6,7,8,9 - hexahydropyrazole [1,5 -a][1,3]diazocin -6 -yl) -4H -1 ,2,4-triazole-3-carboxamide

[0430] Method B (58 mg, 75% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.27 (s, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.29 - 7.21 (m, 3H), 6.36 (d, J = 2.0 Hz, 1H), 4.42 - 4.29 ( m, 1H), 4.09 (s, 2H), 3.97 - 3.80 (m, 2H), 3.21 (s, 3H), 2.07 - 1.96 (m, 1H), 1 .93 - 1.77 (m, 2H), 1.66 - 1.53 (m, 1H). LCMS RT = 3.61 min., m/z = 380.2 = (M + H)+.

[0431] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.61 min., ESI+ found [M+H] = 380.2. Example 94 1 -benzyl -N -(4 -methyl -5 -oxo -4,5,6,7,8,9 - hexahydropyrazole [1,5 -a][1,3] diazocin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide

[0432] Method B (104 mg, 80% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.24 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 - 7.27 (m, 5H), 6.36 (d, J = 2.0 Hz, 1H), 5.47 (s , 2H), 4.42 - 4.28 (m, 1H), 3.98 - 3.77 (m, 2H), 3.21 (s , 3H), 2.08 - 1.95 (m, 1H ), 1.92 - 1.76 (m, 2H), 1.67 - 1.54 (m, 1H). LCMS RT = 3.72 min., m/z = 380.2 = (M + H) + .

[0433] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.72 min. , ESI+ found (M+H] = 380.2. Example 95 N -(4 -methyl -5 -oxo -4,5,6,7,8,9 - hexahydropyrazole [1,5 -a][1,3]diazocin -6 -yl) -5 -(1 - phenylethyl) -4H -1,2,4 -triazole -3 -carboxamide

[0434] Method B (34 mg, 56% yield) 1H NMR (400 MHz, DMSO - d 6) δ 8.31 - 8.20 (m, 1H), 7.59 - 7.54 (m, 1H ), 7.36 - 7.17 (m, 6H), 6.41 - 6.32 (m, 1H), 4.47 - 4.24 (m, 2H), 4.02 - 3.76 (m , 2H), 3.22 (s, J = 2.4 Hz, 3H), 2.05 - 1.97 (m, 1H), 1.92 - 1.76 (m, 2H), 1.64 - 1.58 (m, 4H). LCMS RT = 3.85 min., m/z = 394.2 = (M + H)+.

[0435] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.85 min., ESI+ found [M+H] = 394.2. Example 96 5 -(4-fluorobenzyl) -N -(4 -methyl -5 -oxo - 4,5,6,7,8,9 -hexahydropyrazole [1,5 -a][1,3] diazocin -6 - yl) -4H -1,2,4 -triazole -3 -carboxamide

[0436] Method B (24 mg, 40% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.32 - 8.22 (m, 1H), 7.61 - 7.49 (m, 1H) , 7.34 - 7.25 (m, 2H), 7.18 - 7.09 (m, 2H), 6.41 - 6.31 (m, 1H), 4.41 - 4.28 (m, 1H), 4.09 (s, 2H), 3.98 - 3.79 (m, 2H), 3.21 (s, 3H), 2.08 - 1.96 (m, 1H), 1.94 - 1.77 (m, 2H), 1.68 - 1.52 (m, 1H). LCMS RT = 3.72 min., m/z = 398.1 = (M + H)+.

[0437] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.72 min., ESI+ found [M+H] = 398.1 Example 97 5 -(2,3 -difluorobenzyl) -N -(4 -methyl -5 -oxo - 4,5,6,7,8,9 -hexa hydropyrazole [1,5 -a] [1,3] diazocin -6 -il) -4H -1,2,4 -triazole -3 -carboxamide.

[0438] Method B (41 mg, 60% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.34 - 8.25 (m, 1H), 7.56 (d, J = 2.0 Hz , 1H), 7.39 - 7.27 (m, 1H), 7.23 - 7.10 (m, 2H), 6.35 (d, J = 2.0 Hz, 1H), 4.41 - 4.29 (m, 1H), 4.17 (s, 2H), 3.97 - 3.78 (m, 2H), 3.21 (s, 3H), 2.07 - 1.97 (m, 1H), 1.96 - 1.77 (m, 2H), 1.67 - 1.53 (m, 1H). LCMS RT = 3.81 min., m/z = 4.16.2 (M + H)+.

[0439] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.81 min., ESI+ found [M+H] = 416.2 Example 98 (S) -5 -(4 -fluorobenzyl) -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepine - 6 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[0440] Method B (55 mg, 94% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.57 - 8.50 (m, 1H), 7.49 (d, J = 2.0 Hz , 1H), 7.38 - 7.24 (m, 2H), 7.20 - 7.08 (m, 2H), 6.34 (d, J = 2.1 Hz, 1H), 4.42 - 4.25 (m, 2H), 4.24 - 4.13 (m, 1H), 4.09 (s, 2H), 3.25 (s, 3H), 2.67 - 2.53 (m, 1H), 2.44 - 2.29 (m, 1H). LCMS RT = 3.63 min., m/z = 384.1 (M + H])+.

[0441] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.63 min., ESI+ found [M+H] = 384.1, Example 99 (S) -5 -(2,3 -difluorobenzyl) -N -(4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[0442] Method B (42 mg, 80% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.62 - 8.51 (m, 1H), 7.49 (d, J = 2.0 Hz , 1H), 7.39 - 7.28 (m, 1H), 7.23 - 7.09 (m, 2H), 6.34 (d, J = 2.0 Hz, 1H), 4.41 - 4.26 (m, 2H), 4.23 - 4.14 (m, 3H), 3.24 (s, 3H), 2.62 - 2.55 (m, 1H), 2.44 - 2, 33 (m, 1H). LCMS RT = 3.71 min., m/z = 402.1 (M + H])+.

[0443] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.71 min., ESI+ found [M+H] = 402.1, N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 - (1-phenylethyl)-4H -1,2,4 -triazole -3 -carboxamide

[0444] Method B (54 mg, 74% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.52 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.36 - 7.18 (m, 6H), 6.34 (d, J = 2.0 Hz, 1H), 4.42 - 4.26 (m, 4H), 4.24 - 4.13 ( m, 1H), 3.25 (s, 3H), 1.63 (d, J = 7.3 Hz, 3H). LCMS RT = 3.75 min., m/z = 380.2 (M + H])+.

[0445] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.75 min., ESI+ found [M+H] = 380.2. (S) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -4 - phenoxypicolinamide

[0446] Method B (22 mg, 35% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.62 - 8.54 (m , 1H), 7.57 - 7.45 (m, 3H), 7.39 - 7.30 (m, 2H), 7.27 - 7.17 (m, 3H), 6.33 (d, J = 2.0 Hz, 1H), 4.44 - 4.14 (m, 3H), 3.25 (s, 3H), 2.74 - 2.61 (m, 1H), 2.41 - 2, 27 (m, 1H). LCMS RT = 4.59 min., m/z = 378.2 (M + H])+.

[0447] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.59 min., ESI+ found [M+H] = 378.2, Example 102 5 -benzyl -N -(1 -methyl -2 -oxo -1,2,3,4,5,6 - hexahydroimidazo[1,5 -a][1,3]diazocin -3 -yl) -4H -1 ,2,4 - triazole -3 -carboxamide Step 1: N -(1H -imidazol -5 -yl)formamide

[0448] A solution of 3H-imidazole-4-ylamine (7.9g, 96.2mmol) in formic acid (32ml) was heated at 110°C for 2h in a sealed vessel. The reaction mass was cooled to RT and concentrated for drying in vacuum. The residue was co-distilled with methanol (3 x 60 ml) to provide N -(3H-imidazol-4-yl)-formamide (9.0 g, 84.18%) as a white solid : 1H NMR (400 MHz, DMSO -d6) δ 12.38 (s, 1H), 10.51 (s, 1H), 8.16 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 6.47 (s, 1H). Step 2: N -methyl -1H -imidazole -5 -amine

[0449] To a stirred solution of N -(3H-imidazol-4-yl)-formamide (4.5g, 40.5 mmol) in tetrahydrofuran (170mL) under ice-cooled condition was added lithium hydride and aluminum (2M solution in tetrahydrofuran, 61 mL, 121.6 mmol) very slowly under nitrogen and the reaction mixture was allowed to gradually warm to room temperature and stirred for 6 h. The reaction was terminated with solid sodium sulfate and stirred at RT for 30 min. The reaction mixture was diluted with ethyl acetate and filtered through a bed of Celite and the filtrate was concentrated for drying in vacuum to provide crude N -methyl -1H -imidazole -5 -amine (3.17g, 81%) in the form of a colorless liquid, which was used in the next step in the condition in which it was found. Step 3: 5-chloro-N-(1-(5-chloropentanoyl)-1H-imidazol-5-yl)pentanamide

[0450] To a stirred solution of N -methyl -1H -imidazole -5 -amine (6.1 g, 62.1 mmol) in anhydrous dichloromethane (300 mL) cooled to 0°C was added N,N - diisopropylethylamine (32.8 mL, 188.4 mmol) followed by dropwise addition of 5-chloropentanoyl chloride (19.5 mL, 150.7 mmol) under nitrogen. To the resulting mixture was added 4-dimethyl aminopyridine (0.767 mg, 6.28 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to drying in vacuum and the resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 20 to 25% ethyl acetate in hexane) to provide 5 -chloro -N - (1-(5-chloropentanoyl)-1H-imidazol-5-yl)pentanamide (17.5 g, 83%) as a yellow oil: LCMS RT = 1.67 min., m/z = 334 .3 [M]+, 336.3 [M+2]+ Step 4: 5-chloro-N-(1H-imidazol-5-yl)pentanamide

[0451] To 5-chloro-N-(1-(5yl)pentanamide (17.5 g, 52.4 mmol) in ethanol (105 mL) was added sodium hydroxide (2.1 g, 52.4 mmol ) in water (52.5 mL) and the mixture was allowed to sit at RT for 5 min. The reaction mixture was concentrated to drying in vacuum, diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The filtrate was washed with water, brine, dried over sodium sulfate and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 45 to 50% ethyl acetate in hexane) to provide 5-chloro-N-(1H-imidazol-5-yl)pentanamide (8.8 g, 78%) as a yellow oil: 1H NMR (400 MHz, DMSO -d6) δ 12.77 (s, 1H), 7.75 (s, 1H), 6.22 (s, 1H), 3.56 (br. s, 2H), 3.09 (s , 3H), 2.17 (s, 1H), 1.99 (br. s, 2H), 1.60 (br. s, 4H). LCMS RT = 2.57 min., m/z = 216, 1 (M+H)+. Step 5: 1 -methyl -3,4,5,6 -tetra hydroimidazo [1,5 -a][1,3] diazocin -2(1H) -one

[0452] To a solution of 5-chloro-N-(1H-imidazol-5-yl) pentanamide (8.8 g, 40.8 mmol) in anhydrous acetonitrile (350 mL) was added cesium carbonate (26.6 g, 81.6 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 45 to 50% ethyl acetate in hexane) to provide 1 - methyl -3, 4,5,6 -tetra hydroimidazo [1,5 -a][1,3] diazocin - 2(1H) -one (5.6 g, 77%) as a yellow solid: 1H NMR (400 MHz, DMSO -d6) δ 7.49 (s, 1H), 6.28 (s, 1H), 4.30 (br. d, J = 14.09 Hz), 3.75 (t, J = 12 .1Hz, 1H), 3.15 (s, 3H), 2.29 -2.25 (m, 1H), 1.93 -1.89 (m, 2H), 1.67 -1.55 ( m, 2H),1.44 -1.38 (m, 1H). LCMS RT = 1.90 min., m/z = 180.2 (M + H)+. Step 6: 3 -iodo -1 -methyl -3,4,5,6 -tetrahydroimidazo[1,5 -a][1,3]diazocin -2(1H) -one

[0453] To a solution of 1 -methyl -3,4,5,6 - tetrahydroimidazo [1,5 -a][1,3] diazocin -2(1H) -one (0.730 mg, 4.1 mmol) in anhydrous dichloromethane (65 mL) under nitrogen cooled to ~-10°C in a salt/ice bath was added N,N,N',N'-tetramethyl ethylenediamine (6.5 mL, 24.4 mmol) followed by iodotrimethylsilane (3.5 mL, 24.4 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time iodine (3.1 g, 12.2 mmol) was added. The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with sodium bisulfite (1 x 150 mL), water (1 x 100 mL), saline solution (1 x 100 mL) and dried over anhydrous sodium sulfate and concentrated for drying in vacuum to obtain provide 3-iodo-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (1.15 g, 93% yield in raw) in the form of a light yellow solid, used in the next step in the condition in which it was found: 1H NMR (400 MHz, DMSO -d6) δ 7.54 (s, 1H), 6.42 - 6.39 (s, 1H), 4.29 (dd, J = 14.6, 3.9 Hz, 1H), 4.06 -3.98 (m, 1H), 3.78 -3.71 (m, 2H ), 3.16 (s, 3H), 2.31 -2.26 (s, 2H), 1.84 -1.81 (m, 1H), 1.72 -1.61 (m, 1H). LCMS RT = 2.54 min., m/z = 306.1 (M + H)+. Step 7: 3 -azide -1 -methyl -3,4,5,6 -tetra hydroimidazo[1,5 -a][1,3] diazocin -2(1H) -one

[0454] To a solution of 3 -iodo -1 -methyl - 3,4,5,6 -tetra hydroimidazo [1,5 -a][1,3] diazocin -2(1H) -one (1.1 g , 3.61 mmol crude) in N,N-dimethylformamide (15 mL) sodium azide (0.94 g, 14.4 mmol) was added, and the reaction mixture was stirred at RT for 17 H. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 100 mL), saline solution (1 x 100 mL), dried over sodium sulfate and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 25 to 30% ethyl acetate in hexane) to provide 3-azide-1-methyl-3,4,5,6-tetra hydroimidazo [1,5 -a][1,3] diazocin -2(1H) -one (0.600 g, 76 %) as a yellow solid: 1H NMR (400 MHz, DMSO -d6) δ 7, 53 (s, 1H), 6.38 (s, 1H), 4.32 (d, J = 14.7 Hz, 1H), 3.84 (t, J = 12.2 Hz, 1H), 3, 22 (s, 3H), 3.21 -3.17 (m, 1H), 2.05 -1.98 (m, 3H), 1.26 -1.23 (m, 1H). LCMS RT = 1.33 min., m/z = 221.3 (M + H)+. Step 8: 3 -amino -1 -methyl -3,4,5,6 -tetra hydroimidazo [1,5 -a][1,3] diazocin -2(1H) -one

[0455] To a solution of 3-azide -1 -methyl - 3,4,5,6 -tetra hydroimidazo [1,5 -a][1,3] diazocin -2(1H) - one (0.400 mg, 1 .82 mmol) in methanol (12 mL) was added 10% palladium on carbon (0.200 g) under argon. The reaction mixture was subjected to stirring under hydrogen (flask pressure) under RT for 3 h. The reaction mixture was filtered through Celite, the cake washed with methanol and the combined filtrate was concentrated for drying in vacuum to provide 3-amino-1-methyl-3,4,5,6-tetrahydroimidazo [1,5 -a][1,3] diazocin -2(1H) -one (0.27 mg, 77%) in the form of a light yellow liquid that was used in the next step in the condition it was in: 1H NMR ( 400 MHz, DMSO -d6) δ 7.51 (s, 1H), 6.30 (s, 1H), 4.27 (dd, J = 14.4, 5.3 Hz, 1H), 3.75 ( t, J = 11.3 Hz, 1H), 3.17 (s, 3H), 2.73 -2.67 (m, 1H), 1.99 -1.87 (m, 2H), 1,661.47 (m, 3H). LCMS RT = 3.64 min., m/z = 195.1 (M + H)+. Step 9: 5-Benzyl -N -(1-methyl -2 -oxo - 1,2,3,4,5,6 -hexahydroimidazo [1.5yl) -4H -1,2,4 -triazol -3 - carboxamide

[0456] Method B (19.6 mg, 25% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.31 - 8.21 (m, 1H), 7.56 (d, J = 2, 0 Hz, 1H), 7.37 - 7.18 (m, 5H), 6.59 (s, 0H), 6.36 (d, J = 2.0 Hz, 1H), 4.41 - 4, 29 (m, 1H), 4.09 (s, 2H), 3.98 - 3.76 (m, 2H), 3.21 (s, 3H), 2.06 - 1.98 (m, 1H) , 1.93 - 1.79 (m, 2H), 1.68 - 1.52 (m, 1H). LCMS RT = 3.46 min., m/z = 380.2 (M + H)+.

[0457] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.46 min., ESI+ found [M+H] = 380.2. 1 -benzyl -N -(1 -methyl -2 -oxo -1,2,3,4,5,6 - hexahydroimidazo[1,5 -a][1,3]diazocin -3 -yl) -1H -1 ,2,4 - triazole -3 -carboxamide

[0458] Method B (44 mg, 56% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.24 (d, J = 7.1 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.42 - 7.26 (m, 6H), 6.36 (d, J = 2.0 Hz, 1H), 5.47 (s , 2H), 4.42 - 4.29 (m, 1H), 3.97 - 3.76 (m, 2H), 3.21 (s, 3H), 2.07 - 1.97 (m, 1H ), 1.92 - 1.77 (m, 2H), 1.68 - 1.53 (m, 1H). LCMS RT = 3.55 min., m/z = 380.2 (M + H)+.

[0459] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.55 min., ESI+ found [M+H] = 380.2, 1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 4,5,6,7,8,9 -hexa hydropyrazole [1,5 -a][1,3] diazocin -6 - yl ) -1H -1,2,4 -triazole -3 -carboxamide Step 1: 5-chloro-N-(1-(5-chloropentanoyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-methyl pentanamide

[0460] To a stirred solution of N,5-dimethyl-1H-pyrazol-3-amine (6 g, 43.7 mmol) in anhydrous dichloromethane (300 mL) cooled to 0°C was added N,N - diisopropyl ethylamine (22.8 mL, 131.2 mmol) followed by dropwise addition of 5-chloropentanoyl chloride (13.5 mL, 104.96 mmol) under nitrogen. To the resulting mixture was added 4-dimethyl aminopyridine (0.534 mg, 4.37 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to drying in vacuum to provide 5-chloro-N-(1-(5-chloropentanoyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (1.3 g, 76%) in the form of a yellow oil used in the condition in which it was found in the next step: LCMS RT = 1.79 min., m/z = 374.1 (M)+, 376.1(M+2 )+ Step 2: 5-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methyl pentanamide

[0461] To a stirred solution of 5-chloro-N-(1-(5-chloropentanoyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (21.5 g, crude) in ethanol (115 mL) sodium hydroxide (2.29 g, 57.4 mmol) in water (57.6 mL) was added and the mixture was allowed to sit at RT for 5 min. The reaction mixture was concentrated to drying in vacuum, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 45 to 50% ethyl acetate in hexane) to provide 5-chloro-N -(3-cyclopropyl -1H - pyrazol -5 -yl) -N -methylpentanamide (4.2 g, 34%) in the form of a yellow oil, used in the next step in the condition in which it was: 1H NMR ( 400 MHz, DMSO -d6) δ 12.47 (s, 1H), 5.89 (s, 1H), 3.56 (br. s, 2H), 3.04 (s, 3H), 2.18 ( br.s, 2H), 1.87 (br.s, 1H), 1.61 -1.57 (m, 4H), 0.92 (d, J = 6 Hz, 2H), 0.69 (br. .s, 2H). LCMS RT = 1.49 min., m/z = 256 (M)+, 258 (M+2)+ Step 3: 2 -cyclopropyl -4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one

[0462] To a solution of 5-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (4.2 g, 19.47 mmol) in anhydrous acetonitrile (200 mL) was added cesium carbonate (12.69 g, 38.95 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 45 to 50% ethyl acetate in hexane) to give 2-cyclopropyl-4-methyl -6,7,8,9 - tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one (3.5 g, 82%) as an off-white solid: 1H NMR ( 400 MHz, DMSO -d6) δ 5.99 (s, 1H), 4.30 (br. d, J = 10.04 Hz), 3.64 (t, J = 12.32 Hz, 1H), 3 .11 (s, 3H), 2.27 -2.22 (m, 1H), 1.87 -1.78 (m, 3H), 1.69 (t, J = 11.8 Hz), 1, 54 -1.51 (m, 1H),1.39 -1.33 (m, 1H) 0.85 -0.82 (m, 2H), 0.63 (br. S, 2H). LCMS RT = 1.39 min., m/z = 220.0 (M + H)+. Step 4: 2 -cyclopropyl -6 -iodo -4 -methyl - 6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one

[0463] To a solution of 2-cyclopropyl -4 - methyl -6,7,8,9 -tetrahydropyrazole [1,5-a][1,3] diazocin -5(4H) -one (2.5 g , 11.4 mmol) in anhydrous dichloromethane (65 mL) under nitrogen cooled to ~ -10°C in a salt/ice bath was added N,N,N',N'-tetramethyl ethylenediamine (18.2 mL, 68 .4 mmol) followed by iodotrimethylsilane (9.7 mL, 68.4 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time iodine (8.6 g, 34.2 mmol) was added. The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with sodium bisulfite (1 x 150 mL), water (1 x 100 mL), saline solution (1 x 100 mL) and dried over anhydrous sodium sulfate and concentrated for drying in vacuum to obtain provide 2-cyclopropyl -6 -iodo -4 -methyl -6,7,8,9 - tetrahydropyrazole [1,5 -a][1,3] diazocin -5(4H) -one (4g, yield of product in crude) in the form of a light yellow oil, which was used in the next stage in its current condition. Step 4: 6-azide -2-cyclopropyl -4 -methyl - 6,7,8,9 -tetrahydropyrazole [1,5-a][1,3]diazocin -5(4H) -one.

[0464] To a solution of 2-cyclopropyl -6 - iodo -4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5-a][1,3] diazocin -5(4H) -one ( 4 g, 15.4 mmol crude product) in N,N-dimethylformamide (60 mL) sodium azide (3 g, 65.0 mmol) was added, and the reaction mixture was stirred at RT for 17 H. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 100 mL), saline solution (1 x 100 mL), dried over sodium sulfate and concentrated for drying in vacuum. . The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 25 to 30% ethyl acetate in hexane) to provide 6-azide-2-cyclopropyl-4-methyl-6,7,8 ,9-tetrahydropyrazole [1,5-a][1,3] diazocin -5(4H)-one (2 g, 66% over two steps) as a yellow solid (0.606 g, 96%) : 1H NMR (400 MHz, DMSO -d6) δ 6.08 (s, 1H), 4.20 (dd, J = 14.8, 5.2 Hz, 1H), 3.72 (dd, J = 14 .8, 11.5 Hz, 1H), 3.30 -3.17 (m, 1H), 3.18 (s, 3H), 1.99 -1.92 (m, 3H), 1.95 ( s, 2H), 1.85 -1.80 (m, 1H), 1.65 -1.60 (m, 1H), 0.85 (dd, J = 8.4, 2.4 Hz, 3H) , 0.64 (dd, J = 7.4, 5.1 Hz, 2H). LCMS RT = 1.51 min., m/z = 261.1 (M + H)+. Step 5: 6 -amino -2 -cyclopropyl -4 -methyl - 6,7,8,9 -tetrahydropyrazole [1,5 -a][1,3]diazocin -5(4H) -one

[0465] To a solution of 6-azide -2 - cyclopropyl -4 -methyl -6,7,8,9 -tetrahydropyrazole [1,5 - a][1,3] diazocin -5(4H) -one ( 3 g, 11.5 mmol) in methanol (50 mL) was added 10% palladium on carbon (1.5 g) under argon. The reaction mixture was subjected to stirring under hydrogen (flask pressure) under RT for 3 h. The reaction mixture was filtered through Celite, the cake washed with methanol and the combined filtrate was concentrated for drying in vacuum to provide 6-amino-2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazole [ 1.5 - a][1.3] diazocin -5(4H) -one (2.2 g, 82%) in the form of a viscous yellow liquid that was used in the next step in the condition in which it was: 1H NMR (400 MHz, DMSO -d6) δ 6.00 (s, 1H), 4.15 (dd, J = 14.2, 4.9 Hz, 1H), 3.64 (dd, J = 14, 2, 11.4 Hz, 1H), 3.13 (s, 3H), 2.74 (d, J = 7.3 Hz, 1H), 1.95 (s, 1H), 1.83 -1, 82 (m, 2H), 1.63 -1.52 (m, 3H), 0.85 (d, J = 6.5 Hz, 2H), 0.63 (s, 2H). LCMS RT = 2.12 min., m/z = 235.2 (M + H)+. Step 6: 1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo -4,5,6,7,8,9 -hexahydropyrazole [1,5 -a][1,3] diazocin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0466] Method B (29 mg, 65% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.21 (d, J = 7.1 Hz, 1H), 7.39 - 7.24 (m, 5H), 6.07 (s, 1H), 5.47 (s, 2H), 4.32 - 4.15 (m, 1H), 3.98 - 3, 67 (m, 2H), 3.17 (s, 3H), 2.03 - 1.72 (m, 4H), 1.67 - 1.50 (m, 1H), 0.93 - 0.79 ( m, 2H), 0.77 - 0.53 (m, 2H). LCMS RT = 4.11 min., m/z = 420.2 (M + H)+.

[0467] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.11 min., ESI+ found [M+H] = 420.2, Example 105 5-benzyl -N -(2-cyclopropyl -4 -methyl -5 -oxo - 4,5,6,7,8,9 -hexahydropyrazole [1,5 -a][1,3] diazocin -6 - yl) -4H -1,2,4 -triazole -3 -carboxamide

[0468] Method B (8.4 mg, 19% yield) 1H NMR (400 MHz, DMSO - d 6) δ 8.44 (s, 0H), 8.28 - 8.17 (m, 1H), 7.42 - 7.18 (m, 4H), 6.68 (s, 1H), 6.07 (s, 1H), 4.29 - 4.18 (m, 1H), 4.09 (s, 2H), 3.93 - 3.72 (m, 2H), 3.17 (s, 3H), 2.03 - 1.74 (m, 4H), 1.65 - 1.50 (m, 1H) , 0.91 - 0.81 (m, 2H), 0.71 - 0.56 (m, 2H). LCMS RT = 3.97 min., m/z = 420.2 (M + H)+.

[0469] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.97 min., ESI+ found [M+H] = 420.2, Example 106 1 -methyl -N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl ) -1 -(2,2,2 -trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[0470] Method B (50 mg, 71% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.94 - 8.88 (m, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.19 - 5.11 (m, 2H) , 4.45 - 4.33 (m, 2H), 4.31 - 4.16 (m, 1H), 3.27 (s, 3H), 3.14 - 3.03 (m, 1H), 2 .99 - 2.87 (m, 1H), 2.78 - 2.62 (m, 1H), 2.41 - 2.29 (m, 1H), 1.50 (s, 3H). LCMS RT = 4.22 min., m/z = 424.1 (M + H)+.

[0471] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.22 min., ESI+ found [M+H] = 424.1. Example 107 1 -benzyl -N -(3,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide

[0472] Method B (50 mg, 64% yield) 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.41 (d, J = 7.7 Hz, 1H), 7.44 - 7.25 (m, 6H), 5.48 (s, 2H), 4.34 - 4.12 (m, 3H), 3.21 (s, 3H), 2.61 - 2, 53 (m, 1H), 2.29 - 2.19 (m, 1H), 2.01 (s, 3H). LCMS RT = 3.71 min., m/z = 380.2 (M + H)+.

[0473] LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.71 min., ESI+ found [M+H] = 380.2. Example 108 5-benzyl -N -(1-methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -[1,3] diazepine [1,2 -b]indazol -3 -yl) -4H - 1,2,4 -triazole -3 -carboxamide

[0474] 5-Benzyl -N -(1-methyl -2 -oxo - 2,3,4,5 -tetrahydro -1H -[1,3] diazepine [1,2 -b]indazole - 3 -yl) -4H -1,2,4 -triazole -3 -carboxamide was prepared from 1H -indazole -3 -amine according to Method Z. Final step yield: 0.057 g, 70%: 1H NMR (400 MHz, DMSO -d6) δ 7.76 (dt, J = 8.5, 1.0 Hz, 1H), 7.62 (dt, J = 8.8, 0.9 Hz, 1H), 7.38 - 7 .18 (m, 6H), 7.12 (ddd, J = 8.5, 6.6, 0.9 Hz, 1H), 4.61 (dd, J = 10.7, 4.1 Hz, 2H ), 4.22 (dt, J = 11.4, 8.0 Hz, 1H), 4.11 (s, 2H), 3.47 (s, 3H), 2.18 (t, J = 7, 4 Hz, 1H), 1.47 (d, J = 7.5 Hz, 1H). LC -MS RT = 4.08 min., m/z = 416.2 (M+H) +.

[0475] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.08 min., ESI+ found [M+H] = 416.2, Example 109

[0476] Method G2 5 -benzyl -N -(1 -methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [4,5]imidazo[1,2 -a][1, 3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide Step 1: methyl 4 -[2 -(methylamino) benzimidazole - 1 -yl] butanoate

[0477] To a solution of N -methyl -1H - benzimidazole -2 -amine (1.36 g, 9.24 mmol, 1.00) in acetonitrile (40 mL) was added cesium carbonate (12 g, 37. 0 mmol, 4 equiv.) followed by methyl 4-bromobutanoate (1.40 mL, 2.01 g, 11.1 mmol, 1.0 equiv.). The reaction mixture was stirred overnight at RT, then filtered through Celite and concentrated to drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane) to provide methyl 4-[2-(methylamino)benzimidazol-1-yl]butanoate (0 .65 g, 28%) as an orange-colored oil.

[0478] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.88 min., ESI+ found [M+H] = 248. Step 2: 1 -methyl -4,5 -dihydro -3H -[1,3] diazepine [1,2 -a] benzimidazole -2 -one

[0479] To a solution of methyl 4 - [2 - (methylamino) benzimidazol -1 -yl] butanoate (0.650 g, 2.63 mmol) in methanol (3 mL) was added a 1M aqueous sodium hydroxide solution (2 .89 mL, 2.891 mmol, 1.100 equiv.). The reaction mixture was stirred at RT for 1 h. The mixture was concentrated to drying in vacuum and resuspended in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (1.38 mL, 7.89 mmol, 3 equiv.) was added to it, followed by hexafluorophosphate. of (7-Azabenzotriazol-1-yloxy) tripyrrolidine phosphonium (1.71 g, 3.15 mmol, 1.2 equiv.). The reaction was stirred for 4 h at RT. The reaction mixture was diluted with isopropyl acetate (50 mL), then mixed with water (50 mL) and saline (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide the product 1-methyl-4,5-dihydro-3H-[1 ,3] diazepine[1,2-a]benzimidazol-2-one (0.41 g, 72%) as a yellow solid.

[0480] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.96 min., ESI+ found [M+H] = 216. Step 3: 3 -iodo -1 -methyl -4,5 -dihydro -3H - [1,3]diazepine[1,2 -a]benzimidazole -2 -one

[0481] To a solution of 1 -methyl -4,5 -dihydro -3H -[1,3] diazepine[1,2 -a]benzimidazole -2 -one (0.375 g, 1.74 mmol) in dichloromethane (10 mL) cooled in a salt/ice bath was added N,N,N',N'-tetramethyl ethylenediamine (1.58 mL, 10.45 mmol, 6 equiv.) followed by iodotrimethylsilane (1.491 mL, 10.45 mmol, 6 equiv.). The reaction mixture was stirred for 1.5 h in the salt/ice bath, then iodine (1.33 g, 5.23 mmol, 3 equiv.) was added, and the mixture was stirred in the ice bath. cooling for another 2 h. The reaction was then terminated by the addition of a saturated sodium sulfite solution (50 mL). The layers were separated, and the aqueous layer was extracted twice more with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 50% isopropyl acetate in heptane) to provide 3-iodo -1 - methyl -4,5 -dihydro -3H - [1,3] diazepine [1,2 -a] benzimidazole -2 -one (0.445 g, 75% yield) as a white solid.

[0482] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.06 min., ESI+ found [M+H] = 342, Step 4: 3 -azide -1 -methyl -4,5 -dihydro -3H - [1,3]diazepine[1,2 -a]benzimidazole -2 -one

[0483] To a solution of 3 -iodo -1 -methyl - 4,5 -dihydro -3H - [1,3] diazepine [1,2 -a] benzimidazole -2 - one (0.45 mg, 1.30 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (0.101 g, 1.57 mmol, 1.2 equiv.). The reaction mixture was stirred for 2 h at RT, filtered through Celite, and concentrated to drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 3-azide -1 - methyl -4,5 -dihydro -3H - [1,3] diazepine [1,2 -a] benzimidazole -2 -one (0.315 g, 94%) as a white solid.

[0484] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.04 min., ESI+ found [M+H] = 257, Step 5: 3 -amino -1 -methyl -4,5 -dihydro -3H - [1,3] diazepine [1,2 -a] benzimidazole -2 -one

[0485] To a solution of 3-azide -1-methyl - 4,5 -dihydro -3H - [1,3] diazepine [1,2 -a] benzimidazole -2 - one (0.315 g, 1.23 mmol, 1 equiv.) in tetrahydrofuran (5 mL) was added water (1 mL) and polystyrene-bound triphenylphosphine resin (1.23 g, ~3 mmol/g charge, 3.69 mmol, 3 equiv.). The reaction mixture was stirred for 16 h at RT, then filtered through Celite and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide 3-amino -1 -methyl -4,5 -dihydro -3H -[1 ,3] diazepine [1,2 -a] benzimidazole -2 -one (0.197 g, 70%) in the form of a colorless oil.

[0486] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.76 min., ESI+ found [M+H] = 231. Step 6: 5 -benzyl -N -(1 -methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [4,5]imidazo[1,2 -a][1,3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[0487] To a solution of 3 -amino -1 -methyl - 4,5 -dihydro -3H - [1,3] diazepine [1,2 -a]benzimidazole -2 - one (0.028 g, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol, 1.5 equiv.), N,N - diisopropylamine (0.064 mL, 0.047 g, 0.36 mmol, 3 equiv.), and (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (0.076 mg, 0.14 mmol, 1.15 equiv.). The reaction mixture was stirred for 16 h under RT, diluted with isopropyl acetate (25 mL), washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated for drying in vacuum. The residue was purified by RP-HPLC preparation (5 to 50% acetonitrile in H2O + 0.1% formic acid) to provide 5-benzyl-N-(1-methyl-2-oxo-2,3, 4,5 - tetrahydro -1H -benzo [4,5]imidazo [1,2 -a][1,3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide (0.014 g, 27%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 14.32 (s, 1H), 8.61 (s, 1H), 7.67 - 7.58 (m, 2H), 7.36 -7.19 (m, 7H), 4.72 - 4.61 (m, 1H), 4.49 (dt, J = 11.5, 7.8 Hz, 1H ), 4.19 - 3.98 (m, 3H), 3.42 (s, 3H), 2.76 - 2.60 (m, 1H), 2.61 - 2.51 (m, 1H). LC -MS RT = 3.97 min., m/z = 416.2 (M+H) +.

[0488] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.97 min., ESI+ found [M+H] = 416.2, Example 110 1-benzyl -N -(1-methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -[1,3] diazepine [1,2 -b]indazol -3 -yl) -1H - 1,2,4 -triazole -3 -carboxamide

[0489] 1-benzyl -N -(1-methyl -2 -oxo - 2,3,4,5 -tetrahydro -1H -[1,3] diazepine[1,2 -b]indazol -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide was prepared from 1H -indazole -3 -amine according to Methods Z and G1, Final step yield: 0.033 g, 52%: 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.57 (d, J = 7.7 Hz, 1H), 7.76 (dt, J = 8.5, 1.0 Hz, 1H ), 7.62 (dt, J = 8.8, 0.9 Hz, 1H), 7.43 - 7.25 (m, 6H), 7.12 (ddd, J = 8.5, 6.6 , 0.9 Hz, 1H), 5.47 (s, 2H), 4.65 - 4.56 (m, 2H), 4.22 (dt, J = 11.5, 7.9 Hz, 1H) , 3.47 (s, 3H), 2.79 - 2.65 (m, 1H), 2.61 - 2.51 (m, 1H). LC -MS RT = 4.26 min., m/z = 416.2 (M+H) +.

[0490] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.26 min., ESI+ found [M+H] = 416.2, Example 111

[0491] 1-Benzyl -N -(1-methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [4,5]imidazo [1,2 - a][1] was prepared ,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 - carboxamide from 3 -amino -1 -methyl -4,5 -dihydro -3H -[1,3] diazepine [1 ,2 -a] benzimidazole -2 -one according to Method G1, Yield: 0.011 g, 22%: 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.69 ( d, J = 7.6 Hz, 1H), 7.68 - 7.56 (m, 2H), 7.43 - 7.17 (m, 8H), 5.49 (s, 2H), 4.71 - 4.60 (m, 1H), 4.48 (dt, J = 11.5, 7.7 Hz, 1H), 4.05 (ddd, J = 14.6, 12.8, 6.5 Hz , 1H), 3.42 (s, 3H), 2.76 - 2.62 (m, 1H), 2.56 - 2.45 (m, 1H). LC -MS RT = 4.08 min., m/z = 416.2 (M+H) +.

[0492] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.08 min., ESI+ found [M+H] = 416.2, Example 112

[0493] G3 Method (S)-1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepine -6 -yl) -1H -1,2,3 -triazole -4 -carboxamide Step 1: 1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,3 -triazole -4 -carboxamide

[0494] To a solution of 6-amino -2 - cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (0.029 g, 0 .13 mmol, 1 equiv.) in N,N-dimethylformamide (2 mL) was added 1-benzyltriazole-4-carboxylic acid (0.040 g, 0.20 mmol, 1.5 equiv.), N,N-diisopropylethylamine (0.069 mL, 0.40 mmol, 3 equiv..), and (7-Azabenzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate (0.082 g, 0.15 mmol, 1.15 equiv..). The reaction mixture was stirred overnight, then was diluted with isopropyl acetate (25 mL), washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated for drying in vacuum. The residue was purified by RP-HPLC preparation (5 to 50% acetonitrile in H2O + 0.1% formic acid) to provide 1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide (0.030 g, 56% yield) as a white solid.

[0495] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.46 min., ESI+ found [M+H] = 406.2.

[0496] 1-benzyl -N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin - 6 -yl) -1H -1,2,3 -triazol -4 - carboxamide was further purified by means of chiral SFC (O -1 Whelk column, 40% methanol + 0.1% ammonium hydroxide isocratic elution) to provide the arbitrarily assigned enantiomers (R) - 1 -benzyl -N -(2 - cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1 ,3] diazepin -6 -yl) -1H -1,2,3 -triazole -4 -carboxamide (0.014 g, 26%) and (S) -5 -1 -benzyl -N -(2 - cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,3 -triazole -4 -carboxamide (0.013 g, 24%) in the form of a white solid:

[0497] Analytical data for the first elution enantiomer (arbitrarily assigned R configuration): SFC RT (O -1 Whelk column, 40% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.): 0.773 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.66 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 7.54 - 7, 15 (m, 5H), 6.05 (s, 1H), 5.65 (s, 2H), 4.39 - 4.19 (m, 3H), 4.09 (ddd, J = 14.6, 12.6, 6.5 Hz, 1H), 3.19 (s, 3H), 2.62 — 2.52 (m, 1H), 2.40 - 2.28 (m, 1H), 1.85 (tt, J = 8.4, 5.0 Hz, 1H), 0.89 - 0.81 (m, 2H), 0.75 - 0.58 (m, 2H) LCMS RT = 4.46 min. , m/z = 406.2 (M+H)+.

[0498] Analytical data for the second elution enantiomer (arbitrarily assigned S configuration): SFC RT: 0.960 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.66 (s, 1H), 8 .60 (d, J = 7.9 Hz, 1H), 7.56 - 7.18 (m, 5H), 6.05 (s, 1H), 5.65 (s, 2H), 4.46 - 4.16 (m, 2H), 4.16 - 3.97 (m, 1H), 3.19 (s, 3H), 2.62 - 2.52 (m, 1H), 2.42 - 2, 28 (m, 1H), 1.85 (tt, J = 8.4, 5.0 Hz, 1H), 0.91 - 0.80 (m, 2H), 0.73 - 0.59 (m, 2H). LCMS RT = 4.42 min., m/z = 406.2 (M+H)+. Example 113

[0499] G4 Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) -[1, 2,4] triazolo [4,3 -a] pyridine -3 -carboxamide Step 1: [5-(trifluoromethyl)-2-pyridyl]hydrazine

[0500] To a solution of 2-chloro-5-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol) in ethanol (10 mL) in a large microwave flask was added hydrazine hydrate (1.25 mL , 22 mmol, 4 equiv..). The flask was capped and heated in a microwave oven at 150°C for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuum to provide [5-(trifluoromethyl)-2-pyridyl]hydrazine (0.95 g, 97%) as a solid bronze color, which was used in the next step without any further purification.

[0501] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.77 min., ESI+ found [M+H] = 178, Step 2: ethyl 2 -oxo -2 -[2 -[5 -(trifluoromethyl) -2 -pyridyl] hydrazino] acetate

[0502] To a solution of [5-(trifluoromethyl)-2-pyridyl] hydrazine (0.95 mg, 5.4 mmol) in tetrahydrofuran (25 mL) cooled to 0°C was added N,N - diisopropylethylamine ( 1.87 mL, 10.7 mmol, 2 equiv.) followed by ethyl 2-chloro-2-oxo-acetate (0.66 mL, 5.9 mmol, 1.1 equiv..). The reaction mixture was allowed to slowly warm to RT with stirring for 16 h. The mixture was concentrated to drying in vacuum and purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 100% isopropyl acetate in heptane) to give ethyl 2 -oxo -2 - [2 - [5-(trifluoromethyl)-2-pyridyl]hydrazino]acetate (0.63 g, 42%) as an orange solid.

[0503] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.15 min., ESI+ found [M+H] = 278, Step 3: ethyl 6 -(trifluoromethyl) -[1,2,4] triazolo [4,3 -a] pyridine -3 -carboxylate

[0504] A suspension of ethyl 2-oxo-2-[2-[5-(trifluoromethyl)-2-pyridyl]hydrazino]acetate (0.63 g, 2.27 mmol) in phosphoryl chloride (6 mL, 64 .6 mmol, 28.4 equiv.) was heated at 100°C for 16 h. The reaction mixture was cooled to RT and concentrated to drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide ethyl 6-(trifluoromethyl)-[1,2,4]triazole[4,3 -a] pyridine -3 - carboxylate (0.266 g, 45%) as an off-white solid.

[0505] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.23 min., ESI+ found [M+H] = 260, Step 4: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 - (trifluoromethyl) - [1,2,4] triazolo [4,3 -a] pyridine -3 - carboxamide

[0506] To a solution of ethyl 6 -(trifluoromethyl) - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxylate (0.266 g, 1.02 mmol) dissolved in tetrahydrofuran (4 mL ) 1M aqueous sodium hydroxide (1.23 mL) was added. The reaction mixture was stirred for 1 h at RT, then concentrated to drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3- chloride yl] ammonium (0.040 g, 0.18 mmol), N,N-diisopropyl ethylamine (0.092 mL, 0.067 g, 0.52 mmol), and (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (0.114 g, 0 .21 mmol). The reaction mixture was subjected to stirring for 16 h under RT, then directly purified via RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid) to give (S) -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 - (trifluoromethyl) -[1,2,4 ] triazolo [4,3 -a] pyridine -3 - carboxamide (0.035 g, 49%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.49 - 9.40 (m , 2H), 8.25 - 8.14 (m, 1H), 7.83 (dd, J = 9.6, 1.8 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.40 - 7.19 (m, 3H), 4.95 (dt, J = 11.6, 7.8 Hz, 1H), 4.76 (dd, J = 11.7, 9.9 Hz, 1H), 4.47 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LC -MS RT = 4.09 min., m/z = 406.1 (M+H) +.

[0507] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.09 min., ESI+ found [M+H] = 406.1. G5 Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 -(trifluoromethyl) -5,6 ,7,8 -tetrahydro -[1,2,4] triazolo [4,3 -a] pyridine - 3 -carboxamide

[0508] To a solution of (S) -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 - yl) -6 - (trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (0.046 g, 0.11 mmol) in methanol (2 mL) was added palladium hydroxide (10%, by weight , 0.024 g, 0.017 mmol, 0.15 equiv.). The reaction mixture was stirred under a balloon of hydrogen gas for 16 h at RT, then filtered through Celite and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane) to provide N -((S) -5 -methyl -4 - oxo -2,3 ,4,5 -tetra hydrobenzo - [b] [1,4] oxazepin -3 -yl) -6 -(trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2,4] triazole [4 ,3 -a] pyridine -3 -carboxamide (0.034 g, 73%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.96 (d, J = 8.0 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.37 - 7.20 (m, 3H), 4.89 - 4.79 (m, 1H), 4.72 - 4.54 ( m, 2H), 4.41 (ddd, J = 9.8, 7.6, 3.4 Hz, 1H), 4.06 (dd, J = 13.3, 10.4 Hz, 1H), 3 .31 (s, 3H), 3.23 - 3.05 (m, 2H), 3.00 - 2.86 (m, 1H), 2.22 - 2.10 (m, 1H), 1.99 - 1.83 (m, 1H). LC -MS RT = 4.56 min., m/z = 410.1 (M+H) +.

[0509] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.56 min., ESI+ found [M+H] = 410.1. Example 114

[0510] G6 Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -6 -(perfluoroethyl) -[1, 2,4] triazolo [4,3 -b] pyridazine -3 -carboxamide Step 1: ethyl 6 -(1,1,2,2,2 -pentafluoroethyl) - [1,2,4] triazolo [4,3 -b] pyridazine -3 -carboxylate

[0511] To a solution of ethyl 6-chloro - [1,2,4] triazolo [4,3 -b] pyridazine -3 -carboxylate (0.2 g, 0.88 mmol) in N,N -dimethylformamide ( 2 mL) copper (1,1,2,2,2-Pentafluoroethyl)(1,10-phenanthroline-KN1,KN10) (0.384 g, 1.06 mmol, 1.2 equiv.) was added. The reaction mixture was heated at 90°C for 24 h, then was diluted with isopropyl acetate (25 mL) and water (25 mL). The layers were separated, and the aqueous layer was extracted twice more with isopropyl acetate (2 x 25 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide ethyl 6 - (1,1,2,2,2-pentafluoroethyl) - [1,2,4] triazolo [4,3 -b] pyridazine -3 -carboxylate (0.031 g, 11%) as a light yellow solid.

[0512] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.20 min., ESI+ found [M+H] = 311, Step 2: (S)-N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -6 - (perfluoroethyl) - [1,2,4] triazolo [4,3 -b] pyridazine -3 - carboxamide

[0513] To a solution of ethyl 6 -(1,1,2,2,2 - pentafluoroethyl) -[1,2,4] triazolo [4,3 -b] pyridazine -3 - carboxylate (0.031 g, 0. 10 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.15 mL). The reaction mixture was stirred for 1 h at 0°C, then concentrated to drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3- chloride yl] ammonium (0.025 g, 0.1 mmol), N,N -diisopropyl ethylamine (0.057 mL, 0.33 mmol), and (7-Azabenzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate (0.071 g, 0.13 mmol). The reaction mixture was stirred for 16 h under RT, then directly purified via RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid) to give (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -6 - (trifluoromethyl) -[1,2,4 ] triazolo [4,3 -a] pyridine -3 - carboxamide (0.015 g, 30%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.30 (d, J = 7 .8 Hz, 1H), 8.90 - 8.79 (m, 1H), 7.93 (d, J = 9.8 Hz, 1H), 7.57 - 7.49 (m, 1H), 7 .41 - 7.23 (m, 3H), 4.97 (dt, J = 11.4, 7.8 Hz, 1H), 4.62 (dd, J = 11.5, 9.9 Hz, 1H ), 4.52 (dd, J = 9.9, 7.8 Hz, 1H), 3.35 (s, 3H). LC -MS RT = 4.81 min., m/z = 457.1 (M+H) +.

[0514] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.81 min., ESI+ found [M+H] = 457.1. Example 115

[0515] Method G7 (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4]oxazepin -3 -yl) -5 -(trifluoromethyl) -1H -indazole -3 -carboxamide

[0516] To a solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] ammonium chloride (0.030 g, 0.13 mmol) in N ,N-dimethylformamide (2 mL) was added 5-(trifluoromethyl)-1H-indazole-3-carboxylic acid (0.036 g, 0.16 mmol, 1.2 equiv., N,N-diisopropyl ethylamine (0.046 mL, 0.26 mmol, 2 equiv.), and (7-azabenzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate (0.078 g, 0.14 mmol, 1.1 equiv.). The reaction mixture was stirred overnight under RT, then it was purified directly via prep RP - HPLC (20 to 70% acetonitrile in water + 0.1% formic acid) to give (S)-N-(5-methyl-4-oxo -2,3,4,5 -tetrahydrobenzo - [b] [1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -1H -indazole -3 -carboxamide (0.036 mg, 67%) in the form of a light brown solid: 1H NMR (400 MHz, DMSO -d6) δ 14.15 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.55 - 8.28 (m, 1H), 7.91 - 7.83 (m, 1H), 7.75 - 7.68 (m, 1H), 7.56 - 7.49 (m, 1H), 7.40 - 7 .22 (m, 3H), 4.96 (dt, J = 11.6, 7.8 Hz, 1H), 4.66 (dd, J = 11.6, 9.9 Hz, 1H), 4, 48 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LC - MS RT = 5.43 min., m/z = 405.1 (M+H) +.

[0517] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.43 min., ESI+ found [M+H] = 405.1. Example 116

[0518] Method G13 N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -6 -(perfluoroethyl) - 5,6, 7,8 -tetrahydro - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide Step 1: ethyl 6 -(1,1,2,2,2 -pentafluoroethyl) - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxylate

[0519] To a solution of ethyl 6-bromo - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxylate (0.100 g, 0.37 mmol) in N,N -dimethyl formamide (2 mL) copper (1,1,2,2,2-pentafluoroethyl) (1,10-phenanthroline -KN1,KN10) (0.201 g, 0.56 mmol, 1.5 equiv.) was added. The reaction mixture was heated at 90°C for 24 h, then was diluted with isopropyl acetate (25 mL) and water (25 mL). The layers were separated, and the aqueous layer was extracted twice more with isopropyl acetate (2 x 25 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to give ethyl 6 - (1,1,2,2,2 - pentafluoroethyl) - [ 1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.055 mg, 0.18 mmol, 48%) as an off-white solid.

[0520] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.24 mln., ESI+ found [M+H] = 310. Step 2: ethyl 6 -(1,1,2,2,2 -pentafluoroethyl) - 5,6,7,8 -tetrahydro - [1,2,4] triazolo [4,3 -a] pyridine -3 - carboxylate

[0521] To a solution of ethyl 6 -(1,1,2,2,2 - pentafluoroethyl) - [1,2,4] triazolo [4,3 -a] pyridine -3 - carboxylate (0.055 g, 0. 18 mmol) in methanol (2 mL) palladium hydroxide (10% by weight, 0.037 g, 0.027 mmol, 0.15 equiv.) was added. The reaction mixture was stirred for 16 h at RT under a hydrogen balloon. The reaction mixture was then filtered through Celite and concentrated to drying in vacuum to provide ethyl 6-(1,1,2,2,2-pentafluoroethyl)-5,6,7,8-tetrahydro-[ 1,2,4] triazolo [4,3 -a] pyridine -3 - carboxylate (0.055 g, 98%) as a white solid which was used without further purification.

[0522] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.14 mln., ESI+ found [M+H] = 314. Step 3: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -6 - (perfluoroethyl) -5, 6,7,8 -tetrahydro - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide

[0523] To a solution of ethyl 6 -(1,1,2,2,2 - pentafluoroethyl) -5,6,7,8 -tetrahydro - [1,2,4] triazolo [4,3 -a] pyridine -3-carboxylate (0.055 g, 0.18 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.200 mL). The reaction mixture was stirred for 1 h at RT, then concentrated to drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3- chloride yl] ammonium (0.030 g, 0.13 mmol), N,N -diisopropyl ethylamine (0.069 mL, 0.39 mmol), and (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (0.086 g, 0.16 mmol) . The reaction mixture was stirred for 16 h under RT, then directly purified via RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid) to give N -( (S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -6 - (perfluoroethyl) -5,6,7,8 - tetrahydro - [1,2,4] triazolo [4,3 -a] pyridine -3 -carboxamide (0.049 g, 81%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8 .95 (dd, J = 8.1, 1.3 Hz, 1H), 7.50 (ddd, J = 7.3, 1.9, 0.9 Hz, 1H), 7.38 - 7.26 (m, 2H), 7.26 - 7.20 (m, 1H), 4.89 - 4.78 (m, 1H), 4.72 - 4.59 (m, 2H), 4.40 (ddd , J = 9.8, 7.6, 3.3 Hz, 1H), 4.13 - 4.02 (m, 1H), 3.32 (s, 3H), 3.17 - 3.08 (m , 1H), 3.00 - 2.88 (m, 1H), 2.26 - 2.15 (m, 1H), 2.01 - 1.83 (m, 1H). LC -MS RT = 5.00 mln., m/z = 460.1 (M+H) +.

[0524] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.00 mln., ESI+ found [M+H] = 460.1 Example 117

[0525] G8 Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 (perfluoroethyl) -1H -pyrazole [3,4 -b] pyridine -3 carboxamide Step 1: methyl 5-bromo-1-(2,4,6-trimethylphenyl)sulfonyl-pyrazolo[3,4-b]pyridine-3-carboxylate

[0526] To a suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (0.500 g, 1.95 mmol) in tetrahydrofuran (10 mL) was added triethylamine (0.544 mL, 3 .93 mmol, 2 equiv.), 2-mesitylenesulfonyl chloride (0.475 g, 2.15 mmol, 1.1 equiv.), and 4-(dimethylamino)pyridine 0.024 mg, 0.20 mmol, 0.1 equiv. ). The reaction mixture was stirred at RT for 16 h, then concentrated to drying in vacuum to provide methyl 5-bromo-1-(2,4,6-trimethylphenyl)sulfonyl-pyrazole [3,4 -b] pyridine -3 - carboxylate (0.855 g, 99%) as an orange solid which was used in the next step without any further purification.

[0527] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.77 mln., ESI+ found [M+H] = 440 Step 2: methyl 5-(1,1,2,2,2-pentafluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

[0528] To a solution of methyl 5-bromo-1-(2,4,6-trimethylphenyl)sulfonyl-pyrazolo[3,4-b]pyridine-3-carboxylate (0.855 g, 1.95 mmol) in 1 - methyl -2 - pyrrolidinone was added (1,1,2,2,2 - pentafluoroethyl)(1,10 -phenanthroline -KN1,KN10)copper (0.990 g, 2.73 mmol, 1.4 equiv.). The reaction mixture was heated at 80°C for 24 h, then was diluted with water (100 mL) and extracted with isopropyl acetate (3 x 50 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over sodium sulfate, and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 25% isopropyl acetate in heptane) to give methyl 5-(1,1,2,2,2-pentafluoroethyl ) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxylate (0.020 g, 3%) in the form of a light yellow oil.

[0529] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.24 mln., ESI+ found [M+H] = 296 Step 3: (S)-N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (perfluoroethyl) -1H - pyrazole [3,4 -b] pyridine -3 - carboxamide

[0530] To a solution of methyl 5 -(1,1,2,2,2 - pentafluoroethyl) -1H -pyrazole [3,4 -b] pyridine -3 - carboxylate (0.020 g, 0.07 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.135 mL). The reaction mixture was stirred at 70°C for 16 h, then concentrated for drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3- chloride yl] ammonium (0.030 g, 0.13 mmol), N,N -diisopropylethyl amine (0.069 mL, 0.39 mmol), and (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (0.086 g, 0.16 mmol) . The reaction mixture was subjected to stirring for 16 h under RT, then it was directly purified by means of RP-HPLC preparation (20 -70% acetonitrile in water + 0.1% formic acid) to give thus ( S) -N - (5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(perfluoroethyl) -1H -pyrazole [3, 4 -b] pyridine -3 -carboxamide (0.005 g, 17%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 14.87 (s, 1H), 8.92 (d , J = 2.2 Hz, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.38 - 7.22 (m, 3H), 4.95 (dt, J = 11.6, 7.9 Hz, 1H), 4.69 (dd, J = 11.6 , 9.9 Hz, 1H), 4.47 (dd, J = 9.9, 7.7 Hz, 1H), 3.33 (s, 3H). LC -MS RT = 5.43 mln., m/z = 456.1 (M+H) +.

[0531] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.43 mln., ESI+ found [M+H] = 456.1 Example 118

[0532] G9 Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4'H,6'H -spiro [cyclopentane -1,5' -pyrrole [1,2 -c] [1,2,3] triazole] -3' -carboxamide Step 1: ethyl 2 -(8 -aza spiro [4,4] nonan -7 - ylidene) -2 -nitro -acetate

[0533] To a solution of 8-aza spiro [4,4] nonan - 7-one (1.39 g, 10 mmol) in dichloromethane (50 mL) was added potassium carbonate (4.15 g, 30 mmol, 3 equiv.) and trimethyloxonium tetrafluoronorate (2.96 g, 20 mmol, 2 equiv.). The reaction mixture was stirred for 16 h under RT, then it was diluted with water (100 mL) and the layers were separated. The aqueous layer was extracted twice more with dichloromethane (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated for drying in vacuum. The residue was resuspended in ethyl nitro acetate (4.45 mL, 40 mmol, 4 equiv.) and heated at 70°C for 7 h. After cooling to rt, the mixture was purified directly by means of flash column chromatography (silica gel, 100 -200 mesh, 0 to 50% isopropyl acetate in heptane) to thus provide ethyl 2-(8-aza spiro[4,4]nonan-7-ylidene)-2-nitro-acetate (1.09 g, 43%) as a yellow oil.

[0534] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.25 mln., ESI+ found [M+H] = 255 Step 2: ethyl spiro[4,6-dihydropyrrole[1,2-c]triazole-5,1'-cyclopentane]-3-carboxylate

[0535] To a solution of ethyl (2E) -2 -(8 -aza spiro [4,4] nonan -7 -ylidene) -2 -nitro -acetate (1.09 g, 4.29 mmol) in acetic acid (13.4 mL) cooled to 0°C was added zinc powder (1.68 g, 25.7 mmol, 6 equiv.). The reaction mixture was heated to RT and stirred for 1 h. After this period of time, the mixture was filtered through Celite, the filtrate was cooled to 0°C, and trifluoroacetic acid (1.13 mL, 15.0 mmol, 3.5 equiv.) was added followed by nitrite. tert-butyl (1.68 mL, 14.1 mmol, 3.3 equiv.). The reaction mixture was heated to RT and stirred for 2 h. After this period of time, water (13.4 mL) was added, and then the entire mixture was concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 70% isopropyl acetate in heptane) to give ethyl spiro[4,6-dihydropyrrole[1,2-c]triazole -5,1'-cyclopentane]-3-carboxylate (0.410 g, 47%).

[0536] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.18 mln., ESI+ found [M+H] = 236 Step 3: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4'H,6'H - spiro [cyclopentane -1,5' -pyrrole [1,2 -c] [1,2,3] triazole] -3' -carboxamide

[0537] To a solution of ethyl spiro [4,6 - dihydropyrrole [1,2 -c] triazole -5,1' - cyclopentane] -3 - carboxylate (0.105 g, 0.45 mmol) dissolved in methanol (1 mL ) 1M aqueous sodium hydroxide (0.893 mL) was added. The reaction mixture was stirred at 50°C for 1 h, then concentrated for drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] ammonium chloride (0.035 g, 0.15 mmol), N,N -diisopropyl ethylamine (0.080 mL, 0.46 mmol), and (7-azabenzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate (0.100 g, 0.18 mmol). The reaction mixture was stirred for 16 h under RT, then directly purified by means of RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid) to thus provide (S) -N -(5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(perfluoroethyl) -1H -pyrazole [3 ,4 -b] pyridine -3 -carboxamide (0.039 g, 66%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.39 (d, J = 8.0 Hz, 1H), 7.53 — 7.46 (m, 1H), 7.38 — 7.19 (m, 3H), 4.84 (dt, J = 11.6, 7.9 Hz, 1H), 4 .61 (dd, J = 11.6, 9.9 Hz, 1H), 4.40 (dd, J = 9.9, 7.7 Hz, 1H), 4.25 (d, J =0.9 Hz, 2H), 3.31 (s, 3H), 2.88 (s, 2H), 1.80 - 1.62 (m, 8H). LC -MS RT = 4.82 mln., m/z = 382.2 (M+H) +.

[0538] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.82 mln., ESI+ found [M+H] = 382.2. (S) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -4'H ,6'H - spiro [cyclopentane -1,5' -pyrrole [1,2 -c] [1,2,3] triazole] -3' -carboxamide

[0539] (S) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 4'H,6'H -spiro[cyclopentane -1,5'-pyrrole[1,2-c][1,2,3]triazole]-3'-carboxamide was prepared from (S)-6- amino -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one according to a METHOD G9, Final step yield: 0.019 g, 30%: 1H NMR (400 MHz, DMSO -d6) δ 8.49 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.32 ( d, J = 2.0 Hz, 1H), 4.43 - 4.27 (m, 2H), 4.25 (d, J = 1.0 Hz, 2H), 4.19 (ddd, J = 14 .6, 12.7, 6.6 Hz, 1H), 3.25 (s, 3H), 2.89 (s, 2H), 2.58 (ddd, J = 12.9, 8.0, 5 .0Hz, 1H), 2.47 - 2.35 (m, 1H), 1.81 - 1.59 (m, 8H). LC - MS RT = 3.80 mln., m/z = 370.2 (M+H) +.

[0540] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.80 mln., ESI+ found [M+H] = 370.2. Example 119 N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -phenyl -5,6 - dihydro -4H -pyrrole[1,2-c] carboxamide

[0541] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -phenyl -5,6 - dihydro -4H -pyrrole [1,2 -c] [1,2,3] triazole -3 - carboxamide was prepared from 4 -phenyl -2 - pyrrolidinone according to METHOD G9. Final step yield: 0.048 g, 78%: 1H NMR (400 MHz, DMSO -d6) δ 8.45 (d, J = 8.1 Hz, 1H), 7.53 - 7.45 (m, 1H) , 7.42 - 7.20 (m, 8H), 4.91 - 4.81 (m, 2H), 4.63 (ddd, J = 11.6, 9.9, 1.5 Hz, 1H) , 4.49 - 4.31 (m, 3H), 3.48 - 3.38 (m, 1H), 3.32 (s, 3H), 3.00 (dd, J = 16.3, 8, 4 Hz, 1H).LC -MS RT = 4.93 mln., m/z = 404.1 (M+H) +.

[0542] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.93 mln., ESI+ found [M+H] = 404.1 Example 120

[0543] (S) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) - 4'H,6'H -spiro[cyclopentane -1,5'-pyrrole[1,2-c][1,2,3]triazole]-3'-carboxamide was prepared according to Method G9,

[0544] 1H NMR (400 MHz, DMSO -d6) â 8.55 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.42 - 7.32 (m, 4H), 7.32 - 7.24 (m, 1H), 6.32 (d, J = 2.0 Hz, 1H), 4.85 (ddd, J = 11.3, 8.1, 3.6 Hz, 1H), 4.50 - 4.27 (m, 3H),

[0545] 4.20 (ddd, J = 14.6, 12.6, 6.6 Hz, 1H), 3.48 - 3.38 (m, 1H), 3.25 (d, J = 1, 6 Hz, 3H), 3.01 (dd, J = 16.4, 8.3 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.48 - 2.37 (m, 1H ).

[0546] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.97 mln., ESI+ found [M+H] = 392.2. Example 121 N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -5 -phenyl -5,6 -dihydro -4H -pyrrole [1,2 -c] [1,2,3] triazole -3 - carboxamide

[0547] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 5-phenyl-5,6-dihydro-4H-pyrrole[1,2-c][1,2,3]triazole-3-carboxamide was prepared from (S)-6-amino-4-methyl-7 ,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) -one and 4 -phenyl -2 -pyrrolidinone according to METHOD G9. Final step yield: 0.013 g, 19%: 1H NMR (400 MHz, DMSO -d6) δ 8.55 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 2.0 Hz , 1H), 7.42 - 7.32 (m, 4H), 7.32 - 7.24 (m, 1H), 6.32 (d, J = 2.0 Hz, 1H), 4.85 ( ddd, J = 11.3, 8.1, 3.6 Hz, 1H), 4.50 - 4.27 (m, 3H),

[0548] 4.20 (ddd, J = 14.6, 12.6, 6.6 Hz, 1H), 3.48 - 3.38 (m, 1H), 3.25 (d, J = 1, 6 Hz, 3H), 3.01 (dd, J = 16.4, 8.3 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.48 - 2.37 (m, 1H ). LC -MS RT = 3.97 mln., m/z = 392.2 (M+H) +.

[0549] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.97 mln., ESI+ found [M+H] = 392.2, Example 122 METHOD G10 (S) -1 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazole [3,4 -d] pyrimidine -6 -carboxamide Step 1: 6-chloro-1-isopropyl-pyrazole[3,4-d]pyrimidine

[0550] To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.417 g, 2.70 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added potassium carbonate (0.745 g, 5.40 mmol, 2 equiv.) and 2-iodine propane (0.540 mL, 5.4 mmol, 2 equiv.). The reaction mixture was stirred for 3 h at 60°C, then diluted with dichloromethane, filtered through Celite, and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 50% isopropyl acetate in heptane) to provide 6-chloro-1-isopropyl-pyrazolo[3,4-d]pyrimidine (0.240 g, 45%) as a white solid. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.11 mln., ESI+ found [M+H] = 197, Step 2: 1-isopropylpyrazole[3,4-d]pyrimidine-6-carbonitrile

[0551] To a solution of sodium cyanide (0.071 g, 1.46 mmol, 1.2 equiv.) in water (1.5 mL) was added 1,4-diazabicyclo[2,2,2]octane (0.025 mL, 0.24 mmol, 0.20000 equiv.), followed by a solution of 6-chloro-1-isopropyl-pyrazolo[3,4-d]pyrimidine (0.240 g, 1.2205 mmol, 1 equiv.) in dimethyl sulfoxide (1.5 mL). The reaction mixture was stirred for 16 h at RT, then diluted with water (50 mL) and extracted with isopropyl acetate (3 x 50 mL). The combined organic layers were washed with brine (75 ml), dried over sodium sulfate, filtered and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 50% isopropyl acetate in heptane) to provide 1-isopropylpyrazole[3,4-d]pyrimidine-6-carbonitrile (0.036 g, 16%) as an orange solid.

[0552] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.14 mln., ESI+ found [M+H] = 188, Step 3: (S) -1 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - pyrazole [ 3,4 -d] pyrimidine -6 -carboxamide

[0553] To a suspension of 1-isopropylpyrazole [3,4-d] pyrimidine-6-carbonitrile (0.036 g, 0.19 mmol) in water (0.5 mL) was added 1M aqueous sodium hydroxide (0.577 mL) . The reaction mixture was stirred at 50°C for 2 h, then concentrated for drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3- chloride yl] ammonium (0.035 g, 0.15 mmol), N,N-diisopropyl ethylamine (0.080 mL, 0.46 mmol), and (7-azabenzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate (0.100 g, 0. 18 mmol). The reaction mixture was stirred for 16 h under RT, then directly purified via RP-HPLC preparation (5 -50% acetonitrile in water + 0.1% formic acid) to give (S) -1 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazole [3,4 -d] pyrimidine -6 - carboxamide (0.028 g, 48%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.46 (s, 1H), 9.13 (d, J = 7 .8 Hz, 1H), 8.51 (s, 1H), 7.58 - 7.49 (m, 1H), 7.39 - 7.24 (m, 3H), 5.27 (p, J = 6.7 Hz, 1H), 4.92 (dt, J = 11.1, 7.9 Hz, 1H), 4.65 - 4.49 (m, 2H), 3.35 (s, 3H), 1.53 (dd, J = 6.7, 0.8 Hz, 6H). LC -MS RT = 4.44 mln., m/z = 381.1 (M+H) +.

[0554] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.44 mln., ESI+ found [M+H] = 381.1 Example 123 N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -phenyl -5,6 - dihydro -8H - [1,2,4] triazolo [5,1 -c] [1,4] oxazine -2 - carboxamide

[0555] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -phenyl -5,6 - dihydro -8H - [1,2,4] triazolo [5,1 -c] [1,4] oxazine -2 - carboxamide was prepared from 5 - phenylmorpholin -3 -one chloride and [(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] ammonium according to METHOD G11. Final step yield: 0.025 g, 39%: 1H NMR (400 MHz, DMSO -d6) δ 8.48 (d, J = 8.0 Hz, 1H), 7.54 - 7.46 (m, 1H) , 7.43 -7.16 (m, 8H), 5.65 (t, J = 4.5 Hz, 1H), 5.13 (d, J = 15.7 Hz, 1H), 5.04 - 4.96 (m, 1H), 4.81 (dt, J = 11.5, 7.9 Hz, 1H), 4.59 (dd, J = 11.6, 9.9 Hz, 1H), 4 .44 - 4.31 (m, 2H), 3.30 (s, 3H). LC -MS RT = 4.57 mln., m/z = 420.1 (M+H) +.

[0556] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.57 mln., ESI+ found [M+H] = 420.1 Example 124 METHOD G11 N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b] [1,2,4] triazole -2 - carboxamide Step 1: 1 -amino -5 -phenyl -pyrrolidin -2 -one

[0557] To a solution of 5-phenylpyrrolidin-2-one (0.200 g, 1.24 mmol) in 1,2-dimethoxyethane (8 mL) was added sodium hydride (60% suspension in mineral oil, 0.099 g, 2 .48 mmol, 2 equiv.). The reaction mixture was stirred for 30 min. under RT, then it was cooled to 0°C. To the cooled mixture was added a solution of O-mesitylene sulfonyl hydroxylamine (0.610 g, 2.83 mmol, 2.3 equiv.) in 1,2-dimethoxyethane (5 mL). The resulting mixture was heated to RT and stirred for 16 h. The reaction was finished with methanol (0.1 mL) and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 7.5% methanol in isopropyl acetate) to provide 1-amino-5-phenyl-pyrrolidin-2-one ( 0.195 g, 89%) as a white solid.

[0558] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.11 mln., ESI+ found [M+H] = 177, Step 2: ethyl 5-phenyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole-2-carboxylate

[0559] To a suspension of 1-amino-5-phenyl-pyrrolidin-2-one (0.150 g, 0.85 mmol) in toluene (1.5 mL) was added acetic acid (0.15 mL, 2.6 mmol, 3 equiv.) followed by ethyl 2-amino-2-thioxo-acetate (0.125 g, 0.94 mmol, 1.1 equiv.). The reaction mixture was heated to 90°C and stirred for 16 h. The mixture was loaded directly onto silica gel and purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to give ethyl 5-phenyl-6,7-dihydro -5H -pyrrole [1,2 -b] [1,2,4] triazole -2 -carboxylate (0.024 g, 11%) in the form of a colorless oil.

[0560] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.09 mln., ESI+ found [M+H] = 258, Step 3: N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) - 5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b] [1,2,4] triazole - 2 -carboxamide

[0561] To a solution of ethyl 5-phenyl-6,7-dihydro-5H-pyrrole [1,2-b] [1,2,4] triazole -2 - carboxylate (0.024 g, 0.09 mmol) in Tetrahydrofuran (0.5 mL) was added 1M aqueous sodium hydroxide (0.187 mL). The reaction mixture was stirred at 50°C for 1 h, then concentrated for drying in vacuum. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazole [1,5-a] [ 1,3] diazepin -5(6H) -one (0.030 g, 0.17 mmol), N,N -diisopropyl ethylamine (0.087 mL, 0.50 mmol), and (7-azabenzotriazole -1-yloxy) hexafluorophosphate tripyrrolidino phosphonium (0.109 g, 0.20 mmol). The reaction mixture was stirred for 16 h under RT, then directly purified via RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid) to give N -( (S) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -5 -phenyl -6, 7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole-2-carboxamide (0.023 g, 34%) as a white solid: 1H NMR (400 MHz, DMSO - d6) δ 8.50 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.44 - 7.32 (m, 3H), 7, 27 - 7.20 (m, 2H), 6.33 (dd, J = 2.0, 1.0 Hz, 1H), 5.57 (dd, J = 8.2, 5.9 Hz, 1H) , 4.41 - 4.24 (m, 2H), 4.24 - 4.12 (m, 1H), 3.24 (d, J = 1.1 Hz, 3H), 3.22 - 3.06 (m, 2H), 3.05 - 2.94 (m, 1H), 2.61 - 2.52 (m, 2H), 2.44 - 2.30 (m, 1H). LC -MS RT = 3.73 mln., m/z = 392.2 (M+H) +.

[0562] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.73 mln., ESI+ found [M+H] = 392.2. Examples 125 and 126

[0563] G12 METHOD

[0564] (R) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b] [1,2,4] triazole -2 -carboxamide and (S) -N -((S) -4 - methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -5 -phenyl -6,7 -dihydro -5H - pyrrole [1,2 -b] [1,2,4] triazole - 2 -carboxamide (1:1)

[0565] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 5-phenyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole-2-carboxamide was further purified via chiral SFC (Lux Cellulose -4 column, 50% methanol + 0.1% isocratic elution of ammonium hydroxide) to provide arbitrarily assigned diastereoisomers (R) -N -((S) - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl) -5 -phenyl -6,7 -dihydro -5H - pyrrole [1,2 -b] [1,2,4] triazole -2 - carboxamide (0.006 g, 9%) and (S) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a] [1 ,3] diazepin -6 -yl) -5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b] [1,2,4] triazole -2 - carboxamide (0.006 g, 9%) in form of white solids:

[0566] Analytical data during the first elution diastereomer (arbitrarily assigned R, S configuration): SFC RT (Lux Cellulose -4 column, 50% methanol + 0.1% ammonium hydroxide isocratic elution, 2.5 min. method): 1.14 mln., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.51 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 2, 0 Hz, 1H), 7.44 - 7.32 (m, 3H), 7.28 - 7.20 (m, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5, 57 (dd, J = 8.2, 5.9 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.32 -4.23 (m, 1H), 4.23 - 4, 13 (m, 1H), 3.24 (s, 3H), 3.21 - 3.14 (m, 1H), 3.14 - 3.04 (m, 1H), 3.04 - 2.93 ( m, 1H), 2.63 - 2.52 (m, 2H), 2.37 (td, J = 12.5, 6.6 Hz, 1H). LCMS RT = 3.76 mln., m/z = 392.2 (M+H)+.

[0567] Analytical data during the second elution diastereomer (arbitrarily assigned S, S configuration): SFC RT: 1.84 mln., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.49 (d , J = 7.7 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.26 - 7.21 (m, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5.57 (dd, J = 8.3, 5.8 Hz, 1H), 4.41 - 4.24 (m, 2H ), 4.24 -4.12 (m, 1H), 3.24 (s, 3H), 3.22 - 3.06 (m, 2H), 3.05 - 2.94 (m, 1H), 2.61 - 2.52 (m, 2H), 2.42 - 2.31 (m, 1H). LCMS RT = 3.76 mln., m/z = 392.2 (M+H)+. Example 127

[0568] METHOD C1 N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -1 - (2,2,2 trifluoroethyl)pyrazole [4,3 -c] pyridine -6 –carboxamide Step 1: 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole[4,3-c]pyridine

[0569] A solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (1.0 g, 5.05 mmol) in N,N-dimethylformamide (9.2 mL) was cooled to 0° C and sodium hydride (60% mass in oil, 0.460 g, 11.5 mmol) was added. After 5 mln., 2,2,2-trifluoroethyl trifluoromethane sulfonate (3.0 g, 12.9 mmol) was added. The reaction was subjected to stirring at 0°C for 10 min. and then heated to RT and stirred for an additional 18 h. The reaction mixture was sealed with a yellow lid and heated under 60°C for 1 h. After cooling to RT, the reaction was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, concentrated for drying in vacuum, and the residue was purified by flash column chromatography (silica gel, 0% to 50% isopropyl acetate - heptane) to provide 6-bromo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (0.925 g, 3.30 mmol, 65% yield): 1H NMR (400 MHz, DMSO -d6) δ 8.95 (s, 1H), 8.47 (s, 1H), 8.20 (s, 1H), 5.47 (q, J = 8.8 Hz, 2H). LRMS RT = 1.25 mln., m/z = 281 (M+H)+. Step 2: N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 -(2,2,2 trifluoroethyl) pyrazole [4,3 -c] pyridine -6 -carboxamide

[0570] Palladium (II) acetate (3.1 mg, 0.0134 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (7.9 mg, 0.0134 mmol), 6-bromo -1 -(2,2,2-trifluoroethyl) pyrazole [4,3 -c] pyridine (75 mg, 0.268 mmol), (3S) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin-4-one (77.2 mg, 0.402 mmol) was added to a screw-capped vial (not subjected to drying). A septum was placed in the vial and secured with electrical tape. Nitrogen was then purged through the glass reaction flask for 15 minutes. The solids were dissolved in toluene (0.53 mL), and triethylamine (0.110 mL, 0.803 mmol) was added. The glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left to stir for 16 h. (NOTE: no solvent remained after heating for 16 h). The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 60% isopropyl acetate in heptane) to give N -[(3S)-5-methyl-4-oxo-2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 -(2,2,2 -trifluoroethyl) pyrazole [4,3 -c] pyridine -6 -carboxamide (102.6 mg, 0.242 mmol, 90% yield) in the form of a yellow solid: 1H NMR (400 MHz, DMSO -d6) δ 9.26 (d, J = 1.2 Hz, 1H), 9.06 (d, J = 8.0 Hz , 1H), 8.59 (d, J = 0.8 Hz, 1H), 8.52 (bs, 1H), 7.57 - 7.47 (m, 1H), 7.40 - 7.24 ( m, 3H), 5.75 - 5.60 (m, 2H), 4.93 (dt, J = 10.8, 8.0 Hz, 1H), 4.62 - 4.48 (m, 2H) , 3.35 (s, 3H). LRMS RT = 5.04 mln., m/z = 420.1 (M+H)+.

[0571] Preparation HPLC Information: Column: Phenomenex Gemini -NX C18 5um, 110A (50 x 30 mm) Mobile Phase: 0.1% ammonium hydroxide in Water (A) / Acetonitrile (B) Gradient Elution Program : 20 to 60% B Pressure: 63 bar (900 psi) Flow rate: 60 mL/min. Column temperature: 25 °C Wavelength: 220 nm Example 128

[0572] METHOD C2

[0573] N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -(tetrahydrofuran -3 -yl ) -1H -pyrazolo [4,3 -c] pyridine -6-carboxamide Step 1: 6 -bromo -1 -(tetrahydrofuran -3 -yl) - 1H -pyrazole [4,3 -c] pyridine

[0574] A suspension of sodium hydride (60% mass in oil, 0.480 g, 12.0 mmol) in N,N-dimethylformamide (9.2 mL) was cooled to 0°C and 6-bromo-1H - pyrazolo[4,3-c]pyridine (1.0 g, 5.05 mmol) was added. After 5 mln., 3-bromotetrahydrofuran (1.80 g, 11.9 mmol) was added. The reaction was stirred at 0°C for 10 ml, heated to RT and stirred for an additional 18 h. Additional sodium hydride (60% mass in oil, 0.230 g, 5.75 mmol) and 3-bromotetrahydrofuran (0.90 g, 5.96 mmol) were added. The reaction was sealed with a yellow lid and heated at 60°C for 4 h. After cooling to RT, the reaction was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, concentrated for drying in vacuum, and the residue was purified by flash column chromatography (silica gel, 0% to 50% isopropyl acetate in heptane ) to provide 6-bromo-1-tetrahydrofuran-3-yl-pyrazolo[4,3-c]pyridine (0.579 g, 2.16 mmol, 43% yield): 1H NMR (400 MHz, DMSO -d6) δ 8.89 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 5.63 - 5.37 (m, 1H), 4.21 - 3.98 (m , 2H), 3.98 - 3.72 (m, 2H), 2.65 - 2.36 (m, 1H), 2.36 - 2.19 (m, 1H). LRMS RT = 1.03 mln., m/z = 269 (M+H)+. Step 2: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 (tetrahydrofuran -3 -yl) -1H -pyrazole [4,3 -c] pyridine -6 -carboxamide

[0575] Palladium (II) acetate (2.6 mg, 0.0112 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (6.6 mg, 0.0112 mmol), 6-bromo -1 -tetrahydrofuran -3 -yl - pyrazolo [4,3 -c] pyridine (60 mg, 0.224 mmol), (3S) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin - 4-one (64.5 mg, 0.336 mmol) was added to a screw-capped vial (not subjected to drying). A septum was placed in the vial and secured with electrical tape. Nitrogen was then purged through the glass reaction flask for 15 minutes. The solids were dissolved in toluene (0.45 mL), and then triethylamine (0.095 mL, 0.671 mmol) was added. The glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left stirring for 17 h. (Note: no solvent remained after heating for 17 h). The crude residue was dissolved in isopropyl acetate, filtered through Celite and concentrated for drying in vacuum. The residue was purified by flash column chromatography (silica gel, 0% to 75% isopropyl acetate in heptane) to provide N-((S)-5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 - (tetrahydrofuran -3 -yl) -1H -pyrazolo [4,3 -c] pyridine -6 -carboxamide (55 mg, 60% yield): 1H NMR (400 MHz, DMSO -d6) δ 9.20 (d, J = 0.8 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.47 - 8.46 (m, 1H), 8.40 - 8.36 (m, 1H), 7.57 - 7.47 (m, 1H), 7.39 - 7.24 (m, 3H), 5 .73 - 5.66 (m, 1H), 4.96 - 4.89 (m, 1H), 4.61 - 4.50 (m, 2H), 4.14 - 4.01 (m, 2H) , 3.96 - 3.82 (m, 2H), 3.35 (s, 3H), 2.51 - 2.39 (m, 1H), 2.34 - 2.19 (m, 1H). LRMS RT = 4.49 mln., m/z = 408.2 (M+H)+.

[0576] Preparation HPLC Information: Column: Phenomenex Gemini -NX C18 5um, 110A (50 x 30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A) / Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 63 bar (900 psi) Flow rate: 60 mL/min. Column temperature: 25 °C Wavelength: 230 nm Examples 129 and 130

[0577] METHOD C3

[0578] 1-Benzyl -N -((1S,4S,7R) -8,8 -difluoro -2 -methyl -3 -oxo -2 -azabicyclo [5,1,0]octan -4 -yl) -1H - 1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -((1R,4S,7S) -8,8 -difluoro -2 -methyl -3 -oxo -2 -azabicyclo [5,1, 0]octan -4 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoic acid

[0579] ((Benzyloxy)carbonyl)-L-lysine (150 g, 535 mmol) was dissolved in water (1.5 L), and the solution was heated to 60°C and adjusted to pH = 9.5 with 4M NaOH, pentacyano(nitroso) disodium “irondiuide” (168 g, 642 mmol) was added slowly with vigorous stirring for 10 min. The reaction mixture was stirred at 60°C and maintained at pH = 9.5 with 4N NaOH for 12 h. The reaction mixture was filtered through a bed of Celite, the filtrate was carefully acidified with hydrochloric acid to pH = 1, and then extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (200 ml), dried over sodium sulfate, filtered and concentrated for drying in vacuum to provide (S)-2-(((benzyloxy)carbonyl)amino acid)-6 -hexanoic hydroxy (260 g, crude) in the form of a brown oil, which was used in the next step without any further purification. Step 2: benzyl(S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxy hexanoate

[0580] A mixture of (S) -2 -(((benzyloxy) carbonyl) amino) -6 -hydroxyhexanoic acid (130 g, 462 mmol), cesium carbonate (75 g, 231 mmol), bromomethylbenzene (79 , g, 462 mmol) in N,N-dimethylformamide (1 L) and the mixture was subjected to stirring at 10 ° C for 18 h under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was diluted with water (5 L), the aqueous phase layer was extracted with ethyl acetate (3 x 1 L). The combined organic was washed with saline solution (200 mL), dried with anhydrous sodium sulfate, filtered and concentrated for drying in vacuum. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 50:1 to 0:1 ethyl acetate in petroleum ether) to provide benzyl (S) -2 -(((benzyloxy) carbonyl)amino)-6-hydroxy hexanoate (222 g, 65%) as a white oil, which was used in the next step without any further purification: HPLC RT = 3.16 min. Step 3: (S)-2-amino-6-hydroxyhexanoic acid

[0581] To a solution of (S) -2 -(((benzyloxy) carbonyl) amino) -6 -hydroxyhexanoate (222 g, 598 mmol) in methanol (1 L) was added 10% Pd/C (20 g) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen [4.46 bar [4.46 bar (50 psi)]] at 50°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated for drying in vacuum to provide (S)-2-amino-6-hydroxyhexanoic acid (85 g, 577 mmol, 97% yield) as a solid colored white, which was used in the next step without any further purification: TLC (Petroleum ether / ethyl acetate=2/1, Rf = 0.45). Step 4: (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxyhexanoic acid

[0582] To a mixture of (S)-2-amino-6-hydroxyhexanoic acid (50 g, 340 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (74 g, 340 mmol) sodium carbonate was added (36 g, 340 mmol) in water (500 mL) and stirred at 10°C for 2 h. The reaction mixture was adjusted to pH = 1 and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated for drying in vacuum. The residue was washed with 2-methoxy-2-methylpropane (300 ml) and dried to provide (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxyhexanoic acid (47 g, 50%) as a white solid, which was used in the next step without any further purification: HPLC RT = 1.83 min. Step 5: (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methylhexanamide

[0583] A mixture of (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxyhexanoic acid (32 g, 115 mmol), 3-(ethylimino methylene amino)-N,N-dimethylpropan -1-amine (33 g, 173 mmol), benzotriazole -1-ol (16 g, 115 mmol) and methanamine (2 M solution in tetrahydrofuran, 144 mL, 287.5 mmol) in tetrahydrofuran (320 mL) were degassed and purged with nitrogen, and the reaction mixture was subjected to stirring at 10 ° C for 2 h under a nitrogen atmosphere. To the reaction mixture, water (200 mL) was added and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 200:1, 50:1 methanol in dichloromethane) to provide (S)-2-(1,3-dioxoisoindolin-2-yl) -6-hydroxy -N -methyl hexanamide (16.5 g, 49% yield), used in the same way in the next step. Step 6: 2 -((3S) -7 -hydroxy -1 -methyl -2 - oxoazepan -3 -yl) isoindoline -1,3 -dione

[0584] To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methylhexanamide (13.8 g, 48 mmol) in dimethyl sulfoxide (84 mL) was added triethylamine ( 24 g, 238 mmol, 33 mL) and pyridine trioxide sulfur complex (38 g, 238 mmol) at 0°C under an argon atmosphere and the mixture was subjected to stirring at 10 -20°C for 2.5 h . The reaction mixture was quenched with water and treated with 1N HCl, and then extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated for drying in vacuum to provide 2-((3S)-7-hydroxy-1-methyl-2-oxoazepan-3-yl)isoindoline - 1,3-dione (21.2 g, crude) in the form of an off-white oil, which was used in the next step without any further purification: TLC (dichloromethane / Methanol = 10/1, Rf = 0.43 ). Step 7: (S)-2 -(1-methyl -2 -oxo -2,3,4,5 - tetrahydro -1H -azepin -3 -yl) isoindoline -1,3 -dione

[0585] A solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methyl hexanamide (21.2 g, 73 mmol) and p-toluenesulfonic acid monohydrate (839 mg, 4.4 mmol) in toluene (200 mL) was stirred under reflux for 1.5 h. After allowing cooling to RT, the reaction mixture was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated for drying in vacuum. The residue was washed with ethyl acetate (10 mL) and dried to provide (S)-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-azepin-3- il) isoindoline -1,3 -dione (4.6 g, 23%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 5.52, 3, 01 Hz, 2H), 7.71 - 7.77 (m, 2H), 5.96 (dd, J = 9.03, 1.51 Hz, 1H), 5.35 - 5.45 (m, 1H ), 5.04 (dd, J = 10.79, 3.26 Hz, 1H), 3.10 (s, 3H), 2.46 - 2.57 (m, 1H), 2.23 - 2, 40 (m, 2H), 1.61 (s, 1H). Step 1: 2 -((4S) -8,8 -difluoro -2 -methyl -3 - oxo -2 -azabicyclo [5,1,0]octan -4 -yl)isoindoline -1,3 - dione

[0586] A solution of sodium chlorodifluoro acetate (1.42 g, 9.25 mmol) in diglyme (5.9 mL) was added dropwise to a refluxed solution of 2 - [(3S) -1 -methyl -2 -oxo -4,5 -dihydro -3H -azepin -3 -yl] isoindoline -1,3 -dione (0.250 g, 0.925 mmol) in diglyme (10 mL) for 25 minutes. After addition, the reaction was allowed to stir for an additional 10 minutes under reflux. After cooling to RT, the reaction mixture was concentrated to drying in vacuum and the residue was purified by flash column chromatography (silica gel, 0% to 70% isopropyl acetate in heptane) to give 2 - [(4S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5,1,0]octan-4-yl] isoindoline-1,3-dione (0.270 g, 0.843 mmol, 91 % yield) in the form of an inseparable ~6.8:1 mixture of diastereomers: 1H NMR (400 MHz, Chloroform -d) δ (main isomer) 7.90 - 7.81 (m, 2H), 7.75 - 7.70 (m, 2H), 5.44 (dd, J = 11.6, 8.0 Hz, 1H), 3.66 -3.30 (m, 1H), 3.26 - 3.11 (m, 1H), 3.02 (s, 3H), 2.25 - 2.15 (m, 1H), 2.04 - 1.90 (m, 2H), 1.85 - 1.72 (m , 1H). LRMS RT = 1.29 mln., m/z = 321 (M+H)+. Step 2: 1-benzyl -N -((1S,4S,7R) -8,8 -difluoro -2 -methyl -3 -oxo -2 -azabicyclo [5,1,0]octan -4 -yl) -1H - 1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -((1R,4S,7S) -8,8 -difluoro -2 -methyl -3 -oxo -2 -azabicyclo [5,1, 0]octan -4 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0587] Hydrazine (0.087 mL, 2.72 mmol) was added to a solution of 2 - [(4S) -8,8 -difluoro -6 - methyl -5 -oxo -6 -azabicyclo [5,1,0] octan -4 -yl] isoindoline -1,3 -dione e (~6.8:1 dr, 0.290 g, 0.905 mmol) in ethanol (9.1 mL). The reaction was heated under 80°C for 2 h. After cooling to RT, the reaction was filtered through a short block of Celite using ethanol. The filtrate was concentrated for drying in vacuum to provide (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[5.1.0]octan-5-one (88.9 mg, 0.467 mmol, 51.6% yield). The crude residue was used in the next step without further purification.

[0588] (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.138 g, 0.254 mmol) was added to a solution of (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo [5,1,0]octan -5 -one (44 mg, 0.231 mmol), 1 -benzyl -1,2,4 -triazole -3 - carboxylic acid (58 mg, 0.289 mmol), and N,N - diisopropylethylamine (0.120 mL, 0.694 mmol), in N,N - dimethylformamide (2.3 mL). The reaction was allowed to stir at RT for 18 h before being concentrated for drying in vacuum. The crude residue was purified by reverse phase preparation HPLC to provide 1-benzyl-N-((1S,4S,7R)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo [5,1,0]octan -4 - yl) -1H -1,2,4 -triazole -3 -carboxamide assigned arbitrarily (56.7 mg, 0.151 mmol, 65% yield) and 1 -benzyl -N - ((1R,4S,7S) -8,8 -difluoro -2 -methyl -3 -oxo -2 -azabicyclo [5,1,0]octan -4 -yl) -1H -1,2,4 -triazole - 3-carboxamide (5.7 mg, 6.6%): 1-benzyl -N -((1S,4S,7R) - 8,8 -difluoro -2 -methyl -3 -oxo -2 -azabicyclo [5, 1,0]octan -4 -yl) -1H -1,2,4 -triazole -3 -carboxamide (assigned arbitrarily): 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8 .19 (m, 2H), 7.45 - 7.20 (m, 5H), 5.49 (s, 2H), 5.00 (dt, J = 10.8, 7.2 Hz, 1H), 3.72 — 3.49 (m, 1H), 2.90 (s, 3H), 2.43 - 1.96 (m, 4H), 1.61 (m, 1H), 1.27 (m, 1H). LRMS RT = 4.18 mln., m/z = 376.1 (M+H)+.

[0589] Preparation HPLC Information: Column: Phenomenex Gemini -NX C18 5um, 110A (50 x 30 mm) Mobile Phase: 0.1% ammonium hydroxide in water (A) / Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 56.17 bar (800 psi) Flow rate: 60 mL/min. Column temperature: 25 °C Wavelength: 210 nm e 1 -benzyl -N -((1R,4S,7S) -8,8 -difluoro -2 - methyl -3 -oxo -2 -azabicyclo [5.1 ,0]octan -4 -yl) -1H - 1,2,4 -triazole -3 -carboxamide (assigned arbitrarily): 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8, 58 (d, J = 4.4 Hz, 1H), 7.43 - 7.27 (m, 5H), 5.48 (s, 2H), 4.43 - 4.33 (m, 1H), 3 .27 - 3.14 (m, 1H), 2.80 (s, 3H), 2.55 - 2.43 (m, 1H), 2.10 - 2.00 (m, 3H), 1.30 - 1.10 (m, 1H). LRMS RT = 3.90 mln., m/z = 376.1 (M+H)+.

[0590] Preparation HPLC Information: Column: Phenomenex Gemini -NX C18 5um, 110A (50 x 30 mm) Mobile Phase: 0.1% ammonium hydroxide in water (A) / Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 56.17 bar (800 psi) Flow rate: 60 mL/min. Column temperature: 25 °C Wavelength: 210 nm Example 131 and 132

[0591] METHOD C3 & C4 Ethyl ( 1S , 4S , 7S , 8R )-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo [5 ,1,0]octane -8 -carboxylate and ethyl (1R,4S,7R,8S) -4 -(1 - benzyl -1H -1,2,4 -triazole -3 -carboxamido) -2 -methyl -3 - oxo -2 -azabicyclo [5,1,0]octane -8 -carboxylate Step 1: ethyl (4S)-4-(1,3-dioxoisoindolin-2-yl)-2-methyl-3-oxo-2-azabicyclo[5,1,0]octane-8-carboxylate

[0592] A solution of ethyl diazoacetate (15% mass in toluene, 1.3 mL, 1.5 mmol) in dichloromethane (3 mL) was added dropwise to a solution of 2-[(3S)-1-methyl -2 -oxo -4,5 -dihydro -3H -azepin -3 -yl] isoindoline -1,3 - dione (0.20 g, 0.74 mmol) and rhodium (II) acetate (6.9 mg, 0.030 mmol) in dichloromethane (5.2 mL) over a period of 4 h. The reaction was then allowed to stir for an additional 12 h. The reaction was then filtered through Celite using isopropyl acetate. The filtrate was concentrated to drying in vacuum and the residue was purified by flash column chromatography (silica gel, 0% to 70% isopropyl acetate in heptane) to give ethyl (4S)-4-(1.3 - dioxoisoindolin -2 -yl) -6 -methyl -5 -oxo -6 -azabicyclo [5,1,0]octane -8 -carboxylate (0.145 g, 0.407 mmol, 55% yield). LRMS RT = 1.28 mln., m/z = 357 (M+H) + . Step 2: ethyl (1S,4S,7S,8R) -4 -(1-benzyl -1H - 1,2,4 -triazole -3 -carboxamido) -2 -methyl -3 -oxo -2 - azabicyclo [5, 1.0]octane -8 -carboxylate and ethyl (1R,4S,7R,8S) -4 -(1-benzyl -1H -1,2,4 -triazole -3 - carboxamido) -2 -methyl -3 -oxo -2 -azabicyclo [5,1,0]octane -8 -carboxylate

[0593] Hydrazine (0.040 mL, 1.18 mmol) was added to a solution of ethyl (4S)-4-(1,3-dioxoisoindolin-2-yl)-6-methyl-5-oxo-6-azabicyclo [5,1,0]octane-8-carboxylate (0.140 g, 0.393 mmol) in ethanol (3.9 mL). The reaction was heated under 80°C for 2 h. After cooling to RT, the reaction was filtered through a short block of Celite using ethanol. The filtrate was concentrated for drying in vacuum and the residue was subjected to the next step without any further purification.

[0594] (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.235 g, 0.432 mmol) was added to a solution of the crude residue, 1-benzyl-1,2,4-triazole-3-carboxylic acid (99 .8 mg, 0.491 mmol), and N,N-diisopropyl ethylamine (0.21 mL, 1.18 mmol), in N,N-dimethylformamide (3.9 mL). The reaction was allowed to stir at RT for 18 h before being concentrated for drying in vacuum. The crude residue was purified by reverse phase preparation HPLC to provide ethyl (1S,4S,7S,8R)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido) -2 -methyl -3 - oxo -2 -azabicyclo [5,1,0]octane -8 -carboxylate arbitrarily assigned (23.5 mg, 0.057 mmol, 14.5% yield) and ethyl (1R,4S,7R ,8S) -4 -(1-benzyl -1H -1,2,4 -triazole -3 -carboxamido) -2 -methyl -3 -oxo -2 -azabicyclo [5,1,0]octane -8 -carboxylate ( 15.6 mg, 0.038 mmol, 9.7% yield).

[0595] Ethyl (1S,4S,7S,8R) -4 -(1-benzyl -1H -1,2,4 -triazole -3 -carboxamido) -2 -methyl -3 -oxo -2 -azabicyclo [5, 1.0]octane -8 -carboxylate: 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.46 - 7.19 (m, 4H), 5.49 (s, 2H), 5.07 (dt, J = 10.8, 7.2 Hz, 1H), 4.09 (m, 2H), 3.41 - 3.20 (m, 1H), 2.85 (s, 3H), 2.30 - 2.12 (m, 2H), 2.01 - 1.77 (m, 2H), 1.60 - 1 .43 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.15 - 0.95 (m, 1H). LRMS RT = 4.19 mln., m/z = 412.2 (M+H)+.

[0596] Preparation HPLC Information: Column: Es Industries Pyridyl Amide (150 x 30 mm) Mobile Phase: Carbon dioxide (A) / Methanol w/ 0.1% ammonium hydroxide (B) Gradient Elution Program: 5 to 60% B Pressure: 173.38 bar (2500 psi) Flow rate: 100 mL/min. Column temperature: 40 °C Wavelength: 254 nm

[0597] Ethyl (1R,4S,7R,8S) -4 -(1-benzyl -1H -1,2,4 -triazole -3 -carboxamido) -2 -methyl -3 -oxo -2 -azabicyclo [5, 1.0]octane -8 -carboxylate: 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.43 - 7.27 (m, 5H), 5.49 (s, 2H), 4.98 (dt, J = 11.2, 7.6 Hz, 1H), 4.16 - 4.02 (m, 2H) , 3.38 - 3.27 (m, 1H), 2.74 (s, 3H), 2.30 -2.22 (m, 1H), 2.16 - 1.94 (m, 2H), 1 .97 - 1.83 (m, 2H), 1.80 - 1.74 (m, 1H), 1.68 -1.61 (m, 1H), 1.20 (t, J = 7.2 Hz , 3H). LRMS RT = 4.22 mln., m/z = 412.2 (M+H)+.

[0598] Preparation HPLC Information: Column: Es Industries Pyridyl Amide (150 x 30 mm) Mobile Phase: Carbon dioxide (A) / Methanol w/ 0.1% Ammonium hydroxide (B) Elution Program Gradient: 5 at 60% B Pressure: 173.38 bar (2500 psi) Flow rate: 100 mL/min. Column temperature: 40 °C Wavelength: 254 nm Example 133

[0599] METHOD X1 5-benzyl -N -(1-methyl -2 -oxo - 2,3,4,5,8,9,10,11 -octahydro -1H - [1,3] diazepine [1,2 -b] indazole - 3 -yl) -4H -1,2,4 -triazole -3 -carboxamide Step 1: 4,5,6,7 -tetrahydro -2H -indazole -3 -amine

[0600] To a solution of 2-oxocycle hexanecarbonitrile (1.71 g, 13.2 mmol) in toluene (23 mL) hydrazine (0.485 mL, 14.5 mmol) was added, and the reaction was subjected to stirring under 85 °C for 5 h. The reaction mixture was concentrated for drying in vacuum and the residue was used in the next step without any further purification: LCMS RT = 0.80 min.; m/z = 138 (M + H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.). Step 2: N -(4,5,6,7 -tetrahydro -2H -indazol -3 -yl)formamide

[0601] 3-Amino-4,5,6,7-tetrahydro-1H-indazole (1.10 g, 7.7 mmol) and formic acid (4.7 mL, 120 mmol) were mixed together, and the reaction was subjected to stirring under 110°C for 3 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 -15% methanol in dichloromethane) to give N - (4,5,6, 7-tetrahydro-2H-indazol-3-yl)formamide (1.143 g, 90% yield) as a yellow solid: 1H NMR (400 MHz, DMSO -d6) δ 11.92 (s, 1H) , 9.85 (dd, J = 7.9, 3.4 Hz, 1H), 8.51 (d, J = 11.0 Hz, 0.55H), 8.08 (d, J = 1.7 Hz, 0.35H), 2.54 — 2.50 (m, 2H), 2.32 (td, J = 6.0, 1.9 Hz, 2H), 1.77 - 1.55 (m, 4H), tautomers were found in NMR; LCMS RT = 1.43 min.; m/z = 166 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.). Step 3: N -methyl -4,5,6,7 -tetrahydro -2H - indazol -3 -amine

[0602] To a solution of N -(4,5,6,7-tetrahydro-1H-indazol-3-yl)formamide (2.08 g, 12.6 mmol) in tetrahydrofuran (120 mL) was added hydride lithium and aluminum (2 mol/L) in tetrahydrofuran (20.0 mL, 40.0 mmol) under 0 ° C, and the reaction was subjected to stirring under 25 ° C for 6 h. Sodium sulfate decahydrate was added, and the mixture was stirred for 18 h. The mixture was filtered through celite, and ethyl acetate was used to rinse the solid. The combined liquid layer was concentrated for drying in vacuum to provide N-methyl-4,5,6,7-tetrahydro-1H-indazol-3-amine (2.03 g, 106% yield) as an oil colorless that was used without any further purification: 1H NMR (400 MHz, DMSO -d6) δ 10.83 (s, 1H), 4.54 (s, 1H), 2.64 (d, J = 5.3 Hz , 3H), 2.45 - 2.37 (m, 2H), 2.23 - 2.15 (m, 2H), 1.69 - 1.56 (m, 4H); LCMS RT = 1.30 min.; m/z = 152 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.). Step 4: 4-chloro-N-(1-(4-chlorobutanoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-N-methylbutanamide

[0603] To a solution of N -methyl -4,5,6,7 - tetrahydro -1H -indazol -3 -amine (2.03 g, 13.4 mmol) and N,N -dimethylpyridin -4 -amine ( 163.7 mg, 1.340 mmol) in dichloromethane (53 mL) and N,N-diisopropylethylamine (5.84 mL) was added 4-chlorobutyryl chloride (3.462 mL, 30.82 mmol) under 0°C, and the reaction was subjected to stirring at 0°C for 30 min, then at 25°C for 8 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in heptane) to provide 4-chloro-N-[ 1-(4-chlorobutanoyl)-4,5,6,7-tetrahydroindazol-3-yl]-N-methyl-butanamide (3.44 g, 71% yield) in the form of an oil: LCMS RT = 3, 11 min.; m/z = 360 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 5: 4-chloro-N-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-3-yl)butanamide

[0604] To a solution of 4-chloro-N-[1-(4-chlorobutanoyl)-4,5,6,7-tetrahydroindazol-3-yl]-N-methyl-butanamide (3.44 g, 9. 55 mmol) in ethanol (17 mL), sodium hydroxide (1 mol/L) in water (9.5 mL, 9.55 mmol) was added, and the reaction was stirred at 25 ° C for 5 min. The reaction mixture was concentrated to drying in vacuum and the residue was used without further purification: LCMS RT = 2.10 min.; m/z = 256 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 6: 1 -methyl -4,5,8,9,10,11 -hexahydro -1H - [1,3] diazepine [1,2 -b] indazole -2(3H) -one

[0605] To a solution of 4-chloro-N-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-3-yl)butanamide (2.81 g, 11.0 mmol) in N ,N-dimethylformamide (49 mL) was added cesium carbonate (5.37 g, 16.5 mmol), and the reaction was stirred under 65 ° C for 18 h. The reaction mixture was diluted with ethyl acetate and water, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 -100% ethyl acetate in heptane) to give 1 -methyl - 4,5,8,9,10,11 -hexahydro - 3H - [1,3] diazepine [1,2 -b] indazol -2 -one (2.03 g, 63% yield) as a white solid: 1H NMR (400 MHz, Chloroform -d) δ 4.18 (t, J = 6.7 Hz, 2H), 3.24 (s, 3H), 2.65 (dd, J = 6.4, 5.6 Hz, 2H), 2.53 - 2.42 (m, 2H), 2.42 - 2.25 (m, 4H), 1.90 - 1.74 (m, 4H); 1H NMR (400 MHz, DMSO -d6) δ 4.13 - 4.04 (m, 2H), 2.73 (d, J = 0.6 Hz, 3H), 2.56 - 2.47 (m, 2H), 2.43 (t, J = 5.9 Hz, 2H), 2.23 - 2.07 (m, 4H), 1.79 - 1.61 (m, 4H); LCMS RT = 1.78 min.; m/z = 220 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 7: 3 -iodo -1 -methyl -4,5,8,9,10,11 - hexahydro -1H - [1,3] diazepine [1,2 -b] indazole -2(3H) - one

[0606] To a solution of 1-methyl -4,5,8,9,10,11 - hexahydro -3H - [1,3] diazepine [1,2 -b] indazol -2 -one (1.00 g , 3.42 mmol) in dichloromethane (29 mL) was added N,N,N',N'-tetramethyl ethylenediamine (3.09 mL, 20.5 mmol) under -10°C (salt bath/ice 1/ 1), followed by fresh iodotrimethylsilane (2.93 mL, 20.5 mmol), and the reaction was subjected to stirring in a salt/ice bath (under -10 ~ -15°C) for 1.5 h. Iodine (2.60 g, 10.3 mmol) was added, and the reaction was subjected to stirring in a salt/ice bath (under -10 ~ -15°C) for 2 h. the crude mixture was diluted with ethyl acetate and sodium sulfite, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 -70% ethyl acetate in dichloromethane) to give 3-iodo -1 - methyl -4,5,8,9,10 ,11-hexahydro -3H - [1,3] diazepine [1,2 -b] indazol -2 -one (0.87 g, 74% yield) as a white powder: 1H NMR (400 MHz , Chloroform -d) δ 4.56 (dd, J = 9.3, 7.7 Hz, 1H), 4.23 - 4.13 (m, 2H), 3.29 (s, 3H), 3, 02 - 2.89 (m, 1H), 2.81 - 2.70 (m, 1H), 2.69 - 2.62 (m, 2H), 2.53 - 2.43 (m, 2H), 1.93 - 1.69 (m, 4H); 1H NMR (400 MHz, DMSO -d6) δ 4.56 (dd, J = 8.7, 7.8 Hz, 1H), 4.14 - 4.07 (m, 2H), 3.17 (s, 3H), 2.91 - 2.77 (m, 1H), 2.62 - 2.54 (m, 1H), 2.47 - 2.39 (m, 2H), 1.82 - 1.63 ( m, 4H); LCMS RT = 1.25 min.; m/z = 346 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 8: 3 -azide -1 -methyl -4,5,8,9,10,11 - hexahydro -1H - [1,3] diazepine [1,2 -b] indazole -2(3H) - one

[0607] To a solution of 3 -iodo -1 -methyl - 4,5,8,9,10,11 -hexahydro -3H - [1,3] diazepine [1,2 -b] indazol -2 -one ( 880 mg, 2.55 mmol) in N,N-dimethylformamide (3.0 mL) sodium azide (222 mg, 3.3142 mmol) was added, and the reaction was stirred at 25°C for 4 h . The crude mixture was diluted with ethyl acetate and water, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was used without further purification: LCMS RT = 2.10 min.; m/z = 261 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 9: 3 -amino -1 -methyl -4,5,8,9,10,11 - hexahydro -1H - [1,3] diazepine [1,2 -b] indazole -2(3H) - one

[0608] To a solution of 3-azide -1 -methyl - 4,5,8,9,10,11 -hexahydro -3H - [1,3] diazepine [1,2 -b] indazol -2 -one ( 330 mg, 1.27 mmol) in tetrahydrofuran (5.3 mL) and water (1.2 mL) was added triphenylphosphine, bound to the polymer (7.61 mmol), and the reaction was subjected to stirring at 25°C for 6 p.m. The crude mixture was filtered through celite, and concentrated to drying in vacuum. The crude residue was used without further purification: LCMS RT = 1.39 min.; m/z = 235 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 10: 5-Benzyl -N -(1-methyl -2 -oxo - 2,3,4,5,8,9,10,11 -octahydro -1H - [1,3] diazepine [1,2 -b ] indazol -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[0609] To a solution of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (32 mg, 0.16 mmol) in N,N-dimethylformamide (0.1 mL) and acetonitrile ( 0.25 mL) hexafluorophosphate 1 - [bis(dimethylamino) methylene] -1H - 1,2,3 -triazolo [4,5 -b] pyridinium 3 -oxide (62 mg, 0.16 mmol) was added under 0° C, and the reaction was subjected to stirring at 0°C for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepine[1,2-b]indazol-2-one (25 mg, 0) was then added. .11 mmol). The reaction was subjected to stirring at 25°C for 18 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by RP-HPLC to provide 5-benzyl-N-(1-methyl-2-oxo-4,5,8,9,10,11 -hexahydro -3H - [1,3] diazepine [1,2 -b] indazol -3 -yl) -4H -1,2,4 - triazole -3 -carboxamide (11 mg, 25% yield) in the form of a white powder: 1H NMR (400 MHz, DMSO -d6) δ 8.30 (d, J = 7.7 Hz, 1H), 7.38 - 7.16 (m, 5H), 4.35 - 4.08 (m, 3H), 4.06 (s, 2H), 3.19 (s, 3H), 2.65 - 2.51 (m, 3H), 2.49 - 2.40 (m, 2H), 2.27 - 2.16 (m, 1H), 1.87 - 1.59 (m, 4H); LCMS RT = 4.15 min.; m/z = 420.2 (M+H)+. Example 134

[0610] METHOD X2 1-Benzyl -N -(2 -(2,2-difluorocyclopropyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: N - [5 - (2,2 -difluorocyclopropyl) -1H - pyrazol -3 -yl]formamide

[0611] To a solution of 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine (1.01 g, 6.35 mmol) in toluene (9.40 mL) was added formic acid (3. 8 mL), and the reaction was stirred at 110°C for 3 h. The crude mixture was concentrated for drying in vacuum, and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in dichloromethane) to give N - [5 -( 2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide (420 mg, 35% yield) as a light brown solid: 1H NMR (400 MHz, DMSO -d6) δ 12.42 ( s, 1H), 10.47 (s, 0.70H), 10.10 (s, 0.30H), 8.62 (d, J = 11.0 Hz, 0.30H), 8.14 (d , J = 1.8 Hz, 0.80H), 6.39 (s, 0.70H), 5.90 (d, J = 1.9 Hz, 0.30H), 3.04 - 2.85 ( m, 1H), 2.15 - 2.00 (m, 1H), 1.96 - 1.81 (m, 1H); tautomers were found in NMR; LCMS RT = 1.18 min.; m/z = 188 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 2: 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine

[0612] To a solution of N - [5 - (2,2 - difluorocyclopropyl) -1H -pyrazol -3 -yl]formamide (787 mg, 4.2 mmol) in tetrahydrofuran (37 mL) was added lithium hydride and aluminum (2 mol/L) in tetrahydrofuran (6.38 mL, 12.6 mmol) under 0 ° C, and the reaction was subjected to stirring under 25 ° C for 6 h. Sodium sulfate decahydrate was added, and the mixture was stirred for 18 h. The mixture was filtered through celite, and ethyl acetate was used to rinse the solid. The liquid combined layer was concentrated for drying in vacuum to provide 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (950 mg) as a colorless oil which was used without any further purification: 1H NMR (400 MHz, DMSO -d6) δ 11.45 (s, 1H), 5.23 (bs, 1H), 2.81 - 2.66 (m, 1H), 2.61 (d, J = 5.3 Hz, 3H), 1.98 - 1.87 (m, 1H), 1.77 - 1.65 (m, 1H); LCMS RT = 1.06 min.; m/z = 174 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 3: 4-chloro-N-(1-(4-chlorobutanoyl)-5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

[0613] To a solution of 5 -(2,2 - difluorocyclopropyl) -N -methyl -1H -pyrazol -3 -amine (810 mg, 4.7 mmol) and N,N -dimethylpyridin -4 -amine (57 mg , 0.47 mmol) in dichloromethane (19 mL) and N,N-diisopropylethylamine (2.0 mL, 12 mmol) was added 4-chlorobutyl chloride (1.2 mL, 10 mmol) under 0°C, and at reaction was subjected to stirring under 0~25°C for 18 h. The reaction mixture was concentrated to drying in vacuum and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in heptane) to give 4-chloro-N -(1 -(4-chlorobutanoyl) -5 -(2,2 - difluorocyclopropyl) -1H -pyrazol -3 -yl) -N - methylbutanamide (332 mg, 56% yield): 1H NMR (400 MHz, DMSO - d6) δ 6.86 (s, 1H), 3.74 (t, J = 6.5 Hz, 2H), 3.71 - 3.62 (m, 2H), 3.43 - 3.33 (m , 2H), 3.23 (t, J = 7.3 Hz, 2H), 2.73 - 2.62 (m, 2H), 2.18 - 1.87 (m, 6H), CH3 was not observed in NMR, probably by overlap with the HDO peak at 3.30 ppm; LCMS RT = 3.07 min.; m/z = 382 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 4: 4-chloro-N-(5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methyl butanamide

[0614] To a solution of 4-chloro-N-[1-(4-chlorobutanoyl)-5-(2,2-difluorocyclopropyl) pyrazol-3-yl]-N-methyl-butanamide (332 mg, 0.87 mmol) in ethanol (1.4 mL), sodium hydroxide (1 mol/L) in water (0.87 mL) was added, and the reaction was stirred at 25°C for 5 min. The reaction mixture was concentrated to drying in vacuum and the residue was used without further purification: LCMS RT = 2.03 min.; m/z = 278 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 5: 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

[0615] To a solution of 4-chloro-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (240 mg, 0.86 mmol) in N, N -dimethylformamide (3.9 mL) was added cesium carbonate (422 mg, 1.30 mmol), and the reaction was stirred under 65 ° C for 18 h. The crude mixture was diluted with ethyl acetate and citric acid solution (10% aq.), and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-75% ethyl acetate in dichloromethane) to provide 2-(2,2-difluorocyclopropyl)-4-methyl-7, 8-dihydro-6H-pyrazole[1,5-a][1,3]diazepin-5-one (118 mg, 56% yield) in the form of a colorless oil: 1H NMR (400 MHz, DMSO -d6) δ 6.18 - 6.13 (m, 1H), 4.21 - 4.12 (m, 2H), 3.15 (s, 3H), 2.86 (td, J = 12.1, 8, 0 Hz, 1H), 2.27 - 2.17 (m, 4H), 2.03 - 1.90 (m, 1H), 1.88 - 1.75 (m, 1H); LCMS RT = 1.70 min.; m/z = 242 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 6: 2 -(2,2-difluorocyclopropyl) -6 -iodo - 4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[0616] To a solution of 2 -(2,2 - difluorocyclopropyl) -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (118 mg , 0.49 mmol) in dichloromethane (4.0 mL) cooled to -10°C in a salt/ice bath was added N,N,N',N'-tetramethyl ethylenediamine (0.44 mL, 2.9 mmol), followed by iodotrimethylsilane (0.42 mL, 2.9 mmol), and the reaction was stirred under -10 ° C for 1.5 h. Iodine (372 mg, 1.47 mmol) was added, and the reaction was stirred for 2 h. The crude mixture was diluted with ethyl acetate and sodium sulfite solution, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% ethyl acetate in heptane) to provide 2-(2,2-difluorocyclopropyl)-6-iodine-4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (53 mg, 29% yield) as a white solid: 1H NMR ( 400 MHz, Chloroform -d) δ 5.95 (dd, J = 2.4, 1.1 Hz, 1H), 4.62 (ddd, J = 9.2, 7.4, 4.7 Hz, 1H ), 4.31 - 4.14 (m, 2H), 3.33 (s, 3H), 3.05 - 2.89 (m, 1H), 2.84 - 2.67 (m, 2H), 1.91 - 1.76 (m, 1H), 1.78 - 1.65 (m, 1H); LCMS RT = 2.15 min.; m/z = 368 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 7: 6-azide -2 -(2,2-difluorocyclopropyl) -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[0617] To a solution of 2 -(2,2-difluoro cyclopropyl) -6 -iodo -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (53 mg, 0.14 mmol) in N,N-dimethylformamide (0.20 mL) was added sodium azide (11.6 mg, 0.17 mmol), and the reaction was stirred under 25 °C for 2 h. The crude mixture was used without further purification: LCMS RT = 2.06 min.; m/z = 283 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 8: 6-amino -2 -(2,2-difluorocyclopropyl) -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[0618] To a solution of 6-azide -2 -(2,2-difluorocyclopropyl)-4-methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (41 mg, 0.14 mmol) in tetrahydrofuran (0.5 mL) and water (0.15 mL) polymer-binding triphenylphosphine (0.87 mmol) was added, and the reaction was subjected to stirring under 25 °C for 18 h. The crude mixture was filtered through celite, and concentrated to drying in vacuum. The crude material was used without further purification: LCMS RT = 1.19 min.; m/z = 257 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 9: 1-benzyl -N - [2 -(2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepine -6 -yl] -1,2,4 -triazole -3 -carboxamide

[0619] To a solution of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (62 mg, 0.29 mmol) in N,N-dimethylformamide (1.0 mL) was added 1 - [bis(dimethylamino) methylene] -1H -1,2,3 -triazolo [4,5 -b] pyridinium 3 -oxid hexafluorophosphate (112 mg, 0.29 mmol) under 0 ° C, and the reaction was subjected to stirring at 0°C for 20 min. 6-Amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (37 mg) was added. , 0.14 mmol, 37 mg). The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 1-benzyl-N-[2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole[ 1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (36.5 mg, 57%) in the form of a white powder: 1H NMR ( 400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.44 - 7.25 (m, 5H), 6.34 - 6.23 (m, 1H), 5.48 (s, 2H), 4.36 - 4.25 (m, 2H), 4.23 - 4.09 (m, 1H), 3.22 (d, J = 2.1 Hz, 3H), 2.99 - 2.78 (m, 1H), 2.67 - 2.53 (m, 1H), 2.44 - 2.31 (m, 1H), 2 .02 - 1.80 (m, 2H); LCMS RT = 4.36 min.; m/z = 442.2 (M+H)+. Example 135

[0620] METHOD X3 Step 1: 1-benzyl -N -(1-methyl -2 -oxo - 2,3,4,5,8,9,10,11 -octahydro -1H - [1,3] diazepine [1,2 -b ] indazol -3 -yl) -1H -1,2,3 -triazole -4 -carboxamide

[0621] To a solution of 1-benzyl-1H-1,2,3-triazole-4-carboxylic acid (75 mg, 0.35 mmol) in N,N-dimethylformamide (1.0 mL) was added 1 -[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (136 mg, 0.35 mmol) under 0°C, and the reaction was subjected to stirring at 0°C for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepine[1,2-b]indazol-2-one (41 mg, 0 .17 mmol). The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H- [1,3] diazepine [1,2 -b] indazol -3 -yl) -1H -1,2,3 -triazole -4 -carboxamide (42 mg, 57% yield) in the form of a white powder : 1H NMR (400 MHz, DMSO -d6) δ 8.65 (s, 1H), 8.49 (d, J = 7.7 Hz, 1H), 7.46 - 7.25 (m, 5H), 5.65 (s, 2H), 4.41 - 4.03 (m, 3H), 3.18 (s, 3H), 2.59 - 2.51 (m, 3H), 2.48 - 2, 40 (m, 2H), 2.35 - 2.22 (m, 1H), 1.86 - 1.57 (m, 4H); LCMS RT = 4.55 min.; m/z = 420.2 (M+H)+. Example 136 Step 1: 1-benzyl -N -(1-methyl -2 -oxo - 2,3,4,5,8,9,10,11 -octahydro -1H - [1,3] diazepine [1,2 -b ] indazol -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0622] To a solution of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (75 mg, 0.35 mmol) in N,N-dimethylformamide (1.0 mL) hexafluorophosphate was added of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid (136 mg, 0.35 mmol) under 0°C, and the reaction was subjected stirring at 0°C for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepine[1,2-b]indazol-2-one (41 mg, 0 .17 mmol). The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 1-benzyl-N-(1-methyl-2-oxo-4,5,8,9,10,11-hexahydro-3H-[1,3 ] diazepine [1,2 -b] indazol -3 -yl) -1,2,4 -triazole -3 -carboxamide (40 mg, 54% yield) as a white powder: 1H NMR (400 MHz , DMSO -d6) δ 8.82 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.46 - 7.24 (m, 5H), 5.48 (s, 2H), 4.37 - 4.06 (m, 3H), 3.19 (s, 3H), 2.66 - 2.52 (m, 3H), 2.48 - 2.39 (m, 2H) , 2.32 - 2.17 (m, 1H), 1.87 - 1.59 (m, 4H); LCMS RT = 4.35 min.; m/z = 420.2 (M+H)+. Example 137

[0623] METHOD X3 Step 1: (5S) -N -(1 -methyl -2 -oxo 2,3,4,5,8,9,10,11 -octahydro -1H - [1,3] diazepine [1,2 -b] indazol -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro - 1H -indazol -3 -carboxamide

[0624] To a solution of (S) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylic acid (61 mg, 0.26 mmol) in N,N -dimethyl formamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (136 mg, 0.35 mmol) under 0°C, and the reaction was subjected to stirring under 0°C for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepine[1,2-b]indazol-2-one (41 mg, 0) was then added. .17 mmol). The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP - HPLC to provide (5S) -N -(1-methyl -2 -oxo - 2,3,4,5,8,9,10,11 -octahydro -1H - [1,3] diazepine [1,2 -b] indazol -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro - 1H -indazol -3 -carboxamide (28.3 mg, 34 % yield): 1H NMR (400 MHz, DMSO -d6) δ 12.97 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 4.37 - 4.03 (m , 3H), 3.19 (s, 3H), 3.06 - 2.95 (m, 1H), 2.84 - 2.74 (m, 1H), 2.72 - 2.52 (m, 5H ), 2.50 - 2.40 (m, 3H), 2.28 - 2.16 (m, 1H), 2.14 - 2.08 (m, 1H), 1.88 - 1.55 (m , 5H); LCMS RT = 4.84 min.; m/z = 451.2 (M+H)+. Example 138

[0625] METHOD X4 Step 1: 5-ethoxy-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine -3 -carboxamide

[0626] A solution of 5-ethoxy-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (76 mg, 0.19 mmol) under 0°C, and the reaction was subjected to stirring at 0°C for 20 min. (3S)-3-Amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (25 mg, 0.13 mmol) was then added. The reaction was subjected to stirring at 25°C for 18 h. The reaction mixture was purified by RP-HPLC to provide 5-ethoxy-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] -1H -pyrazolo[4,3-b]pyridine-3-carboxamide (11.5 mg, 23% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 13.90 (bs, 1H), 9.15 (d, J = 7.1 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.54 - 7.46 (m, 1H) , 7.40 - 7.23 (m, 3H), 6.92 (d, J = 9.1 Hz, 1H), 5.10 - 4.95 (m, 1H), 4.72 - 4.57 (m, 3H), 4.31 (dd, J = 11.3, 9.8 Hz, 1H), 3.37 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H) ; LCMS RT = 4.80 min.; m/z = 382.1 (M+H)+. Example 139

[0627] METHOD X5 5 -isopropyl -N - [(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -1H -pyrazolo [4,3 -b] pyridine -3 - carboxamide Step 1: 5-isopropenyl-1H-pyrazole[4,3-b]pyridine

[0628] Bis (tricyclohexylphosphine) palladium (0) (129 mg, 0.19 mmol), 5 -chloro -1H -pyrazolo [4,3 -b] pyridine (301 mg, 1.9 mmol) and pinacol acid ester boronic isopropenyl (471 mg, 2.66 mmol) were mixed in acetonitrile (6.0 mL) and sodium carbonate (2 mol/L) in water (2.9 mL, 5.7 mmol), and the reaction was subjected in the microwave at 110°C for 2 h. The crude mixture was diluted with ethyl acetate and citric acid solution (5% in water) under pH 9, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in dichloromethane) to provide 5-isopropenyl-1H-pyrazolo[4,3-b]pyridine ( 274 mg, 58% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 13.27 (s, 1H), 8.27 (s, 1H), 7.96 ( dd, J = 8.9, 1.0 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 5.91 - 5.83 (m, 1H), 5.38 (d , J = 1.5 Hz, 1H), 2.22 (dd, J = 1.5, 0.8 Hz, 3H); LCMS RT = 1.44 min.; m/z = 160 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 2: 5-isopropyl-1H-pyrazole[4,3-b]pyridine

[0629] A solution of 5-isopropenyl -1H - pyrazolo [4,3 -b] pyridine (201 mg, 0.82 mmol) in ethyl acetate (4.0 mL) and methanol (1.0 mL) was Palladium on activated carbon (10% by weight) (86 mg) was added, and the reaction was subjected to stirring with a H2 balloon at 65°C for 4 h. The crude mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layers were combined and concentrated for drying in vacuum, and the crude residue (244 mg) was used without further purification: 1H NMR (400 MHz, DMSO -d6) δ 13.15 (s, 1H), 8. 18 (s, 1H), 7.91 (dd, J = 8.7, 1.1 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 3.15 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H); LCMS RT = 1.18 min.; m/z = 162 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 3: 3 -iodo -5 -isopropyl -1H -pyrazolo[4,3-b]pyridine

[0630] To a solution of 5-isopropyl-1H-pyrazolo[4,3-b]pyridine (219 mg, 0.96 mmol) in N,N-dimethylformamide (4.85 mL) was added potassium hydroxide ( 162 mg, 2.9 mmol), followed by iodine (441 mg, 1.74 mmol), and the reaction was stirred under 50 ° C for 1 h, and then under 25 ° C for 1 h. The crude mixture was diluted with ethyl acetate and washed with sodium sulfite solution until the color of the organic layer was unchanged. The aqueous layers were combined and extracted through ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 -40% ethyl acetate in heptane) to provide 3 -iodo -5 -isopropyl -1H - pyrazole [4,3 - b] pyridine (192 mg, 69% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 13.60 (s, 1H), 7.93 (d, J = 8 .7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 3.18 (hept, J = 6.9 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H); LCMS RT = 1.22 min.; m/z = 288 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 4: methyl 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylate

[0631] 3 -Iodo -5 -isopropyl -1H -pyrazolo [4,3 -b] pyridine (110 mg, 0.38 mmol), 4,5 -bis(diphenylphosphine) -9,9 -dimethylxanthene (44 mg, 0.076 mmol) and palladium(II) acetate (8.6 mg, 0.038 mmol) were mixed in triethylamine (0.80 mL, 5.75 mmol), methanol (1.6 mL) and N,N-dimethylformamide ( 1.2 mL), and the yellow solution was stirred under a carbon monoxide atmosphere at room temperature for 10 min. and then under 60°C for 2 days. The crude mixture was dried in vacuum and the crude residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 30% ethyl acetate in dichloromethane) to give methyl 5-isopropyl -1H -pyrazolo[4,3-b]pyridine-3-carboxylate (96 mg, 114% yield) in the form of an off-white powder: 1H NMR (400 MHz, DMSO -d6) δ 13.95 (bs, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 3.20 (hept, J = 6 .9 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); LCMS RT = 1.13 min.; m/z = 220 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 5: 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid

[0632] To a solution of methyl 5 -isopropyl -1H - pyrazolo [4,3 -b] pyridine -3 -carboxylate (83 mg, 0.38 mmol) in tetrahydrofuran (2.0 mL), water (1.0 mL) and methanol (1.0 mL), sodium hydroxide (150 mg, 3.8 mmol) was added, and the reaction was stirred under 40 ° C for 4 h. Hydrochloric acid solution (1.0 M) was added and the final pH was 3. The solution was concentrated for drying in vacuum, and the crude residue was used without further purification: LCMS RT = 1.37 min.; m/z = 206 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 6: 5-isopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine -3 -carboxamide

[0633] A solution of 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) was 1 - [bis(dimethylamino)methylene] -1H - 1,2,3 -triazolo [4,5 -b] pyridinium 3 -oxid hexafluorophosphate (91 mg, 0.23412 mmol) was added under 0 ° C, and the reaction was subjected to stirring at 0°C for 20 min. (3S)-3-Amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (25 mg, 0.13 mmol) was added. The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 5-isopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] -1H -pyrazole [4,3 - b] pyridine -3 -carboxamide (43.2 mg, 87% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 13.88 (bs, 1H), 9.65 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.55 - 7.48 (m, 1H) , 7.46 (d, J = 8.8 Hz, 1H), 7.38 - 7.26 (m, 3H), 5.04 (dt, J = 11.3, 7.3 Hz, 1H), 4.66 (dd, J = 9.8, 7.4 Hz, 1H), 4.32 (dd, J = 11.3, 9.8 Hz, 1H), 3.37 (s, 3H), 3 .30 - 3.24 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H); LCMS RT = 4.92 min.; m/z = 380.2 (M+H)+. Example 140

[0634] METHOD X6 1-benzyl -N -(1-methyl -9,9 -dioxide -2 -oxo - 1,2,3,4,5,10 -hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: 2,6-dihydro-4H-thiene[3,4-c]pyrazol-3-amine

[0635] To a solution of 4-cyano-3-tetrahydrothiophenone (1.01 g, 7.78 mmol) in toluene (11.5 mL) was added hydrazine (0.33 mL, 9.7 mmol), and the reaction was subjected to stirring at 90°C for 10 h. The reaction mixture was concentrated to drying in vacuum and the residue was used without further purification: LCMS RT = 1.29 min.; m/z = 170 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 2: N -(4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)formamide

[0636] 4,6 -dihydro -1H -thiene [3,4 -c] pyrazole -3 - amine (442 mg, 2.98 mmol) and formic acid (1.3 mL) were mixed together, and the reaction was subjected to stirring at 110°C for 3 h. The crude reaction mixture was diluted with ethyl acetate (300 mL) and water (30 mL), and sodium hydroxide solution (aq, 50% w/w) was added dropwise under 0°C to change the pH of the aqueous layer at 7. The two layers were separated. The aqueous layer was extracted with ethyl acetate (50 ml x 2). The organic layers were combined, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue (2.68 g of yellow solid) was used without further purification: LCMS RT = 1.39 min; m/z = 170 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 3: N -methyl -4,6 -dihydro -2H -thiene [3,4 - c ] pyrazol -3 -amine

[0637] To a solution of N -(4,6-dihydro-1H-thiene [3,4-c] pyrazol-3-yl)formamide (2.68 g, 15.8 mmol) in tetrahydrofuran (201 mL) lithium aluminum hydride (2 mol/L) in tetrahydrofuran (23.8 mL, 47.5 mmol) was added under 0°C, and the reaction was subjected to stirring under 25°C for 2.5 h, resulting in a brown solution. Sodium sulfate decahydrate was added, and the mixture was stirred for 18 h. The mixture was filtered through celite, and ethyl acetate was used to rinse the celite solid. The liquid combined layer was concentrated to drying in vacuum, and the crude residue (3.43 g) was used without further purification: LCMS RT = 1.58 min.; m/z = 156 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 4: 4-chloro-N-[1-(4-chlorobutanoyl)-4,6-dihydrothiene[3,4-c]pyrazol-3-yl]-N-methyl-butanamide

[0638] To a solution of N -methyl -4,6 -dihydro -1H - thiene [3,4 -c] pyrazol -3 -amine (3.43 g, 22.1 mmol) and N,N -dimethylpyridin - 4-amine (270 mg, 2.21 mmol) in dichloromethane (88 mL) and N,N-diisopropylethylamine (7.71 mL, 44.2 mmol) was added 4-chlorobutyl chloride (4.47 mL, 39. 8 mmol) under 0°C, and the reaction was stirred under 0°C for 30 min, then under 25°C for 2 h. The reaction solution was diluted with ethyl acetate (350 mL), and washed with water (final pH~7). The organic layer was dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in heptane) to give 4-chloro-N-[1-(4-chlorobutanoyl)-4.6 -dihydrothiene[3,4-c]pyrazol-3-yl]-N-methyl-butanamide (3.785 g, 47% yield) as a yellow oil: LCMS RT = 3.46 min.; m/z = 364 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 5: 4-chloro-N-(4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)-N-methyl-butanamide

[0639] To a solution of 4 -chloro -N - [1 -(4 - chlorobutanoyl) -4,6 -dihydrothiene [3,4 -c] pyrazol -3 -yl] - N -methyl -butanamide (3.78 g, 10.4 mmol) in ethanol (16 mL), sodium hydroxide (1 mol/L) in water (10 mL, 10 mmol) was added, and the reaction was stirred at 0 ° C for 15 min. The crude mixture was diluted with ethyl acetate and water, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude material (3.40 g white solid) was used without further purification: LCMS RT = 1.87 min.; m/z = 260 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 6: 1 -methyl -1,4,5,10 -tetrahydro -8H - thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H) - ona

[0640] To a solution of 4-chloro-N-(4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)-N-methyl-butanamide (2.70 g, 10. 4 mmol) in N,N-dimethylformamide (47 mL) cesium carbonate (4.41 g, 13.5 mmol) was added, and the reaction was stirred under 60 ° C for 1.5 h. The crude mixture was diluted with ethyl acetate and citric acid under pH 8, and the two layers were separated. The aqueous layer was extracted through ethyl acetate twice. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 1-methyl-1,4,5,10-tetrahydro-8H-thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H) -one (1.91 g, 62% yield) as a colored oil slightly yellow, which crystallized under scratch or addition of seed crystal: 1H NMR (400 MHz, DMSO -d6) δ 4.14 (t, J = 6.7 Hz, 2H), 3.88 (s, 4H), 3.12 (s, 3H), 2.33 - 2.15 (m, 4H); 1H NMR (400 MHz, Chloroform -d) d 4.21 (t, J = 6.8 Hz, 2H), 4.03 - 3.95 (m, 2H), 3.89 - 3.82 (m, 2H), 3.23 (s, 3H), 2.50 - 2.30 (m, 4H); LCMS RT = 1.66 min.; m/z = 224 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 7: 3 -iodo -1 -methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin - 2(3H)-one

[0641] To a solution of 1-methyl -1,4,5,10 - tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin - 2(3H)-one (1001 mg, 3.3621 mmol, 75%, by weight, purity) in dichloromethane (28 mL) was added N,N,N',N'-tetramethyl ethylenediamine (4.05 mL, 27 mmol) under -20°C (dry ice acetone bath), followed by iodotrimethylsilane (3.84 mL, 27 mmol), and the reaction was subjected to stirring in a dry ice acetone bath (-20 ~ -15°C) for 3 h. Iodine (3.41 g, 13.5 mmol) was added, and the reaction was subjected to stirring in a dry ice acetone bath (under -15 ~ -10°C) for 2 h. The crude mixture was diluted with ethyl acetate and sodium thiosulfate solution (10% aq., 10 mL), and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in heptane) to provide 3-iodo-1-methyl-1,4,5,10 - tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H) -one (0.80 g, 68% yield) in forms an off-white solid: 1H NMR (400 MHz, Chloroform -d) δ 4.65 (dd, J = 8.5, 7.6 Hz, 1H), 4.19 (ddd, J = 8.3 , 5.9, 1.5 Hz, 2H), 4.03 - 3.95 (m, 2H), 3.93 - 3.85 (m, 2H), 3.29 (s, 3H), 3, 05 - 2.89 (m, 1H), 2.85 - 2.71 (m, 1H); LCMS RT = 1.97 min.; m/z = 350 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 8: 3 -azide -1 -methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin - 2(3H)-one

[0642] To a solution of 3 -iodo -1 -methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1, 3] diazepin-2(3H)-one (310 mg, 0.89 mmol) in N,N-dimethylformamide (3.50 mL) was added sodium azide (89 mg, 1.33 mmol), and the reaction was subjected to stirring at 25°C for 2 h. The reaction mixture was concentrated to drying in vacuum and was diluted with ethyl acetate and water (pH ~ 8). The two layers were separated. The aqueous layer was extracted through ethyl acetate twice. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude material (436 mg) was used without further purification: LCMS RT = 1.07 min.; m/z = 265 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 9: 3 -azide -1 -methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin - 2(3H)-one 9,9-dioxide

[0643] To a solution of 3-azide -1 -methyl - 1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 - a] [1, 3] diazepin-2(3H)-one (355 mg, 1.34 mmol) in acetic acid (0.081 mL, 1.41 mmol) and dichloromethane (11 mL) was added 3-chloroperoxy benzoic acid (722 mg, 3. 22 mmol) under 0°C, and the reaction was subjected to stirring under 0°C for 1 h. A second part of 3-chloroperoxy benzoic acid (96 mg, 0.43 mmol) was added, and the reaction was stirred at 25 ° C for 30 min. The crude mixture was diluted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 -60% ethyl acetate in heptane) to provide 3-azide -1 -methyl -1,4,5,10 - tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H) -one 9,9 -dioxide (360 mg, 90% yield ) in the form of a white solid: 1H NMR (400 MHz, Chloroform -d) δ 4.55 - 4.39 (m, 1H), 4.33 - 4.16 (m, 5H), 3.91 (dd, J = 10.6, 7.9 Hz, 1H), 3.32 (s, 3H), 2.88 - 2.74 (m, 1H), 2.30 (dddd, J = 13.5 , 10.7, 6.6, 1.8 Hz, 1H); 1H NMR (400 MHz, DMSO -d6) δ 4.53 (d, J = 14.7 Hz, 1H), 4.48 - 4.25 (m, 5H), 4.13 (dd, J = 11, 3, 7.9 Hz, 1H), 3.25 (s, 3H), 2.84 - 2.64 (m, 1H), 2.17 (dddd, J = 13.2, 11.4, 6, 1, 1.7Hz, 1H); LCMS RT = 1.52 min.; m/z = 297 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 10: 3-amino -1 -methyl -1,4,5,10 tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2 (3H)-one 9,9 -dioxide

[0644] To a suspension of 3-azide -1-methyl - 1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 - a] [1, 3] diazepin-2(3H)-one 9,9-dioxide (291 mg, 0.84 mmol) in tetrahydrofuran (6.9 mL) and water (0.93 mL) was added polymer-binding triphenylphosphine (5, 1 mmol), and the reaction was subjected to stirring at 25°C for 12 h. The reaction mixture was filtered through celite, and the celite solid was rinsed through a solution of methanol in dichloromethane (10% v/v) twice. The solutions were combined and concentrated for drying in vacuum, and the crude material (284 mg) was used without further purification: LCMS RT = 0.52 min.; m/z = 271 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.). Step 11: 1-benzyl -N -(1-methyl -9,9 -dioxide - 2 -oxo -1,2,3,4,5,10 -hexahydro -8H -thiene [3',4':3, 4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[0645] To a suspension of 1-benzyl-1H - 1,2,4-triazole -3-carboxylic acid (68 mg, 0.32 mmol) in N,N - dimethylformamide (1.0 mL) and N, N-diisopropyl ethylamine (0.055 mL, 0.32 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (123 mg , 0.32 mmol) under 0°C, and the reaction was subjected to stirring under 0°C for 20 mln., resulting in a yellow solution. 3 -Amino -1 - methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H )-one 9,9-dioxide (57 mg, 0.21 mmol) was added. The reaction was subjected to stirring at 25°C for 18 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by RP-HPLC to provide 1-benzyl-N-(1-methyl-9,9-dioxide-2-oxo-1,2,3 ,4,5,10 - hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide (61 mg, 63% yield) in the form of a white powder: 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.49 (d, J = 7.7 Hz, 1H), 7.46 - 7.23 (m, 5H), 5.49 (s, 2H), 4.56 - 4.33 (m, 6H), 4.34 - 4 .19 (m, 1H), 3.20 (s, 3H), 2.73 - 2.60 (m, 1H), 2.41 - 2.28 (m, 1H); LCMS RT = 3.47 min.; m/z = 456.1 (M+H)+. Example 141 5-benzyl -N -(1-methyl -9,9 -dioxide -2 -oxo - 1,2,3,4,5,10 -hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 - carboxamide Step 1: 5 -benzyl -N -(1 -methyl -9,9 - dioxide -2 -oxo -1,2,3,4,5,10 -hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -4H -1,2,4 - triazole -3 -carboxamide

[0646] To a suspension of 5-benzyl-4H - 1,2,4-triazole -3-carboxylic acid (65 mg, 0.32 mmol) in N,N - dimethylformamide (1.0 mL) and N, N-diisopropyl ethylamine (0.052 mL, 0.32 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (123 mg , 0.32 mmol) under 0°C, and the reaction was subjected to stirring under 0°C for 20 mln., resulting in a yellow solution. 3 -Amino -1 - methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H )-one 9,9-dioxide (57 mg, 0.21 mmol) was added. The reaction was subjected to stirring at 25°C for 18 h. The reaction mixture was concentrated to drying in vacuum and the residue was purified by RP-HPLC to provide 5-benzyl-N-(1-methyl-9,9-dioxide-2-oxo-1,2,3 ,4,5,10 - hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide (8 mg, 8.3% yield) in the form of a white powder: 1H NMR (400 MHz, DMSO -d6) δ 8.47 (bs, 1H), 7.40 — 7.17 (m, 5H), 4.56 - 4.33 (m, 6H), 4.33 - 4.20 (m, 1H), 4.10 (s, 2H), 3.20 (s, 3H), 2.75 - 2.59 (m, 1H), 2.41 - 2.29 (m, 1H); LCMS RT = 3.42 min.; m/z = 456.1 (M+H)+. Example 142

[0647] METHOD X7 1-benzyl -N -(1-methyl -2 -oxo -1,2,3,4,5,10 - hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a ] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: 3 -amino -1 -methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin - 2(3H)-one

[0648] To a solution of 3-azide -1 -methyl - 1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 - a] [1, 3] diazepin-2(3H)-one (235 mg, 0.89 mmol) in tetrahydrofuran (3.0 mL) and water (1.0 mL) was added polymer-bound triphenylphosphine, (5.4 mmol), and the reaction was subjected to stirring at 25°C for 5 h. The reaction mixture was filtered through Celite, and the Celite solid was rinsed through a solution of methanol in dichloromethane (10% v/v, 3 mL) twice. The organic solutions were combined and concentrated for drying in vacuum, and the crude material (285 mg) was used without further purification: LCMS RT = 1.3 min; m/z = 239 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 2: 1-benzyl -N -(1-methyl -2 -oxo - 1,2,3,4,5,10 -hexahydro -8H -thiene [3',4':3,4] pyrazole [1, 5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[0649] To a suspension of 1-benzyl-1H - 1,2,4-triazole -3-carboxylic acid (71 mg, 0.33 mmol) in N,N - dimethylformamide (1.0 mL) and N, N-diisopropyl ethylamine (0.050 mL, 0.29 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (129 mg , 0.33 mmol) under 0°C, and the reaction was subjected to stirring under 0°C for 20 mln., resulting in a yellow colored solution. 3 -Amino -1 - methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H )-one (53 mg, 0.22 mmol) was added. The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thiene [3' ,4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 - triazole -3 -carboxamide (75 mg, 80% yield) in the form of a white powder: 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H, NH), 7.44 - 7.26 (m, 5H), 5.48 (s, 2H), 4.40 (dt, J = 11.4, 7.8 Hz, 1H), 4.31 - 4.12 (m, 2H ), 3.99 - 3.78 (m, 4H), 3.19 (s, 3H), 2.73 - 2.56 (m, 1H), 2.37 - 2.21 (m, 1H); LCMS RT = 3.99 min.; m/z = 424.1 (M+H)+. Example 143

[0650] METHOD X8 5 -chloro -N - [(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -1H -pyrazolo [4,3 -b] pyridine -3 - carboxamide Step 1: 5-chloro-3-iodo-1H-pyrazole[4,3-b]pyridine

[0651] To a solution of 5-chloro-1H-pyrazolo [4,3-b] pyridine (501 mg, 3.16 mmol) in N,N-dimethylformamide (16 mL) was added potassium hydroxide (532 mg , 9.49 mmol), followed by iodine (1.45 g, 5.70 mmol) under 0°C, and the reaction was stirred under 0°C for 30 mln., then under 25°C for 3 0 mln., and finally under 50°C for 1 h. The crude mixture was diluted with ethyl acetate and washed with sodium sulfite solution until the color of the organic layer no longer changed color. The aqueous layers were combined and extracted through ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum to provide 5-chloro-3-iodo-1H-pyrazole [4 ,3 - b] pyridine (770 mg, 87% yield) which was used without any further purification: 1H NMR (400 MHz, DMSO -d6) δ 13.89 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H); LCMS RT = 1.92 min.; m/z = 280 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 2: methyl 5-chloro-1H-pyrazolo[4,3-b]pyridine-3-carboxylate

[0652] 5 -chloro -3 -iodo -1H -pyrazolo [4,3 -b] pyridine (250 mg, 0.85 mmol), 4,5 -bis(diphenylphosphine) -9,9 -dimethylxanthene (49 mg, 0.085 mmol) and palladium(II) acetate (9.5 mg, 0.042 mmol) were mixed in triethylamine (2.6 mL), methanol (2.6 mL) and N,N-dimethylformamide (2.5 mL). ), and the yellow solution was subjected to stirring under a carbon monoxide atmosphere at room temperature for 10 min. and then under 70°C for 2 days. The crude mixture was concentrated to drying in vacuum, and the crude residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in dichloromethane) to provide methyl 5 - chloro -1H -pyrazole [4,3 -b] pyridine -3 -carboxylate (0.12 g, 67% yield) in the form of an off-white powder: 1H NMR (400 MHz, DMSO -d6) δ 14.36 ( s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H); LCMS RT = 1.48 min.; m/z = 212 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 3: 5-Chloro-1H-pyrazole[4,3-b]pyridine-3-carboxylic acid

[0653] To a solution of methyl 5 -chloro -1H - pyrazolo [4,3 -b] pyridine -3 -carboxylate (30.0 mg, 0.142 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.25 mL) sodium hydroxide (1 mol/L) in water (0.25 mL) was added, and the reaction was subjected to stirring at 25°C for 8 h. Hydrochloric acid (1.0 M, 0.60 mL) was then added, resulting in a clear solution with pH ~6. The solution was concentrated for drying in vacuum, and the crude material was used without further purification: LCMS RT = 0.91 min.; m/z = 198 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 4: 5-chloro-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine -3 -carboxamide

[0654] A solution of 5-chloro-1H-pyrazole [4,3-b] pyridine-3-carboxylic acid (35 mg, 0.18 mmol) in N,N-dimethylformamide (1.0 mL) was Added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (70 mg, 0.18 mmol) and N,N-diisopropyl ethylamine ( 0.042 mL) under 0°C, and the reaction was subjected to stirring under 0°C for 20 min. (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol) was then added. The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 5-chloro-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] -1H -pyrazole [4,3 -b] pyridine -3 -carboxamide (12 mg, 27% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 14.22 (bs , 1H), 8.75 (d, J = 7.3 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H ), 7.52 (dd, J = 6.9, 2.5 Hz, 1H), 7.39 - 7.24 (m, 3H), 4.97 (dt, J = 11.4, 7.4 Hz, 1H), 4.59 (dd, J = 9.9, 7.5 Hz, 1H), 4.44 (dd, J = 11.4, 9.9 Hz, 1H), 3.36 (s , 3H); LCMS RT = 4.37 min.; m/z = 372.1 (M+H)+. Example 144

[0655] METHOD X9 5-cyclopropyl -N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1H -pyrazolo [4,3 -b] pyridine -3 - carboxamide Step 1: 5-bromo-1H-pyrazole[4,3-b]pyridine

[0656] To a suspension of 5-chloro-1H-pyrazolo [4,3-b] pyridine (81 mg, 0.51 mmol) in propionitrile (0.51 mL) was added bromine trimethylsilane (0.135 mL, 1.0 mmol), and the reaction was stirred at 100°C for 16 h. A second part of bromine trimethylsilane (0.14 mL, 1.0 mmol) was added, and the suspension was stirred at 110°C. for 6 h. The crude mixture was finished with ice water. Sodium carbonate was added with a pH change to 9. The aqueous layer was extracted through a solution of methanol in ethyl acetate (10% v/v) twice. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude material (189 mg beige solid) was used without further purification: 1H NMR (400 MHz, DMSO -d6) δ 13.59 (s, 1H), 8.29 (d, J = 1.0 Hz, 1H), 8.02 (dd, J = 8.7, 1.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H); LCMS RT = 1.63 min.; m/z = 198 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 2: 5-cyclopropyl-1H-pyrazolo[4,3-b]pyridine

[0657] To a solution of 5-bromo-1H-pyrazolo [4,3-b] pyridine (77 mg, 0.37 mmol), palladium (II) acetate (8.3 mg, 0.037 mmol) and S - Phos (31 mg, 0.074 mmol) in tetrahydrofuran (1.5 mL) was added cyclopropylzinc bromide (0.5 mol/L) in tetrahydrofuran (4 mL, 2.2 mmol), and the reaction was stirred under 110 °C for 18 h. The crude mixture was diluted with ethyl acetate and citric acid solution (10% aq.) to pH 9, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in dichloromethane) to provide 5-cyclopropyl-1H-pyrazolo[4,3-b]pyridine ( 33 mg, 56% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 13.12 (bs, 1H), 8.10 (s, 1H), 7.93 - 7.82 (m, 1H), 7.28 (d, J = 8.7 Hz, 1H), 2.27 - 2.16 (m, 1H), 0.99 - 0.92 (m, 4H) ; LCMS RT = 1.06 min.; m/z = 160 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 3: 5-cyclopropyl-3-iodo-1H-pyrazolo[4,3-b]pyridine

[0658] To a solution of 5-cyclopropyl -1H - pyrazolo [4,3 -b] pyridine (290 mg, 1.82 mmol) in N,N - dimethylformamide (9.26 mL) was added potassium hydroxide ( 307 mg, 5.52 mmol), followed by iodine (832 mg, 3.3 mmol) under 25 ° C, and the reaction was subjected to stirring under 50 ° C for 1 h. The crude mixture was diluted with ethyl acetate and washed with sodium sulfite solution until the color of the organic layer did not change. The aqueous layers were combined and extracted through ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered through celite, and concentrated for drying in vacuum. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in dichloromethane) to provide 5-cyclopropyl-3-iodo-1H-pyrazole[4,3- b] pyridine (122 mg, 23% yield) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 13.56 (s, 1H), 7.86 (d, J = 8 .7 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 2.30 - 2.20 (m, 1H), 1.05 - 0.93 (m, 4H); RT = 1.22 min.; m/z = 286 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 4: 5-cyclopropyl-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine and 5-cyclopropyl-3-iodo-1-(tetrahydro-2H-pyran-2-yl) -1H -pyrazole [4,3 -b] pyridine

[0659] To a suspension of 5-cyclopropyl-3-iodo-1H-pyrazolo[4,3-b]pyridine (67 mg, 0.23 mmol) in dichloromethane (2.0 mL) was added 4-methylbenzene hydrate sulfonamide (4.45 mg, 0.023 mmol), followed by 3,4-dihydro-2H-pyran (59 mg, 0.70 mmol), and the reaction was subjected to stirring under 25°C for 18 h, resulting in a colorless solution. More 3,4-dihydro-2H-pyran (59 mg, 0.705 mmol) was added, and the reaction solution was kept at 40 ° C for 3.5 h. The solution was concentrated for drying in vacuum, and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% dichloromethane in heptane) to provide 5-cyclopropyl-3-iodo- 1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (31 mg, 36% yield) and 5-cyclopropyl-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H -pyrazolo[4,3-b]pyridine (15 mg, 18% yield):

[0660] Analytical data during an isomer: 1H NMR (400 MHz, DMSO -d6) δ 7.97 (d, J = 9.0 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H ), 5.88 - 5.78 (m, 1H), 4.02 - 3.90 (m, 1H), 3.78 - 3.65 (m, 1H), 2.49 - 2.38 (m , 1H), 2.30 - 2.16 (m, 1H), 2.13 - 1.91 (m, 1H), 1.83 - 1.39 (m, 3H), 1.06 - 0.93 (m, 4H); LCMS RT = 1.47 min.; m/z = 370 (M+H)+.

[0661] Analytical data during the other isomer: 1H NMR (400 MHz, DMSO -d6) δ 8.08 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 5.83 (dd, J = 9.7, 2.4 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.78 - 3.65 (m, 1H), 2 .38 - 2.21 (m, 2H), 2.07 - 1.91 (m, 2H), 1.79 - 1.40 (m, 3H), 1.07 - 0.91 (m, 4H) ; LCMS RT = 1.62 min.; m/z = 370 (M+H)+.

[0662] LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.)

[0663] Note: Following Steps 5 and 6 further, the two isomers provided 5-cyclopropyl -N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin - 3 -yl] -1H -pyrazolo [4,3 -b] pyridine -3 -carboxamide (i.e. final product). Step 5: 5 -cyclopropyl -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -(tetrahydro -2H -pyran -2 -yl) -1H -pyrazole [4,3 -b] pyridine -3 -carboxamide

[0664] 5-Cyclopropyl-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (31 mg, 0.084 mmol), (3S)-3-amino-5-methyl hydrochloride 2,3 - dihydro -1,5 -benzoxazepin -4 -one (29 mg, 0.13 mmol), 4,5 - bis(diphenylphosphine) -9,9 -dimethylxanthene (7.3 mg, 0.013 mmol) and acetate of palladium (II) (1.9 mg, 0.0084 mmol) were mixed in triethylamine (0.076 mL), N,N-dimethylformamide (0.10 mL) and toluene (5 mL), and the solution was yellow in color. was subjected to stirring under a carbon monoxide atmosphere at room temperature for 10 min. and then under 80°C for 18 h. The crude mixture was concentrated to drying in vacuum, and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in dichloromethane) to provide 5-cyclopropyl- N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 -tetrahydropyran -2 -yl -pyrazolo [4,3 -b] pyridine - 3-carboxamide (20 mg, 52% yield) as a light brown solid: LCMS RT = 3.30 min.; m/z = 462 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.05% formic acid for 5 min.) Step 6: 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine -3 -carboxamide

[0665] To a solution of 5-cyclopropyl -N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 -tetrahydropyran -2 -yl -pyrazole[4,3-b]pyridine-3-carboxamide (20 mg, 0.043 mmol) in methanol (0.26 mL) and dichloromethane (0.50 mL) hydrochloride (4 mol/L) was added in 1.4 -dioxane (0.12 mL, 0.48 mmol), and the reaction was subjected to stirring under 25 ° C for 1 h. Then N,N-diisopropylethylamine (0.11 mL) was added. The crude mixture was concentrated for drying in vacuum. The crude material was purified by RP-HPLC to provide 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] -1H -pyrazole [4,3 - b] pyridine -3 -carboxamide (13.2 mg, 81% yield) as a white powder: 1H NMR (400 MHz, DMSO -d6) δ 9.50 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.38 - 7.27 (m, 3H), 5.01 (dt, J = 11.3, 7.3 Hz, 1H, CHN), 4.64 (dd, J = 9.8, 7.4 Hz, 1H), 4.29 (dd, J = 11.3, 9.9 Hz, 1H), 3.38 (s, 3H), 2.41 - 2.28 ( m, 1H, Ar -CH), 1.43 - 1.33 (m, 1H), 1.27 - 1.17 (m, 1H), 1.15 - 1.05 (m, 2H); LCMS RT = 4.73 min.; m/z = 378.2 (M+H)+. Example 145 5-benzyl -N -(1-methyl -2 -oxo -1,2,3,4,5,10 - hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a ] [1,3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide Step 1: 5 -benzyl -N -(1 -methyl -2 -oxo - 1,2,3, 4,5,10 -hexahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -4H -1,2,4 - triazole -3 - carboxamide

[0666] To a solution of 5-benzyl -4H - 1,2,4 -triazole -3 -carboxylic acid (113 mg, 0.556 mmol) in N,N -dimethylformamide (1.5 mL) and N,N - Diisopropyl ethylamine (0.0776 mL, 0.44 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (216 mg , 0.56 mmol,) under 0°C, and the reaction was subjected to stirring under 0°C for 20 mln., resulting in a brown colored solution. 3 -Amino -1 - methyl -1,4,5,10 -tetrahydro -8H -thiene [3',4':3,4] pyrazole [1,5 -a] [1,3] diazepin -2(3H )-one (53 mg, 0.22 mmol) was added. The reaction was subjected to stirring at 25°C for 18 h. The crude material was purified by RP-HPLC to provide 5-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thiene [3' ,4':3,4] pyrazole [1,5 -a] [1,3] diazepin -3 -yl) -4H -1,2,4 - triazole -3 -carboxamide (54 mg, 57% yield) in the form of a white powder: 1H NMR (400 MHz, DMSO -d6) δ 14.40 (bs, 1H), 8.48 (bs, 1H), 7.42 - 7.16 (m, 5H) , 4.40 (dt, J = 11.4, 7.8 Hz, 1H), 4.32 - 4.15 (m, 2H), 4.11 (s, 2H), 4.02 - 3.78 (m, 4H), 3.19 (s, 3H), 2.69 - 2.56 (m, 1H), 2.40 - 2.25 (m, 1H); LCMS RT = 3.87 min.; m/z = 424.1 (M+H)+.

[0667] Examples 146 -170 were prepared according to the previously mentioned Methods and were purified according to the Chiral Methods of the later section. Table 2 provides data for these compounds.

[0668] CHIRAL METHODS Example 171

[0669] WX Method (S) -1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: (S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one and ( R) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[0670] 6 -amino -2 -cyclopropyl -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one was subjected to SFC separation a peak 1 obtained as (S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one and peak 2 as (R) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one.

[0671] SFC Condition: Column: Chiralpak OD 250 x 30 mm ID, 5 μm Mobile Phase: A: CO2 B: Ethanol (0.05% NH4OH) Isocratic: 20% B in 6 min. Flow rate: 50 mL/min. Column temperature: 40°C, BPR: 100 bar (Peak 1: 3.11 min.) (Peak 2: 3.53 min.). Step 2: (S)-1-benzyl -N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0672] A mixture of (S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one (200 mg, 0.91 mmol), 1 -benzyl - 1H -1,2,4 -triazole -3 -carboxylic acid (0.19 g, 0.91 mmol), 1H -benzo [d] [1, 2,3] triazol -1 -ol (180 mg, 1.36 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (260 mg, 1.36 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (30-60% acetonitrile/0.1% HCl in water) to give (S)-1-benzyl-N-(2 -cyclopropyl -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (120 mg, 32%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.41 - 7.28 (m, 5H), 6.06 (s, 1H), 5.48 (s, 2H), 4.34 - 4.22 (m, 2H ), 4.12 - 4.04 (m, 1H), 3.19 (s, 3H), 2.61 - 2.54 (m, 1H), 2.37 - 2.29 (m, 1H), 1.88 - 1.81 (m, 1H), 0.89 - 0.81 (m, 2H), 0.70 - 0.61 (m, 2H). LCMS RT = 0.98 min.; m/z = 406.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.98 mln., ESI+ found [M+H] =406.2.

[0673] WX METHOD B 7 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,6,7, 8 -tetra hydroimidazo [1,5 -a] pyridine -1 -carboxamide) Step 1: Methyl 2 -(4-bromopyridin-2 -yl) acetate

[0674] A mixture of 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (2.2 g, 11.5 mmol), 4-bromopyridinan-oxide (1.0 g, 5.7 mmol), N,N - diisopropyl ethylamine (2.2 g, 17.2 mmol) and bromine [tri(1-pyrrolidinyl)] phosphonium hexafluorophosphate (3.0 g, 6.3 mmol) in tetrahydrofuran (20 mL) was subjected to stirring under 25°C for 1 h and then diluted with ethyl acetate (30 mL). The resulting mixture was washed with water (3 x 30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide methyl 2-(4-bromopyridin-2-yl) acetate (1, 0 g, 75%): LCMS RT = 0.52 min.; m/z = 232.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.520 mln., ESI+ found [M+H] = 232.0 . Step 2: (E)-methyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino) acetate

[0675] To a solution of methyl 2-(4-bromopyridin-2-yl) acetate (4.0 g, 17.4 mmol) in acetic acid (60 mL) was added sodium nitrite (1.2 g, 17 .4 mmol) in water (30 mL) under 0°C. After addition, the mixture was stirred at 25°C for 40 min. Water (30 mL) was added and the mixture was stirred for an additional 1 h. The reaction was concentrated for drying under reduced pressure and the residue was collected in ethyl acetate (100 mL), washed with water (2 x 50 mL), saline solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% methanol in dichloromethane) to provide (E)-methyl 2-(4-bromopyridin-2-yl)-2 - (hydroxyimino) acetate (3.6 g, 80%) as a yellow oil: LCMS RT = 0.65 min.; m/z = 261.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.651 mln., ESI+ found [M+H] = 261.0 Step 3: methyl 2 -amino -2 -(4 -bromopyridin -2 -yl) acetate

[0676] A mixture of zinc (1.8 g, 27.8 mmol) and (E)-methyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino) acetate (3.6 g, 13.9 mmol) in methanol (56 mL) and water (36 mL) formic acid (36 mL, 961.9 mmol) was slowly added over 30 min. under 0°C. After addition, the mixture was stirred at 25°C for 5 h and then diluted with ethyl acetate (50 ml). The organic layer was washed with water (3 x 30 ml). The combined aqueous layers were concentrated under reduced pressure to provide crude methyl 2-amino-2-(4-bromopyridin-2-yl) acetate (3.0 g, 88%) as a yellow oil, which was used as it was in the next step without any further purification. Step 4: methyl 7-bromoimidazo[1,5-a]pyridine-1-carboxylate

[0677] A mixture of methyl 2-amino-2-(4-bromo-2-pyridyl) acetate (500 mg, 2.0 mmol) and triethyl orthoformate (2 mL, 2.0 mmol) was heated to 150°C under microwave conditions for 10 min. The mixture was concentrated under reduced pressure and purified by prep TLC (50% ethyl acetate in petroleum ether) to provide methyl 7-bromoimidazo[1,5-a]pyridine-1-carboxylate (210 mg, 40 %) as a brown oil: LCMS RT = 0.65 min.; m/z = 257.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.654 mln., ESI+ found [M+H] = 257.0 Step 5: methyl 7-methylimidazo[1,5-a]pyridine-1-carboxylate

[0678] A mixture of methyl 7-bromoimidazo[1,5-a]pyridine-1-carboxylate (210 mg, 0.8 mmol), potassium carbonate (227 mg, 1.7 mmol) and trimethylboroxine (310 mg, 2.5 mmol) in 1,4-dioxane (5 mL) was treated with tetrakis (triphenylphosphine) palladium (0) (47 mg, 0.04 mmol). The resulting mixture was heated at 120°C for 4 h under nitrogen. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep TLC (50% ethyl acetate in petroleum ether) to provide methyl 7-methylimidazo[1,5-a]pyridine-1-carboxylate (110 mg, 70%) as a yellow solid, which was used in the next step without any further purification. Step 6: methyl 7-methyl -5,6,7,8 -tetrahydroimidazo[1,5-a]pyridine-1-carboxylate

[0679] A mixture of methyl 7-methylimidazo[1,5-a]pyridine-1-carboxylate (90 mg, 0.47 mmol) and 10% palladium on carbon (50 mg, 0.05 mmol) in methanol (10 mL) was hydrogenated [4.46 bar (50 psi)] under 25oC for 18 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC (7% methanol in dichloromethane) to give methyl 7-methyl-5,6,7,8-tetrahydro imidazo[1,5-a]pyridine-1-carboxylate (50 mg , 54%) as a yellow oil: LCMS RT = 1.24 min.; m/z = 195.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate over 3 min.) retention time 1.239 mln., ESI+ found [M+H] = 195.1 Step 7: 7-Methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid

[0680] To a solution of methyl 7-methyl -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine -1 - carboxylate (18 mg, 0.09 mmol) in tetrahydrofuran (2 mL) and water (2 mL) lithium hydroxide (11 mg, 0.46 mmol) was added. The resulting mixture was stirred at 25oC for 12 h, adjusted to pH = 4 by adding hydrochloric acid (1.0 M) and concentrated under reduced pressure. The residue was extracted with dichloromethane (30 ml) and ethyl acetate (1 x 30 ml). The combined organic layers were concentrated under reduced pressure to provide 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid (15 mg, 90%) as solids. white color, which was used in the next step without any further purification. Step 8: 7-methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 5.6, 7,8 -tetrahydroimidazo [1,5 -a] pyridine -1 - carboxamide

[0681] To a solution of 7-methyl -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine -1 -carboxylic acid (22 mg, 0.12 mmol) and (3S) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (23 mg, 0.12 mmol) in N,N -dimethylformamide (2 mL) was added hexafluorophosphate (7 - azabenzotriazole - 1-yloxy) tripyrrolidine phosphonium (76 mg, 0.15 mmol). The resulting mixture was stirred for 12 h at 25°C and then concentrated to drying under reduced pressure. The residue was purified by RP - HPLC (27 -57% methanol in water and 0.05% ammonium hydroxide) to provide 7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 5,6,7,8 -tetrahydroimidazo [1,5 -a] pyridine -1 - carboxamide (6.6 mg , 15%) as a white solid: 1H NMR (400 MHz, CD3OD) δ7.55 - 7.53 (m, 1H), 7.43 - 7.41 (m, 1H), 7.32 - 7.29 (m, 2H), 7.11 - 6.92 (m, 1H), 4.97 - 4.96 (m, 1H), 4.59 - 4.55 (m, 1H), 4 .35 - 4.21 (m, 2H), 3.94 - 3.93 (m, 1H), 3.42 - 3.41 (m, 3H), 3.31 - 3.24 (m, 1H) , 2.41 - 2.34 (m, 1H), 2.01 - 1.98 (m, 2H), 1.63 - 1.59 (m, 1H), 1.12 - 1.09 (m, 3H). LCMS RT = 0.74 min.; m/z = 355.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.740 mln., ESI+ found [M+H] = 355.0, Example 172

[0682] WX METHOD (S) -1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) - 1H -1,2,4 -triazole -3 -carboxamide

[0683] A mixture of 1-benzyltriazole-4-carboxylic acid (20 mg, 0.10 mmol), (S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazole [1, 5 -a] [1,3] diazepin -5(6H) -one (15 mg, 0.08 mmol), N1 -((ethylimino)methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (22 mg, 0.11 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (19 mg, 0.11 mmol) in N,N-dimethylformamide (5 mL) was subjected stirring under 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (17-47% acetonitrile/0.05% ammonium bicarbonate in water) to give (S)-1-benzyl-N-( 2,4 - dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (12.1 mg, 39%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.85 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.39 - 7.29 (m, 5H), 6.13 (s, 1H), 5.49 (s, 2H), 4.15 - 4.10 (m, 2H), 4.08 - 4.06 (m, 1H), 3.21 (s, 3H), 2.59 - 2.54 (m, 1H), 2.35 - 2.29 (m, 1H) , 2.16 (s, 3H). LCMS RT = 0.909 min.; m/z = 380.4 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.909 mln., ESI+ found [M+H] = 380.4, Example 173

[0684] WX Method D 6 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine -3 -carboxamide Step 1: 6 -(prop -1 -en -2 -yl)imidazo[1,5 -a]pyridine

[0685] A mixture of 6-bromoimidazo[1,5-a] pyridine (500 mg, 2.5 mmol), potassium isopropyl trifluoroborate (750 mg, 5.0 mmol), cesium carbonate (1.654 g, 5 .0 mmol) and 1,1'-bis(diphenylphosphine) ferrocene palladium(II) dichloride (185 mg, 0.1 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was heated at 80°C for 3 h under nitrogen. After cooling, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with prep TLC (10% methanol in dichloromethane) to provide 6-(prop-1-en-2-yl)imidazo[1,5-a]pyridine (300 mg, 74%) as a brown colored oil. LCMS RT = 0.26 min.; m/z = 158.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.26 mln., ESI+ found [M+H] =158.8 Step 2: 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

[0686] A mixture of 6 -(prop -1 -en -2 -yl) imidazo [1,5 -a] pyridine (300 mg, 1.9 mmol) and 10% palladium on carbon (2 02 mg, 0. 2 mmol) in methanol (30 mL) was hydrogenated [4.46 bar [4.46 bar (50 psi)]] under 20°C for 72 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC (10% methanol in dichloromethane) to provide 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (150 mg, 48%) as of a brown oil, which was used in the next step without any further purification. Step 3: Ethyl 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

[0687] To a solution of 6-isopropyl-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine (300 mg, 1.8 mmol) in tetrahydrofuran (5 mL) was added n-butyl lithium ( 2.5 M, 1.1 mL, 2.7 mmol) under -78°C. Stirring was continued at -78°C for 1 h, then ethyl chloroformate (1300 mg, 12.3 mmol) was added dropwise. The resulting mixture was stirred at -78°C for 1 h and finalized by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 100% dichloromethane) to provide ethyl 6 -isopropyl - 5,6,7,8 -tetrahydroimidazo[1,5-a]pyridine -3 - carboxylate (100 mg, 23%) in the form of a brown oil, which was used in the next step without any further purification. Step 4: 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid

[0688] A mixture of 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (100 mg, 0.45 mmol) and potassium hydroxide (252 mg, 4 .5 mmol) in ethanol (5 mL) and water (1 mL) was stirred under 25°C for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH = 4 by adding hydrochloric acid (2.0 M). The mixture was concentrated under reduced pressure to provide crude 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid (80 mg, 85%) as a solid white in color, which was used in the next step without any further purification. Step 5: 6 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 5.6, 7,8 -tetrahydroimidazo [1,5 -a] pyridine -3 - carboxamide

[0689] A mixture of (S) -3 -amino -5 -methyl -2,3 -dihydrobenzo [b] [1,4] oxazepin -4(5H) -one (40 mg, 0.2 mmol), acid 6 -isopropyl -5,6,7,8 -tetrahydroimidazo [1,5 -a] pyridine -3 -carboxylic acid (43 mg, 0.2 mmol), 1H -benzo [d] [1,2,3] triazole - 1 -ol (42 mg, 0.3 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (59 mg, 0.3 mmol) in N,N -dimethyl formamide (5 mL) was stirred at 25°C for 16 h. After evaporation of the solvent under reduced pressure, the residue was purified by means of haRP-HPLC (acetonitrile 46 - 76%/0.05% ammonium hydroxide in water) to provide 6-isopropyl -N -((S) - 5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine - 3-carboxamide (10 mg, 14%): 1H NMR (400 MHz, DMSO -d6) δ 8.27 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 6.8 Hz , 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.21 (m, 1H), 6.81 (s, 1H), 4.83 - 4.75 (m, 1H) ), 4.63 - 4.51 (m, 2H), 4.43 - 4.37 (m, 1H), 3.69 - 3.62 (m, 1H), 3.31 (s, 3H), 2.95 - 2.87 (m, 1H), 2.67 - 2.58 (m, 1H), 1.93 - 1.85 (m, 1H), 1.68 - 1.54 (m, 2H ), 1.41 - 1.28 (m, 1H), 0.92 - 0.88 (m, 6H). LCMS RT = 0.84 min.; m/z = 393.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.84 mln., ESI+ found [M+H] =393.1 Example 174

[0690] WX METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -1',4',6',7' - tetrahydrospiro [cyclopropane -1,5' -indazole] -3' - carboxamide Step 1: 8 -methylene -1,4 -dioxaspiro[4,5]decane

[0691] To a suspension of (bromomethyl) triphenylphosphonium (34.12 g, 96.04 mmol) in tetrahydrofuran (200 mL) was added potassium tert-butoxide (10.8 g, 96.0 mmol) in parts under 0 °C. The resulting mixture was subjected to stirring at 0°C for 1 h and then a solution of 1,4-dioxaspiro[4,5]decan-8-one (5.0 g, 32.0 mmol) in tetrahydrofuran (20 mL) was added. was added drop by drop. After addition, the reaction mixture was slowly heated to 23°C and stirred for 18 h. The reaction mixture was quenched by adding water (120 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 5% ethyl acetate in petroleum ether) to provide 8-methylene-1,4-dioxaspiro[4,5]decane (3.9 g, 79%) as a yellow colored oil: 1H NMR (400 MHz, CDCl3) δ 4.67 (s, 2H), 3.98 (s, 4H), 2.37 - 2 .30 (m, 4H), 1.73 - 1.70 (m, 4H). Step 2: Spiro [2.5]octan -6 -one

[0692] To a solution of 8-methylene -1,4 dioxaspiro [4.5] decane (3.9 g, 25.3 mmol) in toluene (7.2 mL) was added diethylzinc (1.0 M, 63 .2 mL, 63.2 mmol) under -40°C. The mixture was stirred for 10 min. and then diiodomethane (33.9 g, 126.4 mmol) was added dropwise. After addition, the resulting mixture was allowed to warm to 24°C and stirred for 18 h. The reaction mixture was poured into ice-cold saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 60 mL). The organic extracts from the combined layer were washed with water (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% ethyl acetate in petroleum ether) to provide a colorless oil. A mixture of this oil and trifluoroacetic acid (2.9 mL, 38.9 mmol) in tetrahydrofuran (8 mL) and water (7 mL) was stirred under 23°C for 2 h. The mixture was adjusted to pH = 7 by addition of aqueous sodium hydroxide (2 M) and extracted with diethyl ether (3 x 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude spiro[2.5]octan-6-one (1 .4 g, 44.6% over 2 steps) in the form of a colorless oil: 1H NMR (400 MHz, CDCl3) δ 2.40 (t, J = 6.8 Hz, 4H), 1.67 (t, J = 6.4 Hz, 4H), 0.47 (s, 4H). Step 3: Ethyl 2 -oxo -2 -(6 -oxospiro [2.5]octan -7 -yl) acetate

[0693] To a solution of spiro [2.5]octan-6-one (500 mg, 4.03 mmol) in ethanol (5 mL) was added sodium ethanoxide and diethyl oxalate (588 mg, 4.0 mmol) under 0°C. After addition, the mixture was allowed to warm to 20°C and stirred for 20 h. The solvent was removed under reduced pressure to give crude ethyl 2-oxo-2-(6-oxospiro[2.5]octan-7-yl)acetate (800 mg, 88%) as a yellow solid , which was used in the next step in the form in which it was found without any further purification. Step 4: Ethyl spiro [1,3a,4,6,7,7a -hexahydroindazole 5,1'-cyclopropane]-3 -carboxylate

[0694] To a solution of ethyl 2-oxo-2-(6-oxospiro [2.5]octan-7-yl)acetate (800 mg, 3.57 mmol) in glacial acetic acid (3 mL) was added hydrazine (0.12 mL, 3.92 mmol) under 0°C. The mixture was stirred for 18 h at 23°C and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give ethyl spiro [1, 3a,1,4,6,7 - tetrahydroindazole -5,1'-cyclopropane] -3 -carboxylate (50 mg, 6.4%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 4.41 - 4.30 (m, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.62 (s, 2H), 1.62 (t, J = 6.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.44 (s, 4H). LCMS RT = 0.817 min.; m/z = 220.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.817 mln., ESI+ found [M+H] = 220.9, Step 5: Spiro [1,3a,4,6,7,7a -hexahydroindazole - 5,1' -cyclopropane] -3 -carboxylic acid

[0695] A mixture of ethyl spiro [1,3a,1,4,6,7 - tetrahydroindazole -5,1' -cyclopropane] -3 -carboxylate (50 mg, 0.23 mmol) and hydrated lithium hydroxide (27 mg, 1.13 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred under 23°C for 18 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The solution was then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide spiro[1,3a,1,4,6,7-tetrahydro indazol-5,1'-cyclopropane]-3-carboxylic acid in crude (40 mg, 91%) as a white solid: LCMS RT = 1.456 min; m/z = 193.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.04% formic acid for 3 min.) retention time 1.456 mln., ESI+ found [M+H] = 193.2. Step 6 (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1',4',6', 7' - tetrahydrospiro [cyclopropane -1,5' -indazole] -3' - carboxamide

[0696] A mixture of spiro [1,3a,1,4,6,7 - tetrahydroindazole -5,1' -cyclopropane] -3 -carboxylic acid (40 mg, 0.21 mmol), (3s) -3 - amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (44 mg, 0.23 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol ( 33 mg, 0.25 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL ) was subjected to stirring at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 38 -68%/0.05% ammonia in water) to give (S)-N-(5-methyl-4-oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1',4',6',7' -tetrahydrospiro [cyclopropane -1,5' -indazole] -3 '-carboxamide (18.7 mg, 24%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 12.90 (s, 1H), 7.92 (d, J = 7 .6 Hz, 1H), 7.48 (d, J = 6.0 Hz, 1H), 7.37 - 7.16 (m, 3H), 4.85 - 4.75 (m, 1H), 4 .53 - 4.44 (m, 1H), 4.42 - 4.35 (m, 1H), 3.31 (s, 3H), 2.63 (t, J = 5.6 Hz, 2H), 2.41 (s, 2H), 1.49 (t, J = 5.6 Hz, 2H), 0.46 - 0.20 (m, 4H). LCMS RT = 0.856 min.; m/z = 367.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.856 mln., ESI+ found [M+H] = 367.1. Example 175

[0697] WX METHOD RRRRRR 5 -benzyl -N -(9 -methyl -8 -oxo -6,7,8,9 - tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) - 4H -1 ,2,4-triazole-3-carboxamide

[0698] A mixture of (5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (22 mg, 0.11 mmol), 7-amino-9-methyl-6,7-dihydro-5H -imidazo [1,2 -a] [1,3] diazepin - 8(9H) -one (20 mg, 0.11 mmol), N1 hydrochloride - ((ethylimino)methylene) -N3,N3 -dimethyl propane - 1,3-diamine (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide ( 4 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (14 - 24% methanol in water and 0.05% ammonium hydroxide). to give 5-benzyl -N -(9-methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) - 4H -1,2,4 -triazole -3 -carboxamide (5 mg, 12%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.34 - 7.22 (m, 5H) , 7.09 (s, 1H), 6.96 (s, 1H), 4.53 - 4.48 (m, 1H), 4.32 - 4.26 (m, 1H), 4.16 (s , 2H), 4.10 - 4.02 (m, 1H), 3.38 (s, 3H), 2.77 - 2.90 (m, 1H), 2.29 - 2.21 (m, 1H) ).LCMS RT = 1.21 min.; m/z = 366.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.21 mln., ESI+ found [M+H] = 366.1. Example 176

[0699] WX METHOD SSSSSS F (5S) -N -(9 -methyl -8 -oxo -6,7,8,9 -tetrahydro - 5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) -5 - ( trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0700] A mixture of (5S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (26 mg, 0.11 mmol), 7-amino-9- methyl -6,7 - dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (20 mg, 0.11 mmol), N -((ethylimino)methylene hydrochloride ) - N ,N3 -dimethyl propane -1,3 -diamine (26 mg, 0.13 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (18 mg, 0.13 mmol ) in N,N-dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (17 - 47% methanol in water and 0.05% ammonium hydroxide) to give (5S) -N -(9 -methyl -8 -oxo -6,7,8,9 - tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide (10.7 mg, 24%) as a white solid: 1H NMR (400 MHz, CD3OD) δ7.09 (d, J = 1.2 Hz, 1H), 6.96 (d, J = 1.2 Hz, 1H), 4.52 - 4.47 (m, 1H), 4.32 - 4.26 (m, 1H), 4.07 - 4.05 ( m, 1H), 3.39 (s, 3H), 3.14 - 3.10 (m, 1H), 2.88 - 2.84 (m, 2H), 2.76 - 2.70 (m , 1H), 2.64 - 2.48 (m, 2H), 2.21 - 2.20 (m, 2H), 1.74 - 1.69 (m, 1H). LCMS RT = 0.69 min.; m/z = 397.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.69 mln., ESI+ found [M+H] = 397.0. Example 177

[0701] WX METHOD TTTTTT 1 -(3,4-difluorobenzyl) -N -(9 -methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7- il) -1H -pyrazole -3 -carboxamide

[0702] A mixture of 1 - [(3,4-difluorophenyl) methyl] pyrazol -3 -carboxylic acid (26 mg, 0.11 mmol), 7 -amino -9 -methyl -6,7 -dihydro -5H - imidazo [1,2 - a] [1,3] diazepin -8(9H) -one (20 mg, 0.11 mmol), N1 -((ethylimino)methylene) -N3,N3 -dimethyl propane hydrochloride -1 ,3-diamine (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 - 40% methanol in water and 0.05% ammonium hydroxide) to give 1 -(3,4-difluorobenzyl) -N - (9-methyl -8 -oxo - 6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) -1H -pyrazole -3 -carboxamide (10 .8 mg, 24%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J = 2.4 Hz, 1H), 7.27 - 7.21 (m , 2H), 7.09 — 7.01 (m, 2H), 6.95 (d, J = 1.2 Hz, 1H), 6.75 - 6.74 (m, 1H), 5.38 ( s, 2H), 4.53 - 4.48 (m, 1H), 4.31 - 4.26 (m, 1H), 4.06 - 4.03 (m, 1H), 3.38 (s, 3H) 2.85 - 2.79 (m, 1H), 2.29 - 2.23 (m, 1H). LCMS RT = 1.99 min.; m/z = 401.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min.) retention time 1.99 mln., ESI+ found [M+H] = 401.1. Example 178

[0703] WX METHOD UUUUUU 1 -(3,4-difluorobenzyl) -N -(9 -methyl -8 -oxo -6,7,8,9 - tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 - il) - 1H -imidazole -4 -carboxamide

[0704] A mixture of 1 - [(3,4 - difluorophenyl) methyl] imidazole -4 -carboxylic acid (26 mg, 0.11 mmol), 7 -amino -9 -methyl -6,7 -dihydro -5H - imidazo [1,2 - a] [1,3] diazepin -8(9H) -one (20 mg, 0.11 mmol), N1 -((ethylimino) methylene hydrochloride) -N3,N3 -dimethyl propane -1 ,3-diamine (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 - 43% methanol in water and 0.05% ammonium hydroxide) to give 1 -(3,4-difluorobenzyl) -N - (9-methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin - 7 -yl) -1H -imidazole -4 -carboxamide (13 .1 mg, 29%) as a white solid: H NMR (400 MHz, CD3OD) δ 7.78 (s, 1H), 7.67 (s, 1H), 7.28 - 7.23 (m, 2H), 7.11 — 7.08 (m, 2H), 6.94 (d, J = 1.6 Hz, 1H), 5.23 (s, 2H), 4.50 - 4, 46 (m, 1H), 4.31 - 4.26 (m, 1H), 4.07 - 4.02 (m, 1H), 3.38 (s, 3H), 2.86 - 2.80 ( m, 1H), 2.25 - 2.19 (m, 1H). LCMS RT = 1.85 min.; m/z = 401.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.85 mln., ESI+ found [M+H] = 401.1. Example 179

[0705] WX METHOD DDDDDD (S) -5 -benzyl -N -(1 -isopropyl -4 -methyl -5 - oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin - 6 -yl) -4H -1,2,4 -triazole -3 -carboxamide Step1: 1 -isopropyl -4 -nitro -1H -pyrazole

[0706] To a solution of 4-nitro-1H-pyrazole (10.0 g, 88.4 mmol) in N, N -dimethylformamide (50 mL) was added potassium carbonate (36.7 g, 265.3 mmol) and stirred under 25°C for 1 h, then 2-iodopropane (17.6 mL, 176.9 mmol) was added. The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 1-isopropyl-4-nitro-pyrazole (11.0 g, 80%) in the form of a yellow solid: 1H NMR (400MHz, CD3OD) δ 8.58 (s, 1H), 8.09 (s, 1H), 4.61 - 4.54 (m, 1H) , 1.52 (d, J = 6.4 Hz, 6H). Step 2: 5 -chloro -1 -isopropyl -4 -nitro -1H pyrazole

[0707] To a cooled solution (isopropyl-4-nitro-pyrazole (5.0 g, 32.2 mmol) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl) azanide (1.0 M, 34.9 mL, 34.9 mmol) dropwise. The mixture was stirred under -78°C for 30 min. and then hexachloroethane (8.36 g, 35.3 mmol) was added. The mixture was stirred under 25°C for 18 h and finalized by addition of saturated aqueous ammonium chloride (80 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (50 mL), saline solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether ) to provide 5-chloro-1-isopropyl-4-nitro-pyrazole (5.0 g, 82%) as a colorless solid: 1H NMR (400MHz, CD3OD) δ 8.26 (s, 1H), 4.85 - 4.80 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H). Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-((1-isopropyl-4-nitro-1H-pyrazol-5-yl)oxy)propanoic acid

[0708] A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (4.38 g, 21.4 mmol) in N,N-dimethylformamide (30 mL) was Sodium hydride (1.1 g, 28.5 mmol, 60%) was added under 0°C. The mixture was subjected to stirring at 0°C for 1 h. On this occasion, 5-chloro-1-isopropyl-4-nitro-pyrazole (2.7 g, 14.2 mmol) was added. After addition, the mixture was subjected to stirring at 20°C for another 3 h, and then finalized by adding water (30 ml). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica (0 - 100% ethyl acetate in petroleum ether) to provide (S) -2 -((tert -butoxycarbonyl)amino) -3 -((1 -isopropyl) acid -4-nitro-1H-pyrazol-5-yl)oxy) propanoic acid (0.7 g, 14%) as a yellow oil: LCMS RT = 0.68 min.; m/z = 302.9 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.68 mln., ESI+ found [M -55] = 302.9. Step 4: (S)-3-((4-amino-1-isopropyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino) propanoic acid

[0709] A mixture of (S) -2 -((tert - butoxycarbonyl) amino) -3 -((1 -isopropyl -4 -nitro -1H - pyrazol -5 -yl) oxy)propanoic acid (0.2 g , 0.56 mmol) and 10% palladium on carbon (59 mg, 0.06 mmol) in methanol (20 mL) was hydrogenated [4.46 bar [4.46 bar (50 psi)]] under 25°C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide (S)-3-((4-amino-1-isopropyl-1H-pyrazol-5-yl)oxy acid)-2-((tert-butoxycarbonyl )amino) propanoic acid (180 mg, 98%) as a black oil: LCMS RT = 0.558 min.; m/z = 328.9 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.558 mln., ESI+ found [M+H] = 328.9, Step 5: (S) -tert -butyl(1 -isopropyl -5 -oxo -4,5,6,7 - tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -6 - yl) carbamate

[0710] To a solution of (S)-3-((4-amino-1-isopropyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (540 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (378 mg, 1.97 mmol). The reaction mixture was stirred at 25°C for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide (S)-tert-butyl(1-isopropyl-5-oxo- 4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin - 6 -yl)carbamate (170 mg, 33%) as a brown solid: LCMS RT = 0.79 min.; m/z = 254.9 (M -56)+. LCMS (5 -95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79mln., ESI+ found [M -56] + = 254.9, Step 6: (S) -tert -butyl(1 -isopropyl -4 -methyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin - 6-yl)carbamate

[0711] To a solution of (S) -tert -butyl (1 isopropyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 - b] [1,4] oxazepin -6 -yl) carbamate (170 mg, 0.55 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (151 mg, 1.10 mmol) and iodomethane (94 mg, 0.66 mmol). The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide (S)-tert-butyl(1-isopropyl-4-methyl -5 -oxo -4,5,6,7 -tetrahydro -1H - pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) carbamate (120 mg, 68%) in the form of an oil green color. LCMS RT = 0.69 min.; m/z = 268.9 (M+H)+. trifluoroacetic acid for 1.5 min.) retention time 0.69 mln., ESI+ found [M - 56] + = 268.9. Step 7: (S) -6 -amino -1 -isopropyl -6,7 -dihydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -5(4H) -one

[0712] A mixture of (S) -tert -butyl (1 - isopropyl -4 -methyl -5 -oxo -4,5,6,7 -tetrahydro -1H - pyrazole [3,4 -b] [1,4 ] oxazepin-6-yl) carbamate (100 mg, 0.31 mmol) and hydrochloric acid (4 M in EtOAc, 5.0 mL, 20.0 mmol) in ethyl acetate (5 mL) was subjected to stirring under 25 °C for 2 h. The reaction mixture was adjusted to pH = 8 by addition of ammonium hydroxide and then concentrated under reduced pressure to provide (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazole [3 ,4 -b] [1,4] crude oxazepin -5(4H) -one (69 mg, 100%) as a white solid, which was used in the next step without any further purification. Step 8: (S)-5-benzyl -N -(1-isopropyl -4 - methyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4 ] oxazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[0713] A mixture of (S) -6 -amino -1 -isopropyl - 6,7 -dihydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -5(4H) - one (13 mg , 0.06 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (12 mg, 0.06 mmol), 1H-benzo[d][1,2,3]triazole - 1-ol (9 mg, 0.07 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (13 mg, 0.07 mmol) in N,N-dimethyl formamide (4 mL) was stirred under 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (0-40% acetonitrile/0.1% ammonium hydroxide in water) to provide (S)-5-benzyl-N-( 1 -isopropyl -4 -methyl -5 -oxo -4,5,6,7 -tetrahydro -1H - pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) -4H -1,2, 4 - triazole -3 -carboxamide (7 mg, 28%) as white solids: 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.35 - 7.21 (m, 5H), 4.67 - 4.64 (m, 1H), 4.60 - 4.53 (m, 2H), 4.45 - 4.40 (m, 1H), 4.18 (s, 2H) , 3.37 (s, 3H), 1.45 - 1.40 (m, 6H). LCMS RT = 0.99 min.; m/z = 410.3 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.99 mln., ESI+ found [M+H] = 410.3. Example 180

[0714] WX FFFFFF METHOD (S) -1 -(3,4-difluorobenzyl) -N -(1 -isopropyl - 4 -methyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 - b] [1,4] oxazepin -6 -yl) -1H -imidazole -4 -carboxamide

[0715] A mixture of (S) -6 -amino -1 -isopropyl - 6,7 -dihydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -5(4H) - one (17 mg , 0.08 mmol), 1 - [(3,4 - difluorophenyl)methyl] pyrazole -3 -carboxylic acid (19 mg, 0.08 mmol), 1H -benzo [d] [1,2,3] triazole - 1 -ol (13 mg, 0.09 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (17 mg, 0.09 mmol) in N,N - dimethyl formamide (4 mL) was stirred under 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (0 - 40% acetonitrile/0.1% ammonium hydroxide in water) to give (S)-1-(3,4-difluorobenzyl ) -N -(1 - isopropyl -4 -methyl -5 -oxo -4,5,6,7 -tetrahydro -1H - pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) -1H -imidazole -4 - carboxamide (13 mg, 39%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.78 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 7.29 - 7.18 (m, 2H), 7.12 - 7.10 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 5.39 (s, 2H), 4.67 - 4.53 (m, 3H), 4, 44 - 4.39 (m, 1H), 3.37 (s, 3H), 1.46 - 1.40 (m, 6H). LCMS RT 1.117 min.; m/z = 445.3 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.117 mln., ESI+ found [M + H] + = 445.3. Example 181

[0716] WX METHOD IIIIII (S) -5 -benzyl -N -(1,4 -dimethyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -6 - il) - 4H -1,2,4 -triazole -3 -carboxamide

[0717] A mixture of (S) -6 -amino -1,4 -dimethyl - 6,7 -dihydropyrazole [3,4 -b] [1,4] oxazepin -5 -one (24 mg, 0.12 mmol ), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (25 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (19 mg, 0.15 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to give (S)-5-benzyl-N -(1,4 -dimethyl -5 -oxo -4,5,6,7 -tetrahydro -1H - pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) -4H -1,2, 4 - triazole -3 -carboxamide: 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 1H), 7.38 - 7.31 (m, 5H), 4.98 - 4.93 (m, 1H ), 4.72 - 4.69 (m, 1H), 4.58 - 4.53 (m, 1H), 4.34 (s, 2H), 3.72 (s, 3H), 3.37 ( s, 3H). LCMS RT = 0.74 min.; m/z = 382.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.74 mln., ESI+found [M+H] = 382.1. Example 182

[0718] WX METHOD JJJJJJ (S)-1-(3,4-difluorobenzyl)-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1, 4] oxazepin -6 -yl) -1H -pyrazole -3 -carboxamide

[0719] A mixture of (S) -6 -amino -1,4 -dimethyl - 6,7 -dihydropyrazole [3,4 -b] [1,4] oxazepin -5 -one (24 mg, 0.12 mmol ), 1 - [(3,4-difluorophenyl)methyl] pyrazole - 3 -carboxylic acid (32 mg, 0.13 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (19 mg, 0.15 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to give (S)-1-(3.4 - difluorobenzyl) -N -(1,4 -dimethyl -5 -oxo -4,5,6,7 - tetrahydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -6 -yl) - 1H -pyrazole -3 -carboxamide (14 mg, 27%) as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.79 (s, 1H), 7.65 (s, 1H), 7.26 - 7.21 (m, 2H), 7.12 - 7.10 (m, 1H), 6.79 (d, J = 2.0 Hz, 1H), 5.39 (s, 2H) , 4.81 - 4.78 (m, 1H), 4.68 - 4.65 (m, 1H), 4.50 - 4.45 (m, 1H), 3.71 (s, 3H), 3 .37 (s, 3H). LCMS RT = 0.80 min.; m/z = 417.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.80 mln., ESI+found [M+H] = 417.1. Example 183

[0720] WX METHOD LOL (S)-1-(3,4-difluorobenzyl)-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1, 4] oxazepin -6 -yl) -1H -imidazole -4 -carboxamide

[0721] A mixture of (S) -6 -amino -1,4 -dimethyl - 6,7 -dihydropyrazole [3,4 -b] [1,4] oxazepin -5 -one (24 mg, 0.12 mmol ), 1 - [(3,4-difluorophenyl) methyl] imidazole -4 -carboxylic acid (32 mg, 0.13 mmol), 1H -benzo [d] [1,2,3] triazole -1 -ol (19 mg, 0.15 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to give (S) -1 -(3,4 - difluorobenzyl) -N -(1,4 -dimethyl -5 -oxo -4,5,6,7 - tetrahydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -6 -yl) - 1H - imidazole -4 -carboxamide (16 mg, 32%) as a white solid: 1H NMR (400 MHz, CD3OD) δ9.24 (s, 1H), 8.24 (s, 1H), 7.62 (s, 1H), 7.52 — 7.50 (m, 1H), 7.40 - 7.35 (m, 2H), 5.50 (d, J = 6.0 Hz, 2H), 5, 00 - 4.93 (m, 1H), 4.65 - 4.57 (m, 2H), 3.70 (s, 3H), 3.35 (s, 3H). LCMS RT = 0.74 min.; m/z = 417.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.74 mln., ESI+found [M+H] = 417.0. Examples 184 and 185

[0722] Unsubstituted acid from Method K and WX Method C (R) -1 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - ( trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide Step 1: Ethyl 1 -ethyl -5 -(trifluoromethyl) - 4,5,6,7 -tetrahydro -1H -indazole -3 -carboxylate

[0723] To a solution of ethyl 5 -(trifluoromethyl) - 4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylate (600 mg, 2.3 mmol) in N,N -dimethylformamide (15 mL ) potassium carbonate (474 mg, 3.4 mmol) and iodoethane (426 mg, 2.8 mmol) were added. The mixture was stirred at 25°C for 15 h and finalized by adding ice water (10 ml). The resulting mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep TLC (30% ethyl acetate in petroleum ether) to give ethyl 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole- 3 - carboxylate (300 mg, 45%) in the form of a white solid: 1H NMR (400 MHz, CD3OD) δ 4.37 — 4.31 (m, 1H), 4.16 - 4.10 (m , 1H), 3.32 - 3.29 (m, 1H), 2.96 - 2.93 (m, 1H), 2.78 - 2.50 (m, 3H), 2.34 - 2.23 (m, 1H), 1.78 - 1.73 (m,1H), 1.40 (q, J = 7.2 Hz, 6H). Step 2: 1-Ethyl -5 -(trifluoromethyl)-4,5,6,7 tetrahydro -1H -indazole -3 -carboxylic acid

[0724] A mixture of ethyl 1 -ethyl -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylate (388 mg, 1.3 mmol) and potassium hydroxide (375 mg , 6.7 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 25°C for 15 h. The solvent was removed under reduced pressure. The residue was dissolved in water (10 mL) and adjusted to pH = 3 by addition of hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (263 mg, 75%) as white solids: LCMS RT = 1.13 min.; m/z = 263.0 (M+H)+. formic acid for 2.0 min.) retention time 1.13 mln., ESI+ found [M+H] = 263.0. Step 3: (R) -1 -ethyl -N -((S) -5 -methyl -4 -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide and

[0725] (S) -1 -ethyl -N -((S) -5 -methyl -4 -oxo 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide

[0726] To a solution of 1-ethyl -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxylic acid (263 mg, 1.0 mmol) in N,N -dimethyl formamide (5 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (193 mg, 1.0 mmol), (E) hydrochloride -3 -(ethyldiazenyl) -N,N -dimethylpropan -1 -amine (8 mg, 0.04 mmol) and 1 -benzo [d] [1,2,3] triazol -1 -ol (385 mg, 2, 0 mmol). The resulting solution was stirred at 25°C for 13 h and then concentrated under reduced pressure. The residue was purified by RP - HPLC (48 -78% acetonitrile in water and 0.05% FA) to provide 1-ethyl -N -((S) -5 -methyl -4 -oxo -2, 3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide (360 mg, 82 .2%) in the form of a white solid.

[0727] The retro exposed racemate was separated using chiral SFC to provide:

[0728] Peak 1 (retention time 0.545 mln., 96.0% ee, arbitrarily assigned R configuration) (61 mg, 16.9%): 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.41 (m, 1H), 7.35 - 7.23 (m, 3H), 4.96 - 4.89 (m, 1H), 4.62 - 4.56 (m, 1H), 4.39 - 4 .36 (m, 1H), 4.12 - 4.08 (m, 2H), 3.41 (s, 3H), 3.11 - 3.06 (m, 1H), 2.92 - 2.86 (m, 1H), 2.72 - 2.46 (m, 3H), 2.23 - 2.13 (m, 1H), 1.74 - 1.71 (m, 1H), 1.41 (t , J = 7.2 Hz, 3H). LCMS RT = 0.84 min.; m/z = 437.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 1.5 min.) retention time 0.84 mln., ESI+ found [M+H] = 437.2.

[0729] Peak 2 (retention time 0.908 mln., 93.0% ee, arbitrarily assigned S configuration) (55 mg, 13.5%): 1H NMR (400 MHz, CD3OD) δ 7.43 - 7.41 (m, 1H), 7.32 - 7.23 (m, 3H), 4.97 - 4.93 (m, 1H), 4.60 - 4.55 (m, 1H), 4.37 - 4 .32 (m, 1H), 4.11 - 4.07 (m, 2H), 3.41 (s, 3H), 3.12 - 3.07 (m, 1H), 2.84 - 2.78 (m, 1H), 2.72 - 2.41 (m, 3H), 2.27 - 2.15 (m, 1H), 1.73 - 1.70 (m, 1H), 1.40 (t , J = 7.2 Hz, 3H). LCMS RT = 0.84 min.; m/z = 437.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 1.5 min.) retention time 0.84 mln., ESI+ found [M+H] = 437.2, Example 186

[0730] WX BB METHOD 5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1,4,5, 7 - tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide Step1: 2 -ethyltetrahydro -2H -pyran -4 -ol

[0731] A mixture of propionaldehyde (5.0 g, 86.0 mmol) and but -3 -en -1 -ol (6.2 g, 86.0 mmol) in 20% sulfuric acid (100 mL) was subjected to stirring at 80°C for 12 h. The mixture was cooled and then adjusted to pH = 9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 20 to 30% ethyl acetate in petroleum ether) to give 2-ethyltetrahydro-2H-pyran-4-ol (10.0 g , 91%) in the form of a light yellow oil: 1H NMR (400 MHz, CDCI3) δ 4.03 - 3.98 (m, 1H), 3.80 - 3.72 (m,1H), 3 .42 - 3.35 (m, 1H), 3.21 - 3.14 (m, 1H), 1.98 - 1.93 (m, 1H), 1.90 - 1.84 (m, 2H) , 1.63 - 1.42 (m, 3H), 1.22 - 1.13 (m, 1H), 0.93 (t, J = 7.6 Hz, 3H). Step 2: 2 -ethyldihydro -2H -pyran -4(3H) -one

[0732] To a solution of 2-ethyltetrahydro-2H-pyran-4-ol (10.0 g, 76.8 mmol) in dichloromethane (50 mL) was added pyridinium chlorochromate (22.7 g, 105.6 mmol ) in parts for 5 min. The reaction was stirred for 18 h at 25°C and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2-ethyldihydro-2H-pyran-4(3H)-one ( 8.3 g, 84%) in the form of a light yellow oil, which was used in the next step as it was: 1H NMR (400 MHz, CDCl3) δ 4.30 - 4.25 (m, 1H ), 3.73 - 3.61 (m, 1H), 3.52 - 3.46 (m, 1H), 2.62 - 2.53 (m, 1H), 2.42 - 2.23 (m , 3H), 1.72 - 1.62 (m, 1H), 1.60 - 1.50 (m, 1H), 0.96 (t, J = 7.6 Hz, 3H) Step 3: ethyl 5 -ethyl -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxylate

[0733] To a solution of 2-ethyldihydro-2H-pyran-4(3H)-one (4.5 g, 35.1 mmol) was added pyrrolidine (125 mg, 1.75 mmol) and ethyl diazoacetate (2. 0 g, 17.5 mmol). The mixture was stirred for 15 h at 25°C and then diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give ethyl 5-ethyl -1,4 ,5,7 - tetrahydropyran [3,4 -c] pyrazole -3 -carboxylate (640 mg, 16%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ4.94 (d, J = 14.8 Hz, 1H), 4.71 (d, J = 14.4, 1H), 4.42 - 4.36 (m, 2H), 3.51 - 3.45 (m, 1H), 2.94 - 2.89 (m, 1H), 2.61 - 2.54 (m, 1H), 1.78 - 1.66 (m, 2H), 1.41 - 1.38 (m, 3H ), 1.07 - 1.03 (m, 3H). Step 4: 5-ethyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0734] A mixture of ethyl 5-ethyl -1,4,5,7 - tetrahydropyran [3,4 -c] pyrazole -3 -carboxylate (50 mg, 0.22 mmol) and hydrated lithium hydroxide (94 mg, 2.23 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to provide crude 5-ethyl-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (40 mg, 91.4%) as a light yellow solid, which was used in the next step without any further purification. Step 5: 5-ethyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1,4, 5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide

[0735] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (43 mg, 0.22 mmol), 5-ethyl acid -1, 4,5,7-tetrahydropyran[3,4-c]pyrazole-3-carboxylic acid (40 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47 mg, 0.24 mmol) and 1-hydroxybenzotriazole (33 mg, 0.24 mmol) in N,N-dimethylformamide (3 mL) was stirred under 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 24 -54 with 0.05% ammonium hydroxide in water) to give 5-ethyl -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide (9 mg, 11%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.42 - 7.40 (m, 1H), 7.30 - 7.28 (m, 2H), 7.24 - 7.21 (m, 1H), 5.00 - 4.94 (m, 1H), 4.82 - 4.67 (m, 1H), 4.60 - 4.58 ( m, 2H), 4.36 - 4.35 (m, 1H), 3.42 - 3.41 (m, 4H), 2.85 - 2.80 (m, 1H), 2.52 - 2, 32 (m, 1H), 1.70 - 1.60 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H). LCMS RT = 1.03 min.; m/z = 371.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.03 mln., ESI+ found [M+H] = 371.2. Example 187

[0736] WX METHOD F 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4,5,6,7 - tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 - carboxamide Step 1: Methyl 2-(4-methylpyridin-2-yl) acetate

[0737] A mixture of 2-(4-bromo-2-pyridyl) methyl acetate (600 mg, 2.6 mmol), potassium carbonate (721 mg, 5.2 mmol), trimethylboroxine (982 mg, 7, 8 mmol) and tetrakis (triphenylphosphine) palladium (0) (47 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was heated at 120 ° C for 4 h under nitrogen. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate) to provide 2-(4-methylpyridin-2-yl) methyl acetate (350 mg, 81% ) in the form of a brown oil, which was used in the next step without any further purification. Step 2: methyl 5 -methyl - [1,2,3] triazolo [1,5 - a] pyridine -3 -carboxylate

[0738] To a solution of 2-(4-methylpyridin-2-yl) methyl acetate (300 mg, 1.82 mmol) in acetonitrile (10 mL) was added 4-acetamido benzene sulfonyl azide (436 mg, 1. 82 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (415 mg, 2.72 mmol) under 0°C. The resulting mixture was stirred at 20°C for 2 h and then concentrated under reduced pressure. The residue was purified with prep TLC (50% ethyl acetate in petroleum ether) to give methyl, methyl 5-methyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate ( 200 mg, 57%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.71(d, J = 6.8 Hz, 1H), 8.05 (s, 1H), 6 .98 (d, J = 6.8 Hz, 1H), 4.05 (s, 3H), 2.54 (s, 3H Step 3: methyl 5 -methyl -4,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxylate

[0739] A mixture of methyl 5-methyl - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxylate (200 mg, 1.0 mmol) and 10% palladium on carbon (111 mg, 0.1 mmol) in methanol (5 mL) was hydrogenated [4.46 bar [4.46 bar (50 psi)]] under 25°C for 48 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide methyl 5 -methyl -4,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -crude carboxylate (200 mg, 98%) as a brown solid: LCMS RT = 1.22 min.; m/z = 196.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide over 3.0 min.) retention time 1.22 mln., ESI+ found [M+H] =196.1 Step 4: 5-Methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid

[0740] A mixture of methyl 5 -methyl -4,5,6,7 - tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 - carboxylate (100 mg, 0.51 mmol) and potassium hydroxide (287 mg, 5.1 mmol) in ethanol (5 mL) and water (1 mL) was stirred under 25°C for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH = 4 by addition of hydrochloric acid (2.0 M). The solution was concentrated under reduced pressure to provide crude 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid (80 mg , 86%) in the form of a white solid, which was used in the next step without any further purification. Step 6: 5-methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 4.5, 6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxamide

[0741] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (40 mg, 0.21 mmol), 5 -methyl -4 acid, 5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxylic acid (38 mg, 0.21 mmol), 1H -benzo [d] [1,2,3 ] triazol -1 -ol (42 mg, 0.31 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (59 mg, 0.31 mmol) in N, N -dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (60 to 90% acetonitrile in water and 0.05% ammonium hydroxide) to give 5-methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4,5,6,7 - tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 - carboxamide (20 mg, 27%) as a white solid: 1H NMR (400 MHz, DMSO - d 6) δ 8.42 - 8.39 (m , 1H), 7.51 - 7.47 (m, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.21 (m, 1H), 4.88 - 4.81 (m, 1H), 4.65 - 4.57 (m, 1H), 4.55 - 4.47 (m, 1H), 4.42 - 4.36 (m, 1H), 4.24 - 4 .20 (m, 1H), 3.31 (s, 3H), 3.15 - 3.07 (m, 1H), 2.44 - 2.31 (m, 2H), 2.01 - 1.95 (m, 1H), 1.72 - 1.63 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). LCMS RT = 0.81 min.; m/z = 356.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.81 mln., ESI+ found [M+H] =356.1, Example 188

[0742] WX METHOD HHHHHH (S) -N -((S) -1,4 -dimethyl -5 -oxo -4,5,6,7 - tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -6 - il) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H -indazole -3 - carboxamide Step1: 1 -methyl -4 -nitro -1H -pyrazole

[0743] To a solution of 4-nitro-1H-pyrazole (10.0 g, 88.4 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (36.67 g, 265.3 mmol) and iodomethane (25.1 g, 176.8 mmol). The mixture is stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 1-methyl-4-nitro-1H-pyrazole (10.0 g, 89%) in the form of a yellow solid, which was used in the next step without any further purification. Step 2: 5 -chloro -1 -methyl -4 -nitro -1H - pyrazole

[0744] To a cooled solution (-78°C) of 1-methyl-4-nitro-1H-pyrazole (5.0 g, 39.4 mmol) in tetrahydrofuran (50 mL) was added bis(trimethylsilyl) azanide lithium (1.0 M, 39.4 mL, 39.4 mmol) dropwise. The mixture was stirred at -78°C for 30 min, and hexachloroethane (11.1 g, 47.2 mmol) was added. After addition, the mixture was stirred at 25°C for 18 h and then finalized by addition of saturated aqueous ammonium chloride (80 ml). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 5-chloro-1-methyl-4-nitro-1H-pyrazole (5.0 g, 79%) in the form of a white solid, which was used in the next step as it was. Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-((1-methyl-4-nitro-1H-pyrazol-5-yl)oxy)propanoic acid

[0745] A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (3.1 g, 14.9 mmol) in N,N-dimethylformamide (50 mL) was Sodium hydride (1.2 g, 29.7 mmol, 60%) was added under 0°C. The mixture was stirred at 0°C for 1 h and then 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.0 g, 12.4 mmol) was added. Stirring was continued at 20°C for 3 h, and the reaction mixture was finished by adding hydrochloric acid (2.0 M, 30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide (S)-2-((tert-butoxycarbonyl)amino acid) -3 -((1 -methyl -4 -nitro -1H -pyrazol -5 -yl)oxy) propanoic acid (0.6 g, 15%) in the form of a yellow oil. LCMS RT = 0.77 min.; m/z = 352.9 (M+Na)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.77 mln., ESI+ found [M+Na] + = 352.9. Step 4: (S)-3-((4-amino-1-methyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0746] A mixture of (S) -2 -((tert - butoxycarbonyl)amino) -3 -((1 -methyl -4 -nitro -1H -pyrazol -5 -yl)oxy) propanoic acid (600 mg, 1 .82 mmol) and 10% palladium on carbon (193 mg, 0.18 mmol) in methanol (50 mL) was hydrogenated [4.46 bar (50 psi)] under 20°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide (S)-3-((4-amino-1-methyl-1H-pyrazol-5-yl)oxy acid)-2-((tert - butoxycarbonyl) amino) propanoic acid (500 mg, 92%) in the form of a yellow oil: LCMS RT = 0.523 min.; m/z = 301.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.523 mln., ESI+ found [M+H] + = 301.1. Step 5: (S) -tert -butyl(1-methyl -5 -oxo - 4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin - 6 -yl) carbamate

[0747] To a solution of (S) -3 -((4 -amino -1 -methyl -1H -pyrazol -5 -yl) oxy) -2 -((tert - butoxycarbonyl) amino) propanoic acid (0.5 g, 1.66 mmol) in N,N-dimethylformamide (10 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (383 mg, 2.00 mmol ). The reaction mixture was stirred at 20°C for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide (S)-tert-butyl(1-methyl-5-ox o - 4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin - 6 -yl)carbamate (200 mg, 43%) in the form of a yellow oil. Step 6: (S) -tert -butyl(1,4 -dimethyl -5 -oxo - 4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin - 6 - il) carbamate

[0748] To a solution of (S) -tert -butyl (1-methyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxaze pin -6-yl) carbamate (0.2 g, 0.71 mmol) in N,N-dimethylformamide (10 mL) was added iodomethane (121 mg, 0.85 mmol) and potassium carbonate (196 mg, 1. 42 mmol). The reaction mixture was stirred at 20°C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide (S)-tert-butyl(1,4-dimethyl-5- oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) carbamate (200 mg, 95%) in the form of a yellow oil. LCMS RT = 0.61 min.; m/z = 226.8 (M -56)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.61 mln., ESI+ found [M -56] + = 226.8. Step 7: (S) -6 -amino -1 -methyl -6,7 -dihydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -5(4H) -one

[0749] A mixture of (S) -tert -butyl (1,4 - dimethyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] ox azepin-6-yl) carbamate (200 mg, 0.67 mmol) and hydrochloric acid (4 M in EtOAc, 2 mL, 8 mmol) in ethyl acetate (5 mL) was subjected to stirring under 20°C for 2 h . The reaction mixture was adjusted to pH = 8 by adding ammonium hydroxide. The mixture was then concentrated under reduced pressure to provide (S)-6-amino-1-methyl-6,7-dihydro-1H-pyrazole [3,4-b] [1,4] oxazepin -5(4H) -one (130 mg, 101%) as a yellow solid, which was used in the next step without any further purification. Step 8: (S)-N -((S) -1,4 -dimethyl -5 -oxo - 4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepine - 6 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro -1H - indazole -3 -carboxamide

[0750] A mixture of (S) -6 -amino -1,4 -dimethyl - 6,7 -dihydropyrazole [3,4 -b] [1,4] oxazepin -5 -one (24 mg, 0.12 mmol ), (5S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (32 mg, 0.13 mmol), 1H-benzo[d][1.2 .3] triazol -1 -ol (19 mg, 0.15 mmol) and N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to give (S) -N -((S) - 1,4 -dimethyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -6 -yl) - 5 -(trifluoromethyl) -4, 5,6,7 -tetrahydro -1H -indazole -3 - carboxamide (10 mg, 20%) as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.65 (s, 1H), 5.06 - 4.95 (m, 1H), 4.68 — 4.65 (m, 1H), 4.49 — 4.44 (m, 1H), 3.72 (s, 3H), 3, 37 (s, 3H), 3.20 - 3.15 (m, 1H), 2.94 - 2.84 (m, 1H), 2.79 - 2.49 (m, 3H), 2.27 - 2.18 (m, 1H), 1.82 - 1.67 (m, 1H). LCMS RT = 0.79 min.; m/z = 413.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79 mln., ESI+found [M+H] = 413.0. Example 189

[0751] WX METHOD S 2,2-difluoro -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1',4',6',7' - tetrahydrospiro [cyclopropane -1,5' -indazole] -3' - carboxamide Step 1: 1,1 -difluorospiro [2,5]octan -6 -one

[0752] To a mixture of 8-methylene -1,4 - dioxaspiro [4,5] decane (1.2 g, 7.8 mmol), sodium fluoride (33 mg, 0.78 mmol) in xylene (5 mL) a solution of trimethylsilyl-2,2-difluoro-2-(fluorosulfonyl) acetate (4.9 g, 19.5 mmol) in xylene (4 mL) was added dropwise over a period of 1 h under 120°C. After addition, the mixture was stirred for an additional 1 h and then cooled to 20°C. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl in petroleum ether) to provide a yellow colored oil. The material was diluted with tetrahydrofuran (30 mL) and hydrochloric acid (35%, 3 mL) added. The resulting mixture was stirred at 20°C for 16 h and then adjusted to pH = 7 by addition of saturated aqueous sodium bicarbonate. The solution was then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 1,1-difluorospiro[2.5]octan-6-one (300 mg, 24.2% over 2 steps) in the form of a colorless oil: 1H NMR (400 MHz, CDC13) δ 2.51 — 2.39 (m, 4H), 2.01 - 1.95 (m , 4H), 1.26 (t, J = 8.4 Hz, 2H). Step 2: ethyl 2 -(1,1 -difluoro -6 -oxospiro [2,5]octan -5 -yl) -2 -oxoacetate

[0753] To a solution of 1,1-difluorospiro [2,5] octan-6-one (300 mg, 1.87 mmol) in ethanol (15 mL) was added sodium ethanoxide (140 mg, 2.06 mmol ) and diethyl oxalate (274 mg, 1.87 mmol) at 0°C. After addition, the mixture was allowed to warm to 20°C for 20 h. The solution was concentrated under reduced pressure to provide crude ethyl 2-(1,1-difluoro-6-oxospiro[2,5]octan-5-yl)-2-oxoacetate (480 mg, 99%) as a yellow solid, which was used in the next step without any further purification. Step 3: ethyl 2,2-difluoro-1',4',6',7'-tetrahydrospiro[cyclopropane-1,5'-indazole]-3'-carboxylate

[0754] To a solution of ethyl 2 -(1,1-difluoro -6 - oxospiro [2,5] octan -5 -yl) -2 -oxoacetate (480 mg, 1.84 mmol) in acetic acid (5 mL ) hydrazine hydrate (130 mg, 2.03 mmol, 50%) was added under 0°C. The reaction was stirred at 25°C for 1 h and then terminated by addition of saturated aqueous sodium bicarbonate. The mixture was extracted with methonal/dichloromethane (1:10) (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide ethyl 2,2-difluoro-1',4',6', 7'-tetrahydrospiro [cyclopropane -1,5'-indazole]-3'-carboxylate (150 mg, 32%) as a yellow oil: LCMS RT = 0.688 min.; m/z = 256.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.688 mln., ESI+ found [M+H] =256.8. Step 4: 2,2-difluoro-1',4',6',7'-tetrahydrospiro[cyclopropane-1,5'-indazole]-3'-carboxylic acid

[0755] A mixture of ethyl 2,2-difluoro-1',4',6',7'-tetrahydrospiro [cyclopropane-1,5'-indazole]-3'-carboxylate (150 mg, 0.59 mmol) and lithium hydroxide hydrate (140 mg, 5.85 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred for 20 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by addition of hydrochloric acid (1.0 M). The aqueous layer was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 2,2-difluoro-1',4',6',7'-tetrahydrospiro[cyclopropane-1,5'-indazole] acid. -3'-carboxylic acid (50 mg, 37%) in the form of a white solid, which was used in the next step without any further purification. Step 5: 2,2-difluoro -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1',4',6',7' -tetrahydrospiro [cyclopropane -1,5' -indazole] -3' -carboxamide

[0756] A mixture of 2,2-difluoro-1',4',6',7'-tetrahydrospiro[cyclopropane-1,5'-indazole]-3'-carboxylic acid (50 mg, 0.22 mmol ), 1H -benzo [d] [1,2,3] triazol -1 -ol (36 mg, 0.26 mmol), (3S) -3 - amino -5 -methyl -2,3 -dihydro -1, 5-Benzoxazepin -4 -one (46 mg, 0.24 mmol) and N1 -((ethylimino) methylene) - N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (50 mg, 0.26 mmol) in N N-dimethylformamide (5 mL) was stirred at 20°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (34-64% acetonitrile in water and 0.05% hydrochloric acid) to give 2,2-difluoro-N-((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1',4',6',7' -tetrahydrospiro [cyclopropane -1 ,5'-indazol]-3'-carboxamide (37 mg, 41%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 13.04 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.24 - 7.22 ( m, 1H), 4.85 - 4.80 (m, 1H), 4.51 - 4.47 (m, 1H), 4.42 - 4.38 (m, 1H), 3.31 (s, 3H), 2.79 - 2.74 (m, 1H), 2.70 - 2.67 (m, 2H), 2.59 - 2.55 (m, 1H), 1.80 - 1.78 ( m, 2H), 1.38 - 1.32 (m, 1H), 1.28 - 1.23 (m, 1H). LCMS RT = 0.836 min.; m/z = 403.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.836 mln., ESI+ found [M+H] =403.1.

[0757] Example 190 was prepared according to a WX Method B (see Example 171 described previously). The data is shown in Table 2. Example 191

[0758] WX GG METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - [1,2 ,3] triazolo [1,5 -a] pyridine -3 -carboxamide Step 1: Methyl 2 - [4 -(trifluoromethyl) -2 - pyridyl] acetate

[0759] A mixture of 1 -oxide -4 -(trifluoromethyl) pyridin -1 -ium (500 mg, 3.1 mmol), N, N - diisopropylethylamine (1.2 g, 9.2 mmol), 1 -( tert-butyldimethylsilyloxy)-1-methoxyethene (1.1 g, 6.1 mmol) and bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (1.6 g, 3.4 mmol) in tetrahydrofuran (15 mL) was heated under 45°C for 2 h and then poured into water (20 ml). The resulting solution was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide methyl 2-[4-(trifluoromethyl)-2-pyridyl acetate ] crude (485 mg, 72%) as a yellow oil: LCMS RT = 0.633 min.; m/z = 219.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.633 mln., ESI+ found [M+H] = 219.9. Step 2: Methyl 5 -(trifluoromethyl)triazole [1,5 - a] pyridine -3 -carboxylate

[0760] To a solution of methyl 2-[4-(trifluoromethyl)-2-pyridyl] acetate (480 mg, 2.19 mmol) in acetonitrile (12 mL) was added 1,8-diazabicyclo[5,4,0 ] undec-7-ene (500 mg, 3.29 mmol) and 4-acetamido benzene sulfonyl azide (526 mg, 2.19 mmol) under 0°C. The resulting mixture was allowed to warm to 25°C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to give methyl 5-(trifluoromethyl) triazolo[1,5-a]pyridine-3-carboxylate (380 mg, 71%) as a yellow solid: 1H NMR (400 MHz, DMSO - ds) δ 9.53 (d, J = 7, 2 Hz, 1H), 8.48 (s, 1H), 7.71 — 7.68 (m, 1H), 3.98 (s, 3H). LCMS RT = 0.749 min.; m/z = 245.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.749 mln., ESI+ found [M+H] = 245.9. Step 3: 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylic acid

[0761] A mixture of methyl 5 -(trifluoromethyl) triazolo [1,5 -a] pyridine -3 -carboxylate (75 mg, 0.31 mmol) and hydrated lithium hydroxide (36 mg, 1.53 mmol) in tetrahydrofuran (5 mL) was stirred at 23°C for 18 h. The organic solvent was evaporated under reduced pressure, and the aqueous residue was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure to provide crude 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylic acid (40 mg, 57%) as a white solid, which was used in the next step without any further purification. Step 4: (S) -N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) - [1 ,2,3] triazolo [1,5 -a] pyridine -3 - carboxamide

[0762] A mixture of 5 -(trifluoromethyl) triazolo [1,5 -a] pyridine -3 -carboxylic acid (40 mg, 0.17 mmol), (3s) -3 -amino -5 -methyl -2,3 -dihydro -1,5 - benzoxazepin -4 -one (37 mg, 0.19 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (28 mg, 0.21 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (40 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring under 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 39 -69%/0.05% ammonia in water) to give (S)-N-(5-methyl-4-oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoro methyl) - [1,2,3] triazolo [1,5 -a] pyridine -3 - carboxamide (37.3 mg, 53%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.47 (d, J = 7.6 Hz, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 7.67 — 7.61 (m, 1H), 7.56 - 7.49 (m, 1H), 7, 38 - 7.22 (m, 3H), 5.00 - 4.91 (m, 1H), 4.77 - 4.70 (m, 1H), 4.48 - 4.43 (m, 1H), 3.33 (s, 3H). LCMS RT = 0.861 min.; m/z = 406.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.861 mln., ESI+ found [M+H] = 406.0. Example 192

[0763] WX HH Method N -((S) -5 -methyl -4 -oxo tetrahydrobenzo [b] [1,4] oxazepin -3 (trifluoromethyl) -4,5,6,7 -tetrahydro [1,5 -a] pyridine -3 - carboxamide Step 1: Methyl 5 -(trifluoromethyl) -4,5,6,7 - tetrahydrotriazole [1,5 -a] pyridine -3 -carboxylate

[0764] A mixture of methyl 5 -(trifluoromethyl) triazolo [1,5 -a] pyridine -3 -carboxylate (150 mg, 0.61 mmol) and 10% palladium on carbon (65 mg, 0.06 mmol) in methanol (5 mL) was hydrogenated [4.46 bar (50 psi)] under 25°C for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude methyl 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate (82 mg , 54%) as a yellow oil: LCMS RT = 0.704 min.; m/z = 249.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.704 mln., ESI+ found [M+H] = 249.9. Step 2: 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazole[1,5-a]pyridine-3-carboxylic acid

[0765] A mixture of methyl 5 -(trifluoromethyl) - 4,5,6,7 -tetrahydrotriazole [1,5 -a] pyridine -3 - carboxylate (82 mg, 0.33 mmol) and hydrated lithium hydroxide (39 mg, 1.65 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred under 23°C for 18 h. After evaporation of the organic solvent, the residue of the aqueous layer was adjusted to pH = 5 by adding hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure to provide crude 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid (60 mg, 77%) as a white solid, which was used in the next step without any further purification. Step 3: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -4 ,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxamide

[0766] A mixture of 5 -(trifluoromethyl) - 4,5,6,7 -tetrahydrotriazolo [1,5 -a] pyridine -3 - carboxylic acid (60 mg, 0.26 mmol), 1H -benzo [d ] [1,2,3] triazol -1 -ol (41 mg, 0.31 mmol), (3s) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (54 mg, 0.28 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethyl propane-1,3-diamine hydrochloride (59 mg, 0.31 mmol) in N,N-dimethylformamide ( 5 mL) was subjected to stirring at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 33 -63%/0.05% ammonia in water) to give N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -4,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxamide (45.8 mg, 44%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.56 - 8.49 (m , 1H), 7.53 - 7.46 (m, 1H), 7.40 - 7.15 (m, 3H), 4.91 - 4.80 (m, 1H), 4.68 - 4.60 (m, 2H), 4.44 - 4.23 (m, 2H), 3.31 (s, 3H), 3.15 - 3.02 (m, 1H), 2.89 - 2.79 (m , 1H), 2.53 - 2.51 (m, 1H), 2.34 - 2.26 (m, 1H), 2.13 - 1.99 (m, 1H). LCMS RT = 0.833 min.; m/z = 410.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.833 mln., ESI+ found [M+H] = 410.0. Example 193

[0767] WX METHOD L (S) -N -(5-methyl -4 -oxo -2,3,4,5 tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -2 (trifluoromethyl) imidazo [1,5 -a] pyrimidine -8 carboxamide Step 1: ethyl 2 -((diphenylmethylene) amino) -2 -(4 -(trifluoromethyl) pyrimidin -2 -yl) acetate

[0768] A mixture of 2-chloro-4-(trifluoromethyl) pyrimidine (2.0 g, 11.0 mmol), potassium carbonate (2.3 g, 16.4 mmol), tetrabutyl ammonium bromide (1. 8 g, 5.5 mmol) and ethyl n -(diphenylmethylene) glycinate (1.5 g, 5.5 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was heated under 100°C for 12 h. After cooling, the reaction mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with water (3 x 50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give ethyl 2-(benzhydrylidene amino)-2-(4-(trifluoromethyl ) pyrimidin-2-yl) acetate (1.9 g, 42%) as a yellow oil: LCMS RT = 0.90 min.; m/z = 414.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.90 mln., ESI+found [M+H] = 414.1. Step 2: Ethyl 2-amino-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate hydrochloride

[0769] To a solution of ethyl 2 -(benzhydrylidene amino) -2 -(4 -(trifluoromethyl) pyrimidin -2 -yl) acetate (200 mg, 0.48 mmol) in dichloromethane (10 mL) was slowly added hydrochloric acid (1.0 M, 12 mL, 12 mmol). The reaction mixture was stirred for 3 h under 25°C and the layers were separated. The aqueous layer was washed with dichloromethane (2 x 20 mL) and then concentrated under reduced pressure to provide crude ethyl 2-amino-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate hydrochloride (100 mg, 83%) as a light yellow solid: LCMS RT = 0.41 min.; m/z = 250.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.41 mln., ESI+found [M+H] = 250.1. Step 3: ethyl 2-formamido -2 -(4 - (trifluoromethyl)pyrimidin -2 -yl) acetate

[0770] Formic acid (98%, 0.8 mL) was added to acetic anhydride (2 mL) under 0°C. The resulting solution was stirred for 4 h at 50°C. This anhydride solution was added slowly into a solution of ethyl 2-amino-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate hydrochloride (100 mg, 0.40 mmol) in tetrahydrofuran (5 mL) under 0 °C. After addition, stirring continued for another 6 h. The reaction mixture was finished by adding water (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (4 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -20% methanol in dichloromethane) to provide ethyl 2-formamido-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate (70 mg, 63%) as a light yellow solid: LCMS RT = 0.63 min.; m/z = 278.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.63 mln., ESI+found [M+H] = 278.1. Step 4: ethyl 2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate

[0771] A solution of ethyl 2-formamido-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate (70 mg, 0.25 mmol) in phosphoryl trichloride (2 mL) was heated at 115°C for 12 h under nitrogen. After cooling, the reaction mixture was poured into ice water (30 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with brine (2 x 30 mL), dried over sodium sulfate and concentrated under reduced pressure to provide ethyl 2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (55 mg, 84%) as a light yellow solid: LCMS RT = 1.78 min.; m/z = 260.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 7.0 min.) retention time 1.78 mln., ESI+found [M+H] = 260.1. Step 5: (S)-N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -2 - (trifluoromethyl) imidazo [1 ,5 -a] pyrimidine -8 - carboxamide

[0772] A mixture of (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one (40 mg, 0.21 mmol) and ethyl 2 -(trifluoromethyl) imidazo[1,5-a]pyrimidine-8-carboxylate (54 mg, 0.21 mmol) in tetrahydrofuran (20 mL) was added trimethylaluminum (2.0 M, 0.62 mL, 1.25 mmol) dropwise under nitrogen atmosphere. The mixture was stirred at 75°C for 15 h, cooled and then finalized by addition of saturated aqueous sodium potassium tartrate (10 ml). The resulting mixture was stirred at 25°C for 1 h and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (40-70% acetonitrile/0.05% ammonium hydroxide in water) to provide (S)-N-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxamide (14 mg, 16%) as a solid yellow color: 1H NMR (400 MHz, DMSO -d6) δ 9.14 (d, J = 6.8 Hz, 1H), 8.68 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.36 - 7.25 (m, 3H), 4.95 - 4.88 (m, 1H), 4.55 - 4.44 (m, 2H), 3.34 (s, 3H). LCMS RT = 1.233 min.; m/z = 406.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.233 mln., ESI+ found [M+H] = 406.1,

[0773] Example 194 was prepared according to a GG Method (see Example 35). The data is shown in Table 2, Example 195

[0774] WX METHOD VVVVVV 1-benzyl -N -(9-methyl -8 -oxo -6,7,8,9 - tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) -1H -1 ,2,4-triazole-3-carboxamide

[0775] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (41 mg, 0.20 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo [ 1,2 -a] [1,3] diazepin - 8(9H) -one (30 mg, 0.17 mmol), N1 hydrochloride - ((ethylimino)methylene) -N3,N3 -dimethyl propane -1,3 - diamine (45 mg, 0.25 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (34 mg, 0.25 mmol) in N,N -dimethylformamide (4 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (46-76% acetonitrile/0.05% ammonium in water) to give 1-benzyl-N-(9-methyl-8- oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 - a] [1,3] diazepin -7 -yl) -1H -1,2,4 -triazole -3 - carboxamide (26, 6 mg, 42%) as a colorless solid: 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 7 .39 - 7.30 (m, 5H), 7.13 (s, 1H), 6.88 (s, 1H), 5.48 (s, 2H), 4.32 - 4.22 (m, 2H ), 3.95 - 3.90 (m, 1H), 3.25 (s, 3H), 2.67 - 2.65 (m, 1H), 2.39 - 2.33 (m, 1H). LCMS RT = 1.36 min.; m/z = 366.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.36 mln., ESI+ found [M+H] = 366.1. Example 196

[0776] WX METHOD WWWWWW 1-benzyl -N -(9-methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) -1H-1 ,2,3-triazole-4-carboxamide

[0777] A mixture of 1-benzyltriazole-4-carboxylic acid (41 mg, 0.20 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo [1,2-a] [1 .3] diazepin -8(9H) -one (30 mg, 0.17 mmol), N1 -((ethylimino)methylene) - N3 ,N3 -dimethyl propane -1,3 -diamine hydrochloride (45 mg, 0. 25 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (34 mg, 0.25 mmol) in N,N -dimethylformamide (4 mL) was subjected to stirring at 25ºC for 12 H. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (46-76% acetonitrile/0.05% ammonium in water) to give 1-benzyl-N-(9-methyl-8-oxo -6,7,8,9 - tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin -7 -yl) -1H -1,2,3 -triazole -4 -carboxamide (12 mg, 19%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.68 (s, 1H), 8.66 (s, 1H), 7.38 - 7.33 (m , 5H), 7.12 (s, 1H), 6.88 (s, 1H), 5.65 (s, 2H), 4.32 - 4.23 (m, 2H), 3.94 - 3, 90 (m, 1H), 3.25 (s, 3H), 2.67 (s, 1H), 2.37 - 2.33 (m, 1H). LCMS RT = 1.425 min.; m/z = 366.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.425 mln., ESI+ found [M+H] = 366.1. Example 197

[0778] WX METHOD GGGGGG (S)-5-benzyl -N -(1-isopropyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazolo [3,4 -b] [1,4] oxazepine -6 -yl ) -4H -1,2,4 -triazole -3 -carboxamide

[0779] A mixture of acid (S) -6 -amino -1 - isopropyl -6,7 -dihydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -5(4H) -one (15 mg, 0.07 mmol), 5 -benzyl -4H - 1,2,4 -triazole -3 -carboxylic acid (15 mg, 0.07 mmol), 1H - benzo [d] [1,2,3] triazole - 1 -ol (13 mg, 0.09 mmol) and N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (17 mg, 0.09 mmol) in N,N - dimethyl formamide (4 mL) was stirred under 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (12-42% acetonitrile/0.05% ammonium hydroxide in water) to give (S)-5-benzyl-N-(1 -isopropyl -5 - oxo -4,5,6,7 -tetrahydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide (8 mg, 28%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.34 - 7.26 (m, 5H), 7.25 - 7.20 (m, 1H), 4.87 - 4.68 (m, 1H), 4.67 - 4.64 (m, 1H), 4.55 - 4.51 (m, 1H), 4.41 - 4.36 ( m, 1H), 4.18 (s, 2H), 1.41 (d, J = 7.2 Hz, 6H). LCMS RT = 0.93 min.; m/z = 396.2 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.05% ammonium bicarbonate over 3 min.) retention time 0.93/mln., ESI+ found [M+H] = 396.2. Example 198

[0780] WX METHOD YYYYYY 1 -benzyl -N -(6 -oxo -4,5,6,7,8,9 -hexahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -7 -yl) -1H -1, 2,4 - triazole -3 -carboxamide

[0781] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (40 mg, 0.20 mmol), 7-amino-4,5,8,9-tetrahydro-3-oxa- 1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (40 mg, 0.19 mmol), N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (44 mg, 0.23 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL) was subjected stirring under 25°C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25-55 acetonitrile/0.05% ammonium hydroxide in water) to give 1-benzyl-N-(6-oxo- 4,5,6,7,8,9 -hexahydro -3 -oxa -1,5a,9a - triazabenzo [cd] azulen -7 -yl) -1H -1,2,4 -triazole -3 - carboxamide (24 mg, 31%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.84 (s, 1H), 8.71 (d, J = 6.8 Hz, 1H), 7.40 - 7.31 (m, 5H), 7.27 (s, 1H), 5.50 (s, 2H), 4.76 (t, J = 8.0 Hz, 1H), 4.41 - 4.29 (m, 4H), 3.96 (t, J = 8.0 Hz, 1H), 3.32 - 3.28 (m, 1H), 2.50 - 2.27 (m, 2H ). LCMS RT = 1.09 min.; m/z = 394.2 (M+H)+. LCMS (0 to 60% acetonitrile in water +0.03% trifluoroacetic acid for 2 min.) retention time 1.09 mln., ESI+ found [M+H] =394.2. Example 199

[0782] WX METHOD XXXXXX 5 -benzyl -N -(6 -oxo -4,5,6,7,8,9 -hexahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -7 -yl) -4H -1, 2,4 - triazole -3 -carboxamide Step 1: 4 -benzylmorpholin -3 -one

[0783] To a solution of morpholin-3-one (10.0 g, 98.9 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (3.96 g, 98.9 mmol, 60%). The reaction mixture was stirred at 0°C for 0.5 h and then benzyl bromide (16.9 g, 98.9 mmol) was added. The reaction mixture was stirred at 20°C for 15 h and then poured into ice water (100 ml). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 75% ethyl acetate in petroleum ether) to provide 4-benzylmorpholin-3-one (10.0 g, 53%) in the form of a colorless oil, which was used in the next stage as it was. Step 2: 7-benzyl-1,5,6,7-tetrahydropyrazole[4,3-b][1,4]oxazine

[0784] N,N-dimethylformamide (9.9 g, 135.4 mmol) was added dropwise to a solution of phosphoryl trichloride (16.8 g, 110.0 mmol) in 1,2-dichloroethane ( 40 mL) under 0°C. The mixture was allowed to stir for 10 min. and then 4-benzylmorpholin-3-one (7.0 g, 36.6 mmol) in 1,2-dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0°C for 30 ml, at 25°C for 3 h and at 45°C for 1 h. The solvent was removed under reduced pressure and the residue was diluted with ethanol (80 ml). The solution was cooled to 0°C and hydrazine hydrate (18.3 g, 366.0 mmol, 85%) added dropwise. After addition, the mixture was stirred for 1 h at -5°C, for 2 h at 25°C and for 15 h at 60°C to provide a clear, dissolved, dark red solution that gradually emerged. . Then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 7-benzyl-1,5,6,7-tetrahydropyrazole [4, 3-b] [1,4] oxazine (3.0 g, 38%) as a white solid: LCMS RT = 0.84 min.; m/z = 216.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.84 mln., ESI+ found [M+H] =216.2. Step 3: 1,5,6,7-tetrahydropyrazole[4,3-b][1,4]oxazine

[0785] To a solution of 7-benzyl -1,5,6,7 -tetrahydropyrazole [4,3-b] [1,4] oxazine (3.0 g, 13.9 mmol) in 2-propanol ( 50 mL) 10% palladium on carbon (5.93 g, 5.57 mmol) was added. The reaction mixture was stirred at 20°C under a hydrogen atmosphere [2.04 bar (15 psi)] for 15 h and then filtered. The filtrate was concentrated under reduced pressure to provide 1,5,6,7-tetrahydropyrazole[4,3-b][1,4]oxazine (1.7 g, 98%) as a yellow oil , which was used in the next step without any further purification. Step 4: 4 -chloro -1 -(5,6 -dihydropyrazole [4,3 - b] [1,4] oxazin -7(1H) -yl)butan -1 -one

[0786] A solution of 1,5,6,7-tetrahydropyrazole [4,3-b] [1,4] oxazine (1.8 g, 14.4 mmol) in 4-chlorobutanoyl chloride (10.1 g , 71.9 mmol) was subjected to stirring at 50°C for 1 h. The reaction mixture was terminated by slowly adding methanol (20 mL) and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 4-chloro-1-(5,6-dihydropyrazole [4,3 -b] [1,4] oxazin -7(1H) -yl) butan -1 -one (3.0 g, 91%) as a yellow solid: LCMS RT = 0.86 min.; m/z = 230.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.86 mln., ESI+ found [M+H] =230.2. Step 5: 4,5,8,9 -tetrahydro -3 -oxa -1,5a,9a - triazabenzo [cd] azulen -6(7H) -one

[0787] To a solution of 4 -chloro -1 -(5,6 - dihydropyrazole [4,3 -b] [1,4] oxazin -7(1H) -yl)butan -1 - one (500 mg, 2 .18 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.4 g, 4.35 mmol). The reaction mixture was stirred at 25°C for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 4,5,8,9-tetrahydro-3-oxa-1, 5a,9a -triazabenzo [cd] azulen -6(7H) -one (300 mg, 71%) as a white solid: LCMS RT = 0.83 min.; m/z = 194.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.83 mln., ESI+ found [M+H] =194.1. Step 6: 7 -iodine -4,5,8,9 -tetrahydro -3 -oxa - 1,5a,9a -triazabenzo [cd] azulen -6(7H) -one

[0788] A solution of 4,5,8,9 -tetrahydro -3 -oxa - 1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (100 mg, 0.52 mmol) in dichloromethane ( 10 mL) was treated with iodotrimethylsilane (621 mg, 3.11 mmol) and N1,N1,N2,N2 - tetramethylethane -1,2 -diamine (360 mg, 3.11 mmol) under -15oC. The mixture was stirred under -15°C for 1.5 h, then iodine (394 mg, 1.55 mmol) was added in one portion. After addition, the mixture was stirred at -15°C for 2 h and then finalized by addition of saturated aqueous sodium sulfite solution (5%, 40 mL). The mixture was extracted with dichloromethane (3 x 40 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 7 -iodo -4,5,8,9 -tetrahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (80 mg, 48%) in the form of a light yellow solid, which was used in the next step in the form in which it was . Step 7: 7 -azide -4,5,8,9 -tetrahydro -3 -oxa - 1,5a,9a -triazabenzo [cd] azulen -6(7H) -one

[0789] To a solution of 7 -iodo -4,5,8,9 - tetrahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (50 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (14 mg, 0.21 mmol). The reaction mixture was stirred at 25°C for 2 h and then poured into ice-cold water (5 ml). The solution was extracted with dichloromethane (2 x 10 mL). The combined organic layers were concentrated under reduced pressure to provide 7-azide -4,5,8,9 -tetrahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (36 mg, 98%) as a light yellow oil: LCMS RT = 1.39 min.; m/z = 235.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.39 mln., ESI+ found [M+H] =235.1... Step 8: 7 -amino -4,5,8,9 -tetrahydro -3 -oxa - 1,5a,9a -triazabenzo [cd] azulen -6(7H) -one

[0790] A mixture of 7-azide -4,5,8,9 -tetrahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (36 mg, 0.15 mmol ) and 10% palladium on carbon (164 mg, 0.15 mmol) in methanol (10 mL) was hydrogenated (15 psi) under 25°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 7-amino -4,5,8,9 -tetrahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -6(7H )-one (30 mg, 94%) in the form of a black oil, which was used in the next step without any further purification. 5 -benzyl -N -(6 -oxo -4,5,6,7,8,9 -hexahydro -3 -oxa -1,5a,9a -triazabenzo [cd] azulen -7 -yl) -4H -1, 2,4 - triazole -3 -carboxamide

[0791] A mixture of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (40 mg, 0.20 mmol), 7-amino-4,5,8,9-tetrahydro-3- oxa -1,5a,9a -triazabenzo [cd] azulen -6(7H) -one (40 mg, 0.19 mmol), N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride -1,3 -diamine (44 mg, 0.23 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL) was subjected to stirring at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (10-40 acetonitrile/0.05% ammonium hydroxide in water) to give 5-benzyl-N-(6-oxo- 4,5,6,7,8,9 -hexahydro -3 -oxa -1,5a,9a - triazabenzo [cd] azulen -7 -yl) -4H -1,2,4 -triazole -3 - carboxamide (13 .9 mg, 18%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 14.48 (br. s., 1H), 8.75 (s, 1H), 7, 36 - 7.22 (m, 6H), 4.80 - 4.72 (m, 1H), 4.39 - 4.24 (m, 4H), 4.13 (s, 2H), 4.00 - 3.92 (m, 1H), 3.30 - 3.27 (m, 1H), 2.50 - 2.27 (m, 2H). LCMS RT = 1.09 min.; m/z = 394.2 (M+H)+. LCMS (0 to 60% acetonitrile in water +0.03% trifluoroacetic acid for 2 min.) retention time 1.09 mln., ESI+ found [M+H] =394.2. Example 200

[0792] WX METHOD T (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -6 -(trifluoromethyl) - [1,2 ,4] triazolo [4,3 -a] pyrazine -3 -carboxamide Step 1: 2-hydrazinyl-5-(trifluoromethyl)pyrazine

[0793] To a mixture of 2-chloro-5-(trifluoromethyl) pyrazine (2.0 g, 11.0 mmol) in ethanol (20 mL) was added hydrazine hydrate (50%, 2.2 g, 21. 9 mmol). The mixture was stirred at 45°C for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane) to provide 2-hydrazinyl-5-(trifluoromethyl) pyrazine (1.2 g, 62%) as a yellow solid: LCMS RT = 1.393 min.; m/z = 179.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% formic acid for 3 min.) retention time 1.393 mln., ESI+ found [M+H] =179.1. Step 2: ethyl 2 -oxo -2 -(2 -(5 -(trifluoromethyl) pyrazin -2 -yl) hydrazinyl) acetate

[0794] To a solution of 2-hydrazinyl -5 - (trifluoromethyl) pyrazine (1.1 g, 6.2 mmol) and triethylamine (937 mg, 9.26 mmol) in dichloromethane (20 mL) was added ethyl chloride oxalyl (1.0 g, 7.4 mmol) under 0°C. The mixture was stirred at 25°C for 20 h and then quenched by addition of water (30 ml). The resulting mixture was extracted with dichloromethane (3 x 35 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give ethyl 2 - oxo -2 - (2 - (5-(trifluoromethyl)pyrazin-2-yl)hydrazinyl)acetate (1.5 g, 87%) as a dark yellow solid: LCMS RT = 1.511 min.; m/z = 279.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% formic acid for 3 min.) retention time 1.511 mln., ESI+ found [M+H] =279.1. Step 3: ethyl 6 -(trifluoromethyl) - [1,2,4] triazolo [4,3 -a] pyrazine -3 -carboxylate

[0795] A mixture of ethyl 2 -oxo -2 -(2 -(5 - (trifluoromethyl) pyrazin -2 -yl) hydrazinyl) acetate (1.0 g, 3.6 mmol) and p -toluene sulfonic acid (310 mg, 1.8 mmol) in toluene (20 mL) was heated under 115°C for 20 h. After cooling, the solution was diluted with water (20 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate ( 600 mg, 64%) as a red solid: LCMS RT = 0.613 min.; m/z = 261.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.613 mln., ESI+ found [M+H] =261.1. Step 4: (S) -N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -6 - (trifluoromethyl) - [1 ,2,4] triazolo [4,3 -a] pyrazine -3 - carboxamide

[0796] A mixture of (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one (50 mg, 0.26 mmol) and ethyl 6 -(trifluoromethyl) -[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (61 mg, 0.23 mmol) in tetrahydrofuran (3 mL) was added trimethylaluminum (2.0 M, 0.78 mL, 1.56 mmol). The mixture was subjected to stirring at 50°C for 15 h and then finalized by addition of saturated aqueous sodium potassium tartrate (10 ml). Stirring was continued for 1 h and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using haRP-HPLC (30 -60% acetonitrile in water and 0.05% ammonium hydroxide) to provide (S) -N -(5 -methyl -4 -oxo -2,3, 4,5-tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -6 -(trifluoromethyl) - [1,2,4] triazolo [4,3 -a] pyrazine -3 -carboxamide (16 mg , 17%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.74 (s, 1H), 9.67 (s, 1H), 9.31 (s, 1H) , 7.55 - 7.52 (m, 1H), 7.35 - 7.26 (m, 3H), 4.96 - 4.92 (m, 1H), 4.81 - 4.74 (m, 1H), 4.49 - 4.44 (m, 1H), 3.33 (s, 3H). LCMS RT = 0.830 min.; m/z = 407.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.830 mln., ESI+ found [M+H] =407.0. Example 201

[0797] WX METHOD Y 5 -ethyl -5 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5, 7 - dihydrofuro [3,4 -c] pyridazine -3 –carboxamide Step 1: 3-chloro-5-ethyl-5-methylfuro[3,4-c]pyridazin-7(5H)-one

[0798] To a solution of 6-chloropyridazine-3-carboxylic acid (2.5 g, 15.8 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropyl azanide (2.0 M, 19.7 mL, 39 .4 mmol) under -78°C. The reaction mixture was stirred under -78°C for 1 h, and then butan-2-one (10.2 g, 141.9 mmol) was added. The reaction mixture was heated to 25°C and stirred for 16 h and then terminated by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 3-chloro-5-ethyl-5-methylfuro[3,4- c] pyridazin -7(5H) -one (300 mg, 9%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 2.16 - 2, 08 (m, 1H), 2.02 - 1.96 (m, 1H), 1.73 (s, 3H), 0.87 (t, J = 7.6 Hz, 3H). Step 2: 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazin-7-ol

[0799] To a solution of 3-chloro-5-ethyl-5-methylfuro[3,4-c]pyridazin-7(5H)-one (300 mg, 1.41 mmol) in toluene (15 mL) was added diisobutylaluminum hydride (1.0 M, 2.82 mL, 2.82 mmol) dropwise under -70°C. After addition, stirring was continued at -70°C for 2 h and the reaction mixture was terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 3-chloro-5-ethyl-5-methyl-5.7 - dihydrofuro [3,4 -c] pyridazin -7 -ol (250 mg, 83%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 3: 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine

[0800] To a solution of 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazin-7-ol (250 mg, 1.16 mmol) in dichloromethane (20 mL ) boron trifluoride diethyl etherate (826 mg, 5.82 mmol) was added under 0°C. Stirring continued for 30 min. under 0°C, and then triethyl silane (677 mg, 5.82 mmol) was added. The mixture was stirred for an additional 3 h at 25°C and then quenched by addition of saturated aqueous sodium bicarbonate. The resulting solution was extracted with dichloromethane (3 x 20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% ethyl acetate in petroleum ether) to provide 3-chloro-5-ethyl-5-methyl-5.7 -dihydrofuro [3,4-c] pyridazine (100 mg, 43%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 4: methyl 5 -ethyl -5 -methyl -5,7 -dihydrofuro [3,4 -c] pyridazine -3 –carboxylate

[0801] A mixture of 3-chloro-5-ethyl-5-methyl - 5,7-dihydrofuro [3,4-c] pyridazine (100 mg, 0.50 mmol), 1,1'-bis dichloride ( diphenylphosphine) palladium ferrocene (37 mg, 0.05 mmol) and triethylamine (255 mg, 2.52 mmol) in methanol (20 mL) was heated at 80°C for 4 h under carbon oxide [3.77 bar (40 psi)]. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 5-ethyl-5- methyl -5,7 -dihydrofuro [3,4 -c] pyridazine -3 -carboxylate (80 mg, 72%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 5: 5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxylic acid

[0802] A mixture of methyl 5 -ethyl -5 -methyl -5,7 -dihydrofuro [3,4 -c] pyridazine -3 - carboxylate (80 mg, 0.36 mmol) and hydrated lithium hydroxide (75.6 mg, 1.8 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred under 25°C for 2 h. After evaporation of the organic solvent under reduced pressure into the aqueous layer, it was acidified to pH = 5 by adding hydrochloric acid (1.0 M) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 5-ethyl-5-methyl-5,7-dihydrofuro acid [ 3,4 -c] pyridazine -3 -carboxylic crude (60 mg, 80%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 6: 5 -ethyl -5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 5,7 -dihydrofuro [3,4 -c] pyridazine -3 -carboxamide

[0803] A mixture of 5-ethyl -5 -methyl -5,7 -dihydrofuro [3,4 -c] pyridazine -3 -carboxylic acid (60 mg, 0.29 mmol), (3S) -3 -amino - 5 -methyl -2,3 -dihydro -1,5 - benzoxazepin -4 -one (66 mg, 0.34 mmol), N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 - hydrochloride diamine (66 mg, 0.34 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (46 mg, 0.34 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (30-60% acetonitrile/0.05% HCl in water) to give 5-ethyl-5-methyl-N-((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,7 -dihydrofuro [3,4 -c] pyridazine -3 - carboxamide (44.4 mg, 40%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.28 (d, J = 4.4 Hz, 1H), 8.14 (s , 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.34 - 7.25 (m, 3H), 5.26 (s, 2H), 4.97 - 4.92 ( m, 1H), 4.72 - 4.67 (m, 1H), 4.51 - 4.46 (m, 1H), 3.34 (s, 3H), 1.90 - 1.78 (s, 2H), 1.46 (s, 3H), 0.74 - 0.71 (m, 3H). LCMS RT = 0.831 min.; m/z = 383.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.831 mln., ESI+ found [M+H] += 383.1. Example 202

[0804] WX METHOD II (S)-1-ethyl -N -(5-methyl -4 -oxo -2,3,4,5 - [1,4] oxazepin -3 -yl) -1H -pyrazolo [4,3 -c] pyridine -6 -carboxamide Step 1: Methyl 1-ethylpyrazole[4,3-c]pyridine-6-carboxylate

[0805] To a solution of methyl 1H -pyrazolo[4,3-c]pyridine-6-carboxylate (300 mg, 1.70 mmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (702 mg, 5.06 mmol) and iodoethane (528 mg, 3.39 mmol). The reaction mixture was subjected to stirring at 45°C for 30 min. and then concentrated under reduced pressure. The residue was purified using haRP-HPLC (acetonitrile 7 -37/0.05% ammonia in water) to provide:

[0806] Methyl 1 -ethylpyrazole [4,3 -c] pyridine -6 - carboxylate (175 mg, 55%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.16 ( s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 4.60 - 4.54 (m, 2H), 3.91 (s, 3H), 1.41 (t , J = 7.6 Hz, 3H). LCMS RT = 1.185 min.; m/z = 206.1 (M+H)+.

[0807] Methyl 2 -ethylpyrazole [4,3 -c] pyridine -6 -carboxylate (110 mg, 35%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.23 ( s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 4.61 - 4.54 (m, 2H), 3.88 (s, 3H). 1.54 (t, J = 7.6 Hz, 3H). LCMS RT = 1.242 min.; m/z = 206.1 (M+H)+.

[0808] LCMS (0 to 60% acetonitrile in water + 0.04% formic acid for 3 min.) retention time 1.185 mln., ESI+ found [M+H] = 206.1, 1.242 mln., ESI+ found [M+H] = 206.1 Step 2: 1-ethylpyrazole[4,3-c]pyridine-6-carboxylic acid

[0809] A mixture of methyl 1-ethylpyrazole [4,3-c] pyridine-6-carboxylate (50 mg, 0.24 mmol) and lithium hydroxide hydrate (29 mg, 1.22 mmol) in tetrahydrofuran (5 mL ) and water (2 mL) was stirred at 25 °C for 18 h. The organic solvent was removed under reduced pressure and the residue of the aqueous layer was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure to provide crude 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 86%) as a white solid, which was used in the next step. without any further purification. Step 3: (S)-1-ethyl -N -(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - pyrazole [4,3 -c] pyridine -6 -carboxamide

[0810] A mixture of 1-ethylpyrazole [4,3-c]pyridine-6-carboxylic acid (40 mg, 0.21 mmol), (3s)-3-amino-5-methyl-2,3-dihydro- 1,5-benzoxazepin-4-one (44 mg, 0.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (34 mg, 0.25 mmol) and N1 hydrochloride -((ethylimino)methylene) - N3,N3 -dimethylpropane -1,3 -diamine (48 mg, 0.25 mmol) in N,N -dimethylformamide (5 mL) was subjected to stirring at 25°C for 1 h . The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (30-60% acetonitrile/0.05% ammonia in water) to give (S)-1-ethyl-N-(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazolo [4,3 -c] pyridine -6 -carboxamide (29.9 mg, 39.0%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.18 (s, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.57 - 7.47 (m, 1H), 7.41 - 7.23 (m, 3H), 4.97 - 4, 88 (m, 1H), 4.61 - 4.49 (m, 4H), 3.34 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H). LCMS RT = 0.812 min.; m/z = 366.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.812 mln., ESI+ found [M+H] = 366.1. Example 203

[0811] WX METHOD EEEEEE (S) -1 -benzyl -N -(1 -isopropyl -5 -oxo -4,5,6,7 -tetrahydro -1H -pyrazolo [3,4 -b] [1,4] oxazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide

[0812] A mixture of (S) -6 -amino -1 -isopropyl - 6,7 -dihydro -1H -pyrazole [3,4 -b] [1,4] oxazepin -5(4H) - one (27 mg , 0.13 mmol), 1-benzyl -1,2,4 -triazole -3 -carboxylic acid (27 mg, 0.13 mmol), 1H -benzo [d] [1,2,3] triazole -1 - ol (21 mg, 0.15 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (30 mg, 0.15 mmol) in N,N-dimethylformamide ( 4 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (0 - 40% acetonitrile/0.1% ammonium hydroxide in water) to give (S) -1 - benzyl -N -( 1 -isopropyl -5 -oxo -4,5,6,7 -tetrahydro -1H - pyrazole [3,4 -b] [1,4] oxazepin -6 -yl) -1H -1,2,4 - triazole - 3-carboxamide (7 mg, 14%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.37 (s, 5H), 7.20 (s, 1H), 5.49 (s, 2H), 4.83 (s , 1H), 4.67 — 4.64 (m, 1H), 4.56 — 4.48 (m, 1H), 4.40 — 4.36 (m, 1H), 1.43 - 1.40 (m, 6H). LCMS RT = 0.958 min.; m/z = 396.2 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.958 mln., ESI+ found [M + H] + = 396.2. Example 204

[0813] WX METHOD LLLLLL benzyl -N -(1-methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2 ,4 - triazole -3 -carboxamide Step 1: ethyl 4 -(5 -nitro -1H -imidazol -1 -yl)butanoate

[0814] A mixture of 5-nitro-1H-imidazole (60.0 g, 530.0 mmol), ethyl 4-bromobutyrate (109.0 g, 557.0 mmol) and potassium carbonate (146.0 g, 1.1 mol) in N,N-dimethylformamide (300 mL) was heated at 120°C for 2 h. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide ethyl 4 -(5 -nitro -1H -imidazol -1 -yl ) butanoate (7.0 g, 6%) in the form of a colorless oil, which was used in the next step without any further purification. Step 2: ethyl 4 -(5 -amino -1H -imidazol -1 -yl) butanoate

[0815] A mixture of ethyl 4 -(5-nitro -1H - imidazol -1 -yl) butanoate (7.0 g, 30.8 mmol) and 10% palladium on carbon (32.8 g, 30.8 mmol ) in 1,4-dioxane (300 mL) was hydrogenated (15 psi) under 25°C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide ethyl 4-(5-amino-1H-imidazol-1-yl)butanoate (4.0 g, 65%) as a brown oil: LCMS RT = 1.25 min.; m/z = 198.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium hydroxide for 3.0 min.) retention time 1.25 mln., ESI+ found [M+H] =198.2. Step 3: 4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0816] To a solution of ethyl 4 -(5-amino -1H - imidazol -1 -yl) butanoate (500 mg, 2.5 mmol) in ethanol (20 mL) was added sodium ethanolate (863 mg, 12. 7 mmol). The mixture was stirred at 25°C for 4 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 4,5 -dihydro -1H -imidazo [1,5 -a] [1,3 ] diazepin -2(3H) -one (200 mg, 52%) as a white solid. 1H NMR (400MHz, DMSO -d6) δ 9.66 (s, 1H), 7.48 (s, 1H), 6.53 (s, 1H), 4.04 (t, J = 6.8 Hz, 2H), 2.23 - 2.18 (m, 2H), 2.15 - 2.07 (m, 2H). Step 4: 1 -methyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0817] To a solution of 4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (200 mg, 1.23 mmol) in N,N - dimethylformamide (10 mL) was added cesium carbonate (431 mg, 1.32 mmol) and iodomethane (175 mg, 1.23 mmol). The mixture was stirred at 25°C for 3 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 1-methyl-4,5-dihydro-1H -imidazo [1,5 -a] [1,3] diazepin - 2(3H) -one (100 mg, 46%) in the form of a white solid, which was used in the next step in the form in which it was found . Step 5: 3 -iodo -1 -methyl -4,5 -dihydro -1H - imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0818] To a solution of 1 -methyl -4,5 -dihydro -3H - imidazo [1,5 -a] [1,3] diazepin -2 -one (100 mg, 0.61 mmol) in dichloromethane (10 mL) N1,N1,N2,N2 - tetramethylethane -1,2 - diamine (946 mg, 7.26 mmol) and iodotrimethylsilane (1.45 g, 7.26 mmol) were added under -15°C. The mixture was stirred at -15°C for 1.5 h, and then iodine (922 mg, 3.63 mmol) was added. Stirring continued for 3 h and the reaction was terminated by addition of saturated aqueous sodium sulfite solution (5%, 5 mL). The solution was extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (100 - 200 mesh silica gel, 0 to 10% methanol in dichloromethane) to provide 3-iodo -1 -methyl -4,5 -dihydro -1H -imidazo [1.5 -a] [1,3] diazepin -2(3H) -one (10 mg, 6%) as a light yellow solid: LCMS RT = 1.34 min.; m/z = 292.0 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.34 mln., ESI+ found [M+H] =292.0. Step 6: 3 -amino -1 -methyl -4,5 -dihydro -1H - imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0819] To a solution of 3 -iodo -1 -methyl -4,5 - dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (10.0 mg, 0.03 mmol) in N,N-dimethylformamide (3 mL) was added ammonium hydroxide (0.01 mL, 0.34 mmol). The reaction mixture was stirred at 80°C for 2 h and then concentrated under reduced pressure to provide 3-amino-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1, 3] diazepin -2(3H) -one (6 mg, 97%) in the form of a yellow oil, which was used in the next step without any further purification. Step 7: 1-benzyl -N -(1-methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) - 1H -1,2,4 -triazole -3 -carboxamide

[0820] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (6.8 mg, 0.03 mmol), 3-amino-1-methyl-4,5-dihydro-1H- imidazo [1,5 -a] [1,3] diazepin - 2(3H) -one (6.0 mg, 0.03 mmol), N1 hydrochloride - ((ethylimino)methylene) -N3,N3 -dimethylpropane - 1,3 -diamine (7.7 mg, 0.04 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (5.4 mg, 0.04 mmol) in N,N -dimethylformamide (2 mL) was stirred under 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 0 -40/0.1% ammonium in water) to give 1 -benzyl -N -(1 -methyl -2 - oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide (1,8 mg, 14%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.62 (s, 1H), 7.37 - 7.33 (m, 5H), 6.99 (s, 1H), 5 .47 (s, 2H), 4.85 - 4.59 (m, 1H), 4.45 - 4.39 (m, 1H), 4.03 - 3.97 (m, 1H), 3.35 (s, 3H), 2.79 - 2.72 (m, 1H), 2.20 - 2.15 (m, 1H). LCMS RT = 1.67 min.; m/z = 366.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate 3 min.) retention time 1.67 mln., ESI+ found [M+H] =366.1. Example 205

[0821] WX METHOD I 5 -(4-fluorophenyl) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1, 4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide Step1: 2 -(4-fluorophenyl) tetrahydro -2H -pyran -4 -ol

[0822] A mixture of 4-fluorobenzaldehyde (10.0 g, 86.0 mmol) and but -3 -en -1 -ol (11.6 g, 161.2 mmol) in 20% sulfuric acid (100 mL ) was subjected to stirring at 80°C for 12 h. The mixture was cooled and then adjusted to pH = 9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 20 to 30% ethyl acetate in petroleum ether) to provide 2 -(4-fluorophenyl) tetrahydro -2H -pyran -4 -ol (9.5 g, 56%) in the form of a light yellow oil, which was used in the next step without any further purification. Step 2: 2 -(4-fluorophenyl) dihydro -2H -pyran - 4(3H) -one

[0823] To a solution of 2 -(4-fluorophenyl) tetrahydro -2H -pyran -4 -ol (9.5 g, 48.4 mmol) in dichloromethane (50 mL) was added pyridiniochloro chromate (12.0 g, 55.7 mmol) in parts over 5 min. The reaction was stirred for 18 h at 25°C and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 2 -(4 - fluorophenyl) dihydro -2H -pyran -4( 3H)-one (7.2 g, 77%) in the form of a light yellow oil, which was used in the next step without any further purification. Step 3: ethyl 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazole-3-carboxylate

[0824] To a solution of 2-(4-fluorophenyl) dihydro-2H-pyran-4(3H)-one (2.00 g, 10.3 mmol) was added pyrrolidine (37 mg, 0.5 mmol) and ethyl diazo acetate (0.59 g, 5.2 mmol). The mixture was stirred for 15 h at 25°C and then diluted with water (30 ml). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide ethyl 5-(4-fluorophenyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 - carboxylate (130 mg, 4%) as a light yellow solid: 1H NMR (400 MHz, CDC13) δ7.42 - 7.39 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 5.11 - 5.07 (m, 1H), 4.92 - 4.89 (m, 1H ), 4.61 - 4.55 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.17 - 3.13 (m, 1H), 2.93 - 2, 86 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H). Step 4: 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0825] A mixture of ethyl 5 -(4-fluorophenyl) - 1,4,5,7 - tetrahydropyran [3,4 -c] pyrazol -3 - carboxylate (170 mg, 0.59 mmol) and lithium hydroxide hydrate (140 mg, 5.86 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to provide crude 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (70 mg, 46%) in form a light yellow solid: 1H NMR (400 MHz, DMSO -d6) δ7.51 - 7.45 (m, 2H), 7.23 - 7.16 (m, 2H), 4.92 - 4 .88 (m, 1H), 4.82 - 4.79 (m, 1H), 4.66 - 4.62 (m, 1H), 3.11 - 3.06 (m, 1H), 2.71 - 2.64 (m, 1H). Step 5: 5 -(4-fluorophenyl) -N -((S) -5 -methyl - 4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 - yl) -1,4,5,7 -tetra hydropyran [3,4 -c] pyrazole -3 - carboxamide

[0826] A mixture of 5 -(4-fluorophenyl) - 1,4,5,7 -tetrahydropyran [3,4 -c] pyrazol -3 - carboxylic acid (35 mg, 0.13 mmol), 1H -benzo [ d] [1,2,3] triazol -1 -ol (22 mg, 0.16 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro - 1,5 -benzoxazepine -4 - one (26 mg, 0.13 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (28 mg, 0.16 mmol) in N,N -dimethylformamide (3 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated to drying under reduced pressure and the residue was purified by haRP-HPLC (13 to 43% acetonitrile in water and 0.05% hydrochloric acid) to give 5-(4-fluorophenyl)-N - ((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide (41 mg, 70%) as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.48 — 7.38 (m, 3H), 7.30 - 7.28 (m, 3H), 7.09 - 7.06 (m, 2H), 4.98 - 4.93 (m, 2H), 4.88 - 4.83 (m, 1H), 4 .61 - 4.58 (m, 2H), 4.57 - 4.33 (m, 1H), 3.40 (s, 3H), 3.13 - 3.08 (m, 1H), 2.80 - 2.74 (m, 1H). LCMS RT = 1.12 min.; m/z = 437.2(M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.12 mln., ESI+ found [M+H] + = 437.2. Example 206

[0827] WX Method J 5 -(3,4-difluorophenyl) -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide Step1: 2 -(3,4-difluorophenyl) tetrahydro -2H - pyran -4 -ol

[0828] A mixture of 3,4-difluoro benzaldehyde (10.0 g, 70.4 mmol) and but -3 -en -1 -ol (5.1 g, 70.4 mmol) in 20% sulfuric acid (20 mL) was subjected to stirring at 80°C for 12 h. The mixture was cooled and then adjusted to pH = 9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2 -(3,4 - difluorophenyl) tetrahydro -2H -pyran -4 -ol (9.2 g, 61%) as a light yellow oil: 1H NMR (400 MHz, CDCI3) δ 7.17 — 7.04 (m, 2H), 7.00 (s, 1H ), 4.24 — 4.21 (m, 1H), 4.13 - 4.09 (m, 1H), 3.88 - 3.81 (m, 1H), 3.51 (t, J = 12 .0 Hz, 1H), 2.37 (br. s., 1H), 2.10 - 2.07 (m, 1H), 1.92 - 1.88 (m, 1H), 1.60 - 1 .50 (m, 1H), 1.43 - 1.35 (m, 1H). Step 2: 2 -(3,4-difluorophenyl) dihydro -2H - pyran -4(3H) -one

[0829] To a solution of 2 -(3,4-difluorophenyl) tetrahydro -2H -pyran -4 -ol (9.2 g, 43.0 mmol) in dichloromethane (50 mL) was added pyridiniochloro chromate (11.1 g, 51.5 mmol) portionwise over 5 min. The reaction was stirred for 18 h at 25°C and then filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2 -(3,4 - difluorophenyl) dihydro -2H - pyran -4(3H) -one (6.5 g, 71%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ7.50 - 7.44 (m, 1H), 6, 88 (t, J = 8.0 Hz, 1H), 6.80 - 6.74 (m, 1H), 4.87 - 4.84 (m, 1H), 4.42 - 4.37 (m, 1H), 3.85 - 3.78 (m, 1H), 2.73 - 2.61 (m, 2H), 2.55 - 2.49 (m, 1H), 2.42 - 2.38 ( m, 1H). Step 3: ethyl 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazole-3-carboxylate

[0830] To a solution of 2-(3,4-difluorophenyl) dihydro-2H-pyran-4(3H)-one (2.0 g, 9.4 mmol) in dimethyl sulfoxide (15 mL) was added pyrrolidine (34 mg, 0.5 mmol) and ethyl diazoacetate (538 mg, 4.7 mmol). The reaction was stirred for 16 h at 25°C and then diluted with water (30 mL). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 35% ethyl acetate in petroleum ether) to give ethyl 5 -(3 ,4 - difluorophenyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxylate (180 mg, 6%) as a light yellow solid: 1H NMR (400 MHz , CDCl3) δ7.30 - 7.27 (m, 1H), 7.16 - 7.13 (m, 2H), 5.12 - 5.08 (m, 1H), 4.92 - 4.88 ( m, 1H), 4.61 - 4.55 (m, 1H), 4.37 (q, J = 7.6 Hz, 2H), 3.17 - 3.12 (m, 1H), 2.91 - 2.80 (m, 1H), 1.34 (t, J = 7.6 Hz, 3H). Step 4: 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0831] A mixture of ethyl 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyran [3,4-c] pyrazole-3-carboxylate (180 mg, 0.58 mmol) and sodium hydroxide Hydrated lithium (139 mg, 5.80 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to provide crude 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (60 mg, 37 %) in the form of a light yellow solid: 1H NMR (400 MHz, DMSO - d 6) δ7.58 - 7.45 (m, 2H), 7.36 (s, 1H), 5.00 - 4 .96 (m, 1H), 4.88 - 4.85 (m, 1H), 4.72 - 4.70 (m, 1H), 3.18 (d, J = 12.0 Hz, 1H), 2.75 - 2.68 (m, 1H). Step5: 5 -(3,4-difluorophenyl) -N -((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl ) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 - carboxamide

[0832] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (20 mg, 0.11 mmol), 5 -(3,4 -difluorophenyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxylic acid (30 mg, 0.11 mmol), 1H - benzo [d] [1,2,3] triazole - 1 -ol (17 mg, 0.13 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (23 mg, 0.13 mmol) in N.N - dimethylformamide (3 mL) was subjected to stirring at 25°C for 2 h. The reaction was concentrated to drying under reduced pressure and the residue was purified by haRP-HPLC (13 to 43% acetonitrile in water and 0.05% hydrochloric acid) to give 5-(3,4-difluorophenyl)- N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1,4,5,7 -tetrahydropyran [ 3,4 -c] pyrazole -3 -carboxamide (27 mg, 55%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.40 - 7.21 (m, 7H), 5 .00 - 4.95 (m, 2H), 4.86 - 4.82 (m, 1H), 4.60 - 4.56 (m, 2H), 4.37 - 4.33 (m, 1H) , 3.31 (s, 3H), 3.16 - 3.12 (m, 1H), 2.75 - 2.67 (m, 1H). LCMS RT = 1.15 min.; m/z = 455.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.15 mln., ESI+ found [M+H] + = 455.2. Example 207

[0833] WX METHOD K 5 -(2,4-difluorophenyl) -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide Step1: 2 -(2,4-difluorophenyl) tetrahydro -2H - pyran -4 -ol

[0834] A mixture of 2,4-difluoro benzaldehyde (10.0 g, 70.4 mmol) and but -3 -en -1 -ol (5.1 g, 70.4 mmol) in 20% sulfuric acid (20 mL) was subjected to stirring at 80°C for 12 h. The mixture was cooled and then adjusted to pH = 9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2 -(2,4 - difluorophenyl) tetrahydro -2H -pyran - 4-ol (9.2 g, 61%) as a light yellow oil: 1H NMR (400 MHz, CDCI3) δ7.44 - 7.38 (m, 1H), 6.84 (t, J = 8.4 Hz, 1H), 6.77 - 6.71 (m, 1H), 4.55 (d, J = 11.0 Hz, 1H), 4.14 - 4.10 (m, 1H) , 3.93 - 3.85 (m, 1H), 3.55 (t, J = 12.0 Hz, 1H), 2.19 (br. s., 1H), 2.12 (m, 1H) , 1.94 - 1.90 (m, 1H), 1.64 - 1.53 (m, 1H), 1.49 - 1.39 (m, 1H). Step 2: 2 -(2,4-difluorophenyl) dihydro -2H - pyran -4(3H) -one

[0835] To a solution of 2 -(2,4-difluorophenyl) tetrahydro -2H -pyran -4 -ol (5.0 g, 23.5 mmol) in dichloromethane (50 mL) was added pyridiniochloro chromate (6.5 g, 28.0 mmol) in parts for 5 min. The reaction was stirred for 18 h at 25°C and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2 -(2,4 - difluorophenyl) dihydro -2H -pyran - 4(3H)-one (3.3 g, 66%) as a light yellow oil: 1H NMR (400 MHz, CD3OD) δ7.24 - 7.09 (m, 2H), 7.04 ( s, 1H), 4.59 - 4.56 (m, 1H), 4.42 - 4.37 (m, 1H), 3.83 - 3.76 (m, 1H), 2.72 - 2, 59 Step 3: ethyl 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazole-3-carboxylate

[0836] To a solution of 2-(2,4-difluorophenyl) dihydro-2H-pyran-4(3H)-one (2.5 g, 11.8 mmol) in dimethyl sulfoxide (12 mL) was added pyrrolidine (84 mg, 1.2 mmol) and ethyl diazoacetate (1.3 g, 11.8 mmol). The mixture was stirred for 15 h at 25°C and then diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with brine (60 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (0 to 40% ethyl acetate in petroleum ether) to provide ethyl 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyran [3 ,4 -c] pyrazole -3 -carboxylate (185 mg, 5%) as a light yellow oil: 1H NMR (400 MHz, CDC13) δ7.56 - 7.50 (m, 1H), 6, 92 - 6.88 (m, 1H), 6.83 - 6.78 (m, 1H), 5.11 (d, J = 14.6 Hz, 1H), 4.93 - 4.85 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.19 - 3.14 (m, 1H), 2.88 - 2.81 (m, 1H), 1.34 (t , J = 7.2 Hz, 3H). Step 4: 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid

[0837] A mixture of ethyl 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyran [3,4-c] pyrazole-3-carboxylate (160 mg, 0.52 mmol) and sodium hydroxide Hydrated lithium (124 mg, 5.20 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to provide crude 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (75 mg, 52% ) in the form of a light yellow solid, which was used in the next step without any further purification. Step5: 5 -(2,4-difluorophenyl) -N -((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 - carboxamide

[0838] A mixture of 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (30 mg, 0.11 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (17 mg, 0.13 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepine -4 -one (21 mg, 0.11 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (23 mg, 0.13 mmol) in N,N - dimethylformamide (2 mL) was stirred at 25°C for 12 h. The reaction was concentrated to drying under reduced pressure and the residue was purified by haRP-HPLC (13 to 43% acetonitrile in water and 0.05% hydrochloric acid) to give 5-(2,4-difluorophenyl)- N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1,4,5,7 -tetrahydropyran [3 ,4 -c] pyrazole -3 -carboxamide (11 mg, 23%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.57 - 7.21 (m, 6H), 6, 97 - 6.94 (m, 1H), 4.99 - 4.86 (m, 3H), 4.60 - 4.58 (m, 2H), 4.40- 4.36 (m, 1H), 3.41 (s, 3H), 3.16 - 3.08 (m, 1H), 2.81 - 2.70 (m, 1H). LCMS RT = 1.14 min.; m/z = 455.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.14 mln., ESI+ found [M+H] + = 455.2, Example 208

[0839] WX RRRR Method

[0840] 1-benzyl -N -(4-methyl -5 -oxo -2 -phenyl - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: N -(5 -phenyl -1H -pyrazol -3 -yl)formamide

[0841] A mixture of 5-phenyl-1H-pyrazole-3-amine (2.5 g, 15.7 mmol) and formic acid (10 mL, 15.71 mmol) was subjected to stirring at 110 ° C in a vessel sealed for 2 h. The mixture was concentrated under reduced pressure and the residue was washed with water (50 mL) to provide crude N -(5-phenyl-1H-pyrazol-3-yl)formamide (2.7 g, 92%) in the form of a white solid: LCMS RT = 1.149 min.; m/z = 187.9 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.149 mln., ESI+ found [M+H] = 187.9. Step 2: N -methyl -5 -phenyl -1H -pyrazol -3 -amine

[0842] To a solution of N -(5-phenyl-1H-pyrazol-3-yl)formamide (2.1 g, 11.2 mmol) in tetrahydrofuran (100 mL) was added borane (1.0 M, 45 .0 mL, 45.0 mmol). The mixture was stirred at 0°C for 2 h and then finalized by addition of methanol (30 mL) and hydrochloric acid (10%, 5 mL). The resulting mixture was heated at 70°C for 30 ml, and then adjusted to pH = 8 by addition of aqueous sodium hydroxide (10%). The mixture was then concentrated to drying and the residue was collected in ethyl acetate (100 mL), washed with water (2 x 50 mL), saline solution (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. . The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give N -methyl -5 -phenyl -1H -pyrazol -3 -amine (1.9 g, 95%) as a white solid: LCMS RT = 0.52 min.; m/z = 173.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.52 mln., ESI+ found [M+H] = 173.8. Step 3: 4-chloro-N-methyl-N-(5-phenyl-1H-pyrazol-3-yl)butanamide

[0843] A mixture of N -methyl -5 -phenyl -1H - pyrazole -3 -amine (1.9 g, 11.6 mmol) and 4-chlorobutanoyl chloride (5.2 mL, 46.2 mmol) was subjected to stirring at 60°C for 16 h. The reaction was concentrated under reduced pressure. The residue was collected in ethyl acetate (300 mL) and washed with water (100 mL) and saline solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 4-chloro-N-methyl-N-(5-phenyl-1H -pyrazol -3 -yl) butanamide (2.3 g, 66%) in the form of a white solid, which was used in the next step in the form in which it was. Step 4: 4 -methyl -2 -phenyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[0844] To a solution of 4-chloro-N-methyl-N-(3-phenyl-1H-pyrazol-5-yl) butanamide (2.1 g, 7.6 mmol) in N,N-dimethylformamide ( 10 mL) cesium carbonate (4.9 g, 15.1 mmol) was added. The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 4-methyl-2-phenyl-7,8-dihydro-4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (1.8 g, 96%) as a white solid: LCMS RT = 0.66 min.; m/z = 241.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.66 mln., ESI+ found [M+H] = 241.8. Step 5: 6 -iodo -4 -methyl -2 -phenyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[0845] To a solution of 4-methyl -2 -phenyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (1.6 g, 6.6 mmol) in anhydrous dichloromethane (20 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (10.4 g, 79.6 mmol) followed by iodotrimethyl silane (15.9 g, 79.6 mmol) under -15°C. The resulting solution was subjected to stirring 2 h under -15°C and iodine (10 g, 39.80 mmol) was added in one portion. After stirring for 2 h at -15°C, the reaction mixture was quenched by adding saturated sodium bisulfite (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6 -iodo -4 -methyl - 2-phenyl -7,8 -dihydro -4H -pyrazole [1,5 - a] [1,3] diazepin -5(6H) -one (1.3 g, 55.0%) as a solid white color: 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 1.6 Hz, 2H), 7.43 - 7.32 (m, 3H), 6.40 (s, 1H), 4.71 - 4.67 (m, 1H), 4.34 - 4.24 (m, 2H), 3.41 (s, 3H), 3.05 - 2.99 (m, 1H), 2, 85 - 2.82 (m, 1H). LCMS RT = 0.71 min.; m/z = 367.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.71 mln., ESI+ found [M+H] = 367.8. Step 6: 6 -amino -4 -methyl -2 -phenyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[0846] A solution of 6 -iodo -4 -methyl -2 -phenyl - 7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one (550 mg , 1.5 mmol) and ammonium hydroxide (2 mL, 2.25 mmol, 36%) in N,N-dimethylformamide (10 mL) was subjected to stirring under 100 ° C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 3% methanol in dichloromethane) to give 6-amino-4-methyl-2-phenyl- 7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (200 mg, 52%) as a white solid: 1H NMR (400 MHz , CDCl3) δ 7.76 (d, J = 2.0 Hz, 2H), 7.42 - 7.32 (m, 3H), 6.35 (s, 1H), 4.47 - 4.42 ( m, 1H), 4.17 - 4.12 (m, 1H),3.52 - 3.49 (m, 1H), 3.39 (s, 3H), 2.88 - 2.82 (m, 1H), 1.95 - 1.91 (m, 1H). Step 7: 1-benzyl -N -(4-methyl -5 -oxo -2 - phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0847] A mixture of 6-amino -4 -methyl -2 -phenyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (30 mg , 0.12 mmol), 1-benzyl -1,2,4 -triazole -3 -carboxylic acid (24 mg, 0.12 mmol), 1H -benzo [d] [1,2,3] triazole -1 - ol (24 mg, 0.18 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) and N,N-diisopropylethylamine (30 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (33% to 63% acetonitrile, 0.05% ammonium hydroxide in water) to give 1-benzyl-N -(4 - methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 - carboxamide (16 mg, 31%) as a white solid: 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1 H), 7.82 (d, J = 7.2 Hz, 2 H), 7.45 - 7.35 (m, 8 H), 6.71 (s, 1 H), 5.49 (s, 2 H), 4.67 - 4.32 (m, 3 H), 3.42 (s, 3 H), 2.97 - 2.88 (m, 1 H), 2.38 - 2.29 (m, 1 H). LCMS RT = 0.71 min.; m/z = 442.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.71 mln., ESI+ found [M+H] = 442.0. Example 209

[0848] WX SSSS METHOD 5-Benzyl -N -(4-methyl -5 -oxo -2 -phenyl - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0849] A mixture of 6-amino -4 -methyl -2 -phenyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (30 mg , 0.12 mmol), 5-benzyl -1H -1,2,4 -triazole -3 -carboxylic acid (24 mg, 0.12 mmol), 1H -benzo [d] [1,2,3] triazole - 1-ol (24 mg, 0.18 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) and N,N-diisopropyl ethylamine (45 mg, 0.35 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (27% to 57% acetonitrile, 0.05% ammonium hydroxide in water) to give 5-benzyl-N -(4 - methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 - carboxamide (4 mg, 7.3%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 6.8 Hz, 2 H), 7 .45 - 7.30 (m, 8 H), 6.71 (s, 1 H), 4.64 - 4.34 (m, 3 H), 4.17 (s, 2 H), 3.42 (s, 3 H), 2.93 - 2.87 (m, 1 H), 2.33 - 2.31 (m, 1 H). LCMS RT = 0.69 min.; m/z = 442.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.69 mln., ESI+ found [M+H] = 442.0. Example 210

[0850] WX Method H

[0851] N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(2,2, 2 - trifluoroethyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide Step 1: 2 -(2,2,2-trifluoroethyl) tetrahydro -2H -pyran -4 -ol

[0852] To a stirred mixture of 3,3,3-trifluoropropanal (5.0 g, 44.6 mmol) and 3-buten-1-ol (4.8 g, 66.9 mmol) acid was added 20% sulfuric acid (5 mL) under 0°C. The mixture was subjected to stirring at 80°C for 3 h. After cooling, the mixture was adjusted to pH = 9 by slow addition of NaHCO3. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 2-(2, 2,2-trifluoroethyl)tetrahydro-2H-pyran-4-ol (1.7 g, 20%) in the form of a yellow oil, which was used in the next step without any further purification. Step 2: 2 -(2,2,2-trifluoroethyl)dihydro -2H - pyran -4(3H) -one

[0853] To a suspension of 2 -(2,2,2-trifluoroethyl) tetrahydro -2H -pyran -4 -ol (200 mg, 1.1 mmol) and molecular sieves (4Å) in dichloromethane (10 mL) was added pyridiniochlorochromate (281 mg, 1.3 mmol) portionwise over 5 min. The mixture was stirred at 25°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, 100 - 200 mesh, 10 to 20% ethyl acetate in petroleum ether) to give 2 -(2,2,2 - trifluoroethyl)dihydro -2H -pyran -4(3H) -one in the form of a colorless oil (136 mg, 64%) in the form of a brown colored oil, which was used in the next step without any further purification. Step 3: ethyl 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylate

[0854] A stirred solution of 2 - (2,2,2-trifluoroethyl) dihydro -2H -pyran -4(3H) -one (100 mg, 0.55 mmol) in dimethyl sulfoxide (6 mL) was Pyrrolidine (6 mg, 0.08 mmol) was added. The mixture was stirred at 20°C for 15 ml, then ethyl diazoacetate (125 mg, 1.1 mmol) was added. The mixture was stirred at 20°C for 15 h and then poured into water (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 10 to 30% ethyl acetate in petroleum ether) to give ethyl 5-(2,2,2-trifluoroethyl)-1,4 ,5,7-tetrahydropyran[3,4-c]pyrazole-3-carboxylate as a brown solid (50 mg, 31%): LCMS RT = 0.796 min.; m/z = 278.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.796 mln., ESI+ found [M+H] = 278.9. Step 4: 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydro pyran[3,4-c]pyrazol-3-carboxylic acid

[0855] A mixture of ethyl 5 -(2,2,2 - trifluoroethyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxylate (50 mg, 0.18 mmol) and Potassium hydroxide (20 mg, 0.36 mmol) in ethanol (8 mL) and water (2 mL) was stirred under 25°C for 24 h. The reaction was concentrated to drying under reduced pressure and the residue was adjusted to pH = 2 by addition of hydrochloric acid (2.0 M). The solvent was removed, and the residue was dissolved in methanol (10 mL). The mixture was filtered and the filtrate was concentrated to drying under reduced pressure to provide 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-acid carboxylic acid (40 mg, 88%) as a yellow solid: LCMS RT = 0.787 min.; m/z = 251.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.787 mln., ESI+ found [M+H] = 251.1. Step 5: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(2,2, 2 - trifluoroethyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide

[0856] A mixture of N1 - ((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (43 mg, 0.24 mmol), 1H -benzo [d] [1,2,3 ] triazol -1 -ol (32 mg, 0.24 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro - 1,5 -benzoxazepin -4 -one (31 mg, 0.16 mmol), and 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyran[3,4-c]pyrazol-3-carboxylic acid (40 mg, 0.16 mmol) in N, N -dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated to drying under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 46 -76% / 0.05% NH4OH in water) to give N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5 -(2,2,2 -trifluoroethyl) -1,4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide (6.2 mg, 9%) in the form of a yellow solid: 1H NMR (400 MHz, DMSO - d 6) δ 13.06 (s, 1H), 8.05 — 8.02 (m, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.32 - 7.22 (m, 3H), 4.84 (m, 2H), 4.71 - 4, 54 (m, 1H), 4.43 - 4.42 (m, 1H), 4.42 - 4.40 (m, 1H), 3.81 (s, 1H), 3.31 (s. 3H) , 2.84 - 2.80 (m, 1H), 2.67 - 2.63 (m. 2H), 2.61 - 2.50 (m, 1H). LCMS RT = 1.063 min.; m/z = 425.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.063 mln., ESI+ found [M+H] = 425.2. Example 211

[0857] WX Method M

[0858] (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4',7' -dihydro - 1'H -spiro [cyclobutane -1,5' -pyran [3,4 -c] pyrazole] - 3' -carboxamide Step 1: 5 -oxaspiro [3,5] nonan -8 -yl methane sulfonate

[0859] To a mixture of cyclobutanone (6.0 g, 85.6 mmol) and 3-buten-1-ol (6.2 g, 85.6 mmol) was added methanesulfonic acid (17.3 g, 179. 8 mmol). The mixture was stirred at 25°C for 15 h and then adjusted to pH = 9 by addition of saturated aqueous sodium bicarbonate. The resulting solution was extracted with dichloromethane (4 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 10 -20% ethyl acetate in petroleum ether) to provide 5-oxaspiro[3,5]nonan-8-yl methanesulfonate (17 .4 g, 92%) as a yellow colored oil: 1H NMR (400 MHz, CDC13) δ 4.87 - 4.80 (m, 1H), 3.84 - 3.78 (m, 1H) , 3.51 - 3.44 (m, 1H), 3.02 (s, 3H), 2.27 - 2.22 (m, 1H), 2.19 - 2.11 (m, 1H), 2 .04 - 1.98 (m, 4H), 1.82 - 1.65 (m, 4H). Step 2: 5 -oxaspiro [3,5] nonan -8 -ol

[0860] To a solution of 5-oxaspiro [3,5] nonan-8-yl methanesulfonate (22.0 g, 100 mmol) in tetrahydrofuran (180 mL) was added methylmagnesium bromide (3.0 M, 50 mL, 150 mmol) under 0oC. After addition, the mixture was stirred at 25°C for 20 h and then finalized by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (5 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 20 to 30% ethyl acetate in petroleum ether) to provide 5-oxaspiro[3.5]nonan-8-ol (12 .9 g, 90%) in the form of a colorless oil: 1H NMR (400 MHz, CDCI3) δ 3.84 - 3.75 (m, 2H), 3.45 - 3.38 (m, 1H), 2 .19 - 2.10 (m, 2H), 2.00 - 1.90 (m, 4H), 1.85 - 1.73 (m, 2H), 1.70 - 1.58 (m, 1H) , 1.52 - 1.35 (m, 2H). Step 3: 5 -oxaspiro [3,5] nonan -8 -ol

[0861] To a solution of 5-oxaspiro [3.5] nonan-8-ol (12.9 g, 90.5 mmol) in dichloromethane (240 mL) was added pyridiniochloro chromate (23.4 g, 108.6 mmol) in parts for 5 min. The reaction was stirred for 16 h at 25°C and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 5-oxaspiro[3.5]nonan-8-one (11 .5 g, 91%) in the form of a colorless oil: 1H NMR (400 MHz, CDCI3) δ 3.87 - 3.84 (m, 2H), 2.54 (s, 2H), 2.39 - 2 .36 (m, 2H), 2.17 - 2.09 (m, 2H), 1.98 - 1.92 (m, 2H), 1.82 - 1.74 (m, 1H), 1.67 - 1.55 (m, 1H). Step 4: ethyl 4',7' -dihydro -1'H -spiro [cyclobutane -1,5' -pyran [3,4 -c] pyrazole] -3' - carboxylate

[0862] To a stirred solution of 5-oxaspiro [3,5] nonan-8-one (4.9 g, 35.1 mmol) in dimethyl sulfoxide (40 mL) was added pyrrolidine (120 mg, 1. 8 mmol), followed by ethyl diazoacetate (2.0 g, 17.5 mmol). The mixture was stirred at 25°C for 15 h and then poured into water (60 ml). The resulting mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give ethyl 4',7' - dihydro -1'H -spiro [ cyclobutane -1,5'-pyran[3,4-c]pyrazole]-3'-carboxylate (0.80 g, 19%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ4.79 (s, 2H), 4.43 - 4.38 (m, 2H), 2.96 (s, 2H), 2.29 - 2.21 (m, 2H ), 1.95 - 1.84 (m, 3H), 1.81 - 1.69 (m, 1H), 1.43 - 1.40 (m, 3H). Step 5: 4',7'-dihydro-1'H-spiro[cyclobutane-1,5'-pyran[3,4-c]pyrazol]-3'-carboxylic acid

[0863] A mixture of ethyl 4',7' -dihydro -1'H - spiro [cyclobutane -1,5' -pyran [3,4 -c] pyrazole] -3' - carboxylate (50 mg, 0.21 mmol) and lithium hydroxide hydrate (76 mg, 3.2 mmol)) in tetrahydrofuran (4 mL) and water (1 mL) was stirred for 20 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to provide crude 4',7'-dihydro-1'H-spiro[cyclobutane-1,5'-pyran[3,4-c]pyrazol]-3'-carboxylic acid ( 49 mg, 100%) as a white solid: LCMS RT = 0.539 min.; m/z = 208.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.539 mln., ESI+ found [M+H] = 208.8. Step 6: (S)-N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4',7' -dihydro -1'H -spiro [cyclobutane -1,5' -pyran [3,4 -c] pyrazole] - 3' -carboxamide

[0864] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (30 mg, 0.16 mmol), 1H - benzo [d] [ 1,2,3] triazol -1 -ol (31 mg, 0.23 mmol), 4',7' -dihydro acid -1'H -spiro [cyclobutane -1,5' -pyran [3,4 -c ] pyrazole] -3'-carboxylic acid (49 mg, 0.23 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (44 mg, 0.23 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25oC for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by haRP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to give (S)-N-(5-methyl- 4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4',7' - dihydro -1'H -spiro [cyclobutane -1,5' - pyran [3,4 -c] pyrazole] - 3' -carboxamide (16.9 mg, 27%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 12.99 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.50 - 7.48 (m, 1H), 7.35 - 7.27 (m, 2H), 7.25 - 7 .22 (m, 1H), 4.87 - 4.80 (m, 1H), 4.65 (s, 2H), 4.55 - 4.50 (m, 1H), 4.43 - 4.39 (m, 1H), 3.32 (s, 3H), 2.74 (s, 2H), 2.12 - 2.05 (m, 2H), 1.79 - 1.64 (m, 4H). LCMS RT = 1.021 min.; m/z = 383.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.021 mln., ESI+ found [M+H] + = 383.2. Example 212

[0865] WX DDDDDD Method 5 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -phenyl - 1, 4,5,7 -tetrahydropyran [3,4 -c] pyrazole -3 -carboxamide

[0866] A mixture of 5-methyl-5-phenyl-4,7-dihydro-1H-pyran[3,4-c]pyrazol-3-carboxylic acid (42 mg, 0.16 mmol), (3S)- 3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (31 mg, 0.16 mmol), 1H -benzo [d] [1,2,3] triazole -1 - ol (44 mg, 0.33 mmol). Then N1 - ((ethylimino) methylene) - N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (62 mg, 0.33 mmol) in N,N - dimethylformamide (5 mL) was subjected to stirring under 25° C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 48 -78 with 0.05% formic acid in water) to give 5-methyl -N -((S) -5 - methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - phenyl -1,4,5,7 -tetrahydropyran [3,4 -c ] pyrazole -3 - carboxamide (25 mg, 36%) as a white solid: 1H NMR (400MHz, CD3OD) δ 7.42 - 7.23 (m, 9H), 5.05 - 5.00 (m, 1H), 4.73 - 4.69 (m, 1H), 4.61 - 4.59 (m, 1H), 4.39 - 4.35 (m, 2H), 3.53 - 3 .48 (m, 1H), 3.40 (s, 3H), 2.96 - 2.91 (m, 1H), 1.51 (s, 3H). LCMS RT = 3.37 min.; m/z = 433.4 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.1% formic acid for 7.0 min.) retention time 3.37 mln., ESI+ found [M+H] =433.4. Example 213

[0867] WX JJ METHOD

[0868] (S) -1 -isopropyl -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - pyrazole [ 4,3 -c] pyridine -6 -carboxamide Step 1: Methyl 1-isopropylpyrazole[4,3-c]pyridine-6-carboxylate

[0869] To a solution of methyl 1H -pyrazolo[4,3-c]pyridine-6-carboxylate (300 mg, 1.69 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (702 mg, 5.08 mmol) and 2-iodopropane (576 mg, 3.39 mmol). The reaction mixture was stirred at 45°C for 3 h and then concentrated under reduced pressure. The residue was purified using haRP-HPLC (acetonitrile 12 -42/0.05% ammonia in water) to provide:

[0870] Methyl 1 -isopropylpyrazole [4,3 -c] pyridine -6 -carboxylate (150 mg, 40.4%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9, 16 (s, 1H), 8.48 - 8.43 (m, 2H), 5.27 - 5.16 (m, 1H), 3.91 (s, 3H), 1.49 (d, J = 6.4Hz, 6H).

[0871] Methyl 2 -isopropylpyrazole [4,3 -c] pyridine -6 -carboxylate (70 mg, 19%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.22 ( d, J = 1.2 Hz, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 5.02 - 4.91 (m, 1H), 3.88 (s, 3H ), 1.58 (d, J = 6.8 Hz, 6H). Step 2: 1-isopropyl pyrazolo[4,3-c]pyridine-6-carboxylic acid

[0872] A mixture of methyl 1-isopropylpyrazole [4,3-c] pyridine-6-carboxylate (50 mg, 0.23 mmol) and lithium hydroxide hydrate (27 mg, 1.14 mmol) in tetrahydrofuran (5 mL ) and water (2 mL) was stirred at 25°C for 18 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure to provide 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 85%) as a white solid, which was used in the next step without any another purification. Step 3: (S) -1 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - pyrazole [ 4,3 -c] pyridine -6 -carboxamide

[0873] A mixture of 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 0.19 mmol), (3S)-3-amino-5-methyl-2,3-dihydro- 1,5-benzoxazepin-4-one (41 mg, 0.21 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol) and N hydrochloride -((ethylimino)methylene)-N,N3-dimethylpropane-1,3-diamine (45 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 1 h . The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (36-66% acetonitrile/0.05% ammonia in water) to give (S)-1-isopropyl-N-(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazolo [4,3 -c] pyridine -6 -carboxamide (32.7 mg, 43%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.17 (s, 1 H), 9.02 (d, J = 8.0 Hz, 1H), 8 .44 (s, 1H), 8.30 (s, 1H), 7.53 - 7.47 (m, 1H), 7.37 - 7.24 (m, 3H), 5.23 - 5 .11 (m, 1H), 4.97 - 4.87 (m, 1H), 4.89 - 4.49 (m, 2H), 3.34 (s, 3H), 1.52 - 1.41 (m, 6H). LCMS RT = 0.834 min.; m/z = 380, 0(M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.834 mln., ESI+ found [M+H] = 380.0. Example 214 is omitted. Example 215

[0874] WX Method MMMMMM 1-benzyl -N -(1,9 -dimethyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 –carboxamide

Step 1: ethyl 4 -(4 -methyl -5 -nitro -1H - imidazol -1 -yl)butanoate

[0875] A mixture of 5-methyl-4-nitro-1H - imidazole (58.0 g, 456.0 mmol), ethyl 4-bromobutyrate (107.0 g, 548.0 mmol) and potassium carbonate (75 .7 g, 548.0 mmol) in N,N-dimethylformamide (250 mL) was stirred at 120°C for 2 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over concentrated sodium sulfate under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide ethyl 4 -(4 -methyl -5 -nitro -1H -imidazole - 1-yl)butanoate (33.6 g, 30%) in the form of a yellow oil, which was used in the next step as is. Step 2: ethyl 4 -(5 -amino -4 -methyl -1H - imidazol -1 -yl) butanoate

[0876] A mixture of ethyl 4 -(4-methyl -5 -nitro - 1H -imidazol -1 -yl) butanoate (33.6 g, 139.0 mmol) and 10% palladium on carbon (11.9 g, 11.2 mmol) in 1,4-dioxane (1.5 L) was hydrogenated [4.46 bar (50 psi)] under 25°C for 24 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to provide ethyl 4-(5-amino-4-methyl-1H-imidazol-1-yl)butanoate (33.4 g, 79%) as an oil black in color. LCMS RT = 1.366 min.; m/z = 212.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3.0 min.) retention time 1.366 mln., ESI+ found [M+H] = 212.2. Step 3: 9 -methyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0877] A mixture of ethyl 4 -(5-amino -4 -methyl - 1H -imidazol -1 -yl) butanoate (30.0 g, 142.0 mmol) and sodium ethoxide (48.3 g, 710. 0 mmol) in ethanol (200 mL) was stirred at 25oC for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 9-methyl-4,5-dihydro- 1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (8.0 g, 34%) in the form of a yellow oil, which was used in the next step in the form in which was found. Step 4: 1,9 -dimethyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0878] To a solution of 9 -methyl -4,5 -dihydro -1H - imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (2.0 g, 12.1 mmol ) and cesium carbonate (3.9 g, 12.1 mmol) in N,N-dimethylformamide (30 mL) methyl iodide (1.72 g, 12.1 mmol) was added. The reaction mixture was stirred at 25°C for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 1,9 - dimethyl -4,5 - dihydro - 1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (1.0 g, 46%) in the form of a white solid, which was used in the next step in the form in which it was. Step 5: 3 -iodo -1,9 -dimethyl -4,5 -dihydro -1H - imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0879] To a solution of 1,9 -dimethyl -4,5 -dihydro - 1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (100 mg, 0.56 mmol ) in dichloromethane (10 mL) was added N1,N1,N2,N2 -tetramethylethane -1,2-diamine (872 mg, 6.7 mmol) and iodotrimethylsilane (1.3 g, 6.7 mmol) under -15° W. The mixture was stirred at 15°C for 1.5 h and then iodine (849 mg, 3.35 mmol) was added in one portion. The reaction mixture was stirred at 30°C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 3-iodo-1,9-dimethyl-4,5-dihydro-1H-imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (120 mg, 71%) as a light yellow solid. LCMS RT = 1.44 min.; m/z = 306.0 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.1% ammonium bicarbonate for 3 min.) retention time 1.44 mln., ESI+ found [M+H] =306.0. Step 6: 3 -azide -1,9 -dimethyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0880] To a solution of 3 -iodo -1,9 -dimethyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (120 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (35 mg, 0.53 mmol). The reaction mixture was stirred at 25°C for 2 h and diluted with ice water (5 mL). The solution was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 3-azide-1,9-dimethyl-4,5-dihydro-1H-imidazo [ 1,5 -a] [1,3] diazepin -2(3H) -one (80 mg, 92%) as a yellow solid. LCMS RT = 1.29 min.; m/z = 221.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min.) retention time 1.29 mln., ESI+ found [M+H] =221.1. Step 7: 3 -amino -1,9 -dimethyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[0881] A mixture of 3-azide -1,9 -dimethyl -4,5 - dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (80 mg, 0 .36 mmol) and 10% palladium on carbon (386 mg, 0.36 mmol) in methanol (20 mL) was hydrogenated (15 psi) under 25°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin- 2(3H)-one (60 mg, 85%) in the form of a yellow oil, which was used in the next step without any further purification. Step 8: 1-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl ) -1H -1,2,4 -triazole -3 -carboxamide

[0882] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (20 mg, 0.1 mmol), 3-amino-1,9-dimethyl-4,5-dihydro-1H- imidazo [1,5 -a] [1,3] diazepin - 2(3H) -one (19 mg, 0.1 mmol), N1 hydrochloride - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1, 3-diamine (24 mg, 0.12 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (18 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL ) was subjected to stirring at 30°C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (10 - 40 acetonitrile/0.05% ammonium hydroxide in water) to give 1-benzyl -N -(1.9 -dimethyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide (7.2 mg, 19%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.55 (s, 1H), 7.41 — 7.33 (m, 5H), 5.47 (s, 2H), 4.87 - 4.54 (m, 1H), 4.36 - 4.31 (m, 1H), 3.98 - 3 .91 (m, 1H), 3.35 (s, 3H), 2.75 - 2.63 (m, 1H), 2.22 (s, 3H), 2.15 - 2.07 (m, 1H ). LCMS RT = 0.91 min.; m/z = 380.3 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.91 mln., ESI+ found [M+H] =380.3. Example 216

[0883] WX TTTT Method 1-benzyl -N -(4-methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,3 -triazole -4 -carboxamide

[0884] A mixture of 6-amino -4 -methyl -2 -phenyl-7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one (30 mg , 0.12 mmol), 1-benzyltriazol-4-carboxylic acid (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol), N1 -((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (34 mg, 0.18 mmol) and N,N -diisopropylethylamine (45 mg, 0.35 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (35% to 65% acetonitrile, 0.05% ammonium hydroxide in water) to give 1-benzyl-N-(4-methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,3 -triazole -4 - carboxamide (8 mg, 16%) as a white solid: 1H NMR (400 MHz, CDC13) δ7.95 - 7.92 (m, 2 H), 7.76 (d, J = 7.2, 2 H), 7.44 - 7.28 (m, 8 H), 6.41 (s, 1 H), 5.58 (s, 2 H), 4.81 - 4.76 ( m, 1 H), 4.55 - 4.49 (m, 1 H), 4.25 - 4.20 (m, 1 H), 3.42 (s, 3 H), 3.16 - 3, 09 (m, 1 H), 2.16 - 2.08 (m, 1 H). LCMS RT = 0.72 min.; m/z = 442.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.72 mln., ESI+ found [M+H] = 442.0. Example 217

[0885] WX CC METHOD (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,7 - dihydrofuro [3,4 -d] pyrimidine -2 –carboxamide Step 1: 2-chloro-7,7-dimethyl-5H-furo[3,4-d]pyrimidine

[0886] A mixture of 2,4-dichloro-7,7-dimethyl - 5H -furo[3,4-d] pyrimidine (500 mg, 2.28 mmol) and zinc (448 mg, 6.85 mmol) in Water (10 mL) was heated under reflux for 3 h. After cooling, the reaction mixture was extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with water (3 x 15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2-chloro-7,7-dimethyl-5H-furo [3 ,4-d] pyrimidine (150 mg, 36%) as a white solid: LCMS RT = 1.54 min.; m/z = 185.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% ammonium bicarbonate over 1.5 min.) retention time 1.54/mln., ESI+ found [M+H] = 185.1. Step 2: 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carbonitrile

[0887] A mixture of 2 -chloro -7,7 -dimethyl -5H - fur [3,4 -d] pyrimidine (150 mg, 0.81 mmol), 1,4 - diazabicyclo [2,2,2]octane (18 mg, 0.16 mmol) and sodium cyanide (40 mg, 0.81 mmol) in dimethyl sulfoxide (8 mL) and water (8 mL) were added under stirring under 25°C for 12 h. The reaction mixture was diluted with dichloromethane (30 ml) and washed with water (3 x 30 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 7,7-dimethyl-5H-furo[3,4-d] pyrimidine-2-carbonitrile (80 mg, 56%) as a white solid: LCMS RT = 0.54 min.; m/z = 175.9 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.54/mln., ESI+ found [M+H] = 175.9. Step 3: methyl 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carboxylate

[0888] A solution of 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carbonitrile (80 mg, 0.46 mmol) in methanol (2 mL) was added acetyl chloride (72 mg , 0.91 mmol) under 0°C. The resulting mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by prep haTLC (50% ethyl acetate in petroleum ether, Rf = 0.4) to give methyl 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2 -carboxylate (12 mg, 13%) as a yellow oil: LCMS RT = 0.65 min.; m/z = 209.1 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 0.65/mln., ESI+ found [M+H] = 209.1. Step 4: (S)-7,7-dimethyl -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5, 7 - dihydrofuro [3,4 -d] pyrimidine -2 -carboxamide

[0889] To a solution of methyl 7,7 -dimethyl -5H - fur [3,4 -d] pyrimidine -2 -carboxylate (12 mg, 0.06 mmol) and (3S) -3 -amino -5 -methyl -2,3-dihydro-1,5-benzoxazepin -4-one (12 mg, 0.06 mmol) in tetrahydrofuran (4 mL) was added trimethylaluminum (2.0 M, 0.17 mL, 0.35 mmol) . The mixture was subjected to stirring at 25oC for 12 h and then finalized by addition of saturated aqueous ammonium chloride. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by haRP-HPLC (acetonitrile 27 - 57/0.05% ammonium hydroxide in water) to provide (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo - 2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxamide (4 mg, 19%) in the form of a white solid: 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.47 — 7.45 (m, 1H), 7.35 — 7.32 (m, 2H) , 7.28 — 7.27 (m, 1H), 5.16 (s, 2H), 5.06 - 5.04 (m, 1H), 4.69 - 4.68 (m, 1H), 4 .52 - 4.47 (m, 1H), 3.45 (s, 3H), 1.54 (s, 6H). LCMS RT = 1.53 min.; m/z = 369.1 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.53/mln., ESI+ found [M+H] = 369.1. Example 218

[0890] WX METHOD P (S) -7,7 -dimethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,7 - dihydrothiene [3,4 -d] pyrimidine -2 -carboxamide Step1: 2-chloro-7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine

[0891] A mixture of 2,4-dichloro-7,7-dimethyl - 5H -thiene [3,4-d] pyrimidine (1.0 g, 4.3 mmol) and zinc (0.8 g, 12, 8 mmol) in water (20 mL) was heated under 100°C for 12 h. After cooling, the mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 15% ethyl acetate in petroleum ether) to provide 2-chloro-7,7-dimethyl-5,7-dihydrothiene [3,4 -d] pyrimidine (400 mg, 47%) as a white solid: 1H NMR (400MHz, METHANOL -d4) δ 8.60 (s, 1H), 4.18 (s, 2H ), 1.69 (s, 6H). Step2: 7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine-2-carbonitrile

[0892] To a solution of 2-chloro-7,7-dimethyl-5H-thiene [3,4-d] pyrimidine (250 mg, 1.25 mmol) in dimethyl sulfoxide (10 mL) and water (10 mL) sodium cyanide (122 mg, 2.49 mmol) and 1,4-diazabicyclo[2,2,2] octane (28 mg, 0.25 mmol) were added. The reaction mixture was stirred at 30°C for 12 h and then diluted with ethyl acetate (20 ml). The organic layer was washed with water (3 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 7,7 -dimethyl -5,7 - dihydrothiene [3,4 - d] pyrimidine-2-carbonitrile (150 mg, 63%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: methyl 7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine-2-carboxylate

[0893] To a solution of 7,7-dimethyl-5,7-dihydrothiene [3,4-d] pyrimidine-2-carbonitrile (40 mg, 0.18 mmol) in methanol (3 mL) was added acetyl chloride (140 mg, 1.78 mmol). The reaction mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure to provide crude methyl 7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine-2-carboxylate ( 38 mg, 95%) as a white solid: LCMS RT = 1.5 min.; m/z = 224.9 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.600 mln., ESI+ found [M + H] + = 224.9. Step 4: (S)-7,7-dimethyl -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5, 7 - dihydrothiene [3,4 -d] pyrimidine -2 -carboxamide

[0894] To a solution of methyl 7,7-dimethyl-5,7-dihydrothiene [3,4-d] pyrimidine-2-carboxylate (38 mg, 0.17 mmol) in tetrahydrofuran (4 mL) was added ( 3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (36 mg, 0.19 mmol) and trimethylaluminum (2.0 M, 0.5 mL, 1, 00 mmol). The reaction mixture was stirred at 30°C for 12 h and then concentrated to drying under reduced pressure. The residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% FA in water) to provide (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2, 3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5,7 - dihydrothiene [3,4 -d] pyrimidine -2 -carboxamide (2.1 mg, 3%) in the form of a white solid: 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 7.45 — 7.41 (m, 1H), 7.34 — 7.28 (m, 2H) , 7.25 - 7.22 (m, 1H), 4.69 - 4.63 (m, 2H), 4.44 - 4.39 (m, 1H), 4.23 (s, 2H), 3 .42 (s, 3H), 1.71 (s, 6H). LCMS RT = 1.065 min.; m/z = 385.2 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.1% trifluoroacetic acid for 2 min.) retention time 1.065 mln., ESI+ found [M + H] + = 385.2. Example 219

[0895] WX QQ Method (S) -1 -(2,3-difluorobenzyl) -N -(2,4 -dimethyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0896] A mixture of 1 - [(2,3 - difluorophenyl)methyl] -1,2,4 -triazole -3 -carboxylic acid (37 mg, 0.15 mmol), (6S) -6 -amino -2 ,4-dimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.10 mmol), 1H -benzo [d] [1, 2,3] triazol -1 -ol (21 mg, 0.15 mmol) and N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (30 mg, 0.15 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to give 1-[(2,3-difluorophenyl)methyl ] -N - [(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2 ,4-triazole -3 - carboxamide (15.5 mg, 36%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.52 ( d, J = 8.0 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.27 - 7.15 (m, 2H), 6.12 (s, 1H), 5.61 (s, 2H), 4.34 - 4.23 (m, 2H), 4.11 4.04 (m, 1H), 3.21 (s, 3H), 2.62 - 2.54 (m, 1H), 2.36 2.28 (m, 1H), 2.16 (s, 3H). LCMS RT = 1.143 min. ; m/z 416.3 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03 trifluoroacetic acid for 2 min.) retention time 1.143 mln., ESI+ found [M+H] + = 416.3. Example 220

[0897] WX RR Method (S) -1 -(3,4-difluorobenzyl) -N -(2,4 -dimethyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0898] A mixture of 1 - [(3,4 - difluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylic acid (37 mg, 0.15 mmol), (6S) -6 -amino -2 ,4-dimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.10 mmol), 1H -benzo [d] [1, 2,3] triazole -1 -ol (21 mg, 0.15 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (30 mg, 0.15 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 23 - 53%/0.05% ammonium hydroxide in water) to give (S) -1 -(3,4 - difluorobenzyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H - 1,2,4 -triazole -3 - carboxamide (18.1 mg, 41%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8 .52 (d, J = 8.0 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.19 - 7.17 (m, 1H), 6.12 (s, 1H), 5.48 (s, 2H), 4.35 - 4.23 (m, 2H), 4.11 - 4.04 (m, 1H), 3.21 (s, 3H), 2.62 - 2, 54 (m, 1H), 2.36 - 2.28 (m, 1H), 2.16 (s, 3H). LCMS RT = 1, 158 min. ; m/z = 416.3 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.158 mln., ESI+ found [M+H] + = 416.3. Example 221

[0899] WX WW Method (S) -1 -(2,4-difluorobenzyl) -N -(2,4 -dimethyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[0900] A mixture of 1 - [(2,4 - difluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylic acid (30 mg, 0.12 mmol), (6R) -6 -amino -2 ,4-dimethyl -7,8 -dihydro - 6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.10 mmol), 1H -benzo [d] [1, 2,3] triazole -1 -ol (21 mg, 0.15 mmol) and N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (28 mg, 0.15 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (20 - 50% acetonitrile/0.05% ammonium hydroxide in water) to give (S)-1-(2,4-difluorobenzyl ) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 - a] [1,3] diazepin -6 -yl) -1H -1 ,2,4 -triazole -3 - carboxamide (32 mg, 74%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1 H), 7.48 - 7 .45 (m, 1H), 7.05 - 7.00 (m, 2H), 6.11 (s, 1H), 5.52 (s, 2H), 4.54 - 4.49 (m, 1H ), 4.33 - 4.23 (m, 2H), 3.32 (s, 3H), 2.85 - 2.83 (m, 1H), 2.25 - 2.24 (m, 4H). LCMS RT = 0.760 min.; m/z = 416.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.760 mln., ESI+ found [M+H] =416.1. Example 222

[0901] WX Method XX (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(4-fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide

[0902] A mixture of 1 - [(4-fluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylic acid (27 mg, 0.12 mmol), (6R) -6 -amino -2,4 -dimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.10 mmol), 1H - benzo [d] [1,2, 3] triazole -1 -ol (21 mg, 0.15 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (28 mg, 0.15 mmol) in N N-dimethylformamide (5 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (20 - 50% acetonitrile/0.05% ammonium hydroxide in water) to give (S)-N-(2,4-dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 -(4 -fluorobenzyl) -1H -1,2 ,4-triazole-3-carboxamide (31.4 mg, 80%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.42 - 7, 38 (m, 2H), 7.12 - 7.08 (m, 2H), 6.11 (s, 1H), 5.46 (s, 2H), 4.55 - 4.50 (m, 1H) , 4.30 - 4.22 (m, 2H), 3.32 (s, 3H), 2.86 - 2.80 (m, 1H), 2.29 - 2.23 (m, 4H). LCMS RT = 3.87 min.; m/z = 424.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.745 mln., ESI+ found [M+H] =398.0. Example 223

[0903] WX Method AAAA

[0904] (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(3,4-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: Methyl 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylate

[0905] To a mixture of methyl 1H -1,2,4 -triazole -3 -carboxylate (10.0 g, 78.7 mmol) and potassium carbonate (21.8 g, 157.4 mmol) in N, N-dimethylformamide (200 mL) was added 3,4-difluorobenzyl chloride (19.6 g, 94.4 mmol) dropwise under 0°C. The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 1 - [(3,4-difluorophenyl) methyl] -1 ,2,4-triazole-3-carboxylate (6.7 g, 34%) in the form of a white solid, which was used in the next step as is. Step 2: 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

[0906] A mixture of methyl 1 - [(3,4 - difluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (2.0 g, 7.9 mmol) and potassium hydroxide (886 mg, 15.8 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (20 mL). The aqueous solution was adjusted to pH = 4 by adding hydrochloric acid (1.0 M). The solid product was collected through filtration, washed with water (3 x 25 mL) and dried under vacuum to provide 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole acid. 3 - carboxylic acid (1.6 g, 85%) in the form of a white solid: 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1 H), 7.36 - 7.21 (m, 3H), 5.47 (s, 2H).

[0907] (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(3,4-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[0908] A mixture of 1 - [(3,4 - difluorophenyl) methyl] 1,2,4 -triazole -3 -carboxylic acid (26 mg, 0.11 mmol), (6S) -6 -amino -2 - cyclopropyl -4 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [1 ,2,3] triazol -1 -ol (18 mg, 0.14 mmol). mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% HCl in water) to give (S)-N-(2-cyclopropyl-4-methyl- 5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(3,4 -difluorobenzyl) -1H -1, 2,4 -triazole -3 - carboxamide (26 mg, 65%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 7.36 - 7.20 (m, 3H), 6.29 (s, 1H), 5.49 (s, 2H), 4.71 - 4.67 (m, 1H), 4.45 - 4.35 (m, 2H), 3.21 (s, 3H), 2.88 - 2.86 (m, 1H), 2.40 - 2.38 (m, 1H), 1.12 - 1.11 (m, 2H), 0, 90 - 0.88 (m, 2H). LCMS RT = 1.02 min.; m/z = 442.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.02 mln., ESI+ found [M+H] = 442.2. Example 224

[0909] WX EEEE Method

[0910] (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,4-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[0911] A mixture of 1 - [(2,4 - difluorophenyl)methyl] -1,2,4 -triazole -3 -carboxylic acid (26 mg, 0.11 mmol), (6S) -6 -amino -2 -cyclopropyl -4 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), N1 -((ethylimino) hydrochloride ) methylene) -N3,N3 -dimethyl propane -1,3 -diamine (24 mg, 0.14 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (18 mg, 0. 14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (27 -57% acetonitrile in water and 0.05% ammonium hydroxide) to provide (S) -N -(2 - cyclopropyl - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 - (2,4 - difluorobenzyl) - 1H -1,2,4 -triazole -3 -carboxamide (27.9 mg, 70%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7 .50 — 7.46 (m, 1H), 7.06 — 6.99 (m, 2H), 6.00 (s, 1H), 5.53 (s, 2H), 4.52 - 4.49 (m, 1H), 4.29 - 4.19 (m, 2H), 3.18 (s, 3H), 2.85 - 2.80 (m, 1H), 2.25 - 2.23 (m , 1H), 1.92 - 1.89 (m, 1H), 0.95 - 0.92 (m, 2H), 0.75 - 0.72 (m, 2H). LCMS RT = 0.79 min.; m/z = 442.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.79 mln., ESI+ found [M+H] =442.1. Example 225

[0912] WX GGGG Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(4-fluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[0913] A mixture of 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (24 mg, 0.11 mmol), (6S)-6-amino-2-cyclopropyl -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [1, 2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (24 mg, 0.14 mmol) in N,N - dimethylformamide (3 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (27 -57% acetonitrile in water and 0.05% ammonium hydroxide) to give (S) -N -(2-cyclopropyl - 4-methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a ] [1,3] diazepin -6 -yl) -1 - (4 -fluorobenzyl) -1H - 1,2,4 -triazole -3 - carboxamide (29.9 mg, 78%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.40 - 7.36 (m, 2H), 7.10 - 7.06 (m, 2H), 5.98 (s, 1H), 5.44 (s, 2H), 4.51 - 4.47 (m , 1H), 4.27 - 4.18 (m, 2H), 3.29 (s, 3H), 2.84 - 2.78 (m, 1H), 2.24 - 2.21 (m, 1H) ), 1.90 - 1.85 (m, 1H), 0.92 - 0.90 (m, 2H), 0.72 - 0.70 (m, 2H). LCMS RT = 0.78 min.; m/z = 424.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.78 mln., ESI+ found [M+H] =424.1. Example 226

[0914] WX NNNNNN Method 5-Benzyl -N -(1,9-dimethyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[0915] A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (21 mg, 0.10 mmol), 3-amino-1,9-dimethyl-4,5-dihydro- 1H -imidazo [1,5 -a] [1,3] diazepin - 2(3H) -one (20 mg, 0.10 mmol), N1 hydrochloride - ((ethylimino)methylene) -N3,N3 -dimethylpropane - 1,3-diamine (24 mg, 0.12 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) in N,N-dimethylformamide ( 4 mL) was subjected to stirring at 25oC for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 10 - 40/0.05% ammonium hydroxide in water) to give 5-benzyl -N -(1.9 - dimethyl -2 -oxo -2,3,4,5 -tetrahydro - 1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 - triazole -3 - carboxamide (2.4 mg, 6%) as a white solid: H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.34 - 7.24 (m, 5H), 4.57 - 4.55 (m, 1H), 4.37 - 4.31 (m, 1H), 4.18 - 4.16 (m, 2H), 3.97 - 3.91 (m, 1H) ), 3.31 (s, 3H), 2.72 - 2.65 (m, 1H), 2.22 (s, 3H), 2.11 - 2.07 (m, 1H). LCMS RT = 0.84 min.; m/z = 380.2 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.84/mln., ESI+ found [M+H] = 380.2. Example 227

[0916] WX Method OOOOOO 1-Benzyl -N -(1,9-dimethyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,3 -triazole -4 -carboxamide

[0917] A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (21 mg, 0.10 mmol), 3-amino-1,9-dimethyl-4,5-dihydro- 1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (20 mg, 0.10 mmol), N1 -((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride 1,3-diamine (24 mg, 0.12 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) in N,N-dimethylformamide ( 4 mL) was subjected to stirring at 25oC for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 15 - 45/0.05% ammonium hydroxide in water) to give 1-benzyl -N -(1.9 - dimethyl -2 -oxo -2,3,4,5 -tetrahydro - 1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,3 - triazole -4 - carboxamide (7 mg, 18%), as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.55 (s, 1H),7.40 - 7.33 (m, 5H), 5.64 (s, 2H), 4.58 - 4.53 (m, 1H), 4.37 - 4.32 (m, 1H), 3.97 - 3, 92 (m, 1H), 3.31 (s, 3H), 2.70 - 2.64 (m, 1H), 2.22 (s, 3H), 2.17 - 2.12 (m, 1H) . LCMS RT = 0.94 min.; m/z = 380.1 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.05% trifluoroacetic acid for 2 min.) retention time 0.94/mln., ESI+ found [M+H] = 380.1. Example 228

[0918] WX KK Method

[0919] (S) -5 -isopropyl -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - indazole - 3-carboxamide Step 1: Methyl 5 -isopropenyl -1h -indazole -3 - carboxylate

[0920] A mixture of methyl 5-bromo-1h-indazole-3-carboxylate (400 mg, 1.56 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (114 mg, 0.16 mmol) , cesium carbonate (1000 mg, 3.14 mmol) and potassium isopropenyl trifluoronorate (348 mg, 2.36 mmol) in dioxane (5 mL) and water (1 mL) was heated under 120°C for 1 h under conditions of microwaves. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 5-isopropenyl -1h -indazole -3 - carboxylate (175 mg, 52%) as a white solid: LCMS RT = 3.173 min.; m/z = 216.9 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid 7 min.) retention time 3.173 mln., ESI+ found [M+H] = 216.9. Step 2: Methyl 5 -isopropyl -1h -indazole -3 - carboxylate

[0921] A mixture of methyl 5-isopropenyl -1h - indazole -3 -carboxylate (70 mg, 0.32 mmol) and 10% palladium on carbon (35 mg, 0.32 mmol) in methanol (5 mL) was hydrogenated (15 psi) under 25°C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude methyl 5-isopropyl-1h-indazole-3-carboxylate (64 mg, 91%) as a light yellow solid: LCMS RT = 3.307 min.; m/z = 219.0 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid 7 min.) retention time 3.307 mln., ESI+ found [M+H] + = 219.0. Step 3: 5-isopropyl-1h-indazole-3-carboxylic acid

[0922] A mixture of methyl 5-isopropyl -1H - indazole -3 -carboxylate (64 mg, 0.29 mmol) and hydrated lithium hydroxide (35 mg, 1.47 mmol) in tetrahydrofuran (5 mL) and water ( 2 mL) was subjected to stirring at 25 °C for 18 h. The organic solvent was removed under reduced pressure, and the aqueous residue was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The solid was removed by filtration and the aqueous layer was concentrated under reduced pressure to provide 5-isopropyl-1H-indazole-3-carboxylic acid (40 mg, 67%) as a white solid: LCMS RT = 1.711 min.; m/z = 205.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.04% formic acid for 3 min.) retention time 1.711 mln., ESI+ found [M+H] = 205.1. Step 4: (S)-5-isopropyl -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -indazole - 3 -carboxamide

[0923] A mixture of (3s) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (41 mg, 0.22 mmol), 5 -isopropyl acid -1h - indazole -3 -carboxylic acid (40 mg, 0.20 mmol), N -((ethylimino) methylene) - N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (45 mg, 0.24 mmol) and 1H - benzo [d][1,2,3]triazol-1-ol (32 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was stirred under 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (46-76% acetonitrile/0.05% ammonia in water) to give (S)-5-isopropyl-N-(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - indazole -3 -carboxamide (31.5 mg, 41.5% yield) in form of a white solid: 1H NMR (400 MHz, DMSO - d6) δ 13.65 (br.s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.89 ( s, 1H), 7.60 - 7.49 (m, 2H), 7.40 — 7.23 (m, 4H), 4.99 — 4.89 (m, 1H), 4.68 — 4, 58 (m, 1H), 4.52 — 4.43 (m, 1H), 3.34 (s, 3H), 3.04 — 2.93 (m, 1H), 1.22 (d, J = 6.8Hz, 6H). LCMS RT = 1.173 min.; m/z = 379.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid 7 min.) retention time 1.173 mln., ESI+ found [M+H] = 379.1. Example 229

[0924] WX Z Method 1 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -(2,2, 2 - trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide Step 1: 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)furo[3,4-c]pyridin-3(1H)-one

[0925] To a solution of 2,2,6,6-tetramethyl piperidine (13.5 g, 95.6 mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M, 50.0 mL, 125.0 mmol) under -78°C. The reaction was stirred at -78°C for 1 h, and 6-chloronicotinic acid (5.0 g, 31.7 mmol) in tetrahydrofuran (30 mL) was added. Stirring was continued at -78°C for 2 h, then 4,4,4-trifluorobutan-2-one (4.0 g, 31.7 mmol) was added. After addition, the reaction mixture was heated to 25°C for 16 h and then terminated by addition of saturated aqueous ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-chloro-1-methyl - 1 -(2,2,2 -trifluoroethyl) hole [3,4 -c] pyridin -3(1H) -one (4.0 g, 47%) as a yellow colored oil: 1H NMR (400 MHz, CDCI3) δ 8.96 ( s, 1H), 7.48 (s, 1H), 2.95 — 2.88 (m, 1H), 2.82 - 2.76 (m, 1H), 1.77 (s, 3H). Step 2: 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridin-3-ol

[0926] To a solution of 6-chloro-1-methyl -1 - (2,2,2-trifluoroethyl) fur [3,4 -c] pyridine -3(1H) -one (3.5 g, 13, 2 mmol) in toluene (15 mL) was added diisobutyl aluminum hydride (1.0 M, 26.4 mL, 26.4 mmol) dropwise under -70°C. After addition, stirring was continued at -70°C for 2 h and the reaction mixture was terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 6-chloro-1-methyl -1 - (2.2, 2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridin-3-ol (3.5 g, 99%) in the form of a yellow-colored oil, which was used in the next step in the form in which was found. Step 3: 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine

[0927] To a solution of 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro [3,4-c] pyridin-3-ol (3.4 g, 12.7 mmol) in dichloromethane (50 mL) trifluoroacetic acid (7.2 g, 63.5 mmol) was added dropwise under 0°C. The reaction was subjected to stirring for 30 min. under 0°C, and triethyl silane (7.4 g, 63.5 mmol) was added. After addition, the mixture was allowed to warm to 25°C for 3 h and then finished by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% ethyl acetate in petroleum ether) to provide 6-chloro-1-methyl -1 - (2.2, 2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine (3.0 g, 94%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 4: methyl 1 -methyl -1 -(2,2,2 - trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxylate

[0928] A solution of 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine (3.0 g, 11.9 mmol) , 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (872 mg, 1.19 mmol) and triethylamine (6.0 g, 59.6 mmol) in methanol (80 mL) was heated at 80°C for 4 h under carbon oxide (40 psi). The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 1 -methyl -1 - (2,2,2 - trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine - 6 - carboxylate (2.5 g, 76%) in the form of a yellow oil, which was used in the step next in the form in which it was. Step 5: 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

[0929] A mixture of methyl 1 -methyl -1 - (2,2,2 - trifluoroethyl) -1,3 - dihydrofuro [3,4 - c ] pyridine -6 - carboxylate (2.5 g, 9.1 mmol ) and lithium hydroxide hydrate (1.9 g, 45.4 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was stirred under 25°C for 2 h. The organic solvent was evaporated under reduced pressure and the resulting aqueous layer was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 1-methyl-1-(2,2,2-trifluoroethyl acid )-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (2.3 g, 91%) as a yellow solid, which was used in the next step without any further purification. Step 6: 1 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 - (2 ,2,2-trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine - 6 -carboxamide

[0930] A mixture of 1-methyl -1 -(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (49 mg, 0.19 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (25 mg, 0.19 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 - benzoxazepine -4 -one (30 mg, 0.16 mmol) and N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (36 mg, 0.19 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (43-73% acetonitrile with 0.05% HCl in water) to give 1-methyl-N-((S)-5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -(2,2,2 - trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide (45.7 mg, 67%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.05 (s, 1H), 7.46 - 7.43 (m, 1H), 7.34 — 7.31 (m, 2H), 7.27 — 7.24 (m, 1H), 5.21 (s, 2H) , 5.04 — 5.01 (m, 1H), 4.67 — 4.62 (m, 1H), 4.44 - 4.41 (m, 1H), 3.43 (s, 3H), 2 .90 - 2.79 (m, 2H), 1.57 (s, 3H). LCMS RT = 0.878 min.; m/z = 436.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.878 mln., ESI+ found [M+H] = 436.1. Example 230

[0931] WX Method U (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -7 - (trifluoromethyl)imidazo [1,5 - c] pyrimidine -1 -carboxamide Step 1: ethyl 2 -((diphenylmethylene) amino) -2 -(6 -(trifluoromethyl) pyrimidin -4 -yl) acetate

[0932] To a solution of 2-((diphenylmethylene)amino) acetate (3.0 g, 11.2 mmol) in tetrahydrofuran (60 mL) was added potassium tert-butoxide (1.0 M, 12.3 mL , 12.3 mmol) dropwise under -78°C. After being subjected to agitation for 30 min. under -78°C, 4-chloro-6-trifluoromethyl pyrimidine (3.1 g, 16.8 mmol) was added and the resulting mixture was allowed to warm to 0°C and stirred for another 0.5 H. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (3 x 35 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give ethyl 2 - ((diphenylmethylene) amino) -2 - (6 - ( trifluoromethyl)pyrimidin-4-yl)acetate (3.5 g, 23%) as a red oil: LCMS RT = 1.001 min.; m/z = 414.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 1.001 mln., ESI+ found [M+H] =414.0. Step 2: Ethyl 2-amino-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate hydrochloride

[0933] A mixture of ethyl 2 -((diphenylmethylene) amino) -2 -(6 -(trifluoromethyl) pyrimidin -4 -yl) acetate (3.5 g, 2.5 mmol) and hydrochloric acid (36%, 514 mg, 5.08 mmol) in dichloromethane (25 mL) was stirred at 25°C for 1 h. The solution was diluted with water (20 mL) and washed with dichloromethane (2 x 25 mL). The aqueous phase was concentrated to drying to provide crude ethyl 2-amino-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate hydrochloride (600 mg, 95%) as a yellow oil: LCMS RT = 0.244 min.; m/z = 249.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.244 mln., ESI+ found [M+H] = 249.8. Step 3: ethyl 7-(trifluoromethyl)imidazo[1,5-c]pyrimidine-1-carboxylate

[0934] Formic acid (98%, 2 mL) was added dropwise to acetic anhydride (4.0 mL) under 0°C. The resulting solution was stirred for 4 h at 0°C, and then added to a solution of ethyl 2-amino-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate hydrochloride (600 mg, 2. 41 mmol) in tetrahydrofuran (10 mL) under 0°C. After addition, the mixture was stirred at 25°C for 6 h, and then diluted with water (30 ml). The mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give ethyl 7-(trifluoromethyl ) imidazo [1,5 -c] pyrimidine - 1 -carboxylate (600 mg, 96%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8, 43 (s, 1H), 8.35 (s, 1H), 4.50 — 4.45 (m, 2H), 1.45 (t, J = 7.2 Hz, 3H). Step 4: (S) -N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -7 - (trifluoromethyl) imidazo [1 ,5 -c] pyrimidine -1 - carboxamide

[0935] A mixture of (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one (50 mg, 0.26 mmol) and ethyl 7 -(trifluoromethyl) imidazo[1,5-c]pyrimidine-1-carboxylate (60.67 mg, 0.23 mmol) in tetrahydrofuran (3 mL) trimethylaluminum (2.0 M, 0.78 mL, 1.56 mmol) was added. The mixture was subjected to stirring at 50°C for 15 h and then finalized by addition of saturated aqueous sodium potassium tartrate (10 mL). The solution was stirred at 25°C for 1 h and then extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by haRP-HPLC (32 -62% acetonitrile in water and 0.05% ammonium hydroxide) to give (S) -N -(5 -methyl -4 -oxo -2,3 ,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -7 - (trifluoromethyl)imidazo [1,5 -c] pyrimidine -1 -carboxamide (31 mg, 27%) in the form of a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.51 (s, 1H), 8.82 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.34 - 7.25 (m, 3H), 4.95 - 4.89 (m, 1H) , 4.66 - 4.61 (m, 1H), 4.47 - 4.29 (m, 1H), 3.33 (s, 3H): LCMS RT = 0.845 min.; m/z = 406.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.845 mln., ESI+ found [M+H] =406.0. Example 231

[0936] WX DD Method

[0937] 1 -(methoxymethyl) -1 -methyl -N -((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl ) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide Step 1: 6 -chloro -1 -(methoxymethyl) -1 -methyl -3H -furo [3,4 -c] pyridin -3 -one

[0938] To a stirred solution of 2,2,6,6-tetramethyl piperidine (4.1 g, 29.0 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M, 15 mL, 37.5 mmol) dropwise under -78°C. The mixture was stirred at -78oC for 40 min. and then 6-chloronicotinic acid (1.5 g, 9.5 mmol) in tetrahydrofuran (20 mL) was added. The resulting mixture was stirred at -78°C for another 2 h, and then methoxy acetone (839 mg, 9.52 mmol) was added dropwise. After addition, the reaction was heated to 25°C and stirred for 16 h before being terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -50% ethyl acetate/petroleum ether) to provide 6-chloro-1-(methoxymethyl)-1-methyl-3H -furo [3,4 -c] pyridin -3 -one (1.5 g, 69%) in the form of a yellow oil, which was used in the next step as is. Step 2: 6 -chloro -1 -(methoxymethyl) -1 -methyl -3H -furo [3,4 -c] pyridin -3 -ol

[0939] To a solution of 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-one (1.5 g, 6.6 mmol) in toluene ( 40 mL) diisobutyl aluminum hydride (1.0 M, 13.0 mL, 13.0 mmol) was added dropwise under -70°C. After addition, stirring was continued at -70°C for 2 h and the reaction mixture was terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-chloro-1-(methoxymethyl)-1-methyl-3H -furo[3,4-c]pyridin-3-ol crude (1.5 g, 99%) as a yellow colored oil, which was used in the next step without any further purification. Step 3: 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine

[0940] To a solution of 6 -chloro -1 -(methoxymethyl) -1 -methyl -3H -furo [3,4 -c] pyridin -3 -ol (280 mg, 1.22 mmol) in dichloromethane (20 mL ) trifluoroacetic acid (695 mg, 6.10 mmol) was added dropwise under 0°C. The reaction was subjected to stirring for 30 min. under 0°C, and triethyl silane (425 mg, 3.66 mmol) was added. After addition, the mixture was allowed to warm to 25°C for 3 h and then finished by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether) to provide 6-chloro-1-(methoxymethyl)-1-methyl-3H -furo [3,4 -c] pyridine (200 mg, 77%) as a yellow oil: LCMS RT = 0.45 min.; m/z = 214.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.45/mln., ESI+ found [M+H] = 214.1. Step 4: methyl 1 -(methoxymethyl) -1 -methyl -3H - fur [3,4 -c] pyridine -6 -carboxylate

[0941] A solution of 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine (200 mg, 0.94 mmol), 1,1'-bis(dichloride) diphenylphosphine) ferrocene palladium (68 mg, 0.09 mmol) and triethylamine (947 mg, 9.36 mmol) in methanol (10 mL) was heated at 80 ° C for 12 h under carbon oxide (25 psi). The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether) to give methyl 1 -(methoxymethyl) -1 -methyl -3H - fur [3,4 -c] pyridine -6 -carboxylate (160 mg, 72%) as a yellow oil: LCMS RT = 0.52 min.; m/z = 238.0 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.52/mln., ESI+ found [M+H] = 238.0. Step 5: 1 -(methoxymethyl) -1 -methyl -N -((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl ) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[0942] To a solution of methyl 1 -(methoxymethyl) -1 - methyl -3H -furo [3,4 -c] pyridine -6 -carboxylate (20 mg, 0.08 mmol) and (3S) -3 -amino -5-methyl -2,3 -dihydro -1,5 - benzoxazepin -4 -one (18 mg, 0.09 mmol) in tetrahydrofuran (4 mL) was added and trimethylaluminum (2.0 M, 0.25 mL, 0.51 mmol). The reaction mixture was stirred at 25°C for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 30 - 60/0.05% ammonium hydroxide in water) to give 1 - (methoxymethyl) -1 -methyl -N -( (S) -5 - methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1,3 - dihydrofuro [3,4 -c] pyridine - 6-carboxamide (2 mg, 7%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.93 (s, 1H), 7.45 — 7.43 (m, 1H), 7.34 — 7.32 (m, 2H), 7.26 - 7.24 (m, 1H), 5.18 (s, 2H), 5.05 - 5, 00 (m, 1H), 4.67 - 4.65 (m, 2H), 4.43 - 4.40 (m, 1H), 3.57 - 3.51 (m, 2H), 3.43 ( s, 3H), 3.27 (s, 3H), 1.46 (s, 3H). LCMS RT = 1.73 min.; m/z = 398.1 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.73/mln., ESI+ found [M+H] = 398.1. Example 232

[0943] WX Q Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4,5 -dihydro - 2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine] -6' - carboxamide Step 1: 6' -chloro -4,5 -dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridin] -3' -one

[0944] To a stirred solution of lithium diisopropylamide (2.0 M, 12.7 mL, 25.4 mmol) in tetrahydrofuran (50 mL) was added a solution of 6-chloronicotinic acid (1.0 g, 6.35 mmol) in tetrahydrofuran (10 mL) under -78°C. After addition, the mixture was stirred under -78°C for 3 h, and then a solution of 3-oxotetrahydrofuran (5.5 g, 63.5 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture was heated to 25°C and stirred for 12 h before being finalized by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -40% methanol in dichloromethane) to provide 6'-chloro-4,5-dihydro-2H,3'H-spiro [ furan -3,1' -fur [3,4 -c] pyridin] -3' -one (0.6 g, 41.8%) as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.90 (s, 1H), 4.29 - 4.13 (m, 2H), 4.09 (s, 2H), 2.70 - 2.38 (m , 2H). LCMS RT = 0.995 min.; m/z = 226 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3.0 min.) retention time 0.995 mln., ESI+ found [M+H] = 226. Step 2: 6' -chloro -4,5 -dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridin] -3' -ol

[0945] To a solution of 6' -chloro -4,5 -dihydro - 2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridin] -3' - one (550 mg, 2.44 mmol) in toluene (65 mL) was added diisobutylaluminum hydride (1.0 M, 7.3 mL, 7.3 mmol) dropwise under -70°C. After addition, the mixture was stirred at -60°C for 4 h and then finalized by addition of saturated aqueous ammonium chloride (70 ml). The mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with aqueous NaOH (2%, 2 x 50 mL) and water (20 mL). The combined aqueous layers were adjusted to pH = 4 by adding hydrochloric acid (2.0 M) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 6'-chloro-4,5-dihydro-2H,3'H-spiro[furan-3,1'-furo[3, Crude 4-c]pyridin]-3'-ol (450 mg, 81%) as a yellow oil: LCMS RT = 0.521 min.; m/z = 228.1 (M+H)+. LCMS (10 to 80% acetonitrile in water +0.05% ammonium bicarbonate for 3.0 min.) retention time 0.521 mln., ESI+ found [M+H] = 228.1. Step 3: 6' -chloro -4,5 -dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine

[0946] A mixture of 6' -chloro -4,5 -dihydro - 2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridin] -3' -ol (450 mg , 2.0 mmol) and trifluoroacetic acid (1.1 g, 9.9 mmol) in dichloromethane (20 mL) was stirred for 0.5 h at 0°C, and then triethylsilane (689 mg, 5.9 mmol) was added. The resulting mixture was heated to 25°C and stirred for 50 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 40% ethyl acetate in petroleum) to give 6'-chloro-4.5- dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine (140 mg, 33%) as a colorless oil: LCMS RT = 1.119 min.; m/z = 212.1 (M+H)+. LCMS (10 to 80% acetonitrile in water +0.05% ammonium bicarbonate for 3.0 min.) retention time 1.119 mln., ESI+ found [M+H] = 212.1. Step 4: methyl 4,5 -dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine] -6' -carboxylate

[0947] A mixture of 6' -chloro -4,5 -dihydro - 2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine (140 mg, 0.66 mmol) , 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (48 mg, 0.07 mmol) and triethylamine (669 mg, 6.6 mmol) in methanol (15 mL) was stirred at 80°C for 12 h under carbon oxide [4.46 bar (50 psi)]. The mixture was concentrated and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 70% ethyl acetate in petroleum ether) to give methyl 4,5-dihydro-2H,3 'H -spiro [furan -3,1' -furo [3,4 -c] pyridine] -6' -carboxylate (40 mg, 25%) in the form of a brown-colored oil, which was used in the next step of the the way it was. Step 5: 4,5-dihydro-2H,3'H-spiro[furan-3,1'-furo[3,4-c]pyridine]-6'-carboxylic acid.

[0948] A mixture of 4,5 -dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine] -6' -carboxylate (40 mg, 0.17 mmol ) and potassium hydroxide (28 mg, 0.51 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred for 1 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M). The aqueous layer was concentrated under reduced pressure to provide crude 4,5-dihydro-2H,3'H-spiro[furan-3,1'-furo[3,4-c]pyridine]-6'-carboxylic acid (11 mg, 30%) in the form of a yellow solid, which was used in the next step as is. Step 6: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -4,5 -dihydro - 2H, 3'H -spiro [furan -3,1' -furo [3,4 -c] pyridine] -6' - carboxamide

[0949] A mixture of 4,5-dihydro-2H,3'H-spiro[furan-3,1'-furo[3,4-c]pyridine]-6'-carboxylic acid (11 mg, 0.05 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (11 mg, 0.08 mmol), N1 - ((ethylimino) methylene) -N3,N3 -dimethylpropane -1 hydrochloride, 3-diamine (15.0 mg, 0.08 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (10 mg, 0.05 mmol ) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The solvent was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.225% FA in water) to give N -((S)-5-methyl-4-oxo-2, 3,4,5 -tetra hydrobenzo [b] [1,4] oxazepin -3 -yl) -4,5 -dihydro -2H,3'H -spiro [furan -3,1' -furo [3,4 - c] pyridine] -6' - carboxamide (14 mg, 70.8%) in the form of a yellow colored oil: 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.99 (s , 1H), 7.47 - 7.41 (m, 1H), 7.37 — 7.28 (m, 2H), 7.27 — 7.21 (m, 1H), 5.18 (s, 2H ), 5.00 — 5.05 (m, 1H), 4.67 — 4.61 (m, 1H), 4.44 — 4.36 (m, 1H), 4.15 — 4.02 (m , 2H), 3.96 — 3.99 (m, 1H), 3.90 — 3.83 (m, 1H), 3.43 (s, 3H), 2.38 — 2.23 (m, 2H) ). LCMS RT = 0796 min.; m/z = 396 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.796 mln., ESI+ found [M+H] +=396. Example 233

[0950] WX Method QQQQQQ (1R) -1 -ethyl -1 -methyl -N -(9 -methyl -8 -oxo - 6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin - 7 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide Step 1: ethyl 4 -(2 -nitroimidazol -1 -yl)butanoate

[0951] A mixture of 2-nitroimidazole (10.0 g, 88.4 mmol), ethyl 4-bromobutyrate (17.2 g, 88.4 mmol) and potassium carbonate (22.4 g, 176.9 mol ) in N,N-dimethylformamide (20 mL) was heated at 120°C for 2 h. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide ethyl 4-(2-nitroimidazol-1-yl)butanoate (9 .0 g, 45%) in the form of a colorless oil: 1H NMR (400MHz, CDCl3) δ 7.11 (d, J = 10.4 Hz, 2 H), 4.48 (t, J = 7.2 Hz, 2 H), 4.16 - 4.08 (m, 3 H), 2.35 (t, J = 7.2 Hz, 2 H), 2.20 - 2.15 (m, 2 H) , 1.28 - 1.20 (m, 4 H). Step 2: ethyl 4 -(2 -amino -1H -imidazol -1 -yl) butanoate

[0952] A mixture of ethyl 4-(2-nitroimidazol-1-yl) butanoate (7.0 g, 30.8 mmol) and 10% palladium on carbon (32.8 g, 30.8 mmol) in 1 ,4-dioxane (300 mL) was hydrogenated (15 psi) under 25°C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide ethyl 4-(2-amino-1H-imidazol-1-yl)butanoate (5.0 g, 81%) as a brown oil. which was used in the next step without any further purification. Step 3: 6,7 -dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one

[0953] To a solution of ethyl 4 -(2-amino -1H - imidazol -1 -yl) butanoate (4.5 g, 22.8 mmol) in ethanol (50 mL) was added sodium ethoxide (7.7 g, 114.1 mmol). The mixture was subjected to stirring at 25°C for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 6,7-dihydro-5H-imidazo[1, 2 -a] [1,3] diazepin -8(9H) -one (2.0 g, 58%) as a white solid: 1H NMR (400MHz, DMSO -d6) δ 10.12 (br .s., 1 H), 7.00 (s, 1 H), 6.71 (s, 1 H), 4.01 (t, J = 6.8 Hz, 2 H), 2.29 - 2 .21 (m, 2 H), 2.19 - 2.06 (m, 2 H). Step 4: 9 -methyl -6,7 -dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one

[0954] To a solution of 6,7 -dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (1.8 g, 11.9 mmol) in N, N-dimethylformamide (50 mL) was added cesium carbonate (3.9 g, 11.9 mmol) and iodomethane (1.7 g, 11.9 mmol). The mixture was stirred at 25°C for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 9-methyl-6,7-dihydro-5H-imidazo[1,2-a] [1,3] diazepin -8(9H) -one (1.5 g, 76%) as a white solid: 1H NMR (400MHz, DMSO - d6) δ 7.04 (d, J = 1 .6 Hz, 1 H), 6.79 (d, J = 1.2 Hz, 1 H), 3.99 (t, J = 6.8 Hz, 2 H), 3.17 (s, 3 H ), 2.23 - 2.13 (m, 4 H). Step 5: 7 -azide -9 -methyl -6,7 -dihydro -5H - imidazo [1,2 -a] [1,3] diazepine -8(9H) -one

[0955] To a mixture of 9 -methyl -6,7 -dihydro -5H - imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (1.2 g, 7.3 mmol ) in tetrahydrofuran (50 mL) lithium diisopropylamide (2.0 M, 10.9 mL, 21.7 mmol) was added dropwise under -78 °C. After stirring at -78°C for 30 ml, p-toluene sulfonyl azide (4.3 g, 21.8 mmol) in tetrahydrofuran (5 ml) was added. After addition, the mixture was stirred at -78°C for 2 h then allowed to warm to 25°C for another 15 h. The reaction was terminated by addition of acetic acid (0.4 mL) and stirred for 3 h at 25°C. Then the mixture was adjusted to pH = 8 by adding saturated aqueous sodium carbonate. The mixture was concentrated to drying and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 7-azide -9 -methyl -6,7 - dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (800 mg, 53%) in the form of a yellow oil, which was used in the next step in the form which was found. Step 6: 7 -amino -9 -methyl -6,7 -dihydro -5H - imidazo [1,2 -a] [1,3] diazepine -8(9H) -one

[0956] The mixture of 7-azide -9 -methyl -6,7 -dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (800 mg, 3.8 mmol ) and 10% palladium on carbon (50 mg, 0.05 mmol) in methanol (10 mL) was hydrogenated [2.04 bar (15 psi)] under 25°C for 15 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H) -one (300 mg, 43%) in the form of a yellow oil, which was used in the next step without any further purification. Step 7: (1R) -1 -ethyl -1 -methyl -N -(9 -methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3 ] diazepin -7 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide

[0957] A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (23 mg, 0.11mmol), 7-amino-9-methyl -6,7 -dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (20 mg, 0.11 mmol), N1 -((ethylimino) methylene hydrochloride) -N3,N3 -dimethyl propane -1,3 -diamine (26 mg, 0.13 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 20 - 50/0.05% ammonium hydroxide in water) to give (1R) -1 -ethyl -1 -methyl -N -(9 -methyl -8 -oxo -6,7,8,9 -tetrahydro -5H -imidazo [1,2 -a] [1,3] diazepin - 7 -yl) -1,3 -dihydrofuro [3, 4 -c] pyridine -6 -carboxamide (4 mg, 9.9%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.87 (s , 1H), 7.13 (s, 1H), 7.00 - 6.99 (m, 1H), 5.21 - 5.13 (m, 2H), 4.58 - 4.55 (m, 1H) ), 4.35 - 4.30 (m, 1H), 4.12 - 4.10 (m, 1H), 3.41 (s, 3H), 2.95 - 2.92 (m, 1H), 2.32 - 2.26 (m, 1H), 1.89 - 1.83 (m, 2H), 1.47 (s, 3H), 0.80 - 0.76 (m, 3H). LCMS RT = 1.81 min.; m/z = 370.1 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.05% ammonium bicarbonate over 3 min.) retention time 1.81 mln., ESI+ found [M+H] = 370.1. Example 234

[0958] WX WWWW Method 1-benzyl -N -(4-methyl -5 -oxo -2 -(tetrahydro - 2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: N -(3-bromo-1H-pyrazol-5-yl)formamide

[0959] A mixture of 3-bromo-1H-pyrazole-5-amine (16.0 g, 98.8 mmol) and formic acid (50 mL, 98.8 mmol) was subjected to stirring at 110 ° C in a vessel sealed for 2 h. The mixture was concentrated under reduced pressure and the residue was washed with water (50 mL) to provide N -(3-bromo-1H-pyrazol-5-yl)formamide (15.0 g, 80%) as a white solid, which was used in the next step without any further purification. Step 2: 3-bromo-N-methyl-1H-pyrazol-5-amine

[0960] To a solution of N -(3-bromo-1H-pyrazol-5-yl)formamide (15.0 g, 79.0 mmol) in tetrahydrofuran (200 mL) was added borane (1.0 M, 315 .8 mL, 315.8 mmol). The mixture was stirred at 0°C for 2 h and then finalized by addition of methanol (30 mL) and hydrochloric acid (10%, 5 mL). The mixture was then heated under reflux for 30 min. and adjusted to pH = 8 by addition of aqueous sodium hydroxide (10%). The mixture was concentrated under reduced pressure and the residue was collected in ethyl acetate (100 mL), washed with water (2 x 50 mL), saline solution (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. . The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 3-bromo-N-methyl-1H-pyrazol-5-amine (13.0 g, 94%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: N -(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide

[0961] A mixture of 3-bromo-N-methyl-1H-pyrazol-5-amine (13.5 g, 76.7 mmol) and 4-chlorobutanoyl chloride (33.5 mL, 300 mmol) was subjected to stirring under 60°C for 3 h. After cooling, methanol (50 mL) was added into the mixture carefully and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide N -(3-bromo-1H-pyrazol-5-yl) -4-chloro-N-methylbutanamide (17.0 g, 79%) in the form of a colorless oil, which was used in the next step without any further purification. Step 4: 2 -bromo -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[0962] To a mixture of N -(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide (17.0 g, 60.6 mmol) in N,N-dimethylformamide (100 mL) cesium carbonate (39.5 g, 121.2 mmol) was added and stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with ethyl acetate (200 ml). The mixture was washed with water (2 x 100 mL), brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2-bromo-4-methyl-7,8-dihydro- 4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (12.0 g, 76%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 6.05 (s, 1H), 4.22 (t, J = 6.4 Hz, 2H), 3.24 (s, 3H), 2.43 - 2.32 (m, 4H). Step 5: 2 -(3,6 -dihydro -2H -pyran -4 -yl) -4 - methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5( 6H) -one

[0963] A mixture of 2-bromo-4-methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (500 mg, 2.1 mmol), pinacol ester 3,6-dihydro-2h-pyran-4-boronic acid (646 mg, 3.1 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (150 mg, 0.2 mmol) and potassium carbonate (566 mg, 4.1 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was heated at 110°C for 30 min. under microwave conditions. The mixture was concentrated under reduced pressure and the residue was purified by prep haTLC (50% ethyl acetate in petroleum ether, Rf = 0.3) to give 2-(3,6-dihydro-2H-pyran -4 -yl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (400 mg, 79%) in the form of a white solid. LCMS RT = 1.14 min.; m/z = 248.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate over 3 min.) retention time 1.14 mln., ESI+ found [M+H] = 248.1. Step 6: 4 -methyl -2 -(tetrahydro -2H -pyran -4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) -one

[0964] A mixture of 2 -(3,6-dihydro -2H -pyran -4 -yl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepine -5(6H)-one (650 mg, 2.6 mmol) and 10% palladium on carbon (2.8 g, 2.6 mmol) in methanol (20 mL) was hydrogenated (15 psi) under 25°C for 12 p.m. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazole[1,5-a] [1,3] diazepin - 5(6H) -one (510 mg, 78%) as a white solid: LCMS RT = 0.574 min.; m/z = 250.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.574 mln., ESI+ found [M+H] = 250.1. Step 7: 6 -iodo -4 -methyl -2 -(tetrahydro -2H - pyran -4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5( 6H) -one

[0965] To a solution of 4-methyl -2 -(tetrahydro - 2H -pyran -4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5( 6H)-one (510 mg, 2.1 mmol) in dichloromethane (20 mL) was added N1,N1,N2,N2 -tetramethylethane -1,2 - diamine (1.4 g, 12.3 mmol), followed by iodotrimethylsilane (2.5 g, 12.3 mmol) under -15°C. The resulting solution was stirred 2 h under -15°C, and iodine (1.6 g, 6.1 mmol) was added in one portion. After stirring for 2 h at -15°C, the reaction mixture was terminated by adding saturated sodium bisulfite (30 mL). The mixture was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6 -iodo -4 -methyl -2 - (tetrahydro -2H - pyran - 4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) -one (520 mg, 67.7% yield) in the form of a brown solid: LCMS RT = 0.65 min.; m/z = 376.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.65 mln., ESI+ found [M+H] = 376.0. Step 8: 6 -azide -4 -methyl -2 -(tetrahydro -2H - pyran -4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5( 6H)-one

[0966] A mixture of 6 -iodo -4 -methyl -2 - (tetrahydro -2H -pyran -4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepine -5(6H)-one (510 mg, 1.4 mmol) and sodium azide (106 mg, 1.6 mmol) in N,N-dimethylformamide (2 mL) was stirred for 2 h under 25° W. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-azide -4 - methyl -2 -(tetrahydro -2H -pyran -4 -yl) -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one (340 mg, 86 %) as a light yellow oil: LCMS RT = 0.63 min.; m/z = 291.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.63 mln., ESI+ found [M+H] = 291.2. Step 9: 6 -amino -4 -methyl -2 -(tetrahydro -2H - pyran -4 -yl) -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5( 6H) -one

[0967] A mixture of 6 -azide -4 -methyl -2 - (tetrahydro -2H -pyran -4 -yl) -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepine -5(6H)-one (340 mg, 1.2 mmol) and 10% palladium on carbon (124 mg, 0.12 mmol) in methanol (30 mL) was hydrogenated [2.04 bar (15 psi)] under 25°C for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide 6-amino-4-methyl-2-tetrahydropyran-4-yl-7,8-dihydro-6H-pyrazolo[1,5-a][1. 3] crude diazepin-5-one (300 mg, 97%) as a white solid, which was used in the next step without any further purification. Step 10: 1-benzyl -N -(4-methyl -5 -oxo -2 - (tetrahydro -2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 - a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[0968] A mixture of 6 -amino -4 -methyl -2 -tetrahydropyran -4 -yl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one ( 20 mg, 0.08 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (15.4 mg, 0.08 mmol), 1H-benzo[d][1,2,3] triazol -1 -ol (15 mg, 0.11 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (18 mg, 0.11 mmol) in N,N -dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (25-35% acetonitrile in water and 0.05% ammonium hydroxide) to give 1-benzyl-N-(4 -methyl -5 -oxo -2 - (tetrahydro -2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 - il) -1H -1,2,4 - triazole -3 -carboxamide (26.3 mg, 76%) as a white solid: 1H NMR (400MHz, CD3OD) δ8.56 (s, 1H), 7.36 - 7.32 (m, 5H), 6.19 (s, 1H), 5.47 (s, 2H), 4.53 - 4.51 (m, 1H), 4.50 - 4, 48 (m, 1H), 4.33 - 4.31 (m, 1H), 4.01 - 3.99 (m, 2H), 3.57 - 3.51 (m, 2H), 3.33 ( s, 3H), 2.89 - 2.84 (m, 2H), 2.26 - 2.25 (m, 1H), 1.90 - 1.85 (m, 2H), 1.79 - 1, 75 (m, 2H). LCMS RT = 1.67 min.; m/z = 450.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.67 mln., ESI+ found [M+H] = 450.2. Example 235

[0969] WX Method XXXX 5-benzyl -N -(4-methyl -5 -oxo -2 -(tetrahydro - 2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[0970] A mixture of 6-amino -4 -methyl -2 - tetrahydropyran -4 -yl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.08 mmol), 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (15 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazole -1 -ol (15 mg, 0.11 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (18 mg, 0.11 mmol) in N,N -dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (10 - 40% acetonitrile in water and 0.05% ammonium hydroxide) to give 5-benzyl -N -(4 - methyl -5 - oxo -2 -(tetrahydro -2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl ) -1H -1,2,4 - triazole -3 -carboxamide (11.4 mg, 32%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 7.30 - 7, 20 (m, 5H), 6.19 (s, 1H), 4.30 - 4.28 (m, 2H), 4.25 - 4.22 (m, 3H), 3.87 - 3.84 ( m, 2H), 3.30 - 3.26 (m, 2H), 3.18 (s, 3H), 2.78 - 2.73 (m, 1H), 2.42 - 2.40 (m, 2H), 1.80 - 1.56 (m, 4H). LCMS RT = 1.64 min.; m/z = 450.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.64 mln., ESI+ found [M+H] = 450.2. Example 236

[0971] WX ZZZZ Method (1R) -1 -ethyl -1 -methyl -N -(4 -methyl -5 -oxo -2 -(tetrahydro -2H -pyran -4 -yl) pyrazole [1,5 -a] [1,3] diazepine -6 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[0972] A mixture of 6-amino -4 -methyl -2 - tetrahydropyran -4 -yl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.08 mmol), (R) -1 - ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxylic acid (15 mg, 0.08 mmol), 1H - benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (18 mg, 0.11 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (31 -61% acetonitrile in water and 0.05% ammonium hydroxide) to give (1R)-1-ethyl -1 -methyl -N -(4 -methyl -5 -oxo -2 - (tetrahydro -2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1 ,3] diazepin -6 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide (16 mg, 46%) as a white solid: 1H NMR (400 MHz, CD3OD ) δ8.56 (s, 1H), 7.86 (s, 1H), 6.20 (s, 1H), 5.16 — 5.15 (m, 2H), 4.59 - 4.52 (m , 1H), 4.36 - 4.34 (m, 1H), 4.29 - 4.25 (m, 1H), 4.02 - 4.00 (m, 2H), 3.58 - 3.53 (m, 2H), 3.35 (s, 3H), 2.94 - 2.87 (m, 2H), 2.30 - 2.21 (m, 1H), 1.89 - 1.81 (m , 6H), 1.46 (s, 3H), 0.77 (t, J = 7.2 Hz, 3H). LCMS RT = 0.79 min.; m/z = 454.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79 mln., ESI+ found [M+H] = 454.2. Example 237

[0973] WX YYYY Method 1-benzyl -N -(4-methyl -5 -oxo -2 -(tetrahydro - 2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl) -1H -1,2,3 -triazole -4 - carboxamide

[0974] A mixture of 6-amino -4 -methyl -2 - tetrahydropyran -4 -yl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.08 mmol), 1 - benzyltriazole -4 -carboxylic acid (16 mg, 0.08 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (15 mg, 0. 11 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (18 mg, 0.11 mmol) in N,N -dimethylformamide (4 mL) was subjected to stirring at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (28 -38% acetonitrile in water and 0.05% ammonium hydroxide) to give 1-benzyl -N -(4 - methyl -5 -oxo -2 - (tetrahydro -2H -pyran -4 -yl) -5,6,7,8 - tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl ) -1H -1,2,3 - triazole -4 -carboxamide (17 mg, 49.3%) as a white solid: 1H NMR (400 MHz, CD3OD) δ8.34 (s, 1H), 7.37 - 7.32 (m, 5H), 6.18 (s, 1H), 5.63 (s, 2H), 4.53 - 4.48 (m, 1H), 4.34 - 4, 32 (m, 1H), 4.26 - 4.17 (m, 1H), 4.01 - 3.98 (m, 2H), 3.57 -3.51 (m, 2H), 3.33 ( s, 3H), 2.88 - 2.82 (m, 2H), 2.28 - 2.21 (m, 1H), 1.87 - 1.76 (m, 4H). LCMS RT = 1.72 min.; m/z = 450.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.72 mln., ESI+ found [M+H] = 450.1. Example 238

[0975] WX Method V (S) -5 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazole [3,4 -b] pyridine -3 -carboxamide Step 1: methyl 5 -(prop -1 -en -2 -yl) -1H - pyrazole [3,4 -b] pyridine -3 -carboxylate

[0976] A mixture of methyl 5-bromo-1H-pyrazole [3,4-b] pyridine-3-carboxylate (375 mg, 1.46 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride ( 54 mg, 0.07 mmol), potassium isopropenyl trifluoro norate (433 mg, 2.93 mmol) and cesium carbonate (1193 mg, 3.66 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated under 120°C for 45 min. under microwave conditions. After cooling, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 5 -( prop -1 -en -2 -yl) -1H -pyrazole [3,4 -b] pyridine -3 -carboxylate (130 mg, 41%) as a white solid: LCMS RT = 0.769 min.; m/z = 217.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + formic acid for 1.5 min.) retention time 0.769 mln., ESI+ found [M+H] = 217.8. Step 2: methyl 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

[0977] A mixture of methyl 5 -(prop -1 -en -2 -yl) -1H -pyrazole [3,4 -b] pyridine -3 -carboxylate (130 mg, 0.60 mmol) and 10% palladium in carbon (64 mg, 0.60 mmol) in methanol (15 mL) was hydrogenated [2.04 bar (15 psi)] under 25°C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude methyl 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (100 mg, 76%) as a colorless oil : LCMS RT = 0.765 min.; m/z = 219.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.765 mln., ESI+ found [M+H] = 219.9. Step 3: 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid

[0978] A mixture of methyl 5 -isopropyl -1H - pyrazole [3,4 -b] pyridine -3 -carboxylate (50 mg, 0.23 mmol) and hydrated lithium hydroxide (96 mg, 2.28 mmol) in Tetrahydrofuran (5 mL) and water (1 mL) were stirred for 20 h under 20°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 4 by adding hydrochloric acid (1.0 M). The solution was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (40 mg, 85%) in forms a white solid: LCMS RT = 0.599 min.; m/z = 205.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.599 mln., ESI+ found [M+H] = 205.8. Step 4: (S)-5-isopropyl -N -(5-methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - pyrazole [3,4 -b] pyridine -3 -carboxamide

[0979] A mixture of 5 -isopropyl -1H - pyrazolo [3,4 -b] pyridine -3 -carboxylic acid (40 mg, 0.19 mmol), (3S) -3 -amino -5 -methyl -2, 3 -dihydro -1,5 - benzoxazepin -4 -one (41 mg, 0.21 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (32 mg, 0.23 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethyl propane-1,3-diamine hydrochloride (45 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred under 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by haRP-HPLC (30 -60% acetonitrile in water and 0.05% hydrochloric acid) to provide (S)-5-isopropyl-N-(5-methyl-4-oxo- 2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxamide (29 mg, 39%) in the form of a white solid: 1H NMR (400 MHz, DMSO -d6) δ 14.22 (s, 1H), 8.57 - 8.54 (m, 2H), 8.22 (d, J = 1.6 Hz , 1H), 7.53 - 7.52 (m, 1H), 7.51 - 7.26 (m, 3H), 4.96 - 4.91 (m, 1H), 4.69 - 4.63 (m, 1H), 4.48 - 4.43 (m, 1H), 3.33 (s, 3H), 3.14 - 3.07 (m, 1H), 1.26 (d, J = 7 .2 Hz, 6H): LCMS RT = 0.840 min.; m/z = 380.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.840 mln., ESI+ found [M+H] = 380.1. Example 239

[0980] WX W Method (S) -5 -cyclopropyl -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H - pyrazole [3,4 -b] pyridine -3 -carboxamide Step 1: methyl 5 -bromo -1 -((2 -(trimethylsilyl) ethoxy) methyl) -1H -pyrazole [3,4 -b] pyridine -3 - carboxylate

[0981] To a solution of methyl 5-bromo-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (200 mg, 0.78 mmol) in tetrahydrofuran (5 mL) was added triethylamine (158 mg, 1 .56 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (195 mg, 1.17 mmol). The reaction was stirred at 25°C for 20 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole[3,4-b ] pyridine-3-carboxylate (300 mg, 99%) as a yellow oil: LCMS RT = 0.999 min.; m/z = 387.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.999 mln., ESI+ found [M+H] = 387.8. Step 2: Cesium 5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

[0982] A mixture of methyl 5 -bromo -1 -((2 - (trimethylsilyl) ethoxy) methyl) -1H -pyrazole [3,4 -b] pyridine -3 -carboxylate (100 mg, 0.26 mmol), cesium carbonate (211 mg, 0.65 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (9 mg, 0.01 mmol) and cyclopropyl boronic acid (45 mg, 0.52 mmol) in 1 ,4-dioxane (2.5 mL) and water (0.5 mL) were heated under 120°C for 60 min. under microwave conditions. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide cesium 5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate in crude (120 mg, 100%) as a dark solid: LCMS RT = 0.866 min.; m/z = 333.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.866 mln., ESI+ found [M+H] = 333.9. Step 3: (S) -5 -cyclopropyl -N -(5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1 -( (2 -(trimethylsilyl) ethoxy) methyl) -1H -pyrazole [3,4 - b] pyridine -3 -carboxamide

[0983] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (40 mg, 0.21 mmol), cesium 5 -cyclopropyl -1 - ((2 -(trimethylsilyl) ethoxy) methyl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxylate (107 mg, 0.23 mmol) and (7 -azabenzotriazol -1 -yloxy) tripyrrolidine phosphonium hexafluoro phosphate (130 mg, 0.25 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 25°C for 20 h. The solution was diluted with water (10 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep haTLC (25% ethyl acetate in petroleum ether) to give (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -((2 -(trimethylsilyl)ethoxy)methyl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxamide (65 mg, 61%) as a white solid: LCMS RT = 0.868 min.; m/z = 531.0 (M+Na)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.868mln., ESI+ found [M+Na] = 531.0. Step 4: (S)-5-cyclopropyl -N -(5-methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1H -pyrazole [3,4 -b] pyridine -3 -carboxamide

[0984] To a solution of (S) -5 -cyclopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole[3,4-b]pyridine-3-carboxamide (60 mg, 0.12 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0 .09 mL, 1.18 mmol). The mixture was stirred at 25°C for 1 h and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.05% hydrochloric acid) to give (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2 ,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1H -pyrazolo [3,4 -b] pyridine -3 - carboxamide (29 mg, 38%) in the form of a solid white in color: 1H NMR (400 MHz, DMSO -d6) δ 14.20 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 7 .98 (s, 1H), 7.52 - 7.50 (m, 1H), 7.34 - 7.25 (m, 3H), 4.94 - 4.90 (m, 1H), 4.68 - 4.62 (m, 1H), 4.47 - 4.42 (m, 1H), 3.32 (s, 3H), 2.15 - 2.09 (m, 1H), 1.04 - 1 .00 (m, 2H), 0.74 - 0.71 (m, 2H). LCMS RT = 0.844 min.; m/z = 378.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.844 mln., ESI+ found [M+H] = 378.1. Example 240

[0985] WX SS Method (S) -5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) - 4H -1,2,4 -triazole -3 -carboxamide

[0986] A mixture of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (47 mg, 0.23 mmol), (6S)-6-amino-2,4-dimethyl-7, 8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (30 mg, 0.15 mmol), 1H -benzo [d] [1,2,3] triazole -1 -ol (31 mg, 0.23 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (44 mg, 0.23 mmol) in N,N -dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified using haSFC (SFC80; Chiralpak OD (100 mm*4.6 mm, 3 um); supercritical CO2 / ethanol+DEA=5/40; 2.8 ml/ min.) to provide (S) -5 -benzyl -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin - 6 -yl) -4H -1,2,4 -triazole -3 -carboxamide (32 mg, 54%) as a white solid: 1H NMR (400 MHz, CD3OD): δ 7, 41 - 7.31 (m, 5H), 6.43 (s, 1H), 4.73 - 4.68 (m, 1H), 4.52 - 4.47 (m, 1H), 4.43 - 4.38 (m, 3H), 3.38 (s, 3H), 2.93 - 2.83 (m, 1H), 2.48 - 2.41 (m, 4H). LCMS RT = 1.089 min.; m/z = 380.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.089 mln., ESI+ found [M+H] + = 380.1. Example 241

[0987] WX TT Method (R) -5 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) - 4H -1,2,4 -triazole -3 -carboxamide

[0988] A mixture of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (47 mg, 0.23 mmol), (6R)-6-amino-2,4-dimethyl-7, 8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (30 mg, 0.15 mmol), 1H -benzo [d] [1,2,3] triazole -1 -ol (31 mg, 0.23 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (44 mg, 0.23 mmol) in N,N -dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (20 - 50% acetonitrile/0.05% hydrogen chloride in water) to give (R) -5 -benzyl -N -(2 ,4-dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -4H -1,2,4 - triazole -3-carboxamide (39.8 mg, 67%) as a white solid: 1H NMR (400 MHz, CD3OD): δ7.41 - 7.33 (m, 5H), 6.39 (s, 1H), 4.70 - 4.63 (m, 1H), 4.49 - 4.39 (m, 2H), 4.36 (s, 2H), 3.37 (s, 3H), 2.92 - 2.82 (m, 1H), 2.46 - 2.41 (m, 1H), 2.39 (s, 3H). LCMS RT = 1,090 min.; m/z = 380.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.090 mln., ESI+ found [M+H] + = 380.1. Example 242

[0989] WX UUU Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( (2 -methylpyridin -4 -yl)methyl) -1H -1,2,4 -triazole -3 - carboxamide

[0990] To a suspension of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (150 mg, 0.48 mmol) and potassium carbonate (197 mg, 1.43 mmol) in N,N -dimethylformamide (6 mL) 4-(Chloromethyl)-2-methylpyridine hydrochloride (102 mg, 0.57 mmol) was added. The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (40 -70% methanol/0.05% ammonium hydroxide in water) to give N -(2-cyclopropyl-4-methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 - ((2 -methylpyridin -4 -yl) methyl) -1H - 1,2,4 -triazole -3 -carboxamide (28 mg, 14%): 1H NMR (400MHz, CD3OD) δ 8.66 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.20 (s, 1H), 7.11 (d, J = 5.2 Hz, 1H), 6.01 (s, 1H), 5.54 (s, 2H), 4, 55 - 4.51 (m, 1H), 4.32 - 4.28 (m, 1H), 4.23 - 4.19 (m, 1H), 2.87 - 2.80 (m, 1H), 2.51 (s, 3H), 2.28 - 2.21 (m, 1H), 1.93 - 1.87 (m, 1H), 0.97 - 0.90 (m, 2H), 0, 77 - 0.70 (m, 2H). LCMS RT = 1.31 min.; m/z = 421.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.31 mln., ESI+ found [M+H] =421.2. Example 243

[0991] WX BBBB Method (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -ethyl - 1 - methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[0992] A mixture of (1S)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (19 mg, 0.09 mmol), (S)-hydrochloride 3 -amino -6,8 -difluoro -2,3 - dihydrobenzo [b] [1,4] oxazepin -4(5H) -one (20 mg, 0.09 mmol), N1 -((ethylimino)methylene hydrochloride ) -N3,N3 - dimethylpropane -1,3 -diamine (20 mg, 0.10 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (14 mg, 0.10 mmol) in N,N - dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (0 - 40% acetonitrile/0.1% ammonium hydroxide in water) to give (S) -N -((S ) -6,8 - difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -ethyl -1 - methyl -1,3 -dihydrofuro [ 3,4 -c] pyridine -6 -carboxamide (6.6 mg, 17%) as a white solid: 1H NMR (400MHz, CD3OD) δ 8.57 (s, 1H), 7.90 ( s, 1H), 6.99 - 6.84 (m, 2H), 5.22 - 5.13 (m, 2H), 5.09 - 5.05 (m, 1H), 4.72 - 4, 68 (m, 1H), 4.55 - 4.48 (m, 1H), 1.89 - 1.83 (m, 2H), 1.47 (s, 3H), 0.78 (t, J = 7.2Hz, 3H). LCMS RT = 1.09 min.; m/z = 404.1 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.09 mln., ESI+ found [M + H] + = 404.1. Example 244

[0993] WX Method AAAAA (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -ethyl - 1 - methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide Step 1: (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-2-nitrophenoxy)propanoic acid

[0994] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (1.0 g, 4.87 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (234 mg, 9.75 mmol) at 0ºC and 1,3,5-trifluoro-2-nitrobenzene (863 mg, 4.87 mmol). The reaction mixture was stirred at 15°C for 16 h and adjusted to pH = 4 by addition of hydrochloric acid (2.0 M). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to provide (S)-2-((tert-butoxycarbonyl)amino acid) Crude -3 -(3,5 -difluoro -2 -nitrophenoxy)propanoic acid (1.2 g, 68%) as a yellow solid, which was used in the next step without any further purification. LCMS RT = 0.772 min.; m/z = 385.1 (M+Na)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.772 mln., ESI+ found [M+Na] + = 385.1. Step 2: (S)-3-(2-amino-3,5-difluorophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0995] A mixture of (S) -2 -((tert - butoxycarbonyl) amino) -3 - (3,5 -difluoro -2 -nitrophenoxy) propanoic acid (1.2 g, 3.31 mmol) and palladium in 10% carbon (353 mg, 0.33 mmol) in methanol (30 mL) was hydrogenated (15 psi) under 15°C for 3 h. After filtration, the filtrate was concentrated under reduced pressure to provide (S)-3-(2-amino-3,5-difluorophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.8 g, 73%) in the form of a black solid, which was used in the next step without any further purification. Step 3: (S)-tert-butyl(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) carbamate

[0996] A mixture of (S)-3-(2-amino-3,5-difluorophenoxy)-2-((tert-butoxycarbonyl)amino) propanoic acid (0.8 g, 2.41 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine (463 mg, 2.41 mmol) in N,N -dimethylformamide (20 mL) was stirred at 15°C for 2 H. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide (S)-tert-butyl (6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (0.4 g, 53%) as a solid yellow color: LCMS RT = 0.87 min.; m/z = 258.8 (M -56)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.817 mln., ESI+ found [M -56] + = 258.8. Step 4: (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride

[0997] A mixture of (S) -tert -butyl (6,8 - difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl)carbamate (0 .4 g, 1.27 mmol) and hydrochloric acid (4M in EtOAc, 4.0 mL, 16.0 mmol) in ethyl acetate (10 mL) was stirred under 15°C for 1 h. The mixture was concentrated under reduced pressure to provide crude (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride ( 300 mg, 94%) as a white solid, which was used in the next step without any further purification. Step 5: (R) -N -((S) -6,8 -difluoro -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 - ethyl -1 - methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide

[0998] A mixture of (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -6 -carboxylic acid (19 mg, 0.09 mmol), (S) -3 - amino -6,8 -difluoro -2,3 -dihydrobenzo [b] [1,4] oxazepin -4(5H) -one hydrochloride (20 mg, 0.09 mmol), N1 -((ethylimino)methylene hydrochloride ) -N3,N3 - dimethylpropane -1,3 -diamine (20 mg, 0.10 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (14 mg, 0.10 mmol) in N,N - dimethylformamide (4 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (0-40% acetonitrile/0.1% ammonium hydroxide in water) to give (R)-N-((S ) -6,8 -difluoro - 4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide (7.1 mg, 19%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7, 90 (s, 1H), 6.99 - 6.84 (m, 2H), 5.17 - 5.13 (m, 2H), 5.09 - 5.05 (m, 1H), 4.72 - 4.68 (m, 1H), 4.55 - 4.48 (m, 1H), 1.89 - 1.83 (m, 2H), 1.47 (s, 3H), 0.78 (t, J = 7.6 Hz, 3H). LCMS RT = 1.09 min.; m/z = 404.1 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.09 mln., ESI+ found [M + H] + = 404.1. Example 245

[0999] WX BBBB Method (R) -N -((S) -2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01000] A mixture of (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -6 -carboxylic acid (23 mg, 0.11 mmol), 6S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), N1 -( hydrochloride (ethylimino) methylene) -N3,N3 - dimethyl propane -1,3 -diamine (24 mg, 0.14 mmol) and 1H - benzo [d] [1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17 -47% acetonitrile in water and 0.05% ammonium bicarbonate) to give (R) -N -((S) - 2-cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -ethyl -1 - methyl -1,3 -dihydrofuro [3,4 - c] pyridine -6 -carboxamide (15.3 mg, 41%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.61 ( s, 1H), 7.92 (s, 1H), 6.06 (s, 1H), 5.25 — 5.21 (m, 2H), 4.63 - 4.59 (m, 1H), 4 .38 - 4.23 (m, 2H), 3.38 (s, 3H), 3.02 - 2.93 (m, 1H), 2.31 - 2.30 (m, 1H), 1.96 - 1.88 (m, 3H), 1.51 (s, 3H), 1.00 - 0.98 (m, 2H), 0.84 - 0.79 (m, 5H). LCMS RT = 1.06 min.; m/z = 410.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.06 mln., ESI+ found [M+H] = 410.2. Example 246

[01001] WX ZZ Method 1 -((4,4-difluorocyclohexyl) methyl) -N -(2,4 - dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 –carboxamide Step 1: N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) - 1H - 1,2,4 -triazole -3 -carboxamide

[01002] A mixture of 6-amino -2,4-dimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (2.4 g, 12. 4 mmol), N1 -((ethylimino) methylene hydrochloride - N3,N3 -dimethyl propane -1,3 -diamine (3.3 g, 18.5 mmol), 1H -benzo [d] [1.2, 3] triazol -1 -ol (170 mg, 1.24 mmol) and 1H -1,2,4 -triazol -3 -carboxylic acid (1.7 g, 14.8 mmol) in N,N -dimethylformamide ( 60 mL) was subjected to stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 3% methanol in dichloromethane) to give N -(2,4 - dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (2,8 g, 75%) in the form of a white solid, which was used in the next step in the form in which it was. Step 2: 1 -((4,4-difluorocyclohexyl) methyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01003] A mixture of N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 4-(bromomethyl) -1,1 - difluoro cyclohexane (250 mg, 1.17 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (46 -76% methanol/0.05% ammonium hydroxide in water) to give 1 -((4,4 - difluorocyclohexyl) methyl) -N -(2,4 - dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 - carboxam (40.2 mg, 8%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 6.10 (s, 1H), 4.52 - 4.49 (m, 1H), 4.29 — 4.17 (m, 4H), 3.29 (s, 3H), 2.85 - 2.80 (m, 1H), 2.27 - 2, 22 (m, 4H), 2.20 - 2.04 (m, 4H), 1.78 - 1.67 (m, 3H), 1.34 - 1.27 (m, 2H). LCMS RT = 0.751 min.; m/z = 422.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.751mln., ESI+ found [M+H] =422.1. Example 247

[01004] WX AAA Method 1 -(cyclobutylmethyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01005] A mixture of N -(2,4-dimethyl -5 -oxo -7,8-dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added (bromomethyl)cyclobutane ( 258 mg, 1.73 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (42 - 72% methanol/0.05% ammonium hydroxide in water) to provide 1 -(cyclobutylmethyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (50.4 mg , 16%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 6.09 (s, 1H), 4.51 — 4.48 (m, 1H), 4.29 - 4.19 (m, 4H), 3.28 (s, 3H), 2.87 - 2.83 (m, 2H), 2.23 - 2.04 (m, 4H) , 2.05 - 2.03 (m, 2H), 1.92 - 1.90 (m, 2H), 1.84 - 1.80 (m, 2H). LCMS RT = 0.736 min.; m/z = 358.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.736mln., ESI+ found [M+H] =358.1. Example 248

[01006] WX BBB Method 1 -((3,3-difluorocyclobutyl) methyl) -N -(2,4 - dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01007] A mixture of N -(2,4-dimethyl -5 -oxo -7,8-dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H-1 ,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 3-(bromomethyl) -1,1 - difluoro-cyclobutane (320 mg, 1.73 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (42 - 72% methanol / 0.05% ammonium hydroxide in water) to give 1 -((3,3-difluorocyclobutyl) methyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (50 mg, 15%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 6.12 (s, 1H), 4.54 - 4 .52 (m, 1H), 4.41 (d, J = 6.8 Hz, 2H), 4.32 - 4.22 (m, 2H), 3.31 (s, 3H), 2.85 - 2.68 (m, 2H), 2.66 - 2.64 (m, 2H), 2.48 - 2.44 (m, 2H), 2.30 - 2.26 (m, 4H). LCMS RT = 0.715 min.; m/z = 394.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.715mln., ESI+ found [M+H] =394.1. Example 249

[01008] WX DDD Method 1 -(4-chlorobenzyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) -1H -1,2,4 -triazole -3 -carboxamide

[01009] A mixture of N -(2,4-dimethyl -5 -oxo -7,8-dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H-1 ,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 4-chlorobenzyl bromide (355 mg, 1.73 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (46-76% methanol/0.05% ammonium hydroxide in water) to provide 1-(4-chlorobenzyl)-N-(2,4-dimethyl-5-oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (60.4 mg, 17%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 7.37 - 7.32 (m, 4H), 6.32 (s , 1H), 5.46 (s, 2H), 4.63 - 4.61 (m, 1H), 4.40 - 4.30 (m, 2H), 3.29 (s, 3H), 2, 88 - 2.82 (m, 1H), 2.38 - 2.32 (m, 4H). LCMS RT = 0.767 min.; m/z = 414.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.767mln., ESI+ found [M+H] =414.1. Example 250

[01010] WX EEE Method N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(3, 3,3 - trifluoropropyl) -1H -1,2,4 -triazole -3 -carboxamide

[01011] A mixture of N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 1-iodine-3 ,3,3-trifluoro propane (387 mg, 1.73 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (25 - 55% methanol/0.05% ammonium hydroxide in water) to provide N -(2,4-dimethyl-5-oxo - 5,6,7, 8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(3,3,3 -trifluoropropyl) -1H -1,2,4 -triazole -3 - carboxamide (41.2 mg, 10%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 6.10 (s, 1H), 4.56 - 4.52 (m, 3H), 4.29 - 4.20 (m, 2H), 3.29 (s, 3H), 2.90 - 2.83 (m, 3H), 2.29 - 2, 24 (m, 4H). LCMS RT = 0.701 min.; m/z = 386.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.701 mln., ESI+ found [M+H] =386.0. Example 251

[01012] WX GGG Method 1 -(cyclopentylmethyl) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01013] A mixture of N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl)-1H - 1,2,4-Triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added bromomethyl cyclopentane (282 mg, 1.73 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (40 - 70% methanol / 0.05% ammonium hydroxide in water) to provide 1 -(cyclopentylmethyl) -N -(2,4 -dimethyl -5 - oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (70.4 mg , 22%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 6.12 (s, 1H), 4.57 — 4.52 (m, 1H), 4.35 - 4.15 (m, 4H), 3.34 (s, 3H), 2.91 - 2.81 (m, 1H), 2.53 - 2.44 (m, 1H) , 2.30 - 2.23 (m, 4H), 1.70 - 1.58 (m, 6H), 1.34 - 1.28 (m, 2H). LCMS RT = 1.157 min.; m/z = 372.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.157 mln., ESI+ found [M+H] + = 372.2. Example 252

[01014] WX LL Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(1,1,1 - trifluoropropan -2 -yl) -4,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 –carboxamide Step 1: 4 -bromo -1 -oxide -pyridin -1 -ium

[01015] To a solution of 4-bromopyridine hydrochloride (20.0 g, 102.9 mmol) in water (200 mL) and dichloromethane (300 mL) was added sodium carbonate (16.4 g, 154.3 mmol ). The mixture was extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over sodium sulfate, and then 3-chloroperoxybenzoic acid (35.5 g, 205.7 mmol) was added. After addition, the mixture was stirred under 34°C for 2 h, and then washed with saturated aqueous sodium sulfite solution (200 mL), saturated aqueous sodium carbonate (200 mL), brine (200 mL) , dried over sodium sulfate and concentrated under reduced pressure to provide crude 4-bromo-1-oxido-pyridin-1-ium (10.0 g, 56%) as a white solid, which it was used in the next step without any further purification. Step 2: Methyl 2 -(4 -bromo -2 -pyridyl) acetate

[01016] To a solution of 4-bromopyridinan-oxide (5.0 g, 28.7 mmol) in tetrahydrofuran (150 mL) was added 1-(tert-butyldimethyl silyloxy)-1-methoxy ethene (10.8 g, 57.5 mmol), bromine hexafluorophosphate [tri(1-pyrrolidinyl)] phosphonium (14.7 g, 31.6 mmol) and N,N - diisopropylethylamine (11.1 g, 86.2 mmol) under 25°C . The reaction was heated at 45°C for 2 h. After cooling, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide methyl 2-(4-bromo-2-pyridyl)acetate (2 .6 g, 39%) as a yellow colored oil: 1H NMR (400 MHz, MeOD) δ 8.33 (d, J = 5.6 Hz, 1H), 7.67 (s, 1H), 7.57 — 7.53 (m, 1H), 3.90 - 3.80 (m, 2H), 3.71 (s, 3H). LCMS RT = 0.474 min.; m/z = 229.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.474 mln., ESI+ found [M+H] = 229.8 Step 3: Methyl 5-bromotriazole[1,5-a]pyridine-3-carboxylate

[01017] To a solution of methyl 2-(4-bromo-2-pyridyl) acetate (2.7 g, 11.6 mmol) in acetonitrile (300 mL) was added 1,8-diazabicyclo [5,4,0 ] undec-7-ene (2.6 g, 17.3 mmol) and 4-acetamido benzene sulfonyl azide (2.8 g, 11.6 mmol) under 0°C. After addition, the mixture was allowed to warm to 25°C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide methyl 5-bromotriazole [1 .5 -a] pyridine -3 - carboxylate (2.2 g, 74%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 7.56 (d, J = 6.0 Hz, 1H), 3.93 (s, 3H). LCMS RT = 0.714 min.; m/z = 255.7 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.714 mln., ESI+ found [M+H] = 255.7. Step 4: Methyl 5 - [1 -(trifluoromethyl)vinyl] triazolo [1,5 -a] pyridine -3 -carboxylate

[01018] A mixture of methyl 5-bromotriazole [1,5-a] pyridine-3-carboxylate (100 mg, 0.40 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (28 mg, 0 .04 mmol), cesium carbonate (254 mg, 0.78 mmol) and hexylene glycol ester of 1-(trifluoromethyl)vinylboronic acid (130 mg, 0.58 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated under 110°C for 30 min. under microwave conditions. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 35% ethyl acetate in petroleum ether) to give methyl 5-[1-(trifluoromethyl )vinyl] triazolo[1,5-a]pyridine-3-carboxylate (70 mg, 66%) as a yellow solid: 1H NMR (400 MHz, MeOD) δ 9.08 (d, J = 7 .6 Hz, 1 H), 8.29 (s, 1 H), 7.47 - 7.43 (m, 1 H), 6.36 - 6.31(m, 2 H), 4.00 ( s, 3 H). LCMS RT = 0.812 min.; m/z = 271.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.812 mln., ESI+ found [M+H] = 271.8. Step 5: Methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazole[1,5-a]pyridine-3-carboxylate

[01019] A mixture of methyl 5 - [1 - (trifluoromethyl) vinyl] triazole [1,5 -a] pyridine -3 - carboxylate (60 mg, 0.22 mmol) and 10% palladium on carbon (23 mg, 0.22 mmol) 02 mmol) in methanol (5 mL) was hydrogenated [4.46 bar (50 psi)] under 45°C for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazole [1 ,5-a] pyridine-3-carboxylate (47 mg, 77%) as a yellow solid: LCMS RT = 0.778 min.; m/z = 277.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.778 mln., ESI+ found [M+H] = 277.9. Step 6: 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,-tetrahydrotriazole[1,5-a]pyridine-3-carboxylic acid

[01020] A mixture of methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazole [1,5-a] pyridine-3-carboxylate (47 mg , 0.17 mmol) and lithium hydroxide hydrate (20 mg, 0.85 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred under 29 °C for 18 h. After evaporation of the organic materials under reduced pressure, the aqueous residue was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The solid was removed by filtration and the aqueous layer was concentrated under reduced pressure to provide 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazole acid [1 crude pyridine-3-carboxylic acid (25 mg, 56%) as a white solid: LCMS RT = 1,560 min.; m/z = 264.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.04% formic acid for 3 min.) retention time 1.560 mln., ESI+ found [M+H] = 264.1. Step 7: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(1,1, 1 - trifluoropropan -2 -yl) -4,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxamide

[01021] A mixture of 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazole [1,5-a] pyridine-3-carboxylic acid (25 mg , 0.09 mmol), (3s) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (20 mg, 0.10 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (15 mg, 0.11 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (22 mg, 0. 11 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (40 -70% acetonitrile/0.05% ammonia in water) to give N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (1,1,1 - trifluoropropan -2 -yl) -4,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine -3 -carboxamide (11.5 mg, 27%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.43 (d, J = 6.4 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.36 - 7.19 (m, 3H), 4.90 - 4.78 ( m, 1H), 4.65 - 4.53 (m, 2H), 4.39 (t, J = 8.4 Hz, 1H), 4.31 - 4.17 (m, 1H), 3.30 (s, 3H), 3.21 - 3.04 (m, 1H), 2.79 - 2.59 (m, 2H), 2.35 - 2.18 (m, 1H), 2.14 - 1 .99 (m, 1H), 1.97 - 1.77 (m, 1H), 1.16 - 1.02 (m, 3H). LCMS RT = 0.853 min.; m/z = 438.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.853 mln., ESI+ found [M+H] = 438.1. Example 253

[01022] WX FFF Method 1 -(cyclohexylmethyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01023] A mixture of N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide (200 mg, 0.69 mmol) and potassium carbonate (287 mg, 2.07 mmol) in N,N-dimethylformamide (5 mL) were added cyclohexylmethyl bromide (245 mg, 1.38 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (50 - 80% methanol/0.05% ammonium hydroxide in water) to provide 1 -(cyclohexylmethyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (55.5 mg , 21%) as a white solid: 1H NMR (400 MHz, CD3OD): δ 8.46 (s, 1H), 6.12 (s, 1H), 4.57 - 4.52 (m , 1H), 4.35 - 4.18 (m, 2H), 4.11 (d, J = 8.0, 2H), 3.34 (s, 3H), 2.91 - 2.81 (m , 1H), 2.30 - 2.23 (m, 4H), 1.96 - 1.91 (m, 1H), 1.76 - 1.68 (m, 3H), 1.63 - 1.56 (m, 2H), 1.33 - 1.19 (m, 3H), 1.06 - 0.97 (m, 2H). LCMS RT = 1.226 min.; m/z = 386.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.226 mln., ESI+ found [M+H] + = 386.2. Example 254

[01024] WX NNN Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( (tetrahydro -2H -pyran -4 -yl)methyl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide

[01025] A mixture of 6-amino -2 -cyclopropyl -4 - methyl -7,8 -dihydro -6H -pyrazolo [1,5 -a] [1,3] diazepin -5 -one (3.6 g, 16.3 mmol), 1H -1,2,4 -triazole -3 - carboxylic acid (2.2 g, 19.6 mmol), 1H -benzo [d] [1,2,3] triazole -1 -ol (220 mg, 1.6 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (4.4 g, 24.5 mmol) in N,N-dimethylformamide (60 mL) was subjected to stirring at 25°C for 12 h. After removing the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 3% methanol in dichloromethane) to give N -(2-cyclopropyl-4-methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide ( 2.6 g, 46%) as a white solid: LCMS RT = 1.07 mln., m/z = 316.1 (M + H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate over 3 min.) retention time 1.07 mln., ESI+ found [M+H] = 316.1. Step 2: N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) - 1 -((tetrahydro -2H -pyran -4 -yl)methyl) -1H -1,2,4 -triazole -3 -carboxamide

[01026] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol ) and 4-(bromomethyl) tetrahydropyran (213 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (40 -70% methyl alcohol in water and 0.05% ammonium hydroxide) to give N -(2-cyclopropyl-4-methyl - 5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -((tetrahydro -2H -pyran -4 -yl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (46 mg, 14%): 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 6.03 (s, 1H) , 4.60 - 4.56 (m, 2H), 4.34 - 4.30 (m, 1H), 4.18 -4.16 (m, 2H), 4.00 - 3.94 (m, 2H), 3.44 - 3.40 (m, 2H), 3.38 - 3.34 (m, 3H), 2.87 - 2.86 (m, 1H), 2.28 - 2.26 ( m, 2H), 1.92 - 1.91 (m, 1H), 1.50 - 1.41 (m, 2H), 1.39 - 1.28 (m, 2H), 0.97 - 0, 94 (m, 2H), 0.78 - 0.75 (m, 2H). LCMS RT = 1.57 mln., m/z = 414.2 [M + H] +. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.57 mln., ESI+ found [M+H] = 414.2. Example 255

[01027] WX OOO Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( (4,4-difluorocyclohexyl)methyl)-1H-1,2,4-triazole-3-carboxamide

[01028] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol ) and 4-(bromomethyl)-1,1-difluorocyclohexane (253 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55 -85% methyl alcohol in water and 0.05% ammonium hydroxide) to give N -(2-cyclopropyl-4-methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 - ((4,4 -difluoro cyclohexyl) methyl) - 1H -1,2,4 -triazole -3 -carboxamide (28.3 mg, 8%): H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 6.00 (s, 1H), 4.55 - 4.50 (m, 1H), 4.29 - 4.18 (m, 4H), 3.33 (s, 3H), 2.88 - 2.83 (m, 1H), 2, 27 - 2.22 (m, 1H), 2.05 - 2.04 (m, 3H), 1.90 - 1.66 (m, 5H), 1.35 - 1.32 (m, 2H), 0.95 - 0.92 (m, 2H), 0.75 - 0.72 (m, 2H). LCMS RT = 1.79 min.; m/z = 448.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.79 mln., ESI+ found [M+H] = 448.2. Example 256

[01029] WX PPP Method 1 -(cyclobutylmethyl) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) -1H -1,2,4 -triazole -3 -carboxamide

[01030] To a solution of N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol ) and (bromomethyl) cyclobutane (177 mg, 1.19 mmol). The mixture was stirred at 25ºC for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55-85% methyl alcohol in water and 0.05% ammonium hydroxide) to give 1-(cyclobutylmethyl)-N-( 2 - cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2, 4 - triazole -3 -carboxamide (57.2 mg, 18%): 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 6.01 (s, 1H), 4.55 — 4, 50 (m, 1H), 4.34 - 4.28 (m, 4H), 3.32 (s, 3H), 2.90 - 2.84 (m, 2H), 2.26 - 2.08 ( m, 1H), 1.95 - 1.93 (m, 2H), 1.92 - 1.83 (m, 5H), 0.99 - 0.93 (m, 2H), 0.76 - 0, 73 (m, 2H). LCMS RT = 1.73 min.; m/z = 384.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.73 mln., ESI+ found [M+H] = 384.2. Example 257

[01031] WX QQQ Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( 4-fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide

[01032] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol ) and 4-fluorobenzyl chloride (172 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (50 -80% methyl alcohol in water and 0.05% ammonium hydroxide) to give N -(2-cyclopropyl-4-methyl - 5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(4-fluorobenzyl) -1H -1,2, 4 -triazole -3 - carboxamide (52.4 mg, 15%): 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.31 - 7.27 (m, 2H), 7, 10 - 7.06 (m, 2H), 5.78 (s, 1H), 5.36 (s, 2H), 4.78 - 4.74 (m, 1H), 4.40 - 4.34 ( m, 1H), 4.13 - 4.06 (m, 1H), 3.34 (s, 3H), 3.19 - 3.14 (m, 1H), 2.04 - 2.01 (m, 1H), 2.00 - 1.88 (m, 1H), 0.95 - 0.93 (m, 2H), 0.75 - 0.74 (m, 2H). LCMS RT = 1.76 min.; m/z = 424.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.76 mln., ESI+ found [M+H] = 424.2. Example 258

[01033] WX RRR Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( 3,3,3 -trifluoropropyl) -1H -1,2,4 -triazole -3 - carboxamide

[01034] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL), potassium carbonate (329 mg, 2.38 mmol) and 1 - iodine -3,3,3 -trifluoropropane (266 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (50 -70% methyl alcohol in water and 0.05% ammonium hydroxide) to give N -(2-cyclopropyl-4-methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3]diazepin -6 -yl) -1 -(3,3,3 -trifluoropropyl) -1H - 1,2,4 - triazole -3 -carboxamide (42.7 mg, 13%): 1H NMR (400 MHz, DMSO -d6) δ8.72 (s, 1H), 8.55 (d, J = 7, 6 Hz, 1H), 6.05 (s, 1H), 4.52 (t, J = 6.8 Hz, 2H), 4.31 - 4.22 (m, 2H), 4.20 - 4, 07 (m, 1H), 3.18 (s, 3H), 3.00 - 2.90 (m, 2H), 2.57 -2.55 (m, 1H), 2.33 -2.30 ( m, 1H), 1.85 - 1.81 (m, 1H), 0.85 - 0.82 (m, 2H), 0.66 - 0.63 (m, 2H). LCMS RT = 1.65 min.; m/z = 412.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.65 mln., ESI+ found [M+H] = 412.1. Example 259

[01035] WX SSS Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( (6 -methylpyridin -2 -yl)methyl) -1H -1,2,4 -triazole -3 - carboxamide

[01036] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol ) and 2-(bromomethyl)-6-methylpyridine (221 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (45 -75% methyl alcohol in water and 0.05% ammonium hydroxide) to give N -(2-cyclopropyl-4-methyl - 5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 - ((6 -methylpyridin -2 -yl)methyl) -1H - 1,2,4 -triazole -3 -carboxamide (36.6 mg, 11%): 1H NMR (400 MHz, DMSO -d6) δ8.79 (s, 1H), 8.52 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8 .0 Hz, 1H), 6.03 (s, 1H), 5.51 (s, 2H), 4.34 - 4.19 (m, 2H), 4.12 - 4.07 (m, 1H) , 3.17 (s, 3H), 2.54 - 2.52 (m, 1H), 2.40 (s, 3H), 2.35 - 2.30 (m, 1H), 1.88 - 1 .80 (m, 1H), 0.84 - 0.82 (m, 2H), 0.65 - 0.62 (m, 2H). LCMS RT = 1.46 min.; m/z = 421.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.46 mln., ESI+ found [M+H] = 421.2. Example 260

[01037] WX Method XXX N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( cyclopropylmethyl) -1H -1,2,4 -triazole -3 -carboxamide

[01038] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethyl formamide (5 mL) was added (bromomethyl) cyclopropane (461 mg, 1.72 mmol) and potassium carbonate (358 mg, 2.59 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (40 - 70% methanol / 0.05% ammonium hydroxide in water) to give N -(2-cyclopropyl-4-methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 1 -(cyclopropylmethyl) -1H -1,2,4 -triazole -3 -carboxamide (95.9 mg, 33%) as a white solid: H NMR (400 MHz, DMSO -d6) δ 8.68 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H), 4.33 - 4.22 (m, 2H), 4.12 - 4.08 (m, 3H), 3.20 (s, 3H ), 2.58 - 2.55 (m, 1H), 2.34 - 2.30 (m, 1H), 1.86 - 1.83 (m, 1H), 1.30 - 1.26 (m , 1H), 0.87 - 0.84 (m, 2H), 0.68 - 0.65 (m, 2H), 0.56 - 0.53 (m, 2H), 0.41 - 0.38 (m, 2H). LCMS RT = 0.73 min.; m/z = 370.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.73mln., ESI+ found [M+H] =370.1. Example 261

[01039] WX WWW Method 1 -(cyclopentylmethyl) -N -(2 -cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) -1H -1,2,4 -triazole -3 -carboxamide

[01040] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (200 mg, 0.69 mmol) in N,N -dimethylformamide (5 mL) was added bromomethyl cyclopentane (135 mg, 0.83 mmol) and potassium carbonate (287 mg, 2.07 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55-85% methanol in water and 0.05% ammonium hydroxide) to give 1-(cyclopentylmethyl)-N-(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (41.5 mg, 15%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 5.99 (s, 1H), 4 .53 - 4.48 (m, 1H), 4.27 - 4.17 (m, 4H), 3.28 (s, 3H), 2.85 - 2.80 (m, 1H), 2.48 - 2.47 (m, 1H), 2.22 - 2.10 (m, 1H), 1.88 - 1.78 (m, 1H), 1.75 - 1.66 (m, 6H), 1 .28 - 1.25 (m, 2H), 0.93 - 0.90 (m, 2H), 0.73 - 0.71 (m, 2H). LCMS RT = 0.79 min.; m/z = 398.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.79 mln., ESI+ found [M+H] =398.1. Example 262

[01041] WX Method III 1 -((2,2-difluorocyclopropyl) methyl) -N -((S) - 2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01042] A mixture of N - [(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl ] -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N -dimethylformamide (5 mL) was added 2-(bromomethyl)-1,1-difluoro-cyclopropane (177 mg, 1.04 mmol). The mixture was subjected to stirring at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by haRP-HPLC (40 - 70% methanol/0.05% ammonium hydroxide in water) to give 1 -((2,2-difluorocyclopropyl ) methyl) -N -((S) -2,4 - dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) -1H -1,2,4 -triazole -3 -carboxamide (62.6 mg, 19%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H ), 6.10 (s, 1H), 4.55 — 4.43 (m, 2H), 4.33 - 4.20 (m, 3H), 3.29 (s, 3H), 2.87 - 2.80 (m, 1H), 2.29 - 2.24 (m, 5H), 1.64 - 1.60 (m, 1H), 1.48 - 1.42 (m, 1H). LCMS RT = 0.696 min.; m/z = 380.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.696mln., ESI+ found [M+H] =380.1. Example 263

[01043] WX PPPPPP Method (1R) -N -(1,9 -dimethyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide

[01044] A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (11 mg, 0.05 mmol), 3-amino-1, 9 -dimethyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one (10 mg, 0.05 mmol), N1 -((ethylimino) hydrochloride ) methylene) -N3,N3 - dimethylpropane -1,3 -diamine (12 mg, 0.06 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (9 mg, 0.06 mmol) in N,N - dimethylformamide (4 mL) was stirred at 25oC for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 17 - 47/0.05% ammonium hydroxide in water) to give (1R) -N -(1.9 - dimethyl -2 - oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1 -ethyl -1 -methyl -1,3 - dihydrofuro [3,4 - c] pyridine -6 -carboxamide (8 mg, 38%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 5.21 - 5.16 (m, 2H), 4.87 - 4.57 (m, 1H), 4.39 - 4.33 (m , 1H), 4.00 - 3.96 (m, 1H), 3.34 (s, 3H), 2.78 - 2.76 (m, 1H), 2.23 (s, 3H), 2, 15 - 2.11 (m, 1H), 1.89 - 1.83 (m, 2H), 1.47 (s, 3H), 0.80 - 0.76 (m, 3H). LCMS RT = 1.87 min.; m/z = 384.2 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.05% ammonium bicarbonate over 3 min.) retention time 1.87/mln., ESI+ found [M+H] = 384.2. Example 264

[01045] WX Method UUUU (3R) -3 -ethyl -3 -methyl -N -(4 -methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide

[01046] A mixture of 6-amino -4 -methyl -2 -phenyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (20 mg , 0.08 mmol), (1R) -1 -ethyl -1 -methyl -3H - fur [3,4 -c] pyridine -6 -carboxylic acid (16 mg, 0.08 mmol), 1H -benzo [d ] [1,2,3] triazol -1 -ol (16 mg, 0.12 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (22 mg, 0 .12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (38% to 68% acetonitrile, 0.05% ammonium hydroxide in water) to give (3R)-3-ethyl-3- methyl -N -(4 -methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl) -1 ,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (21 mg, 60%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.86 - 7.80 (m, 3H), 7.43 - 7.31 (m, 3H), 6.70 (s, 1H), 5.19 — 5.12 (m, 2H), 4, 68 - 4.36 (m, 3H), 3.42 (s, 3H), 3.02 - 2.94 (m, 1H), 2.35 - 2.27 (m, 1H), 1.87 - 1.82 (m, 2H), 1.45 (s, 3H), 0.78 - 0.74 (m, 3H). LCMS RT = 0.76 min.; m/z = 446.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.76 mln., ESI+ found [M+H] = 446.1. Example 265

[01047] WX VVVV Method (3S) -3 -ethyl -3 -methyl -N -(4 -methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide

[01048] A mixture of 6-amino -4 -methyl -2 -phenyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (30 mg , 0.12 mmol), (1S) -1 -ethyl -1 -methyl -3H - fur [3,4 -c] pyridine -6 -carboxylic acid (24 mg, 0.12 mmol), 1H -benzo [d ] [1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (34 mg, 0 .18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (38% to 68% acetonitrile, 0.05% ammonium hydroxide in water) to provide (3S)-3-ethyl-3- methyl -N -(4 -methyl -5 -oxo -2 -phenyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl) -1 ,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (19.2 mg, 36.2%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.55 (s , 1H), 7.86 - 7.80 (m, 3H), 7.43 - 7.31 (m, 3H), 6.70 (s, 1H), 5.19 - 5.12 (m, 2H ), 4.68 - 4.36 (m, 3H), 3.42 (s, 3H), 3.02 - 2.94 (m, 1H), 2.35 - 2.29 (m, 1H), 1.87 - 1.82 (m, 2H), 1.45 (s, 3H), 0.78 - 0.74 (m, 3H). LCMS RT = 0.75 min.; m/z = 446.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.75 mln., ESI+ found [M+H] = 446.1, Example 266

[01049] WX UU Method N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -methyl -1 -(2,2,2-trifluoroethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01050] A mixture of 1-methyl -1 -(2,2,2-trifluoroethyl)-3H-furo[3,4-c]pyridine-6-carboxylic acid (48 mg, 0.19 mmol), (6R ) -6 -amino -2,4 -dimethyl -7,8 - dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (30 mg, 0.15 mmol), 1H - benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (38 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 31 - 61%/0.05% ammonium hydroxide in water) to give N -((S) -2,4 - dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -methyl -1 -(2,2,2 -trifluoroethyl) -1,3 - dihydrofuro [3,4 -c] pyridine -6 -carboxamide (57.6 mg, 84%) as a light red solid: 1H NMR (400 MHz, CD3OD): δ 8.61 (s, 1H), 8.03 (s, 1H), 6.13 (s, 1H), 5.20 (s, 2H), 4.63 - 4.57 (m, 1H), 4 .35 - 4.24 (m, 2H), 3.35 (s, 3H), 2.92 - 2.81 (m, 3H), 2.32 - 2.25 (m, 4H), 1.57 (s, 3H). LCMS RT = 1.234 min.; m/z = 438.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.234 mln., ESI+ found [M+H] + = 438.2, Example 267

[01051] WX Method A 1 -cyclopropyl -1 -methyl -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide Step 1: 6-chloro-1-cyclopropyl-1-methylfuro[3,4-c]pyridin-3(1H)-one

[01052] To a mixture of 2,2,6,6-tetramethyl piperidine (54.0 g, 381 mmol) in tetrahydrofuran (500 mL) was added n-butyllithium (203 mL, 508 mmol, 2.5 M in tetrahydrofuran) under -78°C. After stirring at -78°C for 40 ml, 6-chloronicotinic acid (20.0 g, 127 mmol) in tetrahydrofuran (200 ml) was added to the mixture and stirred for 2 h at -78°C. 1-Cyclopropylethanone (107.0 g, 1269 mmol) was added dropwise into the mixture under -78°C. The reaction was allowed to warm to 25°C and stirred for 16 h. The reaction was terminated by addition of saturated aqueous ammonium chloride and acidified to pH = 4 using hydrochloric acid (2.0 M). The reaction was extracted with ethyl acetate (3 x 300 ml). The organics were washed with water (2 x 100 mL), brine (100 mL). The combined organic layers were dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethyl acetate (60 ml) to give 6-chloro-1-cyclopropyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (24.0 g , 84%) in the form of a white solid, which was used in the next step in the form in which it was. Step 2: 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol

[01053] To a mixture of 6-chloro-1-cyclopropyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (24.0 g, 107 mmol) in toluene (500 mL) was added diisobutylaluminum hydride (236 mL, 236 mmol, 1.0 M in toluene) and then stirred for 2 h under -78°C. The mixture was finalized by adding saturated aqueous ammonium chloride under -78°C and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-chloro-1-cyclopropyl-1,3 -dihydrofuro[3,4-c]pyridin-3-ol (23.0 g, 95%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 3: 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine

[01054] To a mixture of 6-chloro-1-cyclopropyl - 1,3-dihydrofuro[3,4-c]pyridin-3-ol (23.0 g, 102 mmol) and 2,2,2-trifluoroacetic acid (58.1 g, 510 mmol) in dichloromethane (100 mL) was added triethylsilane (59.3 g, 510 mmol) under 0°C. After addition, the mixture was stirred for 2 h and then adjusted to pH = 8 by addition of 5% aqueous sodium hydroxide. The mixture was concentrated for drying under reduced pressure. The residue was collected in ethyl acetate (200 mL). The organics were washed with water (2 x 100 mL), saline solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 100% petroleum ether) to provide 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro [3,4 -c] pyridine (17.0 g, 79.6%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.14 (s, 1H) , 5.07 — 4.99 (m, 2H), 1.47 (s, 3H), 1.18 - 1.16 (m, 1H), 0.52 - 0.29 (m, 4H). Step 4: methyl 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate

[01055] A mixture of 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (5.0 g, 24 mmol), 1,1'-bis(dichloride) diphenylphosphine) palladium ferrocene (1.7 g, 2.4 mmol) in methanol (100 mL) was subjected to stirring at 80 ° C under carbon dioxide atmosphere [2.73 bar (25 psi)] for 16 h. The reaction was filtered and the filtrate was concentrated to drying under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 1-cyclopropyl-1-methyl-1,3-dihydrofuro [3 ,4-c] pyridine-6-carboxylate (5.3 g, 95%) as a colorless oil: LCMS RT = 0.65 min.; m/z = 233.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.65 mln., ESI+ found [M+H] = 233.8. Step 5: 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

[01056] A mixture of methyl 1 -cyclopropyl -1 - methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxylate (5.3 g, 23.0 mmol) and lithium hydroxide (5. 4 g, 227.0 mmol) in tetrahydrofuran (50 mL) and water (50 mL) was stirred under 25°C for 16 h. The mixture was adjusted to pH = 6 by adding hydrochloric acid (1.0 M). The resulting solution was concentrated for drying under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c ] pyridine - 6-carboxylic acid (3.6 g, 72.3%) as a white solid: 1H NMR (400 MHz, MeOD) δ8.53 (s, 1H), 7.98 (s, 1H ), 5.13- 5.05 (m, 2H), 1.52 (s, 3H), 1.34- 1.27 (m, 1H), 0.50 - 0.30 (m, 4H). Step 6: 1 -cyclopropyl -1 -methyl -N -((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01057] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (30 mg, 0.16 mmol), 1-cyclopropyl acid -1 - methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxylic acid (34 mg, 0.16 mmol), N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 - hydrochloride diamine (45 mg, 0.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL) was subjected to stirring at 25°C for 16 h. The mixture was concentrated to drying under reduced pressure and the residue was purified by haRP-HPLC to provide 1-cyclopropyl-1-methyl-N-((S)-5-methyl-4-oxo-2,3, 4,5-tetrahydro benzo[b] [1,4] oxazepin -3 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide (24 mg, 38%) in the form of a solid white: 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.95 (s, 1H), 7.47 — 7.28 (m, 4H), 5.17 - 5, 03 (m, 3H), 4.69 - 4.65 (m, 1H), 4.45 - 4.40 (m, 1H), 3.45 (s, 3H), 1.52 (s, 3H) , 1.31 - 1.26 (m, 1H), 0.50 - 0.28 (m, 4H). LCMS RT = 0.76 min.; m/z = 394.0 (M+H)+. Example 268

[01058] WX CCC Method N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(4 - fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide

[01059] A mixture of N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 4-fluorobenzyl bromide (327 mg, 1.73 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by haRP-HPLC (46 - 76% methanol/0.05% ammonium hydroxide in water) to provide N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 -(4 - fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide (43.7 mg, 13%) as a white solid: 1H NMR (400 MHz, DMSO - d 6) δ 8.81 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H) , 7.40 - 7.36 (m, 2H), 7.23 - 7.19 (m, 2H), 6.12 (s, 1H), 5.47 (s, 2H), 4.32 - 4 .26 (m, 2H), 4.12 - 4.09 (m, 1H), 3.21 (s, 3H), 2.50 - 2.44 (m, 2H), 2.16 (s, 3H ). LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.748mln., ESI+ found [M+H] =398.1. Example 269

[01060] WX VVV Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( (3,3-difluorocyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

[01061] To a suspension of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) and potassium carbonate (329 mg, 2.38 mmol) in N,N -dimethylformamide (5 mL) 3-(bromomethyl)-1,1-difluoro-cyclobutane (293 mg, 1.59 mmol) was added. The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (47 -77% methanol in water and 0.05% ammonia) to give N -(2-cyclopropyl-4-methyl-5-oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) - 1 -((3,3-difluorocyclobutyl) methyl) -1H -1, 2,4-triazole-3-carboxamide (40 mg, 12%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 8.01 (d, J = 6.4 Hz, 1H), 5.76 (s, 1H), 4.76 - 4.73 (m, 1H), 4.39 - 4.30 (m, 3H), 4.11 - 4.05 (m, 1H), 3.33 (s, 3H), 3.20 - 3.12 (m , 1H), 2.78 - 2.70 (m, 3H), 2.39 - 2.33 (m, 2H), 1.90 - 1.87 (m, 2H), 0.94 - 0.91 (m, 2H), 0.75 - 0.72 (m, 2H). LCMS RT = 0.95 min.; m/z = 420.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.95 mln., ESI+ found [M+H] = 420.2. Example 270

[01062] WX HHH Method N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(1 -(4-fluorophenyl)ethyl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: (S)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl ) - 1H -1,2,4 -triazole -3 -carboxamide and (R) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01063] N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2, 4 - triazole -3 -carboxamide (2.8 g, 9.8 mmol) was separated using chiral SFC (SFC80; Chiralpak OD (150 mm*4.6 mm, 3 um); Supercritical CO2/MeOH+NH3^ H2O = 20/20; 2.5 ml/min.) to provide:

[01064] (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl ) - 1H -1,2,4 -triazole -3 -carboxamide (Peak 1, RT = 3.259 min.) (1.2 g, 40%);

[01065] (R) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl ) - 1H -1,2,4-triazole -3 -carboxamide (Peak 2, RT = 3.846 min.) (1.5 g, 54%). Step 2: N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl ) -1 -(1 -(4-fluorophenyl)ethyl) -1H -1,2,4 -triazole -3 - carboxamide

[01066] A mixture of N - [(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl ] -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N -dimethylformamide (5 mL) was added 1-(1-bromomethyl)-4-fluorobenzene (263 mg, 1.30 mmol). The mixture was subjected to stirring at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by haRP-HPLC (50 - 80% methanol/0.05% ammonium hydroxide in water) to give N -((S) -2, 4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 -(1 -(4 - fluorophenyl) ethyl) -1H -1,2,4 -triazole -3 -carboxamide(21.2 mg, 6%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.51 (s , 1H), 8.53(d, J = 7.6 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.22 - 7.18 (m, 2H), 6.13 ( s, 1H), 5.86 - 5.81 (m, 1H), 4.32 - 4.25 (m, 2H), 4.12 - 4.07 (m, 1H), 3.21 (s, 3H), 2.67 - 2.50 (m, 2H), 2.16 (s, 3H), 1.84 (d, J = 7.2 Hz, 3H). LCMS RT = 0.759 min.; m/z = 412.3 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.759mln., ESI+ found [M+H] =412.3. Example 271

[01067] WX KKK Method N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(1-phenylethyl) -1H -1,2,4 -triazole -3 -carboxamide

[01068] A mixture of N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] di azepin -6 - yl] -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N -dimethylformamide (5 mL) was (1-bromoethyl)benzene (240 mg, 1.3 mmol) was added and the mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by haRP-HPLC (50 - 80% methanol/0.05% ammonium hydroxide in water) to give N -((S) -2, 4 -dimethyl -5 -oxo -5, 6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 - (1 -phenylethyl) -1H - 1,2,4 -triazole -3 -carboxamide (24.8 mg, 7%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.87 (s, 1H), 8 .53 (d, J = 8.0 Hz, 1H), 7.38 - 7.30 (m, 5H), 6.13 (s, 1H), 5.84 - 5.78 (m, 1H), 4.33 - 4.23 (m, 2H), 4.12 - 4.09 (m, 1H), 3.21 (s, 3H), 2.59 - 2.57 (m, 1H), 2, 37 - 2.34 (m, 1H), 2.16 (s, 3H), 1.85 (d, J = 7.2 Hz, 3H). LCMS RT = 0.758 mln., m/z = 394.1 (M + H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.758mln., ESI+ found [M+H] =394.1. Example 272

[01069] WX FFFFF Method (S) -1 -(2,3 -difluorobenzyl) -N -(2,3,4 - trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01070] A mixture of 1 - [(2,3 - difluorophenyl)methyl] -1,2,4 -triazole -3 -carboxylic acid (26 mg, 0.11 mmol), (6S) -6 -amino -2 ,3,4 -trimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [ 1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) - N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% ammonium bicarbonate in water) to provide (S)-1-(2,3-difluorobenzyl) -N - (2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H - 1,2,4 -triazole -3 - carboxamide (27.9 mg, 71%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 7.29 — 7.26 (m, 1H), 7.18 - 7.15 (m, 2H), 5.59 (s, 2H), 4.43 - 4.38 (m, 1H), 4.24 - 4 .18 (m, 2H), 3.30 (s, 3H), 2.78 - 2.70 (m, 1H), 2.19 (m, 4H), 2.00 (s, 3H). LCMS RT = 0.972 min.; m/z = 430.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.972 mln., ESI+ found [M+H] = 430.2. Example 273

[01071] WX GGGGG Method (S) -1 -(3,4-difluorobenzyl) -N -(2,3,4 - trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01072] A mixture of 1 - [(3,4 - difluorophenyl)methyl] -1,2,4 -triazole -3 -carboxylic acid (26 mg, 0.11 mmol), (6S) -6 -amino -2 ,3,4 -trimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [ 1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) - N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% ammonium bicarbonate in water) to give (S)-1-(3,4-difluorobenzyl) -N - (2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H - 1,2,4 -triazole -3 - carboxamide (31.3 mg, 80%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.32 - 7.24 (m, 2H), 7.18 - 7.17 (m, 1H), 5.45 (s, 2H), 4.39 - 4.39 (m, 1H), 4.24 - 4 .18 (m, 2H), 3.30 (s, 3H), 2.81 - 2.73 (m, 1H), 2.20 - 2.16 (m, 4H), 2.00 (s, 3H ). LCMS RT = 0.98 min.; m/z = 430.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.98 mln., ESI+ found [M+H] = 430.2. Example 274

[01073] WX DDDDD Method (S)-1-benzyl -N -(2,3,4-trimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01074] A mixture of (1-benzyl-1,2,4-triazole-3-carboxylic acid (22.1 mg, 0.11 mmol), (6S)-6-amino-2,3,4-trimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.14 mmol) in N,N -dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 17 - 47/0.05% ammonium bicarbonate in water) to give (S)-1-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1,5-a] [ 1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (23.5 mg, 65%) as a white solid. 11H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.38 - 7.32 (m, 5H), 5.46 (s, 2H), 4.44 - 4.39 (m, 1H), 4.24 - 4 .18 (m, 2H), 3.30 (s, 3H), 2.81 - 2.73 (m, 1H), 2.21 - 2.18 (m, 4H), 2.00 (s, 3H ). LCMS RT = 0.94 min.; m/z = 394.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.94 mln., ESI+ found [M+H] = 394.2. Example 275

[01075] WX VV Method (R) -N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide

[01076] A mixture of (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -6 -carboxylic acid (38 mg, 0.19 mmol), (6R) -6 - amino -2,4 -dimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (30 mg, 0.15 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (25 mg, 0.19 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (38 mg, 0. 19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (30 - 60% acetonitrile/0.05% ammonium hydroxide in water) to give (R) -N -((S) - 2,4 -dimethyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 -ethyl -1 -methyl - 1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (25.5 mg, 43%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.87 (s, 1H), 6.13 (s, 1H), 5.21 - 5.16 (m, 2H), 4.59 - 4.55 (m, 1H), 4.33 - 4.24 (m, 2H), 3.35 (s, 3H), 2.95 - 2.88 (m, 1H), 2.29 - 2.22 (m, 4H), 1.89 - 1 .83 (m, 2H), 1.47 (s, 3H), 0.77 (t, J = 7.6 Hz, 3H). LCMS RT = 1.197 min.; m/z = 384.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.197 mln., ESI+ found [M+H] + = 384.2. Example 276

[01077] WX CCCCC Method (R) -1 -ethyl -1 -methyl -N -((S) -2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a ] [1,3] diazepin -6 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide Step 1: N -(4,5-dimethyl-1H-pyrazol-3-yl)formamide

[01078] A solution of 4,5-dimethyl-1H-pyrazole-3-amine (15.0 g, 135.0 mmol) in formic acid (75 mL) was heated at 110°C for 3 h in a sealed vessel . The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 15% methanol in dichloromethane) to give N -(4,5-dimethyl -1H -pyrazol-3-yl)formamide (15.0 g, 80%) as an off-white solid, which was used in the next step without any further purification. Step 2: N -4,5 -trimethyl -1H -pyrazol -3 -amine

[01079] To a solution of N -(5-methyl -1H -pyrazol - 3 -yl)formamide (15.0 g, 107.8 mmol) in tetrahydrofuran (500 mL) was slowly added lithium aluminum hydride (8 .2 g, 215.2 mmol) under 0°C. After addition, the reaction mixture was allowed to warm to 25°C and stir for 16 h. The reaction was terminated by addition of solid sodium sulfate decahydrate and stirred at 25°C for 30 min. The resulting mixture was diluted with ethyl acetate (200 mL), filtered through celite, and concentrated under reduced pressure to provide N -4,5-trimethyl -1H -pyrazole -3 -amine (14.0 g, 104%) as a yellow oil, which was used in the next step in the form in which it was . Step 3: 4-chloro-N-(3,4-dimethyl-1H-pyrazol-5-yl)-N-methyl butanamide

[01080] A solution of N -4,5-trimethyl -1H -pyrazole -3 -amine (14.0 g, 111.8 mmol) in 4-chlorobutanoyl chloride (30.0 mL, 295.0 mmol) was heated at 60°C for 2 h. After cooling, methanol (30 mL) was added carefully. The mixture was stirred at 20°C for another 1 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 4-chloro-N-(3,4-dimethyl-1H-pyrazol-5-yl )-N-methyl butanamide (18.0 g, 70%) as an orange oil: LCMS RT = 1.08 min.; m/z = 230.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.08 mln., ESI+ found [M+H] = 230.1. Step 4: 2,3,4 -trimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[01081] To a solution of 4-chloro-N-(3,4-dimethyl-1H-pyrazol-5-yl)-N-methyl butanamide (18.0 g, 78.4 mmol) in N,N-dimethyl formamide (200 ml) cesium carbonate (51.1 g, 156.7 mmol) was added, and the resulting suspension was subjected to stirring under 20°C for 16 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 2,3,4-trimethyl-7,8-dihydro-4H-pyrazole [1, 5 -a] [1,3] diazepin -5(6H) -one (11.0 g, 73%) as a colorless oil: LCMS RT = 0.57 min.; m/z = 193.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.57 mln., ESI+ found [M+H] = 193.9. Step 5: 6 -iodo -2,3,4 -trimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[01082] To a solution of 2,4 -dimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (2.0 g, 10.4 mmol) in dichloromethane (50 mL) was added N1,N1,N2,N2 - tetramethylethane -1,2 -diamine (7.2 g, 62.1 mmol) followed by iodotrimethyl silane (12.4 g, 62.1 mmol) under -15°C. The resulting solution was stirred 2 h under -15°C, and iodine (7.9 g, 31.1 mmol) was added in one portion. Stirring was continued at -15°C for 2 h, and the reaction mixture was terminated by addition of saturated sodium bisulfite (100 mL). The mixture was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 6 -iodo -2,3,4 - trimethyl -7,8 - dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one in the form of a brown solid (2.30 g, 70%) in the form of a yellow oil, which was used in the next stage as it was. Step 6: 6 -azide -2,3,4 -trimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5 (6H) -one

[01083] To a solution of 6 -iodo -2,3,4 -trimethyl - 7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) - one (2 .0 g, 6.3 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (611.1 mg, 9.4 mmol). The reaction mixture was stirred at 20°C for 2 and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 6-azide -2,3,4-trimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (1.35 g, 92%) as a light orange oil: LCMS RT = 0.64 min.; m/z = 235.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.64 mln., ESI+ found [M+H] = 235.1. Step 7: (S) -6 -amino -2,3,4 -trimethyl -7,8 - dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one and ( R) -6 -amino -2,3,4 -trimethyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[01084] A mixture of 6-azide -2,3,4-trimethyl - 7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one (1, 4 g, 5.8 mmol) and 10% palladium on carbon (613 mg, 0.58 mmol) was hydrogenated [4.46 bar (50 psi)] under 25°C for 10 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide 6-amino-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin- 5(6H)-one (1.3 g, 104%) as a colorless oil. Then the product was separated using chiral SFC to provide:

[01085] (S) -6 -amino -2,3,4 -trimethyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one (Peak 1, Retention time: 3.19 min.) (580 mg, 44.6% yield);

[01086] (R) -6 -amino -2,3,4 -trimethyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one (Peak 2, Retention time: 3.66 min.) (500 mg, 38% yield);

[01087] SFC Condition: Column: Chiralpak AD -3 150x4.6mm ID, 3 μm Mobile Phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 mln., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35°C Wavelength: 220 nm. Step 8: (R)-1-ethyl-1-methyl-N-((S)-2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1 ,5 - a] [1,3] diazepin -6 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01088] A mixture of (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -6 -carboxylic acid (23 mg, 0.11 mmol), (6S) -6 - amino -2,3,4 -trimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [ d] [1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% ammonium bicarbonate in water) to give (R)-1-ethyl-1-methyl-N -((S) -2,3,4 -trimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (16.6 mg, 45.5% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.86 (s, 1H), 5.20 - 5.12 (m, 2H), 4.48 - 4.44 (m, 1H), 4.26 - 4.21 (m, 2H), 3.34 (s, 3H), 2.87 - 2.81 (m, 1H), 2.19 - 2.16 (m, 4H) , 2.02 (s, 3H), 1.87 - 1.82 (m, 2H), 1.46 (s, 3H), 0.76 (t, J = 7.6 Hz, 3H). LCMS RT = 1.022 min.; m/z = 398.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.022 mln., ESI+ found [M+H] = 398.2. Example 277

[01089] WX R Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(perfluoroethyl) - [1,2 ,3] triazolo [1,5 -a] pyridine - 3 -carboxamide Step 1: tert -butyl 2 -(4 - (perfluoroethyl)pyridin -2 -yl) acetate

[01090] To a stirred mixture of 2-chloro-4-(1,1,2,2,2-pentafluoroethyl) pyridine (100 mg, 0.43 mmol), tert-butyl acetate (37 mg, 0. 32 mmol) and chloro(2-di-t-butylphosphine - 2',4',6'-tri-i-propyl - 1,1'-biphenyl) [2-(2-aminoethyl) phenyl] palladium (II) (30 mg, 0.04 mmol) in toluene (4 mL) was added lithium bis(trimethylsilyl) amide (1.0 M, 0.86 mL, 0.86 mmol) dropwise under 0 ° C under nitrogen. After addition, the reaction was stirred at 0°C for 30 ml, then allowed to warm to 25°C for 12 h. The reaction was terminated by addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep haTLC (10% ethyl acetate in petroleum ether) to give tert-butyl 2-(4-(perfluoroethyl) pyridin-2-yl) acetate (10 mg, 7.4% ) in the form of a yellow oil, which was used in the next stage in the form in which it was. Step 2: tert -butyl 5 -(1,1,2,2,2 - pentafluoroethyl) triazolo [1,5 -a] pyridine -3 -carboxylate

[01091] A mixture of tert-butyl 2-(4-(perfluoroethyl) pyridin-2-yl) acetate (80 mg, 0.26 mmol), 4-acetamidobenzene sulfonyl azide (68 mg, 0.28 mmol) and 1, 8-diazabicyclo[5,4,0]undec-7-ene (74 mg, 0.49 mmol) in acetonitrile (5 mL) was stirred under 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep haTLC (20% ethyl acetate in petroleum ether, Rf = 0.5) to give tert-butyl 5-(1.1 ,2,2,2-pentafluoroethyl)triazolo[1,5-a]pyridine-3-carboxylate (30 mg, 35%) as a white solid: LCMS RT = 0.916 min.; m/z = 281.8 (M+H -56)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.916 mln., ESI+ found [M+H -56] +=281.8. Step 3: tert -butyl 5 -(1,1,2,2,2 - pentafluoroethyl) -4,5,6,7 -tetrahydrotriazole [1,5 -a] pyridine -3 -carboxylate

[01092] A mixture of tert -butyl 5 -(1,1,2,2,2 - pentafluoroethyl) triazolo [1,5 -a] pyridine -3 - carboxylate (30 mg, 0.09 mmol) and 10% palladium on carbon (10 mg, 0.09 mmol) in methanol (10 mL) was hydrogenated [3.42 bar (35 psi)] under 25°C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)-,5,6,7-tetrahydrotriazolo[1,5-a]pyridine -3 - carboxylate (30 mg, 98%) as a gray solid: LCMS RT = 0.873 min.; m/z = 285.9 (M+H -56)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.873 mln., ESI+ found [M+H -56] +=285.9. Step 4: 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazole[1,5-a]pyridine-3-carboxylic acid

[01093] To a solution of tert -butyl 5 -(1,1,2,2,2 - pentafluoroethyl) -4,5,6,7 -tetrahydrotriazole [1,5 -a] pyridine -3 -carboxylate (30 mg, 0.09 mmol) in dichloromethane (6 mL) trifluoroacetic acid (1 mL, 13.4 mmol) was added under 25°C. The reaction mixture was stirred for 12 h and then concentrated under reduced pressure to provide 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazole acid [1,5 -a] crude pyridine -3-carboxylic acid (30 mg, 119%) as a colorless oil: LCMS RT = 0.718 min.; m/z = 286.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.718 mln., ESI+ found [M+H] = 286.1. Step 5: N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (perfluoroethyl) -4 ,5,6,7 -tetrahydro - [1,2,3] triazolo [1,5 -a] pyridine - 3 -carboxamide

[01094] A mixture of 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazole [1,5-a] pyridine-3-carboxylic acid (30 mg, 0 .11 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (32 mg, 0.23 mmol), (3S) -3 -amino - 5 -methyl -2,3 -dihydro -1,5-benzoxazepin -4 -one (23 mg, 0.12 mol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (47 mg, 0.25 mmol ) in N,N-dimethylformamide (3 mL) was stirred at 25°C for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% FA in water) to give N -((S)-5-methyl-4-oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(perfluoroethyl) -4,5,6,7 - tetrahydro - [1,2,3] triazolo [1 ,5 -a] pyridine -3 - carboxamide (8.5 mg, 18%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.40 (m, 1H), 7.36 - 7.26 (m, 2H), 7.26 - 7.20 (m, 1H), 5.00 - 4.97 (m, 1H), 4.72 - 4.68 (m, 1 H), 4.62 - 4.57 (m, 1H), 4.43 - 4.39 (m, 1H), 4.38 - 4.29 (m, 1H), 3.54 - 3.45 ( m, 1H), 3.42 (s, 3H), 3.05 - 2.93 (m, 2H), 2.48 - 2.44 (m, 1H), 2.19 - 2.07 (m, 1H). LCMS RT = 0.864 min.; m/z = 460.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.864 mln., ESI+ found [M+H] = 460.1. Example 278

[01095] WX YYY Method N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -( (6 -methylpyridin -3 -yl)methyl) -1H -1,2,4 -triazole -3 - carboxamide

[01096] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added 5-(bromomethyl)-2-methylpyridine (636 mg, 1.72 mmol) and potassium carbonate (358 mg, 2.59 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (40-70% methanol/0.05% ammonium hydroxide in water) to give N -(2-cyclopropyl-4-methyl-5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 - ((6 -methylpyridin -3 -yl) methyl) - 1H -1,2,4 -triazole -3 -carboxamide (33 mg, 10%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 7.75 - 7.73 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.00 (s, 1H) , 5.51 (s, 2H), 4.54 - 4.49 (m, 1H), 4.29 - 4.15 (m, 2H), 3.31 (s, 3H), 2.86 - 2 .80 (m, 1H), 2.53 (s, 3H), 2.28 - 2.23 (m, 1H), 1.92 - 1.87 (m, 1H), 0.95 - 0.92 (m, 2H), 0.75 - 0.72 (m, 2H). LCMS RT = 0.53 min.; m/z = 421.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.53 mln., ESI+ found [M+H] =421.1. Example 279

[01097] WX Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -1H -pyrazole [ 3,4 -b] pyridine -3 -carboxamide Step 1: methyl 5 -bromo -1 -(tetrahydro -2H - pyran -2 -yl) -1H - pyrazole [3,4 -b] pyridine -3 - carboxylate

[01098] To a solution of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (500 mg, 1.95 mmol) in dichloromethane (20 mL) was added pyridin-1-io4 -methylbenzene sulfonate (49 mg, 0.20 mmol) and 3,4-dihydro-2h-pyran (329 mg, 3.91 mmol). After addition, the mixture was subjected to stirring at 60°C for 6 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (25 ml). The separated organic layer was washed with saturated aqueous sodium bicarbonate (10 mL), dried over sodium sulfate and concentrated to provide methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H- crude pyrazole[3,4-b]pyridine-3-carboxylate (600 mg, 90%) as a yellow solid: LCMS RT = 0.811 min.; m/z = 340.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.811mln., ESI+ found [M+H] = 340.0. Step 2: methyl 5 -iodo -1 -(tetrahydro -2H -pyran -2 -yl) -1H - pyrazolo [3,4 -b] pyridine -3 -carboxylate

[01099] A mixture of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (300 mg, 0.88 mmol), cupric iodide (8 mg, 0.04 mmol), (1R,2R) -N1,N2 - dimethylcyclohexane -1,2 -diamine (13 mg, 0.09 mmol) and sodium iodide (264 mg, 1.76 mmol ) in 1,4-dioxane (3 mL) was heated under 110°C for 20 h in a sealed tube. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide methyl 5 -iodo -1 -(tetrahydro -2H -pyran -2 - il) -1H - pyrazolo [3,4 -b] pyridine -3 -carboxylate (330 mg, 97%) as a white solid: LCMS RT = 0.824 min.; m/z = 388.0 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% formic acid for 2.0 min.) retention time 0.824 mln., ESI+ found [M+H] = 388.0. Step 3: methyl 5 -trifluoromethyl -1 -(tetrahydro -2H -pyran -2 -yl) -1H - pyrazolo [3,4 -b] pyridine -3 - carboxylate

[01100] A mixture of methyl 5 -iodo -1 -(tetrahydro -2H -pyran -2 -yl) -1H -pyrazole [3,4 -b] pyridine -3 - carboxylate (220 mg, 0.57 mmol), cupric iodide (108 mg, 0.57 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (218 mg, 1.14 mmol) in N,N-dimethylacetamide (2.5 mL) was heated under 100 °C for 2 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give methyl 5-trifluoromethyl-1-( tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (100 mg, 53%) as a white solid: LCMS RT = 0.884 mln., m /z = 330.0 [M + H] +. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.884mln., ESI+ found [M+H] = 330.0. Step 4: Methyl 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

[01101] A mixture of methyl 5-trifluoromethyl -1 - (tetrahydro -2H -pyran -2 -yl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxylate (80 mg, 0.24 mmol) and trifluoroacetic acid (277 mg, 2.43 mmol) in dichloromethane (5 mL) was stirred at 25°C for 2 h. The solvent was removed under reduced pressure to give crude methyl 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (50 mg, 84%) as a yellow solid: LCMS RT = 0.699 min.; m/z = 246.0(M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.699 mln., ESI+ found [M+H] = 246.0. Step 5: 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid

[01102] A mixture of methyl 5 -(trifluoromethyl) -1H -pyrazole [3,4 -b] pyridine -3 -carboxylate (50 mg, 0.20 mmol) and hydrated lithium hydroxide (86 mg, 2.04 mmol ) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 20°C for 20 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH =4 by addition of hydrochloric acid (1.0 M). The solution was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (40 mg, 85% ) as a white solid: LCMS RT = 0.612 min.; m/z = 232.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.612 mln., ESI+ found [M+H] = 232.1. Step 6: (S)-N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -1H - pyrazole [3,4 -b] pyridine -3 - carboxamide

[01103] A mixture of 5 -(trifluoromethyl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxylic acid (40 mg, 0.19 mmol), (3S) -3 -amino -5 -methyl - 2,3-dihydro -1,5 - benzoxazepin -4 -one (37 mg, 0.19 mmol), N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (40 mg , 0.21 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (28 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring under 15°C for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by haRP-HPLC (40-70% acetonitrile in water and 0.05% hydrochloric acid) to give (S)-N-(5-methyl-4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxamide ( 19 mg, 25%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 8.4 Hz, 1H), 8.69 (d, J = 1.2 Hz, 1H), 7.53 - 7.51 (m, 1H), 7.35 - 7.26 (m, 3H), 4.98 - 4.93 (m, 1H), 4.71 - 4.66 (m, 1H), 4.48 - 4.44 (m, 1H), 3.33 (s, 3H). LCMS RT = 0.848 min.; m/z = 406.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.848 mln., ESI+ found [M+H] = 406.0. Example 280

[01104] WX Method HHHHH (S) -1 -(2,4-difluorobenzyl) -N -(2,3,4 - trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01105] A mixture of 1 -[(2,4 - difluorophenyl)methyl] -1,2,4 -triazole -3 -carboxylic acid (28 mg, 0.12 mmol), (6S) -6 -amino -2 ,3,4 -trimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [ 1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) - N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (50-80% MeOH/0.05% ammonium hydroxide in water) to provide (S)-1-(2,4-difluorobenzyl ) -N -(2,3,4 - trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 - a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (30 mg, 73%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7.49 — 7.43 (m, 1H), 7.05 - 6.98 (m, 2H), 5.52 (s, 2H), 4.44 - 4.40 (m, 1H), 4.24 - 4, 19 (m, 2H), 3.31 (s, 3H), 2.81 - 2.73 (m, 1H), 2.22 - 2.19 (s, 4H), 2.01 (s, 3H) . LCMS RT = 0.76 min.; m/z = 430.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.76 mln., ESI+ found [M+H] =430.1. Example 281

[01106] WX Method IIII (S) -1 -(4-fluorobenzyl) -N -(2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01107] A mixture of 1 - [(4 - fluorophenyl)methyl] -1,2,4 -triazole -3 -carboxylic acid (24 mg, 0.11 mmol), (6S) -6 -amino -2,3 ,4-trimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [1, 2,3] triazole -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.14 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (20-50% MeOH/0.05% ammonium hydroxide in water) to provide (S)-1-(4-fluorobenzyl)- N -(2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole -3 -carboxamide (10.2 mg, 27%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8, 42 (d, J = 7.6 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.23 — 7.19 (m, 2H), 5.47 (s, 2H), 4 .25 - 4.09 (m, 3H), 3.19 (s, 3H), 2.50 — 2.49 (m, 1H), 2.25 - 2.10 (m, 1H), 2.09 (s, 3H), 1.93 (s, 3H). LCMS RT = 0.76 min.; m/z = 412.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.76mln., ESI+ found [M+H] =412.1. Example 282

[01108] WX HHHH Method (S)-5-benzyl -N -(2-cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1,3,4 -oxadiazole -2 -carboxamide

[01109] A mixture of 5-benzyl-1,3,4-oxadiazole-2-carboxylic acid (28 mg, 0.14 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7, 8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H - benzo [d] [1,2,3] triazole -1 -ol (18 mg, 0.14 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (24 mg, 0.14 mmol) in N,N -dimethylformamide (3 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (45 - 75% methanol/0.05% ammonium hydroxide in water) to give (S)-5-benzyl -N -( 2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) - 1,3,4 - oxadiazole -2 -carboxamide (13.9 mg, 37%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.35 - 7.28 (m, 5H), 6.02 (s , 1H), 4.50 - 4.45 (m, 1H), 4.33 - 4.21 (m, 4H), 3.32 (s, 3H), 2.81 - 2.75 (m, 1H ), 2.35 - 2.31 (m, 1H), 1.92 - 1.88 (m, 1H), 0.95 - 0.92 (m, 2H), 0.75 - 0.72 (m , 2H). LCMS RT = 1.238 min.; m/z = 407.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.238 mln., ESI+ found [M+H] + = 407.1. Example 283

[01110] WX KKKKK Method 1-benzyl -N -((6S) -2 -(2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide Step 1: Butyl 2,2-difluorocyclopropane carboxylate

[01111] To a solution of 2,2-difluorocyclopropane carboxylic acid (30.0 g, 245.8 mmol) in acetonitrile (300 mL) was added 1,8-diazabicyclo [5,4,0] undec-7-ene (37.4 g, 245.8 mmol) and 1-iodobutane (49.8 g, 270.3 mmol) under 0°C. The resulting mixture was stirred at 25°C for 12 h and then quenched by addition of water (300 mL). The solution was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to provide crude butyl 2,2-difluorocyclopropane carboxylate (30.0 g, 69%) as a yellow oil, which was used in the next step without any further purification. Step 2: 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile

[01112] To a solution of acetonitrile (10 mL, 185.2 mmol) in tetrahydrofuran (500 mL) n-butyl lithium (2.5 M, 74.0 mL, 185.2 mmol) was added dropwise under - 78°C. The resulting mixture was stirred at -78°C for 30 minutes, then butyl 2,2-difluorocycle propane carboxylate (30.0 g, 168.4 mmol) was added. The mixture was then allowed to warm to 25°C and stir for another 2 h. The reaction mixture was concentrated under reduced pressure to provide crude 3-(2,2-difluorocyclopropyl)-3-oxopropane nitrile (20.0 g, 82%) as a yellow oil, which was used in the next step without any further purification. Step 3: 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine

[01113] A mixture of 3-(2,2-difluorocyclopropyl)-3-oxo-propanenitrile (20.0 g, 137.8 mmol) and hydrazine hydrate (50 mL, 85%) in 2-methyl -1 -propanol (100 mL) was heated to 80°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to provide 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine (16, 0 g, 73%) in the form of a yellow oil. LCMS RT = 0.93 min.; m/z = 160.1 (M+H)+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 minutes) retention time 0.93 mln., ESI+ found [M+H] = 160.1. Step 4: N -(5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)formamide

[01114] A solution of 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine (16.0 g, 100.5 mmol) in formic acid (80 mL) was heated at 110°C for 15 H. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give N-[5-(2,2-difluorocycle propyl ) - 1H -pyrazol-3-yl]formamide (14.0 g, 74%) as a yellow solid: LCMS RT = 1.35 min.; m/z = 188.1 (M+H)+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3.0 min.) retention time 1.35 mln., ESI+found [M+H] = 188.1. Step 5: 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine

[01115] To a solution of N -[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide (10.0 g, 53.4 mmol) in tetrahydrofuran (200 mL) was added hydride of lithium and aluminum (4.1 g, 106.9 mmol) in small parts under 0°C. The reaction mixture was subjected to stirring under 25°C for another 12 h, and then slowly quenched by adding water (5 mL), 10% aqueous sodium hydroxide (5 mL). The resulting mixture was filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to provide 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (7.0 g, 76%) in form of a colorless oil, which was used in the next step without any further purification. Step 6: 4-chloro-N-(5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

[01116] A solution of 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (9.0 g, 51.9 mmol) in 4-chlorobutanoyl chloride (20 mL) was subjected stirring for 4 h under 60°C. After cooling, the reaction mixture was slowly quenched by adding methanol (10 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 4-chloro-N-[5-(2, 2-difluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (11.0 g, 76%) as a yellow oil: LCMS RT = 0.76 min.; m/z = 277.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.76 mln., ESI+found [M+H] = 277.9. Step 7: 2 -(2,2-difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[01117] A mixture of 4-chloro-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (11.0 g, 39.6 mmol) and Cesium carbonate (25.8 g, 79.2 mmol) in N,N-dimethylformamide (200 mL) was stirred under 25°C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane to give 2 -(2,2 - difluorocyclopropyl) -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5-a] [1,3] diazepin -5 -one (9.0 g, 94%) as a yellow oil: LCMS RT = 2.36 min.; m/z = 242.1 (M+H)+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 2.36 mln., ESI+ found [M+H] = 242.1. Step 8: 2 -(2,2-difluorocyclopropyl) -6 -iodo - 4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[01118] To a solution of 2 -(2,2-difluoro cyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one (3.6 g, 17.5 mmol) in dichloromethane (200 mL) was added tetramethyl ethylenediamine (20.4 g, 175.4 mmol) and iodotrimethyl silane (35.1 g, 175.4 mmol) under -15 °C. The resulting mixture was stirred at -15°C for 1.5 h and then iodine (22.3 g, 87.7 mmol) was added in one portion. The reaction mixture was stirred at -15°C for 3 h and then quenched by addition of saturated sodium bisulfite solution (70 ml). The solution was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane) to provide 2 -(2,2-difluorocyclopropyl)-6 -iodo -4 - methyl -7 ,8-dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) -one (3.6 g, 62%) in the form of a colorless oil, which was used in the next step in the form it was in. Step 9: 6 -azide -2 -(2,2-difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one

[01119] To a solution of 2 -(2,2-difluoro cyclopropyl) -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5 (6H)-one (7.2 g, 19.6 mmol) in N,N-dimethylformamide (40 mL) was added sodium azide (1.9 g, 29.4 mmol). The reaction mixture was stirred at 25°C for 2 h and then poured into ice-cold water (5 mL). The solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-azide-2-(2,2-difluorocyclopropyl)- Crude 4-methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (5.0 g, 90%) in the form of an oil light yellow color: LCMS RT = 2.86 min.; m/z = 283.1 (M+H)+. LCMS (0 to 30% acetonitrile in water + 0.03% ammonium hydroxide for 3.0 min.) retention time 2.86 mln., ESI+ found [M+H] =283.1. Step 10: 6 -amino -2 -(2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) - one

[01120] To a solution of 6-azide -2 -(2,2 - difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5( 6H)-one (5.0 g, 17.7 mmol) in tetrahydrofuran (100 mL) and water (20 mL) was added polymer-binding triphenylphosphine (25 g, ~3 mmol/g charge). The mixture was shaken at 25°C for 16 h and then filtered through a short wad of Celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to provide 6-amino-2-(2,2-difluoro cyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one in the form of a colorless oil (4.5 g, 99% ): LCMS RT = 1.52 min.; m/z = 257.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium hydroxide for 3.0 min.) retention time 1.52 mln., ESI+ found [M+H] =257.1. Step 11: (S)-6-amino -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -5(6H) -one;

[01121] (R) -6 -amino -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -5(6H) -one;

[01122] (R) -6 -amino -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -5(6H) -one and

[01123] (S) -6 -amino -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -5(6H) -one

[01124] 6 -amino -2 - (2,2 -difluoro cyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) - ona (1.9 g, 7.7 mmol) was separated by haSFC to provide:

[01125] Peak 1 (Retention time: 2.26 min.), assigned by trials as:

[01126] (S) -6 -amino -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -5(6H) -one (380 mg, 20.0% yield);

[01127] Peak 2 (Retention time: 2.46 min.), assigned by trials as:

[01128] (R) -6 -amino -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3 ] diazepin -5(6H) -one (400 mg, 21.0% yield);

[01129] Peak 3 (Retention time: 2.64 min.), assigned by trials as:

[01130] (R) -6 -amino -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (390 mg, 20.5% yield);

[01131] Peak 4 (Retention time: 3.26 min.), assigned by trials as:

[01132] (S) -6 -amino -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (380 mg, 20.0% yield);

[01133] SFC Condition: Column: Chiralpak AD 100x4.6 mm ID, 3 μm Mobile Phase: A: CO2 B: Methanol (0.05% DEA) Isocratic: from 5% to 40% B in 4, 5 min. and keeping 40% for 2.5 mln., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40°C, BPR: 120 bar.

[01134] 1-benzyl -N -((6S) -2 -(2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[01135] A mixture of (6S) -6 -amino -2 - (2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (100 mg, 0.39 mmol), 1 -benzyl -1H -1,2,4 -triazole -3 -carboxylic acid (120 mg, 0.59 mmol), 1H -benzo [ d] [1,2,3] triazol -1 -ol (79 mg, 0.59 mmol) and N1 -((ethylimino) methylene) - N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (110 mg , 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (22-52% acetonitrile/0.05% ammonium hydroxide in water) to give 1-benzyl-N-((6S)-2 -(2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide as a white solid (100 mg, 57%): 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8, 56 (d, J = 7.6 Hz, 1H), 7.41 - 7.28 (m, 5H), 6.29 (d, J = 8.8 Hz, 1H), 5.48 (s, 2H ), 4.35 - 4.26 (m, 2H), 4.19 - 4.07 (m, 1H), 3.22 (d, J = 1.6 Hz, 3H), 2.94 - 2, 87 (m, 1H), 2.41 - 2.32 (m, 2H), 2.00 - 1.93 (m, 1H), 1.89 - 1.81 (m, 1H). LCMS RT = 0.99 min.; m/z = 442.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.99 mln., ESI+ found [M+H] =442.2. Example 284

[01136] WX NNNNN Method 1-benzyl -N -((6R) -2 -(2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [ 1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[01137] A mixture of (6R) -6 -amino -2 - (2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (106 mg, 0.41 mmol), 1 -benzyl -1H -1,2,4 -triazole -3 -carboxylic acid (83 mg, 0.41 mmol), 1H -benzo [ d] [1,2,3] triazol -1 -ol (79 mg, 0.59 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (110 mg , 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (25 -55% acetonitrile in water and 0.05% ammonium hydroxide) to give 1-benzyl -N - [(6R) - 2 -(2,2-difluorocyclopropyl)-4 -methyl -5 -oxo -2,6,7,8 -tetrahydro -1H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (105.3 mg, 57%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.40 - 7.29 (m, 5H), 6.28 (d, J = 8.8 Hz, 1H), 5.48 (s , 2H), 4.33 - 4.29 (m, 2H), 4.17 - 4.16 (m, 1H), 3.321 (s, 3H), 2.93 - 2.88 (m, 1H), 2.59 - 2.50 (m, 1H), 2.37 - 2.36 (m, 1H), 1.96 - 1.84 (m, 2H). LCMS RT = 1.77 min.; m/z = 442.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.77 mln., ESI+ found [M+H] = 442.2. Example 285

[01138] WX LLLLL Method 5 -benzyl -N -((6S) -2 -(2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -4H -1,2,4 - triazole -3 -carboxamide

[01139] A mixture of (6S) -6 -amino -2 - (2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (100 mg, 0.39 mmol), 5 -benzyl -4H -1,2,4 -triazole -3 -carboxylic acid (79 mg, 0.39 mmol), 1H -benzo [ d] [1,2,3] triazol -1 -ol (79 mg, 0.59 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (110 mg, 0.59 mmol) in N,N - dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (22-52% acetonitrile/0.05% ammonium hydroxide in water) to give 5-benzyl-N-((6S)-2 -(2,2-difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 4H -1,2,4 - triazole -3 -carboxamide as a white solid (100 mg, 57%): 1H NMR (400 MHz, DMSO -d6) δ 7.34 - 7.21 (m, 5H), 6.29 (d, J = 8.4 Hz, 1H), 4.35 - 4.26 (m, 2H), 4.20 - 4.15 (m, 1H), 4.11 (s , 2H), 3.22 (d, J = 1.6 Hz, 3H), 2.93 - 2.88 (m, 1H), 2.59 - 2.57 (m, 1H), 2.44 - 2.35 (m, 1H), 2.01 - 1.93 (m, 1H), 1.90 - 1.81 (m, 1H). LCMS RT 0.98= min.; m/z = 442.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.98 mln., ESI+ found [M+H] =442.2. Example 286

[01140] WX MMMMM Method 5 -benzyl -N -((6R) -2 -(2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -4H -1,2,4 - triazole -3 -carboxamide

[01141] A mixture of (6R) -6 -amino -2 - (2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (100 mg, 0.39 mmol), 5 -benzyl -4H -1,2,4 -triazole -3 -carboxylic acid (79 mg, 0.39 mmol), 1H -benzo [ d] [1,2,3] triazol -1 -ol (79 mg, 0.59 mmol) and N -((ethylimino) methylene) -N ,N3 - dimethylpropane -1,3 -diamine hydrochloride (110 mg, 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (20 -50% acetonitrile in water and 0.05% ammonium hydroxide) to give 5-benzyl -N - ((6R) - 2 -(2,2-difluorocyclopropyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) - 4H -1,2,4 -triazole -3 -carboxamide (101 mg, 58% yield) as a white solid: 1H NMR (400 MHz, DMSO - d 6) δ7.32 - 7.20 ( m, 5H), 6.26 (d, J = 8.0 Hz, 1H), 4.32 - 4.27 (m, 2H), 4.15 - 4.09 (m, 3H), 3.19 (s, 3H), 2.89 - 2.86 (m, 1H), 2.66 - 2.63 (m, 1H) 2.56 - 2.55 (m, 1H), 1.95 - 1, 85 (m, 1H), 1.84 - 1.82 (m, 1H). LCMS RT = 1.74 min.; m/z = 442.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.74 mln., ESI+ found [M+H] = 442.2. Example 287

[01142] WX NN Method 1-cyclopropyl -N -((S) -2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 - il) -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide Step 1: (6S)-6-amino -2,4 -dimethyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (6R) - 6 -amino -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[01143] 6-amino -2,4 -dimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one (1.5 g, 7, 7 mmol) was separated using chiral SFC (SFC13; Chiralpak OD (250 mm *30 mm, 5 μ m); supercritical CO2 / MeOH + NH3 • H2O = 20/20; 60 ml/min.) to provide:

[01144] (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (Peak 1, RT = 2.757 min.) (400 mg, 27%) as white solids.

[01145] (6R) -6 -amino -2,4 -dimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (Peak 2, RT = 3.846 min.) (350 mg, 23%) as white solids. Step 2: 1-cyclopropyl -N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01146] A mixture of (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.10 mmol), 1 -cyclopropyl -1 -methyl -3H - fur [3,4 -c] pyridine -6 -carboxylic acid (23 mg, 0.10 mmol), N1 -((ethylimino) methylene) - hydrochloride of N3,N3 - dimethylpropane -1,3 -diamine (30 mg, 0.16 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (21 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (25% to 55% acetonitrile, 0.05% ammonium hydroxide in water) to give 1-cyclopropyl-N-((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 -methyl -1,3 -dihydrofuro[3,4-c]pyridine-6-carboxamide (13 mg, 30%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7, 92 (s, 1H), 6.10 (s, 1H), 5.13 - 5.04 (m, 2H), 4.58 - 4.55 (m, 1H), 4.35 - 4.22 ( m, 2H), 3.33 (s, 3H), 2.92 - 2.85 (m, 1H), 2.27 - 2.21 (m, 4H), 1.48 (s, 3H), 1 .28 - 1.23 (m, 1H), 0.47 - 0.25 (m, 4H). LCMS RT = 0.68 min.; m/z = 396.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.68 mln., ESI+ found [M+H] = 396.0. Example 288

[01147] WX TTT Method 1 -(4-chlorobenzyl) -N -(2-cyclopropyl -4 -methyl-5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3]diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01148] To a solution of N -(2-cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol ) and 1-(bromomethyl)-4-chlorobenzene (244 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55 -85% methyl alcohol in water and 0.05% ammonium hydroxide) to give 1 -(4-chlorobenzyl) -N -( 2 - cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2, 4 - triazole -3 -carboxamide (63.3 mg, 18%): 1H NMR (400 MHz, DMSO -d6) δ8.80 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H ), 7.42 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.04 (s, 1H), 5.47 (s, 2H ), 4.29 - 4.21 (m, 2H), 4.19 — 4.05 (m, 1H), 3.17 (s, 3H), 2.57 - 2.45 (m, 2H), 1.86 - 1.80 (m, 1H), 0.84 - 0.82 (m, 2H), 0.65 - 0.59 (m, 2H). LCMS RT = 1.84 min.; m/z = 440.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.84 mln., ESI+ found [M+H] = 440.1. Example 289

[01149] WX JJJ Method (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -((1-methylcyclopropyl) methyl) -1H -1,2,4 -triazole -3 – carboxamide Step 1: 1-(iodomethyl)-1-methylcyclopropane

[01150] To a stirred suspension of triphenylphosphine (457 mg, 1.74 mmol) in dichloromethane (10 mL) was added imidazole (118 mg, 1.74 mmol) and iodine (442 mg, 1.74 mmol) under 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and a solution of 1-methylcyclopropane methanol (100 mg, 1.16 mmol) in dichloromethane (5 mL) was added. The reaction mixture was allowed to warm to 25°C and stirred for 2 h and then terminated by addition of brine (10 ml). The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), aqueous sodium thiosulfate (5%, 10 mL), dried over sodium sulfate and evaporated under reduced pressure to provide 1-(iodomethyl)-1- methylcyclopropane (200 mg, 88%) in the form of a colorless oil, which was used in the next step without any further purification. Step 2: (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a] [1,3] dia zepin -6 - il) - 1 -((1-methylcyclopropyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide

[01151] A mixture of (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (147 mg, 0.51 mmol) and potassium carbonate (141 mg, 1.02 mmol) in N,N - dimethylformamide (3 mL ) 1-(iodomethyl)-1-methyl cyclopropane (100 mg, 0.51 mmol) was added. The mixture was subjected to stirring at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by haRP-HPLC (0 - 40% acetonitrile/0.1% ammonium hydroxide in water) to give (S) -N -(2, 4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 - ((1 - methylcyclopropyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide (12 mg, 7%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 6, 14 (s, 1H), 4.88 - 4.54 (m, 1H), 4.34 - 4.32 (m, 1H), 4.27 - 4.24 (m, 1H), 4.15 ( s, 2H), 3.35 (s, 3H), 2.92 - 2.85 (m, 1H), 2.32 - 2.26 (m, 4H), 1.05 (s, 3H), 0 .76 - 0.73 (m, 2H), 0.50 - 0.47 (m, 2H). LCMS RT = 1.36 mln., m/z = 358.2 (M + H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide over 3 min.) retention time 1.36 mln., ESI+ found [M+H] + = 358.2. Example 290

[01152] WX JJJJ Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(1 -(4-fluorophenyl)ethyl) -1H -1,2,4 -triazole -3 -carboxamide

[01153] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (328 mg, 2.38 mmol) and 1-(1-bromoethyl)-4-fluorobenzene (193 mg, 0.95 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55 -85% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(1 -(4-fluorophenyl)ethyl ) -1H -1,2,4 -triazole -3 -carboxamide (40.1 mg, 11%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.85 (s, 1H), 8.52 (d, J = 7.6 Hz, 1H), 7.40 — 7.37 (m, 2H), 7.22 — 7.18 (m, 2H), 6.06 (s , 1H), 5.86 - 5.81 (m, 1H), 4.32 - 4.21 (m, 2H), 4.09 - 4.08 (m, 1H), 3.19 (s, 3H ), 2.59 - 2.55 (m, 1H), 2.40 - 2.32 (m, 1H), 1.87 - 1.83 (m, 4H), 0.87 - 0.84 (m , 2H), 0.67 - 0.64 (m, 2H). LCMS RT = 0.80 min.; m/z = 438.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.80 mln., ESI+ found [M+H] =438.2. Example 291

[01154] WX KKKK Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -((2,2-difluorocyclopropyl) methyl) -1H -1,2,4 - triazole -3 -carboxamide

[01155] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (328 mg, 2.38 mmol) and 2-(bromomethyl)-1,1-difluoro-cyclopropane (163 mg, 0.95 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (47 -77% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -((2,2 -difluoro cyclopropyl) methyl) -1H -1,2,4 - triazole -3 -carboxamide (57 mg, 18%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.70 (s, 1H ), 8.56 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H), 4.45 - 4.30 (m, 4H), 4.24 - 4.09 (m, 1H), 3.20 (s, 3H), 2.61 - 2.58 (m, 1H), 2.34 - 2.32 (m, 2H), 1.87 - 1.85 (m, 1H) , 1.83 - 1.80 (m, 1H), 1.77 - 1.67 (m, 1H), 0.86 - 0.84 (m, 2H), 0.69 - 0.64 (m, 2H). LCMS RT = 0.74 min.; m/z = 406.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.74 mln., ESI+ found [M+H] =406.1. Example 292

[01156] WX LLLL Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(1 -phenylethyl) -1H -1,2,4 -triazole -3 - carboxamide

[01157] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 0.79 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (328 mg, 2.38 mmol) and (1 - bromoethyl) benzene (176 mg, 0.95 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55 -85% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(1 -phenylethyl) -1H -1 ,2,4 -triazole -3 - carboxamide (34 mg, 10%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.87 (s, 1H), 8.54 ( d, J = 7.6 Hz, 1H), 7.36 - 7.32 (m, 5H), 6.06 (s, 1H), 5.82 — 5.80 (m, 1H), 4.32 - 4.21 (m, 2H), 4.12 - 4.08 (m, 1H), 3.19 (s, 3H), 2.57 - 2.50 (m, 1H), 2.37 - 2 .33 (m, 1H), 1.86 - 1.84 (m, 4H), 0.86 - 0.84 (m, 2H), 0.67 - 0.65 (m, 2H). LCMS RT = 0.79 min.; m/z = 420.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.79 mln., ESI+ found [M+H] =420.1. Example 293

[01158] WX BBBBBBB Method 5-benzyl -N -(1-methyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1 ,2,4-triazole-3-carboxamide

[01159] A mixture of 5-benzyl -1H -1,2,4 - triazole -3 -carboxylic acid (20 mg, 0.10 mmol), 3 -amino -1 - methyl -4,5 -dihydro -3H - imidazo [1,5 -a] [1,3] diazepin -2 -one (15 mg, 0.08 mmol), 1H -benzo [d] [1,2,3] triazol -1 - ol (17 mg, 0.12 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was subjected stirring at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05%NH4HCO3 in water) to give 5-benzyl-N-(1-methyl-2-oxo- 2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (8.4 mg , 27% yield) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.31 - 7.24 (m, 5H), 7.01 ( s, 1H), 4.45 - 4.41 (m, 2H), 4.16 (s, 2H), 4.04 - 3.96 (m, 1H), 3.35 (s, 3H), 2 .80 - 2.72 (m, 1H), 2.21 - 2.13 (m, 1H). LCMS RT = 1.118 min.; m/z = 366.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate over 3.0 min.) retention time 1.118 mln., ESI+ found [M+H] = 366.1. Example 294

[01160] WX Method ZZZZZZ (1R) -1 -ethyl -1 -methyl -N -(1 -methyl -2 -oxo - 2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin - 3 -yl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01161] A mixture of (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine -6 -carboxylic acid (21 mg, 0.10 mmol), 3 -amino -1 - methyl -4,5 -dihydro -3H -imidazo [1,5 - a] [1,3] diazepin -2 -one (15 mg, 0.08 mmol), 1H -benzo [d] [1,2,3 ] triazol -1 -ol (17 mg, 0.12 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (22 mg, 0.12 mmol) in N, N -dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 17 - 47/0.05% NH4HCO3 in water) to give (1R) -1 - ethyl -1 -methyl -N -( 1 -methyl -2 -oxo -2,3,4,5 -tetrahydro - 1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1,3 - dihydrofuro [3,4 - c] pyridine -6 -carboxamide (9.8 mg, 32%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.87 (s, 1H ), 7.65 (s, 1H), 7.01 (s, 1H), 5.16 - 5.15 (m, 2H), 4.65 - 4.60 (m, 1H), 4.66 - 4.41 (m, 1H), 4.05 - 3.98 (m, 1H), 3.37 (s, 3H), 2.84 - 2.80 (m, 1H), 2.21 - 2, 17 (m, 1H), 1.88 - 1.82 (m, 2H), 1.46 (s, 3H), 0.77 (t, J = 7.2 Hz, 3H). LCMS RT = 1.385 min.; m/z = 370.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3.0 min.) retention time 1.385 mln., ESI+ found [M+H] = 370.2. Example 295

[01162] WX Method AAAAAA 1-benzyl -N -(1-methyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1 ,2,3-triazole-4-carboxamide

[01163] A mixture of 1-benzyltriazole -4 - carboxylic acid (20 mg, 0.10 mmol), 3 -amino -1 -methyl -4,5 - dihydro -3H -imidazo [1,5 -a] [1 ,3] diazepin -2 -one (15 mg, 0.08 mmol), 1H -benzo [d] [1,2,3] triazol -1 -ol (17 mg, 0.12 mmol) and N1 - hydrochloride ((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (22 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring at 25°C for 12 h . The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% NH4HCO3 in water) to give 1-benzyl-N-(1-methyl-2-oxo- 2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,3 -triazole -4 -carboxamide (12.1 mg , 39%) in the form of a white solid: 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.61 (s, 1H), 7.36 - 7.32 (m, 5H), 6.98 (s, 1H), 5.63 (s, 2H), 4.61 - 4.56 (m, 1H), 4.44 - 4.38 (m, 1H), 4.03 - 3.98 (m, 1H), 3.34 (s, 3H), 2.75 - 2.69 (m, 1H), 2.24 - 2.18 (m, 1H). LCMS RT = 1.329 min.; m/z = 366.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3.0 min.) retention time 1.329 mln., ESI+ found [M+H] = 366.2. Example 296

[01164] WX MM Method N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(1,1,1 -trifluoro propan -2 -yl) -1H -pyrazole [3,4 -b] pyridine -3 - carboxamide Step 1: Methyl 5-bromo-1-(2-trimethylsilyl ethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate

[01165] To a solution of methyl 5-bromo-1h-pyrazolo[3,4-b]pyridine-3-carboxylate (1.0 g, 3.91 mmol) in tetrahydrofuran (20 mL) was added triethylamine (790 mg , 7.81 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (977 mg, 5.86 mmol). The mixture was stirred at 25°C for 4 h and then diluted with water (10 ml). The mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 6% ethyl acetate in petroleum ether) to provide methyl 5-bromo-1-(2-trimethylsilyl ethoxymethyl) pyrazole [3 ,4-b] pyridine-3-carboxylate (560 mg, 37%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 2: Methyl 5 - [1 -(trifluoromethyl) vinyl] -1 - (2 -trimethylsilyl ethoxymethyl) pyrazolo [3,4 -b] pyridine - 3 -carboxylate

[01166] A mixture of methyl 5-bromo-1-(2-trimethylsilyl ethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate (560 mg, 1.45 mmol), hexylene glycol acid ester 1-( trifluoromethyl) vinylboronic acid (482 mg, 2.17 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (106 mg, 0.14 mmol) and cesium carbonate (944 mg, 2.9 mmol) in 1,4-dioxane (4 mL) and water (1 mL) were heated under 110 °C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% ethyl acetate in petroleum ether) to give methyl 5 - [1 - (trifluoromethyl)vinyl]-1-(2-trimethylsilyl ethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate (450 mg, 77%) as a white solid: LCMS RT = 0.999 min.; m/z = 402.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.999 mln., ESI+ found [M+H] = 402.1. Step 3: Methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate

[01167] A mixture of methyl 5 - [1 - (trifluoromethyl) vinyl] -1 - (2 -trimethylsilyl ethoxymethyl) pyrazole [3,4 -b] pyridine -3 -carboxylate (150 mg, 0.37 mmol) and 10 % palladium on carbon (40 mg, 0.04 mmol) in methanol (5 mL) was hydrogenated [4.46 bar (50 psi)] under 25°C for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole[3,4-b ] crude pyridine-3-carboxylate (111 mg, 74%) as a white solid: LCMS RT = 0.998 min.; m/z = 404.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.998 mln., ESI+ found [M+H] = 404.1. Step 4: 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilyl ethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylic acid

[01168] A mixture of methyl 5 -(2,2,2-trifluoro-1-methyl-ethyl)-1 -(2-trimethylsilyl ethoxymethyl) pyrazolo [3,4-b] pyridine -3 -carboxylate (111 mg, 0.28 mmol) and lithium hydroxide hydrate (33 mg, 1.38 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred under 29°C for 18 h. The organic solvent was evaporated under reduced pressure and the aqueous residue was adjusted to pH = 5 by addition of hydrochloric acid (1.0 M). The solid was removed by filtration and the aqueous layer was concentrated under reduced pressure to provide 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilylethoxymethyl)pyrazolo acid [3. 4-b] crude pyridine-3-carboxylic acid (68 mg, 63%) as a white solid: LCMS RT = 2.077min.; m/z = 390.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.04% formic acid for 3 min.) retention time 2.077 mln., ESI+ found [M+H] = 390.1. Step 5: 5-(2,2,2-trifluoro-1-methyl-ethyl)-1h-pyrazolo[3,4-b]pyridine-3-carboxylic acid

[01169] To a solution of 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilyl ethoxymethyl) pyrazolo [3,4-b] pyridine-3-carboxylic acid (68 mg , 0.17 mmol) in water (5 mL) was added hydrochloric acid (4.0 M in dioxane, 0.2 mL, 0.80 mmol). The reaction mixture was stirred at 25°C for 18 h and then concentrated under reduced pressure to provide 5-(2,2,2-trifluoro-1-methyl-ethyl)-1H-pyrazole acid [3,4- b] pyridine -3-carboxylic acid (32 mg, 70%) as a white solid: LCMS RT = 0.716 min.; m/z = 259.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.716 mln., ESI+ found [M+H] = 259.9. Step 6: N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -(1,1, 1 - trifluoropropan -2 -yl) -1H -pyrazolo [3,4 -b] pyridine -3 -carboxamide

[01170] A mixture of 5-(2,2,2-trifluoro-1-methyl-ethyl)-1h-pyrazole [3,4-b] pyridine-3-carboxylic acid (32 mg, 0.12 mmol), (3s) -3 -amino -5 -methyl - 2,3 -dihydro - 1,5 -benzoxazepin -4 -one (26 mg, 0.13 mmol), 1H -benzo [d] [1,2,3] triazole -1 -ol (20 mg, 0.15 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (28 mg, 0.15 mmol) in N, N - dimethylformamide (5 mL) was stirred at 25°C for 3 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 41 -51%/0.05% ammonia in water) to give N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (1,1,1 - trifluoropropan -2 -yl) -1H -pyrazole [3,4 -b ] pyridine -3 -carboxamide (24 mg 45%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 14.35 (br. s, 1H), 8.72 - 8.57 (m, 2H), 8.44 (s, 1H), 7.56 — 7.47 (m, 1H), 7.40 - 7.19 (m, 3H), 4.98 - 4.89 (m , 1H), 4.71 - 4.63 (m, 1H), 4.50 - 4.43 (m, 1H), 4.17 - 4.06 (m, 1H), 3.34 (m, 3H), 1.51 (d, J = 7.2 Hz, 3H). LCMS RT = 0.850 min.; m/z = 434.4 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.850 mln., ESI+ found [M+H] = 434.4. Example 297

[01171] WX CCCCCCC Method (S) -1 -benzyl -N -(1tetrahydro -1H -imidazo [1,5 -a] -1,2,4 -triazole -3 -carboxamide

[01172] 1-Benzyl -N -(1 tetrahydro -1H -imidazo [1,5 -a] -1,2,4 -triazol -3 -carboxamide (20 mg, 0.055 mmol) was separated using chiral SFC ( Column: Chiralpak AS -3 150x4.6mm I.D., 3 μm Mobile Phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintained at 40% for 2.5 mln., then 5% B for 2.5 min. Flow rate: 2.5 ml/min. Column temperature: 35°C) to give (S)-1-benzyl -N -( 1-methyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepin -3 -yl) -1H -1,2,4 -triazole - 3-carboxamide. (RT = 4.174 mln., 8.3 mg, 41%) as a white solid. LCMS RT = 1.664 min.; m/z = 366.1(M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3.0 min.) retention time 1.664 mln., ESI+ found [M+H] = 366.1. Example 298

[01173] WX FFFF Method (R) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,4-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01174] A mixture of (6R) -6 -amino -2 - cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazol [1,5 -a] [1,3] diazepin -5 -one ( 20 mg, 0.09 mmol), 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), 1H-benzo[d] [1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) - N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (24 mg, 0. 14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (26 -56% acetonitrile in water and 0.05% ammonium hydroxide) to give (R) -N -(2-cyclopropyl - 4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] (2,4 -difluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide ( 9.2 mg, 22%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.46 - 7.44 (m, 1H), 7, 04 - 6.97 (m, 2H), 5.99 (s, 1H), 5.51 (s, 2H), 4.52 - 4.47 (m, 1H), 4.28 - 4.26 ( m, 1H), 4.22 - 4.17 (m, 1H), 3.29 (s, 3H), 2.83 - 2.78 (m, 1H), 2.23 - 2.20 (m, 1H), 1.91 - 1.86 (m, 1H), 0.93 - 0.91 (m, 2H), 0.72 - 0.70 (m, 2H) LCMS RT = 0.79 min. ; m/z = 442.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.79 mln., ESI+ found [M+H] =442.1 Example 299

[01175] WX EE Method (S) -N -(5 -methyl -4 -oxo -2,3,4,5 –tetra hydrobenzo [b] [1,4] oxazepin -3 -yl) -2',3',5',6 ' - tetrahydro -3H -spiro [fur [3,4 -c] pyridine -1,4' - pyran] -6 –carboxamide Step 1: 6 -chlorospiro [fur [3,4 -c] pyridine - 1,4' -tetrahydropyran] -3 -one

[01176] To a stirred solution of 2,2,6,6-tetramethyl piperidine (2.7 g, 19.0 mmol) in tetrahydrofuran (30 mL) was added n-butyl lithium (2.5 M, 10 mL, 25.0 mmol) dropwise under -78°C. The mixture was stirred at -78oC for 40 min. and then 6-chloronicotinic acid (1.0 g, 6.4 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture was stirred at -78°C for another 2 h, and then tetrahydro-4h-pyran-4-one (1.3 g, 12.7 mmol) was added dropwise. After addition, the reaction was heated to 25°C and stirred for 16 h before being terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure.

[01177] The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 20% ethyl acetate in petroleum ether) to provide 6-chlorospiro [fur [3,4-c] pyridine -1,4' - tetrahydropyran] -3 -one (900 mg, 59%) as a yellow colored oil: 1H NMR (400 MHz, DMSO -d6) δ 8.94 (s, 1H), 8, 16 (s, 1H), 4.01 - 3.86 (m, 2H), 3.67 - 3.64 (m, 2H). Step 2: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4'-tetrahydropyran]-3-ol

[01178] To a solution of 6-chlorospiro [furo[3,4-c]pyridine-1,4'-tetrahydropyran]-3-one (900 mg, 3.76 mmol) in dichloromethane (40 mL) was added hydride of diisobutylaluminum (1.0 M, 9.0 mL, 9.0 mmol) dropwise under -70°C. After addition, stirring was continued at -70°C for 2 h and the reaction mixture was terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-chlorospiro[3H-furo[3,4-c]pyridine- 1,4'-tetrahydropyran]-3-ol (790 mg, 87%) as a yellow oil: LCMS RT = 0.49 min.; m/z = 241.9 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.49/mln., ESI+ found [M+H] = 241.9. Step 3: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4'-tetrahydropyran]

[01179] To a solution of 6-chlorospiro [3H-furo [3,4-c] pyridine -1,4'-tetrahydropyran] -3 -ol (400, mg, 1.66 mmol) in dichloromethane (10 mL) Trifluoroacetic acid (944 mg, 8.28 mmol) was added dropwise under 0°C. The reaction was subjected to stirring for 30 min. under 0°C, and triethyl silane (577 mg, 4.97 mmol) was added. After addition, the mixture was allowed to warm to 25°C for 3 h and then finished by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-chlorospiro[3H-furo[3,4-c]pyridine- 1,4'-tetrahydropyran] (340 mg, 91%) as a yellow oil: LCMS RT = 0.93 min.; m/z = 226.1 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.93/mln., ESI+ found [M+H] = 226.1. Step 4: methyl spiro[3H-furo[3,4-c]pyridine-1,4'-tetrahydropyran]-6-carboxylate

[01180] A solution of 6-chlorospiro [3H-furo [3,4-c] pyridine -1,4'-tetrahydropyran] (340 mg, 1.41 mmol), 1,1'-bis(diphenylphosphine) dichloride palladium ferrocene (103 mg, 0.14 mmol) and triethylamine (1.4 g, 14.1 mmol) in methanol (20 mL) was heated at 80°C for 12 h under carbon oxide (25 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide methyl spiro[3H-furo[3,4-c]pyridine-1 ,4'-tetrahydropyran]-6-carboxylate (160 mg, 46%) as a yellow solid: LCMS RT = 0.55 min.; m/z = 249.8 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.55/mln., ESI+ found [M+H] = 249.8. Step 5: spiro[3H-furo[3,4-c]pyridine-1,4'-tetrahydropyran]-6-carboxylic acid

[01181] A mixture of methyl spiro [3H -furo [3,4 - c] pyridine -1,4' -tetrahydropyran] -6 -carboxylate (30 mg, 0.12 mmol) and hydrated lithium hydroxide (14 mg, 0.60 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred under 25°C for 2 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH = 4 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to provide crude spiro[3H-furo[3,4-c]pyridine-1,4'-tetrahydropyran]-6-carboxylic acid (25 mg, 88%) as a solid white: LCMS RT = 1.07 min.; m/z = 236.1 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.05% trifluoroacetic acid for 3 min.) retention time 1.07/mln., ESI+ found [M+H] = 236.1. Step 6: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -2',3',5 ',6' - tetrahydro -3H -spiro [fur [3,4 -c] pyridine -1,4' - pyran] -6 -carboxamide

[01182] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (20 mg, 0.11 mmol), spiro acid [3H -furo [ 3,4 -c] pyridine -1,4' - tetrahydropyran] -6 -carboxylic acid (25 mg, 0.11 mmol), N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 - hydrochloride diamine (24 mg, 0.13 mmol) and 1H -benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was subjected to stirring at 25oC for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (acetonitrile 27 -57/0.05% ammonium hydroxide in water) to give (S) -N -(5-methyl -4 - oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -2',3',5',6' - tetrahydro -3H -spiro [hole [3,4 - c] pyridine -1,4' - pyran] -6 -carboxamide (19 mg, 44%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7 .93 (s, 1H), 7.44 - 7.43 (m, 1H), 7.34 - 7.31 (m, 2H), 7.26 - 7.25 (m, 1H), 5.20 (s, 2H), 5.05 - 5.02 (m, 1H), 4.67 - 4.64 (m, 1H), 4.43 - 4.40 (m, 1H), 3.92 - 3 .41 (m, 4H), 3.31 (s, 3H), 2.09 - 2.01 (m, 2H), 1.68 - 1.65 (m, 2H). LCMS RT = 2.20 min.; m/z = 410.1 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 2.20/mln., ESI+ found [M+H] = 410.1. Example 300

[01183] WX EEEEE Method (S) -5 -benzyl -N -(2,3,4 -trimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[01184] A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (20 mg, 0.10 mmol) (6S)-6-amino-2,3,4-trimethyl-7 ,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d] [1,2,3] triazole - 1-ol (18 mg, 0.14 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethyl formamide (5 mL) was stirred under 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by haRP-HPLC (17-47 acetonitrile/0.05% ammonium bicarbonate in water) to give (S)-5-benzyl-N-(2, 3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -4H -1,2,4 - triazole -3 -carboxamide (12.2 mg, 37%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.31 - 7.23 (m, 5H), 4.44 - 4 .39 (m, 1H), 4.22 - 4.18 (m, 2H), 4.15 (s, 2H), 3.30 (s, 3H), 2.81 - 2.72 (m, 1H) ), 2.18 - 2.16 (m, 4H), 2.00 (s, 3H). LCMS RT = 0.74 min.; m/z = 394.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.74 mln., ESI+ found [M+H] = 394.1. Example 301

[01185] WX MMM Method (S) -1 -(2,6-difluorobenzyl) -N -(2,4 -dimethyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01186] A mixture of N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] dia zepin -6 - yl] -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.21 mmol) and potassium carbonate (86 mg, 0.62 mmol) in N,N -dimethylformamide (5 mL) was 2-(bromomethyl)-1,3-difluoro-benzene (52 mg, 0.25 mmol) was added. The mixture was subjected to stirring at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by haRP-HPLC (45 - 75% methanol/0.05% ammonium hydroxide in water) to provide (S) -1 -(2, 6-difluorobenzyl) -N -(2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide (23.8 mg, 27%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7 .45 - 7.42 (m, 1H), 7.05 - 7.01 (m, 2H), 6.08 (s, 1H), 5.57 (s, 2H), 4.48 - 4.46 (m, 1H), 4.27 -4.25 (m, 1H), 4.24 - 4.19 (m, 1H), 3.29 (s, 3H), 2.83 - 2.77 (m , 1H), 2.25 - 2.21 (m, 4H). LCMS RT = 0.739 mln., m/z = 416.1 (M + H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.739 mln., ESI+ found [M+H] = 416.1. Example 302

[01187] WX MMMM Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,6-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01188] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.19 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2-(bromomethyl)-1,3-difluoro-benzene (47 mg, 0.23 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (52 -82% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,6 -difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide (29 mg, 35%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.49 - 7.42 (m, 1H), 7.08 - 7.02 (m, 2H), 5.99 (s, 1H), 5.59 (s, 2H), 4.52 - 4.47 (m, 1H), 4.28 - 4.24 (m, 1H), 4.22 - 4.18 (m, 1H), 3.31 (s, 3H), 2.85 - 2.78 (m, 1H) , 2.24 - 2.22 (m, 1H), 1.91 - 1.88 (m, 1H), 0.94 - 0.91 (m, 2H), 0.74 - 0.72 (m, 2H). LCMS RT = 0.78 min.; m/z = 422.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.78 mln., ESI+ found [M+H] = 442.2. Example 303

[01189] WX NNNN Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(3,5-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01190] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.19 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (66 mg, 0.48 mmol) and 3,5-difluorobenzyl bromide (47 mg, 0.23 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55 -85% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(3,5 -difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide (18.4 mg, 22%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 6, 97 - 6.91 (m, 3H), 5.99 (s, 1H), 5.49 (s, 2H), 4.54 - 4.50 (m, 1H), 4.28 - 4.26 ( m, 1H), 4.21 - 4.14 (m, 1H), 3.30 (s, 3H), 2.86 - 2.80 (m, 1H), 2.29 - 2.24 (m, 1H), 1.91 - 1.87 (m, 1H), 0.94 - 0.91 (m, 2H), 0.74 - 0.71 (m, 2H). LCMS RT = 0.80 min.; m/z = 442.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.80 mln., ESI+ found [M+H] =442.1. Example 304

[01191] WX Method OOOO (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,5-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01192] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.19 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2,5-difluorobenzyl bromide (47 mg, 0.23 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (53-83% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 - methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -(2,5 -difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide (15.5 mg, 18%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.31 - 7.25 (m, 3H), 6.06 (s, 1H), 5.54 (s, 2H), 4.30 - 4.26 (m, 2H), 4.25 -4.21 (m, 1H), 3.19 (s, 3H), 2.54 -2.52 (m, 1H), 2.50 - 2 .33 (m, 1H), 1.85 - 1.83 (m, 1H), 0.86 - 0.84 (m, 2H), 0.68 - 0.64 (m, 2H). LCMS RT = 0.78 min.; m/z = 442.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.78 mln., ESI+ found [M+H] =442.1. Example 305

[01193] WX LLL Method (S) -1 -(2,5-difluorobenzyl) -N -(2,4 -dimethyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01194] A mixture of N - [(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 - yl] -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.21 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (86 mg, 0.62 mmol) and bromide of 2.5 - difluorobenzyl (52 mg, 0.25 mmol). The mixture was subjected to stirring at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by haRP-HPLC (50 - 80% methanol/0.05% ammonium hydroxide in water) to provide (S) -1 - (2, 5-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)- 1H -1,2,4 -triazole -3 -carboxamide (28.4 mg, 32%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7 .18 - 7.11 (m, 3H), 6.09 (s, 1H), 5.53 (s, 2H), 4.53 - 4.48 (m, 1H), 4.30 - 4.27 (m, 1H), 4.25 - 4.19 (m, 1H), 3.30 (s, 3H), 2.84 - 2.78 (m, 1H), 2.28 - 2.22 (m , 4H). LCMS RT = 0.751 mln., m/z = 416.1 (M + H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.751mln., ESI+ found [M+H] =416.1. Example 306

[01195] WX PPPP Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,3 -dichlorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01196] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.19 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2,3-dichlorobenzyl bromide (55 mg, 0.23 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (55 -85% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,3 -dichlorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide (13.6 mg, 15%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.84 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.21 (d , J = 8.0 Hz, 1H), 6.06 (s, 1H), 5.64 (s, 2H), 4.31 - 4.23 (m, 2H), 4.21 - 4.07 ( m, 1H), 3.19 (s, 3H), 2.58 - 2.50 (m, 1H), 2.44 - 2.32 (m, 1H), 1.85 - 1.83 (m, 1H), 0.86 - 0.84 (m, 2H), 0.68 - 0.64 (m, 2H). LCMS RT = 0.83 min.; m/z = 474.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.83 mln., ESI+ found [M+H] =474.1. Example 307

[01197] WX QQQQ Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,4 -dichlorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01198] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.19 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2,4 - dichlorobenzyl bromide (55 mg, 0.23 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (60 -90% methanol in water and 0.05% ammonium hydroxide) to give (S)-N-(2-cyclopropyl-4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin - 6 -yl) -1 -(2,4 -dichlorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide (16.7 mg, 18%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7, 52 (d, J = 1.6 Hz, 1H), 7.41 - 7.30 (m, 2H), 5.99 (s, 1H), 5.57 (s, 2H), 4.53 - 4 .48 (m, 1H), 4.28 - 4.26 (m, 1H), 4.20 - 4.17 (m, 1H), 3.29 (s, 3H), 2.85 - 2.78 (m, 1H), 2.27 - 2.22 (m, 1H), 1.91 - 1.86 (m, 1H), 0.93 - 0.91 (m, 2H), 0.77 - 0 .71 (m, 2H). LCMS RT = 0.83 min.; m/z = 474.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.83 mln., ESI+ found [M+H] =474.1. Example 308

[01199] WX Method IIII (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1 -((1-methylcyclopropyl)methyl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: (S) -N -(2 -cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide and (R) -N -(2 -cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[01200] A mixture of 6-amino -2 -cyclopropyl -4 - methyl -7,8 -dihydro -6H -pyrazolo [1,5 -a] [1,3] diazepin -5 -one (3.6 g, 16.3 mmol), N1 -((ethylimino) methylene) -N3,N3 -dimethyl propane -1,3 -diamine hydrochloride (4.4 g, 24.5 mmol), 1H -benzo [d] [1, 2,3] triazol -1 -ol (220 mg, 1.63 mmol) and 1H -1,2,4 -triazol -3 -carboxylic acid (2.2 g, 19.6 mmol) in N,N -dimethyl formamide (60 mL) was stirred at 25°C for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-3% methanol in dichloromethane) to give N -(2-cyclopropyl-4-methyl-5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide (2 .6 g, 46%) as a white solid: LCMS RT = 1.068 min.; m/z = 316.1 (M+H)+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium bicarbonate for 3.0 min.) retention time 1.068 mln., ESI+ found [M+H] = 316.1.

[01201] 2.4 g of this material was separated using chiral SFC to provide:

[01202] (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (peak 1, retention time: 3.657 min.) (700 mg, 28%).

[01203] (R) -N -(2-cyclopropyl -4 -methyl -5 -oxo 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 6 - il) -1H -1,2,4 -triazole -3 -carboxamide (peak 2, retention time: 4,150 min.) (900 mg, 36%).

[01204] SFC Condition: Column: Chiralcel OD -3 50x4.6mm ID, 3um Mobile Phase: A: CO2 B: methanol (0.05% DEA) Gradient: maintained 5% for 0.2 mln., then 5 % to 40% B in 1.4 min. and held 40% for 1.05 mln., then 5% B for 0.35 min. Flow rate: 4mL/min. Column temperature:40°C. Step 2: (S) -N -(2 -cyclopropyl -4 -methyl -5 oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 - il) -1 -((1-methylcyclopropyl)methyl) -1H - 1,2,4 -triazole -3 -carboxamide

[01205] To a solution of (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (126 mg, 0.40 mmol) in N,N -dimethylformamide (3 mL) was added potassium carbonate (88 mg, 0.63 mmol) and 1-(iodomethyl)-1-methyl-cyclopropane (93 mg, 0.48 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by haRP-HPLC (0 to 40% acetonitrile in water and 0.1% ammonium hydroxide) to provide (S)-N-(2-cyclopropyl- 4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1 -((1-methylcyclopropyl)methyl) -1H -1,2,4 -triazole -3 -carboxamide (30 mg, 20%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 6, 00 (s, 1H), 4.55 - 4.51 (m, 1H), 4.30 — 4.24 (m, 1H), 4.22 - 4.19 (m, 1H), 4.12 ( s, 2H), 3.30 (s, 3H), 2.89 - 2.83 (m, 1H), 2.27 - 2.24 (m, 1H), 1.92 - 1.87 (m, 1H), 1.03 (s, 3H), 0.94 - 0.91 (m, 2H), 0.75 - 0.71 (m, 4H), 0.47 - 0.44 (m, 2H) . LCMS RT = 0.96 min.; m/z = 384.3 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 2 min.) retention time 0.96 mln., ESI+ found [M+H] = 384.3. Example 309

[01206] WX Method N 7 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -7 -propyl -5, 7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxamide Step 1: 2-chloro-7-methyl-7-propylfuro[3,4-d]pyrimidin-5(7H)-one

[01207] To a stirred solution of 2,2,6,6-tetramethyl piperidine (13.4 g, 94.6 mmol) in tetrahydrofuran (80 mL) was added n-butyl lithium (2.5 M, 50 .5 mL, 126.2 mmol) dropwise under -78°C. The mixture was stirred at -78oC for 40 min. and then 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.5 mmol) in tetrahydrofuran (20 mL) was added. The resulting mixture was stirred at -78°C for another 2 h, and then 2-pentanone (5.4 g, 63.1 mmol) was added dropwise. After addition, the reaction was heated to 25°C and stirred for 16 h before being terminated by addition of saturated aqueous ammonium chloride. The solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2-chloro-7-methyl-7-propylfuro [3, 4 - d] pyrimidin -5(7H) -one (1.9 g, 26%) in the form of a yellow colored oil: 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 2.06 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.68 (s, 3H), 1.39 - 1.36 (m, 1H), 0.99 - 0, 95 (m, 1H), 0.90 - 0.86 (m, 3H). Step 2: 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

[01208] To a stirred solution of 2-chloro-7-methyl-7-propylfuro[3,4-d]pyrimidin-5(7H)-one (1.9 g, 8.3 mmol) in toluene ( 30 mL) diisobutyl aluminum hydride (1.0 M, 20.8 mL, 20.8 mmol) was added dropwise under -78°C. After addition, the mixture was stirred at -78°C for 1 h and then finalized by addition of saturated aqueous ammonium chloride (10 mL) and saturated aqueous sodium potassium tartrate (30 mL). Stirring was continued for 2 h at 25°C and the mixture was then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 2-chloro-7-methyl-7-propyl-5,7- dihydrofuro[3,4-d]pyrimidin-5-ol (820 mg, 43%) as a light yellow oil: LCMS RT = 0.640 min.; m/z = 228.7 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.640 mln., ESI+ found [M+H] + = 228.7. Step 3: 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine

[01209] A stirred solution of 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (820 mg, 3.6 mmol) in dichloromethane (20 mL) trifluoroacetic acid (1.33 mL, 17.9 mmol) was added under 0°C. The mixture was stirred at 0°C for 30 ml, then triethylsilane (2.86 ml, 17.9 mmol) was added dropwise under 0°C. After addition, the mixture was heated to 25°C and stirred for 15 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 2-chloro-7-methyl - 7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine (700 mg, 92%) in the form of a light yellow oil. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.707 mln., ESI+ found [M+H] + = 212.8. Step 4: 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile

[01210] To a stirred solution of 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d] pyrimidine (700 mg, 3.3 mmol) in dimethyl sulfoxide (5 mL) a solution of sodium cyanide (322 mg, 6.6 mmol) in water (5 mL) and 1,4-diazabicyclo[2,2,2] octane (74 mg, 0.66 mmol) was added. The mixture was stirred at 25°C for 15 h and then poured into water (10 mL). The resulting solution was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 7-methyl-7-propyl-5,7-dihydrofuro [3, 4 -d] pyrimidine -2 - carbonitrile (200 mg, 30%) as a light yellow oil: LCMS RT = 0.708 min.; m/z = 203.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.708 mln., ESI+ found [M+H] + = 203.8. Step 5: methyl 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate

[01211] A stirred solution of 7 - methyl -7 - propyl -5,7 - dihydrofuro [3,4 - d ] pyrimidine -2 - carbonitrile (200 mg, 0.98 mmol) in methanol (4 mL) Hydrochloric acid (4.0 M in MeOH, 2.5 mL, 10 mmol) was added under 0°C. The resulting mixture was heated to 25°C and stirred for 15 h. The mixture was concentrated under reduced pressure to provide crude methyl 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (120 mg, 52%) as solids. white color: LCMS RT = 0.656 min.; m/z = 236.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.656 mln., ESI+ found [M+H] + = 236.9. Step 6: 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid

[01212] A mixture of methyl 7 -methyl -7 -propyl - 5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxylate (120 mg, 0.51 mmol) and lithium hydroxide (121 mg, 5 .1 mmol) in tetrahydrofuran (12 mL) and water (6 mL) was stirred for 20 h under 25°C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M) and then extracted with ethyl acetate (3 x 45 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (100 mg, 88%) in the form of a light yellow oil, which was used in the next step without any further purification. Step 7: 7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -7 - propyl - 5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxamide

[01213] A mixture of 7-methyl -7 -propyl - 5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxylic acid (48 mg, 0.22 mmol), (3S) -3 -amino - 5 -methyl -2,3 -dihydro -1,5 - benzoxazepin -4 -one (35 mg, 0.18 mmol), N1 - ((ethylimino)methylene) -N3, N3 -dimethyl propane -1,3 hydrochloride - diamine (42 mg, 0.22 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (29 mg, 0.22 mmol) in N,N -dimethylformamide (4 mL) was subjected to stirring at 25°C for 1 h. The solvent was evaporated under reduced pressure and the residue purified by haRP-HPLC (acetonitrile 36 -66%/0.05% ammonium hydroxide in water) to give 7-methyl -N -((S) - 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -7 -propyl -5,7 -dihydrofuro [3,4 -d] pyrimidine - 2-carboxamide (33.5 mg, 46%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 7.46 - 7.44 (m, 1H ), 7.36 - 7.24 (m, 3H), 5.20 - 5.12 (m, 2H), 5.08 - 5.03 (m, 1H), 4.71 - 4.66 (m , 1H), 4.48 - 4.42 (m, 1H), 3.44 (s, 3H), 1.96 - 1.79 (m, 2H), 1.54 - 1.38 (m, 4H ), 1.08 - 0.95 (m, 1H), 0.89 - 0.85 (m, 3H). LCMS RT = 1.056 min.; m/z = 397.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.056 mln., ESI+ found [M+H] + = 397.2. Example 310

[01214] WX AA Method 7 -ethyl -7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5, 7 - dihydrofuro [3,4 -d] pyrimidine -2 -carboxamide Step 1: 2-chloro-7-ethyl-7-methylfuro[3,4-d]pyrimidin-5(7H)-one

[01215] To a stirred solution of 2,2,6,6-tetramethyl piperidine (13.5 g, 96.6 mmol) in tetrahydrofuran (300 mL) was added n-butyl lithium (2.5 M, 50 mL, 126.0 mmol) dropwise under -78oC. The mixture was stirred at -78oC for 40 min. and then 2-chloropyrimidine-5-carboxylic acid (6.0 g, 31.5 mmol) in tetrahydrofuran (20 mL) was added. The resulting mixture was stirred at -78°C for another 2 h, and then butan-2-one (6.8 g, 94.6 mmol) was added dropwise. After addition, the reaction was heated to 25°C and stirred for 16 h before being terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 2-chloro-7-ethyl-7-methylfuro[3,4- d] pyrimidin -5(7H) -one (1.0 g, 15%) in the form of a yellow colored oil: 1H NMR (400 MHz, CDC13) δ 9.07 (s, 1H), 2.15 - 2.03 (m, 2H), 1.69 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H). Step 2: 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

[01216] To a solution of 2-chloro-7-ethyl-7-methylfuro[3,4-d]pyrimidin-5(7H)-one (1.0 g, 4.7 mmol) in toluene (30 mL) Diisobutyl aluminum hydride (1.0 M, 9.4 mL, 9.4 mmol) was added dropwise under -70°C. After addition, stirring was continued at -70oC for 2 h and the reaction mixture was terminated by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 2-chloro-7-ethyl-7-methyl-5,7- dihydrofuro [3,4 -d] pyrimidin -5 -ol (0.70g, 70%) in the form of a yellow oil which was used in the next step as it was. Step 3: 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine

[01217] To a solution of 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (700 mg, 3.3 mmol) in dichloromethane (20 mL ) trifluoroacetic acid (1.86 g, 63.5 mmol) was added dropwise under 0°C. The reaction was subjected to stirring for 30 min. under 0°C, and triethyl silane (1.9 g, 16.5 mmol) was added. After addition, the mixture was allowed to warm to 25°C over 3 h and then finished by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% ethyl acetate in petroleum ether) to provide 2-chloro-7-ethyl-7-methyl-5,7- dihydrofuro [3,4-d] pyrimidine (450 mg, 69%) in the form of a yellow oil. Step 4: 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile

[01218] To a stirred solution of 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d] pyrimidine (450 mg, 2.27 mmol) in dimethyl sulfoxide (5 mL) and water (2 mL) were added sodium cyanide (222 mg, 54 mmol) and 1,4-diazabicyclo[2,2,2] octane (74 mg, 0.66 mmol). The mixture was stirred at 25°C for 16 h and then poured into water (10 ml). The resulting solution was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 -200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 7-ethyl-7-methyl-5,7-dihydrofuro [3 ,4-d] pyrimidine-2-carbonitrile (140 mg, 33%) in the form of a yellow oil, which was used in the next step as it was. Step 5: methyl 7 -ethyl -7 -methyl -5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxylate

[01219] To a solution of 7-ethyl -7 -methyl -5,7 - dihydrofuro [3,4 -d] pyrimidine -2 -carbonitrile (140 mg, 0.74 mmol) in methanol (4 mL) was added acid hydrochloric acid (4.0 M in MeOH, 2.0 mL, 8 mmol) under 0oC. The resulting mixture was heated to RT and stirred for 16 h. Then the mixture was concentrated under reduced pressure to provide crude methyl 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (120 mg, 73%) as a white solid, which was used in the next step without any further purification. Step 6: 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid

[01220] A mixture of methyl 7-ethyl -7 -methyl -5,7 -dihydrofuro [3,4 -d] pyrimidine -2 - carboxylate (120 mg, 0.54 mmol) and hydrated lithium hydroxide (113 mg, 2.70 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25oC for 2 h. After evaporation of the organic solvent under reduced pressure, the aqueous residue was adjusted to pH = 5 by adding hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 1-methyl-1-(2,2,2-trifluoroethyl acid )-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (90 mg, 80%) as a yellow solid, which was used in the next step without further purification. Step 7: 7 -ethyl -7 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) - 5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxamide

[01221] A mixture of 7-ethyl -7 -methyl -5,7 -dihydrofuro [3,4 -d] pyrimidine -2 -carboxylic acid (20 mg, 0.10 mmol), (3S) -3 -amino - 5 -methyl -2,3 -dihydro -1,5 - benzoxazepin -4 -one (20 mg, 0.10 mmol), N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane -1,3 - hydrochloride diamine (22 mg, 0.11 mmol) and 1H -benzo [d][1,2,3] triazol -1 -ol (15 mg, 0.11 mmol) in N,N -dimethylformamide (5 mL) was subjected stirring at 25oC for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (31-61% acetonitrile/0.05% NH4OH in water) to give 7-ethyl-7-methyl-N-((S) - 5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,7 -dihydrofuro [3,4 -d] pyrimidine -2 - carboxamide (24.20 mg, 65%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 7.46 - 7.43 (m, 1H), 7.34 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 6.19 - 6.15 (m, 2H), 6.08 - 6.03 (m, 1H) ), 4.71 - 4.66 (m, 1H), 4.47 - 4.44 (m, 1H), 3.44 (s, 3H), 2.01 - 1.85 (m, 2H), 1.49 (s, 3H), 0.80 (t, J = 7.2 Hz, 3H). LCMS RT = 0.793 min.; m/z = 383.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.793 min., ESI+ found [M+H] = 383.1. Example 311

[01222] WX YYYYY Method 1 -(2,3-difluorobenzyl) -N -((S) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[01223] A mixture of (S) -6 -amino -2 - ((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (60 mg, 0.23 mmol), (1 -[(2,3 -difluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (84 mg, 0.35 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (47 mg, 0.35 mmol) and N1 - ((ethylimino)methylene) -N3,N3 hydrochloride -dimethylpropane -1,3 -diamine (63 mg, 0.35 mmol) in N,N -dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC medium (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -(2,3 - difluorobenzyl) -N -((S) -2 -((R) -2 ,2-difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1 ,2,4-triazole-3-carboxamide (11.9 mg, 11%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 7.2 9 - 7.25(m, 1H), 7.17 - 7.12 (m, 2H), 6.20 (s, 1H), 6.58 (s, 2H), 4.53 - 4.48 (m , 1H), 4.36 - 4.23 (m, 2H), 3.31 (s, 3H), 2.84 - 2.79 (m, 2H), 2.26 - 2.21 (m, 1H ), 1.87 - 1.80 (m, 2H). LCMS RT = 0.81 min.; m/z = 478.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.81 min., ESI+ found [M+H] =478.2. Example 312

[01224] WX SSSSS Method 1 -(2,3-difluorobenzyl) -N -((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide

[01225] A mixture of (R) -6 -amino -2 -((R) -2,2 - propyl difluorocycle) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -[(2,3 -difluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (42 mg , 0.18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 hydrochloride - ((ethylimino) methylene) -N3,N3 - dimethylpropane-1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (25 -55% acetonitrile in water and 0.05% ammonium hydroxide) to give 1 -(2,3 - difluorobenzyl) -N - ((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (38.8 mg, 69%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8 .63 (s, 1H), 7.32 - 7.27 (m, 1H), 7.19 - 7.16 (m, 2H), 6.21 (s, 1H), 6.60 (s, 2H ), 4.55 - 4.50 (m, 1H), 4.36 - 4.34 (m, 1H), 4.27 - 4.24 (m, 1H), 3.33 (s, 3H), 2.88 - 2.80 (m, 2H), 2.28 - 2.26 (m, 1H), 1.90 - 1.78(m, 2H). LCMS RT = 0.80 min.; m/z = 478.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.80 min., ESI+ found [M+H] = 478.1. Example 313

[01226] WX ZZZZZ Method 1 -(3,4-difluorobenzyl) -N -((S) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01227] A mixture of (S) -6 -amino -2 - ((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (60 mg, 0.23 mmol), 1 -[(3,4 -difluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (84 mg , 0.35 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (47 mg, 0.35 mmol) and N1 hydrochloride - ((ethylimino) methylene) -N3,N3 - dimethylpropane-1,3-diamine (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (32-62% acetonitrile/0.05% ammonium hydroxide in water) to give 1-(3,4-difluorobenzyl)-N- ((S) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (18 mg, 16%) as a white solid: H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7.34 - 7.26 (m, 2H), 7.25- 7.18 (m, 1H), 6.20 (s, 1H), 6.45(s, 2H), 4.55 - 4.50 (m, 1H), 4.36 - 4.34 (m, 1H), 4.26 - 4.23 (m, 1H), 3.30 (s, 3H), 2, 85 - 2.80 (m, 2H), 2.27 - 2.26 (m, 1H), 1.89 - 1.77 (m, 2H). LCMS RT = 0.81 min.; m/z = 478.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.81 min., ESI+ found [M+H] =478.1. Example 314

[01228] WX TTTTT Method 1 -(3,4-difluorobenzyl) -N -((R) -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H-1,2,4 -triazole -3 -carboxamide

[01229] A mixture of (R) -6 -amino -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazolo[1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -[(3,4 -difluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylic acid (42 mg , 0.18 mmol), 1H -benzo [d][1,2,3]triazol -1 -ol (24 mg, 0.18 mmol) and N1 hydrochloride - ((ethylimino) methylene) -N3,N3 - dimethylpropane-1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (31 -61% acetonitrile in water and 0.05% ammonium hydroxide) to give 1 -(3,4 - difluorobenzyl) -N - ((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (37.1 mg, 66%) as a white solid: H NMR (400 MHz, CD3OD) δ 8 .60 (s, 1H), 7.35 - 7.26 (m, 2H), 7.20 - 7.19 (m, 1H), 6.21 (s, 1H), 6.46 (s, 2H ), 4.55 - 4.50 (m, 1H), 4.37 - 4.35 (m, 1H), 4.27 - 4.24 (m, 1H), 3.33 (s, 3H), 2.88 - 2.80 (m, 2H), 2.28 - 2.27 (m, 1H), 1.90 - 1.78(m, 2H). LCMS RT = 0.81 min.; m/z = 478.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.81 min., ESI+ found [M+H] = 478.1. Example 315

[01230] WX AAAAAA Method 1 -(2,4-difluorobenzyl) -N -((S) -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H-1,2,4 -triazole -3 -carboxamide

[01231] A mixture of (S) -6 -amino -2 - ((R) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazolo[1,5 -a][ 1,3] diazepin -5(6H) -one (60 mg, 0.23 mmol), 1 -[(2,4 -difluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (84 mg , 0.35 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (47 mg, 0.35 mmol) and N - ((ethylimino) methylene hydrochloride) -N3,N3 - dimethylpropane-1,3-diamine (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile/0.05% ammonium hydroxide in water) to give 1 -(2,4 - difluorobenzyl) -N - ((S) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (28.8 mg, 25%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8 .58 (s, 1H), 7.44 (s, 1H), 7.01 — 7.00 (m, 2H), 6.20 (s, 1H), 6.51 (s, 2H), 4, 52 - 4.50 (m, 1H), 4.35 - 4.22 (m, 2H), 3.31 (s, 3H), 2.82 - 2.80 (m, 2H), 2.26 - 2.23 (m, 1H), 1.87 - 1.80 (m, 2H). LCMS RT = 0.80 min.; m/z = 478.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.80 min., ESI+ found [M+H] =478.1. Example 316

[01232] WX UUUUU Method 1 -(2,4-difluorobenzyl) -N -((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01233] A mixture of (R) -6 -amino -2 - ((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -[(2,4 -difluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (42 mg , 0.18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 hydrochloride - ((ethylimino) methylene) -N3,N3 - dimethylpropane-1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (25 -55% acetonitrile in water and 0.05% ammonium hydroxide) to give 1 -(2,4 - difluorobenzyl) -N - ((R) -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (24.2 mg, 43%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8 .59 (s, 1H), 7.49 - 7.43 (m, 1H), 7.06 - 6.98 (m, 2H), 6.21 (s, 1H), 6.53 (s, 2H ), 4.54 - 4.49 (m, 1H), 4.38 - 4.34 (m, 1H), 4.27 - 4.24 (m, 1H), 3.33 (s, 3H), 2.87 - 2.77 (m, 2H), 2.27 - 2.26 (m, 1H), 1.90 - 1.78(m, 2H). LCMS RT = 0.80 min.; m/z = 478.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.80 min., ESI+ found [M+H] = 478.2. Example 317

[01234] WX BBBBBB Method N -((S) -2 -((R) -2,2 -difluorocyclopropyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3]diazepin -6 -yl) -1 -(4-fluorobenzyl) -1H -1,2,4 - triazole -3 -carboxamide

[01235] A mixture of (S) -6 -amino -2 - ((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (60 mg, 0.23 mmol), 1 -[(4-fluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (78mg, 0. 35 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (47 mg, 0.35 mmol) and N1 -((ethylimino) methylene hydrochloride) -N3,N3 -dimethylpropane -1 ,3-diamine (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to give N -((S) -2 -((R ) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(4 - fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide(18.3 mg, 17%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.41 - 7.37 (m, 2H), 7.11 - 7.07 (m, 2H), 6.20 (s, 1H), 6.45(s, 2H), 4.54 - 4.49 (m, 1H), 4.35 - 4.33 (m, 1H), 4.26 - 4.23 (m, 1H), 3.30 (s, 3H), 2, 84 - 2.78(m, 2H), 2.27 - 2.25(m, 1H), 1.89 - 1.78(m, 2H). LCMS RT = 0.80 min.; m/z = 460.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.80 min., ESI+ found [M+H] =460.1. Example 318

[01236] WX VVVVV Method N -((R) -2 -((R) -2,2 -difluorocyclopropyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3]diazepin -6 -yl) -1 -(4-fluorobenzyl) -1H -1,2,4 - triazole -3 -carboxamide

[01237] A mixture of (R) -6 -amino -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -[(4-fluorophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (39 mg, 0 .18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride 1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (31 - 61% acetonitrile in water and 0.05% ammonium hydroxide) to give N -((R) -2 -((R ) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (17.1 mg, 31.5% yield) as a white solid: 1H NMR (400 MHz, CD3OD ) δ 8.58 (s, 1H), 7.42 - 7.39 (m, 2H), 7.11 (t, J = 8.4 Hz, 2H), 6.21 (s, 1H), 6 .46 (s, 2H), 4.55 - 4.51 (m, 1H), 4.37 - 4.35 (m, 1H), 4.27 - 4.24 (m, 1H), 3.33 (s, 3H), 2.88 - 2.80 (m, 2H), 2.28 - 2.27 (m, 1H), 1.97 - 1.80 (m, 2H). LCMS RT = 0.79 min.; m/z = 460.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79 min., ESI+ found [M+H] = 460.1. Example 319

[01238] WX CCCCCC Method (S) -N -((S) -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1.5 - a][1,3] diazepin -6 -yl) -1 -ethyl -1 -methyl -1,3 - dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01239] A mixture of (S) -6 -amino -2 - ((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (60 mg, 0.23 mmol), (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine - 6 -carboxylic acid (58 mg, 0.28 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (47 mg, 0.35 mmol) and N1 - ((ethylimino)methylene) -N3 hydrochloride N3-dimethylpropane-1,3-diamine (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (35 -65% acetonitrile / 0.05% ammonium hydroxide in water) to give (S) -N -((S) -2 - ((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide (25mg, 24%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.86 (s, 1H), 6.21 (s, 1H), 6.19 - 6.15 (m, 2H), 4.55 - 4.39 (m, 1H), 4.38 - 4.35 (m, 1H), 4.30 - 4.26 (m, 1H), 3.30 (s, 3H), 2.92 - 2.81 (m , 2H), 2.26 - 2.25(m, 1H), 1.94 - 1.78(m, 4H), 1.45(s, 3H), 0.78- 0.74 (m, 3H) ). LCMS RT = 0.83 min.; m/z = 446.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.83 min., ESI+ found [M+H] =446.1. Example 320

[01240] WX PPPPP Method 1 -(2,3-difluorobenzyl) -N -((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01241] A mixture of (S) -6 -amino -2 - ((S) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -(2,3-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxylic acid (42 mg, 0.18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride -1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile/0.05% ammonium hydroxide in water) to give 1 -(2,3 - difluorobenzyl) -N - ((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide as a white solid (13.7 mg, 24%): H NMR (400 MHz, CD3OD) δ 8 .62 (s, 1H), 7.33 - 7.24 (m, 1H), 7.22 - 7.13 (m, 2H), 6.19 (s, 1H), 6.60 (s, 2H ), 4.54 - 4.49 (m, 1H), 4.42 - 4.33 (m, 1H), 4.30 - 4.19 (m, 1H), 3.33 (s, 3H), 2.90 - 2.75 (m, 2H), 2.28 -2.24 (m, 1H), 1.94 - 1.85 (m, 1H), 1.82 - 1.74 (m, 1H) ). LCMS RT = 1.00 min.; m/z = 478.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.00 min., ESI+ found [M+H] =478.2. Example 321

[01242] WX Method OOOOO 1 -(3,4-difluorobenzyl) -N -((S) -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H-1,2,4 -triazole -3 -carboxamide

[01243] A mixture of (S) -6 -amino -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazolo[1,5 -a][ 1,3] diazepin -5(6H)-one (30 mg, 0.12 mmol),1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H -benzo [d][1,2,3]triazol -1 -ol (39 mg, 0.29 mmol) and N1 -((ethylimino)methylene)-N3,N3 -dimethylpropane hydrochloride -1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to give 1 -(3,4 - difluorobenzyl) -N - ((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (16.1 mg, 28%) as a white solid: H NMR (400 MHz, CD3OD) δ 8 .60 (s, 1H), 7.36 - 7.23 (m, 2H), 7.21 - 7.19 (m, 1H), 6.20 (s, 1H), 6.46 (s, 2H ), 4.54 -4.49 (m, 1H), 4.42 - 4.34 (m, 1H), 4.30 - 4.20 (m, 1H), 3.33 (s, 3H), 2.91 - 2.75 (m, 2H), 2.31 - 2.22 (m, 1H), 1.92 - 1.88 (m, 1H), 1.83 - 1.74 (m, 1H ). LCMS RT = 1.01 min.; m/z = 478.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.01 min., ESI+ found [M+H] =478.2. Example 322

[01244] WX QQQQQ Method 1 -(2,4-difluorobenzyl) -N -((S) -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H-1,2,4 -triazole -3 -carboxamide

[01245] A mixture of (S) -6 -amino -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -(2,4-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxylic acid (42 mg, 0.18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride -1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile/0.05% ammonium hydroxide in water) to give 1 -(2,4 - difluorobenzyl) -N - ((S) -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide as a white solid (28.4 mg, 50%): 1H NMR (400 MHz, CD3OD) δ 8 .58 (s, 1H), 7.50 - 7.42 (m, 1H), 7.06 - 6.96 (m, 2H), 6.19 (s, 1H), 6.52 (s, 2H ), 4.53 - 4.48 (m, 1H), 4.41 - 4.33 (m, 1H), 4.28 - 4.17 (m, 1H), 3.33 (s, 3H), 2.90 - 2.76 (m, 2H), 2.30 -2.19 (m, 1H), 1.95 - 1.84 (m, 1H), 1.83 - 1.73 (m, 1H) ). LCMS RT = 1.00 min.; m/z = 478.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.00 min., ESI+ found [M+H] =478.2. Example 323

[01246] WX RRRRR Method N -((S) -2 -((S) -2,2 -difluorocyclopropyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3]diazepin -6 -yl) -1 -(4-fluorobenzyl) -1H -1,2,4 - triazole -3 -carboxamide

[01247] A mixture of (S) -6 -amino -2 -((S) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), 1 -(4-fluorobenzyl) -1H -1,2,4 -triazole -3 - carboxylic acid (39 mg, 0. 18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 - ((ethylimino)methylene) -N3,N3 -dimethylpropane hydrochloride -1 ,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile/0.05% ammonium hydroxide in water) to give N -((S) -2 -((S ) - 2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(4-fluorobenzyl)-1H -1,2,4 -triazole -3 -carboxamide as a white solid (23.4 mg, 43%): 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.40 (dd, J = 6.0, 8.4 Hz, 2H), 7.10 (t, J = 8.8 Hz, 2H), 6.19 (s, 1H) , 6.46 (s, 2H), 4.53 - 4.45 (m, 1H), 4.41 - 4.34 (m, 1H), 4.30 - 4.20 (m, 1H), 3 .33 (s, 3H), 2.90 - 2.75 (m, 2H), 2.29 - 2.14 (m, 1H), 1.95 - 1.85 (m, 1H), 1.83 - 1.73 (m, 1H). LCMS RT = 0.99 min.; m/z = 460.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.99 min., ESI+ found [M+H] =460.2. Example 324

[01248] WX WWWWW Method (R) -N -((R) -2 -((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 - a][1,3] diazepin -6 -yl) -1 -ethyl -1 -methyl -1,3 - dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01249] A mixture of (R) -6 -amino -2 -((R) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine - 6 -carboxylic acid (24 mg, 0.12 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 - ((ethylimino)methylene) -N3 hydrochloride N3-dimethylpropane-1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (42 - 62% acetonitrile in water and 0.05% hydrochloric acid) to give (R) -N -((R) -2 - ((R) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 - il) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide (20 mg, 38%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.87 (s, 1H), 6.23 (s, 1H), 6.21 - 6.16 (m, 2H), 4.59 - 4.55 (m, 1H), 4.39 - 4.37 (m, 2H), 3.36 (s, 3H), 2.94 - 2.79 (m, 2H), 2.28 - 2.26 (m , 1H), 1.92 - 1.78(m, 4H), 1.47 (s, 3H), 0.78(t, J = 6.8 Hz, 3H). LCMS RT = 0.84 min.; m/z = 446.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.84 min., ESI+ found [M+H] = 446.2. Example 325

[01250] Method WX XXXXX (R) -N -((S) -2 -((S) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 - a][1,3] diazepin -6 -yl) -1 -ethyl -1 -methyl -1,3 - dihydrofuro [3,4 -c] pyridine -6 -carboxamide

[01251] A mixture of (S) -6 -amino -2 - ((S) -2,2 - difluorocyclopropyl) -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -5(6H) -one (30 mg, 0.12 mmol), (1R) -1 -ethyl -1 -methyl -3H -furo [3,4 -c] pyridine - 6 -carboxylic acid ( 29 mg, 0.14 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.18 mmol) and N1 - ((ethylimino)methylene) -N3 hydrochloride, N3-dimethylpropane-1,3-diamine (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17 -47/0.05% ammonium chloride in water) to give (R) -N -((S) -2 - ((S) -2,2 -difluorocyclopropyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl ) -1 -ethyl -1 -methyl -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxamide (20 mg, 38%) as a white solid: 1H NMR (400 MHz, CD3OD ) δ 8.56 (s, 1H), 7.87 (s, 1H), 6.21 (s, 1H), 6.20 - 6.16 (m, 2H), 4.58 - 4.53 ( m, 1H), 4.38 - 4.27 (m, 2H), 3.35 (s, 3H), 2.98 - 2.78(m, 2H), 2.27 - 2.17 (m, 1H), 1.92 - 1.78(m, 4H), 1.46 (s, 3H), 0.76 (t, J = 3.6 Hz, 3H). LCMS RT = 1.08 min.; m/z = 446.3 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.08 min., ESI+ found [M+H] = 446.3. Example 326

[01252] WX OO Method N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -7 -ethyl -7 -methyl -5,7 -dihydrofuro [3,4 -d] pyrimidine -2 - carboxamide

[01253] A mixture of 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (20 mg, 0.10 mmol), (S)-6-amino- 2,4 -dimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (20 mg, 0.10 mmol), N1 -( hydrochloride (ethylimino) methylene) -N3,N3 - dimethyl propane -1,3 -diamine (22 mg, 0.11 mmol) and 1H - benzo[d][1,2,3] triazole -1 -ol (16 mg, 0.11 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25oC for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 31 -61%/0.05% NH4OH in water) to give N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -7 -ethyl -7 -methyl -5,7 -dihydrofuro [3 ,4 -d] pyrimidine -2 - carboxamide (29.0 mg, 77%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 6.13 ( s, 1H), 6.18 - 6.12 (m, 2H), 4.62 - 4.57 (m, 1H), 4.34 - 4.25(m, 2H), 3.35 (s, 3H), 2.97 - 2.92 (m, 1H), 2.32 - 2.27 (m, 4H), 1.99 - 1.85 (m, 2H), 1.49 (s, 3H) , 0.80 (t, J = 7.6 Hz, 3H). LCMS RT = 0.729 min.; m/z = 386.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.729 min., ESI+ found [M+H] = 386.1. Example 327

[01254] WX O Method (S)-4-(1-hydroxycyclobutyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide Step 1: 1-(2-chloro-4-pyridyl)cyclobutanol

[01255] To a solution of 2-chloro-4-iodopyridine (2.4 g, 10.0 mmol) in tetrahydrofuran (100 mL) was added isopropyl magnesium chloride (13.0 mL, 13.0 mmol, 1. 0 M in tetrahydrofuran) under -45oC for 5 min. under nitrogen. After being subjected to agitation for 45min. under -45oC, cyclobutanone (2.1 g, 30.0 mmol) was added. The mixture was allowed to warm to 25°C and stirred for 15 h. The mixture was finished by adding saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, washed with brine (1 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 1-(2-chloro-4-pyridyl) cyclobutanol (500 mg, 27%) in the form of a colorless oil, which was used in the next step without any further purification. Step 2: methyl 4 -(1-hydroxycyclobutyl) picolinate

[01256] A mixture of 1,1'-bis(diphenylphosphine) palladium ferrocene dichloride (80 mg, 0.11 mmol), triethylamine (331 mg, 3.27 mmol) and 1-(2-chloro-4-pyridyl ) cyclobutanol (200 mg, 1.09 mmol) in methanol (10 mL) was stirred at 70oC for 15 h under carbon oxide [3.42 bar [3.42 bar (35 psi)]]. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide methyl 4-(1-hydroxycyclobutyl) picolinate (120 mg, 53%) as a yellow solid: LCMS RT = 0.554 min.; m/z = 207.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.554 min., ESI+ found [M+H]+ = 207.8. Step 3: 4 -(1-hydroxycyclobutyl) picolinic acid

[01257] A mixture of methyl 4-(1-hydroxycyclobutyl) picolinate (60 mg, 0.29 mmol) and potassium hydroxide (32 mg, 0.58 mmol) in ethanol (4 mL) and water (1 mL) was subjected to stirring for 2 h at 25oC. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH = 3 by adding hydrochloric acid (1.0 M). The aqueous layer was concentrated under reduced pressure to provide crude 4-(1-hydroxycyclobutyl) picolinic acid (100 mg, 100%) as a white solid, which was used in the next step without further purification. Step 4: (S) -4 -(1-hydroxycyclobutyl) -N - (5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) picolinamide

[01258] A mixture of 4-(1-hydroxycyclobutyl) picolinic acid (100.0 mg, 0.52 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepine -4-one (30.0 mg, 0.16 mmol), 1-hydroxybenzotriazole (26.0 mg, 0.19 mmol) and 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (36.9 mg , 0.19 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25°C for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to provide (S)-4-(1-hydroxycyclobutyl)-N -(5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) picolinamide (30.0 mg, 36%) as a solid white color: 1H NMR (400 MHz, CD3OD): δ 8.63 (d, J = 6.6 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.72 - 7 .70(m, 1H), 7.46 - 7.44 (m, 1H), 7.35 - 7.24 (m, 3H), 6.06 - 4.99 (m, 1H), 4.67 - 4.63 (m, 1H), 4.43 - 4.38 (m, 1H), 3.43 (s, 3H), 2.52 - 2.36 (m, 4H), 2.14 - 2 .01 (m, 1H), 1.89 - 1.78(m, 1H). LCMS RT = 0.992 min.; m/z = 368.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.992 min., ESI+ found [M+H]+ = 368.2. Example 328

[01259] WX E Method (S) -4 -(1-hydroxycyclopentyl) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) picolinamide Step 1: 1-(2-chloropyridin-4-yl)cyclopentanol

[01260] To a solution of 2-chloro-4-iodopyridine (6.0 g, 20.9 mmol) in tetrahydrofuran (100 mL) was added isopropyl magnesium chloride (1.0 M, 27.2 mL, 27. 2 mmol) dropwise under -45oC for 5 min. Stirring was continued at -45°C for 45 min. Cyclopentanone (6.3 g, 62.7 mmol) was added dropwise. The resulting mixture was allowed to warm to 25°C and stirred for another 15 h before being finalized by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 1-(2-chloropyridin-4-yl) cyclopentanol (500 mg, 12% ) in the form of a colorless oil. LCMS RT = 1.42 min.; m/z = 198.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide for 3.0 min.) retention time 1.42 min., ESI+ found [M+H] =198.1. Step 2: Methyl 4 -(1-hydroxycyclopentyl) picolinate

[01261] A mixture of 1-(2-chloropyridin-4-yl) cyclopentanol (100 mg, 0.5 mmol), triethylamine (154 mg, 1.5 mmol) and 1,1'-bis(diphenylphosphine) dichloride palladium ferrocene) (37 mg, 0.05 mmol) in methanol (50 mL) was stirred at 70oC for 15 h under carbon oxide atmosphere [3.42 bar (35 psi)]. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide methyl 4-(1-hydroxy cyclopentyl) picolinate (80 mg, 71%) in the form of a light yellow oil, which was used in the next step without any further purification. Step 3: 4 -(1-hydroxycyclopentyl) picolinic acid

[01262] A mixture of methyl 4-(1-hydroxycyclopentyl) picolinate (80 mg, 0.36 mmol) and potassium hydroxide (40 mg, 0.72 mmol) in ethanol (5 mL) and water (1 mL) was subjected to stirring at 25oC for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH = 4 by adding hydrochloric acid (2.0 M). The mixture was concentrated under reduced pressure to provide crude 4-(1-hydroxycyclopentyl)picolinic acid (60 mg, 80%) as a yellow solid, which was used in the next step without further purification. Step 4: (S) -4 -(1-hydroxycyclopentyl) -N -(5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) picolinamide

[01263] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (30.0 mg, 0.12 mmol), N1 -( (ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine (33.7 mg, 0.18 mmol), 1H - benzo [d][1,2,3] triazole -1 -ol (23, 7 mg, 0.18 mmol) and 4-(1-hydroxycyclopentyl) picolinic acid (36.0 mg, 0.18 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25oC for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to provide (S)-4-(1-hydroxy cyclopentyl)- N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) picolinamide (26.9 mg, 57.4%) in the form of a white solid: 1H NMR (400 MHz, CD3OD) δ 8.58 (d, J = 6.2 Hz,1H), 8.15 (s, 1H), 7.67 - 7.65 (m, 1H), 7.46 - 7.41 (m, 1H), 7.35 - 7.29 (m, 2H), 7.27 - 7.22 (m, 1H), 6.05 -4.96 ( m, 1H), 4.67 - 4.58 (m, 1H), 4.43 - 4.36 (m, 1H), 3.43 (s, 3H), 2.03 - 1.84 (m, 8H). LCMS RT = 1.03 min.; m/z = 382.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.03 min., ESI+ found [M+H] =382.2. Example 329

[01264] WX YY Method (R) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -(4-fluorobenzyl) -4H -1,2,4 -triazole -3 -carboxamide

[01265] A mixture of 5 -(4-fluorobenzyl) - 4H -1,2,4 -triazole -3 -carboxylic acid (82 mg, 0.37 mmol), (6R) -6 -amino -2,4 - dimethyl -7,8 -dihydro -6H - pyrazole [1,5 - a] [1,3] diazepin -5 -one (60 mg, 0.31 mmol), 1H -benzo [d][1,2,3 ] triazol -1 -ol (63 mg, 0.46 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 - diamine hydrochloride (83 mg, 0.46 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (12 - 42% acetonitrile/0.05% ammonium hydroxide in water) to give (R) -N -(2,4 - dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -5 -(4 -fluorobenzyl) -4H -1,2 ,4 - triazole -3 -carboxamide (17.5 mg, 14%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.31 - 7.27 (m, 2H), 7, 06 - 6.99 (m, 2H), 6.10 (s, 1H), 4.54 - 4.49 (m, 1H), 4.30 - 4.28 (m, 2H), 4.13 ( s, 2H), 3.30 (s, 3H), 2.86 - 2.80 (m, 1H), 2.27 - 2.21 (m, 4H). LCMS RT = 0.735 min.; m/z = 398.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.735min., ESI+ found [M+H] =398.1. Example 330

[01266] WX JJJJJ Method (S) -5 -(4-fluorobenzyl) -N -(2,3,4 -trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[01267] A mixture of 5 -[(3-fluorophenyl) methyl] -4H -1,2,4 -triazole -3 -carboxylic acid (76 mg, 0.35 mmol), (6S) -6 -amino -2 ,3,4 -trimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (60 mg, 0.29 mmol), 1H -benzo [d][ 1,2,3] triazol -1 -ol (58 mg, 0.43 mmol) and N1 -((ethylimino) methylene) -N3,N3 - dimethylpropane -1,3 -diamine hydrochloride (78 mg, 0.43 mmol ) in N,N - dimethylformamide (5 mL) was stirred at 25oC for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (15-45% acetonitrile/0.05% ammonium hydroxide in water) to provide (S)-5-(4-fluorobenzyl)- N -(2,3,4 - trimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl) -4H -1 ,2,4 -triazole -3 - carboxamide (29.5mg, 25%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 7.28 - 7.27 (m, 2H), 7 .05 - 7.01 (m, 2H), 4.43 - 4.38 (m, 1H), 4.22 - 4.20 (m, 2H), 4.13 (s, 2H), 3.30 (s, 3H), 2.80 - 2.73 (m, 1H), 2.19 - 2.17 (m, 4H), 2.00 (s, 3H). LCMS RT = 0.754 min.; m/z = 412.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% formic acid for 1.5 min.) retention time 0.754min., ESI+ found [M+H] =412.1. Example 331

[01268] WX CCCC Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(2,3-difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxamide

[01269] A mixture of 1 -[(2,3 - difluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylic acid (26 mg, 0.11 mmol), (6S) -6 -amino -2 -cyclopropyl -4 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), N1 -((ethylimino) hydrochloride ) methylene) -N3,N3 -dimethyl propane -1,3 -diamine (24 mg, 0.14 mmol) and 1H -benzo [d][1,2,3] triazol -1 -ol (18 mg, 0. 14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (17 -47% acetonitrile in water and 0.05% hydrogen chloride) to give (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl) -1 -(2,3 -difluorobenzyl) -1H - 1,2,4 -triazole -3 -carboxamide (18.9 mg, 47%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 7, 33 - 7.26 (m, 1H), 7.19 - 7.18 (m, 2H), 6.34 (s, 1H), 6.63 (s, 2H), 4.73 - 4.69 ( m, 1H), 4.48 - 4.36 (m, 2H), 3.31 (s, 3H), 2.90 - 2.84 (m, 1H), 2.41 (m, 1H), 2 .03 - 2.01 (m, 1H), 1.16 - 1.14 (m, 2H), 0.93 - 0.91 (m, 2H). LCMS RT = 1.00 min.; m/z = 442.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.00 min., ESI+ found [M+H] = 442.1. Example 332

[01270] WX DDDD Method (S) -N -(2 -cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -(4-fluorobenzyl) -4H -1,2,4 -triazole -3 - carboxamide

[01271] A mixture of 5 -[(4-fluorophenyl) methyl] -4H -1,2,4 -triazole -3 -carboxylic acid (30 mg, 0.14 mmol), (6S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (20 mg, 0.09 mmol), 1H -benzo [d][ 1,2,3] triazol -1 -ol (18 mg, 0.14 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (26 mg, 0.14 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25oC for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (28 -58% acetonitrile in water and 0.05% hydrogen chloride) to give (S) -N -(2-cyclopropyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -5 -(4 -fluorobenzyl) -4H -1 ,2,4 -triazole -3 - carboxamide (23 mg, 57%) as a white solid: 1H NMR (400 MHz, CD3OD): 7.35 - 7.32 (m, 2H), 7, 11 - 7.07 (m, 2H), 6.16 (s, 1H), 4.62 - 4.57 (m, 1H), 4.41 - 4.23 (m, 4H), 3.33 ( s, 3H), 2.90 -2.79 (m, 1H), 2.37 - 2.29 (m, 1H), 1.99 - 1.93 (m, 1H), 1.05 - 1, 03 (m, 2H), 0.87 - 0.78(m, 2H). LCMS RT = 1.18 min.; m/z = 424.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.18 min., ESI+ found [M+H]+ = 424.1.

[01272] The compounds of Examples 333 -338 and methods for their preparation are illustrated in Table 3 below. Example 339 1 -[(4-fluorophenyl) methyl] -N -[rac -(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01273] Method B (57 mg, 89% yield)

[01274] 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.45-7.33 (m, 2H), 7.28 - 7.14 (m, 2H), 6.34 (d, J = 2.0 Hz, 1H), 6.47 (s, 2H), 4.40 - 4.11 (m, 3H), 3.24 (s, 3H), 2.64 - 2.56 (m, 1H), 2.42 - 2.30 (m , 1H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.62 min., ESI+ found [M+H] = 384.2. Example 340 1 -[(2,4-difluorophenyl) methyl] -N -[rac -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01275] Method B (53 mg, 79% yield)

[01276] H NMR (400 MHz, DMSO -d6) δ 8.79 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.54 - 7.40 (m, 2H ), 7.38 - 7.25(m, 1H), 7.20 - 7.04 (m, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.52 (s, 1H), 4.46 - 4.09 (m, 3H), 3.24 (s, 3H), 2.66 - 2.54 (m, 1H), 2.43 - 2.30 (m, 1H) . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.69 min., ESI+ found [M+H] = 402.1. Example 341 1 -[(3,4-difluorophenyl) methyl] -N -[rac -(6S) -4-methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ]diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01277] Method B (68 mg, 99% yield)

[01278] 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.53 – 7.39 (m, 2H ), 7.30 – 7.11 (m, 2H), 6.34 (d, J = 2.0 Hz, 1H), 6.61 (s, 2H), 4.42 – 4.13 (m, 3H), 3.24 (s, 3H), 2.65 - 2.54 (m, 1H), 2.44 - 2.29 (m, 1H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.77 min., ESI+ found [M+H] = 402.1. Example 342 1 -[(2,3-difluorophenyl) methyl] -N -[rac -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide.

[01279] Method B (52 mg, 78% yield)

[01280] H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.58 - 7.35 (m, 3H ), 7.30 - 7.04 (m, 1H), 6.34 (d, J = 2.1 Hz, 1H), 6.48 (s, 2H), 4.43 - 4.12 (m, 3H), 3.24 (s, 3H), 2.63 - 2.56 (m, 1H), 2.44 - 2.30 (m, 1H). LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.69 min., ESI+ found [M+H] = 402.1. Example 343

[01281] GH1 Method 1 -[(2,6-difluorophenyl) methyl] -N -[(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -6 -yl] -1,2,4 -triazole -3 -carboxamide Step 1: (S) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - 4H -1,2,4 -triazole -3 -carboxamide

[01282] To a solution of (6S) -6 -amino -4 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (1200 mg, 6 .66 mmol, 1.0 equiv.) in DMF (15 mL) was added 4H-1,2,4-triazole-3-carboxylic acid (904 mg, 8.0 mmol, 1.2 equiv.), N, N -diisopropylethylamine (3.48 mL, 20.0 mmol, 3.0 equiv.), and PYAOP (4159 mg, 7.66 mmol, 1.15 equiv.) lastly. The reaction mixture was stirred overnight, then concentrated to drying in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide N(S)-N-(4-methyl-5-oxo-5.6, 7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -4H -1,2,4 -triazole -3 -carboxamide (1500 mg, 82% yield) in the form of a white solid which was used in the next stage as it was. LCMS RT = 0.71 min. [method 2 min.], m/z = 256 [M + H]+. Step 2: 1 -[(2,6-difluorophenyl) methyl] -N - [(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01283] To a suspension of N -[(6S) -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - il] - 4H-1,2,4-triazole-3-carboxamide (500 mg, 1.8 mmol, 1.0 equiv.) in acetonitrile (10 mL) was added potassium carbonate (502 mg, 3.63 mmol, 2.0 equiv.) 0 equiv.) followed by 2,6-difluorobenzyl bromide (465 mg, 2.18 mmol, 1.2 equiv.). The reaction mixture was stirred for 16 h at RT, then filtered through Celite and concentrated to drying in vacuo. The residue was purified by RP-HPLC to provide 1-[(2,6-difluorophenyl)methyl]-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole[ 1,5-a][1,3] diazepin -6 -yl] - 1,2,4 -triazole -3 -carboxamide (348 mg, 48% yield) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.57 - 7.44 (m, 2H), 7 .23 - 7.10 (m, 2H), 6.33 (d, J = 2.0 Hz, 1H), 6.56 (s, 2H), 4.42 - 4.09 (m, 3H), 3.24 (s, 3H), 2.65 - 2.53 (m, 1H), 2.42 - 2.30 (m, 1H). LCMS RT = 3.67 min. [10 min. method], m/z = 402.2 [M + H]+. Example 344 (5S) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -5 - ( trifluoromethyl) -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01284] The title compound was prepared from (S) -6 -amino -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H ) -one and (S) -5 -(trifluoromethyl) pyrrolidin -2 -one commercially available according to METHOD G11. Final stage yield: 71%, obtained as a white solid. 1H NMR (400 MHz, DMSO - d6) δ 8.60 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.49 (td, J = 7.8, 6.9, 3.4 Hz, 1H), 4.44 - 4.26 (m, 2H), 4.20 ( ddd, J = 14.5, 12.7, 6.6 Hz, 1H), 3.25(s, 3H), 3.15 - 2.92 (m, 3H), 2.82 - 2.70( m, 1H), 2.65 - 2.54 (m, 1H), 2.44 - 2.32 (m, 1H). LCMS RT = 3.38 min. [10 min. method], m/z = 384.1 [M + H]+. Example 345 N -[(3S)-6 -fluoro -8 -methyl -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] -5 -isopropyl -6,7 - dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01285] The title compound was prepared from (S) -3 -amino -6 -fluoro -8 -methyl -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one and commercially available ethyl 5-methyl-4-oxo-hexanoate according to the GH2 METHOD. Final stage yield: 47%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.35 (dd, J = 7.7, 6.2 Hz, 1H), 6.99 (dd, J = 10, 7, 1.8 Hz, 1H), 6.89 (s, 1H), 4.90 - 4.80 (m, 1H), 4.63 - 4.53 (m, 1H), 4.47 (dd , J = 10.1, 7.3 Hz, 1H), 4.34 (dt, J = 9.1, 4.9 Hz, 1H), 2.92 - 2.83 (m, 2H), 2, 79 - 2.65 (m, 1H), 2.48 - 2.35 (m, 1H), 2.30 (s, 3H), 2.23 - 2.09 (m, 1H), 0.95 ( dd, J = 6.9, 1.5 Hz, 3H), 0.81 (dd, J = 6.9, 0.9 Hz, 3H). LCMS RT = 4.76 min. [method 10 min.], m/z = 388.1 [M + H]+. Example 346

[01286] GH2 Method 5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide Step 1: tert -butyl(2-isopropyl-5-oxopyrrolidin-1-yl) carbamate

[01287] To a solution of ethyl 5-methyl-4-oxo-hexanoate (1000 mg, 6.80 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL) was added acetic acid (10 mL, 174.5 mmol , 30 equiv.) and tert -butyl carbazate (1151 mg, 8.71 mmol, 1.5 equiv.). The reaction mixture was subjected to stirring for 16 h under 50°C. After cooling the mixture to RT, sodium cyanoborohydride was added (547 mg, 8.71 mmol, 1.5 equiv.). The reaction mixture was further stirred for 4 h at RT. After this period, the reaction was completed with 10% Na2HPO4 (150 mL) and extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were washed with 10% Na2HPO4 (2 x 150 mL), water and brine, dried over sodium sulfate, and concentrated for drying in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide tert -butyl(2-isopropyl-5-oxopyrrolidin-1-yl)carbamate na form a light yellow oil (800 mg, 57% yield) which was used in the next step as it was. LCMS RT = 1.20 min. [method 2 min.], m/z = 243 [M + H]+. Step 2: 2 -isopropyl -5 -oxopyrrolidin -1 -amino 2,2,2 -trifluoroacetate

[01288] To a solution of tert-butyl (2-isopropyl - 5-oxopyrrolidin-1-yl) carbamate in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml). The reaction mixture was stirred for 1.5 h under RT. Toluene (10 ml) was added, and the mixture was concentrated to drying in vacuo. The residue was resuspended in toluene and concentrated to drying twice more providing 2-isopropyl-5-oxopyrrolidin-1-amino 2,2,2-trifluoroacetate in the form of a colorless oil which was used immediately in the next step without any purification. LCMS RT = 0.80 min. [method 2 min.], m/z = 143 [M + H]+ for C7H15N2O. Step 3: ethyl 5 -isopropyl -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate

[01289] To a solution of 2-isopropyl-5-oxopyrrolidin-1-amino 2,2,2-trifluoroacetate (850 mg, 3.3 mmol, 1.0 equiv.) in acetonitrile (10 mL) was added ethyl 2 -ethoxy-2-imino-acetate (0.48 mL, 500 mg, 3.5 mmol, 1.1 equiv.). The resulting mixture was subjected to stirring for 1 h under RT, and then subjected to microwave irradiation under 160°C for 50 min. The reaction mixture was concentrated to drying in vacuo, and the resulting residue was purified by means of column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide ethyl 5-isopropyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2, 4] triazole -2 -carboxylate in the form of a light yellow oil (102 mg, 14% yield) which was used in the next step as it was. LCMS RT = 1.08 min. [method 2 min.], m/z = 224 [M + H]+. Step 4: sodium 5 -isopropyl -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate

[01290] To a solution of ethyl 5-isopropyl-6,7-dihydro-5H-pyrrole [1,2-b][1,2,4] triazole-2-carboxylate (106 mg, 0.47 mmol, 1 .0 equiv.) in tetrahydrofuran (2 mL) was added 1M aqueous sodium hydroxide (0.5 mL, 1.0500 equiv.). The reaction mixture was stirred for 1 h under 50°C, then concentrated to drying in vacuo to provide 5-isopropyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2 ,4] sodium triazole-2-carboxylate in the form of a brown solid which was used immediately in the next step without any purification. LCMS RT = 0.90 min. [method 2 min.], m/z = 196 [M + H]+ for C9H13N3O2. Step 5: 5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide

[01291] To a solution of (6S) -6 -amino -4 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (35 mg, 0 .19 mmol, 1.0 equiv.) in N,N-dimethylformamide (2 mL) 5-isopropyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole was added -2 -sodium carboxylate (52 mg, 0.237 mmol, 1.22 equiv.), N,N -diisopropyl ethylamine (0.102 mL, 0.58 mmol, 3.0 equiv.), and PYAOP (127 mg, 0. 23 mmol, 1.2 equiv.). The reaction mixture was stirred overnight, then concentrated to drying in vacuo. The residue was purified by RP-HPLC to provide 5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a][1 ,3] diazepin -6 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (68 mg, 98% yield) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.45(dd, J = 11.1, 7.8 Hz, 1H), 7.49 (dd, J = 2.0, 0.6 Hz, 1H) , 6.34 (dd, J = 2.0, 1.2 Hz, 1H), 4.45- 4.24 (m, 3H), 4.24 - 4.11 (m, 1H), 3.25 (d, J = 1.5 Hz, 3H), 2.92 - 2.81 (m, 2H), 2.78- 2.54 (m, 2H), 2.46 - 2.28 (m, 2H ), 2.15 (pd, J = 6.8, 4.7 Hz, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.81 (dd, J = 6.8, 1.6Hz, 3H). LCMS RT = 3.71 min. [10 min. method], m/z = 358.2 [M + H]+. Example 347 (5S) -N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -5 -(trifluoromethyl) -6, 7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide

[01292] The title compound was prepared from (S) -3 -amino -6 -fluoro -8 -methyl -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one and (S)-5-(trifluoromethyl)pyrrolidin-2-one is commercially available according to METHOD G11. Final stage yield: 57%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 10.01 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 6.99 (ddd, J = 10.7, 1, 8, 0.8 Hz, 1H), 6.90 (s, 1H), 6.58 - 6.43 (m, 1H), 4.86 (dt, J = 11.1, 7.5 Hz, 1H ), 4.60 (dd, J = 11.2, 10.1 Hz, 1H), 4.46 (dd, J = 10.1, 7.3 Hz, 1H), 3.16 - 2.96 ( m, 3H), 2.84 - 2.70(m, 1H), 2.35 - 2.27 (m, 3H). LCMS RT = 4.60 min. [10 min. method], m/z = 414.1 [M + H]+. Example 348 (5S) -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] -5 -(trifluoromethyl) -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide

[01293] The title compound was prepared from (S) -3 -amino -6,8 -difluoro -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one and (S ) -5 -(trifluoromethyl)pyrrolidin - 2 -one commercially available according to METHOD G11. Final stage yield: 84%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.52 (d, J = 7.7 Hz, 1H), 7.24 (ddd, J = 10.4, 9.1, 2.9 Hz, 1H) , 7.04 (ddd, J = 9.4, 2.9, 1.8 Hz, 1H), 6.57 - 6.44 (m, 1H), 4.92 (dt, J = 11.1, 7.4 Hz, 1H), 4.66 (dd, J = 11.1, 10.2 Hz, 1H), 4.52 (dd, J = 10.2, 7.1 Hz, 1H), 3, 15 - 2.97 (m, 4H), 2.83 - 2.71 (m, 1H). LCMS RT = 4.34 min. [10 min. method], m/z = 418.1 [M + H]+. Example 349 5-ethyl -N -[(3S)-6-fluoro -8 -methyl -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01294] The title compound was prepared from (S) -3 -amino -6 -fluoro -8 -methyl -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one and commercially available ethyl 4-oxo-hexanoate according to the GH2 METHOD. Final stage yield: 23%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.35 (dd, J = 7.8, 2.7 Hz, 1H), 6.98 (ddd, J = 10, 7, 1.8, 0.8 Hz, 1H), 6.89 (s, 1H), 4.90 - 4.79 (m, 1H), 4.58 (ddd, J = 11.2, 10, 1, 6.5 Hz, 1H), 4.46 (ddd, J = 10.1, 7.3, 1.8 Hz, 1H), 4.43 - 4.34 (m, 1H), 2.93 - 2.76 (m, 3H), 2.37 - 2.31 (m, 1H), 2.30 (t, J = 0.7 Hz, 3H), 1.96 - 1.83 (m, 1H ), 1.78- 1.64 (m, 1H), 0.91 (td, J = 7.4, 1.0 Hz, 3H). LCMS RT = 4.44 min. [10 min. method], m/z = 374.1 [M + H]+. Example 350 (5S) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -5 -(trifluoromethyl) -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01295] The title compound was prepared from (S) -3 -amino -5 -methyl -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one and (S) - 5 -(trifluoromethyl)pyrrolidin - 2 -one commercially available according to METHOD G11. Final stage yield: 84%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.52 (d, J = 8.0 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.38 - 7.20 (m, 3H), 6.56 - 6.44 (m, 1H), 4.84 (dt, J = 11.5, 7.8 Hz, 1H), 4.59 (dd, J = 11.5, 9, 9 Hz, 1H), 4.42 (dd, J = 9.9, 7.7 Hz, 1H), 3.32 (s, 3H), 3.12 - 2.97 (m, 3H), 2, 81 - 2.71 (m, 1H). LCMS RT = 4.86 min. [10 min. method], m/z = 396.1 [M + H]+. Example 351 5 -ethyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01296] The title compound was prepared from (6S) -6 -amino -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one and commercially available ethyl 4-oxo-hexanoate according to the GH2 METHOD. Final stage yield: 77%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.44 (t, J = 7.5 Hz, 1H), 7.49 (dd, J = 2.0, 0.5 Hz, 1H), 6.34 (dd, J = 2.1, 0.8 Hz, 1H), 4.43 - 4.12 (m, 4H), 3.25(d, J = 1.5 Hz, 3H), 2.94 - 2.76 (m, 3H), 2.69 - 2.54 (m, 1H), 2,452.27 (m, 2H), 1.95 - 1.83 (m, 1H), 1.78 - 1, 63 (m, 1H), 0.91 (td, J = 7.4, 1.0 Hz, 3H). LCMS RT = 3.87 min. [10 min. method], m/z = 344.2 [M + H]+. Examples 352 and 354

[01297] GH_chiral_1 Method (5S) -5 -isopropyl -N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide and (5R) -5 -isopropyl -N -[(3S) -6 -fluoro -8 -methyl -4 - oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01298] N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] -5 -isopropyl -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide was further purified via chiral SFC (SFC conditions: Column: Regis Whelk O -1 (s,s) 50x4, 6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 45% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40°C, BPR: 120 bar) to provide arbitrarily assigned diastereomers (5S)-5 -isopropyl -N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 - benzoxazepine -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide (0.008 g, 10%) and (5R) -5 -isopropyl - N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H - pyrrole [1, 2-b][1,2,4] triazole -2 -carboxamide (0.008 g, 10%).

[01299] Analytical data for the first eluting diastereomer (arbitrarily assigned S,S configuration): SFC RT (Whelk O -1 (S,S) column, 45% methanol + 0.1% isocratic elution ammonium hydroxide, method 2.5 min.): 0.57 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 6.99 (dd, J = 10.9, 1.8 Hz, 1H), 6.89 (d, J = 1.8 Hz, 1H), 4.85 (dt, J = 11.1 , 7.5 Hz, 1H), 4.58 (t, J = 10.7 Hz, 1H), 4.47 (dd, J = 10.1, 7.3 Hz, 1H), 4.34 (dt , J = 9.0, 4.8 Hz, 1H), 2.92 — 2.82 (m, 2H), 2.79 - 2.64 (m, 1H), 2.42 (dtd, J = 16 .0, 8.7, 8.2, 4.8 Hz, 1H), 2.30 (s, 3H), 2.22 - 2.08 (m, 1H), 0.95 (d, J = 6 .8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). LCMS RT = 6.12 min., m/z = 388.2 [M + H]+.

[01300] Analytical data for the second eluting diastereomer (arbitrarily assigned S,R configuration): SFC RT 0.85 min., 99% ee. 1H NMR (400 MHz, DMSO -d6) δ 10.01 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 6.99 (ddd, J = 10.8, 1, 9, 0.8 Hz, 1H), 6.89 (dt, J = 1.9, 1.0 Hz, 1H), 4.85 (dt, J = 11.0, 7.5 Hz, 1H), 4.57 (dd, J = 11.1, 10.1 Hz, 1H), 4.47 (dd, J = 10.1, 7.3 Hz, 1H), 4.34 (dt, J = 8, 4, 4.9 Hz, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.78-2.65 (m, 1H), 2.47 - 2.36 (m, 1H ), 2.33 - 2.28 (m, 3H), 2.21 - 2.09 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H) LCMS RT = 6.14 min., m/z = 388.2 [M + H]+. Example 353

[01301] GH_chiral_2 Method (5R) -5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide and (5S) -5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H -pyrrole [1,2 -b][1, 2,4] triazole -2 - carboxamide

[01302] 5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide was further purified via chiral SFC (SFC conditions: Column: Regis Whelk O -1 (s ,s) 50x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 45% B in 2.5 min Flow rate: 4mL/min Column temperature: 40°C, BPR: 120 bar) to provide arbitrarily assigned diastereomers (5R) -5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (0.018 g, 27%) and (5S) -5 -isopropyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (0.019 g, 28%) as white solids:

[01303] Analytical data for the first elution diastereomer (arbitrarily assigned S,R configuration): SFC RT (Whelk O -1 (S,S) column, 45% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.): 0.90 min., 99% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.46 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 4.43 - 4.14 (m, 4H), 3.25(s, 3H), 2, 91 - 2.82 (m, 2H), 2.78- 2.54 (m, 2H), 2.46 - 2.29 (m, 2H), 2.21 - 2.09 (m, 1H), 0.94 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). LCMS RT = 4.18 min., m/z = 358.2 [M + H]+.

[01304] Analytical data for the second elution diastereomer (arbitrarily assigned S,S configuration): SFC RT 1.02 min., 99% ee. 1H NMR (400 MHz, DMSO -d6) δ 8.43 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 4.44 - 4.14 (m, 4H), 3.25(s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.77 - 2.56 (m, 2H), 2.46 - 2.30 (m, 2H), 2.22 - 2.09 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H ), 0.81 (d, J = 6.8 Hz, 3H). LCMS RT = 4.17 min., m/z = 358.2 [M + H]+. Example 355 5 -ethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide

[01305] The title compound was prepared from (S) -3 -amino -5 -methyl -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one and ethyl 4-oxo -commercially available hexanoate according to the GH2 METHOD. Final stage yield: 13%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.37 (dd, J = 8.0, 3.9 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.37 - 7, 21 (m, 3H), 4.88 - 4.77 (m, 1H), 4.56 (ddd, J = 11.5, 9.9, 7.0 Hz, 1H), 4.46 - 4, 34 (m, 2H), 3.31 (s, 3H), 2.93 -2.75 (m, 3H), 2.39 - 2.27 (m, 1H), 1.96 - 1.82 ( m, 1H), 1.77 - 1.63 (m, 1H), 0.91 (td, J = 7.5, 1.1 Hz, 3H). LCMS RT = 4.28 min. [10 min. method], m/z = 356.1 [M + H]+. Example 356

[01306] GH3 METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -1 -(trifluoromethyl) - 1H -pyrazole [ 4,3 -c] pyridine -6 –carboxamide Step 1: 6-bromo-1-(bromodifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

[01307] To a suspension of 6-bromo-1H-pyrazolo [4,3-c] pyridine (2000 mg, 10.1 mmol, 1.0 equiv.) in acetonitrile (40 mL) was added cesium carbonate (9872 mg, 30.3 mmol, 3.0 equiv.) and dibromodifluoromethane (1.85 mL, 4238 mg, 20.2 mmol, 2.0 equiv.). The vessel was capped, and the reaction mixture was heated with vigorous stirring at 50°C for 16 h. After this period of time, the mixture was diluted with dichloromethane and filtered through Celite. The filtrate was concentrated for drying in vacuo to obtain the product 6-bromo-1-(bromodifluoromethyl)-1H-pyrazolo[4,3-c]pyridine as a dark red solid which was used in the next step without any further purification. LCMS RT = 1.45 min. [method 2 min.], m/z = 328 [M + H]+. Step 2: 6-bromo-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

[01308] A suspension of 6-bromo-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (crude product from the previous step) in dichloromethane (100 mL) cooled to -78°C was silver tetrafluoroborate (2949 mg, 16.2 mmol, 1.5 equiv.) was added. The reaction mixture was allowed to warm to RT slowly overnight. After this period of time, the mixture was diluted with dichloromethane/methanol (1:1), filtered through Celite, and concentrated to drying in vacuo to provide 6-bromo-1-(trifluoromethyl)pyrazole[4,3-c ] pyridine (1700 mg, 63% yield) as a yellow solid which was used without further purification. LCMS RT = 1.34 min. [method 2 min.], m/z = 266 [M]+. Step 3: methyl 1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

[01309] A high pressure vessel with gas inlet was charged successively with 6-bromo-1-(trifluoromethyl)pyrazolo[4,3-c]pyridine (1700 mg, 6.4 mmol, 1.0 equiv.), methanol (30 mL), triethylamine (8.9 mL, 64 mmol, 10 equiv.), and [1,1'-bis(diphenylphosphine) ferrocene] palladium(II) dichloro (480 mg, 0.64 mmol, 0. 10 equiv.). The reactor was flushed once with carbon monoxide gas, then pressurized to 9.28 bar (120 psi) of carbon monoxide. The reaction was heated at 80°C for 16 h. After this period of time, the gas was released and the mixture was filtered through Celite and concentrated for drying in vacuo. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide methyl 1 -(trifluoromethyl) pyrazole [4,3 -c] pyridine -6 - carboxylate (263 mg, 17% yield) as an off-white solid. LCMS RT = 1.15 min. [method 2 min.],m/z = 246 [M + H]+. Step 4: sodium 1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

[01310] To a solution of methyl 1 -(trifluoromethyl) pyrazolo [4,3 -c] pyridine -6 -carboxylate (263 mg, 1.1 mmol, 1.0 equiv.) in tetrahydrofuran (4 mL) was added hydroxide 1M sodium (1.18 mL, 1.1 equiv.). The reaction mixture was stirred for 2 h under 50 °C, then concentrated to drying in vacuo to provide sodium 1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate in form a brown residue that was used directly in the next reaction without any purification. LCMS RT = 0.90 min. [method 2 min.], m/z = 233 [M + H]+ for C8H4F3N3O2. Step 5: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -1 - (trifluoromethyl) -1H -pyrazole [4,3 -c] pyridine -6 - carboxamide

[01311] To a solution of (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one (229 mg, 1 mmol) in N,N -dimethylformamide (2 mL ) sodium 1-(trifluoromethyl)pyrazolo[4,3-c]pyridine-6-carboxylate (271 mg, 1.07 mmol, 1.07 equiv.), N,N-diisopropyl ethylamine (0.523 mL, 3 mmol, 3 equiv.), and PYAOP (651 mg, 1.2 mmol, 1.2 equiv.). The reaction mixture was subjected to stirring for 16 h under RT. After this period of time, the mixture was concentrated to drying in vacuo and purified by means of RP-HPLC to provide (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -1 -(trifluoromethyl) -1H -pyrazole [4,3 -c] pyridine -6 -carboxamide (303 mg, 75% yield) as a solid white in color. 1H NMR (400 MHz, DMSO - d6) δ 9.41 (d, J = 1.1 Hz, 1H), 9.12 (d, J = 7.8 Hz, 1H), 8.94 (s, 1H ), 8.21 (p, J = 1.3 Hz, 1H), 7.52 (dd, J = 7.4, 2.1 Hz, 1H), 7.39 - 7.23 (m, 3H) , 4.93 (dt, J = 11.3, 7.8 Hz, 1H), 4.66 - 4.48 (m, 2H), 3.35 (s, 3H). LCMS RT = 6.53 min. [10 min. method], m/z = 406.1 [M + H]+. Example 357 (5S) -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 - tetrahydro -1 -benzazepin -3 -yl] -5 -(trifluoromethyl) -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide

[01312] The title compound was prepared from (S) -3 -amino -7,9 -difluoro -1,3,4,5 -tetrahydro -2H - benzo [b]azepin -2 -one and (S ) -5 -(trifluoromethyl) pyrrolidin -2 -one commercially available according to METHOD G11. Final stage yield: 73%, obtained as a white solid. 1H NMR (400 MHz, DMSO - d6) δ 9.97 (s, 1H), 8.34 (d, J = 7.5 Hz, 1H), 7.27 (ddd, J = 10.1, 9, 0, 2.8 Hz, 1H), 7.20 – 7.10 (m, 1H), 6.55 – 6.43 (m, 1H), 4.36 (dt, J = 11.5, 7, 8 Hz, 1H), 3.12 – 2.97 (m, 3H), 2.85 – 2.70(m, 3H), 2.48 – 2.38 (m, 1H), 2.31 – 2 .18 (m, 1H). LCMS RT = 4.30 min. [10 min. method], m/z = 416.1 [M + H]+. Examples 358 and 359

[01313] GH_chiral_3 Method (5R) -5 -ethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] [1,2 -b][1,2 ,4] triazole -2 -carboxamide and (5S) -5 -ethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6 ,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide

[01314] 5-ethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1 ,2 -b][1,2,4] triazole -2 -carboxamide was further purified by means of chiral SFC (SFC conditions: Column: QUIRALCEL OX 50x4.6 mm I.D., 3 μm, Mobile phase: A: CO2 B : Methanol (0.1% NH4OH) Isocratic: 35% B in 2.5 min Flow rate: 4mL/min Column temperature: 40°C, BPR: 120 bar) to provide arbitrarily assigned diastereomers (5R) - 5 -ethyl -N -[(3S) -5 -methyl -4 -oxo - 2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H - pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide and (5S) -5 - ethyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepine - 3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide.

[01315] Analytical data for the first elution diastereomer (arbitrarily assigned S,R configuration): SFC RT (QUIRALCEL -OX column, 35% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.) : 0.80 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.37 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.6, 2.0 Hz, 1H), 7.38 - 7.16 (m, 3H), 4.82 (dt, J = 11.5, 7.8 Hz, 1H), 4.57 (dd, J = 11 .5, 9.9 Hz, 1H), 4.47 - 4.33 (m, 2H), 3.32 (s, 3H), 2.97 - 2.75 (m, 3H), 2.39 - 2.26 (m, 1H), 1.89 (ddd, J = 13.9, 7.4, 6.2 Hz, 1H), 1.78- 1.63 (m, 1H), 0.91 ( t, J = 7.4 Hz, 3H). LCMS RT = 4.45min., m/z = 356.1 [M + H]+.

[01316] Analytical data for the second elution diastereomer (arbitrarily assigned S,S configuration): SFC RT 1.13 min., 99% ee. 1H NMR (400 MHz, DMSO -d6) δ 8.36 (d, J = 8.0 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.38 - 7.20 (m, 3H), 4.83 (dt, J = 11.5, 7.8 Hz, 1H), 4.55 (dd, J = 11.4, 9.9 Hz, 1H), 4.46 - 4.33 (m, 2H), 3.32 (s, 3H), 2.92 - 2.76 (m, 3H), 2.38 - 2.25(m, 1H), 1.88 (dtd, J = 14 .9, 7.4, 6.1 Hz, 1H), 1.70(dt, J = 14.0, 7.2 Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H) . LCMS RT = 4.47 min., m/z = 356.1 [M + H]+. Example 360

[01317] GH4 METHOD & GH3 METHOD N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -1 -(trifluoromethyl) pyrazole [3,4 -d] pyrimidine -6 -carboxamide Step 1: methyl 1H -pyrazolo[3,4-d]pyrimidine-6-carboxylate

[01318] A high-pressure vessel equipped with a gas inlet was charged successively with 6-chloro-1H-pyrazole [3,4-d] pyrimidine (1000 mg, 6.47 mmol, 1.0 equiv.), 2 - butanol (30 mL), triethylamine (9.0 mL, 64.7 mmol, 10.0 equiv.), and [1,1'-bis(diphenylphosphine) ferrocene] palladium(II) dichloro (483 mg, 0.65 mmol, 0.10 equiv.). The reactor was flushed once with carbon monoxide gas, then pressurized to 9.28 bar (120 psi) carbon monoxide. The reaction was heated at 80°C for 16 h. After this period of time, the gas was released and the mixture was filtered through Celite and concentrated for drying in vacuo. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane) to provide methyl 1H -pyrazolo[3,4-d]pyrimidine-6-carboxylate (470mg, 41% yield) in the form of a yellow solid. Note that the sec-butyl ester initially formed was transesterified to the methyl ester during chromatography. LCMS RT = 0.84 min. [method 2 min.], m/z = 179 [M + H]+. N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -1 -(trifluoromethyl) pyrazole [3,4 -d] pyrimidine -6 -carboxamide

[01319] The remainder of the synthesis was completed using methyl 1H -pyrazolo [3,4 -d] pyrimidine -6 - carboxylate according to the GH3 METHOD Steps 1, 2, 4, and 6. Yield of the final step: 15 %, obtained in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ 9.67 (s, 1H), 9.15 (d, J = 7.7 Hz, 1H), 8.92 (s, 1H), 7.57 - 7 .50 (m, 1H), 7.39 - 7.24 (m, 3H), 4.91 (dt, J = 10.9, 7.9 Hz, 1H), 4.64 - 4.50 (m , 2H), 3.35 (s, 3H). LCMS RT = 4.84 min. [10 min. method], m/z = 407.1 [M + H]+. Example 361

[01320] METHOD GH5 and METHOD GH2 5 -(1-methylimidazol -2 -yl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 - dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 –carboxamide Step 1: ethyl 4 -(methoxy(methyl)amino) -4 - oxobutanoate

[01321] To a solution of N,O-dimethyl hydroxylamine hydrochloride (4444.9 mg, 46.6 mmol, 1.5 equiv.) in dichloromethane (100 mL) cooled to 0°C was added triethylamine (12.7 mL, 91.1 mmol, 3.0 equiv.) followed by ethyl 4-chloro-4-oxo-butanoate (4.329 mL, 5000 mg, 30.4 mmol, 1.0 equiv.). The reaction mixture was stirred and allowed to warm to RT slowly overnight. After this period of time, water (100 mL) was added, the layers separated, and the aqueous layer extracted twice more with dichloromethane (2 x 100 mL). The combined organic layers were washed with 5% citric acid and brine, dried over sodium sulfate, and concentrated for drying in vacuo to provide ethyl 4-[methoxy(methyl)amino]-4-oxo-butanoate (5100 mg, 89% yield) in the form of a yellow oil which was used in the next step without any further purification. Step 2: ethyl 4 -(1 -methyl -1H -imidazol -2 -yl) -4 -oxobutanoate

[01322] To a solution of 1-methylimidazole (2200 mg, 27 mmol, 1.0 equiv.) in tetrahydrofuran (100 mL) cooled to 0°C was added N-butyl lithium (2.5 M in hexanes, 11 mL, 27 mmol, 1.0 equiv.) dropwise. The reaction mixture was subjected to stirring for 30 min. under 0°C, then it was cooled to -78°C. To the mixture was added ethyl 4-[methoxy(methyl)amino]-4-oxo-butanoate (5100 mg, 27 mmol, 1.0 equiv.). The resulting mixture was stirred for 1 h at -78°C, then allowed to warm to RT. After reaching RT, the reaction was terminated with 5% citric acid (150 mL), then extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated for drying in vacuo. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide ethyl 4-(1-methylimidazol-2-yl)-4-oxo-butanoate ( 1200 mg, 21% yield) as a yellow oil. 5 -(1-methylimidazol -2 -yl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 - dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01323] The title compound was prepared from ethyl 4 -(1-methylimidazol-2-yl)-4-oxo-butanoate and dihydrobenzo [b][1,4] oxazepin -4(5H)-one according with the GH2 METHOD. Final stage yield: 53%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.39 (dd, J = 8.0, 6.7 Hz, 1H), 7.54 - 7.45(m, 1H), 7.36 - 7, 18 (m, 4H), 6.84 (d, J = 1.1 Hz, 1H), 6.91 - 6.80 (m, 1H), 4.80 (dt, J = 11.4, 7, 8 Hz, 1H), 4.55 (ddd, J = 11.7, 9.9, 2.2 Hz, 1H), 4.39 (ddd, J = 9.9, 7.7, 4.4 Hz , 1H), 3.79 (d, J = 0.8 Hz, 3H), 3.31 (s, 3H), 3.19 - 2.95 (m, 4H). LCMS RT = 2.70min. [10 min. method], m/z = 408.1 [M + H]+. Example 364

[01324] CS1 Method 1 -benzyl -N -[(1R,4S,7S) -8,8 -difluoro -6 - methyl -5 -oxo -6 -azabicyclo [6,1,0] octan -4 -yl] -1,2, 4 - triazole -3 -carboxamide Step 1: 2 -((4S) -8,8 -difluoro -2 -methyl -3 - oxo -2 -azabicyclo[6,1,0] octan -4 -yl) isoindoline -1,3 - dione

[01325] A solution of sodium chlorodifluoro acetate (1.42 g, 9.25 mmol) in diglyme (6.9 mL) was added dropwise to a refluxing solution of 2 - [(3 S) -1 - methyl -2 -oxo -4,5 -dihydro -3H -azepin -3 -yl] isoindoline -1,3 -dione (0.250 g, 0.925 mmol) in diglyme (10 mL) for 25 minutes. After addition, the reaction was allowed to stir for an additional 10 minutes under reflux. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica, 0% to 70% isopropyl acetate - heptane) to give 2-[(4S) -8,8 -difluoro -6 -methyl -5 - oxo -6 -azabicyclo [6,1,0] octan -4 -yl] isoindoline -1,3 - dione (0.270g, 0.843 mmol, 91% yield) in the form of an inseparable ~6.8:1 mixture of diastereomers. 1H NMR (400 MHz, Chloroform -d) δ (main isomer) 7.90 - 7.81 (m, 2H), 7.75 - 7.70(m, 2H), 6.44 (dd, J = 11 .6, 8.0 Hz, 1H), 3.66 -3.30 (m, 1H), 3.26 - 3.11 (m, 1H), 3.02 (s, 3H), 2.25 - 2.15 (m, 1H), 2.04 - 1.90 (m, 2H), 1.85 - 1.72 (m, 1H). LRMS RT = 1.29 min., m/z = 321 [M = H]+. Step 2: 1 -benzyl -N -[(1R,4S,7S) -8,8 -difluoro -6 -methyl -5 -oxo -6 -azabicyclo [6,1,0] octan -4 -yl] - 1 ,2,4-triazole-3-carboxamide

[01326] Hydrazine (0.087 mL, 2.72 mmol) was added to a solution of 2-[(4S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[6,1,0] octan-4-yl]isoindoline-1,3-dione e (~6.8:1 dr, 0.290 g, 0.905 mmol) in ethanol (9.1 mL). The reaction was heated under 80°C for 2 h. After cooling to room temperature, the reaction was filtered through a short pad of celite using ethanol. The filtrate was evaporated which provided (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[6,1,0]octan-5-one (88.9 mg, 0.467 mmol, 51 .6% yield). The crude residue was used in the next step without further purification.

[01327] PYAOP (0.138 g, 0.254 mmol) was added to a solution of (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[6,1,0]octan-5-one (44 mg, 0.231 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (58 mg, 0.289 mmol), and N,N-diisopropylethylamine (0.120 mL, 0.694 mmol), in N,N -dimethylformamide (2.3 mL). The reaction was allowed to stir at room temperature for 18 h before being concentrated under reduced pressure. The crude residue was purified by preparative HPLC (see below) to provide 1-benzyl -N -((1S,4S,7R) -8,8 -difluoro -2 -methyl -3 -oxo -2 - azabicyclo[6,1,0]octan-4-yl)-1H-1,2,4-triazole-3-carboxamide (56.7 mg, 0.151 mmol, 65% yield).

[01328] 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 7.43 - 7.27 (m, 5H ), 6.48 (s, 2H), 4.43 - 4.33 (m, 1H), 3.27 - 3.14 (m, 1H), 2.80 (s, 3H), 2.55 - 2.43 (m, 1H), 2.10 - 2.00 (m, 3H), 1.30 - 1.10 (m, 1H). LRMS RT = 3.90 min., m/z = 376.1 [M + H]+.

[01329] Information about the preparation HPLC: Column: m, 110A (50 x 30 mm)QPhenomenex Gemini - NX C18 5 Mobile phase: 0.1% Ammonium hydroxide in water (A) / Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 56 bar (800 psi) Flow rate: 60 mL/min. Column temperature: 25 °C Wavelength: 210 nm Example 365

[01330] CS2 Method 1 -benzyl -N -(2 -isopropenyl -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 1,2 ,4-triazole-3-carboxamide Step 1: 2 -bromo -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[01331] Iodotrimethyl silane (7.10 g, 34 mmol) was added to a solution of 2-bromo-4-methyl-7,8-dihydro-6H-pyrazole [1,5-a] [1,3] diazepine -5-one (1.4 g, 6.7 mmol) and N,N,N',N'-tetramethylethylene diamine (6.2 mL, 34 mmol) in dichloromethane (57 mL) under -15°C. After 1h 30 minutes, iodine (4.4 g, 17 mmol) was added and the reaction was allowed to stir for an additional 2 h. Saturated aqueous sodium sulfate and saturated aqueous sodium bicarbonate were added to the reaction. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the residue was purified by column chromatography (silica, 0% to 60% isopropyl heptane acetate) to give 2-bromo-6-iodo-4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (1.56 g, 4.22 mmol, 74% yield).

[01332] 1H NMR (400.33 MHz, Chloroform -d) δ 6.13 (s, 1H), 4.65 (ddd, J = 8.6, 7.4, 3.4 Hz, 1H), 4 .36 - 4.14 (m, 2H), 3.33 (s, 3H), 2.95 (ddt, J = 14.4, 8.7, 7.4 Hz, 1H), 2.77 (dddd , J = 14.4, 8.6, 6.6, 6.0 Hz, 1H). Step 2: tert -butyl (2 -bromo -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) carbamate

[01333] Sodium azide (0.319 g, 4.87 mmol) was added to a solution of 2-bromo-6-iodo-4-methyl-7,8-dihydro-6H-pyrazole [1,5-a] [ 1.3] diazepin -5 -one (1.50 g, 4.05 mmol) in N,N -dimethylformamide (16.2 mL) under room temperature. The reaction was allowed to stir at RT for 1h. The solvent was removed under vacuum and the residue was subjected to the next step immediately without any further purification. Triphenylphosphine (2.15 g, 8.11 mmol) was added to a solution of 6-azide-2-bromo-4-methyl-7,8-dihydro-6H-pyrazole[1.5-a][1.3 ] diazepin-5-one in tetrahydrofuran (40.5 mL) and water (2.0 mL). The reaction was heated at 55°C for 1 h. After cooling to rt the volatiles were removed under vacuum. The residue was dissolved in dichloromethane (40.5 mL), then triethylamine (2.85 mL, 20.3 mmol) and di-tert-butyl dicarbonate (2.23 g, 10.1 mmol) were added sequentially. After 1 h, the volatiles were removed under vacuum and the residue was purified by column chromatography (silica, 20% to 100% isopropyl acetate - heptane) to give tert -butyl N -(2-bromo-4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl)carbamate (1.29 g, 3.59 mmol, 89% yield ). LRMS RT = 1.34 min., m/z = 304 [M - C4H9 + H ]+. Step 3, tert -butyl (2-acetyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) carbamate

[01334] Bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.033 mmol) was added to a solution of tert -butyl N -(2-bromo-4-methyl-5-oxo-7,8-dihydro- 6H-pyrazole[1,5-a][1,3]diazepin-6-yl)carbamate (0.20 g, 0.56 mmol) and Tributyl(1-ethoxyvinyl)tin (0.19 mL, 0.56 mmol) in 1,4-dioxane (10 mL). The glass flask was sealed with a yellow lid and heated at 100°C for 12 h. Silica gel was added and the reaction was evaporated under reduced pressure. The crude material was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate - heptane) to provide tert -butyl N -(2-acetyl-4-methyl-5-oxo-7, 8-dihydro-6H-pyrazole[1,5-a][1,3]diazepin-6-yl) carbamate (0.120 g, 0.372 mmol, 100 mass %, 67% yield).

[01335] 1H NMR (400.33 MHz, Chloroform -d) δ 6.58 (s, 1H), 6.43 (d, J = 7.7 Hz, 1H), 4.46 (dd, J = 14 .4, 8.2 Hz, 1H), 4.33 - 4.03 (m, 2H), 3.35 (s, 3H), 3.06 - 2.88 (m, 1H), 2.56 ( s, 3H), 2.02 (s, 1H), 1.41 (s, 9H). LRMS RT = 1.34 min., m/z = 267 [M - C4H9 + H ]+. Step 4 1 -benzyl -N -(2 -isopropenyl -4 -methyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 ,2,4-triazole-3-carboxamide

[01336] Methylmagnesium bromide ((1.4 mol/L) in THF:toluene (1:3), 1.60 mL, 2.23 mmol) was added to a solution of tert -butyl N -(2-acetyl -4-methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) carbamate (0.120 g, 0.372 mmol) in tetrahydrofuran (3.7 mL) under -10°C. After 2 h, the reaction was terminated with saturated aqueous ammonium chloride. The aqueous layer was extracted with isopropyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, concentrated, and the residue was subjected to the next step without further purification.

[01337] Trifluoroacetic acid (1.0 mL, 13 mmol, 99% by mass) was added to a solution of tert-butyl N -[2-(1-hydroxy-1-methyl-ethyl)-4-methyl- Crude 5-oxo-7,8-dihydro-6H-pyrazole[1,5-a][1,3]diazepin-6-yl]carbamate (50 mg 0.148 mmol) in dichloromethane (2.0 mL) under 0 °C. After 10 min. the reaction was heated to rt and stirred for an additional 30 min. The solvent was removed under reduced pressure and the residue was subjected to the next reaction without further purification.

[01338] PYAOP (88.3 mg, 0.163 mmol) was added to a solution of the crude residue, 1-benzyl-1,2,4-triazole-3-carboxylic acid (37.5 mg, 0.185 mmol), and N,N - diisopropyl ethylamine (0.08 mL, 0.443 mmol), in N,N - dimethylformamide (1.5 mL, 19.1 mmol). The reaction was allowed to stir under RT for 18h. The reaction was concentrated and the residue was purified by preparative HPLC (see below) to provide 1-benzyl-N-(2-isopropenyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole [1,5-a] [1,3] diazepin -6 -yl) -1,2,4 - triazole -3 -carboxamide (25mg, 0.0617 mmol, 41.7% yield)

[01339] 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.9 Hz, 1H), 7.47 - 7.18 (m , 5H), 6.59 (s, 1H), 6.56 - 6.43 (m, 3H), 6.06 (t, J = 1.7 Hz, 1H), 4.42 - 4.28 ( m, 2H), 4.28 - 4.09 (m, 1H), 3.25(s, 3H), 2.72 - 2.53 (m, 1H), 2.38 (dd, J = 12, 5, 6.4 Hz, 1H), 2.04 (s, 3H). LRMS RT = 4.47 min., m/z = 406.2 [M + H]+.

[01340] Preparation HPLC information: Column: m, 110A (50 x 30 mm)QPhenomenex Gemini - NX C18 5 Mobile phase: 0.1% Ammonium hydroxide in water (A) / Acetonitrile (B) Elution program Gradient : 20 -60B Pressure: 56 bar (800 psi) Flow rate: 20 mL/min. Column temperature: 25 °C Wavelength: 254 nm Example 366

[01341] CS3 Method (S) -N -(2 -acetyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -benzyl -1H -1,2,4 -triazole -3 -carboxamide Step 1: (S) -N -(2 -acetyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -benzyl -1H -1,2,4 -triazole -3 -carboxamide

[01342] Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl N -[2-(1-ethoxyvinyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole [1.5 -a] [1,3] diazepin -6 -yl]carbamate (0.550 g, 1.57 mmol) in dichloromethane (20 mL) under rt. After 2 h the solvent was removed under reduced pressure and the residue was subjected to the next reaction without any further purification.

[01343] N,N-diisopropyl ethylamine (0.82, 4.71 mmol) was added to a solution of the crude residue, 1-benzyl-1,2,4-triazole-3-carboxylic acid (0.319 g, 1 .57 mmol), and PYAOP (0.852 g, 1.57 mmol) in N,N-dimethylformamide (16.7 mL) under rt. After 3 h the solvent was removed under reduced pressure. A portion of the crude residue (200 mg) was purified by preparative HPLC (see below) to provide (S)-N-(2-acetyl-4-methyl-5-oxo-5,6,7, 8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -benzyl -1H - 1,2,4 -triazole -3 -carboxamide (16.7 mg, 0 .0385 mmol).

[01344] 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 7.43 - 7.26 (m , 5H), 6.83 (s, 1H), 6.48 (s, 2H), 4.48 (dd, J = 14.5, 7.9 Hz, 1H), 4.41 - 4.26 ( m, 2H), 3.26 (s, 3H), 2.72 - 2.57 (m, 1H), 2.48 (s, 3H), 2.52 - 2.40 (m, 1H). LRMS RT = 3.84 min., m/z = 408.2 [M + H]+.

[01345] Preparation HPLC information: Column: m (150 x 21.2 mm) DPhenomenex Cellulose - 3.5 Mobile phase: Carbon dioxide (A) / 0.1% NH4OH in methanol (B) Elution program Gradient: Isocratic @ 35% Pressure: 100 bar Flow rate: 70mL/min. Column temperature: 40 °C Wavelength: 220 nm Examples 367 and 368

[01346] CS4 Method 1 -benzyl -N -((6S) -2 -(1 -hydroxyethyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: 1-benzyl -N -((6S) -2 -(1-hydroxyethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01347] Sodium borohydride (56.9 mg, 1.47 mmol) was added to a solution of N -(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole [ 1,5-a][1,3]diazepin-6-yl)-1-benzyl-1,2,4-triazole-3-carboxamide (0.300 g (raw), 0.736 mmol) in methanol (4.1 mL) under 0°C. After 5 min, saturated aqueous ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (5 x 40 mL). The combined organic layers were washed with brine, dried with sodium sulfate, concentrated, and the residue was purified by prep HPLC (see below) to give 1 - benzyl - N - ((6S) - 2 -(1-hydroxyethyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H - 1,2,4-triazole-3-carboxamide (Peak 1, 9.4 mg, 0.023 mmol, 3.1% yield) and 1-benzyl-N-((6S)-2-(1-hydroxyethyl)- 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 - triazole - 3-carboxamide (Peak 2, 9.1 mg, 0.022 mmol, 3.0% yield).

[01348] Data for Example 367: 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.43 - 7.27 (m, 5H), 6.26 (s, 1H), 6.48 (s, 2H), 6.08 (d, J = 6.1 Hz, 1H), 4.69 - 4, 58 (m, 1H), 4.38 - 4.24 (m, 2H), 4.20 - 4.07 (m, 1H), 3.23 (s, 3H), 2.64 - 2.45( m, 1H), 2.39 - 2.29 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H). LRMS RT = 3.44 min., m/z = 410.2 [M + H]+.

[01346] Data for Example 368: 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 7.43 - 7.26 (m, 5H), 6.27 (s, 1H), 6.48 (s, 2H), 6.16 (d, J = 4.5 Hz, 1H), 4.72 - 4, 61 (m, 1H), 4.40 - 4.23 (m, 2H), 4.21 - 4.07 (m, 1H), 3.24 (s, 3H), 2.64 - 2.50 ( m, 1H), 2.39 - 2.29 (m, 1H), 1.34 (d, J = 6.5 Hz, 3H). LRMS RT = 3.48 min., m/z = 410.2 [M + H]+.

[01347] Preparation HPLC Information: Step 1: Column: Quiralcel OX, 5 m (D150 x 21.2 mm) Mobile phase: Carbon dioxide (A) / 0.1% NH4OH in methanol (B) Elution program Gradient: Isocratic @ 50% Pressure: 100 bar Flow rate: 70mL/min. Column temperature: 40 °C Wavelength: 220 nm Step 2: Column: Chiralpak AD, 5 m (Ü150 x 21.2 mm) Mobile phase: Carbon dioxide (A) / 0.1% NH4OH in methanol (B ) Elution program Gradient: Isocratic @ 50% Pressure: 100 bar Flow rate: 70mL/min. Column temperature: 40 °C Wavelength: 220 nm Examples 369 and 370

[01348] CS5 Method 1 -benzyl -N -[2 -(1 -fluoro -1 -methyl -ethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[2 -(1 -fluoro -1 -methyl -ethyl) -4 -methyl -5 -oxo -7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide Step 1: 1 -benzyl -N -[2 -(1 -fluoro -1 -methyl - ethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1 ,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[2 -(1 -fluoro -1 -methyl -ethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01349] Bis(2-methoxyethyl) aminosulfur trifluoride (63.3 mg, 0.283 mmol) was added to a solution of 1-benzyl-N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide (30 mg, 0.071 mmol ) in dichloromethane (0.71 mL) under 0°C. After 10 min. the reaction was carefully terminated with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the residue was purified by prep HPLC (see later) to give 1 - benzyl -N - [2 - (1 -fluoro -1 - methyl -ethyl) -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, 10.9 mg, 0.0256 mmol, 36.2% yield) and 1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, 11.9 mg , 0.028 mmol, 39.5% yield).

[01350] Data for G03074389: Peak 1: H NMR (400.33MHz, DMSO -d6) δ 8.82 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.43 - 7.27 (m, 5H), 6.48 (s, 1H), 6.48 (s, 2H), 4.40 - 4.24 (m, 2H), 4.25 - 4.13 (m , 1H), 3.25(s, 3H), 2.66 - 2.54 (m, 1H), 2.44 - 2.32 (m, 1H), 1.71 (d, 7.7 Hz, 3H), 1.66 (d, 7.7 Hz, 3H). LRMS RT = 4.47 min., m/z = 426.3 [M + H]+.

[01351] Data for G03074390: Peak 2: 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7, 43 - 7.27 (m, 5H), 6.48 (s, 1H), 6.48 (s, 2H), 4.40 - 4.27 (m, 2H), 4.25 - 4.13 ( m, 1H), 3.25(s, 3H), 2.66 - 2.53 (m, 1H), 2.44 - 2.32 (m, 1H), 1.71 (d, 7.7 Hz , 3H), 1.66 (d, 7.7 Hz, 3H). LRMS RT = 4.47 min., m/z = 426.3 [M + H]+. Column: Phenomenex Cellulose -3.5 mD, (150 x 21.2 mm) Mobile phase: Carbon dioxide (A) / Pure methanol (B) Elution program Gradient: Isocratic @ 40% Pressure: 100 bar Flow rate: 70mL/min. Column temperature: 40 °C Wavelength: 220 nm Example 371

[01352] CS6 Method 1 -benzyl -N -[2 -(1,1 -difluoroethyl) -4 -methyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl]-1,2,4-triazole-3-carboxamide Step 1: 1-benzyl-N-[2-(1,1-difluoroethyl)-4-methyl-5-oxo-7,8-dihydro-6H- pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01353] Diethylamino sulfur trifluoride (2.73 mL, 19.64 mmol) was added to a solution of N -(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole [1 ,5-a][1,3] diazepin -6 -yl) -1 -benzyl -1,2,4 -triazole -3 -carboxamide (0.400 g (raw), 0.982 mmol) in dichloromethane (2.0 mL ). The reaction was heated under 40°C for 8 h. After that, the reaction was carefully poured into a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with isopropyl acetate (4 x 50 mL). The combined organic layers were washed with brine, dried with concentrated sodium sulfate, and the residue was purified by prep HPLC (see below) to give 1-benzyl-N-[2-(1 ,1 - difluoroethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole - 3 - carboxamide (16.8 mg, 0.039 mmol, 3.98% yield).

[01354] 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 7.43 - 7.26 (m , 5H), 6.65 (s, 1H), 6.48 (s, 2H), 4.45- 4.19 (m, 3H), 3.26 (s, 3H), 2.71 - 2, 54 (m, 1H), 2.51 - 2.36 (m, 1H), 2.00 (t, J = 18.8 Hz, 3H). LRMS RT = 4.55 min., m/z = 430.2 [M + H]+. Column: Es Industries Pyridyl Amide (150 x 21.2 mm) Mobile phase: Carbon dioxide (A) / pure methanol (B) Elution program Gradient: Isocratic @ 20% Pressure: 100 bar Flow rate: 70mL/min. Column temperature: 40 °C Wavelength: 220 nm Example 372

[01355] CS7 Method 1 -benzyl -N -[2 -(1-hydroxy -1 -methyl -ethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazol -3 -carboxamide Step 1: 1 -benzyl -N -[2 -(1-hydroxy -1 -methyl -ethyl) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01356] Methylmagnesium bromide ((1.4 mol/L) in THF: Toluene (1:3), 2.5 mL, 3.44 mmol) was added to a solution of N -(2-acetyl -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a] [1,3] diazepin -6 -yl) -1 -benzyl -1,2,4 -triazole -3 -carboxamide ( 0.350 g (crude), 0.859 mmol) in tetrahydrofuran (4.3 mL) under -50°C. After 45 min. the reaction was terminated with methanol. The solvent was removed under reduced pressure and the residue was purified by prep HPLC (see later) to give 1-benzyl-N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide (33.2 mg, 0.0784 mmol, 9.13% yield).

[01357] 1H NMR (400.33 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.52 (d, J = 7.9 Hz, 1H), 7.43 - 7.25 (m , 5H), 6.28 (s, 1H), 6.48 (s, 2H), 4.97 (s, 1H), 4.39 - 4.25(m, 2H), 4.20 - 4, 07 (m, 1H), 3.23 (s, 3H), 2.60 (ddd, J = 20.6, 7.8, 6.2 Hz, 1H), 2.34 (td, J = 12, 6, 6.6Hz, 1H), 1.45(s, 3H), 1.40(s, 3H). LRMS RT = 3.56 min., m/z = 406.2 [M + H]+. Column: Phenomenex Gemini -NX C18 5 mD, 110A (50 x 30 mm) Mobile phase: 0.1 % Ammonium hydroxide in water (A) / Acetonitrile (B) Elution program Gradient: 5 -50B Pressure: 56 bar ( 800 psi) Flow rate: 60 mL/min. Column temperature: 25 °C Wavelength: 220 nm Example 373

[01358] GZ1 METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -phenyl -[1,2,4 ] triazolo [1,5 -a] pyridine -2 –carboxamide Step 1: 5 -phenyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01359] A mixture of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (580 mg, 2.70 mmol), phenyl boronic acid (496 mg, 4.07 mmol ), 2 M sodium carbonate in water (2.72 ml, 5 mmol) in acetonitrile (9.4 ml) was degassed, and bis(triphenylphosphine) palladium(II) chloride (190 mg, 0.27 mmol) was added under nitrogen. The vial was capped and heated in a microwave to 130°C for 25 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine ( 389 mg, 68%) as a bronze-colored solid, which was used in the next step without further purification. LCMS RT = 1.42 min., m/z = 211 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.42 min., ESI+ found [M+H] = 211, Step 2: 2 -iodine -5 -phenyl -[1,2,4] triazole [1,5 -a] pyridine

[01360] To a solution of 5 -phenyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (1050 mg, 4.99 mmol) and p - toluene sulfonic acid (3.65 g, 19.20 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (2.70 g, 16.00 mmol) and sodium nitrite (865 mg, 12.50 mmol) in water (5 mL) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 2 - iodine -5 - phenyl - [1,2,4] triazole [1, 5 -a] pyridine (780 mg, 49%) as a light yellow solid. LCMS RT = 2.27 min., m/z = 321.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 2.27 min., ESI+ found [M+H] = 321.9. Step 3: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -phenyl - [1, 2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01361] Palladium (II) acetate (6.0 mg, 0.025 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (21.6 mg, 0.037 mmol), 2-iodine-5-phenyl -[1,2,4] triazolo [1,5 - a] pyridine (80 mg, 0.25 mmol), (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepine -4-one (47.9 mg, 0.25 mmol) was added to a screw-capped vial. Nitrogen was then purged through a reaction flask for 15 min. The solids were dissolved in toluene (5 mL), and triethylamine (0.226 mL, 1.62 mmol) was added. A glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask with the carbon monoxide balloon was placed in a heating block at 80°C and left stirring for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 100% isopropyl acetate in heptane) to provide (S)-N-(5-methyl-4-oxo-2.3, 4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 - phenyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (98.0 mg , 95% yield) as a yellow solid: 1H NMR (400 MHz, DMSO - d6) δ 8.79 (d, J = 7.8 Hz, 1H), 8.03 - 7.91 ( m, 3H), 7.88 (m, 1H), 7.65 - 7.55 (m, 3H), 7.50 (ddd, J = 14.5, 7.3, 1.7 Hz, 2H) , 7.41 - 7.22 (m, 3H), 4.90 (dt, J = 11.4, 7.8 Hz, 1H), 4.63 (dd, J = 11.5, 9.9 Hz , 1H), 4.48 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LCMS RT = 6.10 min., m/z = 414.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.10 min., ESI+ found [M+H] = 414.1. Example 374

[01362] GZ10 METHOD (S) -5 -ethyl -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide Step 1: 5 -ethyl -2 -iodine -[1,2,4] triazole [1,5 -a] pyridine

[01363] To a solution of 5-ethyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (800 mg, 4.93 mmol) and p - toluene sulfonic acid (3.60 g, 18.94 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (2.70 g, 16.23 mmol) and sodium nitrite (854 mg, 12.38 mmol) in water (5 mL) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2 x 120 mL) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 5-ethyl-2-iodo-[1,2,4]triazole[1 ,5-a] pyridine (908 mg, 67%) as a light yellow solid. LC-MS RT = 1.80 min., m/z = 273.9 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.80 min., ESI+ found [M+H] = 273.9. Step 2: (S) -5 -ethyl -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01364] Palladium (II) acetate (8.0 mg, 0.037 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (31.8 mg, 0.055 mmol), 5-ethyl-2-iodine -[1,2,4] triazolo [1,5 - a] pyridine (100 mg, 0.37 mmol), (S) -6 -amino -4 -methyl - 7,8 -dihydro -4H -pyrazole [1 .5 -a] [1.3] diazepin -5(6H) -one (66.0 mg, 0.37 mmol) were added to a screw-capped vial. Nitrogen was then purged through the reaction flask for 15 min. The solids were dissolved in toluene (5 mL), and triethylamine (0.33 mL, 2.38 mmol) was added. A glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left stirring for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% dichloromethane in methanol) to provide (S)-5-ethyl-N-(4-methyl-5-oxo-5, 6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (80.0 mg, 62% yield) as a bronze-colored solid: 1H NMR (400 MHz, DMSO - d6) δ 8.87 (d, J = 7.8 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.20 (dq, J = 7.3, 1.2 Hz, 1H), 6.37 ( d, J = 2.0 Hz, 1H), 4.46 - 4.33 (m, 2H), 4.23 (ddd, J = 14.5, 12.6, 6.6 Hz, 1H), 3 .45 - 3.23 (m, 3H), 3.25 - 3.11 (m, 2H), 2.67 (tt, J = 12.9, 8.1 Hz, 1H), 2.44 (td , J = 12.3, 6.5 Hz, 1H), 1.37 (t, J = 7.5 Hz, 3H). LC-MS RT = 3.51 min., m/z = 354.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.51 min., ESI+ found [M+H] = 354.2. Example 375

[01365] (S) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazole [1,5 -a][1,3] diazepin -5(6H) -one according to Method GZ1. The residue was purified using RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid). Final step yield: 52.8 mg, 42%: 1H NMR (400 MHz, DMSO -d6) δ 8.89 (d, J = 7.7 Hz, 1H), 8.04 - 7.83 (m, 4H), 7.65 - 7.54 (m, 3H), 7.53 - 7.44 (m, 2H), 6.36 (d, J = 2.0 Hz, 1H), 4.45- 4 .31 (m, 2H), 4.22 (ddd, J = 14.5, 12.6, 6.6 Hz, 1H), 3.39 - 3.19 (m, 3H), 2.76 - 2 .59 (m, 1H), 2.42 (m, 1H). LC-MS RT = 4.12 min., m/z = 402.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.12 min., ESI+ found [M+H] = 402.1. Example 376

[01366] GZ2 METHOD N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -phenyl -5,6,7, 8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01367] To a solution of (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - phenyl -[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (40 mg, 0.097 mmol) in acetic acid (1 mL) was added platinum(iv) oxide (3 mg, 0.0096 mmol, 0.10 equiv.). The reaction mixture was stirred under a balloon of hydrogen gas for 16 h at RT, then filtered through Celite and concentrated to drying in vacuo. The residue was purified by prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to give N -((S) -5 -methyl -4 -oxo -2.3 ,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -phenyl -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a ] pyridine -2 - carboxamide (16 mg, 40%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 8.39 (t, J = 8.0 Hz, 1H), 7 .49 (dt, J = 7.5, 1.7 Hz, 1H), 7.40 - 7.18 (m, 6H), 7.09 - 7.01 (m, 2H), 6.57 (t , J = 6.8 Hz, 1H), 4.80 (dtd, J = 11.6, 7.8, 2.3 Hz, 1H), 4.57 (ddd, J = 11.5, 9.9 , 8.0 Hz, 1H), 4.38 (dd, J = 9.9, 7.7 Hz, 1H), 3.44 - 3.17 (m, 3H), 3.01 (m, 2H) , 2.45- 2.32 (m, 1H), 2.10 - 1.99 (m, 1H), 1.92 - 1.82 (m, 2H). LC-MS RT = 4.87 min., m/z = 418.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.87 min., ESI+ found [M+H] = 418.2. Example 377

[01368] GZ3 METHOD 5 -cyclohexyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6,7, 8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01369] To a solution of (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - phenyl -[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (40 mg, 0.097 mmol) in acetic acid (1 mL) was added platinum(iv) oxide (3 mg, 0.0096 mmol, 0.10 equiv.). The reaction mixture was stirred under a hydrogen gas balloon for 72 h at RT, then filtered through Celite and concentrated to drying in vacuo. The residue was purified by prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to give N -((S) -5 -methyl -4 -oxo -2.3 ,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -phenyl -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a ] pyridine -2 - carboxamide (10 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO - d 6) δ 8.37 (m, 1H), 7.55 - 7.47 (m, 1H), 7.37 - 7.20 (m, 3H), 4.83 (dtd, J = 11.2, 7.9, 3.1 Hz, 1H), 4.57 (ddd, J = 17.1, 11.5, 9.8 Hz, 1H), 4.42 (dd , J = 9.9, 7.7 Hz, 1H), 4.14 (dt, J = 9.0, 4.3 Hz, 1H), 3.42 - 3.23 (m, 3H), 2, 94 - 2.72 (m, 2H), 2.26 (ms, 1H), 2.00 (m, 2H), 1.90 - 1.57 (m, 6H), 1.32 - 1.21 ( m, 1H), 1.11 (m, 5H). LC-MS RT = 6.60 min., m/z = 424.2 (M+H) + . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.60 min., ESI+ found [M+H] = 424.2. Example 378 (S) -5 -ethyl -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -[1,2,4 ] triazolo [1,5 -a] pyridine -2 -carboxamide

[01370] (S) -5 -ethyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -[1, 2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared correspondingly from (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one , and 5 -ethyl -2 -iodine - [1,2,4] triazolo [1,5 -a] pyridine according to Method GZ10. The residue was purified using RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid). Yield of final step (35 mg, 26% yield) as a white solid: 1H NMR (400 MHz, DMSO - d 6) δ8.78(d, J = 7.9 Hz, 1H), 7 .86 - 7.71 (m, 2H), 7.53 (dd, J = 7.5, 2.0 Hz, 1H), 7.39 - 7.17 (m, 4H), 4.91 (dt , J = 11.5, 7.8 Hz, 1H), 4.64 (dd, J = 11.5, 9.9 Hz, 1H), 4.49 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H), 3.32 - 3.12 (m, 2H), 1.36 (t, J = 7.5 Hz, 3H). LC-MS RT = 4.57 min., m/z = 366.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.57 min., ESI+ found [M+H] = 366.1. Example 379 5 -ethyl -N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01371] 5-ethyl -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -5 -ethyl -N -( 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -[1,2,4] triazole [1 ,5-a] pyridine-2-carboxamide according to Method GZ2 to provide the final product (20 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.43 (dd, J = 10.8, 7.9 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 4.42 - 4.12 (m, 3H), 3.25(d, J = 1.9 Hz, 3H), 2.94 - 2.74 ( m, 2H), 2.67 - 2.52 (m, 1H), 2.37 (dt, J = 13.3, 8.2 Hz, 1H), 2.20 - 1.91 (m, 3H) , 1.87 - 1.65 (m, 4H), 1.24 (s, 2H), 0.91 (t, J = 7.4 Hz, 3H). LC-MS RT = 3.50 min., m/z = 358.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.50 min., ESI+ found [M+H] = 358.2. Example 380 N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -phenyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01372] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-N-(4-methyl- 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -5 -phenyl -[1,2,4] triazole [1 .5 - a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) to provide the final product (23 mg, 28%) as a white solid . 1H NMR (400 MHz, DMSO -d6) δ 8.47 (m, 1H), 7.48 (s, 1H), 7.40 - 7.26 (m, 3H), 7.09 - 7.02 ( m, 2H), 6.33 (t, J = 1.8 Hz, 1H), 6.57 (t, J = 6.8 Hz, 1H), 4.26 (m, 3H), 3.23 ( s, 3H), 3.11 - 2.87 (m, 2H), 2.57 (ddt, J = 12.5, 8.2, 4.3 Hz, 1H), 2.37 (tq, J = 11.8, 6.6 Hz, 2H), 2.05 (ddd, J = 14.6, 7.5, 4.8 Hz, 1H), 1.86 (p, J = 6.4 Hz, 2H ). LC-MS RT = 3.95 min., m/z = 406.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.95 min., ESI+ found [M+H] = 406.2. Example 381 5-cyclohexyl -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01373] 5 -cyclohexiaccordinl -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -N -(4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -5 -phenyl -[1,2,4] triazole [1 ,5-a] pyridine-2-carboxamide according to Method GZ3, The residue was purified by preparation RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to provide the final product (6.1 mg, 97%) as a white solid. 1H NMR (400 MHz, DMSO - d6) δ 8.55 - 8.35 (m, 1H), 7.50 (d, J = 1.9 Hz, 1H), 6.35 (d, J = 2, 2Hz, 1H), 4.41 - 4.31 (m, 1H), 4.26 - 4.10 (m, 2H), 3.45(s, 3H), 2.94 - 2.84 (m , 1H), 2.00 (m, 2H), 1.76 (t, J = 6.2 Hz, 2H), 1.68 (s, 10H), 1.43 (m, 2H), 1.24 (s, 4H), 1.12 (m, 4H). LC-MS RT = 4.71 min., m/z = 412.2 (M+H) + . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.71 min., ESI+ found [M+H] = 412.2. Example 382 (S) -5 -(2,5 -difluorophenyl) -N -(4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01374] (S) -5 -(2,5 -difluorophenyl) -N -(4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide was correspondingly prepared from (S) -6 -amino -4 -methyl - 7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one, and 5 -(2,5 -difluorophenyl) -2 -iodo -[1,2, 4] triazolo [1,5 -a] pyridine according to Method GZ1. The residue was purified using RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid). Final step yield: 59 mg, 48%. 1H NMR (400 MHz, DMSO -d6) δ 8.89 (d, J = 7.7 Hz, 1H), 8.05 (dd, J = 9.0, 1.2 Hz, 1H), 7.90 (dd, J = 9.0, 7.1 Hz, 1H), 7.71 (tt, J = 6.1, 2.1 Hz, 1H), 7.59 - 7.47 (m, 4H), 6.35 (d, J = 2.0 Hz, 1H), 4.44 - 4.29 (m, 2H), 4.21 (ddd, J = 14.4, 12.6, 6.6 Hz, 1H), 3.26 (s, 3H), 2.76 - 2.57 (m, 1H), 2.42 (m, 1H). LC MS RT = 4.26 min., m/z = 438.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.26 min., ESI+ found [M+H] = 438.1. Example 383 5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6,7, 8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01375] 5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6 ,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide was prepared from (S) -5 -ethyl -N -(5 - methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to the Method GZ2 to provide the final product (11.5 mg, 44%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.36 (t, J = 7.5 Hz, 1H), 7.50 (dd, J = 7.5, 1.9 Hz, 1H), 7.37 - 7.20 (m, 3H), 4.83 (dtd, J = 11.5, 7.8, 2.0 Hz, 1H), 4.56 (dt, J = 11.4, 9.7 Hz , 1H), 4.41 (ddd, J = 9.5, 7.7, 1.3 Hz, 1H), 4.17 (d, J = 8.5 Hz, 1H), 2.95 - 2, 76 (m, 2H), 2.18 - 1.91 (m, 3H), 1.86 - 1.65 (m, 3H), 0.91 (td, J = 7.5, 1.4 Hz, 3H). LC-MS RT = 4.52 min., m/z = 370.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.52 min., ESI+ found [M+H] = 370.2. Examples 384 and 385 (S) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (R) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1:1)

[01376] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-N-(4-methyl- 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -5 -phenyl -[1,2,4] triazole [1 .5 - a] pyridine -2 -carboxamide according to Method GZ2. The crude residue was further purified by means of chiral SFC (Chiralpak AD 157 x21.2 mm, 5 µm, elution 30% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (S)-N-(( S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -5 -phenyl -5,6 ,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (7.1 mg, 20%) and (R) -N -((S) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl) -5 -phenyl -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (7.5 mg, 21%) as white solids:

[01377] Analytical data for the first elution diastereomer (arbitrarily assigned R,S configuration): SFC RT (AD column, elution 20% isocratic methanol with carbon dioxide, method 2.5 min.): 0.94 min. , 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.46 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7, 40 - 7.26 (m, 3H), 7.09 - 7.01 (m, 2H), 6.33 (d, J = 2.0 Hz, 1H), 6.57 (t, J = 6, 8 Hz, 1H), 4.41 - 4.11 (m, 3H), 3.24 (s, 3H), 3.10 - 2.90 (m, 2H), 2.57 (ddd, J = 12 .9, 8.0, 6.0 Hz, 1H), 2.37 (tq, J = 12.4, 6.9 Hz, 2H), 2.11 - 1.98 (m, 1H), 1, 86 (p, J = 6.3 Hz, 2H). LCMS RT = 4.00 min., m/z = 406.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.00 min., ESI+ found [M+H] = 406.2.

[01378] Analytical data for the second elution elastomer (arbitrarily assigned S,S configuration): SFC RT (AD column, 20% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.): 1 .28 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.49 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H ), 7.41 - 7.26 (m, 3H), 7.05 (dd, J = 7.0, 1.8 Hz, 2H), 6.33 (d, J = 2.0 Hz, 1H) , 6.57 (t, J = 6.9 Hz, 1H), 4.41 - 4.11 (m, 3H), 3.23 (s, 3H), 3.00 (qt, J = 17.2 , 6.3 Hz, 2H), 2.56 (ddd, J = 12.9, 8.0, 6.0 Hz, 1H), 2.43 - 2.32 (m, 2H), 2.11 - 1.98 (m, 1H), 1.87 (q, J = 6.2 Hz, 2H). LCMS RT = 4.00 min., m/z = 406.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.00 min., ESI+ found [M+H] = 406.2. Example 386 (S) -5 -(2-fluorophenyl) -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01379] (S) -5 -(2-fluorophenyl) -N -(4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide was correspondingly prepared from (S) -6 -amino -4 -methyl -7, 8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one, and 5 -(2-fluorophenyl) -2 - iodo -[1,2,4] triazole [ 1,5 -a] pyridine according to Method GZ1, The residue was purified via preparation RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 18.3 mg, 17%. 1H NMR (400 MHz, DMSO -d6) δ 8.87 (d, J = 7.7 Hz, 1H), 8.07 - 7.85 (m, 2H), 7.80 - 7.62 (m, 2H), 7.52 - 7.32 (m, 4H), 6.35 (d, J = 2.0 Hz, 1H), 4.44 - 4.28 (m, 2H), 4.21 (ddd , J = 14.5, 12.6, 6.6 Hz, 1H), 3.26 (s, 3H), 2.65 (tt, J = 12.9, 8.1 Hz, 1H), 2, 41 (td, J = 12.4, 6.4 Hz, 1H). LC-MS RT = 4.19 min., m/z = 420.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.19 min., ESI+ found [M+H] = 420.1. Example 387 5 -(2-fluorophenyl) -N -((S) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01380] 5 -(2-fluorophenyl) -N -((S) -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -5 -( 2-fluorophenyl) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - [1 ,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) to provide the final product (13.1 mg, 36%) as a solid of White color. 1H NMR (400 MHz, DMSO -d6) δ 8.55 - 8.43 (m, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.29 - 7.14 (m, 2H), 6.94 (td, J = 7.7, 1.7 Hz, 1H), 6.33 (t, J = 1.6 Hz, 1H ), 6.74 (t, J = 6.5 Hz, 1H), 4.41 - 4.11 (m, 3H), 3.43 - 3.21 (m, 4H), 3.07 - 2, 92 (m, 2H), 2.57 (dtd, J = 17.3, 8.8, 8.3, 4.4 Hz, 1H), 2.39 (tt, J = 12.7, 6.0 Hz, 2H), 2.15 - 2.01 (m, 1H), 1.92 (p, J = 6.2 Hz, 2H). LC-MS RT = 3.95 min., m/z = 424.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.95 min., ESI+ found [M+H] = 424.2. Example 388 5 -(2,5-difluorophenyl) -N -((S) -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01381] 5 -(2,5-difluorophenyl) -N -((S) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -5 -(2,5 -difluorophenyl) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl ) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) to provide the final product (8 mg, 20%) as a white solid . 1H NMR (400 MHz, DMSO -d6) δ 8.50 (dd, J = 12.8, 7.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.37 - 7.19 (m, 2H), 6.93 (dt, J = 8.6, 4.2 Hz, 1H), 6.33 (t, J = 1.7 Hz, 1H), 6.75 - 6.66 (m, 1H), 4.41 - 4.11 (m, 3H), 3.35 (d, J = 16.9 Hz, 1H), 3.24 (d, J = 1.7 Hz , 3H), 3.08 - 2.87 (m, 2H), 2.57 (ddt, J = 16.7, 8.6, 3.8 Hz, 1H), 2.38 (dt, J = 12 .3, 6.2 Hz, 2H), 2.09 (q, J = 11.1, 10.3 Hz, 1H), 1.95 (d, J = 7.9 Hz, 2H). LC-MS RT = 4.19 min., m/z = 442.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.19 min., ESI+ found [M+H] = 442.2. Example 389

[01382] GZ14 METHOD (S) -5 -(furan -3 -yl) -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 –carboxamide Step 1: 5 -(furan -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01383] A mixture of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (500 mg, 2.347 mmol), furan-3-boronic acid (394 mg, 2.520 mmol ), tripotassium phosphate (1495 mg, 7.041 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (67 mg, 0.141 mmol) and pre -X -Phos aminobiphenyl palladium chloride (XPhos -Pd -G2) catalyst (52 mg, 0.0705 mmol) was added under nitrogen. The microwave flask was capped and heated at 85°C for 45 minutes. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo, triturated with isopropyl acetate, and the solid filtered to provide 5-(furan-3-yl)-[1,2, 4] triazolo[1,5-a]pyridin-2-amine (400 mg, 85%) as a bronze-colored solid. LC-MS RT = 1.61 min., m/z = 201.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.61 min., ESI+ found [M+H] = 201.1. Step 2: 5 -(furan -3 -yl) -2 -iodine -[1,2,4] triazole [1,5 -a] pyridine

[01384] To a solution of 5 -(furan -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (300 mg, 1.424 mmol) and p-toluene sulfonic acid (1.04 g, 6.467 mmol) in acetonitrile (10 mL) was added a solution of potassium iodide (780 mg, 4.698 mmol) and sodium nitrite (247 mg, 3.573 mmol) in water (2 mL) under 24° W. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 5 -(furan -3 -yl) -2 -iodo -[1,2 ,4] triazolo [1,5 -a] pyridine (248 mg, 56%) as a light yellow solid. LC-MS RT = 2.48 min., m/z = 312.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 2.48 min., ESI+ found [M+H] = 312.1. Step 3: (S) -5 -(furan -3 -yl) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01385] Palladium (II) acetate (7 mg, 0.032 mmol), 4,5 -bis(diphenylphosphine) -9,9 -dimethylxanthene (28 mg, 0.0482 mmol), 5 -(furan -3 -yl) -2 -iodo -[1,2,4] triazolo [1,5 -a] pyridine (100 mg, 0.321 mmol), (S) -6 -amino -4 - methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin - 5(6H) -one (116 mg, 0.643 mmol) were added to a screw-capped vial. Nitrogen was then purged through the reaction flask for 15 min. The solids were dissolved in toluene (3 mL), and triethylamine (0.30 mL, 2.090 mmol) was then added. A glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left stirring for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The residue was purified by prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) to give (S) -5 -(furan -3 -yl) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazole [1, 5-a]pyridine-2-carboxamide as a tan solid (58 mg, 59% yield). 1H NMR (400 MHz, DMSO -d6) δ 9.21 (d, J = 1.4 Hz, 1H), 9.11 (d, J = 7.9 Hz, 1H), 7.97 (t, J = 1.8 Hz, 1H), 7.94 - 7.77 (m, 3H), 7.52 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 2.0 Hz , 1H), 6.38 (d, J = 2.0 Hz, 1H), 4.50 - 4.38 (m, 2H), 4.24 (ddd, J = 14.4, 12.6, 6 .6Hz, 1H), 3.29 (s, 3H), 2.76 - 2.50 (m, 2H). LC-MS RT = 3.95 min., m/z = 392.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.95 min., ESI+ found [M+H] = 392.1. Example 390 N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 - ( tetrahydrofuran -3 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01386] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 5 -(tetrahydrofuran -3 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -5 -(furan -3 -yl) -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) to provide the final product (0.8 mg, 2.5%) as a white solid. LC-MS RT = 3.21 min., m/z = 400.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.21 min., ESI+ found [M+H] = 400.2. Example 391

[01387] GZ9 METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -7 -phenylbenzo [d] thiazol -2 - carboxamide Step 1: 7-phenylbenzo[d]thiazole-2-carboxylic acid

[01388] A mixture of 7-bromobenzo[d]thiazol-2-carboxylic acid (500 mg, 1.88 mmol), phenyl boronic acid (458 mg, 3.76 mmol), potassium phosphate (1195 mg, 6, 64 mmol) in water (0.6 mL) and 1,4-dioxane (2 mL) was degassed, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) palladium(II) dichloro (70mg, 0.094 mmol) was added under nitrogen. The flask was capped and heated at 85°C for 3h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 7-phenylbenzo[d]thiazol-2-carboxylic acid (469 mg, 98%) as a tan solid. fluffy, which was used in the next step without any further purification. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 2.06 min., ESI+ found [M+H] = 256.9. Step 2: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -7 -phenylbenzo [d]thiazole -2 -carboxamide

[01389] To a solution of (S) -3 -amino -5 -methyl - 2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one (93 mg, 0.409 mmol) and acid 7 -phenylbenzo[d]thiazol-2-carboxylic acid (63 mg, 0.272 mmol) in N,N-dimethylformamide (2 mL) was added HATU (135 mg, 0.343 mmol), and N,N-diisopropyl ethylamine (0.16 mL , 0.936 mmol). The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo. The crude residue was purified directly via prep RP-HPLC (40 -80% acetonitrile in water + 0.1% formic acid) to give (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -7 -phenylbenzo [d] thiazol -2 -carboxamide (77 mg, 58%) as a colored solid white: 1H NMR (400 MHz, DMSO -d6) δ 9.26 (d, J = 8.0 Hz, 1H), 8.22 (dd, J = 8.1, 1.0 Hz, 1H), 7 .83 - 7.68 (m, 4H), 7.62 - 7.45 (m, 4H), 7.30 (m, 3H), 4.89 (m, 1H), 4.75 (m, 1H ), 4.48 (m, 1H), 3.33 (s, 3H). LC-MS RT = 6.75 min., m/z = 430.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.75 min., ESI+ found [M+H] = 430.1. Example 392 (S) -N -(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -7 -phenylbenzo [d] thiazol -2 -carboxamide

[01390] (S) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 7-phenylbenzo[d]thiazol-2-carboxamide was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazole[1,5-a][1,3] diazepine -5(6H)-one and 7-phenylbenzo[d]thiazole-2-carboxylic acid according to Method GZ9. The crude residue was purified directly via prep RP-HPLC (30 -70% acetonitrile in water + 0.1% formic acid) to provide the final product (79 mg, 57%) as a solid white in color. 1H NMR (400 MHz, DMSO -d6) δ 9.38 (d, J = 7.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.1 Hz, 1H), 7.83 - 7.67 (m, 4H), 7.62 - 7.45(m, 4H), 6.36 (d, J = 2.0 Hz, 1H), 4.47 - 4.17 (m, 3H ), 3.27 (s, 3H), 2.65 (m, 2H). LC-MS RT = 6.70min., m/z = 418.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.70min., ESI+ found [M+H] = 418.1. Example 393 (S) -5 -(1 -methyl -1H -pyrazol -4 -yl) -N -(4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a ][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01391] (S) -5 -(1-methyl -1H -pyrazol -4 -yl) -N - (4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 - a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was correspondingly prepared from (S) -6 - amino -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one, and 2 -iodo -5 -(1 -methyl -1H - pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine according to Method GZ14. The residue was purified via prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 49.3 mg, 39.5%. 1H NMR (400 MHz, DMSO -d6) δ 9.03 (d, J = 7.8 Hz, 1H), 8.94 (s, 1H), 8.51 (s, 1H), 7.87 - 7 .72 (m, 3H), 7.52 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 4.49 - 4.36 (m, 2H), 4.24 (ddd, J = 14.5, 12.6, 6.6 Hz, 1H), 4.00 (s, 3H), 3.29 (s, 3H), 2.76 - 2 .61 (m, 1H), 2.58 - 2.44 (m, 1H). LC-MS RT = 3.49 min., m/z = 406.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.49 min., ESI+ found [M+H] = 406.2. Example 394

[01392] GZ13 Method (S) -5 -(2,6 -difluorophenyl) -N -(4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 – carboxamide Step 1: 5-(2,6-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[01393] A mixture of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (100 mg, 0.469 mmol), 2,6-difluorophenyl boronic acid (227 mg, 1.408 mmol), potassium fluoride (82 mg, 1.408 mmol) in tetrahydrofuran (6 mL) and water (0.6 mL) was degassed, followed by addition of dipalladium tris(dibenzylideneacetone) (0) (44 mg, 0.0469 mmol ), tri-tert-butylphosphine (1.0 mol/l) in toluene (0.09 mL, 0.094 mmol) under nitrogen. The flask was capped and heated in a microwave oven to 120°C for 15 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 5-(2,6-difluorophenyl)-[1,2,4]triazolo[1,5-a] pyridin-2-amine (102 mg, 88%) as a bronze-colored solid, which was used in the next step without further purification. LC-MS RT = 1.60 min., m/z = 247.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.60 min., ESI+ found [M+H] = 247.0. Step 2: 5 -(2,6-difluorophenyl) -2 -iodine - [1,2,4] triazole [1,5 -a] pyridine

[01394] To a solution of 5 -(2,6-difluorophenyl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine (326 mg, 1.324 mmol) and p-toluene sulfonic acid (967 mg, 6.084 mmol) in acetonitrile (10 mL) was added a solution of potassium iodide (725 mg, 4.369 mmol) and sodium nitrite (229 mg, 3.323 mmol) in water (2 mL) under 24 ° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100 mL) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide 5 -(2,6 - difluorophenyl) -2 -iodo -[1,2,4 ] triazolo [1,5 -a] pyridine (339 mg, 72%) as a light yellow solid. LC-MS RT = 2.20 min., m/z = 357.9 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 2.20 min., ESI+ found [M+H] = 357.9, Step 3: (S) -5 -(2,6 -difluorophenyl) -N -(4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1 ,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01395] Palladium (II) acetate (10 mg, 0.042 mmol), 4,5 -bis(diphenylphosphine) -9,9 -dimethylxanthene (37 mg, 0.063 mmol), 5 -(2,6 -difluorophenyl) -2 -iodine -[1,2,4] triazolo [1,5 -a] pyridine (150 mg, 0.420 mmol), (S) -6 -amino -4 - methyl -7,8 -dihydro -4H -pyrazole [1 ,5 -a] [1,3] diazepin - 5(6H) -one (76 mg, 0.420 mmol) were added to a screw-capped vial. Nitrogen was then purged through the reaction flask for 15 min. The solids were dissolved in toluene (8 mL), and triethylamine (0.38 mL, 2.73 mmol) was added. A glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left stirring for 16 h. The crude residue was dissolved in isopropyl acetate, and was filtered through Celite and concentrated to drying. The crude residue was purified by prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to give (S)-5-(2,6-difluorophenyl)-N - (4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -[1,2,4] triazole [ 1,5 -a] pyridine -2 - carboxamide as a tan solid (141 mg, 77% yield). 1H NMR (400 MHz, DMSO -d6) δ 8.90 (d, J = 7.7 Hz, 1H), 8.10 (dd, J = 9.0, 1.2 Hz, 1H), 7.93 (dd, J = 9.0, 7.1 Hz, 1H), 7.76 (tt, J = 8.5, 6.6 Hz, 1H), 7.59 (dd, J = 7.1, 1 .2 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.39 (t, J = 8.4 Hz, 2H), 6.35 (d, J = 2.0 Hz, 1H), 4.44 - 4.14 (m, 3H), 3.26 (s, 3H), 2.64 (tt, J = 12.9, 8.1 Hz, 1H), 2.50 - 2.35 (m, 1H). LC-MS RT = 4.29 min., m/z = 438.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.29 min., ESI+ found [M+H] = 438.2. Example 395 (S) -5 -(3,6 -dihydro -2H -pyran -4 -yl) -N -(4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1.5 - a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01396] (S) -5 - (3,6 -dihydro -2H -pyran -4 -yl) -N - (4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [ 1,5 - a][1,3] diazepin -6 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was correspondingly prepared from (S) - 6 -amino -4 -methyl -7,8 - dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one, and 5 -(3,6 -dihydro -2H - pyran -4 -yl) -2 -iodo -[1,2,4] triazolo [1,5 -a] pyridine according to Method GZ14. The residue was purified using SFC (5-60% methanol + 0.1% ammonium hydroxide elution with carbon dioxide, HSS C18 Column, 150 x 30 mm) instead. Final step yield: 2.5 mg, 1.0%. LC-MS RT = 3.61 min., m/z = 408.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.61 min., ESI+ found [M+H] = 408.2. Example 396 5 -(2,6-difluorophenyl) -N -((S) -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01397] 5 -(2,6-difluorophenyl) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a ][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide from (S) - 5 -(2,6 -difluorophenyl) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (5 -50% acetonitrile in water + 0.1% formic acid) to provide the final product (26.2 mg, 23%) as a solid of White color. 1H NMR (400 MHz, DMSO -d6) δ 8.48 (dd, J = 20.1, 7.8 Hz, 1H), 7.54 - 7.39 (m, 2H), 7.14 (t, J = 9.2 Hz, 2H), 6.32 (t, J = 1.9 Hz, 1H), 6.85 - 6.70(m, 1H), 4.41 - 4.10 (m, 3H ), 3.23 (d, J = 1.9 Hz, 3H), 3.09 - 2.85 (m, 2H), 2.64 - 2.50 (m, 1H), 2.48 - 2, 29 (m, 2H), 2.20 - 1.97 (m, 3H). LC-MS RT = 4.25min., m/z = 442.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.25min., ESI+ found [M+H] = 442.2. Example 397 5 -(1 -methyl -1H -pyrazol -4 -yl) -N -((S) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a ][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01398] N -((S) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - was prepared il) -5 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide from (S) -5 -(1 -methyl -1H -pyrazole -4 -yl) -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 - il) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to provide the final product (23 mg, 28%) as a white solid . 1H NMR (400 MHz, DMSO -d6) δ 8.52 - 8.38 (m, 1H), 7.65 - 7.59 (m, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.37 (s, 1H), 6.33 (d, J = 2.0 Hz, 1H), 6.47 (t, J = 6.8 Hz, 1H), 4.42 - 4, 12 (m, 3H), 3.79 (s, 3H), 3.24 (d, J = 2.8 Hz, 3H), 3.02 - 2.83 (m, 2H), 2.66 - 2 .52 (m, 1H), 2.43 - 2.24 (m, 2H), 2.19 - 2.05 (m, 1H), 1.93 (m, 2H). LC-MS RT = 3.11 min., m/z = 410.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.11 min., ESI+ found [M+H] = 410.2. Example 398 (S) -5 -(1 -methyl -1H -pyrazol -4 -yl) -N -(5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepine -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01399] Prepared (S) -5 -(1-methyl -1H -pyrazol - 4 -yl) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide correspondingly from (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one, and 2 -iodo -5 - (1 -methyl -1H -pyrazol -4 -yl) - [1,2,4] triazolo [1,5 - a] pyridine according to Method GZ14. The residue was purified using prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 60.8 mg, 32.0%. 1H NMR (400 MHz, DMSO -d6) δ 9.01 - 8.90 (m, 2H), 8.53 (s, 1H), 7.88 - 7.73 (m, 3H), 7.55 ( dd, J = 7.7, 1.8 Hz, 1H), 7.40 - 7.21 (m, 3H), 4.96 (dt, J = 11.5, 7.9 Hz, 1H), 4 .73 (dd, J = 11.6, 9.8 Hz, 1H), 4.51 (dd, J = 9.9, 7.8 Hz, 1H), 4.00 (s, 3H), 3, 35 (s, 3H). LC-MS RT = 4.29 min., m/z = 418.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.29 min., ESI+ found [M+H] = 418.2. Example 399 (S) -5 -(furan -3 -yl) -N -(5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01400] Prepared (S) -5 -(furan -3 -yl) -N -(5 - methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide correspondingly from (3S) -3 -amino -5 - methyl -2,3 -dihydro - 1,5-benzoxazepin-4-one (51.3 mg, 0.267mmol), and 5-(furan-3-yl)-2-iodo-[1,2,4] triazolo[1,5-a]pyridine (83.0 mg, 0.267 mmol), according to Method GZ14. The residue was purified using prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 3.3 mg, 3.0%. 1H NMR (400 MHz, DMSO -d6) δ 9.23 (s, 1H), 9.07 (d, J = 8.2 Hz, 1H), 7.99 (t, J = 1.9 Hz, 1H ), 7.95 - 7.81 (m, 3H), 7.59 - 7.52 (m, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.40 - 7, 24 (m, 3H), 4.99 (dt, J = 11.8, 7.9 Hz, 1H), 4.74 (t, J = 10.7 Hz, 1H), 4.49 (dd, J = 9.9, 7.8 Hz, 1H), 3.35 (s, 3H). LC-MS RT = 4.93 min., m/z = 404.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.93 min., ESI+ found [M+H] = 404.1. Examples 400 and 401

[01401] GZ_chiral_1 Method (S) -5 -(2,6 -difluorophenyl) -N -((S) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (R) -5 -(2 ,6-difluorophenyl) -N -((S) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 - il) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1:1)

[01402] 5 -(2,6-difluorophenyl) -N -((S) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was further purified using chiral SFC ( WhelkO -1; 156 x21.2 mm, 5 µm; elution of 45% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (S) -5 -(2,6-difluorophenyl) -N -((S ) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (32.2 mg, 28%) and (R) -5 -(2,6 -difluorophenyl) -N -(( S) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (21.2 mg, 18%) as white solids:

[01403] Analytical data for the first eluting diastereomer (arbitrarily assigned S,S configuration): SFC RT (Whelko1 s,s, elution from 50% isocratic methanol with carbon dioxide, method 2.5 min.): 0.658 min. ., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.50 (d, J = 7.8 Hz, 1H), 7.54 - 7.41 (m, 2H), 7.14 ( t, J = 9.0 Hz, 2H), 6.33 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 9.3, 6.5 Hz, 1H), 4, 41 - 4.10 (m, 3H), 3.23 (s, 3H), 3.09 - 2.86 (m, 2H), 2.56 (m, 1H), 2.49 - 2.32 ( m, 3H), 2.21 - 1.94 (m, 3H). LCMS RT = 4.22 min., m/z = 442.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.22 min., ESI+ found [M+H] = 442.2.

[01404] Analytical data for the second elution diastereomer (arbitrarily assigned R, S configuration): SFC RT(Whelko1 s,s, 50% isocratic methanol elution, method 2.5 min.): 1.397 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.45(d, J = 7.9 Hz, 1H), 7.54 - 7.41 (m, 2H), 7.14 (t, J = 9.2 Hz, 2H), 6.32 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 9.2, 6.4 Hz, 1H), 4.41 - 4, 11 (m, 3H), 3.23 (s, 3H), 3.12 - 2.87 (m, 2H), 2.57 (m, 1H), 2.38 (m, 3H), 2.20 - 1.98 (m, 3H). LCMS RT = 4.23 min., m/z = 442.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.23 min., ESI+ found [M+H] = 442.2. Examples 402 and 403

[01405] GZ_chiral_2 Method (R) -5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5, 6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide and (S) -5 -ethyl -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 - a] pyridine -2 - carboxamide (1:1)

[01406] 5-ethyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) - 5.6 ,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was further purified by means of chiral SFC (Quiralcel OX; 155 x21.2 mm, 5 µm; elution of 40% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (R) -5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5,6,7,8 -tetrahydro - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (17.6 mg , 16%) (S) -5 -ethyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl ) -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (19.8 mg, 18%) as white solids:

[01407] Analytical data for the first eluting diastereomer (arbitrarily assigned S, S configuration): SFC RT (OX, 35% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.763 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.42 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 7.6, 1 .9 Hz, 1H), 7.38 - 7.20 (m, 3H), 4.82 (dt, J = 11.5, 7.8 Hz, 1H), 4.60 (dd, J = 11, 6, 9.8 Hz, 1H), 4.40 (dd, J = 9.8, 7.7 Hz, 1H), 4.18 (s, 1H), 3.31 (s, 3H), 2, 85 (q, J = 6.9, 6.0 Hz, 2H), 2.18 - 1.91 (m, 3H), 1.86 - 1.65 (m, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS RT = 4.70min., m/z = 370.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.70min., ESI+ found [M+H] = 370.1.

[01408] Analytical data for the second diastereomer (arbitrarily assigned R, S configuration): SFC RT (OX, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method): 1.242 min., 98.9% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.40 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 7.6, 1 .9 Hz, 1H), 7.38 - 7.20 (m, 3H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.57 (dd, J = 11, 5, 9.9 Hz, 1H), 4.40 (dd, J = 9.8, 7.7 Hz, 1H), 4.18 (dt, J = 12.0, 6.2 Hz, 1H), 3.34 (s,3H), 2.92 - 2.79 (m, 2H), 2.18 - 2.02 (m, 2H), 1.98 (q, J = 6.9 Hz, 1H) , 1.86 - 1.66 (m, 3H), 0.90 (t, J = 7.5 Hz, 3H). LCMS RT = 4.72 min., m/z = 370.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.72 min., ESI+ found [M+H] = 370.1. Example 404

[01409] GZ_chiral_3 Method (R) -5 -(1 -methyl -1H -pyrazol -4 -yl) -N -((S) - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1 ,5 - a][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01410] 5 -(1-methyl -1H -pyrazol -4 -yl) -N - ((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1, 5 -a][1,3] diazepin -6 -yl) -5,6,7,8 -tetrahydro - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was purified by of chiral SFC (Chiralpak AD; 153 x21.2 mm, 5 µm; elution of 35% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (R) -5 -(1-methyl -1H -pyrazole - 4 -yl) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl ) -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (6.2 mg, 4.6%) as white solids :

[01411] Analytical data: (arbitrarily assigned R, S configuration): SFC RT (AD, 30% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method): 0.565 min. , 97.8% purity, 96.5% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.49 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.38 (s, 1H), 6.35 (d, J = 2.0 Hz, 1H), 6.47 (t, J = 6 .8 Hz, 1H), 4.42 - 4.12 (m, 3H), 3.79 (s, 3H), 3.24 (s, 3H), 2.93 (td, J = 6.3, 3.2 Hz, 2H), 2.43 - 2.24 (m, 1H), 2.18 - 2.05 (m, 1H), 2.01 - 1.82 (m, 2H). LCMS RT = 3.16 min., m/z = 410.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.16 min., ESI+ found [M+H] = 410.2. Example 405

[01412] GZ4 METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -il) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide Step 1: 5 -(3,6 -dihydro -2H -pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01413] A mixture of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (600 mg, 2.82 mmol), pinacol ester of 3,6-dihydro acid - 2H -pyran -4 -boronic acid (915 mg, 4.22 mmol), potassium triphosphate (1793 mg, 8.45 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2 -dicyclohexylphosphine -2',4',6' -triisopropylbiphenyl (80 mg, 0.17 mmol) and palladium chloride aminobiphenyl precatalyst X -Phos ,XPhos -Pd -G2 (80 mg, 0.08 mmol) were added under nitrogen. The microwave flask was capped and heated to 85°C for 45 minutes. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo, triturated with isopropyl acetate, and the solid filtered to yield 5-(3,6-dihydro-2H-pyran-4 -yl) -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (502 mg, 83%) as a bronze-colored solid. 1H NMR (400 MHz, DMSO -d6) δ 7.43 (dd, J = 8.7, 7.4 Hz, 1H), 7.30 (dd, J = 8.7, 1.3 Hz, 1H) , 7.18 (tt, J = 2.9, 1.5 Hz, 1H), 6.86 (dd, J = 7.4, 1.3 Hz, 1H), 6.00 (s, 2H), 4.32 (q, J = 2.8 Hz, 2H), 3.85 (t, J = 6.4 Hz, 2H), 2.62 (dddd, J = 6.6, 6.2, 3, 3, 1.9Hz, 2H). LCMS RT = 1.08 min., m/z = 217.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.08 min., ESI+ found [M+H] = 217.2. Step 2: 5 -(tetrahydro -2H -pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01414] To a solution of 5 -(3,6 -dihydro -2H - pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (870mg, 4, 02 mmol) in ethanol (15 mL), acetic acid (15 mL) was added, then platinum (iv) oxide (45 mg, 0.20 mmol) was added. The reaction mixture was stirred under a balloon of hydrogen gas for 16 h at RT, then filtered through Celite and concentrated to drying in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1, 5-a]pyridin-2-amine (755 mg, 86%) as an off-white solid. LC-MS RT = 1.15 min., m/z = 219.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.15 min., ESI+ found [M+H] = 219.1. Step 3: 2 -iodine -5 -(tetrahydro -2H -pyran -4 - yl) -[1,2,4] triazolo [1,5 -a] pyridine

[01415] To a solution of 5 -(tetrahydro -2H - pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine (750 mg, 3.44 mmol) and p-toluene sulfonic acid (2.51 g, 13.2 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (1.88 g, 11.34 mmol) and sodium nitrite (595 mg, 8.62 mmol) in water (5 mL) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide 2 -iodo -5 -(tetrahydro -2H -pyran -4 -yl) -[1 ,2,4] triazolo [1,5 -a] pyridine (645 mg, 57%) as a light yellow solid. LC-MS RT = 1.76 min., m/z = 330.0 (M+H) + . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.76 min., ESI+ found [M+H] = 330.0. Step 4: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01416] Palladium (II) acetate (13.6 mg, 0.061 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (52.7 mg, 0.091 mmol), 2-iodine-5-phenyl -[1,2,4] triazolo [1,5 - a] pyridine (200 mg, 0.607 mmol), (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (126.5 mg, 0.668 mmol) were added to a screw-capped vial. Nitrogen was then purged through a reaction flask for 15 min. The solids were dissolved in toluene (10 mL), and triethylamine (0.55 mL, 3.95 mmol) was added. A glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left stirring for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 100% isopropyl acetate in heptane) to give (S)-N-(5-methyl-4-oxo-2.3, 4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (tetrahydro -2H -pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine-2-carboxamide (230 mg, 90% yield) as a yellow solid. 1H NMR (400 MHz, DMSO - d 6) δ 8.80 (d, J = 7.9 Hz, 1H), 7.88 — 7.74 (m, 2H), 7.53 (dd, J = 7 .6, 1.9 Hz, 1H), 7.46 - 7.13 (m, 5H), 4.91 (dt, J = 11.4, 7.8 Hz, 1H), 4.64 (dd, J = 11.5, 9.9 Hz, 1H), 4.49 (dd, J = 9.9, 7.7 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.73 (tt, J = 11.9, 3.6 Hz, 1H), 3.57 (td, J = 11.8, 2.0 Hz, 2H), 3.30 (s, 3H), 2.05 - 1.96 (m, 2H), 1.89 - 1.72 (m, 2H). LCMS RT = 4.37 min., m/z = 422.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.37 min., ESI+ found [M+H] = 422.1. Example 406

[01417] GZ11 Method (S) -5 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -[1,2,4 ] triazolo [1,5 -a] pyridine -2 -carboxamide Step 1: 5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01418] A suspension of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (700 mg, 3.29 mmol) in dioxane (12 mL) was degassed, cooled in ice bath, 1,3-bis(diphenylphosphine) propane nickel (II) chloride (178mg, 0.329 mmol) was added under nitrogen, followed by diisopropyl zinc (1M solution in toluene) via syringe for 10 min. ice bath, was heated to 95°C overnight. The reaction mixture was poured into isopropyl alcohol, and concentrated to drying in vacuo. The residue was diluted with saturated ammonium chloride (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine ( 424 mg, 73%) as a bronze-colored solid which was used in the next step without further purification. LC-MS RT = 0.90 min., m/z = 177.2 (M+H) + . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.90 min., ESI+ found [M+H] = 177.2. Step 2: 2 -iodine -5 -isopropyl -[1,2,4] triazole [1,5 -a] pyridine

[01419] To a solution of 5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (800 mg, 4.54 mmol) and p-toluene sulfonic acid (3.32 g, 17.43 mmol) in acetonitrile (40 mL) was added to a solution of potassium iodide (2.49 g, 14.98 mmol) and sodium nitrite (786 mg, 11.40 mmol) in water (5 mL ) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100 mL) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5 -a] pyridine (534 mg, 41%) as a light yellow solid. LC-MS RT = 1.38 min., m/z = 288.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.38 min., ESI+ found [M+H] = 288.0. Step 3: (S) -5 -isopropyl -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - [1, 2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01420] Palladium (II) acetate (16 mg, 0.069 mmol), 4,5 -bis(diphenylphosphine) -9,9 -dimethylxanthene (61 mg, 0.104 mmol), 2 -iodo -5 -isopropyl -[1, 2,4] triazolo [1,5 -a] pyridine (200 mg, 0.697 mmol), (S) -3 -amino -5 - methyl -2,3 -dihydrobenzo [b] [1,4] oxazepin -4( 5H)-one (147 mg, 0.766 mmol) was added to a screw-capped vial. Nitrogen was then purged through the reaction flask for 15 min. The solids were dissolved in toluene (10 mL), and triethylamine (0.63 mL, 4.53 mmol) was added. A glass reaction flask was purged with a carbon monoxide flask for 5 minutes. The flask, with the carbon monoxide balloon, was placed on a heating block at 80°C and left stirring for 16 h. The reaction mixture was purified by prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to provide (S)-5-isopropyl-N-(5-methyl-4 -oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide in the form of a bronze-colored solid (152.8 mg, 58.0%) that was confirmed by 1H NMR to be 64% purity. 1H NMR (400 MHz, DMSO -d6) δ 8.79 (d, J = 3.3 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.54 (d, J = 2, 0 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.23 - 7.21 (s, 1H), 4.91 (m, 1H), 4.64 (m, 1H), 4.49 (m, 1H), 3.76 (p, J = 6.8 Hz, 1H), 3.33 (s, 3H), 1.38 (dd, J = 6.9, 0.9 Hz , 6H). LC-MS RT = 6.13 min., m/z = 380.1 (M+H) +. LC-MS RT = 6.13 min., m/z = 380.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.13 min., ESI+ found [M+H] = 380.1. Examples 407 and 411 (R) -5 -(1 -methyl -1H -pyrazol -4 -yl) -N -((S) - 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1 ,4] oxazepin -3 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (S) -5 -(1 - methyl -1H -pyrazol -4 -yl) -N -((S) - 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1:1)

[01421] 5 -(1 -methyl -1H -pyrazol -4 -yl) -N - ((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1, 4] oxazepin -3 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was purified using chiral SFC (Quiralpak AD; 153 x21.2 mm, 5 µm; elution of 35% isocratic methanol with carbon dioxide) to provide arbitrarily assigned diastereomers (R) -5 -(1 -methyl -1H -pyrazol -4 -yl) -N -( (S) -5 -methyl - 4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6,7,8 -tetrahydro -[1, 2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (6.0 mg, 8.25%) as white solids, and (S) -5 -(1 -methyl -1H - pyrazol -4 -yl) -N -((S) - 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5,6 ,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (6.0 mg, 8.25%) as white solids:

[01422] Analytical data for the first elution diastereomer (arbitrarily assigned R, S configuration): SFC RT (AD, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, Method 2.5 min. ): 0.600 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.34 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H) , 7.49 (dd, J = 7.6, 2.0 Hz, 1H), 7.39 - 7.19 (m, 4H), 6.47 (t, J = 6.8 Hz, 1H), 4.81 (dt, J = 11.4, 7.7 Hz, 1H), 4.55 (dd, J = 11.5, 9.9 Hz, 1H), 4.39 (dd, J = 9, 9, 7.7 Hz, 1H), 3.78(s, 3H), 3.31 (s, 3H), 2.93 (td, J = 6.4, 2.6 Hz, 2H), 2, 29 (ddd, J = 8.6, 6.2, 3.3 Hz, 1H), 2.12 (dtd, J = 14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03 - 1.83 (m, 2H). LCMS RT = 3.91 min., m/z = 422.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.91 min., ESI+ found [M+H] = 422.1.

[01423] Analytical data for the second diastereomer (arbitrarily assigned S, S configuration): SFC RT (AD, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min.): 0.978min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.34 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J = 7.6, 2.0 Hz, 1H), 7.39 - 7.19 (m, 4H), 6.47 (t, J = 6.8 Hz, 1H), 4.81 (dt, J = 11.4, 7.7 Hz, 1H), 4.55 (dd, J = 11.5, 9.9 Hz, 1H), 4.39 (dd, J = 9.9, 7.7 Hz, 1H), 3.78(s, 3H), 3.31 (s, 3H), 2.93 (td, J = 6.4, 2.6 Hz, 2H), 2.29 (ddd, J = 8 .6, 6.2, 3.3 Hz, 1H), 2.12 (dtd, J = 14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03 - 1.83 (m, 2H). LCMS RT = 3.89 min., m/z = 422.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.89 min., ESI+ found [M+H] = 422.1. Example 408 N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 - a] pyridine -2 -carboxamide

[01424] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H -pyran -4 -yl) -[1,2 ,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by SFC (Whelko1 s,s, elution of 50% isocratic methanol with carbon dioxide) to provide the final product (58.7 mg, 18.3%) as a colored solid white. 1H NMR (400 MHz, DMSO -d6) δ 8.37 (dd, J = 14.1, 8.0 Hz, 1H), 7.50 (dd, J = 7.5, 2.0 Hz, 1H) , 7.37 - 7.20 (m, 3H), 4.89 - 4.77 (m, 1H), 4.57 (ddd, J = 16.0, 11.5, 9.9 Hz, 1H) , 4.41 (dd, J = 9.9, 7.7 Hz, 1H), 4.19 (dt, J = 9.1, 4.8 Hz, 1H), 3.94 - 3.79 (m , 2H), 3.42 - 3.17 (m, 4H), 2.84 (dtt, J = 21.9, 13.8, 6.0 Hz, 2H), 2.45(m,1H), 2.02 (dh, J = 12.7, 7.2 Hz, 2H), 1.93 - 1.79 (m, 1H), 1.80 - 1.68 (m, 1H), 1.56 ( d, J = 13.4 Hz, 1H), 1.40 (dqd, J = 16.1, 12.5, 4.2 Hz, 2H), 1.10 (d, J = 13.3 Hz, 1H ). LC-MS RT = 4.20 min., m/z = 426.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.20 min., ESI+ found [M+H] = 426.2. Examples 409 and 410 (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 - a] pyridine -2 -carboxamide and (S) -N -((S) - 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -5,6 ,7,8 -tetrahydro -[1,2,4] triazolo [1,5 - a] pyridine -2 -carboxamide (1:1)

[01425] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was further purified using chiral SFC (Whelk O -1 ; 154 x21.2 mm, 5 µm; elution of 50% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (R) -N -((S) -5 -methyl -4 -oxo -2, 3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H -pyran -4 -yl) -5,6,7,8 -tetrahydro -[1, 2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (41.9 mg, 13.0%) and (S) -N -((S) -5 -methyl -4 -oxo -2, 3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H -pyran -4 -yl) - 5,6,7,8 -tetrahydro -[1, 2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (58.7mg, 18.3%) as white solids:

[01426] Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC RT (Whelko1 s,s, 50% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2, 5 min.): 0.852 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.37 (dd, J = 14.1, 8.0 Hz, 1H), 7.50 (dd, J = 7.5, 2.0 Hz, 1H), 7.37 - 7.20 (m, 3H), 4.89 - 4.77 (m, 1H), 4.57 (ddd, J = 16, 0, 11.5, 9.9 Hz, 1H), 4.41 (dd, J = 9.9, 7.7 Hz, 1H), 4.19 (dt, J = 9.1, 4.8 Hz , 1H), 3.94 - 3.79 (m, 2H), 3.42 - 3.17 (m, 4H), 2.84 (dtt, J = 21.9, 13.8, 6.0 Hz , 2H), 2.45(m,1H), 2.02 (dh, J = 12.7, 7.2 Hz, 2H), 1.93 - 1.79 (m, 1H), 1.80 - 1.68 (m, 1H), 1.56 (d, J = 13.4 Hz, 1H), 1.40 (dqd, J = 16.1, 12.5, 4.2 Hz, 2H), 1 .10 (d, J = 13.3 Hz, 1H). LCMS RT = 4.18 min., m/z = 426.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.18 min., ESI+ found [M+H] = 426.2.

[01427] Analytical data for the second diastereomer (arbitrarily assigned S,S configuration): SFC RT(Whelko1 s,s, 50% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min .): 1.165 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.37 (dd, J = 14.1, 8.0 Hz, 1H), 7.50 (dd, J = 7.5, 2.0 Hz, 1H), 7.37 - 7.20 (m, 3H), 4.89 - 4.77 (m, 1H), 4.57 (ddd, J = 16.0, 11.5, 9.9 Hz, 1H), 4.41 (dd, J = 9.9, 7.7 Hz, 1H), 4.19 (dt, J = 9.1, 4.8 Hz, 1H ), 3.94 - 3.79 (m, 2H), 3.42 - 3.17 (m, 4H), 2.84 (dtt, J = 21.9, 13.8, 6.0 Hz, 2H ), 2.45(m,1H), 2.02 (dh, J = 12.7, 7.2 Hz, 2H), 1.93 - 1.79 (m, 1H), 1.80 - 1, 68 (m, 1H), 1.56 (d, J = 13.4 Hz, 1H), 1.40 (dqd, J = 16.1, 12.5, 4.2 Hz, 2H), 1.10 (d, J = 13.3 Hz, 1H). LCMS RT = 4.20 min., m/z = 426.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.20 min., ESI+ found [M+H] = 426.2. Example 412

[01428] GZ5 METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - [1,2 ,4] triazolo [1,5 -a] pyridine -2 -carboxamide Step 1: 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[01429] To a solution of 6-(trifluoromethyl) pyridin-2-amine (960 mg, 6.92 mmol) in dioxane (40 mL) was added ethoxycarbonyl isothiocyanate (0.77 mL, 6.52 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was used for the next step without any purification in the form of ethyl N -[[6-(trifluoromethyl)-2-pyridyl] carbamothioyl] carbamate.

[01430] To a solution of hydroxylamine hydrochloride (960 mg, 6.92 mmol), N,N - diisopropylethylamine (0.77 mL, 6.52 mmol) in MeOH (8 mL) and EtOH (8 mL) was added the solution of crude ethyl N -[[6-(trifluoromethyl)-2-pyridyl]carbamothioyl] carbamate in MeOH (8 mL) and EtOH (8 mL). The reaction mixture was stirred at room temperature for 1 hour, heated at 60°C for 18 hours until the reaction was completed. The reaction mixture was cooled, the solvents were evaporated. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo, triturated with isopropyl acetate, and the solid filtered to provide 5-(trifluoromethyl)-[1,2,4]triazole [ 1,5-a] pyridin-2-amine (1066 mg, 89%) as a white solid. LC-MS RT = 1.24 min., m/z = 203.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.24 min., ESI+ found [M+H] = 203.1. Step 2: 2 -iodine -5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine

[01431] To a solution of 5 -(trifluoromethyl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine (1066 mg, 6.06 mmol) and p-toluene sulfonic acid (3 .70g, 19.44 mmol) in acetonitrile (45mL) was added a solution of potassium iodide (2.77 g, 16.71 mmol) and sodium nitrite (877 mg, 12.71 mmol) in water (5 mL ) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide 2-iodo-5-(trifluoromethyl)-[1,2,4]triazole[1 ,5 -a] pyridine (929 mg, 58.6%) as a light yellow solid. LC-MS RT = 1.93 min., m/z = 313.9 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.93 min., ESI+ found [M+H] = 313.9. Step 3: methyl 5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylate

[01432] To a solution of 2-iodine -5 - (trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine (250 mg, 0.798 mmol) in MeOH (15 mL)) in an autoclave Easy Max was added [1,1'-bis(diphenylphosphine) ferrocene] palladium(II) dichloro (60 mg, 0.08 mmol), trimethylamine (1.11 mL, 7.98 mmol). The autoclave was sealed, purged with CO twice, and pressured to 9.3 bar (120 psi). The reaction mixture was stirred vigorously and heated under 80°C for 15 h, concentrated to drying in vacuo. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 15% methanol in dichloromethane) to provide methyl 5 - (trifluoromethyl) - [1,2,4] triazole [1,5 - a] pyridine -2 - carboxylate (179 mg, 91.4%) in the form of an off-white solid. LC-MS RT =1.10 min., m/z = 246.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.10 min., ESI+ found [M+H] = 246.0. Step 4: 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[01433] To a solution of methyl 5 - (trifluoromethyl) - [1,2,4] triazolo [1,5 -a] pyridine -2 - carboxylate (64 mg, 0.261 mmol) in tetrahydrofuran (4 mL) and methanol ( 1mL) lithium hydroxide (1 mol/L) in water (1 mL, 1.0 mmol) was added. The reaction mixture was subjected to stirring at RT for 1 h. After this period of time, the mixture was concentrated for drying in vacuo. The residue was diluted with water (2 mL) and then adjusted to pH = 1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated to drying in vacuo to provide 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ( 60 mg, 99% yield) as a white solid which was used in the next step without further purification. LCMS RT = 0.88 min., m/z = 232.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.88 min., ESI+ found [M+H] = 232.2. Step 5: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -[ 1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01434] To a solution of (S) -3 -amino -5 - methyl -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one (93 mg, 0.409 mmol) and acid 5 -(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (63 mg, 0.272 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (120. 9 mg, 0.327 mmol), and N,N-diisopropylethylamine (0.14 mL, 0.818 mmol. The reaction mixture was subjected to stirring overnight under RT, then it was purified directly via RP-HPLC preparation ( 20 -60% acetonitrile in water + 0.1% formic acid) to give (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1, 4] oxazepin -3 -yl) -5 -(trifluoromethyl) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (66.5 mg, 58%) in the form of a solid white color: 1H NMR (400 MHz, DMSO -d6) δ 8.88 (d, J = 7.8 Hz, 1H), 8.30 (dd, J = 8.3, 2.0 Hz, 1H), 8.00 - 7.89 (m, 2H), 7.53 (dd, J = 7.6, 2.0 Hz, 1H), 7.31 (dddd, J = 21.7, 14.5, 7 .4, 2.0 Hz, 3H), 4.92 (dt, J = 11.4, 7.8 Hz, 1H), 4.66 (dd, J = 11.6, 9.9 Hz, 1H) , 4.49 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LC-MS RT = 4.90 min., m/z = 406.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.90 min., ESI+ found [M+H] = 406.0. Examples 413 – 416

[01435] (R) -5 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01436] (S) -5 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01437] (S) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01438] (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01439] The 64% mixture of (S) -5 -isopropyl - N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 - il) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide and 36% of (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was reduced according to Method GZ2. The crude residue was further purified by means of chiral SFC (Chiralpak ID; 150 x 21.2 mm, 5 µm; elution 35% isocratic methanol with carbon dioxide) to provide four isomers (structural isomers were assigned based on 1H NMR; is understood by diastereomers have been assigned arbitrarily):

[01440] (R) -5 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (26 mg, 23%) as a white solid.

[01441] (S) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (16.1 mg, 14%) as a white solid.

[01442] (S) -5 -isopropyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (22.6 mg, 19.8%) as a white solid .

[01443] (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (12.7 mg, 10.5%) as a white solid .

[01444] Analytical data for the first elution isomer (arbitrarily assigned R, S configuration): SFC RT (OX, 35% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.655 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.34 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H) , 7.49 (dd, J = 7.6, 2.0 Hz, 1H), 7.39 - 7.19 (m, 4H), 6.47 (t, J = 6.8 Hz, 1H), 4.81 (dt, J = 11.4, 7.7 Hz, 1H), 4.55 (dd, J = 11.5, 9.9 Hz, 1H), 4.39 (dd, J = 9, 9, 7.7 Hz, 1H), 3.78(s, 3H), 3.31 (s, 3H), 2.93 (td, J = 6.4, 2.6 Hz, 2H), 2, 29 (ddd, J = 8.6, 6.2, 3.3 Hz, 1H), 2.12 (dtd, J = 14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03 - 1.83 (m, 2H). LCMS RT = 6.026 min., m/z = 384.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.026 min., ESI+ found [M+H] = 384.2.

[01445] Analytical data for the second elution isomer (arbitrarily assigned S, S configuration): SFC RT (OX, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min. ): 0.823 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.36 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.5, 2.0 Hz, 1H), 7.37 - 7.20 (m, 3H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.58 (dd , J = 11.5, 9.8 Hz, 1H), 4.41 (dd, J = 9.9, 7.7 Hz, 1H), 4.24 (d, J = 13.1 Hz, 1H) , 3.31 (s, 3H), 2.84 (q, J = 6.1, 6.5 Hz, 2H), 2.19 - 1.91 (m, 3H), 1.85 - 1.57 (m, 3H), 1.48 - 1.29 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).LCMS RT = 6.12 min., m/z = 384, 2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.12 min., ESI+ found [M+H] = 384.2.

[01446] Analytical data for the third elution isomer (arbitrarily assigned S, S configuration): SFC RT (OX, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min. ): 1.391 min., 98.8% purity, 97.7% ee: : 1H NMR (400 MHz, DMSO -d6) δ 8.34 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J = 7.6, 2.0 Hz, 1H), 7.39 - 7.19 (m, 4H), 6.47 (t, J = 6.8 Hz, 1H), 4.81 (dt, J = 11.4, 7.7 Hz, 1H), 4.55 (dd, J = 11.5, 9.9 Hz, 1H), 4.39 (dd , J = 9.9, 7.7 Hz, 1H), 3.78(s, 3H), 3.31 (s, 3H), 2.93 (td, J = 6.4, 2.6 Hz, 2H), 2.29 (ddd, J = 8.6, 6.2, 3.3 Hz, 1H), 2.12 (dtd, J = 14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03 - 1.83 (m, 2H). LCMS RT = 6.03min., m/z = 384.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.03 min., ESI+ found [M+H] = 384.2.

[01447] Analytical data for the fourth elution isomer (arbitrarily assigned R, S configuration): SFC RT (OX, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min. ): 1.475 min., 100% purity, 100% ee: : 1H NMR (400 MHz, DMSO -d6) δ 8.36 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.5, 2.0 Hz, 1H), 7.37 - 7.20 (m, 3H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.58 ( dd, J = 11.5, 9.8 Hz, 1H), 4.41 (dd, J = 9.9, 7.7 Hz, 1H), 4.24 (d, J = 13.1 Hz, 1H ), 3.31 (s, 3H), 2.84 (q, J = 6.1, 6.5 Hz, 2H), 2.19 - 1.91 (m, 3H), 1.85 - 1, 57 (m, 3H), 1.48 - 1.29 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). LCMS RT = 6.14 min., m/z = 384.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.14 min., ESI+ found [M+H] = 384.2. Example 417 (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - [1 ,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01448] (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was correspondingly prepared from (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b ][1,4] oxazepin -4(5H) -one, and 5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylic acid according to Method GZ6, The residue was purified via prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 123 mg, 78.0%. 1H NMR (400 MHz, DMSO -d6) δ 10.12 (s, 1H), 8.88 (d, J = 7.6 Hz, 1H), 8.31 (dd, J = 8.3, 1, 9 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.25(ddd, J = 10.4, 9.1, 2.9 Hz, 1H), 7.06 (dt, J = 9.3, 2.3 Hz, 1H), 6.00 (dt, J = 10.9, 7.3 Hz, 1H), 4.72 (t, J = 10.6 Hz, 1H), 4 .60 (dd, J = 10.2, 7.1 Hz, 1H). LC-MS RT = 4.72 min., m/z = 428 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.72 min., ESI+ found [M+H] = 428 Example 418 (S) -N -(7,9 -difluoro -2 -oxo -2,3,4,5 - tetrahydro -1H -benzo [b]azepin -3 -yl) -5 - (trifluoromethyl) -[1,2 ,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01449] (S) -N -(7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - (trifluoromethyl) -[ 1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was correspondingly prepared from (S)-3-amino-7,9-difluoro-1,3,4,5-tetrahydro -2H - benzo [b]azepin -2 -one, and 5 -(trifluoromethyl) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylic acid according to Method GZ6, The residue it was purified via prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 80.9 mg, 51.7%. 1H NMR (400 MHz, DMSO -d6) δ 10.02 (s, 1H), 8.72 (d, J = 7.4 Hz, 1H), 8.30 (dd, J = 8.2, 2, 1 Hz, 1H), 8.00 - 7.89 (m, 2H), 7.29 (ddd, J = 10.0, 8.9, 2.8 Hz, 1H), 7.21 - 7.13 (m, 1H), 4.43 (dt, J = 11.5, 7.8 Hz, 1H), 3.37 - 3.22 (m, 3H), 2.87 - 2.74 (m, 2H ), 2.39 - 2.25(m, 1H). LC-MS RT = 4.69 min., m/z = 426 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.69 min., ESI+ found [M+H] = 426 Example 419 (S) -N -(6 -fluoro -8 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) - [1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01450] (S) -N -(6 -fluoro -8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - ( trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was correspondingly prepared from (S)-3-amino-6-fluoro-8-methyl-2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one, and 5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylic acid according to the GZ6 Method. The residue was purified via prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) instead. Final step yield: 86.2 mg, 55%. 1H NMR (400 MHz, DMSO -d6) δ 10.06 (s, 1H), 8.86 (d, J = 7.7 Hz, 1H), 8.31 (dd, J = 8.3, 1, 9 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.00 (dd, J = 10.7, 1.8 Hz, 1H), 6.92 (s, 1H), 4, 94 (dt, J = 11.0, 7.4 Hz, 1H), 4.67 (t, J = 10.7 Hz, 1H), 4.54 (dd, J = 10.2, 7.3 Hz , 1H), 2.31 (s, 3H). LC-MS RT = 4.98 min., m/z = 424.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.98 min., ESI+ found [M+H] = 424.1 Example 420

[01451] GZ12 Method (S) -N -(7,9 -difluoro -2 -oxo -2,3,4,5 - tetrahydro -1H -benzo [b]azepin -3 -yl) -5 -isopropyl - [1,2,4 ] triazolo [1,5 -a] pyridine -2 -carboxamide Step 1: 5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01452] A suspension of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (700 mg, 3.29 mmol) in dioxane (12 mL) was degassed, cooled to ice bath, added 1,3-bis(diphenylphosphine) propane nickel (II) chloride (178mg, 0.329 mmol) under nitrogen, followed by diisopropyl zinc (1M solution in toluene) via syringe for 10 min. ice bath, heated to 95°C overnight. The reaction mixture was poured into isopropyl alcohol, and concentrated for drying in vacuo. The residue was diluted with saturated ammonium chloride (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine ( 424 mg, 73%) as a bronze-colored solid, which was used in the next step without further purification. LCMS RT = 0.90 min., m/z = 177.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.90 min., ESI+ found [M+H] = 177.2. Step 2: 2 -iodine -5 -isopropyl -[1,2,4] triazole [1,5 -a] pyridine

[01453] To a solution of 5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (800 mg, 4.54 mmol) and p -toluene sulfonic acid (3.32 g, 17.43 mmol) in acetonitrile (40 mL) was added a solution of potassium iodide (2.49 g, 14.98 mmol) and sodium nitrite (786 mg, 11.40 mmol) in water (5 mL ) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100 mL) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide 2-iodo-5-isopropyl-[1,2,4]triazole[1 ,5-a] pyridine (534 mg, 41%) as a light yellow solid. LCMS RT = 1.38 min., m/z = 288.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.38 min., ESI+ found [M+H] = 288.0. Step 3: methyl 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[01454] To a solution of 2-iodo-5-isopropyl-[1,2,4] triazole [1,5-a] pyridine (1000 mg, 3.48 mmol) in MeOH (20 mL)) in an autoclave Easy Max autoclave was added [1,1'-bis(diphenylphosphine) ferrocene] palladium(II) dichloro (260 mg, 0.348 mmol), trimethylamine (4.85 mL, 34.83 mmol). The autoclave was sealed, purged with CO twice, and pressured to 9.28 bar (120 psi). The reaction mixture was stirred vigorously and heated under 80°C for 15 h, concentrated to drying in vacuo. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide methyl 5-isopropyl-[1,2,4]triazolo[1,5-a] pyridine -2 - carboxylate (710 mg, 93%) as an off-white solid. LCMS RT = 1.14 min., m/z = 220.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.14 min., ESI+ found [M+H] = 220.1. Step 4: 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[01455] To a solution of methyl 5-isopropyl - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylate (806 mg, 3.68 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) lithium hydroxide (1 mol/L) in water (7 mL, 7.0 mmol) was added. The reaction mixture was subjected to stirring at RT for 1 h. After this period of time, the mixture was concentrated for drying in vacuo. The residue was diluted with water (2 mL) and then adjusted to pH = 1 by adding 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate and concentrated to drying in vacuo to provide 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (716 mg , 95% yield) in the form of a white solid which was used in the next step without any further purification. LCMS RT = 0.96 min., m/z = 206.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.96 min., ESI+ found [M+H] = 206.2. Step 5: (S) -N -(7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 -isopropyl - [1, 2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01456] To a solution of (S) -3 -amino -7,9 - difluoro -1,3,4,5 -tetrahydro -2H -benzo [b]azepin -2 -one (132 mg, 0.532 mmol) and 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (95 mg, 0.460 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (215 mg, 0.560 mmol), and N,N-diisopropyl ethylamine (0.24 mL, 1.39 mmol. The reaction mixture was subjected to stirring overnight under RT, then was purified by means of RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid) to give a tan solid (103.7 mg, 56%) as a mixture of 64% (S) - N -(7 ,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 -isopropyl -[1,2,4] triazolo [1,5 -a ] pyridine -2 -carboxamide and 36% (S) -N -(7,9 -difluoro -2 - oxo -2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 - propyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide This final compound was observed as a single peak through LC-MS, it was confirmed through 1H NMR which demonstrated purity of 64%. 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.63 (dd, J = 7.5, 3.0 Hz, 1H), 7.85 - 7.68 (m, 3H), 7.29 (ddd, J = 10.2, 8.9, 2.8 Hz, 1H), 7.18 (ddt, J = 11.0, 8.7, 1.9 Hz, 3H) , 4.43 (dt, J = 11.6, 7.7 Hz, 1H), 3.77 (h, J = 6.8 Hz, 1H), 3.39 - 3.25 (m, 1H), 2.83 (dd, J = 11.1, 6.5 Hz, 2H), 2.30 (ddt, J = 12.4, 9.3, 4.0 Hz, 1H), 1.39 (d, J = 6.9 Hz, 6H). LC-MS RT = 4.92 min., m/z = 400.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.92 min., ESI+ found [M+H] = 400.1. Example 421

[01457] GZ15 Method (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(1 -methyl -1H - -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide Step 1: 5 -(1 -methyl -1H -pyrazol -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01458] A mixture of 5 -bromo -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (500 mg, 2.347 mmol), 1 -methyl -4 -(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (977 mg, 4.694 mmol), potassium triphosphate (1541 mg, 7.041 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (67 mg, 0.141 mmol) and aminobiphenyl palladium chloride precatalyst X-Phos, XPhos-Pd-G2 (63 mg, 0.071 mmol) was added under nitrogen. The flask The microwave flask was capped and heated at 85°C for 45 minutes. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo, triturated with isopropyl acetate, and the solid filtered to provide 5-(1-methyl-1H-pyrazol-4-yl) -[1,2,4] triazolo [1,5 -a] pyridin -2 - amine (385 mg, 76.7%) as a brown solid. LC-MS RT = 1.10 min., m/z = 216.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.10 min., ESI+ found [M+H] = 216.0. Step 2: 2 -iodine -5 -(1 -methyl -1H -pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine

[01459] To a solution of 5 -(1-methyl -1H - pyrazol -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 - amine (1011 mg, 4.719 mmol) and p -toluene sulfonic acid (3.45g, 18.122 mmol) in acetonitrile (30 mL) was added a solution of potassium iodide (2590 mg, 16.573 mmol) and sodium nitrite (817 mg, 11.845 mmol) in water (5 mL) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x150) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide 2-iodo-5-(1-methyl-1H-pyrazol-4-yl)- [1,2,4] triazolo [1,5 -a] pyridine (800 mg, 52%) as a light yellow solid. LC-MS RT = 2.04 min., m/z = 326.9 (M+H) + . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 2.04 min., ESI+ found [M+H] = 326.9. Step 3: methyl 5 -(1 -methyl -1H -pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylate

[01460] To a solution of 2 -iodine -5 -(1 -methyl -1H -pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine (800 mg, 2.461 mmol) in MeOH (20 mL)) in an Easy Max autoclave was added [1,1'-bis(diphenylphosphine) ferrocene] palladium (II) dichloro (184 mg, 0.246 mmol), trimethylamine (3.43 mL, 24.607 mmol). The autoclave was sealed, purged with CO twice, and pressured to 9.28 bar (120 psi). The reaction mixture was stirred vigorously and heated under 80°C for 15 h, concentrated to drying in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) to provide methyl 5-(1-methyl-1H-pyrazol-4-yl)-[1, 2,4]triazolo[1,5-a]pyridine-2-carboxylate (574 mg, 91%) as a brown solid. LC-MS RT = 0.97 min., m/z = 258.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.97 min., ESI+ found [M+H] = 258.1. Step 4: 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[01461] To a solution of methyl 5 -(1-methyl -1H -pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxylate (574 mg, 2.231 mmol ) in tetrahydrofuran (12 mL) and methanol (3 mL) lithium hydroxide (1 mol/L) in water (4 mL, 1.0 mmol) was added. The reaction mixture was subjected to stirring at RT for 1 h. After this period of time, the mixture was concentrated for drying in vacuo. The residue was diluted with water (15 mL) and then adjusted to pH = 1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated for drying in vacuo to provide 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1, 5-a]pyridine-2-carboxylic acid (381 mg, 70% yield) as a brown solid, which was used in the next step without further purification. LCMS RT = 0.92 min., m/z = 244.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.92 min., ESI+ found [M+H] = 244.1. Step 5: (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(1 - methyl - 1H -pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01462] To a solution of (S) -3 -amino -6,8 - difluoro -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one (95 mg, 0.378 mmol) and 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (80 mg, 0.329 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (153 mg, 0.395 mmol), and N,N-diisopropyl ethylamine (0.23 mL, 1.316 mmol. The reaction mixture was stirred overnight at RT, then purified using RP-HPLC preparation (5 -50% acetonitrile in water + 0.1% formic acid) to provide (S) -N -(6,8 -difluoro -4 -oxo -2,3,4 ,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(1 -methyl -1H - pyrazol -4 -yl) -[1,2,4] triazolo [1,5 -a ] pyridine -2 - carboxamide as a bronze-colored solid (2 mg, 1.4% yield) 1H NMR (400 MHz, DMSO -d6) δ 10.12 (s, 2H), 8.96 - 8.89 (m, 4H), 8.53 (s, 2H), 7.88 - 7.73 (m, 6H), 7.26 (ddd, J = 10.3, 9.0, 2.9 Hz, 2H), 7.07 (dt, J = 9.1, 2.2 Hz, 2H), 6.02 (dt, J = 11.1, 7.5 Hz, 2H), 4.78(t , J = 10.7 Hz, 2H), 4.62 (dd, J = 10.2, 7.2 Hz, 2H), 4.00 (s, 6H), 3.32 - 3.22 (m, 1H), 2.47 (s, 1H). LC-MS RT = 4.31 min., m/z = 440.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.31 min., ESI+ found [M+H] = 440.1. Example 422

[01463] GZ16 Method (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide Step 1: 5 -(3,6 -dihydro -2H -pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01464] A mixture of 5-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (600 mg, 2.82 mmol), pinacol ester of 3,6-dihydro acid - 2H -pyran -4 -boronic acid (915 mg, 4.22 mmol), potassium triphosphate (1793 mg, 8.45 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2 -dicyclohexylphosphine - 2',4',6' - triisopropylbiphenyl (80 mg, 0.17 mmol) and palladium aminobiphenyl precatalyst X -Phos,XPhos -Pd -G2 (80 mg, 0.08 mmol) were added under nitrogen. The microwave flask was capped and heated at 85°C for 45 minutes. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo, triturated with isopropyl acetate, and the solid filtered to yield 5-(3,6-dihydro-2H-pyran-4- il) -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (502 mg, 83%) as a bronze-colored solid. 1H NMR (400 MHz, DMSO -d6) δ 7.43 (dd, J = 8.7, 7.4 Hz, 1H), 7.30 (dd, J = 8.7, 1.3 Hz, 1H) , 7.18 (tt, J = 2.9, 1.5 Hz, 1H), 6.86 (dd, J = 7.4, 1.3 Hz, 1H), 6.00 (s, 2H), 4.32 (q, J = 2.8 Hz, 2H), 3.85 (t, J = 6.4 Hz, 2H), 2.62 (dddd, J = 6.6, 6.2, 3, 3, 1.9Hz, 2H). LCMS RT = 1.08 min., m/z = 217.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.08 min., ESI+ found [M+H] = 217.2. Step 2: 5 -(tetrahydro -2H -pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01465] To a solution of 5 -(3,6 -dihydro -2H - pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (870mg, 4, 02 mmol) in ethanol (15 mL), acetic acid (15 mL) was added, then platinum (iv) oxide (45 mg, 0.20 mmol) was added. The reaction mixture was stirred under a balloon of hydrogen gas for 16 h at RT, then filtered through Celite and concentrated to drying in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated for drying in vacuo to provide 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1, 5-a]pyridin-2-amine (755 mg, 86%) as an off-white solid. LC-MS RT = 1.15 min., m/z = 219.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.15 min., ESI+ found [M+H] = 219.1. Step 3: 2 -iodine -5 -(tetrahydro -2H -pyran -4 - yl) -[1,2,4] triazolo [1,5 -a] pyridine

[01466] To a solution of 5 -(tetrahydro -2H - pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridin -2 -amine (750 mg, 3.44 mmol) and p -toluene sulfonic acid (2.51 g, 13.2 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (1.88 g, 11.34 mmol) and sodium nitrite (595 mg, 8 .62 mmol) in water (5 mL) under 24°C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2x100) and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% iPrOAc in heptane) to provide 2 -iodo -5 -(tetrahydro -2H -pyran -4 -yl) -[1 ,2,4] triazolo [1,5 -a] pyridine (645mg, 57%) as a light yellow solid. LC-MS RT = 1.76 min., m/z = 330.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 5 min.) retention time 1.76 min., ESI+ found [M+H] = 330.0. Step 3: methyl 5 -(tetrahydro -2H -pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylate

[01467] To a solution of 2 -iodo -5 - (tetrahydro -2H -pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine (144 mg, 0.438 mmol) in MeOH (15 mL)) in an Easy Max autoclave was added [1,1'-bis(diphenylphosphine) ferrocene] palladium (II) dichloro (33 mg, 0.0438 mmol), trimethylamine (0.61 mL, 4.375 mmol). The autoclave was sealed, purged with CO twice, and pressured to 9.28 bar (120 psi). The reaction mixture was stirred vigorously and heated under 80°C for 15 h, concentrated to drying in vacuo. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to give methyl 5-(1-methyl-1H-pyrazol-4-yl)-[1, 2,4] triazolo [1,5 -a] pyridine -2 - carboxylate (79 mg, 79%) as a brown solid. 1H NMR (400 MHz, DMSO -d6) δ 7.85 (d, J = 8.9 Hz, 1H), 7.78(dd, J = 9.0, 7.1 Hz, 1H), 7.25 (d, J = 7.1 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.95 (d, J = 1.3 Hz, 3H), 3.72 (tt, J = 12.1, 3.7 Hz, 1H), 3.58 (t, J = 11.6 Hz, 2H), 2.07 - 1.94 (m, 2H), 1.82 (qd, J = 12 ,3, 4.3Hz, 2H). LC-MS RT = 1.10 min., m/z = 262.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.10 min., ESI+ found [M+H] = 262.2. Step 4: 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[01468] To a solution of methyl 5 -(tetrahydro - 2H -pyran -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridine -2 - carboxylate (143 mg, 0.547 mmol) in tetrahydrofuran (12 mL) and methanol (3 mL) was added to lithium hydroxide (1 mol/L) in water (3 mL, 3.010 mmol). The reaction mixture was subjected to stirring at RT for 1 h. After this period of time, the mixture was concentrated for drying in vacuo. The residue was diluted with water (15 mL) and then adjusted to pH = 1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated to drying in vacuo to provide 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5- a] pyridine -2 - carboxylic acid (65 mg, 48% yield) in the form of a bronze-colored solid which was used in the next step without any further purification. LCMS RT = 0.72 min., m/z = 248.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 0.72 min., ESI+ found [M+H] = 248.1. Step 5: (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro - 2H -pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide

[01469] To a solution of (S) -3 -amino -6,8 - difluoro -2,3 -dihydrobenzo [b][1,4] oxazepin -4(5H) -one (112 mg, 0.447 mmol) and 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (85 mg, 0.343 mmol) in N,N-dimethylformamide (1 .5 mL) was added HATU (160 mg, 0.412 mmol), and N,N-diisopropyl ethylamine (0.18 mL, 1.031 mmol. The reaction mixture was stirred overnight at RT, then purified by Preparation RP-HPLC medium (5 -50% acetonitrile in water + 0.1% formic acid) to provide (S) -N -(6,8 -difluoro -4 -oxo -2,3,4, 5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(tetrahydro -2H - pyran -4 -yl) -[1,2,4] triazolo [1,5 -a] pyridine - 2 - carboxamide in the form of a white solid (16.2 mg, 10.0%).1H NMR (400 MHz, DMSO -d6) δ 10.12 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 7.88 - 7.74 (m, 2H), 7.30 - 7.20 (m, 2H), 7.06 (dt, J = 9.3, 2.3 Hz, 1H), 4.99 (dt, J = 11.0, 7.3 Hz, 1H), 4.71 (t, J = 10.7 Hz, 1H), 4.59 (dd, J = 10 .2, 7.2 Hz, 1H), 4.06 - 3.97 (m, 2H), 3.74 (m, 1H), 3.58 (m, 2H), 2.10 - 1.96 ( m, 2H), 1.82 (m, 2H). LC-MS RT = 4.44 min., m/z = 444.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.44 min., ESI+ found [M+H] = 444.1. Example 423 (S) -N -(6 -fluoro -8 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl - [1 ,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01470] (S) -N -(6 -fluoro -8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - isopropyl -[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was correspondingly prepared from (S)-3-amino-6-fluoro-8-methyl-2,3-dihydrobenzo [b][1,4] oxazepin -4(5H) -one, and 5 -isopropyl - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylic acid according to Method GZ12. The residue was purified by means of SFC (5 -40% methanol eluting with carbon dioxide, Column: Pyridyl Amide 150 x 30 mm) to give (S)-N-(6-fluoro-8-methyl-4-oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide which demonstrated 64% purity through 1H NMR, single peak for LC-MS. Final step yield: 74 mg, 40%. 1H NMR (400 MHz, DMSO -d6) δ 10.04 (s, 1H), 8.76 (dd, J = 7.8, 2.6 Hz, 1H), 7.86 - 7.70(m, 2H), 7.21 (dt, J = 6.9, 1.8 Hz, 1H), 7.00 (dd, J = 10.8, 1.8 Hz, 1H), 6.91 (s, 1H ), 4.94 (dt, J = 11.2, 7.4 Hz, 1H), 4.65 (t, J = 10.6 Hz, 1H), 4.54 (ddd, J = 9.3, 7.4, 1.6 Hz, 1H), 3.77 (p, J = 6.9 Hz, 1H), 2.31 (s, 3H), 1.39 (d, J = 6.9 Hz, 6H). LC-MS RT = 6.21 min., m/z = 398.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.21 min., ESI+ found [M+H] = 398.1. Example 424 (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl -[1,2 ,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01471] (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl - [ 1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was correspondingly prepared from (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][ 1,4] oxazepin -4(5H) - one, and 5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylic acid according to Method GZ12. The residue was purified by prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to give (S) -N -(6,8 -difluoro -4 -oxo -2 ,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide which demonstrated 64% purity via 1H NMR, single peak for LC-MS. Final step yield: 69.8 mg, 37.6%. 1H NMR (400 MHz, DMSO -d6) δ 10.12 (s, 1H), 8.78(dd, J = 7.6, 2.7 Hz, 1H), 7.86 - 7.70(m, 2H), 7.30 - 7.17 (m, 2H), 7.06 (dt, J = 9.4, 2.3 Hz, 1H), 6.05 - 4.93 (m, 1H), 4 .71 (t, J = 10.7 Hz, 1H), 4.59 (ddd, J = 10.2, 7.1, 1.5 Hz, 1H), 3.77 (p, J = 6.9 Hz, 1H), 3.38 - 3.23 (m, 1H), 1.39 (d, J = 6.9 Hz, 6H). LC-MS RT = 6.01 min., m/z = 402.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.01 min., ESI+ found [M+H] = 402.1. Examples 425 and 426 (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (S) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [ 1,5 -a] pyridine -2 -carboxamide (1:1)

[01472] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -5 ,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-N-(5-methyl-4-oxo-2 ,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2, The residue was further purified by means of chiral SFC (Cellulose -1; 155 x21.2 mm, 5 µm; elution 20% isocratic methanol with carbon dioxide) to provide arbitrarily assigned diastereomers (R ) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -5, 6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (15 mg, 13%) and (S) -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2 ,4] triazolo [1,5 -a] pyridine -2 -carboxamide (16.5 mg, 14.5%) as white solids:

[01473] Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC RT (Cel -1, 15% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method): 0.989 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.50 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 7, 5, 1.9 Hz, 1H), 7.37 - 7.20 (m, 3H), 6.41 (h, J = 6.8 Hz, 1H), 4.83 (dt, J = 11.5 , 7.8 Hz, 1H), 4.61 (dd, J = 11.6, 9.8 Hz, 1H), 4.42 (dd, J = 9.8, 7.7 Hz, 1H), 3 .42 - 3.18 (m, 3H), 3.07 - 2.87 (m, 2H), 2.39 - 2.15 (m, 2H), 2.02 - 1.87 (m, 2H) . LCMS RT = 4.760 min., m/z = 410.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.760 min., ESI+ found [M+H] = 410.1.

[01474] Analytical data for the second diastereomer (arbitrarily assigned S, S configuration): SFC RT (Cel -1, 15% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method ): 1.372 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.50 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 7.5, 1 .9 Hz, 1H), 7.37 - 7.20 (m, 3H), 6.41 (h, J = 6.8 Hz, 1H), 4.83 (dt, J = 11.5, 7, 8 Hz, 1H), 4.61 (dd, J = 11.6, 9.8 Hz, 1H), 4.42 (dd, J = 9.8, 7.7 Hz, 1H), 3.42 - 3.18 (m, 3H), 3.07 - 2.87 (m, 2H), 2.39 - 2.15 (m, 2H), 2.02 - 1.87 (m, 2H). LCMS RT = 4.81 min., m/z = 410.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.81 min., ESI+ found [M+H] = 410.1. Examples 427 and 428 (R) -N -((S) -6 -fluoro -8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (S) -N -((S) -6 -fluoro - 8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[ 1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1:1)

[01475] N -((S) -6 -fluoro -8 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - ( trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-N-(6-fluoro-8 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The crude residue was further purified by means of chiral SFC (Chiralpak AD; 152 x 21.2 mm, 5 µm; elution of 30% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (R) -N - ((S) -6 -fluoro -8 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -5, 6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (27.2 mg, 32%) and (S) -N -((S) -6 -fluoro -8 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - 5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (26.6 mg, 32.5%) as white solids:

[01476] Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC RT (AD, 25% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.624 min., 98.5% purity, 97% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 6.99 (dd, J = 10.8, 1.8 Hz, 1H), 6.89 (s, 1H), 6.41 (h, J = 6.8 Hz, 1H), 4, 85 (dt, J = 11.1, 7.4 Hz, 1H), 4.61 (t, J = 10.7 Hz, 1H), 4.47 (dd, J = 10.1, 7.2 Hz , 1H), 3.07 - 2.87 (m, 2H), 2.30 (m, 5H), 1.96 (h, J = 6.7 Hz, 2H). LCMS RT = 4.44 min., m/z = 428.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.44 min., ESI+ found [M+H] = 428.1.

[01477] Analytical data for the second diastereomer (arbitrarily assigned S, S configuration): SFC RT (AD, 25% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method) : 1,200 min., 100% ee: 1H 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 6.99 ( dd, J = 10.8, 1.8 Hz, 1H), 6.89 (s, 1H), 6.41 (h, J = 6.8 Hz, 1H), 4.85 (dt, J = 11 .1, 7.4 Hz, 1H), 4.61 (t, J = 10.7 Hz, 1H), 4.47 (dd, J = 10.1, 7.2 Hz, 1H), 3.07 - 2.87 (m, 2H), 2.30 (m, 5H), 1.96 (h, J = 6.7 Hz, 2H). LCMS RT = 4.50 min., m/z = 428.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.50 min., ESI+ found [M+H] = 428.1. Examples 429 and 430 (R) -N -((S) -7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 - (trifluoromethyl) - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (S) -N -((S) -7,9 -difluoro -2 - oxo -2,3,4,5 - tetrahydro -1H -benzo [b]azepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [ 1,5 -a] pyridine -2 -carboxamide (1:1)

[01478] N -((S) -7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - (trifluoromethyl) -5 ,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-N-(7,9-difluoro-2-oxo -2,3,4,5 -tetrahydro -1H - benzo [b]azepin -3 -yl) -5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2.. The crude residue was further purified by means of chiral SFC (Chiralpak AD; 151 x 21.2 mm, 5 µm; elution of 30% isocratic methanol with carbon dioxide) to provide assigned diastereomers arbitrarily (R) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (23.5 mg, 29.7%) and (S) -N -( (S) -7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo [b]azepin -3 -yl) -5 -(trifluoromethyl) -5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (20.6 mg, 26.0%) as white solids:

[01479] Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC RT (AD, 25% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.568 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 9.96 (s, 1H), 8.33 (d, J = 7.5 Hz, 1H) , 7.27 (ddd, J = 10.2, 8.9, 2.8 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.40 (h, J = 6.8 Hz , 1H), 4.34 (dt, J = 11.5, 7.8 Hz, 1H), 3.06 - 2.71 (m, 4H), 2.50 - 2.15 (m, 4H), 1.94 (m, 2H). LCMS RT = 4.16 min., m/z = 430.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.16 min., ESI+ found [M+H] = 430.1.

[01480] Analytical data for the second diastereomer (arbitrarily assigned S, S configuration): SFC RT (AD, 25% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method) : 0.873 min., 98.07% purity, 96.14% ee: 1H NMR (400 MHz, DMSO -d6) δ 9.96 (s, 1H), 8.33 (d, J = 7.5 Hz , 1H), 7.27 (ddd, J = 10.2, 8.9, 2.8 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.40 (h, J = 6 .8 Hz, 1H), 4.34 (dt, J = 11.5, 7.8 Hz, 1H), 3.06 - 2.71 (m, 4H), 2.50 - 2.15 (m, 4H), 1.94 (m, 2H). LCMS RT = 4.22 min., m/z = 430.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.22 min., ESI+ found [M+H] = 430.1. Examples 431 and 432 (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl ) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and (S) -N -((S) -6,8 -difluoro - 4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2, 4] triazolo [1,5 -a] pyridine -2 -carboxamide (1:1)

[01481] N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) -[1,2,4] triazolo [1,5 -a] pyridine -2-carboxamide according to Method GZ2, The crude residue was further purified by means of chiral SFC (Chiralpak AD; 150 x21.2 mm, 5 µm; elution 30% isocratic methanol with carbon dioxide) to provide the arbitrarily assigned diastereomers (R) -N -((S) -6,8 -difluoro -4 -oxo - 2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) - 5 - (trifluoromethyl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (19.8 mg, 17.9%) and (S ) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -(trifluoromethyl) - 5,6,7,8 - tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (21.0 mg, 20.2%) as white solids:

[01482] Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC RT (AD, 25% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.535 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.08 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H) , 7.23 (ddd, J = 10.3, 9.0, 2.9 Hz, 1H), 7.03 (dt, J = 9.4, 2.3 Hz, 1H), 6.42 (h , J = 6.8 Hz, 1H), 4.90 (dt, J = 11.1, 7.3 Hz, 1H), 4.67 (t, J = 10.7 Hz, 1H), 4.53 (dd, J = 10.1, 7.1 Hz, 1H), 3.07 - 2.87 (m, 2H), 2.40 - 2.16 (m, 2H), 1.96 (h, J = 6.6 Hz, 2H). LCMS RT = 4.24 min., m/z = 432.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.24 min., ESI+ found [M+H] = 432.1.

[01483] Analytical data for the second diastereomer (arbitrarily assigned S, S configuration): SFC RT (AD, 25% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min.): 0.849 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.08 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H), 7 .23 (ddd, J = 10.3, 9.0, 2.9 Hz, 1H), 7.03 (dt, J = 9.4, 2.3 Hz, 1H), 6.42 (h, J = 6.8 Hz, 1H), 4.90 (dt, J = 11.1, 7.3 Hz, 1H), 4.67 (t, J = 10.7 Hz, 1H), 4.53 (dd , J = 10.1, 7.1 Hz, 1H), 3.07 - 2.87 (m, 2H), 2.40 - 2.16 (m, 2H), 1.96 (h, J = 6 .6Hz, 2H). LCMS RT = 4.29 min., m/z = 432.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.29 min., ESI+ found [M+H] = 432.1. Example 433 N -((S) -7,9 -difluoro -2 -oxo -2,3,4,5 - tetrahydro -1H -benzo [b]azepin -3 -yl) -5 -(1 -methyl -1H - pyrazole -4 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01484] N -((S) -7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 -(1 -methyl - 1H -pyrazol -4 -yl) -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was prepared from (S) -N - (7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo [b]azepin -3 -yl) -5 - (1 -methyl -1H -pyrazol -4 -yl) - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide according to Method GZ2. The residue was purified by prep RP-HPLC (5 -60% acetonitrile in water + 0.1% formic acid) to provide the final product (7.3 mg, 10.3%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 9.95 (s, 1H), 8.19 (dd, J = 7.6, 4.1 Hz, 1H), 7.62 (s, 1H), 7 .37 (s, 1H), 7.26 (td, J = 9.6, 2.8 Hz, 1H), 7.14 (dd, J = 8.2, 2.7 Hz, 1H), 6, 46 (t, J = 6.8 Hz, 1H), 4.32 (dt, J = 11.4, 7.8 Hz, 1H), 4.08 (q, J = 6.3 Hz, 1H), 3.78(s, 3H), 3.17 (d, J = 6.3 Hz, 3H), 2.92 (dt, J = 10.0, 6.4 Hz, 2H), 2.82 - 2 .71 (m, 2H), 2.33 - 2.17 (m, 2H), 2.12 (m, 1H), 1.92 (dd, J = 20.0, 10.3 Hz, 2H). LC-MS RT = 3.85 min., m/z = 442.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.85 min., ESI+ found [M+H] = 442.1. Examples 434 – 437

[01485] (R) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide;

[01486] (S) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide;

[01487] (S) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide;

[01488] (R) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide;

[01489] The 64% mixture of (S) -N -(7,9 - difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridine - 2 -carboxamide and 36% (S) -N -(7,9 -difluoro -2 -oxo - 2,3,4, 5-Tetrahydro-1H-benzo[b]azepin-3-yl)-5-propyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was reduced according to Method GZ2. The crude residue was further purified by chiral SFC, purified by chiral SFC (Chiralpak ID; 150 x 21.2 mm, 5 µm; elution of 30% isocratic methanol with carbon dioxide) to provide four isomers (structural isomers were assigned based on 1H NMR; diastereomers were assigned arbitrarily):

[01490] (R) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b]azepin -3 -yl) -5 - isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (19.6 mg, 19.8%) as white solids;

[01491] (S) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (8.8 mg, 8.2%) as white solids;

[01492] (S) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (19 mg, 18.6%) as white solids;

[01493] (R) -N -((S) -7,9 -difluoro -2 -oxo - 2,3,4,5 -tetrahydro -1H -benzo [b] azepin -3 -yl) -5 - propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (8.1 mg, 8.2%) as white solids.

[01494] Analytical data for the first elution isomer (arbitrarily assigned R, S configuration): SFC RT (OX, 35% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.719 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 9.95 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H) , 7.27 (ddd, J = 10.1, 8.9, 2.8 Hz, 1H), 7.19 - 7.10 (m, 1H), 4.34 (dt, J = 11.5, 7.8 Hz, 1H), 4.15 (p, J = 4.4 Hz, 1H), 2.95 - 2.85 (m, 1H), 2.72 (dtd, J = 59.4, 7 .0, 6.5, 4.0 Hz, 5H), 2.50 - 2.37 (m, 1H), 2.30 - 2.16 (m, 1H), 2.10 - 1.96 (m , 2H), 1.73 (ddd, J = 10.7, 8.2, 6.2 Hz, 2H), 0.98 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H). LCMS RT = 4.72 min., m/z = 404.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.72 min., ESI+ found [M+H] = 404.1.

[01495] Analytical data for the second elution isomer (arbitrarily assigned S, S configuration): SFC RT (OX, 35% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.950 min., 99.6% purity, 99.2% ee: 1H NMR (400 MHz, DMSO -d6) δ 9.95 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.27 (ddd, J = 10.1, 8.9, 2.8 Hz, 1H), 7.18 - 7.10 (m, 1H), 4.34 (dt, J = 11.5, 7.9 Hz, 1H), 4.21 (d, J = 7.5 Hz, 1H), 2.93 - 2.71 (m, 4H), 2.50 - 2.36 (m , 1H), 2.30 - 1.91 (m, 4H), 1.86 - 1.57 (m, 3H), 1.38 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). LCMS RT = 4.85 min., m/z = 404.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.85 min., ESI+ found [M+H] = 404.1.

[01496] Analytical data for the third elution isomer (arbitrarily assigned S, S configuration): SFC RT (OX, 35% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 1.368 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 9.95 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H) , 7.27 (ddd, J = 10.1, 8.9, 2.8 Hz, 1H), 7.19 - 7.10 (m, 1H), 4.34 (dt, J = 11.5, 7.8 Hz, 1H), 4.15 (p, J = 4.4 Hz, 1H), 2.95 - 2.85 (m, 1H), 2.72 (dtd, J = 59.4, 7 .0, 6.5, 4.0 Hz, 5H), 2.50 - 2.37 (m, 1H), 2.30 - 2.16 (m, 1H), 2.10 - 1.96 (m , 2H), 1.73 (ddd, J = 10.7, 8.2, 6.2 Hz, 2H), 0.98 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H). LCMS RT = 4.78min., m/z = 404.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.78min., ESI+ found [M+H] = 404.1.

[01497] Analytical data for the fourth elution isomer (arbitrarily assigned R, S configuration): SFC RT (OX, 35% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 1.439 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 9.95 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H) , 7.27 (ddd, J = 10.1, 8.9, 2.8 Hz, 1H), 7.18 - 7.10 (m, 1H), 4.34 (dt, J = 11.5, 7.9 Hz, 1H), 4.21 (d, J = 7.5 Hz, 1H), 2.93 - 2.71 (m, 4H), 2.50 - 2.36 (m, 1H), 2.30 - 1.91 (m, 4H), 1.86 - 1.57 (m, 3H), 1.38 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) . LCMS RT = 4.88 min., m/z = 404.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.88 min., ESI+ found [M+H] = 404.1. Examples 438 – 441

[01498] (R) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide;

[01499] (S) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01500] (S) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01501] (R) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01502] The 64% mixture of (S) -N -(6-fluoro -8 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 - il) -5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide and 36% of (S) -N -(6 -fluoro -8 - methyl -4 -oxo - 2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide was reduced according to Method GZ2. The crude residue was further purified by means of chiral SFC (Chiralpak ID; 150 x 21.2 mm, 5 µm; 35% isocratic methanol elution with carbon dioxide) to provide four isomers (structural isomers were assigned based on 1H NMR; arbitrarily assigned diastereomers):

[01503] (R) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (3.5 mg, 6.0%) as solids white in color;

[01504] (S) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1.6 mg, 2.1%) as solids white in color;

[01505] (S) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (4.1 mg, 6.8%) as solids white in color;

[01506] (R) -N -((S) -6 -fluoro -8 -methyl -4 - oxo -2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1.8 mg, 2.4%) as solids white in color.

[01507] Analytical data for the first elution isomer (arbitrarily assigned R, S configuration): SFC RT (AD, 25% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 0.874 min., 99.3% purity, 98.5% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.89 (s, 1H), 4.84 (dt, J = 11.1, 7.5 Hz, 1H), 4.59 (t, J = 10.7 Hz, 1H), 4.46 (dd, J = 10.1, 7.3 Hz, 1H), 4.16 (dt, J = 8.6, 4.6 Hz, 1H), 2.96 — 2.85 (m, 1H), 2.79 (ddd, J = 17.7, 9.9, 6.3 Hz, 1H), 2.72 - 2.59 (m, 1H), 2.30 (s, 3H), 2.07 - 1.98 (m, 2H), 1.73 (ddd, J = 10.8, 8.5, 6.7 Hz, 2H), 0 .98 (d, J = 7.0 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). LCMS RT = 4.94 min., m/z = 402.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.94 min., ESI+ found [M+H] = 402.1.

[01508] Analytical data for the second elution isomer (arbitrarily assigned S, S configuration): SFC RT (AD, 25% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min. ): 1.019 min., 94.3% purity, 88.6% ee: LCMS RT = 6.05 min., m/z = 402.1 (M+H)+.

[01509] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.05 min., ESI+ found [M+H] = 402.1.

[01510] Analytical data for the third elution isomer (arbitrarily assigned S, S configuration): SFC RT (AD, 25% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 1.220 min., 98.3% purity, 96.6% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.00 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.89 (s, 1H), 4.84 (dt, J = 11.1, 7.5 Hz, 1H), 4.59 (t, J = 10.7 Hz, 1H), 4.46 (dd, J = 10.1, 7.3 Hz, 1H), 4.16 (dt, J = 8.6, 4.6 Hz, 1H), 2.96 - 2.85 (m, 1H), 2.79 (ddd, J = 17.7, 9.9, 6.3 Hz, 1H), 2.72 - 2.59 (m, 1H), 2.30 (s, 3H), 2.07 - 1.98 (m, 2H), 1.73 (ddd, J = 10.8, 8.5, 6.7 Hz, 2H), 0 .98 (d, J = 7.0 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). LCMS RT = 4.91 min., m/z = 402.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.91 min., ESI+ found [M+H] = 402.1.

[01511] Analytical data for the fourth elution isomer (arbitrarily assigned R, S configuration): SFC RT (AD, 25% methanol + 0.1% ammonium hydroxide isocratic elution with carbon dioxide, 2.5 min. method ): 1.513 min., 96.8% purity, 91.6% ee: LCMS RT = 6.08 min., m/z = 402.1 (M+H)+.

[01512] LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.08 min., ESI+ found [M+H] = 402.1. Example 442 (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl -[1,2,4 ] triazolo [1,5 -a] pyrazine -2 -carboxamide

[01513] Using 3-phenylpyrazin-2-amine to replace 6-(trifluoromethyl) pyridin-2-amine in step 1 of Method GZ5, the steps follow. (S) -N -(5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl -[1,2,4 ] triazolo [1,5 -a] pyrazine -2 -carboxamide was prepared correspondingly from (S) -3 - amino -5 -methyl -2,3 -dihydrobenzo [b] [1,4] oxazepin -4 (5H)-one, and 8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid according to Method GZ5. Instead, the residue was purified via prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid). Final step yield: 36.5 mg, 22.9%. 1H NMR (400 MHz, DMSO -d6) δ 9.15 - 9.03 (m, 2H), 8.84 - 8.75 (m, 2H), 8.47 (d, J = 4.5 Hz, 1H), 7.70- 7.58 (m, 3H), 7.55 (dd, J = 7.6, 1.9 Hz, 1H), 7.40 - 7.23 (m, 3H), 4 .98 (dt, J = 11.5, 7.8 Hz, 1H), 4.73 (dd, J = 11.6, 9.8 Hz, 1H), 4.51 (dd, J = 9.8 , 7.7 Hz, 1H), 3.35 (s, 3H). LC-MS RT = 6.04 min., m/z = 416.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.04 min., ESI+ found [M+H] = 416.1. Example 443

[01514] GZ7 METHOD 1 -benzyl -N -(4 -methyl -2 -(morpholinomethyl) -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) -1H -1,2,4 -triazole -3 –carboxamide Step 1: 1 -benzyl -N -(2 -bromo -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01515] The title compound was prepared from 5-bromo-1H-pyrazol-3-amine and 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid according to Method Z(Wuxi ). 1H NMR (400 MHz, DMSO - d 6) δ8.82 (s, 1H), 8.62 - 8.57 (m, 1H), 7.39 - 7.30 (m, 5H), 6.57 ( s, 1H), 6.48 (s, 2H), 4.39 - 4.31 (m, 2H), 4.26 - 4.19 (m, 1H), 3.22 (s, 3H), 2 .65 - 2.56 (m, 1H), 2.44 - 2.36 (m, 1H). LCMS RT = 1.23 min., m/z = 444.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.23 min., ESI+ found [M+H] = 444.0. Examples 444 – 447

[01516] (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01517] (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01518] (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01519] (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 -isopropyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01520] The mixture of 64% (S) -N -(6,8 -difluoro -4 - oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) - 5 -isopropyl -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide and 36(S) -N -(6,8 -difluoro -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - [1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide was reduced according to Method GZ2 . The crude residue was further purified by means of chiral SFC (Chiralpak ID; 150 x 21.2 mm, 5 µm; 30% isocratic methanol elution with carbon dioxide) to provide four isomers (structural isomers were assigned based on 1H NMR; the diastereomers were assigned arbitrarily):

[01521] (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (3 mg, 4.3%) as white solids

[01522] (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1.1 mg, 1.7%) as colored solids white

[01523] (R) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -propyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (1.4 mg, 2.1%) as colored solids white

[01524] (S) -N -((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -isopropyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (3.6 mg, 6.5%) as colored solids white.

[01525] Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC RT (Whelko1 s,s, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2, 5 min.): 0.626 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.07 (s, 1H), 8.38 (d, J = 7.7 Hz , 1H), 7.23 (ddd, J = 10.4, 9.0, 2.9 Hz, 1H), 7.03 (dt, J = 9.4, 2.2 Hz, 1H), 4, 90 (dt, J = 11.1, 7.4 Hz, 1H), 4.65 (t, J = 10.7 Hz, 1H), 4.52 (dd, J = 10.2, 7.1 Hz , 1H), 4.17 (dt, J = 8.8, 4.6 Hz, 1H), 2.90 (d, J = 16.6 Hz, 1H), 2.79 (td, J = 12, 3, 10.8, 6.0 Hz, 1H), 2.68 — 2.59 (m, 1H), 2.10 - 1.98 (m, 2H), 1.84 - 1.65 (m, 2H), 0.98 (d, J = 7.1 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). LCMS RT = 4.58 min., m/z = 406.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.58 min., ESI+ found [M+H] = 406.1.

[01526] Analytical data for the second diastereomer (arbitrarily assigned S, S configuration): SFC RT (Whelko1 s, s, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method): 0.675 min., 100% purity, 100% ee: ). LCMS RT = 4.68 min., m/z = 406.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.68 min., ESI+ found [M+H] = 406.1.

[01527] Analytical data for the third elution diastereomer (arbitrarily assigned R,S configuration): SFC RT (Whelko1 s,s, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, 2.5 min. method): 0.918 min., 93.4% purity, 86.8% ee: ). LCMS RT = 4.68 min., m/z = 406.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.68 min., ESI+ found [M+H] = 406.1

[01528] Analytical data for fourth elution diastereomer (arbitrarily assigned S,S configuration) SFC RT (Whelko1 s,s, 35% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide, method 2.5 min.): 0.975 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 10.07 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.23 (ddd, J = 10.4, 9.0, 2.9 Hz, 1H), 7.03 (dt, J = 9.4, 2.2 Hz, 1H), 4.90 (dt, J = 11.1, 7.4 Hz, 1H), 4.65 (t, J = 10.7 Hz, 1H), 4.52 (dd, J = 10.2, 7.1 Hz, 1H), 4.17 (dt, J = 8.8, 4.6 Hz, 1H), 2.90 (d, J = 16.6 Hz, 1H), 2.79 (td, J = 12.3 , 10.8, 6.0 Hz, 1H), 2.68 — 2.59 (m, 1H), 2.10 — 1.98 (m, 2H), 1.84 - 1.65 (m, 2H ), 0.98 (d, J = 7.1 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). LCMS RT = 4.60 min., m/z = 406.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.60 min., ESI+ found [M+H] = 406.1. Example 448

[01529] GZ8 METHOD 1 -benzyl -N -(2 -((3,3 -difluoropyrrolidin -1 - yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: 1 -benzyl -N -(2 -formyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01530] The title compound was prepared from 5-bromo-1H-pyrazol-3-amine and 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid according to Method GZ7 following- if from step 1 to step 3, LCMS RT = 1.08 min. [method 2 min.], m/z = 394 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.08 min., ESI+ found [M+H] = 394.0, Step 2: 1-benzyl -N -(2 -((3,3 - difluoropyrrolidin -1 -yl) methyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01531] To a solution of 3,3-difluoropyrrolidine hydrochloride (40 mg, 0.102 mmol) in dichloroethane (1 mL) was added triethylamine (0.04 mL, 0.305 mmol) and allowed to stir for 10 min . 1-benzyl -N -(2-formyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 was added -yl) -1H -1,2,4 -triazole -3 -carboxamide (40 mg, 0.102 mmol) as one part, sodium triacetoxy borohydride (88 mg, 0.408 mmol) was added and allowed to stir during the night. The reaction was terminated with the addition of saturated aqueous NaHCO3 solution (10 mL) and stirring for 20 min. It was extracted with isopropyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0% to 10% methanol in dichloromethane) to providing 1-benzyl -N -(2 -((3,3-difluoropyrrolidin -1 -yl) methyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1, 5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (69 mg, 72% yield) as a tan solid: 1H NMR ( 400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.28 ( s, 1H), 6.48 (s, 2H), 4.31 (qd, J = 7.9, 2.4 Hz, 2H), 4.15 (ddd, J = 14.5, 12.6, 6.6 Hz, 1H), 3.57 (q, J = 13.4 Hz, 2H), 3.23 (s, 3H), 2.91 (t, J = 13.4 Hz, 2H), 2 .73 (t, J = 7.0 Hz, 2H), 2.67 - 2.54 (m, 1H), 2.43 - 2.10 (m, 3H). LC-MS RT = 2.88 min., m/z = 486.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.88 min., ESI+ found [M+H] = 486.2. Example 449

[01532] Prepared according to Method GZ8. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.51 (d, J = 7.7 Hz, 1H), 7.42 - 7.26 (m, 5H), 6 .26 (s, 1H), 6.48 (s, 2H), 4.36 - 4.24 (m, 2H), 4.14 (ddd, J = 14.5, 12.5, 6.6 Hz , 1H), 3.57 (t, J = 4.6 Hz, 4H), 3.48 - 3.32 (m, 2H), 3.23 (s, 3H), 2.59 (m, 1H) , 2.50 - 2.29 (m, 5H). m/z = 466.2 (M+H) +. Example 450

[01533] GZ8 Method 1-benzyl -N -(2 -((3-fluoroazetidin -1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01534] 1-Benzyl -N -(2 -((3 - fluoroazetidin -1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole was prepared [ 1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide from 1 -benzyl -N - (2 -formyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide and hydrochloride of 3-fluoroazetidine according to Method GZ8 to provide the final product (49 mg, 85%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 6H), 6 .23 (s, 1H), 6.48 (s, 2H), 6.26 - 4.98 (m, 1H), 4.35 - 4.23 (m, 2H), 4.14 (ddd, J = 14.4, 12.5, 6.6 Hz, 1H), 3.67 - 3.44 (m, 5H), 3.26 - 3.12 (m, 6H), 2.58 (tt, J = 13.5, 8.5 Hz, 1H), 2.41 - 2.28 (m, 1H). LC-MS RT = 2.58 min., m/z = 453.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.58 min., ESI+ found [M+H] = 453.2. Example 451 1-benzyl -N -(2 -((3-methoxyazetidin -1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01535] 1-Benzyl -N -(2 -((3 - methoxyazetidin -1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole was prepared [ 1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide from 1 -benzyl -N - (2 -formyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide and hydrochloride of 3-methoxy azetidine according to Method GZ8 to provide the final product (36 mg, 61%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.42 - 7.23 (m, 5H), 6 .21 (s, 1H), 6.48 (s, 2H), 4.29 (ddd, J = 16.8, 8.1, 2.4 Hz, 2H), 4.13 (ddd, J = 14 .5, 12.6, 6.6 Hz, 1H), 3.94 (p, J = 6.8 Hz, 1H), 3.48 (dt, J = 21.7, 13.2 Hz, 4H) , 3.22 (s, 3H), 3.14 (s, 3H), 2.92 - 2.81 (m, 2H), 2.57 (ddd, J = 12.7, 8.0, 4, 9Hz, 1H), 2.41 - 2.28 (m, 1H). LC-MS RT = 2.66 min., m/z = 466.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.66 min., ESI+ found [M+H] = 466.2. Example 452 GZ6 METHOD Step 1: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl - [1, 2,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[01536] Using 3-phenylpyrazin-2-amine to replace 6-(trifluoromethyl) pyridin-2-amine in step 1 of Method GZ5, the steps were followed. (S) -N -(5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) - 8 -phenyl -[1,2,4 ] triazolo [1,5 -a] pyrazine -2 - carboxamide was correspondingly prepared from (S) -3 -amino -5 -methyl -2,3 -dihydrobenzo [b] [1,4] oxazepin -4 (5H)-one, and 8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid according to Method GZ6. Instead, the residue was purified via prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid). Final step yield: 36.5 mg, 22.9%. 1H NMR (400 MHz, DMSO -d6) δ 9.15 - 9.03 (m, 2H), 8.84 - 8.75 (m, 2H), 8.47 (d, J = 4.5 Hz, 1H), 7.70- 7.58 (m, 3H), 7.55 (dd, J = 7.6, 1.9 Hz, 1H), 7.40 - 7.23 (m, 3H), 4 .98 (dt, J = 11.5, 7.8 Hz, 1H), 4.73 (dd, J = 11.6, 9.8 Hz, 1H), 4.51 (dd, J = 9.8 , 7.7 Hz, 1H), 3.35 (s, 3H). LC-MS RT = 6.04 min., m/z = 416.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.04 min., ESI+ found [M+H] = 416.1. Step 2: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl - 5.6 ,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[01537] To a solution of (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetra hydrobenzo [b][1,4] oxazepin -3 -yl) -8 - phenyl -[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (368 mg, 0.88 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added platinum(iv) oxide (20.2 mg, 0.088 mmol). The reaction mixture was stirred under a balloon of hydrogen gas for 16 h at RT, then filtered through Celite and concentrated to drying in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% methanol in dichloromethane) to provide N -((S) -5 -methyl -4 -oxo -2,3,4, 5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine - 2-carboxamide (216 mg, 52% yield) as a bronze-colored solid: 1H NMR (400 MHz, DMSO -d6) δ 8.34 (dd, J = 8.1, 1.9 Hz, 1H ), 7.49 (dt, J = 7.5, 1.5 Hz, 1H), 7.44 — 7.11 (m, 9H), 6.20 (t, J = 6.0 Hz, 1H) , 4.91 - 4.75 (m, 1H), 4.56 (ddd, J = 11.5, 9.9, 4.1 Hz, 1H), 4.37 (ddd, J = 9.9, 7.6, 6.0 Hz, 1H), 4.32 - 4.15 (m, 2H), 3.37 (q, J = 6.3 Hz, 1H), 3.32 - 3.11 (m , 4H). LC-MS RT = 3.26 min., m/z = 419.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.26 min., ESI+ found [M+H] = 419.1. Step 2: 1 -benzyl -N -(4 -methyl -5 -oxo -2 - vinyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01538] To a suspension of 1-benzyl -N -(2-bromo - 4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl)-1,2,4-triazole -3-carboxamide (3860 mg, 8.69 mmol, 1.0 equiv.) in tetrahydrofuran (80 mL) and water (20 mL) was added potassium vinyl trifluoro borate ( 2450 mg, 17.38 mmol, 2.0 equiv.) and cesium fluoride (3959 mg, 26.06 mmol, 3.0 equiv.). The mixture was then degassed for 30 min. with a stream of nitrogen. To the mixture was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (647.5 mg, 0.8688 mmol, 0.10 equiv.). The vessel was capped, and the reaction mixture was heated at 70°C for 4 days. After this period of time the mixture was diluted with dichloromethane (100 mL) and water (150 mL). The layers were separated, and the aqueous layer was extracted twice more with dichloromethane (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dry in vacuo. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 5% methanol in dichloromethane) to provide 1-benzyl -N -(4-methyl -5 -oxo -2 -vinyl -5 ,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (1070mg, 32% yield) in the form of a dark brown solid. LCMS RT = 1.17 min. [2 min. method], m/z = 392 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.17 min., ESI+ found [M+H] = 392.0. Step 3: 1 -benzyl -N -(2 -formyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01539] Ozone was bubbled through a solution of 1-benzyl -N -(4-methyl -5 -oxo -2 -vinyl -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a ][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (1070mg, 2.73 mmol, 1.0 equiv.) in methanol (20 mL) cooled to -78 °C for 45 min. The reaction was terminated with dimethyl sulfide (1.01 mL, 849 mg, 13.7 mmol, 6.0 equiv.) and allowed to warm to RT. The mixture was evaporated to dryness in vacuo, and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to provide 1-benzyl-N-(2 -formyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (600 mg, 56% yield) as a yellow solid. LCMS RT = 1.08 min. [method 2 min.], m/z = 394 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 2 min.) retention time 1.08 min., ESI+ found [M+H] = 394.0. Step 4: 1 -benzyl -N -(4 -methyl -2 - (morpholinomethyl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepine -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01540] To a solution of 1-benzyl -N -(2-formyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (40 mg, 0.102 mmol) and morpholine (0.026 mL, 0.305 mmol) in3 dichloroethane (1 mL) was added acetic acid (0. 01 mL, 0.203 mmol) and allowed to stir for 30 min. Sodium triacetoxy borohydride (65 mg, 0.305 mmol) was added and allowed to stir overnight. The reaction was basified with the addition of aq. saturated with NaHCO3 (10 mL) and stirring for 20 min. Extracted with isopropyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to drying in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% methanol in dichloromethane) to providing 1 -benzyl -N -(4 -methyl -2 -(morpholinomethyl) -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (40 mg, 85% yield) as a bronze-colored solid: 1H NMR (400 MHz, DMSO - d 6) δ 8, 81 (s, 1H), 8.51 (d, J = 7.7 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.26 (s, 1H), 6.48 (s , 2H), 4.36 - 4.24 (m, 2H), 4.14 (ddd, J = 14.5, 12.5, 6.6 Hz, 1H), 3.57 (t, J = 4 .6Hz, 4H), 3.48 - 3.32 (m, 2H), 3.23 (s, 3H), 2.59 (m, 1H), 2.50 - 2.29 (m, 5H) . LC-MS RT = 2.56 min., m/z = 466.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.56 min., ESI+ found [M+H] = 466.2. Example 453 (S) -5 -Benzyl -N -(1 -methyl -9,9 -dioxide -2 - oxo -1,2,3,4,5,10 -hexahydro -8H -thiene [3',4':3 ,4] pyrazole [1,5 -a][1,3] diazepin -3 -yl) -4H -1,2,4 -triazole -3 -carboxamide

[01541] AA Method (10.5 mg, 38% yield for the chiral separation step)

[01542] H NMR (400 MHz, DMSO -d6) δ 8.47 (bs, 1H), 7.40 - 7.17 (m, 5H), 4.56 - 4.33 (m, 6H), 4 .33 - 4.20 (m, 1H), 4.10 (s, 2H), 3.20 (s, 3H), 2.75 - 2.59 (m, 1H), 2.41 - 2.29 (m, 1H); LCMS RT = 3.40 min.; m/z = 456.1 [M + H]+.

[01543] Chiral SFC separation conditions: 20% Methanol (which contains 0.1% ammonium hydroxide) in carbon dioxide; QuiralPak OJ (250 x 21.2 mm); 70mL/min.; 40°C. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.40 min., ESI+ found [M+H] = 456.1. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.58 min., ESI+ found [M+H] = 456.1. Example 454 1 -Benzyl - N -(2 -cyclobutyl -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4 H -pyrazole [1,5 - a ][1,3] diazepin -6 -yl ) -1 H -1,2,4 -triazole -3 -carboxamide

[01544] Method Z (68 mg, 73% yield)

[01545] 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.46 – 7.27 (m, 5H ), 6.23 (s, 1H), 6.48 (s, 2H), 4.38 – 4.23 (m, 2H), 4.17 – 4.05 (m, 1H), 3.52 – 3.38 (m, 1H), 3.23 (s, 3H), 2.39 – 2.06 (m, 5H), 2.02 – 1.76 (m, 3H); LCMS RT = 4.58 min.; m/z = 420.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.58 min., ESI+ found [M+H] = 420.2. Example 455 1 -Benzyl -N -(2 -isopropyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6-yl) -1H -1,2,4 -triazole -3 -carboxamide Method Z (52 mg, 55% yield)

[01546] 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.43 - 7.26 (m, 5H ), 6.18 (s, 1H), 6.48 (s, 2H), 4.39 - 4.23 (m, 2H), 4.20 - 4.03 (m, 1H), 3.22 ( s, 3H), 2.86 (hept, J = 7.0 Hz, 1H), 2.40 - 2.24 (m, 2H), 1.21 (d, J = 6.9 Hz, 6H); LCMS RT = 4.08 min.; m/z = 408.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.08 min., ESI+ found [M+H] = 408.2. Example 456 1 -Benzyl -N -(2 -(cyclopropylmethyl) -4 -methyl -5-oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) -1H -1,2,4 -triazole -3 -carboxamide

[01547] Method Z (65 mg, 69% yield)

[01548] 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 7.45- 7.24 (m, 5H ), 6.21 (s, 1H), 6.48 (s, 2H), 4.37 - 4.04 (m, 3H), 3.23 (s, 3H), 2.47 - 2.29 ( m, 4H), 1.06 - 0.89 (m, 1H), 0.52 - 0.41 (m, 2H), 0.24 - 0.10 (m, 2H); LCMS RT = 4.51 min.; m/z = 420.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.51 min., ESI+ found [M+H] = 420.2. Example 457 (S) -1 -Benzyl -N -(2 -cyclobutyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01549] Method Z (68 mg, 73% yield)

[01550] 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.46 - 7.27 (m, 5H ), 6.23 (s, 1H), 6.48 (s, 2H), 4.38 - 4.23 (m, 2H), 4.17 - 4.05 (m, 1H), 3.52 - 3.38 (m, 1H), 3.23 (s, 3H), 2.39 - 2.06 (m, 5H), 2.02 - 1.76 (m, 3H); LCMS RT = 4.60 min.; m/z = 420.2 [M + H]+.

[01551] Chiral SFC separation condition: 40% Methanol (which contains 0.1% ammonium hydroxide) in carbon dioxide; Cellulose -1 (150 x 21.2 mm); 70mL/min.; 40°C. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.60 min., ESI+ found [M+H] = 420.2. Example 458 (S) -1 -Benzyl -N -(2 -isopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01552] Method Z (18 mg, 72% yield for the SFC chiral separation step)

[01553] 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 7.45- 7.24 (m, 5H ), 6.18 (s, 1H), 6.48 (s, 2H), 4.38 - 4.23 (m, 2H), 4.18 - 4.03 (m, 1H), 3.22 ( s, 3H), 2.86 (hept, J = 6.9 Hz, 1H), 2.66 - 2.53 (m, 1H), 2.41 - 2.26 (m, 1H), 1.21 (dd, J = 6.9, 4.4 Hz, 6H); LCMS RT = 4.45min.; m/z = 408.2 [M + H]+.

[01554] SFC chiral separation condition: 35% Methanol in Carbon dioxide; Cellulose -1 (150 x 21.2 mm); 70mL/min.; 40°C. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.45min., ESI+ found [M+H] = 408.2. Example 459 (S) -1 -benzyl -N -(2 -(cyclopropylmethyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[01555] Method Z (27.8 mg)

[01556] H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.45- 7.22 (m, 5H ), 6.22 (s, 1H), 6.48 (s, 2H), 4.38 - 4.22 (m, 2H), 4.20 - 4.04 (m, 1H), 3.23 ( s, 3H), 2.63 - 2.55 (m, 1H), 2.43 (t, J = 6.5 Hz, 2H), 2.39 - 2.28 (m, 1H), 1.03 - 0.93 (m, 1H), 0.52 - 0.42 (m, 2H), 0.25- 0.12 (m, 2H); LCMS RT = 4.53 min.; m/z = 420.2 [M + H]+.

[01557] SFC chiral separation condition: 35% Methanol in Carbon dioxide; Cellulose -1 (150 x 21.2 mm); 70mL/min.; 40°C. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.53 min., ESI+ found [M+H] = 420.2. Example 460 1 -Benzyl -N -(2-ethyl -4 -methyl -5 -oxo -5,6,7,8-tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01558] Method Z (10.8 mg, 10% yield)

[01559] 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.44 – 7.26 (m, 5H ), 6.16 (s, 1H), 6.48 (s, 2H), 4.40 – 4.23 (m, 2H), 4.15 – 4.04 (m, 1H), 3.22 ( s, 3H), 2.62 – 2.51 (m, 3H), 2.40 – 2.25(m, 1H), 1.18 (t, J = 7.6 Hz, 3H); LCMS RT = 4.14 min.; m/z = 394.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.14 min., ESI+ found [M+H] = 394.2. Example 461 1 -Benzyl -N -(2 -isopropoxy -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01560] Method Z (84 mg, 73% yield)

[01561] 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.43 - 7.26 (m, 5H ), 6.79 (s, 1H), 6.48 (s, 2H), 4.68 (hepta, J = 6.1 Hz, 1H), 4.37 (dt, J = 11.5, 7, 8 Hz, 1H), 4.15 - 4.02 (m, 2H), 3.20 (s, 3H), 2.64 - 2.53 (m, 1H), 2.39 - 2.25(m , 1H), 1.28 (d, J = 6.1 Hz, 3H), 1.26 (d, J = 6.1 Hz, 3H); LCMS RT = 4.44 min.; m/z = 424.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.44 min., ESI+ found [M+H] = 424.2. Example 462 (S) -1 -Benzyl -5 -methyl -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[01562] Method B (57 mg, 56% yield)

[01563] 1H NMR (400 MHz, DMSO -d6) δ 8.46 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.26 - 7.18 (m, 2H), 6.34 (d, J = 2.0 Hz, 1H), 6.44 (s, 2H), 4.44 - 4.12 (m, 3H), 3.25(s, 3H), 2.66 - 2.53 (m, 1H), 2.46 (s, 3H), 2.43 - 2.32 (m , 1H); LCMS RT = 3.78min.; m/z = 380.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.78min., ESI+ found [M+H] = 380.2. Example 463 N -(2 -Ethyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -( 2-fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide

[01564] Method Z (159 mg, 61% yield)

[01565] 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.50 - 7.15 (m, 4H ), 6.16 (s, 1H), 6.55 (s, 2H), 4.39 - 4.22 (m, 2H), 4.14 - 4.00 (m, 1H), 3.22 ( s, 3H), 2.62 - 2.52 (m, 3H), 2.41 - 2.25(m, 1H), 1.18 (t, J = 7.6 Hz, 3H); LCMS RT = 4.27 min.; m/z = 412.2 [M + H]+. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.27 min., ESI+ found [M+H] = 412.2. Example 464 (S) -N -(2 -ethyl -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(2-fluorobenzyl) -1H -1,2,4 -triazole -3 -carboxamide

[01566] Method Z (78mg, 97% yield in the chiral separation step)

[01567] 1H NMR (400 MHz, DMSO -d6) δ 8.80 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 7.47 - 7.18 (m, 4H ), 6.16 (s, 1H), 6.55 (s, 2H), 4.39 - 4.23 (m, 2H), 4.19 - 4.03 (m, 1H), 3.22 ( s, 3H), 2.70- 2.50 (m, 3H), 2.41 - 2.21 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H). Example 465 (R) -5 -(2-fluorophenyl) -N -((S) -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (10.8 mg, 14% yield)

[01568] 1H NMR (400 MHz, DMSO -d6) δ 8.50 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.30 -7.20 (m, 3H), 6.33 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.7, 6.7 Hz, 1H), 4.42 - 4.09 (m, 3H), 3.28 - 3.17 (m, 4H), 3.14 - 2.97 (m, 2H), 2.70 - 2.53 (m, 2H), 2.43 - 2.27 (m, 1H). Example 466 (S) -5 -(2-fluorophenyl) -N -((S) -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (11.1 mg, 14% yield)

[01569] 1H NMR (400 MHz, DMSO -d6) δ 8.53 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.31 - 7.19 (m, 3H), 6.33 (d, J = 2.0 Hz, 1H), 6.78(dd, J = 8.7, 6.7 Hz, 1H), 4.43 - 4.09 (m, 3H), 3.29 - 3.17 (m, 4H), 3.11 - 2.99 (m, 2H), 2.71 - 2.53 (m, 2H), 2.43 - 2.28 (m, 1H). Example 467 (S) -5 -(2 -fluorophenyl) -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl ) - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide (10.8 mg, 14% yield)

[01570] 1H NMR (400 MHz, DMSO -d6) δ 8.43 (d, J = 8.0 Hz, 1H, NH), 7.52 - 7.47 (m, 1H), 7.47 - 7 .40 (m, 1H), 7.34 - 7.19 (m, 6H), 6.78(dd, J = 8.6, 6.7 Hz, 1H), 4.81 (dt, J = 11 .5, 7.8 Hz, 1H), 4.58 (dd, J = 11.6, 9.9 Hz, 1H), 4.39 (dd, J = 9.9, 7.7 Hz, 1H) , 3.30 (s, 3H), 3.27 - 3.18 (m, 1H), 3.16 - 2.95 (m, 2H), 2.70 - 2.54 (m, 1H). Example 468 (R) -5 -(2 -fluorophenyl) -N -((S) -5 -methyl -4 - oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl ) - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide (8.8 mg, 11% yield)

[01571] 1H NMR (400 MHz, DMSO -d6) δ 8.43 (d, J = 8.0 Hz, 1H, NH), 7.53 - 7.45(m, 1H), 7.47 - 7 .39 (m, 1H), 7.35 - 7.19 (m, 6H), 6.78(dd, J = 8.7, 6.7 Hz, 1H), 4.81 (dt, J = 11 .5, 7.8 Hz, 1H), 4.57 (dd, J = 11.5, 9.9 Hz, 1H), 4.39 (dd, J = 9.9, 7.7 Hz, 1H) , 3.31 (s, 3H), 3.28 - 3.17 (m, 1H), 3.11 - 2.98 (m, 2H), 2.68 - 2.56 (m, 1H). Example 469

[01572] WX 135 Method N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -6 - (2,2,2 -trifluoroethyl) -5,6,7, 8 - tetrahydroimidazo[1,5 -a] pyridine -3 –carboxamide Step 1: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol

[01573] To a solution of 6-bromo nicotinaldehyde (3.0 g, 16.13 mmol) in tetrahydrofuran (100 mL) was added (trifluoromethyl) trimethylsilane (467 mg, 3.28 mmol) and tetrabutylammonium fluoride (0. 27 ml, 0.27 mmol) under 0oC. The resulting mixture was heated to 25°C and stirred for 48 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 1 -(6-bromo-3-pyridyl)-2,2, 2-trifluoroethanol (3.8 g, 92%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ8.44(d, J = 2.0 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.11 (q, J = 6.8 Hz, 1H). Step 2: 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinamide

[01574] A mixture of 1 -(6-bromo-3-pyridyl) - 2,2,2-trifluoro-ethanol (3.8 g, 14.84 mmol) and copper (I) cyanide (2.66 g , 29.69 mmol) in 1-methyl-2-pyrrolidinone (50 mL) was heated at 130oC for 10 h. The reaction mixture was poured into 10% ammonium hydroxide (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 60% ethyl acetate in petroleum ether) to provide 5-(2,2,2-trifluoro-1-hydroxy-ethyl )pyridine-2-carboxamide (2 g, 61%) in the form of a yellow oil. LCMS RT = 0.98 min.; m/z = 221.0 (M+H)+. LCMS (10 - 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 0.98/min., ESI+ found [M+H] = 221.0. Step 3: 1-(6-carbamoylpyridin-3-yl)-2,2,2-trifluoroethyl 4-methylbenzene sulfonate

[01575] To a solution of 5-(2,2,2-trifluoro-1-hydroxy-ethyl)pyridine-2-carboxamide (2.0 g, 9.08 mmol) in dichloromethane (50 mL) was added triethylamine ( 1.84 g, 18.17 mmol), p -toluenesulfonyl chloride (2.60 g, 13.63 mmol) and 4-dimethylamino pyridine (222 mg, 1.82 mmol) under 0oC. After addition, the reaction mixture was subjected to stirring at 25°C for 5 h. The reaction mixture was poured into water (5 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 40% ethyl acetate in petroleum ether) to provide [1-(6-carbamoyl-3-pyridyl)-2 sulfonate ,2,2-trifluoro-ethyl]4-methylbenzene (1.8 g, 53%) as a white solid. LCMS RT = 0.72 min.; m/z = 374.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.72 min., ESI+ found [M+H] =374.9. Step 4: 1-(6-cyanopyridin-3-yl)-2,2,2-trifluoroethyl 4-methylbenzene sulfonate

[01576] A solution of [1-(6-carbamoyl-3-pyridyl)-2,2,2-trifluoro-ethyl]4-methylbenzene sulfonate (1.8 g, 4.81 mmol) in tetrahydrofuran (100 mL ) was treated with triethylamine (1.46 g, 14.43 mmol) and trifluoroacetic anhydride (1.52 g, 7.21 mmol) under 0°C. The resulting mixture was subjected to stirring at 25°C for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 33% ethyl acetate in petroleum ether) to provide [1-(6-cyano-3-pyridyl)-2 sulfonate ,2,2-trifluoro-ethyl]4-methylbenzene (1.5 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.70(s, 1H), 7.92 - 7.90 (m, 1H), 7.74 - 7.70(m, 3H), 7.34 - 7.32 (m, 1H), 6.75 (q, J = 6.8 Hz, 1H), 2.46 (s, 3H). Step 5: tert -butyl((5-(2,2,2-trifluoroethyl)pyridin-2-yl)methyl) carbamate

[01577] A mixture of [1-(6-cyano-3-pyridyl)-2,2,2-trifluoro-ethyl]4-methylbenzene sulfonate (1.30 g, 3.65 mmol), Pd/C ( 10%, 389 mg, 0.37 mmol) and hydrochloric acid (36%, 1.11 g, 10.95 mmol) in methanol (100 mL) was hydrogenated [4.46 bar (50 psi)] for 24 h. The reaction mixture was filtered and the filtrate was adjusted to pH = 10 by adding 2N sodium hydroxide (1 mL) and then di-tert-butyldicarbonate (1.59 g, 7.30 mmol) was added to the solution. aforementioned. The reaction mixture was stirred at 25°C for 10 h and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 40% ethyl acetate in petroleum ether) to provide tert -butyl N -[[5 -(2,2,2 - trifluoroethyl)-2-pyridyl] methyl] carbamate (1.0 g, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.47 (s 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.31(d, J = 2.0 Hz, 1H), 6, 54 (s, 1H), 4.47 - 4.45(m, 2H), 3.40 (q, J = 6.8 Hz, 2H), 1.47 (s, 9H). Step 6: (5-(2,2,2-trifluoroethyl)pyridin-2-yl)methanamine hydrochloride

[01578] A solution of tert -butyl N -[[5 -(2,2,2 - trifluoroethyl) -2 -pyridyl] methyl] carbamate (1.0 g, 3.44 mmol) in ethyl acetate (20 mL ) was treated with hydrochloric acid (4N in ethyl acetate, 4.0 mL, 16.0 mmol). The resulting mixture was stirred at 25°C for 1 h and concentrated under reduced pressure to provide crude [5-(2,2,2-trifluoroethyl)-2-pyridyl] methanamine hydrochloride (800 mg, 100%) in the form of a white solid, which was used in the next stage as it was. Step 7: Ethyl 2 -oxo -2 -(((5 -(2,2,2 - trifluoroethyl)pyridin -2 -yl) methyl)amino)acetate

[01579] A mixture of [5-(2,2,2-trifluoroethyl)-2-pyridyl] methanamine hydrochloride (300 mg, 1.32 mmol) and triethylamine (536 mg, 6.29 mmol) in tetrahydrofuran (20 mL) was treated with ethyloxalyl chloride (271 mg, 1.99 mmol) under 0°C. After addition, the reaction mixture was stirred at 25°C for 5 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude ethyl 2-oxo-2-[[5-(2,2,2-trifluoroethyl)-2-pyridyl]methylamino]acetate (400 mg, 100%) as a brown solid. LCMS RT = 0.53 min.; m/z = 290.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.53 min., ESI+ found [M+H] =290.8. Step 8: Ethyl 6-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine-3-carboxylate

[01580] A mixture of ethyl 2 -oxo -2 -[[5 -(2,2,2 - trifluoroethyl) -2 -pyridyl] methylamino] acetate (350 mg, 1.21 mmol) and phosphorus oxychloride (16, 88 g, 110.09 mmol) was heated at 110oC for 10 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide methyl 6-(2,2,2-trifluoroethyl) imidazo [1, 5 - a] pyridine -3 -carboxylate (150 mg, 48%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ9.34 (s, 1H), 7.65(d, J = 2.0 Hz, 1H), 7.31(d, J = 2.0 Hz, 1H), 7 .65 - 7.63(m, 2H), 7.04 — 7.02(m, 1H), 4.52(q, J = 6.8 Hz, 2H), 3.40 (q, J = 6 .8 Hz, 2H), 1.49 (t, J = 4.2 Hz, 2H). Step 9: Ethyl 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

[01581] A mixture of ethyl 6 -(2,2,2 - trifluoroethyl) imidazo[1,5 -a] pyridine -3 -carboxylate (150 mg, 0.55 mmol) and Pd/C (10%, 30 mg ) in methanol (10 mL) was hydrogenated [4.46 bar (50 psi)] under 50°C for 10 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep TLC (50% ethyl acetate in petroleum ether) to give methyl 6-(2,2,2-trifluoroethyl)-5,6,7 ,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (100 mg, 69%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ6.95 (s, 1H), 4.84 - 4.79 (m, 1H), 3.94 - 3.85 (m, 4H), 3.02 - 1H), 2.83 - 2.82 (m, 1H), 2.38-2.09 (m, 5H). Step 10: Potassium 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

[01582] A mixture of methyl 6 - (2,2,2 - trifluoroethyl) -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine -3 -carboxylate (30 mg, 0.11 mmol) in water (1 mL) and tetrahydrofuran (2 mL) was treated with potassium hydroxide (12 mg, 0.23 mmol). The resulting mixture was stirred at 25°C for 1 h and then concentrated under reduced pressure to provide potassium 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine Crude -3-carboxylate (30 mg, 92%) as a white solid, used in the next step in the form in which it was. Step 11: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -6 - (2,2,2 -trifluoroethyl) -5,6 ,7,8 - tetrahydroimidazo[1,5 -a] pyridine -3 -carboxamide

[01583] A mixture of potassium 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (30 mg, 0.10 mmol) , (3S)-3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (24 mg, 0.13 mmol) and (7-Azabenzotriazol -1 -yloxy) tripyrrolidino phosphonium hexafluorophosphate (65 mg, 0.13 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25°C for 10 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (40% to 70% acetonitrile / 0.05% ammonium hydroxide in water) to give N -[(3S)-5-methyl - 4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -6 - (2,2,2 -trifluoroethyl) -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine-3-carboxamide (6.6 mg, 15%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.44 - 7.41 (m, 1H), 7.32 - 7.29 (m, 2H), 7.24 - 7.22 (m, 1H), 6.83 (s, 1H), 4.95 - 4.90 (m, 1H), 4.85 - 4.80 (m, 1H), 4.60 - 4.55 (m, 1H), 4.38 - 4 .34 (m, 1H), 3.85 - 3.83 (m, 1H), 3.41 (s, 3H), 3.01 - 2.96 (m, 1H), 2.80 - 2.78 (m, 1H), 2.35 - 2.30 (m, 3H), 2.08 - 2.05 (m, 1H), 1.62 - 1.60 (m, 1H). LCMS RT = 2.52 min., m/z = 423.1 (M+H)+. LCMS (0 - 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 2.52 min., ESI+ found [M+H] = 423.1. Example 470

[01584] Method WX 001 N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 - (tetrahydrofuran - 2 -ylmethyl) -1,2,4 -triazole -3 - carboxamide

[01585] A mixture of potassium carbonate (328 mg, 2.38 mmol), N -[(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1, 5 -a][1,3] diazepin -6 -yl] - 1H -1,2,4 -triazole -3 -carboxamide (150 mg, 0.48 mmol) and 2 -(bromomethyl) tetrahydrofuran (160 mg, 0 .97 mmol) in N,N - dimethylformamide (5 mL) was stirred at 25oC for 15 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (13 -43% acetonitrile/0.05% ammonium hydroxide in water) to provide N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydrofuran -2 -ylmethyl) -1,2,4 -triazole -3 -carboxamide (29.1 mg, 15%) as white solids. H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 6.01 (s, 1H), 4.56 - 4.51 (m, 1H), 4.38 - 4.23 (m, 5H), 3.84 - 3.74 (m, 2H), 3.32 (s, 3H), 2.87 - 2.85 (m, 1H),2.27 - 2.25(m, 1H) , 2.25 - 2.23 (m, 1H), 1.94 - 1.87 (m, 3H), 1.83 - 1.81 (m, 1H), 0.95 - 0.92 (m, 2H), 0.75 - 0.73 (m, 2H). LC-MS RT = 0.700 min., m/z = 400.1 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.700 min., ESI+ found [M+H] = 400.1. Example 471 1 -[(3,5-difluorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01586] N –Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (50 -80% methanol / 0.05% ammonium hydroxide in water) to provide 1 - [(3,5-difluorophenyl) methyl] -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8-dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -6 -yl] -1,2,4 -triazole -3 -carboxamide (28 mg, 32%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.61 (s, 1H), 6.96 – 6.90 (m, 3H), 6.10 (s, 1H), 6.48 (s, 2H), 4, 54 – 4.49 (m, 1H), 4.2 – 4.27 (m, 1H), 4.24 – 4.19 (m, 1H), 3.29 (m, 3H), 2.85 – 2.79 (m, 1H), 2.28 – 2.21 (m, 4H). LC-MS RT = 0.756 min., m/z = 416.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.756 min., ESI+ found [M+H] =416.1. Example 472

[01587] A mixture of N -[(6S) -2,4 -dimethyl -5 - oxo -7,8-dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] -1H -1,2,4 -triazole -3 -carboxamide (60 mg, 0.21 mmol), 1 -(bromomethyl)-2,3 -dichloro-benzene (59 mg, 0.25 mmol) and potassium carbonate (86 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (55 -85% methanol/0.05% ammonium hydroxide in water) to provide (1 -[(2,3 -dichlorophenyl) methyl] -N -(6S) - 2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 - triazole -3 -carboxamide (19 .4 mg, 21%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 7.55 - 7.53 (m, 1H), 7.33 - 7.29 (m, 1H), 7.22 - 7.20 (m, 1H), 6.09 (s, 1H), 6.63 (s, 2H), 4.53 - 4.48 (m , 1H), 4.29 - 4.27 (m, 1H), 4.22 - 4.15 (m, 1H), 3.30 (s, 3H), 2.85 - 2.78(m, 1H) ), 2.27 - 2.20 (m, 4H). LCMS RT = 0.791 min., m/z = 448.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.791 min., ESI+ found [M+H] = 448.1. Example 473 1 -[(2,4-dichlorophenyl) methyl] -N -[(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01588] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (60 -90% methanol/0.05% ammonium hydroxide in water) to provide 1 - [(2,4-dichlorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6-yl -1,2,4 - triazole -3 -carboxamide (16.7 mg, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.59 (s, 1H), 7.52 (s, 1H), 7.41 - 7.30 (m, 2H), 6.99 (s, 1H), 6, 57 (s, 2H), 4.53 - 4.48 (m, 1H), 4.28 - 4.26 (m, 1H), 4.20 - 4.17 (m, 1H), 3.29 ( s, 3H), 2.85 - 2.78(m, 1H), 2.27 - 2.22 (m, 1H), 1.91 - 1.86 (m, 1H), 0.92 - 0, 91 (m, 2H), 0.77 - 0.71 (m, 2H). LC-MS RT = 0.831 min., m/z = 474.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.831 min., ESI+ found [M+H] = 474.1. Example 474 N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydrofuran -2 - ylmethyl) -1,2,4 -triazole -3 -carboxamide

[01589] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (12-42% acetonitrile/0.05% ammonium hydroxide in water) to provide N - (6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1 -(tetrahydrofuran -2 -ylmethyl) - 1,2,4-triazole-3-carboxamide (68.1 mg, 35%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 6.12 (s, 1H), 4.55 — 4.53 (m, 1H), 4.41 — 4.18 (m, 5H), 3.83 (q, J = 6.8 Hz, 1H), 3.78- 3.71 (m, 1H), 3.33 (s, 3H), 2.91 - 2.82 (m , 1H), 2.33 - 2.19 (m, 4H), 2.12 - 2.05 (m, 1H), 1.94 - 1.79 (m, 2H), 1.73 - 1.65 (m, 1H). LC-MS RT = 1.114 min., m/z = 374.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.114 min., ESI+ found [M+H] = 374.2. Example 475 N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydropyran -3 - ylmethyl) -1,2,4 -triazole -3 -carboxamide

[01590] N -Alkylation prepared in a manner similar to Method WX 001. The crude material was purified via RP-HPLC (22-32% acetonitrile/0.05% ammonium hydroxide in water), and the material partially epimerized was further purified by chiral SFC to provide N -(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepine -6 -yl -1 - (tetrahydropyran -3 -ylmethyl) -1,2,4 -triazole -3 - carboxamide (Peak 1, (Retention time = 1.699 min.) & Peak 2 (Retention time = 1.883 min.) )) (21.2 mg, 52%) in the form of a yellow oil. 1H NMR (400 MHz, CD3OD) δ8.48 (s, 1H), 6.12 (s, 1H), 4.53 - 4.51(m, 1H), 4.31 — 4.19 (m, 4H ), 3.76 - 3.74 (m, 2H), 3.48 - 3.46 (m, 1H), 3.33 (s, 3H), 3.31 - 3.25(m, 1H), 2.85 - 2.83 (m, 1H), 2.28 - 2.22 (m, 5H), 1.73 - 1.70(m, 2H), 1.60 - 1.50 (m, 1H) ), 1.34 - 1.31 (m, 1H). LC-MS RT = 1.176 min., m/z = 388.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.176 min., ESI+ found [M+H] = 388.1.

[01591] SFC condition: column: chiralcel OD -3 50x4.6 mm ID, 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: held 5% for 0.2 min, then from 5% to 40% Bin 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 2.8 mL/min. Column temperature: 40 oC. Example 476 N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydropyran -2 - ylmethyl) -1,2,4 -triazole -3 -carboxamide

[01592] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (0-40% acetonitrile/0.05% ammonium hydroxide in water) to provide N - (6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1 -(tetrahydropyran -2 -ylmethyl) - 1,2,4 -triazole -3 -carboxamide (10 mg, 5%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 6.11 (s, 1H), 4.54 — 4.40 (m, 1H), 4.37 — 4.17 (m, 4H), 3.96 - 3.87 (m, 1H), 3.76 - 3.67 (m, 1H), 3.38 - 3.31 (m, 4H), 2.93 - 2.78 ( m, 1H), 2.26 (s, 4H), 1.86 (s, 1H), 1.67 - 1.65 (m, 1H), 1.61 - 1.46 (m, 3H), 1 .34 - 1.20 (m, 1H) LC-MS RT = 1.298 min., m/z = 388.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.298 min., ESI+ found [M+H] = 388.2. Example 477 N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 - (tetrahydropyran - 2 -ylmethyl) -1,2,4 -triazole -3 - carboxamide

[01593] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (0-40% acetonitrile/0.05% ammonium hydroxide in water) to provide N - (6S) - 2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydropyran -2 - ylmethyl)-1,2,4-triazole-3-carboxamide (38 mg, 19%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 6.03 (s, 1H), 4.55 - 4.53 (m, 1H), 4.37 - 4.13 (m, 4H), 3.93 - 3.82 (m, 1H), 3.79 - 3.67 (m, 1H), 3.44 - 3.36 (m, 1H), 3.34 (s, 3H) , 2.94 - 2.80 (m, 1H), 2.31 - 2.23 (m, 1H), 2.00 - 1.83 (m, 2H), 1.71 - 1.68(m, 1H), 1.63 - 1.48 (m, 3H), 1.39 - 1.21 (m, 1H), 0.97 - 0.94 (m, 2H), 0.84 - 0.68 ( m, 2H). LC-MS RT = 1.458 min., m/z = 414.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.458 min., ESI+ found [M+H] = 414.2. Example 478 N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 - (tetrahydropyran - 3 -ylmethyl) -1,2,4 -triazole -3 - carboxamide

[01594] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (20 -50% acetonitrile/0.05% ammonium hydroxide in water) to provide N - (6S) - 2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydropyran -3 - ylmethyl)-1,2,4-triazole-3-carboxamide (27.4 mg, 14%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.48 (s, 1H), 6.00 (s, 1H), 4.54 - 4.53 (m, 1H), 4.30 - 4.20 (m, 4H ), 3.76 - 3.73 (m, 2H), 3.50 - 3.46 (m, 1H), 3.31 (s, 3H), 3.28 - 3.27 (m, 1H), 2.90 - 2.85 (m, 1H), 2.26 - 2.21 (m, 2H), 1.91 - 1.90 (m, 1H), 1.80 - 1.70 (m, 2H ), 1.70 - 1.65 (m, 1H), 1.40 - 1.35 (m, 1H), 0.94 - 0.92 (m, 2H), 0.75 - 0.70(m , 2H). LC-MS RT = 1.781 min., m/z = 414.2 [M+H] +. LCMS (0 to 60% ammonium hydroxide in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.781 min., ESI+ found [M+H] = 414.2. Example 479 N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydrofuran -3 - ylmethyl) -1,2,4 -triazole -3 -carboxamide

[01595] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (acetonitrile 42 -62%/0.05% ammonium hydroxide in water) to provide N - (6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1 -(tetrahydrofuran -3 -ylmethyl) - 1,2,4 -triazole -3 -carboxamide (19.1 mg, 10%) as white solids. 1H NMR (CD3OD) δ 8.53 (s, 1H), 6.12 (s, 1H), 4.57 - 4.54 (m, 1H), 4.36 - 4.18 (m, 4H), 3.93 - 3.86 (m, 1H), 3.82 - 3.71 (m, 2H), 3.62 - 3.60 (m, 1H), 3.34 (s, 3H), 2, 92 - 2.80 (m, 2H), 2.31 - 2.22 (m, 4H), 2.11 - 2.01 (m, 1H), 1.76 - 1.66 (m, 1H). LC-MS RT = 1.383 min., m/z = 374.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.383 min., ESI+ found [M+H] = 374.2 Example 480 N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 - (tetrahydrofuran - 3 -ylmethyl) -1,2,4 -triazole -3 - carboxamide

[01596] N -Alkylation prepared in a similar manner to Method WX 001. The crude material was purified via RP-HPLC (acetonitrile 42 -62%/0.05% ammonium hydroxide in water) to provide N - (6S) - 2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 -(tetrahydrofuran -3 - ylmethyl)-1,2,4-triazole-3-carboxamide (20.1 mg, 11%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 6.02 (s, 1H), 4.56 - 4.54 (m, 1H), 4.35 - 4.15 (m, 4H), 3.95 - 3.90 (m, 1H), 3.82 - 3.71 (m, 2H), 3.62 - 3.60 (m, 1H), 3.32 (s, 3H) , 2.92 - 2.80 (m, 2H), 2.30 - 2.26 (m, 1H), 2.11 - 2.01 (m, 1H), 1.95 - 1.87 (m, 1H), 1.76 - 1.66 (m, 1H), 0.98 - 0.91 (m, 2H), 0.78- 0.71 (m, 2H). LC-MS RT = 0.813 min., m/z = 400.3 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 0.813 min., ESI+ found [M+H] = 400.3 Example 481

[01519] WX 164 Method N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7 ,1'-cyclopentane]-2-carboxamide Step 1: 2' -chloro -5'H -spiro [cyclopentane - 1,7' -furo [3,4 -d] pyrimidin] -5' -one

[01597] To a solution of 2,2,6,6-tetramethyl piperidine (26.73 g, 189.2 mmol) in tetrahydrofuran (140 mL) was added n-butyllithium (2.5 M in hexanes, 100. 0 mL, 250.0 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (10.0 g, 63.1 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and cyclopentanone (10.61 g, 126.2 mmol) was added. After addition, the reaction mixture was stirred at 25oC for 16 h and finalized by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 2'-chloro-5'H-spiro [cyclopentane -1, 7'-hole [3,4-d] pyrimidin]-5'-one (2.5 g, 18%) as a white solid, which was used in the next step as is. Step 2: 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1'-cyclopentane]-5-ol

[01598] To a solution of 2'-chlorospiro [cyclopentane -1,7'-furo[3,4-d]pyrimidine]-5'-one (1.0 g, 4.45mmol) in toluene (20 mL) Diatyl aluminum hydride (13.4 mL, 13.35 mmol, 1.0 M in toluene) was added under -78°C. The reaction mixture was stirred at -78oC for 2 h and finalized by the addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 2-chlorospiro[5H-furo[3,4-d]pyrimidine -7,1'-cyclopentane]-5-ol crude (800 mg, 79%) in the form of a yellow oil, which was used in the next step as it was. Step 3: 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1'-cyclopentane]

[01599] To a solution of 2-chlorospiro [5H-furo[3,4-d]pyrimidine-7,1'-cyclopentane]-5-ol (800 mg, 3.53 mmol) and trifluoroacetic acid (4, 02 g, 36.30 mmol) in dichloromethane (20 mL) triethylsilane (4.10 g, 36.30 mmol) was added under 0°C. The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 2-chlorospiro [5H - fur [3,4 -d] pyrimidine - 7,1'-cyclopentane] (300 mg, 40%) in the form of a yellow oil, which was used in the next step as it was. Step 4: 5'H -spiro [cyclopentane -1,7' -fur [3,4 -d] pyrimidine] -2' -carbonitrile

[01600] To a solution of 2-chlorospiro [5H-furo[3,4-d]pyrimidine-7,1'-cyclopentane] (300 mg, 1.42 mmol) in dimethyl sulfoxide (10 mL) and water ( 5 mL) 1,4-diazabicyclo[2,2,2] octane (174 mg, 1.55 mmol) and sodium cyanide (120 mg, 2.45 mmol) were added. The reaction mixture was stirred at 20°C for 16 h and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 5'H -spiro [cyclopentane - 1,7'-furopyrimidine] -2'-carbonitrile (250 mg, 87%) in the form of a yellow oil, which was used in the next step as is. Step 5: Methyl 5'H –spiro [cyclopentane -1,7' -furo [3,4 -d] pyrimidine] -2' -carboxylate

[01601] To a solution of 5'H –spiro [cyclopentane - 1,7' -furo [3,4 -d] pyrimidine] -2' -carbonitrile (250 mg, 1.24 mmol) in methanol (3 mL) HCl (4N in methanol, 1.6 mL) was added. The reaction mixture was heated at 70°C for 2 h and concentrated under reduced pressure to provide crude methyl 5'H-spiro[cyclopentane-1,7'-furo[3,4-d]pyrimidine]-2'-carboxylate ( 200 mg, 69%) in the form of a yellow oil, which was used in the next step as is. Step 6: 5'H-Spiro[cyclopentane-1,7'-furo[3,4-d]pyrimidine]-2'-carboxylic acid

[01602] A mixture of methyl 5'H -spiro[cyclopentane -1,7'-furo[3,4-d]pyrimidine]-2'-carboxylate (200 mg, 0.85 mmol) and hydrated lithium hydroxide ( 358 mg, 8.54 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at 20oC for 2 h. The mixture was finalized by adding 1N HCl (3 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 5'H-spiro[cyclopentane-1,7'-furo[3,4-d]pyrimidine]-2'-carboxylic acid in crude (120 mg, 64%) in the form of a yellow oil, which was used in the next step as is. Step 7: N -[(3S)-6,8 -difluoro -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7,1' -cyclopentane] -2 -carboxamide

[01603] A mixture of (3S) -3 -amino -6,8 -difluoro -3,5 -dihydro -2H -1,5 -benzoxazepin -4 -one (30 mg, 0.14 mmol), 5' acid H -spiro [cyclopentane -1,7' -furo [3,4 -d] pyrimidine] -2'-carboxylic acid (36 mg, 0.16 mmol), 1H -benzo [d][1,2,3] triazole -1 -ol (25 mg, 0.19 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane hydrochloride -1,3 - diamine (40 mg, 0.21 mmol) in N,N - dimethylformamide (3 mL) was stirred at 25°C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (40% to 70% acetonitrile/0.05% ammonium hydroxide in water) to give N -[(3S) -6.8 - difluoro -4 -oxo -3,5 -dihydro -2H -1,5 - benzoxazepin -3 -yl]spiro [5H -furo [3,4 -d] pyrimidine - 7,1' -cyclopentane] -2 -carboxamide ( 19.5 mg, 33%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.80 (s, 1H), 6.97 - 6.87 (m, 2H), 6.12 - 6.09 (m, 3H), 4,784.73 (m, 1H ), 4.57 - 4.51 (m, 1H), 2.14 - 2.00 (m, 4H), 1.98 - 1.87 (m, 4H). LCMS RT = 0.718 min., m/z = 416.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.05% ammonium hydroxide for 1.5 min.) retention time 0.718 min., ESI+found [M+H] = 416.9. Example 482 N -[(6S)-4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl] spiro [5H -furo [3, 4 -d] pyrimidine -7,1' -cyclopentane] -2 -carboxamide

[01604] Amide coupling prepared in a manner similar to Method WX 164. The crude material was purified via RP-HPLC (35% to 65% acetonitrile / 0.05% ammonium hydroxide in water) to provide N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,1'-cyclopentane] -2 -carboxamide (25mg, 55%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.80 (s, 1H), 7.46 - 7.44 (m, 1H), 7.34 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 6.12 (s, 2H), 6.07 - 6.02 (m, 1H), 4.69 - 4.68 (m, 1H), 4.46 - 4.43 (m , 1H), 3.44 (s, 3H), 2.08 - 2.04 (m, 4H), 1.95 - 1.93 (m, 4H). LC-MS RT = 2.21 min., m/z = 396.2 [M+H] + LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 2 .21 min., ESI+ found [M+H] = 396.2. Example 483 Method WX 011 N -(S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1 -(((1R ,3S) -3 - trifluoromethyl cyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: 1 -(((1R,3R) -3 -(trifluoromethyl) cyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxylic acid

[01605] A mixture of methyl 1 -(((1R,3R) -3 - (trifluoromethyl) cyclobutyl) methyl) -1H - 1,2,4 -triazole -3 -carboxylate (140 mg, 0.53 mmol) and Lithium hydroxide hydrate (112 mg, 2.66 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was subjected to stirring under 25oC for 1 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 with addition of 1M HCl. The resulting solid was collected through filtration and subjected to drying under reduced pressure to provide 1 - (((1R,3R) -3 -(trifluoromethyl)cyclobutyl) methyl) -1H -1,2,4 -triazole acid Crude 3-carboxylic acid (100 mg, 76%) in the form of white solids, which was used in the next step as is. Step 2: N -(S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl] -1 - ( ((1R,3S) -3 -trifluoromethyl cyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide

[01606] A mixture of 1 -(((1R,3R) -3 - (trifluoromethyl) cyclobutyl) methyl) -1H -1,2,4 - triazole -3 -carboxylic acid (31 mg, 0.12 mmol), 1-hydroxybenzotriazole (25 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) and (6S)-6-amino-2,4-dimethyl- 7,8-dihydro-6H-pyrazole[1,5-a][1,3]diazepin-5-one (24 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring under 20oC for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (46-76% acetonitrile/0.05% ammonium hydroxide in water) to give N-(S)-2,4-dimethyl- 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin - 6 -yl] -1 -(((1R,3S) -3 -trifluoromethyl cyclobutyl) methyl) - 1H -1,2,4 -triazole -3 -carboxamide (20.5 mg, 40%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.51 (s, 1H), 6.12 (s, 1H), 4.57 - 4.52 (m, 1H), 4.40 - 4.22 (m, 4H ), 3.34 (s, 3H), 2.96 - 2.83 (m, 3H), 2.30 - 2.27 (m, 6H), 2.18 - 2.12 (m, 2H). LC-MS RT = 0.940 min., m/z = 426.3 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.940 min., ESI+ found [M+H] = 426.3. Example 484 5 -[(4-fluorophenyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -4H -1,2,4 -triazole -3 -carboxamide

[01607] Amide coupling prepared in a manner similar to Method WX 011. The crude material was purified via RP-HPLC (12 - 42% acetonitrile/0.05% ammonium hydroxide in water) to provide 5 - [(4-fluorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl - 4H -1,2,4 -triazole -3 -carboxamide (10.54 mg, 9%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.28 (dd, J = 6.2, 8.0 Hz, 2H), 7.02 (t, J = 8.8 Hz, 2H), 6.09 (s, 1H), 4.48 - 4.53 (m, 1H), 4.19 - 4.34 (m, 2H), 4.05 - 4.17 (m, 2H), 3.16 - 3.28 ( m, 3H), 2.77 - 2.85 (m, 1H), 2.14 - 2.28 (m, 4H). LC-MS RT = 0.733 min., m/z = 398.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.733 min., ESI+ found [M+H] = 398.1. Example 485

[01608] WX Method 147 1 -cyclopentyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl]pyrazolo [3,4 -d] pyrimidine -6 –carboxamide Step 1: 6-chloro-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine

[01609] A mixture of 6-chloro-1H-pyrazolo[3,4-d] pyrimidine (500 mg, 3.23 mmol), potassium carbonate (894 mg, 6.47 mmol) and cyclopentyl bromide (506 mg , 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80°C for 5 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 15% ethyl acetate in petroleum ether) to give 6-chloro-1-cyclopentyl - 1H -pyrazolo[3,4-d]pyrimidine (350 mg, 47%) in the form of a colorless oil. LCMS RT = 1.064 min.; m/z = 223.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.064 min., ESI+ found [M+H] = 223.1. Step 2: 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

[01610] To a solution of 6-chloro-1-cyclopentyl - 1H -pyrazolo[3,4-d]pyrimidine (300 mg, 1.35 mmol) in dimethyl sulfoxide (10 mL) was added 1,4-diazabicyclo [2,2,2] octane (15 mg, 0.13 mmol) and sodium cyanide (132 mg, 2.69 mmol) in water (1 mL). The mixture was stirred at 25°C for 16 h and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep thin layer chromatography (25% ethyl acetate in petroleum ether) to provide 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (80 mg, 28%) in the form of a yellow solid. LCMS RT = 1.064 min.; m/z = 214.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.064 min., ESI+ found [M+H] = 214.1. Step 3: methyl 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

[01611] To a solution of 1-cyclopentyl -1H - pyrazolo [3,4 -d] pyrimidine -6 -carbonitrile (80 mg, 0.38 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1 .5 mL). The mixture was subjected to stirring at 20°C for 20 h and 50°C for 3 h. The reaction solution was concentrated under reduced pressure to provide crude methyl 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 97%) as a yellow solid. which was used in the next stage as it was. LCMS RT = 0.928 min.; m/z = 247.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.928 min., ESI+ found [M+H] = 247.1. Step 4: 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[01612] A mixture of methyl 1-cyclopentyl -1H - pyrazole [3,4 -d] pyrimidine -6 -carboxylate (30 mg, 0.12 mmol) and lithium hydroxide hydrate (26 mg, 0.61 mmol) in tetrahydrofuran (5 mL) and water (1 mL) were stirred at 25oC for 2 h. The organic solvent was removed under reduced pressure and the aqueous phase was adjusted to pH = 4 by adding 1N HCl. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to provide crude 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (25mg, 88%) in the form of a yellow solid. LCMS RT = 0.978min.; m/z = 233.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.978min., ESI+ found [M+H] = 233.1. Step 5: 1-cyclopentyl -N -[(3S)-5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]pyrazolo [3,4 - d] pyrimidine -6 - carboxamide

[01613] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (23 mg, 0.12 mmol), 1-cyclopentylpyrazole acid [3, 4 -d] pyrimidine -6 - carboxylic acid (25 mg, 0.11 mmol), N1 - ((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (25 mg, 0.13 mmol) , 1H -benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile/0.05% ammonium hydroxide in water) to give 1-cyclopentyl -N - [(3S) - 5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]pyrazolo [3,4 -d] pyrimidine -6 -carboxamide (26.8 mg, 61%) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ9.46 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H), 7.54 — 7, 51 (m, 1H), 7.35 — 7.27 (m, 3H), 6.47 — 6.41 (m, 1H), 4.93 - 4.88 (m, 1H), 4.61 - 4.52 (m, 2H), 3.35 (s, 3H), 2.17 - 2.14 (m, 2H), 2.00 - 1.91 (m, 4H), 1.74 - 1, 71 (m, 2H). LCMS RT = 0.836 min.; m/z = 407.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.836 min., ESI+ found [M+H] = 407.1. Example 486

[01614] WX Method 153 7 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -7 -(2,2,2 -trifluoroethyl) -5H - hole [3,4 -d] pyrimidine -2 -carboxamide Step 1: 2 -chloro -7 -methyl -7 -(2,2,2 - trifluoroethyl) fur [3,4 -d] pyrimidin -5(7H) -one

[01615] To a solution of 2,2,6,6-tetramethyl piperidine (13.5 g, 96.6 mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M in hexanes, 50 .0 mL, 126.0 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (6.0 g, 31.7 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and 4,4,4-trifluorobutan-2-one (4.0 g, 31.74 mmol) was added. After addition, the reaction mixture was stirred at 25°C for 16 h and finalized by addition of saturated ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 2-chloro-7-methyl -7 -(2,2,2 - trifluoroethyl)furo [3,4 -d] pyrimidin -5(7H) -one (1.0 g, 12%) in the form of a yellow oil, which was used in the next step as it was . Step 2: 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

[01616] To a solution of 6-chloro-1-methyl -1 - (2,2,2-trifluoroethyl) fur [3,4 -c] pyridin -3(1H) -one (1.0 g, 3, 75 mmol) in anhydrous toluene (15 mL) was added diatutil aluminum hydride (7.5 mL, 7.50 mmol, 1.0 M in toluene) under -70°C. The resulting solution was stirred at -70oC for 2 h and finalized by adding saturated ammonium chloride (10 mL). The mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 2-chloro-7-methyl -7 -(2,2,2 -trifluoroethyl) -5,7 -dihydrofuro [3,4 -d] pyrimidin -5 -ol (450 mg, 45%) in the form of a yellow oil, which was used in the next step as it was . Step 3: 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidine

[01617] To a solution of 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (450 mg, 1, 68 mmol) in dichloromethane (25mL) trifluoroacetic acid (1.91 g, 16.75 mmol) was added under 0°C. The mixture was stirred at 0°C for 30 min, and triethyl silane (974 mg, 8.38 mmol) was added. After addition, the mixture was stirred for 3 hours at 25°C and finalized by adding saturated sodium bicarbonate solution (20 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 15% ethyl acetate in petroleum ether) to provide 2-chloro-7-methyl -7 -(2,2,2 -trifluoroethyl) -5,7 -dihydrofuro [3,4 -d] pyrimidine (350 mg, 83%) in the form of a yellow oil, which was used in the next step as it was. Step 4: 7-methyl -7 -(2,2,2-trifluoroethyl) -5H -furo[3,4-d]pyrimidine -2-carbonitrile

[01618] To a solution of 2-chloro-7-methyl -7 - (2,2,2-trifluoroethyl) -5H -furo[3,4-d] pyrimidine (350 mg, 1.39 mmol) in sodium sulfoxide dimethyl (6 mL) and water (3 mL) were added 1,4-diazabicyclo[2,2,2]octane (155 mg, 1.39 mmol) and sodium cyanide (160 mg, 3.26 mmol). The reaction mixture was stirred at 25oC for 3 h and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give 7 -methyl -7 - (2,2,2 - methyl 7 - methyl -7 -(2,2,2-trifluoroethyl) -5H - fur [3,4 -d] pyrimidine -2 - carbonitrile (130 mg, 39%) in the form of a yellow-colored oil, which was used in next stage as it was. Step 5: methyl 7-methyl -7 -(2,2,2-trifluoroethyl) -5H - fur [3,4 -d] pyrimidine -2 -carboxylate

[01619] To a solution of 7-methyl -7 -(2,2,2 - trifluoroethyl) -5H -furo [3,4 -d] pyrimidine -2 - carbonitrile (130 mg, 0.53 mmol) in methanol ( 5 mL) HCl (4N in methanol, 5 mL) was added. The reaction mixture was stirred at 25°C for 16 h and concentrated under reduced pressure to provide methyl 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2 -crude carboxylate (120 mg, 81%) in the form of a white solid, which was used in the next step as is. Step 6: 7-Methyl-7-(2,2,2-trifluoroethyl)-5H-fur[3,4-d]pyrimidine-2-carboxylic acid

[01620] A mixture of methyl 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d] pyrimidine-2-carboxylate (120 mg, 0.43 mmol) and carbon hydroxide Hydrated lithium (182 mg, 4.34 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25oC for 1 h. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH = 5 by adding 1N HCl. The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried when washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to provide 7-methyl-7-(2,2,2-trifluoroethyl)-5H-acid crude [3,4-d] pyrimidine-2-carboxylic acid (90 mg, 79%) in the form of a yellow oil, which was used in the next step as is. Step 7: 7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(2,2,2-trifluoroethyl) -5H -hole [3,4 -d] pyrimidine -2 - carboxamide

[01621] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (20 mg, 0.10 mmol), 7 -methyl -7 - acid (2,2,2-trifluoroethyl)-5H-furo[3,4-d] pyrimidine-2-carboxylic acid (27 mg, 0.10 mmol), 1H-benzo[d][1,2,3] triazole - 1 -ol (14 mg, 0.10 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (20 mg, 0.10 mmol) in N,N -dimethylformamide (3 mL) was subjected to stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (28% to 58% acetonitrile/0.05% hydrochloric acid in water) to give 7-methyl-N-[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -7 - (2,2,2 -trifluoroethyl) -5H -furo [3,4 -d] pyrimidine -2 - carboxamide (19.4 mg, 42%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.88 (s, 1H), 7.45- 7.24 (m, 4H), 6.25- 6.21 (m, 2H), 6.08 - 6, 02 (m, 1H), 4.69 - 4.65 (m, 1H), 4.48 - 4.43 (m, 1H), 3.43 (s, 3H), 2.97 - 2.85 ( m, 2H), 1.57 (s, 3H). LCMS RT = 0.806 min., m/z = 437.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.806 min., ESI+ found [M+H] =437.1. Example 487 7 -methyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -7 - (2,2,2 -trifluoroethyl) -5H -furo [3,4 -d] pyrimidine -2 - carboxamide

[01622] Amide coupling prepared in a manner similar to Method WX 153. The crude material was purified using RP-HPLC (25% to 55% acetonitrile/0.05% ammonium hydroxide in water) to provide 7 -methyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -7 - (2,2,2 - trifluoroethyl) -5H -furo [3,4 -d] pyrimidine -2 - carboxamide (22.2 mg, 49%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.50 (s, 1H), 6.12 (s, 1H), 4.57 - 4.52 (m, 1H), 4.31 - 4.22 (m, 4H ), 3.33 (s, 3H), 3.01 - 2.83 (m, 3H), 2.28 - 2.24 (m, 6H), 2.01 - 1.98 (m, 2H). LCMS RT = 0.682 min., m/z = 439.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.682 min., ESI+ found [M+H] = 439.2. Example 488 WX Method 176 4 -(1-hydroxy -1 -methyl -propyl) -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyridine -2 -carboxamide Step 1: 2 -(2 -chloropyridin -4 -yl)butan -2 -ol

[01623] To a solution of 4-bromo-2-chloropyridine (6.0 g, 26.0 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in hexanes, 13.5 mL, 33.8 mmol) dropwise under -78oC. The mixture was stirred at -78°C for 2 h and methyl ethyl ketone (2.81 g, 39.0 mmol) was added dropwise. The resulting mixture was allowed to warm to 25oC over 15 h and finished by adding saturated ammonium chloride. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 2 -(2-chloropyridin-4-yl)butan-2-ol (500 mg, 10%) in the form of a colorless oil. LCMS RT = 0.584 min.; m/z = 186.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.584 min., ESI+ found [M+H] = 186.8. Step 2: Methyl 4-(2-hydroxybutan-2-yl)picolinate

[01624] A mixture of 2-(2-chloropyridin-4-yl)butan-2-ol (200 mg, 1.1 mmol), triethylamine (327 mg, 3.2 mmol) and 1,1'-bis( diphenylphosphine) palladium ferrocene dichloride) (79 mg, 0.1 mmol) in methanol (50 mL) was heated at 70°C for 15 h under CO [3.42 bar (35 psi)] and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 4 -(2-hydroxybutan - 2-yl) picolinate (100 mg, 44%) in the form of a light yellow oil. Step 3: 4 -(2 -hydroxybutan -2 -yl) picolinic acid

[01625] A mixture of 4-(2-hydroxybutan-2-yl) picolinate (100 mg, 0.48 mmol) and potassium hydroxide (54 mg, 0.96 mmol) in ethanol (5 mL) and water (1 mL) was subjected to stirring at 25oC for 12 h. The solvent was removed under reduced pressure and the residue was diluted with water (10 ml). The solution was adjusted to pH = 4 by adding 2N HCl. The mixture was concentrated under reduced pressure to provide crude 4-(2-hydroxybutan-2-yl) picolinic acid (80 mg, 72%) as a yellow solid, which was used in the next step as where he was. Step 4: 4 -(1-hydroxy -1 -methyl -propyl) -N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyridine - 2-carboxamide

[01626] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (51 mg, 0.26 mmol), 4 -(1-hydroxy acid -1 -methyl -propyl)pyridine -2 - carboxylic acid (77 mg, 0.39 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (53 mg, 0.39 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (76 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring at 25oC for 16 h . The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (28% to 58% acetonitrile/0.05% ammonium hydroxide in water) to give 4-(1-hydroxy-1-methyl -propyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyridine -2 -carboxamide (7.0 mg, 7.2% ) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 4.8 Hz, 1H), 8.11 (s, 1H), 7.65 - 7.61 (m, 1H), 7.46 - 7.41 (m, 1H), 7.36 - 7.29 (m, 2H), 7.27 - 7.22 (m, 1H), 6.06 - 4.99 (m, 1H), 4 .68 - 4.62 (m, 1H), 4.59 (s, 1H), 4.44 - 4.37 (m, 1H), 3.43 (s, 3H), 1.85 - 1.77 (m, 2H), 1.50 (s, 3H), 0.76 (t, J = 4.0 Hz, 3H). LCMS RT = 1.00 min.; m/z = 370.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.00 min., ESI+ found [M+H] =370.2. Example 489

[01627] WX Method 158 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] spiro [3H -furo [3,4 -c] pyridine - 1,3' - tetrahydropyran] -6 -carboxamide Step 1: 6 -chlorospiro [hole [3,4 -c] pyridine - 1,3' -tetrahydropyran] -3 -one

[01628] To a solution of 2,2,6,6 - tetramethylpiperidine (2.69 g, 19.0 mmol) in tetrahydrofuran (60 mL) was added n -butyllithium (2.5 M in hexanes, 10.2 mL, 26.4 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 6-chloronicotinic acid (1.0 g, 6.4 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and dihydro-2H-pyran-3(4H)-one (1.27 g, 12.7 mmol) was added. After addition, the reaction mixture was stirred at 25oC for 16 h and finalized by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-chlorospiro[furo[3,4-c]pyridine-1, 3'-tetrahydropyran]-3-one (1.2 g, 79%) as a light yellow solid. LCMS RT = 0.595 min.; m/z = 240.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.595 min., ESI+ found [M+H] = 240.0. Step 2: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3'-tetrahydropyran]-3-ol

[01629] A mixture of 6-chlorospiro [furo[3,4-c]pyridine-1,3'-tetrahydropyran]-3-one (1.2 g, 6.0 mmol) in toluene (60 mL) was Diatyl aluminum hydride (12.0 mL, 12.0 mmol, 1.0 M in toluene) was added at -78°C. The reaction was stirred at -78oC for 2 h and terminated by the addition of saturated ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-chlorospiro[3H-furo[3.4-c ] crude pyridine -1,3' - tetrahydropyran] -3 -ol (1.0 g, 76%) as a colorless oil. LCMS RT = 0.552 min.; m/z = 242.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.552 min., ESI+ found [M+H] = 242.0. Step 3: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3'-tetrahydropyran]

[01630] To a mixture of 6-chlorospiro [3H -furo [3,4 -c] pyridine -1,3' -tetrahydropyran] -3 -ol (1.0 g, 4.1 mmol) and acid 2.2 ,2-trifluoroacetic acid (2.36 g, 20.7 mmol) in dichloromethane (20 mL) was added triethylsilane (1.44 g, 12.4 mmol) under 0°C. The mixture was stirred for 2 h and then adjusted to pH = 8 by addition of 1N sodium hydroxide. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 ml). The solution was washed with water (2 x 50 mL), brine (40 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 6 - chlorospiro [3H -furo[3,4-c]pyridine - 1,3' - tetrahydropyran] (800 mg, 86%) in the form of a yellow oil. Step 4: methyl spiro[3H-furo[3,4-c]pyridine-1,3'-tetrahydropyran]-6-carboxylate

[01631] A mixture of 6-chlorospiro [3H-furo [3,4-c] pyridine -1,3'-tetrahydropyran] (800 mg, 3.55 mmol), 1,1'-bis(diphenylphosphine) dichloride palladium ferrocene (259 mg, 0.35 mmol) in methanol (100 mL) was stirred at 80oC for 16 h under CO (25psi) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give methyl spiro[3H-furo[3 ,4-c]pyridine-1,3'-tetrahydropyran]-6-carboxylate (810 mg, 92%) as a colorless oil. LCMS RT = 0.570min.; m/z = 250.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.570min., ESI+ found [M+H] = 250.1. Step 5: Spiro[3H-furo[3,4-c]pyridine-1,3'-tetrahydropyran]-6-carboxylic acid

[01632] A mixture of methyl spiro [3H -furo [3,4 - c] pyridine -1,3' -tetrahydropyran] -6 -carboxylate (200 mg, 0.80 mmol) and lithium hydroxide (58 mg, 2 .41 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was stirred at 25oC for 3 h. The mixture was adjusted to pH = 6 by adding 1N HCl. The resulting solution was concentrated for drying under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide spiro[3H-furo[3,4-c]pyridine-1,3'-acid tetrahydropyran]-6-carboxylic acid (150 mg, 80%) in the form of a white solid, which was used in the next step as is. Step 6: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] spiro [3H -furo [3,4 -c] pyridine -1, 3'-tetrahydropyran]-6-carboxamide

[01633] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (20 mg, 0.10 mmol), spiro acid [3H -furo [ 3,4 -c] pyridine -1,3' - tetrahydropyran] -6 -carboxylic acid (37 mg, 0.16 mmol), N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 - hydrochloride diamine (21 mg, 0.16 mmol) and 1H -benzo [d][1,2,3] triazol -1 -ol (21 mg, 0.16 mmol) in N,N - dimethylformamide (3 mL) was subjected stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (45% to 75% acetonitrile/0.05% formic acid in water) to give N -[(3S)-5-methyl-4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] spiro [3H -furo [3,4 -c] pyridine -1,3' -tetrahydropyran] -6 -carboxamide (3.1 mg, 7%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.60 (s, 1H), 8.03 (s, 1H), 7.46 - 7.43 (m, 1H), 7.33 - 7.32 (m, 2H ), 7.26 - 7.24(m, 1H), 6.20 (d, J = 8.0 Hz, 2H), 6.05 - 6.00 (m, 1H), 4.67 - 4, 62 (m, 1H), 4.43 - 4.38 (m, 1H), 3.82 (s, 1H), 3.73 - 3.72 (m, 1H), 3.65 - 3.64 ( m, 2H), 3.43 (s, 3H), 2.03 - 2.00 (m, 3H), 1.97 - 1.74 (m, 1H). LCMS RT = 1.722 min.; m/z = 410.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide for 3 min.) retention time 1.722 min., ESI+ found [M+H] = 410.1. Example 490 5 -[(2,3-difluorophenyl) methyl] -N -(6S) -2,3,4 - trimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide

[01634] Amide coupling prepared in a manner similar to Method WX 011. The crude material was purified via RP-HPLC (25 -55% ACN/0.05% ammonium hydroxide in water) to provide 5 - [(2,3-difluorophenyl) methyl] -N -(6S) -2,3,4 -trimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide (12.03 mg, 12%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.20 - 7.10 (m, 3H), 4.43 - 4.38 (m, 1H), 4.23 - 4.19 (m, 4H), 3.30 (s, 3H), 2.78- 2.71 (m, 1H), 2.20 - 2.18 (s, 4H), 2.01 (s, 3H). LC-MS RT = 0.749 min., m/z = 430.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.749 min., ESI+ found [M+H] =430.1. Example 491

[01635] WX Method 009 1 -[(3-methylcyclobutyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: (3-methylcyclobutyl)methanol

[01636] To a solution of 3-methylcyclobutane carboxylic acid (500 mg, 4.38 mmol) in tetrahydrofuran (15 mL) was added LiAlH4 (333 mg, 8.76 mmol) under 0oC. The reaction mixture was subjected to stirring at 0°C for 1 h, and then finished by adding water (0.2 mL), 15% aqueous NaOH (0.2 mL) and water (0.6 mL). The mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide (3-methylcyclobutyl)methanol (400 mg, 91%) as a colorless oil which was used in the next stage in Next stage without any further purification, which was used in the next stage as it was. Step 2: (3-methylcyclobutyl)methyl 4-methylbenzene sulfonate

[01637] To a solution of (3-methylcyclobutyl) methanol (300 mg, 3.0 mmol) in dichloromethane (6 mL) was added 4-dimethylamino pyridine (642 mg, 6.3 mmol) and p-toluene sulfonyl chloride (601 mg, 3.2 mmol). The reaction mixture was stirred at 20oC for 3 h and then terminated by adding saline solution (6 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparation TIC (10% ethyl acetate in petroleum ether, Rf = 0.5) to provide (3-methylcyclobutyl)methyl 4-methylbenzene sulfonate (450 mg, 59%) in form of a colorless oil, which was used in the next stage as it was. Step 3: 1-(bromomethyl)-3-methylcyclobutane

[01638] To a solution of lithium bromide (1229 mg, 14.2 mmol) in acetone (8.0 mL) was added (3-methylcyclobutyl) methyl 4-methylbenzene sulfonate (450 mg, 1.8 mmol). The reaction mixture was heated at 70°C for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude material 1-(bromomethyl)-3-methylcyclobutane (288 mg , 80%) in the form of a colorless oil, which was used in the next step as it was. Step 4: 1 -[(3-methylcyclobutyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01639] A mixture of N -[(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] -1H -1,2,4 -triazole -3 -carboxamide (45 mg, 0.16 mmol), potassium carbonate (65 mg, 0.47 mmol) and 1 -(bromomethyl)-3 -methylcyclobutane (51 mg, 0.31 mmol) in N,N - dimethylformamide (5 mL) was stirred at 20oC for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (22-52% acetonitrile in water and 0.05% ammonium hydroxide) to give 1-[(3-methylcyclobutyl)methyl]-N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole - 3-carboxamide (11.1 mg, 19%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 6.12 (s, 1H), 4.56 - 4.52 (m, 1H), 4.34 - 4.22 (m, 5H), 3.33 (s, 3H), 2.89 - 2.64 (m, 2H), 2.27 - 2.20 (m, 7H), 1.41 - 1.39 (m, 1H) , 1.13 - 1.02 (m, 3H). LCMS RT = 0.942 min., m/z = 372.3 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.942 min., ESI+ found [M+H] = 372.3. Example 492

[01640] WX Method 010 N -(S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -(((1S ,3R) -3 - trifluoromethylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide Step 1: (3-(trifluoromethyl)cyclobutyl)methanol

[01641] To a solution of 3-(trifluoromethyl) cyclobutane carboxylic acid (520 mg, 3.09 mmol) in tetrahydrofuran (15 mL) was added LiAlH4 (235 mg, 6.19 mmol) under 0oC. After addition, the reaction mixture was stirred at 0°C for 2 h and then terminated by adding water (0.2 mL), 15% aqueous NaOH (0.2 mL) and water (0.6 mL). ). The mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide crude (3-(trifluoromethyl)cyclobutyl)methanol (476 mg, 99%) as a colorless oil, which was used in the next stage as it was. Step 2: (3-(trifluoromethyl)cyclobutyl)methyl 4-methylbenzene sulfonate

[01642] To a solution of (3-(trifluoromethyl) cyclobutyl) methanol (476 mg, 3.1 mmol) in dichloromethane (20 mL) was added 4-dimethylamino pyridine (755 mg, 6.2 mmol) and p. -toluenesulfonyl (707 mg, 3.7 mmol). The reaction mixture was stirred at 20°C for 12 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: 100 - 200 mesh, 0 - 30% ethyl acetate in petroleum ether) to provide (3-(trifluoromethyl) cyclobutyl) methyl 4-methylbenzene sulfonate (700 mg, 74%) in the form of a colorless oil, which was used in the next step as is. Step 3: methyl 1 -(((1R,3R) -3 -(trifluoromethyl) cyclobutyl) methyl) -1H -1,2,4 - triazole -3 -carboxylate & methyl 1 -(((1S,3S) -3 -(trifluoromethyl)cyclobutyl) methyl) - 1H -1,2,4 -triazole -3 -carboxylate

[01643] To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (289 mg, 2.3 mmol) and (3-(trifluoromethyl) cyclobutyl) methyl 4-methylbenzene sulfonate (700 mg, 2 .27 mmol) in N,N-dimethylformamide (20 mL) was added 4-dimethylamino pyridine (333 mg, 2.7 mmol), cesium carbonate (2219 mg, 6.8 mmol) and sodium iodide (408 mg, 2.7 mmol). The mixture was stirred at 95oC for 12 h and diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (4 x 20 mL). The combined organic layers were washed with water (3 x 20 mL), brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: 100 - 200 mesh, 0 - 90% ethyl acetate in petroleum ether) to give methyl 1 -((3 -(trifluoromethyl)cyclobutyl) methyl) -1H -1,2,4 - triazole -3 -carboxylate (320 mg, 54%) in the form of a colorless oil.

[01644] This material was further separated using SFC to provide:

[01645] methyl 1 -(((1R,3R) -3 -(trifluoromethyl) cyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxylate (Peak 1, retention time = 4.723 min.) ( 140 mg, 43.4%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 6.12 (s, 1H), 4.57 - 4.52 (m, 1H), 4.31 - 4.22 (m, 4H), 3.33 (s, 3H), 3.01 - 2.83 (m, 3H), 2.28 - 2.24 (m, 6H), 2.01 - 1.98 (m, 2H) ; LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.730 min., ESI+ found [M+H] = 263.9;

[01646] methyl 1 -(((1S,3S) -3 -(trifluoromethyl) cyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxylate (Peak 2, retention time = 6.664 min.) ( 140 mg, 43.4%) as white solids. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 4.27 (d, J = 7.6 Hz, 2H), 4.01 (s, 1H), 2.94 - 2.88 (m, 2H), 2.33 - 2.30 (m, 2H), 2.01 - 1.84 (m, 2H). LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.730 min., ESI+ found [M+H] = 263.9.

[01647] SFC Condition: Column: Chiralcel IC -3 150x4.6 mm I.D., 3 µm Mobile phase: 40% iso-propanol (0.05% DEA) in CO2 Flow rate: 2.5 mL/min. Column temperature:40oC.

[01648] SFC condition: column: chiralcel OD -3 100x4.6mm ID, 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Step 4: 1 -(((1S,3S) -3 -(trifluoromethyl) cyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxylic acid

[01649] A mixture of methyl 1 -(((1S,3S) -3 - (trifluoromethyl) cyclobutyl) methyl) -1H - 1,2,4 -triazole -3 -carboxylate (140 mg, 0.53 mmol) and Lithium hydroxide hydrate (112 mg, 2.66 mmol) in tetrahydrofuran / Methanol / Water (5 mL, 2:2:1) was subjected to stirring at 25oC for 1 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 with addition of 1M HCl. The resulting solid was collected through filtration and subjected to drying under reduced pressure to provide 1 - (((1S,3S) -3 -(trifluoromethyl) cyclobutyl) methyl) -1H - 1,2,4 -triazole acid 3-carboxylic acid (100 mg, 76%) in the form of a white solid, which was used in the next step as is. Step 5: N -(S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl] -1 - ( ((1S,3R) -3 -trifluoromethyl cyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide

[01650] A mixture of 1 -(((1S,3S) -3 - (trifluoromethyl)cyclobutyl) methyl) -1H -1,2,4 - triazole -3 -carboxylic acid (31 mg, 0.12 mmol), 1-hydroxybenzotriazole (25 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) and (6S)-6-amino-2,4-dimethyl- 7,8-dihydro-6H-pyrazole[1,5-a][1,3]diazepin-5-one (24 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring under 20oC for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (46-76% acetonitrile/0.05% ammonium hydroxide in water) to give N-(S)-2,4-dimethyl- 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin - 6 -yl] -1 -(((1S,3R) -3 -trifluoromethyl cyclobutyl) methyl) - 1H -1,2,4 -triazole -3 -carboxamide (36.7 mg, 68%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.50 (s, 1H), 6.12 (s, 1H), 4.57 - 4.52 (m, 1H), 4.31 - 4.22 (m, 4H ), 3.33 (s, 3H), 3.01 - 2.83 (m, 3H), 2.28 - 2.24 (m, 6H), 2.01 - 1.98 (m, 2H). LC-MS RT = 0.927 min., m/z = 426.3 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.927 min., ESI+ found [M+H] = 426.3. Example 493 N -(S) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1 -(((1S,3R ) -3 - trifluoromethyl cyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide

[01651] Amide coupling prepared in a manner similar to Method WX 010. The crude material was purified using RP-HPLC (46 - 76% acetonitrile/0.05% ammonium hydroxide in water) to provide N - (S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1 -(((1S,3R) - 3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (37.9 mg, 68%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.53 (s, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4.55 - 4.41 (m, 2H), 4.31 - 4.29 (m, 3H), 3.37 (s, 3H), 3.01 - 2.85 (m, 3H), 2.30 - 2.25(m , 3H), 2.01 - 1.94 (m, 2H). LC-MS RT = 0.891 min., m/z = 412.3 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.891 min., ESI+ found [M+H] = 412.3. Example 494 N -(S) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -(((1R,3S ) -3 - trifluoromethylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide

[01652] Amide coupling prepared in a manner similar to Method WX 011. The crude material was purified via RP-HPLC (acetonitrile 46 - 76%/0.05% ammonium hydroxide in water) to provide N - (S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl] -1 -(((1R,3S) - 3-trifluoromethyl cyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (26.4 mg, 45%) as white solids. H NMR (400 MHz, CD3OD) δ8.51 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4 .52 - 4.29 (m, 5H), 3.37 (s, 3H), 3.07 - 2.88 (m, 3H), 2.33 - 2.26 (m, 3H), 2.18 - 2.14 (m, 2H). LC-MS RT = 0.903 min., m/z = 412.3 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.903 min., ESI+ found [M+H] = 412.3, Example 495

[01653] WX Method 014 1 -[(1-methylcyclopentyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 –carboxamide Step 1: methyl cyclopentane carboxylate

[01654] To a solution of cyclopentane carboxylic acid (6.0 g, 43.8 mmol) in dichloromethane (30 mL) and methanol (10 mL) was added (trimethylsilyl) diazomethane (2.0 M in hexane, 109 mL, 219.0 mmol) under 25oC. After addition, the solution was stirred at 25°C for 2 h and then concentrated under reduced pressure to provide methyl cyclopentane carboxylate (5 g, 89%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ3.67 (s, 3H), 2.77 - 2.71 (m, 1H), 1.90 1.81 - 1.70(m, 4H), 1.59 - 1.57 (m, 2H). Step 2: Methyl 1-methyl cyclopentane carboxylate

[01655] To a solution of diisopropylamine (7.9 g, 78.0 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexane, 31.2 mL, 78.0 mmol) under -70oC. The mixture was stirred at -70°C for 0.5 h, then methyl cyclopentane carboxylate (6.0 g, 39.0 mmol) was added. After addition, stirring was continued at -70°C for another 0.5 h, and methyl iodide (7.3 mL, 117.0 mmol) was added. The resulting mixture was subjected to stirring at 20oC for 12 h and finalized by the addition of saturated aqueous ammonium chloride (100 mL). The solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude methyl 1-methyl cyclopentane carboxylate (6.5 g, 99%) as a yellow colored oil. 1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 2.11 - 2.05 (m, 2H), 1.69 - 1.66 (m, 4H), 1.48 - 1, 45(m, 2H), 1.24 (s, 3H). Step 3: (1-methylcyclopentyl) methanol

[01656] To a solution of methyl 1-methyl cyclopentane carboxylate (1.0 g, 7.03 mmol) in tetrahydrofuran (15 mL) was added LiAlH4 (533 mg, 14.1 mmol) under 0oC. The reaction mixture was stirred at 0°C for 1 h and then finished by adding water (0.5 mL), 15% aqueous NaOH (0.5 mL) and water (1.5 mL). The mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to provide (1-methylcyclopentyl)methanol (400 mg, 50%) as of a colorless oil. 1H NMR (400MHz, CDCl3) δ 3.39 (s, 2H), 1.67 - 1.62 (m, 4H), 1.50 - 1.47 (m, 2H), 1.32 - 1.30 (m, 2H), 1.02 (s, 3H). Step 4: (1-methylcyclopentyl)methyl 4-methylbenzene sulfonate

[01657] To a solution of (1-methylcyclopentyl) methanol (100 mg, 0.88 mmol) in dichloromethane (6 mL) was added 4-dimethylamino pyridine (214 mg, 1.75 mmol) and p - Toluenesulfonyl (200 mg, 1.05 mmol). The reaction mixture was stirred at 20oC for 2 h and then terminated by adding saline solution (6 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether, Rf = 0.4) to provide (1-methylcyclopentyl)methyl 4-methylbenzene sulfonate (200 mg, 85%) in the form of a colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.77 (s, 2H), 2 .46 (s, 3H), 1.63 - 1.55 (m, 4H), 1.45-1.44 (m, 2H), 1.33 - 1.31 (m, 2H), 0.98 (s, 3H). Step 5: methyl 1 -((1-methylcyclopentyl) methyl) - 1H -1,2,4 -triazole -3 -carboxylate

[01658] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (50 mg, 0.39 mmol) and (1-methylcyclopentyl) methyl 4-methylbenzene sulfonate (106 mg, 0.39 mmol ) in N,N-dimethylformamide (4 mL) was added cesium carbonate (384 mg, 1.18 mmol), sodium iodide (71 mg, 0.47 mmol) and 4-dimethylamino pyridine (58 mg, 0.47 mmol). The mixture was stirred at 100°C for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 ml) and washed with water (2 x 10 ml). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by TIC preparation (50% ethyl acetate in petroleum ether, Rf = 0.5) to provide methyl 1 - [(1 -methylcyclopentyl) methyl] -1,2,4 -triazole - 3-carboxylate (50 mg, 57%) in the form of a colorless oil. LC-MS RT = 0.973 min., m/z = 223.9 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.973 min., ESI+ found [M+H] = 223.9. Step 6: 1-((1-methylcyclopentyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

[01659] A mixture of methyl 1 -[(1 - methylcyclopentyl) methyl] -1,2,4 -triazole -3 -carboxylate (50 mg, 0.22 mmol) and hydrated lithium hydroxide (47 mg, 1.12 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25oC for 1 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 by adding 1M HCl. The resulting mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 1-[(1-methylcyclopentyl)methyl]-1,2,4-triazole-3-carboxylic acid (45 mg, 96%) in the form of a white solid. LC-MS RT = 1.055 min., m/z = 209.9 [M+H] +. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.055 min., ESI+ found [M+H] = 209.9. Step 7: 1 -[(1-methylcyclopentyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01660] To a stirred solution of 1-[(1-methylcyclopentyl) methyl]-1,2,4-triazole-3-carboxylic acid (32 mg, 0.15 mmol) in N,N-dimethylformamide (2 mL) 1-hydroxybenzotriazole (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and (6S)-6-amino-2 were added. 4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (30 mg, 0.15 mmol). The resulting mixture was stirred at 25°C for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (30 -60% acetonitrile/0.05% ammonium hydroxide in water) to provide 1 -[(1-methylcyclopentyl) methyl] -N -(6S) -2.4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (26.4 mg , 44%) in the form of a white solid. 1HNMR (400MHz, CD3OD) δ8.49 (s, 1H), 6.12 (s, 1H), 4.57- 4.52 (m, 1H), 4.31 - 4.22 (m, 2H), 4.18 (s, 2H), 3.34 (s, 3H), 2.90 - 2.83 (m, 1H), 2.30 - 2.23 (m, 4H), 1.71 - 1, 65 (m, 6H), 1.39 - 1.36 (m, 2H), 0.97 (s, 3H). LC-MS RT =0.677 min., m/z = 386.2 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.677 min., ESI+ found [M+H] = 386.2. Examples 496 and 497

[01661] WX Method 015 N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -( ((1S,3R) - 3 -methylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide and N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1R,3S) - 3 -methylcyclobutyl) methyl) -1H -1,2,4 - triazole -3 - carboxamide Step 1: methyl 1 -[(3-methylcyclobutyl) methyl] - 1,2,4 -triazole -3 -carboxylate

[01662] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (120 mg, 0.94 mmol) and (3-methylcyclobutyl) methyl 4-methylbenzene sulfonate (240 mg, 0.94 mmol ) in N,N-dimethylformamide (12 mL) was added 4-dimethylaminopyridine (138 mg, 1.13 mmol), cesium carbonate (923 mg, 2.83 mmol) and sodium iodide (170 mg, 1.13 mmol) . The mixture was stirred at 95°C for 12 h and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with water (2 x 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by TIC preparation (50% ethyl acetate in petroleum ether, Rf = 0.2) to provide methyl 1 - [(3 -methylcyclobutyl) methyl] -1,2,4 -triazole - 3 - carboxylate (70mg, 35%) in the form of a colorless oil. LC-MS RT = 0.730 min., m/z = 209.9 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.730 min., ESI+ found [M+H] = 209.9. Step 2: 1 -((1-methylcyclopentyl) methyl) - 1H -1,2,4 -triazole -3 -carboxylic acid

[01663] A mixture of methyl 1 -[(3 - methylcyclobutyl) methyl] -1,2,4 -triazole -3 -carboxylate (70mg, 0.33 mmol) and hydrated lithium hydroxide (84 mg, 2.01 mmol ) in tetrahydrofuran / methanol / water (5 mL, 2:2:1) was subjected to stirring at 25oC for 1 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 by adding 1M HCl. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude 1-[(3-methylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid material (60 mg, 92%) as a white solid. LC-MS RT = 0.377 min., m/z = 196.9 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.377 min., ESI+ found [M+H] = 196.9. Step 3: N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 1 -(((1S,3R) - 3 -methylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide and N -((S) -4 -methyl -5 -oxo -5,6, 7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1R,3S) - 3 -methylcyclobutyl) methyl) -1H -1,2 ,4-triazole -3 - carboxamide

[01664] To a stirred solution of 1-[(3-methylcyclobutyl) methyl]-1,2,4-triazole-3-carboxylic acid (54 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL) 1-hydroxybenzotriazole (56 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol) and (6S)-6-amino-4- were added. methyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (50 mg, 0.28 mmol). The mixture was stirred at 25°C for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (25 -55% acetonitrile/0.05% ammonium hydroxide in water) to provide 1 -[(3-methylcyclobutyl) methyl] -N -[(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (75 mg, 74 %) in the form of a white solid.

[01665] The racemic compound was further separated using chiral SFC to provide:

[01666] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 1 -(((1S,3R) -3 -methylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time = 4.957 min.) (43.8 mg, 58% ) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.45(s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 1.2 Hz, 1H), 4 .54 - 4.40 (m, 2H), 4.43 - 4.41 (m, 1H), 4.23 (d, J = 7.6 Hz, 2H), 3.36 (s, 3H), 2.88 - 2.83 (m, 1H), 2.68 - 2.64 (m, 1H), 2.31 - 2.17 (m, 4H), 1.44 - 1.36 (m, 2H ), 1.03 (d, J = 6.4 Hz, 3H). LC-MS RT =0.649 min., m/z = 358.2 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.649 min., ESI+ found [M+H] = 358.2.

[01667] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 1 -(((1R,3S) -3 -methylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (Peak 2, Retention time = 6.433 min.) (22.7 mg, 30% ) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.48 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.31 (s, 1H), 4.54 - 4.49 ( m, 2H), 4.34 - 4.29 (m, 3H), 3.36 (s, 3H), 2.87 - 2.82 (m, 2H), 2.49 - 2.40 (m, 1H), 2.29 - 2.20 (m, 1H), 2.01 - 1.94 (m, 2H), 1.76 - 1.71 (m, 2H), 1.12 (d, J = 6.8Hz, 3H). LC-MS RT =0.649 min., m/z = 358.2 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.649 min., ESI+ found [M+H] = 358.2.

[01668] SFC condition: ACID chiralpak column (250 mm 30 mm, 5 um)., 3 um mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 35% to 35% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40 o Examples 498 and 499 N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1S,3R) -3 -methylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide and N -((S) -2,4 -dimethyl -5 -oxo -5,6 ,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1R,3S) -3 -methylcyclobutyl) methyl) -1H -1, 2,4-triazole-3-carboxamide

[01669] The amide coupling was prepared in a manner similar to Method WX 016. The racemic material obtained (110 mg) was chiral purified to provide: N -((S) -2,4 -dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1S,3R) -3 -methylcyclobutyl) methyl ) -1H -1,2,4 - triazole -3 -carboxamide (Peak 1, Retention time = 3.887 min.) (49.1 mg, 44%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.44 (s, 1H), 6.11 (s, 1H), 4.57 - 4.51 (m, 1H), 4.35 - 4.29 (m, 1H ), 4.23 - 4.21 (m, 3H), 3.33 (s, 3H), 2.89 - 2.84 (m, 1H), 2.68 - 2.64 (m, 1H), 2.28 - 2.17 (m, 7H), 1.43 - 1.36 (m, 2H), 1.03 (d, J = 6.4 Hz, 3H). LC-MS RT = 1.531 min., m/z = 372.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.531 min., ESI+ found [M+H] = 372.1.

[01670] N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ) -1 -(((1R,3S) -3 -methylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (Peak 2 Retention time = 4.496 min.) (22.8 mg, 21 %) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.48 (s, 1H), 6.11 (s, 1H), 4.56 - 4.51 (m, 1H), 4.34- 4.29 (m, 3H ), 4.24 - 4.22 (m, 1H), 3.33 (s, 3H), 2.89 - 2.83 (m, 2H), 2.45- 2.43 (m, 1H), 2.25 - 2.19 (m, 4H), 2.01 - 1.94 (m, 2H), 1.76 - 1.69 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H). LC-MS RT = 1.531 min., m/z = 372.0 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.531 min., ESI+ found [M+H] = 372.0.

[01671] SFC condition: column: chiralpak AD -3 (100x4.6 mm), 3 um mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 5 to 40 B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Examples 500 and 501

[01672] WX Method 017 N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1R,3R) -3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole - 3 -carboxamide and N -((S) -2,4 -dimethyl -5 -oxo -5,6 ,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1S,3S) -3 -ethylcyclobutyl) methyl) -1H -1, 2,4-triazole - 3-carboxamide Step 1: (3-ethylcyclobutyl)methanol

[01673] To a solution of 3-ethylcyclobutane carboxylic acid (600 mg, 4.68 mmol) in tetrahydrofuran (10 mL) was added LiAlH4 (355 mg, 9.36 mmol) under 0oC. After addition, the mixture was stirred at 25°C for 16 h and finalized by adding water (0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.3 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude (3-ethylcyclobutyl) methanol (535 mg, 110%) as a colorless oil, which was used in the next step as it was. . Step 2: (3,3-dimethylcyclobutyl)methyl 4-methylbenzene sulfonate

[01674] To a solution of p-toluene sulfonyl chloride (1071 mg, 6.62 mmol) in dichloromethane (10 mL) was added (3-ethylcyclobutyl) methanol (535 mg, 4.69 mmol) and 4-dimethyl aminopyridine (1144 mg, 9.37 mmol). The reaction mixture was subjected to stirring at 20oC for 16 h. Then, the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide (3-ethylcyclobutyl)methyl 4-methylbenzene sulfonate (810 mg, 64 %) in the form of a colorless oil, which was used in the next step as it was. Step 3: methyl 1 -[(3-ethylcyclobutyl) methyl] - 1,2,4 -triazole -3 -carboxylate

[01675] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (383 mg, 3.02 mmol) and (3-ethylcyclobutyl) methyl 4 -methylbenzene sulfonate (810 mg, 3.02 mmol ) in N,N-dimethylformamide (20 mL) was added 4-dimethylamino pyridine (442 mg, 3.62 mmol), cesium carbonate (2.95 g, 9.05 mmol) and sodium iodide (543 mg, 3 .62 mmol). The mixture was stirred at 95oC for 12 h and finalized by adding water (30 mL). The mixture was extracted with ethyl acetate (4 x 20 mL). The combined organic layers were washed with water (3 x 20 mL), brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: 100 - 200 mesh, 0 - 90% ethyl acetate in petroleum ether) to give methyl 1 - [(3-ethylcyclobutyl) methyl] -1,2, 4 - triazole -3 -carboxylate (220 mg, 33%) in the form of a colorless oil, which was used in the next step as it was . Step 4: 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid

[01676] A mixture of methyl 1 -[(3 - ethylcyclobutyl) methyl] -1,2,4 -triazole -3 -carboxylate (100 mg, 0.45 mmol) and hydrated lithium hydroxide (94 mg, 2.24 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25oC for 2 h. The solvent was evaporated under reduced pressure. The residue was diluted with water (20 mL) and adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and dried to yield 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid (74 mg, 79%) in the form of a white solid, which was used in the next stage as it was. Step 5 N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1R,3R) -3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole - 3 -carboxamide and N -((S) -2,4 -dimethyl -5 -oxo -5 ,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1S,3S) -3 -ethylcyclobutyl) methyl) -1H - 1,2,4 -triazole - 3 -carboxamide

[01677] A stirred solution of (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (60 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was added 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid (71 mg, 0.31 mmol) 34 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (89 mg, 0.46 mmol). The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 33 -53%/0.05% ammonium hydroxide in water) to give the racemic compound which was separated by SFC to give: N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1 -(((1R, 3R) -3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.975 min.) (27 mg, 23%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.45(s, 1H), 6.12 (s, 1H), 4.56 - 4.52 (m, 1H), 4.31 - 4.22 (m, 4H), 3.33 (s, 3H), 2.88 - 2.83 (m, 1H), 2.72 - 2.68 (m, 1H), 2.26 - 2.18 (m, 4H) , 2.17 - 2.09 (m, 4H), 1.39 - 1.37 (m, 2H), 0.82 - 0.78(m, 3H). LC-MS RT = 0.804 min., m/z = 386.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.804 min., ESI+ found [M+H] = 386.1.

[01678] N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ) -1 -(((1S,3S) -3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole - 3 -carboxamide (Peak 2, retention time 6.253 min.) (6 mg, 5%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.49 (s, 1 H), 6.12 (s, 1 H), 4.56 - 4.52 (m, 1 H), 4.35 - 4.22 ( m, 4 H), 3.33 (s, 3 H), 2.86 - 2.82 (m, 2 H), 2.26 - 2.23 (m, 4 H), 1.95 - 1, 91 (m, 2 H), 1.80 - 1.76 (m, 2 H),1.49 - 1.46 (m, 2 H), 0.85 - 0.80 (m, 3 H). LC-MS RT = 0.806 min., m/z = 386.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.806 min., ESI+ found [M+H] =386.1

[01679] SFC Condition: Column: Chiralcel AD -3 150x4.6mm ID, 3um Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate), Gradient: from 5% to 40% B in 6.0 min. and held 40% for 2.5 min., then 5% B for 2.5 min., Flow rate: 2.5 mL/min. Column temperature:35 oC. Examples 502 and 503 N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -( ((1R,3R) - 3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 - carboxamide and N -((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -(((1S,3S) - 3 -ethylcyclobutyl) methyl) -1H -1,2,4 - triazole -3 - carboxamide

[01680] Amide coupling prepared in a manner similar to Method WX 017. The crude material was purified via RP-HPLC (22 to 52% acetonitrile/0.05% ammonium hydroxide in water) to provide N - ((S) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1 -((3 - ethylcyclobutyl) methyl) -1H -1,2,4 -triazole -3 -carboxamide (75 mg, 61%) as a white solid. This material was separated using chiral SFC to provide:

[01681] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 1 -(((1R,3R) -3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole - 3 -carboxamide (Peak 1, retention time = 6.49 min.) (25mg, 67%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.44 (s, 1H), 7.52 (s, 1H), 6.30 (s, 1H), 4.54 - 4.38 (m, 2H), 4, 33 - 4.25(m, 1H), 4.22 (d, J = 7.2 Hz, 2H), 3.35 (s, 3H), 2.89 - 2.87 (m, 1H), 2 .67 - 2.64 (m, 1H), 2.28 - 2.25(m, 1H), 2.16 - 2.07 (m, 3H), 1.42 - 1.34 (m, 4H) , 0.79 (t, J = 7.2 Hz, 1H). LCMS RT = 1.62 min., m/z = 372.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.62 min., ESI+found [M+H] = 372.2,

[01682] N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) - 1 -(((1S,3S) -3 -ethylcyclobutyl) methyl) -1H -1,2,4 -triazole - 3 -carboxamide (Peak 2, Retention time = 6.78min.) (26 mg, 67%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.52 (s, 1H), 6.30 (s, 1H), 4.53 - 4.51 (m, 1H), 4 .42 - 4.39 (m, 1H), 4.34 - 4.27 (m, 3H), 3.35 (s, 3H), 2.89 - 2.81 (m, 2H), 2.27 - 2.22 (m, 2H), 1.92 - 1.89 (m, 2H), 1.79 - 1.75 (m, 2H), 1.48 - 1.44 (m, 2H), 0 .82 (t, J = 7.2 Hz, 1H). LCMS RT = 1.62 min., m/z = 372.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.62 min., ESI+found [M+H] = 372.2,

[01683] SFC Conditions: Column: Chiralcel AD -3 150x4.6mm I.D., 3um Mobile phase: A: CO2 B: methanol (0.05% ethyl acetate),Gradient: from 5% to 40% B in 6.0 min. and held 40% for 2.5 min., then 5% B for 2.5 min., Flow rate: 2.5 mL/min. Column temperature: 35oC. Example 504

[01684] WX 100 Method 1 -[(2,5-difluorophenyl) methyl] -N -(3R) -1,9 - dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo[1,5 -a][1,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide

[01685] A mixture of 1-[(2,5-difluorophenyl) methyl]-1,2,4-triazole-3-carboxylic acid (74 mg, 0.31 mmol), 1-(3-dimethylaminopropyl) hydrochloride 3 -ethylcarbodiimide (59 mg, 0.31 mmol), 1 -hydroxybenzotriazole (42 mg, 0.31 mmol) and 3 -amino -1,9 - dimethyl -4,5 -dihydro -3H -imidazo [1,5 - a][1,3] diazepin -2 -one (50 mg, 0.26 mmol) in N,N -dimethylformamide (5 mL) was stirred at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (5% to 35% acetonitrile/0.05% ammonium hydroxide in water) to provide 1-[(2,5-difluorophenyl)methyl ] -N -(1,9 -dimethyl -2 -oxo -4,5 - dihydro -3H -imidazo[1,5 -a][1,3] diazepin -3 -yl) -1,2,4 - triazole -3-carboxamide (70mg, 66%) as a white solid. The racemic compound obtained was separated using chiral SFC to provide:

[01686] 1 -[(2,5-difluorophenyl) methyl] -N - (3R) -1,9 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo[1,5 - a][1 ,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 3.664 min.) (30 mg, 42%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.65 (s, 1H), 8.04 (s, 1H), 7.21 - 7.14 (m, 3H), 6.56 (s, 2H), 4, 63 — 4.58 (m, 1H), 4.47 — 4.41 (m, 1H), 4.07 -4.03 (m, 1H), 3.32 (s, 3H), 2.73 - 2.65 (m, 1H), 2.27 (s, 3H), 2.22 - 2.16 (m, 1H). LCMS RT = 0.557 min.; m/z = 416.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.557 min., ESI+ found [M+H] = 416.0,

[01687] SFC Conditions: Column: Quiralcel OJ -3 100 x 4.6mm ID, 3um, Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 505 1 -benzyl -N -(3R) -1,9 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo[1,5 -a][1,3] diazepin -3 -yl -1,2 ,4-triazole-3-carboxamide

[01688] Amide coupling prepared in a manner similar to Method WX 100. Racemic material was separated using chiral SFC to provide:

[01689] 1 -benzyl -N -[(3R) -1,9 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo[1,5 -a][1,3] diazepin -3 -yl ]-1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 3.944 min.) (57.7 mg, 29%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 7.78(s, 1H), 7.39 – 7.32 (m, 4H), 6.47 (s, 2H), 4, 59 – 4.54 (m, 1H), 4.41 – 4.35 (m, 1H), 4.01 – 3.94 (m, 1H), 3.31 (s, 3H), 2.72 – 2.66 (m, 1H), 2.24 (s, 3H), 2.15 – 2.10 (m, 1H). LCMS RT = 0.508 min.; m/z = 380.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.508 min., ESI+ found [M+H] =380.0

[01690] SFC Conditions: Column: Quiralpak OJ -3 150 x 4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8mL/min. Column temperature: 40oC). Example 506 1 -[(2,5-difluorophenyl) methyl] -N -[(7S) -9 - methyl -8 -oxo -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepine -7 -yl] -1,2,4 -triazole -3 -carboxamide

[01691] Amide coupling prepared in a manner similar to Method WX 100. The racemic material was separated using chiral SFC to provide:

[01692] 1 -[(2,5-difluorophenyl) methyl] -N - [(7S) -9 -methyl -8 -oxo -6,7 -dihydro -5H -imidazo[1,2 - a][1, 3] diazepin -7 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 3.766 min.) (15 mg, 18.6%): 1H NMR (400 MHz, CD3OD) δ8 .61 (s, 1H), 7.19 — 7.10 (m, 3H), 7.09 (s, 1H), 6.95 (s, 1H), 6.53 (s, 2H), 4, 54 - 4.47 (m, 1H), 4.32 - 4.25(m, 1H), 4.09 - 4.02 (m, 1H), 3.38 (s, 3H), 2.87 - 2.79 (m, 1H), 2.30 - 2.24 (m, 1H). LCMS RT = 1.324 min.; m/z = 402.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.324, ESI+ found [M+H] = 402.2.

[01649] SFC Conditions: Column: Quiralcel OJ -3 250x30 mm ID, 10 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 30% to 30%, Flow rate: 80 mL/min., Column temperature: 40oC. Example 507 1 -[(2,5-difluorophenyl) methyl] -N -[(3R) -1 - methyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a] [1,3] diazepine -3 -yl] -1,2,4 -triazole -3 -carboxamide

[01650] Amide coupling prepared in a manner similar to Method WX 100. Racemic material was separated using chiral SFC to provide:

[01651] 1 -[(2,5-difluorophenyl) methyl] -N - [(3R) -1 -methyl -2 -oxo -4,5 -dihydro -3H -imidazo[1,5 - a][1, 3] diazepin -3 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.162 min.) (33.8 mg 33%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.39 - 7 .18 (m, 3H), 6.96 (s, 1H), 6.54 (s, 2H), 4.43 - 4.30 (m, 2H), 3.87 - 3.78(m, 1H) ), 3.23 (s, 3H), 2.44 (s, 1H), 2.28 - 2.22 (m, 1H). LCMS RT = 1.716 min.; m/z = 402.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.716 min., ESI+ found [M+H] = 402.2.

[01652] SFC Conditions: Column: Quiralcel OJ -3 100x4.6 mm I.D., 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8mL/min. Column temperature:40 oC. Example 508

[01653] WX 162 Method N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7,3' - tetrahydrofuran] -2 -carboxamide Step 1: 2' -chloro -4,5 -dihydro -2H,5'H -spiro [furan - 3,7' -furo [3,4 -d] pyrimidin] -5' -one

[01654] To a solution of 2,2,6,6-tetramethyl piperidine (13.36 g, 94.6 mmol) in tetrahydrofuran (60 mL) was added n-butyllithium (2.5 M in hexanes, 50. 5 mL, 126.2 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (6.0 g, 31.5 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and dihydrofuran-3(2H)-one (10.61 g, 126.2 mmol) was added. After addition, the reaction mixture was stirred at 25oC for 16 h and finalized by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 -200 mesh, elution 0 - 30% ethyl acetate in petroleum ether) to give 2'-chloro-4,5-dihydro-2H,5'H -spiro [furan -3,7' -furo [3,4 -d] pyrimidin] -5' -one (700 mg, 10%) in the form of a yellow oil, which was used in the next step of the form where he was. Step 2: 2' -chloro -4,5 -dihydro -2H,5'H -spiro [furan - 3,7' -furo [3,4 -d] pyrimidin] -5' -ol

[01655] To a solution of 2' -chloro -4,5 -dihydro -2H,5'H -spiro [furan -3,7' -furo [3,4 -d] pyrimidin] -5' -one (700 mg, 3.09 mmol) in toluene (35 mL) was added diisobutylaluminum hydride (7.67 mL, 7.67 mmol, 1.0 M in toluene) under -78°C. The mixture was stirred at -78oC for 2 h and finalized by the addition of saturated ammonium chloride (15 mL). The solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2'-chloro-4,5-dihydro-2H,5'H -spiro [furan -3,7' -furo [3,4 -d] pyrimidin] -5' -ol (250 mg, 35%) in the form of a light yellow oil, which was used in the next stage of the form in which it was found. Step 3: 2' -chloro -4,5 -dihydro -2H,5'H -spiro [furan - 3,7' -furo [3,4 -d] pyrimidine]

[01656] To a mixture of 2' -chloro -4,5 -dihydro -2H,5'H -spiro [furan -3,7' -furo [3,4 -d] pyrimidin] -5' -ol (250 mg, 1.1 mmol) and trifluoroacetic acid (0.41 mL, 6.5 mmol) in dichloromethane (20 mL) was added triethylsilane (0.87 mL, 6.5 mmol) under 0°C. The reaction mixture was stirred at 25°C for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 2'-chloro-4,5-dihydro-2H,5'H -spiro [furan -3,7' -furo [3,4 -d] pyrimidine] (190 mg, 81%) in the form of a yellow oil, which was used in the next step as it was. Step 4: 4,5 -dihydro -2H,5'H -spiro [furan -3,7' -fur [3,4 -d] pyrimidine] -2' -carbonitrile

[01657] To a solution of 2'-chloro-4,5-dihydro-2H,5'H-spiro [furan -3,7'-furo [3,4-d] pyrimidine] (190 mg, 0.89 mmol) in dimethyl sulfoxide (10 mL) and water (2 mL) was added 1,4-diazabicyclo[2,2,2] octane (20 mg, 0.18 mmol) and sodium cyanide (189 mg, 3. 87 mmol). The reaction mixture was stirred at 25°C for 7 h and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 4,5 -dihydro -2H,5'H -spiro [furan - 3,7'-fur [3,4-d]pyrimidine]-2'-carbonitrile (120 mg, 66%) in the form of a colorless oil. Step 5: methyl 4,5 -dihydro -2H,5'H -spiro [furan -3,7' - furan [3,4 -d] pyrimidine] -2' -carboxylate

[01658] To a solution of 4,5 -dihydro -2H,5'H - spiro [furan -3,7' -furo [3,4 -d] pyrimidine] -2' - carbonitrile (120 mg, 0.59 mmol) in methanol (5 mL) HCl (4N in methanol, 2.4 mL) was added. The reaction mixture was stirred at 25°C for 15 h and concentrated under reduced pressure to provide methyl 4,5-dihydro-2H,5'H-spiro[furan-3,7'-furo[3,4-d] crude pyrimidine]-2'-carboxylate (130 mg, 93%) as a white solid, which was used in the next step as is. Step 6: 4,5-Dihydro-2H,5'H-spiro[furan-3,7'-furo[3,4-d]pyrimidine]-2'-carboxylic acid

[01659] A mixture of methyl 4,5 -dihydro - 2H,5'H -spiro [furan -3,7' -furo [3,4 -d] pyrimidine] -2' - carboxylate (130 mg, 0.55 mmol) and lithium hydroxide hydrate (132 mg, 6.50 mmol) in tetrahydrofuran (12 mL) and water (3 mL) was stirred under 25oC for 2 h. The mixture was finalized by adding 1N HCl (3 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 4,5-dihydro-2H,5'H-spiro[furan-3,7'-furo[3,4-d] acid crude pyrimidine]-2'-carboxylic acid (100 mg, 82%) as a yellow solid, which was used in the next step as is. Step 7: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl]spiro [5H -furo [3,4 -d] pyrimidine - 7, 3' -tetrahydrofuran] -2 -carboxamide

[01660] A mixture of spiro[5H-furo[3,4-d]pyrimidine-7,3'-tetrahydrofuran]-2-carboxylic acid (69 mg, 0.31 mmol), (3S)-3-amino- 5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol ) and 1-hydroxybenzotriazole (42 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25oC for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (24% to 54% acetonitrile/0.05% ammonium hydroxide in water) to provide N -[(3S)-5-methyl - 4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 - d] pyrimidine -7,3' -tetrahydrofuran] -2 -carboxamide (41 mg, 40 %) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.85 (s, 1H), 7.46 - 7.44 (m, 1H), 7.36 - 7.29 (m, 2H), 7.27 - 7.24 (m, 1H), 6.19 (s, 2H), 6.08 - 6.03 (m, 1H), 4.68 - 4.64 (m, 1H), 4.49 - 4.43 (m , 1H), 4.17 - 4.02 (m, 4H), 3.43 (s, 3H), 2.49 - 2.40 (m, 1H), 2.34 - 2.29 (m, 1H) ). LC-MS RT = 0.891 min., m/z = 397.1 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.891 min., ESI+ found [M+H] = 397.1. Example 509

[01661] WX 175 Method 4 -(1-hydroxycyclopentyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 - carboxamide Step 1: 1 -(2 -bromopyrimidin -4 -yl)cyclopentanol

[01662] To a solution of 2-bromo-4-iodo-pyrimidine (500 mg, 1.8 mmol) and cyclopentanone (221 mg, 2.6 mmol) in tetrahydrofuran (15 mL) was added isopropyl magnesium chloride ( 1.0 M in Tetrahedron, 2.0 mL, 2.0 mmol) under -70oC. The mixture was subjected to stirring at -70oC for 1 h and finalized by the addition of saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL), brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 25% ethyl acetate in petroleum ether) to provide 1-(2-bromopyrimidin-4-yl) cyclopentanol (80 mg, 19%) in the form of a colorless oil. 1H NMR (400MHz, CD3OD) δ8.55 (d, J = 6.0 Hz, 1H), 7.76 (d, J = 6.3 Hz, 1H), 2.21 - 2.13 (m, 2H ), 2.00 - 1.83 (m, 6H). Step 2: 4 -(1-hydroxycyclopentyl)pyrimidine -2 carbonitrile

[01663] To a solution of 1 -(2-bromopyrimidin-4-yl) cyclopentanol (40 mg, 0.16 mmol) in dimethylsulfoxide (2 mL) and water (1 mL) was added 1,4-diazabicyclo [2, 2.2] octane (18 mg, 0.16 mmol) and sodium cyanide (16 mg, 0.33 mmol). The mixture was stirred at 25°C for 16 h and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude 4-(1-hydroxycyclopentyl)pyrimidine-2-carbonitrile (30 mg, 96%) in the form of a yellow oil. 1H NMR (400 MHz, CD3OD) δ8.84 (d, J = 6.6 Hz, 1H), 7.98 (d, J = 6.6 Hz, 1H), 2.19 - 2.17 (m, 2H), 1.99 - 1.87 (m, 6H). Step 3: methyl 4 -(1-hydroxycyclopentyl) pyrimidine -2 - carboxylate

[01664] To a solution of 4-(1-hydroxycyclopentyl)pyrimidine-2-carbonitrile (25 mg, 0.13 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1.5 mL). The mixture was subjected to stirring at 25oC for 20 h. The mixture was concentrated under reduced pressure and the residue was purified by preparation TIC (50% ethyl acetate in petroleum ether, Rf = 0.3) to give methyl 4 -(1-hydroxycyclopentyl) pyrimidine -2 - carboxylate (15 mg, 51%) in the form of a colorless oil. 1H NMR (400 MHz, CD3OD) δ8.86 (d, J = 6.6 Hz, 1H), 7.94 (d, J = 6.6 Hz, 1H), 4.00 (s, 3H), 2 .27 - 2.23 (m, 2H), 1.98 - 1.86(m, 6H). LCMS RT = 0.523 min., m/z = 223.0 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.523 min., ESI+ found [M+H] = 223.0. Step 4: 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylic acid

[01665] A mixture of methyl 4 -(1-hydroxy cyclopentyl) pyrimidine -2 -carboxylate (15 mg, 0.07 mmol) and lithium hydroxide hydrate (14 mg, 0.34 mmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) were stirred at 25oC for 16 h. The solution was adjusted to pH = 4 -5 by adding 1N HCl. The mixture was concentrated under reduced pressure to provide crude 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylic acid (11 mg, 78%) as a yellow solid. LCMS RT = 0.290 min., m/z = 208.9 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.290 min., ESI+ found [M+H] = 208.9. Step 5: 4 -(1-hydroxycyclopentyl) -N -[(3S)-5 -dihydro -1,5 -benzoxazepin -3 -yl] carboxamide

[01666] A mixture of (3S) -2,3 -dihydro -1,5 -benzoxazepin -4 -one 4 -(1-hydroxy cyclopentyl) carboxylic acid (10 mg, 0.05 mmol), 1H triazole -1 - ol (8 mg, 0.06 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (11 mg, 0.06 mmol) in N,N-dimethylformamide (3 mL) was subjected to stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25% to 55% acetonitrile/0.05% ammonium hydroxide in water) to give 4-(1-hydroxycyclopentyl)-N-[ (3S)-5-methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 - carboxamide (10.3 mg, 56%) as a white solid . 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J = 6.2 Hz, 1H), 7.90 (d, J = 4.8 Hz, 1H), 7.47 - 7.42 (m , 1H), 7.36 - 7.29 (m, 2H), 7.28 - 7.23 (m, 1H), 6.05 - 6.00 (m, 1H), 4.71 - 4.67 (m, 1H), 4.44 - 4.39 (m, 1H), 3.44 (s, 3H), 2.28 - 2.24 (m, 2H), 2.03 - 1.96 (m , 6H). LC-MS RT = 0.664 min., m/z = 383.1 [M+H] +. LCMS (0 -60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 2.023 min., ESI+ found [M+H] = 383.1. Example 510

[01667] WX 160 Method N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [ 3,4 -d] pyrimidine -7,3' -tetrahydropyran] -2 -carboxamide Step 1: 2 -chloro -2',3',5',6' -tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,4' -pyran] -5 -one

[01668] To a solution of 2,2,6,6-tetramethyl piperidine (13.36 g, 94.6 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexanes, 26. 2 mL, 63.0 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (6.0 g, 31.5 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and dihydro-2H-pyran-4(3H)-one (9.47 g, 94.6 mmol) was added. After addition, the reaction mixture was stirred at 25oC for 16 h and finalized by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 2-chloro -2',3',5',6' -tetrahydro -5H - spiro [fur [3,4 -d] pyrimidine -7,4' -pyran] -5 -one (1.5 g, 20%) as a yellow solid. Step 2: 2 -chloro -2',3',5',6' -tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,4' -pyran] -5 -ol

[01669] To a solution of 2 -chloro -2',3',5',6' -tetrahydro -5H -spiro [furo [3,4 -d] pyrimidine -7,4' - pyran] -5 -one (100 mg, 0.42 mmol) in tetrahydrofuran (3 mL) was added diisobutyl aluminum hydride (1.66 mL, 1.66 mmol, 1.0 M in toluene). The reaction mixture was stirred at -70oC for 2 h and finished by adding saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by TIC preparation (50% ethyl acetate in petroleum ether, Rf = 0.3) to provide 2-chloro -2',3',5',6'-tetrahydro -5H - spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-5-ol (50 mg, 50%) in the form of a colorless oil. Step 3: 2 -chloro -2',3',5',6' -tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,4' -pyran]

[01670] To a solution of 2 -chloro -2',3',5',6' -tetrahydro -5H -spiro [furo [3,4 -d] pyrimidine -7,4' - pyran] -5 -ol (50 mg, 0.21 mmol) and trifluoroacetic acid (0.4 g, 3.53 mmol) in dichloromethane (5 mL) was added triethylsilane (118 mg, 1.03 mmol) under 0°C. After addition, the mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by TIC preparation (33% ethyl acetate in petroleum ether, Rf = 0.4) to provide 2-chloro-2',3',5',6'-tetrahydro-5H- spiro [furo [3,4 -d] pyrimidine -7,4' - pyran] (30 mg, 64%) as a light yellow solid. Step 4: 2',3',5',6' -tetrahydro -5H -spiro [hole [3,4 -d] pyrimidine -7,4' -pyran] -2 -carbonitrile

[01671] To a solution of 2 -chloro -2',3',5',6' -tetrahydro -5H -spiro [furo [3,4 -d] pyrimidine -7,4' - pyran] (30 mg, 0.13 mmol) in dimethyl sulfoxide (4 mL) and water (2 mL) was added 1,4-diazabicyclo[2,2,2] octane (8 mg, 0.07 mmol) and sodium cyanide (21 mg , 0.43 mmol). The reaction mixture was stirred at 25°C for 12 h and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7, Crude 4'-pyran]-2-carbonitrile (20 mg, 70%) as a light yellow solid. Step 5: methyl 2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2-carboxylate

[01672] To a solution of 2',3',5',6' - tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,4' - pyran] -2 -carbonitrile (20 mg, 0.09 mmol) in methanol (1.5 mL) and HCl (4N in methanol, 0.5 mL) was added. The reaction mixture was subjected to stirring at 25oC for 2 h and 35oC for 15 h. The mixture was concentrated under reduced pressure to provide methyl 2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2-carboxylate crude (15 mg, 65%) as a yellow solid. Step 6: 2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2-carboxylic acid

[01673] A mixture of methyl 2',3',5',6' - tetrahydro -5H -spiro [furo [3,4 -d] pyrimidine -7,4' - pyran] -2 -carboxylate (15 mg, 0.06 mmol) and lithium hydroxide hydrate (7 mg, 0.30 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL) was stirred at 25oC for 16 h. The mixture was finalized by adding 1N HCl (3 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7 acid crude ,4'-pyran]-2-carboxylic acid (10 mg, 70%) as a white solid. Step 7: N -[(6S)-2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,3' -tetrahydropyran] -2 -carboxamide

[01674] To a solution of (3S) -3 -amino -5 - methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (9 mg, 0.05 mmol), 1-hydroxy benzotriazole (7 mg, 0.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9 mg, 0.05 mmol), and spiro[5H-furo[3,4-d]pyrimidine acid-7.4 '-tetrahydropyran]-2-carboxylic acid (10 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was stirred at 25°C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25% to 55% acetonitrile / 0.05% ammonium hydroxide in water) to give N -[(6S) -2.4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,3 '-tetrahydropyran]-2-carboxamide (4 mg, 21%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.85 (s, 1H), 7.46 - 7.44 (m, 1H), 7.35 - 7.31 (m, 2H), 7.26 - 7.25 (m, 1H), 6.19 (s, 2H), 6.07 - 6.03 (m, 1H), 4.71 - 4.68 (m, 1H), 4.66 - 4.42 (m , 1H), 3.99 - 3.97 (m, 2H), 3.87 - 3.82 (m, 2H), 3.44 (s, 3H), 2.24 - 2.21 (m, 2H ), 1.70- 1.67 (m, 2H). LC-MS RT = 1.923 min., m/z = 411.1 (M+H) +. LCMS (0 -60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.923 min., ESI+ found [M+H] = 411.1. Example 511 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,3' - tetrahydropyran] -2 -carboxamide

[01675] Amide coupling prepared in a manner similar to Method WX 160. The crude material was purified via RP-HPLC (20% to 50% acetonitrile / 0.05% ammonium hydroxide in water) to provide N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7,3' - tetrahydropyran ]-2-carboxamide (21 mg, 19.2% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H), 7.46 - 7.44 (m, 1H), 7.36 - 7.30 (m, 2H), 7.27 - 7, 24 (m, 1H), 6.22 (s, 2H), 6.07 - 6.03 (m, 1H), 4.70- 4.66 (m, 1H), 4.47 - 4.42 ( m, 1H), 3.97 - 3.94 (m, 1H), 3.82 - 3.74 (m, 2H), 3.69 - 3.61 (m, 1H), 3.44 (s, 3H), 2.22 - 2.15 (m, 1H), 2.10 - 2.01 (m, 1H), 1.94 - 1.89 (m, 1H), 1.78- 1.72 ( m, 1H). LCMS RT =0.913 min., m/z = 411.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.913 min., ESI+ found [M+H] = 411.2. Example 512 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] spiro [5H -furo [ 3,4 -d] pyrimidine -7,4' -tetrahydropyran] -2 -carboxamide

[01676] Amide coupling prepared in a manner similar to Method WX 160. The crude material was purified via RP-HPLC (8% to 38% acetonitrile, 0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] spiro [5H -furo [3 ,4-d]pyrimidine -7,4'-tetrahydropyran]-2-carboxamide (18.1 mg, 33.8%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H), 6.14 (s, 1H), 6.20 (s, 2H), 4.88 - 4.57 (m, 1H), 4 .33 - 4.26 (m, 2H), 3.98 - 3.88 (m, 2H), 3.85 - 3.82 (m, 2H), 3.36 (s, 3H), 2.96 - 2.91 (m, 1H), 2.30 - 2.21 (m, 6H), 1.69 -1.66 (m, 2H). LC-MS RT =1.052 min., m/z = 413.0 [M+H] +. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.052 min., ESI+ found [M+H] = 413.0. Example 513 5 -[(2,3-difluorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -4H -1,2,4 -triazole -3 -carboxamide and 5 -[(2,3-difluorophenyl) methyl] -N -(6R) -2,4 -dimethyl -5 - oxo -7 ,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -4H -1,2,4 -triazole -3 -carboxamide

[01677] Amide coupling prepared in a manner similar to Method WX 011. The crude material was purified using RP-HPLC (28 -58% acetonitrile / 0.05% ammonium hydroxide in water) to provide 5 - [(2,3-difluorophenyl) methyl] -N -(2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ) -4H - 1,2,4 -triazole -3 -carboxamide (170 mg, 79%) as a white solid. The racemic material was separated using chiral SFC to provide:

[01678] 5 -[(2,3-difluorophenyl) methyl] -N - (6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 - carboxamide (Peak 1, Retention time = 3.977 min.) (77 mg, 48%) as a white solid. 1H NMR (400MHz, CD3OD) δ7.20 - 7.11 (m, 3H), 6.10 (s, 1H), 4.54 - 4.49 (m, 1H), 4.30 - 4.20 ( m, 4H), 3.32 (s, 3H), 2.86 - 2.79 (m, 1H), 2.27 - 2.21 (m, 4H). LC-MS RT = 0.637 min., m/z = 416.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.637 min., ESI+ found [M+H] = 416.1.

[01679] 5 -[(2,3-difluorophenyl) methyl] -N - (6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 - carboxamide (Peak 2, Retention time = 4.582 min.) (77.5 mg, 48%) as a colored solid white. 1H NMR (400MHz, CD3OD) δ7.20 - 7.11 (m, 3H), 6.10 (s, 1H), 4.54 - 4.49 (m, 1H), 4.30 - 4.20 ( m, 4H), 3.32 (s, 3H), 2.86 - 2.79 (m, 1H), 2.27 - 2.21 (m, 4H). LC-MS RT = 0.637 min., m/z = 416.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.637 min., ESI+ found [M+H] = 416.1,

[01680] SFC condition: column: chiralpak OD -3 100x4.6 mm ID, 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 30% to 30% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 514 5 -[(2,3-difluorophenyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide and 5 -[(2,3-difluorophenyl) methyl] -N -(6R) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide

[01681] Amide coupling prepared in a manner similar to Method WX 011. The crude material was purified using RP-HPLC (28 - 58% acetonitrile/0.05% ammonium hydroxide in water) to provide 5 - [(2,3-difluorophenyl) methyl] -N -2 -cyclopropyl -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -4H -1,2,4 -triazole -3 -carboxamide (100 mg, 49%) as a white solid. The racemic material was separated using chiral SFC to provide:

[01682] 5 -[(2,3-difluorophenyl) methyl] -N - (6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide (Peak 1, Retention time = 4.389 min.) (42.7 mg, 42%) as a solid white in color. 1H NMR (400MHz, CD3OD) δ7.26 - 7.07 (m, 3H), 6.01 (s, 1H), 4.53 - 4.50 (m, 1H), 4.33 - 4.16 ( m, 4H), 3.35 - 3.32 (m, 3H), 2.85 - 2.79 (m, 1H), 2.26 - 2.22 (m, 1H), 1.92 - 1, 98 (m, 1H), 0.98 - 0.89 (m, 2H), 0.77 - 0.69 (m, 2H). LC-MS RT = 0.704 min., m/z = 442.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.704 min., ESI+ found [M+H] = 442.1.

[01683] 5 -[(2,3-difluorophenyl) methyl] -N - (6R) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide (Peak 2, Retention time = 4.804 min.) (54.9 mg, 54%) as a solid white in color. 1H NMR (400MHz, CD3OD) δ7.26 - 7.07 (m, 3H), 6.01 (s, 1H), 4.53 - 4.50 (m, 1H), 4.33 - 4.16 ( m, 4H), 3.35 - 3.32 (m, 3H), 2.85 - 2.79 (m, 1H), 2.26 - 2.22 (m, 1H), 1.92 - 1, 98 (m, 1H), 0.98 - 0.89 (m, 2H), 0.77 - 0.69 (m, 2H). LC-MS RT = 0.704 min., m/z = 442.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.704 min., ESI+ found [M+H] = 442.2.

[01684] SFC condition: column: chiralpak OD - 3 100x4.6mm I.D., 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 30% to 30% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8mL/min. Column temperature: 40oC. Examples 515, 516 and 517

[01685] WX 121 Method

[01686] 8 -phenyl -N -[(3S) -5 -methyl -4 -oxo - 2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro -5H - [1, 2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide and

[01687] (8S) -8 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide and

[01688] (8R) -8 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide Step 1: 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole

[01689] To a solution of 3,5-dibromo-1H - 1,2,4-triazole (10 g, 44.1 mmol) in acetonitrile (100 mL) was added 2 -(2-bromoethoxy) tetrahydro -2H - pyran (8.0 mL, 52.9 mmol) and N,N-diisopropylethylamine (8.45 mL, 48.5 mmol). The mixture was stirred at 90°C for 3 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl )-1,2,4-triazole (13 g, 83%) in the form of a colorless oil, which was used in the next step as is. Step 2: [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol

[01690] To a solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2.0 g, 6.6 mmol) in tetrahydrofuran (20 mL) n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) was added at -78°C. The mixture was stirred at -78°C for 1 h and then a solution of benzaldehyde (1.2 g, 11.3 mmol) in THF (2 mL) was added. After addition, the mixture was stirred at -78°C for another 1 h and then finalized by addition of saturated ammonium chloride (10 mL). The resulting mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl) -1,2,4-triazol-3-yl]-phenyl-methanol (1.5 g, 69.7%) in the form of a light yellow oil, which was used in the next step in the form in which it was found. Step 3: 2 -bromo -8 -phenyl -6,8 -dihydro -5H - [1,2,4] triazolo [5,1 -c][1,4] oxazine

[01691] A mixture of [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol (1.5 g, 3.92 mmol) and p -toluene sulfonic acid (863 mg, 6.02 mmol) in toluene (50 mL) was heated under reflux for 5 h. After cooling, the reaction was diluted with ethyl acetate (100 mL), washed with sodium hydroxide (1N, 20 mL), saline solution (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 40% ethyl acetate in petroleum ether) to provide 2-bromo-8-phenyl-6,8-dihydro-5H- [1,2,4] triazolo [5,1 -c][1,4] oxazine (800 mg, 73%) as a yellow oil. LCMS RT = 0.642 min., m/z = 281.6 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.642 min., ESI+ found [M+H] = 281.6 Step 4: methyl 8 -phenyl -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxylate

[01692] A mixture of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 0.02 mmol), 2-bromo-8-phenyl-6,8-dihydro-5H-[1,2, 4] triazolo [5,1 - c][1,4] oxazine (300 mg, 1.07 mmol) and triethylamine (1.45 mL, 10.7 mmol) in methanol (30 mL) was heated at 70oC for 12 h under CO [3.77 bar (40 psi)]. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide methyl 8-phenyl-6,8-dihydro-5H-[1, 2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxylate (100 mg, 20%) as a brown oil. LCMS RT = 0.682 min., m/z = 259.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.682 min., ESI+ found [M+H] = 259.9. Step 5: 8-Phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid

[01693] A mixture of methyl 8 -phenyl -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine - 2 - carboxylate (50 mg, 0. 11 mmol) and lithium hydroxide (8 mg, 0.32 mmol) in tetrahydrofuran (4 mL) and water (1 mL) were stirred under 25oC for 1 h. The mixture was adjusted to pH = 3 by adding 2N HCl and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure to provide 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid crude (25mg, 94% crude yield) in the form of a yellow solid, which was used in the next step as is. Step 6:

[01694] 8 -phenyl -N -[(3S) -5 -methyl -4 -oxo - 2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro -5H - [1, 2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide and

[01695] (8S) -8 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide and

[01696] (8R) -8 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide

[01697] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (23 mg, 0.12 mmol), 1 -(3 - dimethylaminopropyl)-3-ethylcarbodiimide (45 mg, 0.24 mmol), 1-hydroxybenzotriazole (30 mg, 0.23 mmol) and 8-phenyl-6,8-dihydro-5H-[1,2,4]triazole acid [5,1-c][1,4] oxazine -2-carboxylic acid (25 mg, 0.10 mmol) in N,N -dimethylformamide (3mL) was subjected to stirring at 25oC for 12 h. The mixture was concentrated under reduced pressure and the residue purified by RP-HPLC (28% to 58% acetonitrile/0.05% ammonium hydroxide in water) to give 8-phenyl-N-[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1, 4] oxazine -2 -carboxamide (14.5 mg, 33.6%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.80 (s, 1H), 7.46 - 7.44 (m, 1H), 7.34 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 6.12 (s, 2H), 6.07 - 6.02 (m, 1H), 4.69 - 4.68 (m, 1H), 4.46 - 4.43 (m , 1H), 3.44 (s, 3H), 2.08 - 2.04 (m, 4H), 1.95 - 1.93 (m, 4H). LCMS RT = 1.009 min., m/z = 420.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.009 min., ESI+ found [M+H] = 420.2.

[01689] Another batch of racemic material was separated (70 mg) by means of chiral SFC to provide:

[01690] (8S) -8 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide (Peak 1, retention time: 4.182 min.) (10.9 mg, 14%), in the form of a light yellow oil. 1H NMR (400 MHz, CD3OD) δ7.41 - 7.38 (m, 6H), 7.30 - 7.29 (m, 2H), 7.22 - 7.21 (m, 1H), 6.94 (s, 1H), 6.01 -4.96 (m, 1H), 4.58 - 4.53 (m, 1H), 4.47 - 4.35 (m, 4H), 4.30 - 4 .25(m, 1H), 3.38 (s, 3H). LCMS RT = 0.809 min., m/z = 420.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.809 min., ESI+ found [M+H] = 420.0.

[01691] (8R) -8 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide (Peak 2, retention time 6.374 min.) (10 mg, 14%) in the form of an oil light yellow color. 1H NMR (400 MHz, CD3OD) δ7.41 - 7.38 (m, 6H), 7.30 - 7.29 (m, 2H), 7.22 - 7.21 (m, 1H), 6, 94 (s, 1H), 6.01 - 4.96 (m, 1H), 4.57 - 4.47 (m, 2H), 4.40 - 4.35 (m, 3H), 4.25- 4.20 (m, 1H), 3.38 (s, 3H). LCMS RT = 0.809 min., m/z = 420.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.809 min., ESI+ found [M+H] = 420.0.

[01692] SFC Condition: Column: Chiralpak AD - 3 100x4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 518

[01693] Method WX 043 1 -[(2-fluorophenyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: Methyl 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate

[01694] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N - dimethylformamide (200 mL) was added potassium carbonate (21. 7 g, 157.36 mmol) and 2-fluorobenzyl bromide (17.9 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was diluted with saline (30 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 1-[(2-fluorophenyl) methyl]-1,2, 4-triazole-3-carboxylate (6.0 g, 27% yield) in the form of a white solid, which was used in the next step as is. Step 2: 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

[01695] A mixture of methyl 1-[(2-fluorophenyl) methyl]-1,2,4-triazole-3-carboxylate (40.0 g, 170.00 mmol) and potassium hydroxide (19.1 g, 340.12 mmol) in ethanol (800 mL) and water (200 mL) was stirred at 25oC for 12 h. Ethanol was concentrated under reduced pressure and the aqueous solution was adjusted to pH = 4 by adding 2 N HCl. The resulting solid was collected through filtration and dried to yield 1-[(2-fluorophenyl) methyl]-1,2,4-triazol-3-carboxylic acid (33.0 g, 87.7%) in the form of a white solid, which was used in the next stage as it was. Step 3: 1 -[(2-fluorophenyl) methyl] -N -(6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01696] To a stirred solution of 1-[(2-fluorophenyl) methyl]-1,2,4-triazole-3-carboxylic acid (23.9 g, 108.12 mmol) in N,N-dimethyl formamide (6 mL) was added (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20. 0 g, 102.97 mmol), 1-hydroxybenzotriazole (2.78g, 20.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimido hydrochloride (29.61 g, 154.46 mmol). The mixture was subjected to stirring at 20°C for 2 h. The mixture was poured into sat. saline solution, then a white solid was formed. the cake was collected and washed with ethyl acetate. The solid was recrystallized from ethanol/water to provide 1-[(2-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazole [1, 5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (29.1 g, 71%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1H), 7.40 - 7.35 (m, 2H), 7.21 - 7.12 (m, 2H), 6.10 (s, 1H ), 6.54 (s, 2H), 4.54 - 4.49 (m, 1H), 4.29 - 4.15 (m, 2H), 3.31 (s, 3H), 2.87 - 2.79 (m, 1H), 2.27 - 2.20 (m, 4H). LC-MS RT =1.426 min., m/z =398.2 (M+H) +. LCMS (10 to 80% ammonium hydroxide in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 1.426 min., ESI+ found [M+H] = 398.2. Example 519 1 -[(3-fluorophenyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide

[01697] Amide coupling prepared in a manner similar to Method WX 049. The crude material was purified via RP-HPLC (acetonitrile 42 - 62%/0.05 ammonium hydroxide in water) to provide 1 -[ (3-fluorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ] - 1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 1.663 min.) (44 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.60 (s, 1H), 7.42 - 7.36 (m, 1H), 7.17 - 7.06 (m, 3H), 6.11 (s, 1H) ), 6.49 (s, 2H), 4.56 - 4.51 (m, 1H), 4.31 - 4.18 (m, 2H), 3.32 (d, J = 6.2 Hz, 3H), 2.87 - 2.81 (m, 1H), 2.28 - 2.23 (m, 4H). LCMS RT = 0.904 min., m/z = 398.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.904 min., ESI+ found [M+H] = 398.2. Example 520

[01698] Method WX 073 1 -[(2-chlorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: methyl 1 -[(2-chlorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate

[01699] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N - dimethylformamide (200 mL) was added potassium carbonate (21. 8 g, 157.36 mmol) and 2-chlorobenzyl bromide (19.4 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 1-[(2-chlorophenyl ) methyl] -1,2,4 - triazole -3 -carboxylate (6.0 g, 25%) as a white solid, which was used in the next step as it was, which was used in the next stage as it was. Step 2: 1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01700] A mixture of methyl 1-[(2-chlorophenyl) methyl]-1,2,4-triazole-3-carboxylate (6.0 g, 19.87 mmol) and potassium hydroxide (2.2 g, 39.73 mmol) in ethanol (80 mL) and water (15 mL) was stirred at 25oC for 12 h. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The solution was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and subjected to drying under reduced pressure to obtain 1-[(2-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (3.0 g, 64% ) in the form of white solids. 1H NMR (400 MHz, DMSO -d6) δ8.79 (s, 1H), 7.52 - 7.50 (m, 1H), 7.41 - 7.37 (m, 2H), 7.37 - 7 .29 (m, 2H), 6.59 (s, 2H). Step 3: 1 -[(2-chlorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl -1,2,4 -triazole -3 –carboxamide

[01701] A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74 mg, 0.39 mmol), 1-hydroxybenzotriazole (52 mg, 0.39 mmol), 1-[(2-chlorophenyl) acid )methyl]-1,2,4-triazole-3-carboxylic acid (73 mg, 0.31 mmol) and (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazole [1 ,5-a][1,3] diazepin-5-one (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred under 25oC for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (28-58% acetonitrile/0.05% ammonium hydroxide in water) to give 1-[(2-chlorophenyl)methyl]-N - (6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole - 3-carboxamide (34.6 mg, 32%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1H), 7.46 - 7.36 (m, 1H), 7.35 - 7.32 (m, 3H), 6.10 (s, 1H ), 6.60 (s, 2H), 4.54 - 4.49 (m, 1H), 4.33 - 4.19 (m, 2H), 3.30 (s, 3H), 2.85 - 2.79 (m, 1H), 2.27 - 2.21 (m, 4H). LCMS RT = 0.763 min., m/z = 414.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.763 min., ESI+ found [M+H] =414.1. Example 521

[01702] WX Method 077 1 -[(3-chlorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: methyl 1 -[(3-chlorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate

[01703] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N - dimethyl formamide (200 mL) was added potassium carbonate (21 .8 g, 157.36 mmol) and 3-chlorobenzyl bromide (19.4 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 1-[(3-chlorophenyl ) methyl] -1,2,4 - triazole -3 -carboxylate (3.0 g, 15%) in the form of white solids, which were used in the next step as they were. Step 2: 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

[01704] A mixture of methyl 1 -[(3 - chlorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (3.0 g, 11.92 mmol) and potassium hydroxide (1.3 g, 23.84 mmol) in ethanol (80 mL) and water (15 mL) was stirred at 25oC for 12 h. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The solution was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and subjected to drying under reduced pressure to obtain 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (2.0 g, 71% ) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ8.80 (s, 1H), 7.42 - 7.38 (m, 3H), 7.29 - 7.26 (m, 1H), 6.50 (s , 2H). Step 3: 1 -[(3-chlorophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide

[01705] A mixture of 1-hydroxybenzotriazole (52 mg, 0.39 mmol), 1-[(3-chlorophenyl) methyl]-1,2,4-triazole-3-carboxylic acid (73 mg, 0.31 mmol ), (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg, 0.26 mmol ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25oC for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (28-58% acetonitrile/0.05% ammonium hydroxide in water) to give 1-[(3-chlorophenyl)methyl]-N -(6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole - 3-carboxamide (36.01 mg, 34%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.37 - 7.25(m, 4H), 6.10 (s, 1H), 6.46 (s, 2H), 4 .54 - 4.49 (m, 1H), 4.29 - 4.27 (m, 1H), 4.24 - 4.19 (m, 1H), 3.31 - 3.29 (m, 3H) , 2.85 - 2.79 (m, 1H), 2.28 - 2.21 (s, 4H). LC-MS RT = 0.755 min., m/z = 414.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.755 min., ESI+ found [M+H] =414.1. Example 522 1 -[(2-chlorophenyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01706] Amide coupling prepared in a manner similar to Method WX 073. The crude material was purified by means of RP-HPLC (ACN 45 -75%/0.05% ammonium hydroxide in water) to provide 1 - [(2 - chlorophenyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 - yl -1,2,4 -triazole -3 -carboxamide (31.5 mg, 30%) as white solids. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.45- 7.30 (m, 4H), 6.98 (s, 1H), 6.59 (s, 2H), 4 .52 - 4.47 (m, 1H), 4.29 - 4.17 (m, 2H), 3.30 (s, 3H), 2.83 - 2.78(m, 1H), 2.24 - 2.21 (m, 1H), 1.90 - 1.87 (m, 1H), 0.93 - 0.90 (m, 2H), 0.73 - 0.70(m, 2H). LCMS RT = 0.794 min., m/z = 440.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.794 min., ESI+ found [M+H] =440.1. Example 523

[01707] Method WX 066 1 -[(2,3-difluorophenyl) methyl] -N -(6S) -4 - methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide Step 1: methyl 1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylate

[01708] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N - dimethylformamide (200 mL) was added potassium carbonate (21. 8 g, 157.36 mmol) and 2,3-difluorobenzyl bromide (19.6 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to give crude methyl 1 -(2,3 -difluorobenzyl) -1H -1,2,4 -triazole -3 - carboxylate (10.2 g, 51%) in the form of white solids, which was used in the next step as is. Step 2: 1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01709] A mixture of methyl 1 -[(2,3 - difluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (2.0 g, 7.9 mmol) and potassium hydroxide (0.9 g, 16.8 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25oC for 12 h. The ethanol was evaporated and the residue was diluted with water (20 ml). The mixture was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected by filtration and dried to yield 1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (1.6 g, 85%) in form of white solids. 1H NMR (400 MHz, CD3OD) δ8.68 (s, 1H), 7.31 - 7.28 (m, 1H), 7.20 - 7.18 (m, 2H), 6.61 (s, 2H ). Step 3: 1-[(2,3-difluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazole[1,5- a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01710] A mixture of 6 -amino -4 -methyl -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg, 0.20 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol) and 1-[(2, 3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (48 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was stirred at 20°C for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile/0.05% ammonium hydroxide in water) to provide the racemic material ((80 mg, 85%), which was separated using chiral SFC to provide:

[01711] 1 -[(2,3-difluorophenyl) methyl] -N - (6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro - 6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 6.327 min.) (22.8 mg, 29%) as colored solids white. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.48 - 7.42 (m, 1H), 7.05 - 6.97 (m, 2H), 6.66 (s, 1H), 6.52 (s, 2H), 4.53 - 4.44 (m, 2H), 4.39 - 4.33 (m, 1H), 3.36 (s, 3H), 2.89 - 2.84 (m, 1H), 2.35 - 2.29 (m, 1H). LCMS RT = 0.812 min., m/z = 470.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.812 min., ESI+ found [M+H] =470.1.

[01712] SFC Conditions: Column: Chiralcel OD -3 150x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5mL/min. Column temperature: 35 oC. Example 524 5 -[(2,3-difluorophenyl) methyl] -N -(6S) -4 - methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide and 5 - [(2,3 -difluorophenyl) methyl] -N -(6R) -4 - methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide

[01713] Amide coupling prepared in a manner similar to Method WX 011. The raw material was separated using chiral SFC to provide:

[01714] 5 -[(2,3-difluorophenyl) methyl] -N - (6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro - 6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -4H -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time: 2.787 min.) (41 mg, 44%). 1H NMR (400 MHz, DMSO -d6) δ8.69 (s, 1H), 7.37 — 7.31 (m, 1H), 7.19 — 7.13 (m, 2H), 6.94 (s , 1H), 4.50 - 4.44 (m, 1H), 4.36 - 4.32 (m, 2H), 4.19 (s, 2H), 3.27 (s, 3H), 2, 64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.808 min., m/z = 470.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.808 min., ESI+ found [M+H] =470.1.

[01715] 5 -[(2,3-difluorophenyl) methyl] -N - (6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro - 6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -4H -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time: 3.099 min.) (29 mg, 31%). 1H NMR (400 MHz, DMSO -d6) δ8.71 (s, 1H), 7.37 - 7.31 (m, 1H), 7.19 - 7.13 (m, 2H), 6.94 (s , 1H), 4.50 - 4.44 (m, 1H), 4.36 - 4.32 (m, 2H), 4.19 (s, 2H), 3.27 (s, 3H), 2, 64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.808 min., m/z = 470.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.808 min., ESI+ found [M+H] =470.1.

[01716] SFC Condition: Column: Chiralcel OD - 3 150x4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35 C. Example 525

[01717] WX Method 067 1 -[(4-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(4-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: Methyl 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylate

[01718] To a solution of methyl 1H -1,2,4 -triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N – dimethylformamide (200 mL) was added potassium carbonate (21 .8 g, 157.36 mmol) and 4-fluorobenzyl chloride (13.7 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to provide methyl 1-(4-fluorobenzyl) -1H -1,2,4 - triazole -3 -carboxylate (7.8 g, 42%) as white solids. Step 2: 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01719] A mixture of methyl 1 - [(4 - fluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (2.0 g, 8.5 mmol) and potassium hydroxide (954 mg, 17, 0 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25oC for 12 h. The ethanol was evaporated and the residue was diluted with water (20 ml). The mixture was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and dried to yield 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (1.5 g, 81%) in the form of white solids. 1H NMR (400 MHz, CD3OD) δ8.63 (s, 1H), 7.44 - 7.40 (m, 2H), 7.14 - 7.09 (m, 2H), 6.47 (s, 2H ). Step 3: 1 -[(4-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(4-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01720] To a solution of 6-amino -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg , 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole (33 mg, 0.20 mmol) 24 mmol) and 1-[(4-fluorophenyl) methyl]-1,2,4-triazole-3-carboxylic acid (53 mg, 0.24 mmol). The reaction mixture was stirred at 20°C for 2 h and concentrated under reduced pressure. The residue was purified using RP-HPLC (35 -65% acetonitrile / 0.05% ammonium hydroxide in water) to provide racemic material which was separated using chiral SFC to provide:

[01721] 1 -[(4-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time 6.728 min.) (35 mg, 37%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.82 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 7.40 - 7.36 (m, 2H), 7, 21 (t, J = 8.8 Hz, 2H), 6.94 (s, 1H), 6.47 (s, 2H), 4.48 - 4.44 (m, 1H), 4.37 - 4 .30 (m, 2H), 3.27 (s, 3H), 2.64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.810 min., m/z = 452.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.810 min., ESI+ found [M+H] =452.1.

[01722] 1 -[(4-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 7.422 min.) (33 mg, 36%) as white solids. H NMR (400 MHz, DMSO - d 6) δ8.82 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 7.40 - 7.36 (m, 2H), 7 .21 (t, J = 8.8 Hz, 2H), 6.94 (s, 1H), 6.47 (s, 2H), 4.48 - 4.44 (m, 1H), 4.37 - 4.30 (m, 2H), 3.27 (s, 3H), 2.64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.806 min., m/z = 452.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.806 min., ESI+ found [M+H] =452.1.

[01723] SFC Condition: Column: Chiralcel OD - 3 150x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35oC. Example 526 1 -[(2-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01724] Amide coupling prepared in a manner similar to Method WX 043. The racemic compound obtained was separated by means of chiral SFC to provide:

[01725] 1 -[(2-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time = 6.180 min.) (24 mg, 25%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.82 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 7.43 - 7.33 (m, 2H), 7, 26 - 7.20 (m, 2H), 6.94 (s, 1H), 6.55 (s, 2H), 4.49 - 4.44 (m, 1H), 4.36 - 4.30 ( m, 2H), 3.26 (s, 3H), 2.64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.803 min., m/z = 452.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.803 min., ESI+ found [M+H] =452.1.

[01726] 1 -[(2-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time = 6.97 min.) (18 mg, 20%) as white solids . 1H NMR (400 MHz, DMSO -d6) δ8.82 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 7.43 - 7.33 (m, 2H), 7, 26 - 7.20 (m, 2H), 6.94 (s, 1H), 6.55 (s, 2H), 4.49 - 4.44 (m, 1H), 4.36 - 4.30 ( m, 2H), 3.26 (s, 3H), 2.64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.806 min., m/z = 452.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.806 min., ESI+ found [M+H] =452.0,

[01727] SFC Conditions: Chiralcel Column OD - 3 150x4.6mm I.D., 3um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5mL/min. Column temperature: 35 o Example 527

[01728] WX Method 049 1 -[(3-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(3-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: Methyl 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate

[01729] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N - dimethylformamide (200 mL) was added potassium carbonate (21. 8 g, 157.36 mmol) and 3-fluorobenzyl bromide (17.9 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was diluted with saline (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 1 -[(3-fluorophenyl) methyl] -1,2 ,4-triazole-3-carboxylate (6.0 g, 27%) as a white solid. Step 2: 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

[01730] A mixture of methyl 1 -[(3 fluorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (6.0 g, 21.26 mmol) and potassium hydroxide (2.4 g, 42 .52 mmol) in ethanol (80 mL) and water (15 mL) was stirred at 25oC for 12 h. The ethanol was evaporated under reduced pressure and the aqueous residue was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and subjected to drying to obtain crude 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (3.0 g, 64%) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ8.81 (s, 1H), 7.47 - 7.35 (m, 1H), 7.23 - 7.09 (m, 2H), 6.51 (s , 2H). Step 3: 1 -[(3-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(3-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01731] To a solution of 6-amino -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg , 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole (27 mg, 0.20 mmol), 1-[(3-fluorophenyl)methyl]-1,2,4-triazole acid -3-carboxylic acid (44 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol). The reaction mixture was stirred at 20°C for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (30 -60% acetonitrile / 0.1% ammonium hydroxide in water) to provide 1 -(3 -fluorobenzyl) -N -(4 - methyl -5 -oxo -2 -(trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 - triazole -3 -carboxamide (65 mg, 69%). The racemic material was separated using chiral SFC to provide:

[01732] 1 -[(3-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time 6.675 min.) (28 mg, 30%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.84 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 7.46 - 7.40 (m, 1H), 7, 19 - 7.12 (m, 3H), 6.94 (s, 1H), 6.51 (s, 2H), 4.50 — 4.44 (m, 1H), 4.37 — 4.31 ( m, 2H), 3.27 (s, 3H), 2.64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.807 min., m/z = 452.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.807 min., ESI+ found [M+H] =452.0.

[01733] 1 -[(3-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 7.386 min.) (29 mg, 31%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.84 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 7.46 - 7.40 (m, 1H), 7, 19 - 7.12 (m, 3H), 6.94 (s, 1H), 6.51 (s, 2H), 4.50 - 4.44 (m, 1H), 4.37 - 4.31 ( m, 2H), 3.27 (s, 3H), 2.64 - 2.60 (m, 1H), 2.52 - 2.48 (m, 1H). LCMS RT = 0.811 min., m/z = 452.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.811 min., ESI+ found [M+H] =452.1.

[01734] SFC Conditions: Column: Chiralcel OD -3 150x4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5mL/min. Column temperature: 35 oC. Example 528

[01735] WX Method 076 1 -[(2-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -1 -[(2-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -( trifluoromethyl) -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01736] Amide coupling prepared in a manner similar to Method WX 073 (RIP1K_experimental_3rd_WX.doc). The racemic compound obtained was separated using chiral SFC:

[01737] 1 -[(2-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time = 4.393 min.) (20 mg, 40%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 7.47 - 7.42 (m, 1H), 7.42 - 7.28 (m, 3H), 6.68 (s, 1H ), 6.61 (s, 2H), 4.56 - 4.46 (m, 2H), 4.41 - 4.33 (m, 1H), 3.37 (s, 3H), 2.93 - 2.86 (m, 1H), 2.36 - 2.29 (m, 1H). LC-MS RT = 1.838 min., m/z = 468.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.838 min., ESI+ found [M+H] = 468.1.

[01738] 1 -1 -[(2-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time = 6.055 min.) (21 mg, 41%) as white solids . H NMR (400MHz, METHANOL -d4) δ8.58 (s, 1H), 7.47 - 7.42 (m, 1H), 7.42 - 7.28 (m, 3H), 6.68 (s, 1H), 6.61 (s, 2H), 4.56 - 4.46 (m, 2H), 4.41 - 4.33 (m, 1H), 3.37 (s, 3H), 2.93 - 2.86 (m, 1H), 2.36 - 2.29 (m, 1H). LC-MS RT = 1.838 min., m/z = 468.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.838 min., ESI+ found [M+H] = 468.1.

[01739] SFC Condition: Column: Chiralcel OD - 3 100x4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40 o C. Example 529

[01740] Method WX 065 1 -[(2,4-difluorophenyl) methyl] -N -(6S) -4 - methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide and 1 -[(2,4 -difluorophenyl) methyl] -N -(6R) -4 - methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 –carboxamide Step 1: methyl 1 -(2,4-difluorobenzyl) -1H - 1,2,4 -triazole -3 -carboxylate

[01741] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (10.0 g, 78.68 mmol) in N,N - dimethylformamide (200 mL) was added potassium carbonate (21. 8 g, 157.36 mmol) and 2,4-difluorobenzyl bromide (19.6 g, 94.41 mmol). The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was diluted with saline (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -100% ethyl acetate in petroleum ether) to give methyl 1 - (2,4 - difluorobenzyl) -1H -1,2 ,4-triazole-3-carboxylate (7.7 g, 38.6%) as white solids. Step 2: 1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01742] A mixture of methyl 1-[(2,4-difluorophenyl) methyl]-1,2,4-triazole-3-carboxylate (2.0 g, 7.9 mmol) and potassium hydroxide (0. 9 g, 16.8 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25°C for 12 h. The ethanol was evaporated under reduced pressure and the residue was diluted with water (20 ml). The solution was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected by filtration and dried to provide crude 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (1.69 g, 90 %) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.64 (s, 1H), 7.51 - 7.47 (m, 1H), 7.06 - 7.00 (m, 2H), 6.54 - 6.49 (m, 2H). Step 3: 1 -[(2,4-difluorophenyl) methyl] -N -(6S) -4 - methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide and 1 -[(2,4 -difluorophenyl) methyl] -N -(6R) -4 - methyl -5 - oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01743] A mixture of 1 -(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol), 1-[(2,4-difluorophenyl) methyl]-1,2,4- acid -3-carboxylic triazole (55 mg, 0.23 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and 6-amino -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -5 -one (50 mg, 0.20 mmol) in N,N - dimethylformamide (4 mL) was stirred at 25oC for 12 h and concentrated under reduced pressure . The residue was purified by RP-HPLC (0 -40% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2,4 -difluorophenyl) methyl] - N - [4 -methyl - 5 -oxo -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide ( 50 mg, 53%) as a white solid. The racemic material obtained was separated using chiral SFC to provide:

[01744] 1 -[(2,4-difluorophenyl) methyl] -N - (6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro - 6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time = 3.802 min.) (14 mg, 27%) as white solids . 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.48 - 7.42 (m, 1H), 7.05 - 6.97 (m, 2H), 6.66 (s, 1H), 6.52 (s, 2H), 4.53 - 4.44 (m, 2H), 4.39 - 4.33 (m, 1H), 3.36 (s, 3H), 2.89 - 2.84 (m, 1H), 2.35 - 2.29 (m, 1H). LCMS RT = 1.805 min.; m/z = 470.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.805 min., ESI+ found [M+H] = 470.1.

[01745] 1 -[(2,4-difluorophenyl) methyl] -N - (6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro - 6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time = 4.620 min.) (14 mg, 27% yield) as solids White color. 1H NMR (400MHz, CD3OD) δ8.59 (s, 1H), 7.50 - 7.42 (m, 1H), 7.08 - 6.94 (m, 2H), 6.68 (s, 1H) , 6.53 (s, 2H), 4.57 - 4.47 (m, 2H), 4.41 - 4.33 (m, 1H), 3.37 (s, 3H), 2.92 - 2 .84 (m, 1H), 2.35 - 2.29 (m, 1H). LCMS RT = 1.805 min.; m/z = 470.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.805 min., ESI+ found [M+H] = 470.1.

[01746] SFC Condition: Column: Chiralcel OD - 3 100x4.6 mm ID, 3 µm Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8mL/min. Column temperature:40 o C. Example 530 1 -[(2-fluorophenyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01747] Amide coupling prepared in a manner similar to Method WX 043. The crude material was purified using RP-HPLC (42 - 62% acetonitrile/0.05% ammonium hydroxide in water) to provide 1 - [(2-fluorophenyl) methyl] -N -(6S) -2 -cyclopropyl -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6-yl -1,2,4 -triazole -3 -carboxamide (38 mg, 33.6%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 7.41 - 7.36 (m, 2H), 7.21 - 7.15 (m, 2H), 6.00 (s, 1H) ), 6.55 (s, 2H), 4.53 - 4.48 (m, 1H), 4.32 - 4.21 (m, 2H), 3.31 (s, 3H), 2.86 - 2.79 (m, 1H), 2.25- 2.23 (m, 1H), 1.91 - 1.87 (m, 1H), 0.95 - 0.92 (m, 2H), 0, 75 - 0.72 (m, 2H). LC-MS RT = 0.958 min., m/z = 424.2 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.958 min., ESI+ found [M+H] = 424.2. Example 531 1 -[(3-fluorophenyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01748] Amide coupling prepared in a manner similar to Method WX 049. The crude material was purified via RP-HPLC (17 -47% acetonitrile / 0.05 ammonium hydroxide in water) to provide 1 - [ (3-fluorophenyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 1.762 min.) (28 mg, 25%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.61 (s, 1H), 7.40 - 7.36 (m, 1H), 7.17 - 7.08 (m, 3H), 6.00 (s, 1H ), 6.49 (s, 2H), 4.55 - 4.50 (m, 1H), 4.31 - 4.19 (m, 2H), 3.31 (s, 3H), 2.87 - 2.80 (m, 1H), 2.28 - 2.24 (m, 1H), 1.91 - 1.88 (m, 1H), 0.95 - 0.92 (m, 2H), 0, 75 - 0.73 (m, 2H). LCMS RT = 0.958 min., m/z = 424.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.958 min., ESI+ found [M+H] = 424.2. Example 532

[01749] Method WX 070 1 -[(4-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(4-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: methyl 1 -(4-chlorobenzyl) -1H -1, 2, 4 - triazole -3 -carboxylate

[01750] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (3.0 g, 11.92 mmol) in N,N - dimethylformamide (25mL) was added potassium carbonate (4.9 g, 36.76 mmol) and 1-(bromomethyl)-4-chlorobenzene (2.9 g, 14.3 mmol). The mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 1-(4-chlorobenzyl) -1H -1, 2, 4 - triazole -3 -carboxylate (1.6 g, 54%) as white solids. Step 2: 1-(4-chlorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01751] A mixture of methyl 1 -[(4 - chlorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (1.6 g, 6.41 mmol) and potassium hydroxide (719 mg, 12, 82 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25oC for 12 h. The ethanol was evaporated and the residue was diluted with water (20 ml). The mixture was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and subjected to drying to obtain 1-(4-chlorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (1.49 g, 98%) in the form of white solids. 1H NMR (400 MHz, CD3OD) δ8.64 (s, 1H), 7.40 - 7.34 (m, 4H), 6.47 (s, 2H). Step 3: 1 -[(4-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(4-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 - (trifluoromethyl) -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01752] To a solution of 6-amino -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg , 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol), acid 1-[(4- chlorophenyl) methyl] -1,2,4-triazole -3-carboxylic acid (45 mg, 0.20 mmol) 1-hydroxybenzotriazole (27 mg, 0.20 mmol). The reaction mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (0 -40% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -[(4-chlorophenyl) methyl] -N -[4 - methyl -5 - oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (50 mg , 53%) in the form of a white solid. the racemic compound obtained was separated using chiral SFC to provide:

[01753] 1 -[(4-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time = 6.006 min.) (18 mg, 36%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.82 (s, 1H), 8.70- 8.68 (m, 1H), 7.41 - 7.39 (m, 2H), 7.20 - 7 .22 (m, 2H), 6.94 (s, 1H), 6.49 (s, 2H), 4.95 - 4.44 (m, 1H), 4.38 - 4.30 (m, 2H ), 3.26 (s, 3H), 2.66 - 2.63 (m, 1H), 2.32 - 2.29 (m, 1H). LCMS RT = 1.889 min., m/z = 468.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.889 min., ESI+ found [M+H] = 468.1.

[01754] 1 -[(4-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time = 6.159 min.) (16 mg, 32%) as white solids. H NMR (400MHz, DMSO -d6) δ8.82 (s, 1H), 8.70- 8.68 (m,1H), 7.41 — 7.39 (m, 2H), 7.20 - 7, 22 (m, 2H), 6.94 (s, 1H), 6.49 (s, 2H), 4.95 - 4.44 (m, 1H), 4.38 - 4.30 (m, 2H) , 3.26 (s, 3H), 2.66 - 2.63 (m, 1H), 2.32 - 2.29 (m, 1H). LCMS RT = 1.889 min., m/z = 468.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.889 min., ESI+ found [M+H] = 468.1.

[01755] SFC Condition: Column: Chiralcel OD - 3 100x4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40 o C. Example 533

[01756] WX Method 079 1 -[(3-chlorophenyl) methyl] -N -(6S) -4 -methyl -5-oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide and 1 -[(3-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01757] Amide coupling prepared in a manner similar to Method WX 077 (RIP1K_experimental_3rd_WX.doc). The racemic compound obtained was separated by means of SFC to provide: 1 -[(3-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time = 4.658 min.) (14 mg, 27 %) in the form of white solids. 1H NMR (400 MHz, DMSO -d6) δ 8.84 (s, 1H), 8.69 - 8.67 (m, 1H), 7.46 - 7.32 (m, 3H), 7.28 - 7.25(m, 1H), 6.94 (s, 1H), 6.50 (s, 2H), 4.49 - 4.44 (m, 1H), 4.37 - 4.32 (m, 2H), 3.26 (s, 3H), 2.65 (s, 1H), 2.46 - 2.42 (m, 1H). LC-MS RT = 1.883 min., m/z = 468.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.883 min., ESI+ found [M+H] = 468.1.

[01758] 1 -[(3-chlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time = 6.731 min.) (8 mg, 15%) as white solids. 1H NMR (400MHz, METHANOL -d4) δ8.62 (s, 1H), 7.45- 7.32 (m, 3H), 7.29 - 7.28 (m, 1H), 6.68 (s, 1H), 6.48 (s, 2H), 4.58 - 4.47 (m, 2H), 4.41 - 4.33 (m, 1H), 3.37 (s, 3H), 2.91 - 2.86 (m, 1H), 2.36 - 2.31 (m,1H). LC-MS RT = 1.883 min., m/z = 468.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.883 min., ESI+ found [M+H] = 468.1.

[01759] SFC Condition: Column: Chiralcel OD - 3 100x4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40°C. Example 534

[01760] Method WX 069 1 -[(2,3-dichlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide and 1 -[(2,3 -dichlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide Step 1: methyl 1-(2,3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxylate

[01761] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (1.5 g, 11.8 mmol) in N,N -dimethylformamide (25 mL) was added potassium carbonate (3 .3 g, 23.6 mmol) and 1-(bromomethyl)-2,3-dichloro-benzene (3.4 g, 14.16 mmol). The mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 1 -(2,3 - dichlorobenzyl) -1H -1,2,4 - triazole -3 -carboxylate (1.91 g, 57%) in the form of white solids, which was used in the next step as it was. Step 2: 1-(2,3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01762] A mixture of methyl 1 - [(2,3 -dichlorophenyl) methyl] -1,2,4 -triazole -3 -carboxylate solution (1.9 g, 6.68 mmol) and potassium hydroxide (749 mg, 13.36 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25oC for 12 h. The ethanol was evaporated and the residue was diluted with water (20 ml). The mixture was adjusted to pH = 4 by adding 2 N HCl. The resulting solid was collected through filtration and subjected to drying to obtain 1-[(2,3-dichlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (1.7 g, 95%) in the form of white solids. 1H NMR (400 MHz, CD3OD) δ8.69 (s, 1H), 7.59 - 7.57 (m, 1H), 7.37 - 7.24 (m, 2H), 6.66 (s, 2H ). Step 3: 1 -[(2,3-dichlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide and 1 -[(2,3 -dichlorophenyl) methyl] -N -(6R) -4 -methyl -5 - oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01763] To a solution of 6-amino -4 -methyl -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg , 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol) 1-hydroxy benzotriazole (27 mg, 0 .20 mmol) 1-[(2,3-dichlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (54 mg, 0.20 mmol). The reaction mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (0 -40% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2,3 -dichlorophenyl) methyl] - N - [4 -methyl - 5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide ( 50 mg, 49%) as a white solid. The racemic material obtained was separated using chiral SFC to provide:

[01764] 1 -[(2,3-dichlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time = 6.069 min.) (14 mg, 27%) as white solids . 1H NMR (400 MHz, DMSO -d6) δ 8.84 (s, 1H), 8.68 - 8.66 (m, 1H), 7.67 - 7.64 (m, 1H), 7.41 - 7.37 (m, 1H), 7.21 - 7.19 (m, 1H), 6.94 (s, 1H), 6.65 (s, 2H), 4.47 - 4.38 (m, 1H), 4.38 - 4.29 (m, 2H), 3.27 (s, 3H), 2.67 - 2.65 (m, 1H), 2.33 - 2.31 (m, 1H) . LCMS RT = 1.954 min., m/z = 502.0 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.954 min., ESI+ found [M+H] = 502.0.

[01765] 1 -[(2,3-dichlorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time = 6.870min.) (16 mg, 31%) as white solids . H NMR (400MHz, DMSO -d6) δ8.84 (s, 1H), 8.68 -8.66 (m,, 1H), 7.67 - 7.64 (m, 1H), 7.41 - 7 .37 (m,1H), 7.21 - 7.19 (m, 1H), 6.94 (s, 1H), 6.65 (s, 2H), 4.47 - 4.38 (m, 1H ), 4.38 - 4.29 (m, 2H), 3.27 (s, 3H), 2.67 - 2.65 (m, 1H), 2.33 - 2.31 (m, 1H). LCMS RT = 1.954 min., m/z = 502.0 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.954 min., ESI+ found [M+H] = 502.0.

[01766] SFC Condition: Column: Chiralcel OD - 3 100x4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8mL/min. Column temperature: 40o C. Example 535

[01767] WX Method 091 1 -benzyl -N -(2,9 -dimethyl -8 -oxo -6,7,8,9 - tetrahydro -5H -imidazo[1,2 -a][1,3] diazepin -7 -yl) -1H - 1,2,4 -triazole -3 –carboxamide Step 1: 3 -chloro -9 -methyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01768] To a solution of 9 -methyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8 -one (1.2 g, 7.26 mmol) in N N-dimethylformamide (20 mL) was added 1-chloropyrrolidine-2,5-dione (776 mg, 6.81 mmol). The reaction mixture was stirred at 25°C for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 3-chloro-9-methyl -6,7 - dihydro -5H - imidazo [1,2 -a][1,3] diazepin -8 -one (700 mg, 48%) in the form of a light yellow oil, which was used in the next step as it was. Step 2: 2 -bromo -3 -chloro -9 -methyl -6,7 -dihydro -5H - imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01769] To a solution of 3-chloro-9-methyl - 6,7 -dihydro -5H -imidazo[1,2-a] [1,3] diazepin -8 -one (700 mg, 3.51 mmol) in N,N-dimethylformamide (10 mL) 1-bromo-2,5-pyrrolidinedione (499 mg, 2.81 mmol) was added. The reaction mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2-bromo-3-chloro-9-methyl-6,7- dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8 -one (670mg, 68%) in the form of a yellow solid, which was used in the next step as it was . LCMS RT = 1.791 min.; m/z = 278.0 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.791 ESI+ found [M+H] =278.0. Step 3: 3 -chloro -2,9 -dimethyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01770] A mixture of 2 -bromo -3 -chloro -9 - methyl -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -8 - one (670 mg, 2, 41 mmol), cesium carbonate (784 mg, 2.41 mmol), 2,4,6 -trimethyl -1,3,5,2,4,6 -trioxatriborinane (302 mg, 2.41 mmol) and [1 ,1'-Bis(diphenylphosphine)ferrocene]dichloropalladium(II) (176 mg, 0.24 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated at 110oC for 0.5 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 3-chloro-2, 9 -dimethyl -6,7 -dihydro -5H - imidazo[1,2 -a][1,3] diazepin -8 -one (120 mg, 23%) in the form of a yellow oil, which was used in the next stage as it was. Step 4: 3 -chloro -7 -iodo -2,9 -dimethyl -6,7 - dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01771] To a solution of 3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a] [1,3] diazepin -8 -one (250 mg, 1.17 mmol) in dichloromethane (30 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (816 mg, 7.02 mmol) and trimethylsilane iodine (1405 mg, 7.02 mmol) under -15oC. The reaction mixture was stirred at -15°C for 2 h and iodine (891 mg, 3.51 mmol) was added. The mixture was stirred at -15°C for another 2 h and finalized by the addition of saturated aqueous sodium sulfite (10 mL). The solution was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 3-chloro-7-iodo-2,9-dimethyl-6,7-dihydro- 5H -imidazo[1,2 - a][1,3] diazepin -8 -one (280 mg, 71%) in the form of a colorless oil, which was used in the next step as it was. LCMS RT = 1.848 min.; m/z = 256.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.848 ESI+ found [M+H] =256.1. Step 5: 7 -azide -3 -chloro -2,9 -dimethyl -6,7 - dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01772] A mixture of 3-chloro-7-iodo-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3] diazepin-8-one (280 mg, 0.82 mmol) and sodium azide (380 mg, 6.85 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 2 h. The reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by prep TIC (50% ethyl acetate in petroleum ether, Rf = 0.6) to give 7-azide-3-chloro-2, 9 -dimethyl -6,7 -dihydro -5H - imidazo[1,2 -a][1,3] diazepin -8 -one (200 mg, 95%) in the form of a yellow oil, which was used in the next stage as it was. Step 6: 7 -amino -2,9 -dimethyl -6,7 -dihydro -5H - imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01773] A mixture of 7-azide -3 -chloro -2,9 -dimethyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8 -one (200 mg, 0.79 mmol) and Pd/C (10%, 836 mg, 0.79 mmol) in 1,4-dioxane (5 mL) was hydrogenated [2.04 bar (15 psi)] for 5 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 7-amino-2,9-dimethyl-6, 7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8 -one (80 mg, 52%) in the form of a yellow oil, which was used in the next step in the form in which was found. LCMS RT = 1.074 min.; m/z = 196.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.074 ESI+ found [M+H] =196.2. Step 7: 1 -benzyl -N -(2,9 -dimethyl -8 -oxo - 6,7,8,9 -tetrahydro -5H -imidazo[1,2 -a][1,3] diazepin -7 - yl ) -1H -1,2,4 -triazole -3 -carboxamide

[01774] To a solution of 1-benzyl-1,2,4-triazole-3-carboxylic acid (83 mg, 0.41 mmol) in N,N-dimethylformamide (5 mL) was added 7-amino-2, 9 - dimethyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8 -one (80 mg, 0.41 mmol), 1 -(3-dimethyl aminopropyl) hydrochloride -3-ethylcarbodiimide (79 mg, 0.41 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 mmol). The reaction mixture was stirred at 25°C for 1 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (13% to 43% acetonitrile/0.05% ammonium hydroxide in water) to provide 1-benzyl-N-(2,9-dimethyl-8-oxo-6, 7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1,2,4-triazole-3-carboxamide (42 mg, 27%) in the form of a solid White color. 1H NMR (400 MHz, CD3OD) δ8.56 (s, 1H), 7.39 - 7.32 (m, 5H), 6.78(s, 1H), 6.47 (s, 2H), 4, 55 - 4.50 (m, 1H), 4.21 - 4.15(m, 1H), 4.03 - 3.98 (m, 1H), 3.36 (s, 3H), 2.85 - 2.79 (m, 1H), 2.29 - 2.23 (m, 1H), 2.19 (s, 3H). LCMS RT = 1.779 min., m/z = 380.2 (M + H)+. LCMS RT = 1.779 min.; m/z = 380.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.779 min., ESI+ found [M+H] = 380.2. Example 536

[01775] WX Method 149 phenyl -N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl]pyrazolo [3,4 -d] pyrimidine -6 - carboxamide Step 1: 6-chloro-1-phenyl-1H-pyrazole[3,4-d]pyrimidine

[01776] A mixture of 6-chloro-1H-pyrazolo[3,4-d] pyrimidine (200 mg, 1.29 mmol), pyridine (205 mg, 2.59 mmol), copper (II) acetate (470 mg, 2.59 mmol) and phenyl boronic acid (237 mg, 1.94 mmol) in dichloromethane (5 mL) was heated under 80oC for 15 min. under microwave conditions. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 6-chloro-1-phenyl-1H-pyrazole [3,4 - d] pyrimidine (250 mg, 84%) in the form of a light yellow solid, which was used in the next step as it was. Step 2: 1-phenyl-1H-pyrazole[3,4-d]pyrimidine-6-carbonitrile

[01777] To a solution of 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.87 mmol) in dimethyl sulfoxide (10 mL) was added 1,4-diazabicyclo [2,2,2] octane (10 mg, 0.09 mmol) and sodium cyanide (85 mg, 1.73 mmol) in water (1 mL). The mixture was stirred at 25oC for 3 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by TIC preparation (40% ethyl acetate in petroleum ether) to provide 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (80 mg, 42%) in the form of a yellow solid. LCMS RT = 1.037 min.; m/z = 222.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.037 min., ESI+ found [M+H] = 222.1. Step 3: methyl 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

[01778] To a solution of 1-cyclopentyl -1H - pyrazolo [3,4 -d] pyrimidine -6 -carbonitrile (80 mg, 0.36 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1 .5 mL). The mixture was subjected to stirring at 20°C for 20 h and 50°C for 3 h. The reaction solution was concentrated under reduced pressure to provide crude methyl 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 98%) as a yellow solid. LCMS RT = 1.145min.; m/z = 256.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.145min., ESI+ found [M+H] = 256.1. Step 4: 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[01779] A mixture of methyl 1-phenyl -1H - pyrazolo [3,4 -d] pyrimidine -6 -carboxylate (90 mg, 0.37 mmol) and lithium hydroxide hydrate (77 mg, 1.83 mmol) in tetrahydrofuran (5 mL) and water (1 mL) were stirred at 25oC for 2 h. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH = 4 by adding 2N HCl. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to provide crude 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (50 mg, 57%) in form a yellow solid. LCMS RT = 1.015 min.; m/z = 241.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.015 min., ESI+ found [M+H] = 241.1. Step 5: phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl]pyrazolo [3,4 -d] pyrimidine -6 -carboxamide

[01780] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (22 mg, 0.11 mmol), 1-phenylpyrazole acid [3, 4 -d] pyrimidine -6 -carboxylic acid (25 mg, 0.10 mmol), N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (24 mg, 0.12 mmol) , 1H -benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile/0.05% ammonium hydroxide in water) to provide phenyl -N -[(3S)-5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]pyrazolo [3,4 - d] pyrimidine -6 -carboxamide (30.9 mg, 71%) as a solid White color. 1H NMR (400 MHz, DMSO -d6) δ9.61 (s, 1H), 9.17 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 8.23 (d, J = 8.0 Hz, 2H), 7.65 - 7.61 (m, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.45 - 7.40 (m, 1H ), 7.35 - 7.28 (m, 3H), 4.95 - 4.90 (m, 1H), 4.62 - 4.54 (m, 2H). LCMS RT = 0.846 min.; m/z = 416.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.846 min., ESI+ found [M+H] = 416.1. Example 537

[01781] WX Method 174 4 -(1-hydroxycyclobutyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 Step 1: 1 -(2 -bromopyrimidin -4 -yl)cyclobutanol

[01782] To a solution of cyclobutanone (1.48 g, 21.06 mmol) and 2-bromo-4-iodo-pyrimidine (2.0 g, 7.02 mmol) in tetrahydrofuran (60 mL) was added isopropyl magnesium (1.0 M in Tetrahedron, 10.5 mL, 10.5 mmol) under -70oC. The mixture was subjected to stirring at -70oC for 1 h and finalized by the addition of saturated ammonium chloride (30 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 10 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 1-(2-bromopyrimidin-4-yl)cyclobutanol (350 mg, 22%) in the form of a yellow oil. LC-MS RT = 0.52 min., m/z = 228.8 (M+H) +. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.52/min., ESI+ found [M+H] = 228.8. Step 3: 4 -(1-hydroxycyclobutyl)pyrimidine -2 -carbonitrile

[01783] To a solution of 1 -(2-bromopyrimidin-4-yl)cyclobutanol (350 mg, 1.53 mmol) in dimethyl sulfoxide (5 mL) was added 1,4-diazabicyclo [2,2,2] octane (86 mg, 0.76 mmol) and sodium cyanide (149 mg, 3.06 mmol) in water (2.5 mL). The mixture was stirred at 25°C for 16 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 4-(1-hydroxycyclobutyl ) pyrimidine -2 - carbonitrile (260 mg, 97%) as a white solid. LC-MS RT = 0.60 min., m/z = 176.8 (M+H) +. LCMS (5 - 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.60/min., ESI+ found [M+H] = 176.8. Step 4: methyl 4 -(1 - hydroxycyclobutyl)pyrimidine -2 -carboxylate

[01784] To a solution of 4-(1-hydroxycyclobutyl) pyrimidine-2-carbonitrile (100 mg, 0.57 mmol) in methanol (3 mL) was added HCl (4N in methanol, 14.4 mL). The reaction mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was purified by TIC preparation (50% ethyl acetate in petroleum ether, Rf = 0.3) to give methyl 4-(1-hydroxycyclobutyl) pyrimidine-2-carboxylate (16 mg, 14%) in the form of a yellow oil. LC-MS RT = 1.77 min., m/z = 209.0 (M+H) +. LCMS (0 - 60% acetonitrile in water + 0.05% trifluoroacetic acid for 4 min.) retention time 1.77/min., ESI+ found [M+H] = 209.0. Step 5: 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylic acid

[01785] A mixture of methyl 4-(1-hydroxycyclobutyl) pyrimidine-2-carboxylate (16 mg, 0.08 mmol) and lithium hydroxide (9 mg, 0.38 mmol) in tetrahydrofuran (5 mL) and water ( 1 mL) was subjected to stirring at 25oC for 16 h. The mixture was adjusted to pH = 6 by addition of 1N HCl and concentrated under reduced pressure to provide crude 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylic acid (13 mg, 87%) as a solid yellow in color. Step 6: 4 -(1-hydroxycyclobutyl) -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 -carboxamide

[01786] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (22 mg, 0.11 mmol), 4 -(1-hydroxycyclobutyl acid ) pyrimidine-2-carboxylic acid (22 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol) and 1-hydroxybenzotriazole (18 mg, 0.14 mmol) in N,N - dimethylformamide (4 mL) was stirred at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonium hydroxide in water) to give 4-(1-hydroxycyclobutyl)-N-[ (3S)-5-methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 -carboxamide (11.3 mg, 26%) as a white solid . 1H NMR (400 MHz, CD3OD) δ 8.89 (d, J = 6.2 Hz, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.46 - 7.44 (m , 1H), 7.34 - 7.27 (m, 2H), 7.26 - 7.25(m, 1H), 6.06 - 6.04 (m, 1H), 4.73 - 4.72 (m, 1H), 4.44 - 4.42(m, 1H), 3.45(s, 3H), 2.72 - 2.68 (m, 2H), 2.43 - 2.35 (m , 2H), 2.12 - 2.07 (m, 2H). LCMS RT = 1.938 min.; m/z = 369.1 (M+H)+. LCMS (0 -60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.938 min., ESI+ found [M+H] = 369.1. Example 538 1 -[(3-chlorophenyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01787] Amide coupling prepared in a manner similar to Method WX 077. The crude material was purified via RP-HPLC (ACN 35 -65%/0.05% ammonium hydroxide in water) to provide 1 - [(3 - chlorophenyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 - yl -1,2,4 -triazole -3 -carboxamide (41.56 mg, 41%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 7.37 - 7.25(m, 4H), 6.18 (s, 1H), 6.47 (s, 2H), 4 .61 - 4.58 (m, 1H), 4.40 - 4.26 (m, 2H), 3.28 (s, 3H), 2.87 - 2.81 (m, 1H), 2.32 - 2.30 (m, 1H), 1.97 - 1.93 (m, 1H), 1.05 - 1.03 (m, 2H), 0.84 - 0.81 (m, 2H). LC-MS RT = 0.802 min., m/z = 440.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.802 min., ESI+ found [M+H] =440.1. Example 539

[01788] WX Method 142 1 -isopropyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl]pyrazole [ 3,4 -d] pyrimidine -6 -carboxamide Step 1: 6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine

[01789] A mixture of 6-chloro-1H-pyrazole [3,4-d] pyrimidine (500 mg, 3.25 mmol), 2-iodine propane (553 mg, 3.25 mmol) and potassium carbonate (897 mg , 6.50 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25°C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 6-chloro-1-isopropyl-1H-pyrazole [3,4 - d] pyrimidine (300 mg, 47%) in the form of a yellow solid, which was used in the next step as it was. Step 2: 1-isopropyl-1H-pyrazole[3,4-d]pyrimidine-6-carbonitrile

[01790] A solution of 6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.53 mmol) in dimethyl sulfoxide (5 mL) and water (5 mL) was 1,4-diazabicyclo[2,2,2] octane (34 mg, 0.21 mmol) and sodium cyanide (150 mg, 3.05 mmol) were added. The reaction mixture was stirred at 25oC for 3 h and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 1-isopropyl -1H -pyrazolo[3,4-d]pyrimidine - 6-carbonitrile (140 mg, 49%) in the form of a yellow oil, which was used in the next step as is. Step 3: methyl 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

[01791] To a solution of 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (140 mg, 0.75 mmol) in methanol (5 mL) was added HCl (4N in methanol, 4 mL). The reaction mixture was stirred at 25°C for 16 h and concentrated under reduced pressure to provide crude methyl 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (120 mg, 73%) in form of a yellow oil, which was used in the next stage as it was. Step 4: 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[01792] A mixture of methyl 1-isopropyl-1H-pyrazole [3,4-d] pyrimidine-6-carboxylate (120 mg, 0.54 mmol) and lithium hydroxide hydrate (229 mg, 6.45 mmol) in tetrahydrofuran (5 mL) and water (5 mL) were stirred at 25oC for 2 h. The mixture was adjusted to pH = 5 by adding 1N HCl and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure to provide 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 27%) as a colorless oil, which was used in the next stage as it was. Step 5: 1-isopropyl-N-[(6S)-2,4-dimethyl-5yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

[01793] A mixture of (6S) -6 -amino -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (34 mg, 0.17 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (24 mg, 0.17 mmol), 1 -isopropylpyrazole [3,4 -d] pyrimidine -6 -carboxylic acid (30 mg, 0.15 mmol) and N -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 - diamine hydrochloride (33 mg, 0.17 mmol) in N,N -dimethylformamide (3 mL ) was subjected to stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (30% to 60% acetonitrile, 0.05% ammonium hydroxide in water) to give 1 - isopropyl -N -[(6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl]pyrazolo [3,4 -d] pyrimidine -6 -carboxamide (32.8 mg, 58%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 9.35 (s, 1H) 8.38 (s, 1H), 6.14 (s, 1H), 6.47 -6.42 (m, 1H), 4, 65 - 4.60 (m, 1H), 4.37 -4.26 (m, 2H), 3.37 (s, 3H), 3.00 -2.94 (m, 1H), 2.35 - 2.27 (m, 4H), 1.59 (d, J = 6.8Hz, 6H). LCMS RT = 0.733 min., m/z = 383.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.733 min., ESI+ found [M+H] =383.1. Example 540 1 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl]pyrazole [ 3,4 -d] pyrimidine -6 -carboxamide

[01794] Amide coupling prepared in a manner similar to Method WX 149. The crude material was purified using RP-HPLC (30% to 60% acetonitrile/0.05% ammonium hydroxide in water) to provide 1 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]pyrazole [3 ,4-d] pyrimidine-6-carboxamide (20 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ9.58 (s, 1H), 9.20 (d, J = 8.0 Hz, 1H), 8.77 (s, 1H), 8.23 (d, J = 7.6 Hz, 2H), 7.64 - 7.59 (m, 2H), 7.46 - 7.41 (m, 1H), 6.15 (s, 1H), 4.43 - 4 .39 (m, 1H), 4.32 - 4.27 (m, 1H), 4.18 - 4.15 (m, 1H), 3.26 (s, 3H), 2.74 - 2.69 (m, 1H), 2.37 - 2.34 (m, 1H), 2.18 (s, 3H). LCMS RT = 0.792 min.; m/z = 417.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.792 min., ESI+ found [M+H] =417.1. Example 541

[01795] WX Method 071 2 -benzyl -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yltetrazol -5 -carboxamide Step 1: methyl 2 -benzyl -2H -tetrazol -5 -carboxylate

[01796] To a solution of ethyl 2H-tetrazol-5-carboxylate (1.0 g, 7.04 mmol) in N,N-dimethylformamide (20 mL) was added benzyl bromide (1.2 g, 7.04 mmol) and potassium carbonate (972 mg, 7.04 mmol). The mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 2-benzyl-2H - tetrazole -5-carboxylate (200 mg, 13%) in the form of a white solid, which was used in the next step as is. Step 2: 2-benzyl-2H-tetrazol-5-carboxylic acid

[01797] A mixture of methyl 2-benzyltetrazol-5-carboxylate (200 mg, 0.92 mmol) and triethylamine (185 mg, 1.83 mmol) in ethanol (20 mL) was stirred at 25oC for 12 h. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The solution was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and subjected to drying under reduced pressure to obtain 2-benzyl-2H-tetrazol-5-carboxylic acid (130 mg, 69.5%) as white solids. 1H NMR (400 MHz, CD3OD) δ7.44 - 7.36 (m, 5H), 6.94 (s, 2H). Step 3: 2 -benzyl -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yltetrazol - 5-carboxamide

[01798] A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37 mg, 0.19 mmol), 2-benzyltetrazol-5-carboxylic acid (31 mg, 0.15 mmol), (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (25 mg, 0.13 mmol) and 1 -hydroxybenzotriazole (26 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (20-50% acetonitrile/0.05% ammonium hydroxide in water) to give 2-benzyl-N-(6S)-2, 4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yltetrazol -5 -carboxamide (11 mg, 12%) as a solid white in color. 1H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 5H), 6.12 (s, 1H) 6.94 (s, 2H), 4.58 - 4.53 (m, 1H) ), 4.35 - 4.29 (m, 1H), 4.26 - 4.22 (m, 1H), 3.32 (s, 3H), 2.84 - 2.78(m, 1H), 2.34 - 2.25(m, 4H). LCMS RT = 0.938 min., m/z = 381.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.938 min., ESI+ found [M+H] = 381.2. Example 542 2 -benzyl -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yltetrazol -5 -carboxamide

[01799] Amide coupling prepared in a manner similar to Method WX 071. The crude material was purified via RP-HPLC (28 -58% acetonitrile / 0.05% ammonium hydroxide in water) to provide 2 - benzyl -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yltetrazol -5 - carboxamide (10 mg, 11%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.44 - 7.34 (m, 5H), 6.00 (s, 1H), 6.93 (s, 2H), 4.57 - 4.52 (m, 1H ), 4.34 - 4.26 (m, 1H), 4.24 - 4.14 (m, 1H), 3.30 (s, 3H), 2.86 - 2.81 (m, 1H), 2.34 - 2.30 (m, 1H), 1.94 - 1.85 (m, 1H), 0.96 - 0.90 (m, 2H), 0.77 - 0.68 (m, 2H ). LCMS RT = 1.002 min., m/z = 407.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.002 min., ESI+ found [M+H] = 407.2. Example 543 1 -cyclopentyl -N -[(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl]pyrazole [ 3,4 -d] pyrimidine -6 -carboxamide

[01800] Amide coupling prepared in a manner similar to Method WX 147. The crude material was purified via RP-HPLC (26% to 56% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -cyclopentyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole [3 ,4 - d] pyrimidine -6 -carboxamide (30.2 mg, 56%) as a white solid: 1H NMR (400 MHz, DMSO -d6) δ 9.45(s, 1H), 9, 15 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H), 6.16 (s, 1H), 6.49 - 6.41 (m, 1H), 4.47 - 4 .10 (m, 3H), 3.25(s, 3H), 2.77 - 2.66 (m, 1H), 2.38 - 2.29 (m, 1H), 2.23 - 2.11 (m, 5H), 2.06 - 1.86 (m, 4H), 1.80 - 1.65 (m, 2H). LCMS RT = 0.787 min.; m/z = 409.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.787 min., ESI+ found [M+H] = 409.1. Example 544

[01801] WX 161 Method N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [ 3,4 -d] pyrimidine -7,3' -tetra hydropyran] -2 – carboxamide Step 1: 2 -chloro -2',4',5',6' -tetrahydro -5H - spiro [furo [3,4 -d] pyrimidine -7,3' -pyran] -5 -one

[01802] To a solution of 2,2,6,6-tetramethyl piperidine (13.4 g, 94.6 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in3 hexanes, 50. 0 mL, 126.0 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (6.0 g, 31.5 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and dihydro-2H-pyran-3(4H)-one (6.3 g, 63.1 mmol) was added. After addition, the reaction mixture was stirred at 25oC for 16 h and finalized by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 -200 mesh, 30% ethyl acetate in petroleum ether) to give 2-chloro-2',4',5',6'-tetrahydro-5H -spiro [furo [3,4 -d] pyrimidine -7,3' -pyran] -5 -one (900 mg, 12%) in the form of a light yellow solid, which was used in the next step of the form where he was. Step 2: 2 -chloro -2', 4', 5', 6' -tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,3' -pyran] -5 -ol

[01803] To a solution of 2 -chloro -2',4',5',6' -tetrahydro -5H -spiro [furo [3,4 -d] pyrimidine -7,3' - pyran] -5 -one (700 mg, 2.90 mmol) in toluene (30 mL) was added diatyl aluminum hydride (7.3 mL, 7.27 mmol, 1.0 M in toluene) dropwise under -78°C. The mixture was stirred at -78°C for 2 h and finalized by the addition of saturated potassium tartrate tetrahydrate (10 mL). The resulting mixture was stirred at 25°C for 1 h and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, elution with 50% ethyl acetate in petroleum ether) to give 2-chloro -2',4',5',6' - tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,3' - pyran] -5 -ol (260 mg, 37%) in the form of a white solid, which was used in the step next as it was. Step 3: 2 -chloro -2', 4', 5', 6' -tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,3' -pyran]

[01804] To a solution of 2 -chloro -2', 4', 5', 6' -tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,3' -pyran] -5 -ol (260 mg, 1.1 mmol) and 2,2,2-trifluoroacetic acid (1.6 mL, 21.9 mmol) in dichloromethane (25 mL) triethylsilane (1.6 mL, 10.20 mmol) was added. The mixture was stirred at 25°C for 15 h and concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 2-chloro-2',4',5',6'-tetrahydro-5H-spiro[furo[3,4-d] crude pyrimidine-7,3'-pyran] (240 mg, 99%) in the form of a colorless oil, which was used in the next step as is. Step 4: 2', 4', 5', 6' -tetrahydro -5H -spiro [hole [3,4 -d] pyrimidine -7,3' -pyran] -2 -carbonitrile

[01805] To a solution of 2 -chloro -2',4',5',6' -tetrahydro -5H -spiro [furo [3,4 -d] pyrimidine -7,3' - pyran] (410 mg, 1.80 mmol) in dimethyl sulfoxide (20 mL) was added 1,4-diazabicyclo[2,2,2] octane (41 mg, 0.40 mmol) and sodium cyanide (280 mg, 6.70 mmol) in water (4 mL). The mixture was stirred for 7 hours at 25°C and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 -200 mesh, elution 20 - 40% ethyl acetate in petroleum ether) to give 2',4',5',6'-tetrahydro -5H - spiro [furo [3,4 -d] pyrimidine -7,3' - pyran] -2 -carbonitrile (210 mg, 53%) in the form of a colorless oil, which was used in the next step as it was . Step 5: methyl 2',4'5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3'-pyran]-2-carboxylate

[01806] To a solution of 2',4',5',6' - tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,3' - pyran] -2 -carbonitrile (210 mg, 1.00 mmol) in methanol (12 mL) was added HCl (4N in methanol, 2.5 mL) under 0°C. The mixture was stirred at 25°C for 15 h and concentrated under reduced pressure to provide methyl 2',4',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7.3 Crude '-pyran]-2-carboxylate (210 mg, 87%) as a white solid, which was used in the next step as is. Step 6: 2',4',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3'-pyran]-2-carboxylic acid

[01807] A mixture of methyl 2',4',5',6' - tetrahydro -5H -spiro [fur [3,4 -d] pyrimidine -7,3' - pyran] -2 -carboxylate (210 mg, 0.8 mmol) and lithium hydroxide (201 mg, 8.4 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred for 2 h under 25oC. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH = 4 by adding 1N HCl. The mixture was concentrated under reduced pressure to provide 2',4',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3'-pyran]-2-carboxylic acid crude (180 mg, 91%) as a light yellow solid, which was used in the next step as is. Step 7: N -[(6S)-2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,3' -tetrahydropyran] -2 -carboxamide

[01808] Amide coupling prepared in a manner similar to Method WX 160 (RIP1K_experimental_3rd_WX.doc). The crude material was purified using RP-HPLC (20% to 50% acetonitrile/0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,3' -tetrahydropyran] -2 -carboxamide (7.7 mg, 12%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.52 (s, 1H), 6.14 (s, 1H), 6.22 (s, 2H), 4.62 - 4.56 (m, 1H), 4, 34 - 4.24 (m, 2H), 3.95 - 3.90 (m, 1H), 3.79 - 3.65 (m, 3H), 3.35 (s, 3H), 2.96 - 2.90 (m, 1H), 2.31 - 2.20 (m, 5H), 2.07 - 2.03 (m, 1H), 1.94 - 1.90 (m, 1H), 1, 77 - 1.73 (m, 1H). LCMS RT = 0.580 min.; m/z = 413.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.580 min., ESI+ found [M+H] = 413.1. Example 545 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazolo [1,5 -a][1,3] diazepin -6 -yl]spiro [3H -furo [ 3,4 -c] pyridine -1,3' -tetrahydropyran] -6 -carboxamide

[01809] Amide coupling prepared in a manner similar to Method WX 158 (RIP1K_experimental_3rd_WX.doc). The crude material was purified by RP-HPLC (20% to 50% acetonitrile/0.05% hydrochloric acid in water) to provide N -[(6S)-2,4-dimethyl-5-oxo-7 ,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [3H -furo [3,4 -c] pyridine -1,3' -tetrahydropyran] -6 - carboxamide (16.5 mg, 18%). 1H NMR (400 MHz, CD3OD) δ8.59 (s, 1H), 8.03 (s, 1H), 6.12 (s, 1H), 6.24 -6.15 (m, 2H), 4, 59 - 4.54 (m, 1H), 4.36 - 4.19 (m,2H), 3.87 - 3.61 (m, 4H), 3.34 (s,3H), 2.97 - 2.84 (m,1H), 2.28 - 2.19 (m, 4H), 2.07 - 1.89 (m,3H), 1.78 - 1.70 (m,1H). LCMS RT = 0.887 min.; m/z = 412.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.887 min., ESI+ found [M+H] = 412.2. Example 546

[01810] Method WX 095 1 -benzyl -N -(3,9 -dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -7 -yl) -1,2,4 -triazole -3 -carboxamide Step 1: 3,9 -dimethyl -6,7 -dihydro -5H - imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01811] A mixture of 2,4,6-trimethyl - 1,3,5,2,4,6 -trioxatriborinane (500 mg, 4.01 mmol), 3 - chloro -9 -methyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8 -one (400 mg, 2 mmol), bis(1-adamantyl) -butyl -phosphane (36 mg, 0.10 mmol) and carbonate potassium (831 mg, 6.01 mmol) in toluene (3 mL) and water (1 mL) was heated under 110oC for 2 h under microwave conditions. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 3,9-dimethyl-6, 7 -dihydro - 5H -imidazo[1,2 -a][1,3] diazepin -8 -one (80 mg, 22%) in the form of a yellow oil, which was used in the next step in the form in which was found. Step 2: 7 -iodo -3,9 -dimethyl -6,7 -dihydro -5H - imidazo [1,2 -a][1,3] diazepine -8(9H) -one

[01812] To a solution of 3,9 -dimethyl -6,7 - dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (40 mg, 0.22 mmol ) in dichloromethane (10 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (155 mg, 1.37 mmol) and iodotrimethyl silane (268 mg, 1.34 mmol) under -15oC. The reaction mixture was stirred at -15°C for 2 h and iodine (170 mg, 0.67 mmol) was added. The mixture was stirred at -15°C for another 2 h and finalized by the addition of saturated aqueous sodium sulfite (10 ml). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 7-iodo-3,9-dimethyl-6,7-dihydro-5H-imidazo[ 1,2 -a][1,3] diazepin -8(9H) -one (40 mg, 58%) in the form of a colorless oil, which was used in the next step as is. LCMS RT = 1.491 min.; m/z = 306.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.491 ESI+ found [M+H] =306.1. Step 3: 7 -azide -3,9 -dimethyl -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepine -8(9H) -one

[01813] A mixture of 7-iodo -3,9 -dimethyl - 6,7 -dihydro -5H -imidazo [1,2 -a] [1,3] diazepin -8(9H) -one (40 mg, 0 .13 mmol) and sodium azide (70 mg, 1.08 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 2 h and then concentrated under reduced pressure. The residue was purified by TIC preparation (50% ethyl acetate in petroleum ether, Rf = 0.6) to provide 7-azide-3,9-dimethyl-6,7-dihydro-5H-imidazo [ 1,2 -a][1,3] diazepin -8(9H) -one (20 mg, 69%) in the form of a yellow oil, which was used in the next step as it was. Step 4: 7 -amino -3,9 -dimethyl -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -8(9H) -one

[01814] A mixture of 7-azide -3,9 -dimethyl - 6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -8 -one (20 mg, 0.09 mmol ) and Pd/C (10%, 96 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was hydrogenated (15 psi) for 5 h and filtered. The filtrate was concentrated under reduced pressure to provide 7-amino-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one ( 10 mg, 56%) in the form of a yellow oil, which was used in the next step as is. Step 5: 1 -benzyl -N -(2,9 -dimethyl -8 -oxo - 6,7,8,9 -tetrahydro -5H -imidazo[1,2 -a][1,3] diazepin -7 - yl ) -1H -1,2,4 -triazole -3 -carboxamide

[01815] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (10 mg, 0.05 mmol), 7-amino-3,9-dimethyl-6,7-dihydro-5H- imidazo[1,2 -a][1,3] diazepin -8 -one (10 mg, 0.05 mmol), 1 -(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (10 mg, 0.05 mmol ) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25oC for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (13% to 43% acetonitrile/0.05% ammonium hydroxide in water) to provide 1-benzyl-N-(3, 9 -dimethyl - 8 -oxo -6,7 -dihydro -5H -imidazo[1,2 -a][1,3] diazepin -7 - yl) -1,2,4 -triazole -3 -carboxamide (3, 9 mg, 19%) as white solids. H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.39 - 7.35 (m, 5H), 6.71 (s, 1H), 6.47 (s, 2H), 4 .51 - 4.46 (m, 1H), 4.22 - 4.16 (m, 1H), 3.95 - 3.87 (m, 1H), 3.37 (s, 3H), 2.84 - 2.74 (m, 1H), 2.29 - 2.19 (m, 4H). LCMS RT = 1.792 min., m/z = 380.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.792 min., ESI+ found [M+H] = 380.1. Examples 547 and 548

[01816] Method WX 084 1 -benzyl -N -(6S) -4 -methyl -5 -oxo -2 -[(1S) - 2,2 –difluorocycle propylmethyl] -7,8 -dihydro -6H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide and 1 -benzyl -N -(6S) -4 -methyl -5 -oxo -2 -[(1R) - 2,2 -difluorocycle propylmethyl] -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide Step 1: 2 -allyl -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one

[01817] A mixture of 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (4.2 g, 6.74 mmol), cesium fluoride (26.14 g, 172.1 mmol), pinacol ester allylboronic acid (14.46 g, 86.07 mmol), 2 -bromo -4 - methyl -7,8 -dihydro -6h -pyrazole [1,5 -a][1,3] diazepin -5 -one (14.0 g, 53.4 mmol) in tetrahydrofuran (500 mL) was stirred at 70oC under a nitrogen atmosphere for 16 h and then concentrated under reduced pressure. The residue was diluted with dichloromethane (200 mL), washed with water (2 x 100 mL), saline solution (100 mL), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 1% methanol in dichloromethane) to provide 2-allyl-4-methyl-7,8-dihydro-6H-pyrazole [1, 5 -a][1,3] diazepin -5 -one (6.55 g, 60%). LCMS RT = 0.63 min., m/z = 206.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.63 min., ESI+ found [M+H] = 206.8. Step 2: 2 -((2,2-difluorocyclopropyl) methyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin - 5(6H) -one

[01818] A mixture of 2-allyl -4 -methyl -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (6.0 g, 24.4 mmol ), tetrabutylammonium bromide (235 mg, 0.7 mmol) and [bromo(difluoro)methyl]-trimethyl-silane (24.7 g, 121.8 mmol) in toluene (50 mL) was heated under 110oC for 5 h in a sealed tube. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 3% methyl in dichloromethane) to give 2-[(2,2-difluorocycle propyl)methyl ] -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (3.3 g, 53%) as a brown colored oil. LCMS RT = 0.63 min., m/z = 256.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.63 min., ESI+ found [M+H] = 256.9. Step 3: 2 -((2,2-difluorocyclopropyl) methyl) -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H ) -one

[01819] To a solution of 2 -((2,2 - difluorocycle propyl) methyl) -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5( 6H)-one (3.4 g, 13.32 mmol) in dichloromethane (100 mL) was added N1,N1,N3,N3 -tetramethyl propane -1,3 -diamine (20.82 g, 159.84 mmol) and trimethylsilane iodine (32.0 g, 159.84 mmol) under -15oC. The mixture was stirred at -15°C for 1.5 h and iodine (20.28 g, 79.92 mmol) was added in one part. The mixture was stirred for another 3 h and then finalized by the addition of 5% aqueous sodium thiosulfate (200 mL). The solution was extracted with dichloromethane (2 x 200 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 2-((2,2-difluorocycle propyl) methyl) -6 - iodine -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one (2.2 g, 43% ) in the form of a yellow oil. LCMS RT = 0.67 min., m/z = 381.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.67 min., ESI+ found [M+H] = 381.9. Step 4: 6 -azide -2 -((2,2-difluorocyclopropyl) methyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H ) -one

[01820] A mixture of 2 -((2,2-difluorocycle propyl) methyl) -6 -iodo -4 -methyl -7,8 -dihydro - 4H - pyrazole [1,5 -a][1,3] diazepine -5(6H)-one (2.2 g, 6.77 mmol) and sodium azide (0.56 g, 8.66 mmol) in N,N - dimethylformamide (50 mL) was subjected to stirring at 25oC for 16 h and diluted with ethyl acetate (50 mL). The solution was washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 6-azide -2 -((2,2-difluorocycle propyl) methyl ) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (1.5 g, 88%) as a solid White color. LCMS RT = 0.66 min., m/z = 296.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.66 min., ESI+ found [M+H] = 296.9. Step 5: 6 -amino -2 -((2,2-difluorocyclopropyl) methyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H ) -ona

[01821] To a solution of 6 -azide -2 - [(2,2 - difluorocyclopropyl) methyl] -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepine -5-one (1.5 g, 6.06 mmol) in tetrahydrofuran (50 mL) was added water (10 mL) and 80% polymer-binding triphenylphosphine (6.0 g, 18.3 mmol). The mixture was stirred at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% methanol in dichloromethane) to give 6-amino -2 - [(2,2 - difluorocycle propyl) methyl] -4 -methyl -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one (1.0 g, 73%) in the form of an oil yellow in color. LCMS RT = 0.54 min., m/z = 270.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.54 min., ESI+ found [M+H] = 270.8. Step 6: 1-Benzyl -N -(6S) -4 -methyl -5 -oxo -2 -[(1S) - 2,2 -difluorocyclopropylmethyl] -7,8 -dihydro -6H -pyrazole [1,5 -a ][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide and 1 -benzyl -N -(6S) -4 -methyl -5 -oxo -2 -[(1R) - 2 ,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

[01822] A mixture of 6 -amino -2 - [(2,2 - difluorocycle propyl) methyl] -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepine -5 -one (150 mg, 0.56 mmol), 1 -hydroxy benzotriazole (112 mg, 0.83 mmol), 1 -benzyl -1,2,4 -triazole -3 -carboxylic acid (112 mg, 0. 56 mmol) and 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.56 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25oC for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (33% to 63% acetonitrile, 0.05% ammonium hydroxide in water) to give 1-benzyl-N-[2-[ (2,2-difluorocycle propyl) methyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl] -1,2 ,4-triazole-3-carboxamide (110 mg, 44%) as a white solid. The racemate was separated using chiral SFC to provide:

[01823] 1 -benzyl -N -(6S) -4 -methyl -5 -oxo -2 -[(1S) -2,2 -difluorocycle propylmethyl] -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time 4.169 min.) (9.1 mg, 8.3%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 7.48 - 7.20 (m, 5H), 6.23 (s, 1H), 6.43 (s, 2H), 4, 57 - 4.53 (m, 1H), 4.38 - 4.34 (m, 1H), 4.26 - 4.22 (m, 1H), 3.35 (s, 3H), 2.95 - 2.65 (m, 3H), 2.40 - 2.20 (m, 1H), 2.05 - 1.80 (m, 1H), 1.65 - 1.45(m, 1H), 1, 25- 1.10 (m, 1H). LCMS RT = 0.684 min., m/z = 456.0 (M + H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.684 min., ESI+ found [M+H] = 456.0.

[01824] 1 -benzyl -N -(6S) -4 -methyl -5 -oxo -2 -[(1R) -2,2 -difluorocycle propylmethyl] -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 4.225 min.) (8.9 mg, 8.1%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) 8.59 (s, 1H), 7.48 - 7.20 (m, 5H), 6.24 (s, 1H), 6.49 (s, 2H), 4, 57 - 4.53 (m, 1H), 4.37 - 4.35 (m, 1H), 4.28 - 4.23 (m, 1H), 3.35 (s, 3H), 2.95 - 2.65 (m, 3H), 2.40 - 2.20 (m, 1H), 2.05 - 1.80 (m, 1H), 1.65 - 1.45(m, 1H), 1, 25- 1.10 (m, 1H). LCMS RT = 0.694 min., m/z = 456.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.694 min., ESI+ found [M+H] = 456.1.

[01825] SFC Conditions: Method: Column: Quiralpak AY -3, 150 x 4.6 mm I.D., 3 µm Mobile phase: 50% ethanol (0.05% DEA) in CO2 Flow rate: 2.0 mL/ min. Wavelength: 220 nm. Example 549

[01826] WX Method 173 4 -(1-hydroxy -1 -methyl -propyl) -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 -carboxamide Step 1: 2 -bromine -4 -iodine pyrimidine

[01827] A solution of chlorine -(2,2,6,6 - tetramethyl -1 -piperidyl) magnesium (1.5 M in Tetrahedron, 39.0 mL, 58.1 mmol) in tetrahydrofuran (140 mL) was 2-Bromopyrimidine (8.4 g, 52.8 mmol) was added under -55°C for 20 min. The resulting mixture was stirred for 1.5 h at -55°C and zinc dichloride (1 M in Tetrahedron, 58.0 mL, 58.0 mmol) was added slowly. After addition, the mixture was heated to 25°C and the solution of iodine (20.1 g, 79.2 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred for 45 min. and finished by adding saturated ammonium chloride (50 mL) and saturated sodium thiosulfate (150 mL). The mixture was extracted with ethyl acetate (3 x 300 ml). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% petroleum ether in ethyl acetate) to provide 2-bromo-4-iodopyrimidine (4.0 g, 27%) in the form of a white solid. Step 2: 2 -(2 -bromopyrimidin -4 -yl)butan -2 -ol

[01828] To a solution of methyl ethyl ketone (2.0 g, 28.08 mmol) and 2-bromo-4-iodo-pyrimidine (4.0 g, 14.04 mmol) in tetrahydrofuran (30 mL) was added isopropyl magnesium bromide (1.0 M in Tetrahedron, 16.2 mL, 16.2 mmol) under -60oC. The mixture was subjected to stirring at -60oC for 1 h and finalized by the addition of saturated ammonium chloride (30 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 10 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% petroleum ether in ethyl acetate) to provide the product 2 -(2 - bromopyrimidin -4 -yl)butan -2 -ol (1.0 g, 31%) in the form of a yellow oil. LC-MS RT = 2.45min., m/z = 231.0 (M+H) +. LCMS (0-30% acetonitrile in water + 0.03% trifluoroacetic acid for 4.0 min.) retention time 2.45/min., ESI+ found [M+H] = 231.0. Step 3: 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carbonitrile

[01829] To a solution of 2 -(2-bromopyrimidin-4-yl)butan-2-ol (1.0 g, 4.00 mmol) in dimethyl sulfoxide (5 mL) was added 1,4-diazabicyclo [ 2,2,2] octane (243 mg, 2.16 mmol) and sodium cyanide (400 mg, 8.16 mmol) in water (2.5 ml). The mixture was stirred at 25oC for 16 h and extracted with ethyl acetate (3 x 25mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% petroleum ether in ethyl acetate) to provide 4-(1-hydroxy -1-methyl-propyl) pyrimidine - 2-carbonitrile (600 mg, 78%) as a white solid. LC-MS RT = 1.48 min., m/z = 178.0 (M+H) +. LCMS (0 - 30% acetonitrile in water + 0.03% trifluoroacetic acid for 4 min.) retention time 1.48/min., ESI+ found [M+H] = 178.0. Step 4: 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylate

[01830] To a solution of 4-(1-hydroxycyclobutyl) pyrimidine-2-carbonitrile (600 mg, 3.39 mmol) in methanol (5 mL) was added HCl (1M in methanol, 6.77 mL). The reaction mixture was stirred at 25oC for 16 h and finalized by the addition of saturated sodium bicarbonate (20 mL). The resulting solution was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by TIC preparation (50% ethyl acetate in petroleum ether, Rf = 0.3) to provide 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylate (300 mg, 42%) in the form of a yellow oil. LC-MS RT = 2.10 min., m/z = 211.0 (M+H) +. LCMS (0 - 30% acetonitrile in water + 0.03% trifluoroacetic acid for 4 min.) retention time 2.10/min., ESI+ found [M+H] = 211.0. Step 5: 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylic acid

[01831] A mixture of 4-(1-hydroxy-1-methyl-propyl) pyrimidine-2-carboxylate (50 mg, 0.24 mmol) and lithium hydroxide (29 mg, 1.19 mmol) in tetrahydrofuran (5 mL) and water (1 mL) were stirred at 25oC for 16 h. The mixture was adjusted to pH = 6 by adding 1N HCl and then extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude 4-(1-hydroxy-1-methyl-propyl)-pyrimidine-2-carboxylic acid (30 mg, 64%) in the form of a white solid. Step 6: 4 -(1-hydroxy -1 -methyl -propyl) -N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine - 2-carboxamide

[01832] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (29 mg, 0.15 mmol), 4 -(1-hydroxy acid -1-methyl-propyl)pyrimidine -2-carboxylic acid (30 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and 1-hydroxybenzotriazole ( 25mg, 0.18 mmol) in N,N - dimethylformamide (4 mL) was stirred at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (18% to 48% acetonitrile / 0.05% ammonium hydroxide in water) to provide 4 -(1-hydroxy-1-methyl - propyl) -N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrimidine -2 -carboxamide (27 mg, 47%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.89 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 6.2 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.34 - 7.24 (m, 3H), 6.06 - 6.02 (m, 1H), 4.70- 4.66 (m, 1H), 4.47 - 4.42 ( m, 1H), 3.44 (s, 3H), 2.01 - 1.87 (m, 2H), 1.56 (s, 3H), 0.81 - 0.77 (m, 3H). LCMS RT = 1.971 min.; m/z = 371.2 (M+H)+. LCMS (0 -60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.971 min., ESI+ found [M+H] = 371.2. Example 550 5 -[(4-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl] -4H -1,2,4 -triazole -3 - carboxamide and 5 -[(4-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 - (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide

[01833] Amide coupling prepared in a manner similar to Method WX 011. The crude material was purified using RP-HPLC (0 - 40% acetonitrile/0.05% ammonium hydroxide in water) to provide 5 - 1 -(4-fluorobenzyl) -N -(4 -methyl -5 -oxo -2 - (trifluoromethyl) -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (50 mg, 53%) as a white solid. The racemic material was separated using chiral SFC to provide:

[01834] 5 -[(4-fluorophenyl) methyl] -N -(6R) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide (Peak 2, Retention time = 3.822 min.) (14 mg, 27%) as a colored solid white. 1H NMR (400MHz, CD3OD) δ7.33 - 7.29 (m, 2H), 7.07 - 7.03 (m, 2H), 6.67 (s, 1H), 4.56 - 4.47 ( m, 2H), 4.42 - 4.33 (m, 1H), 4.14 (s, 2H), 3.37 (s, 3H), 2.94 - 2.85 (m, 1H), 2 .35 - 2.28 (m, 1H). LC-MS RT = 1.126 min., m/z = 452.1 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.126 min., ESI+ found [M+H] = 452.1.

[01835] 5 -[(4-fluorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -2 -(trifluoromethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl -4H -1,2,4 -triazole -3 -carboxamide (Peak 1, Retention time = 3.495 min.) (16 mg, 31%) as a colored solid white. 1H NMR (400 MHz, CD3OD) δ7.33 - 7.29 (m, 2H), 7.07 - 7.03 (m, 2H), 6.67 (s, 1H), 4.56 - 4.47 (m, 2H), 4.42 - 4.33 (m, 1H), 4.14 (s, 2H), 3.37 (s, 3H), 2.94 - 2.85 (m, 1H), 2.35 - 2.28 (m, 1H). LC-MS RT = 1.128 min., m/z = 452.1 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.128 min., ESI+ found [M+H] = 452.1.

[01836] SFC Conditions: Quiralpak AS Column - H 250x4.6 mm ID, 5 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 6 ,0min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35 oC. Example 551 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [ 3,4 -d] pyrimidine -7,3' -tetrahydrofuran] -2 -carboxamide

[01837] Amide coupling prepared in a manner similar to Method WX 162 (RIP1K_experimental_3rd_WX.doc). The crude material was purified by RP-HPLC (6% to 36% acetonitrile/0.05% ammonium hydroxide in water) to provide N -[(6S)-2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,3' -tetrahydrofuran] -2 -carboxamide (60 mg, 64%). H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H), 6.13 (s, 1H), 6.19 (s, 2H), 4.62 - 4.57 (m, 1H), 4 .37 - 4.21 (m, 2H), 4.18 - 4.00 (m, 4H), 3.35 (s, 3H), 2.99 - 2.88 (m, 1H), 2.50 - 2.41 (m, 1H), 2.35 - 2.27 (m, 5H). LC-MS RT = 1.146 min., m/z = 399.2 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.146 min., ESI+ found [M+H] = 399.2. Example 552 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [ 3,4 -d] pyrimidine -7,1' -cyclopentane] -2 -carboxamide

[01838] Amide coupling prepared in a manner similar to Method WX 164 (RIP1K_experimental_3rd_WX.doc). The crude material was purified by RP-HPLC (17% to 47% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro [5H -furo [3,4 -d] pyrimidine -7,1' -cyclopentane] -2 -carboxamide (42.9 mg, 47%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.79 (s, 1H), 6.13 (s, 1H), 6.11 (s, 2H), 4.59 - 4.57 (m, 1H), 4, 33 - 4.25(m, 2H), 3.35 (s, 3H), 2.98 - 2.91 (m, 1H), 2.31 - 2.25(m, 4H), 2.13 - 1.99 (m, 4H), 1.94 - 1.91 (m, 4H). LC-MS RT = 1,850 min., m/z = 397.2 [M+H] +. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1,850 min., ESI+ found [M+H] = 397.2. Example 553 8 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5,6,7,8 -tetrahydro -[1,2 ,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01839] Amide coupling prepared in a manner similar to Method WX 119 (RIP1K_experimental_3rd_WX.doc). The crude material was purified using PR-HPLC (32% to 62% acetonitrile/0.05% ammonium hydroxide in water) to provide 8-phenyl-N-[(3S)-5-methyl-4- oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide ( 4 mg, 33%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.45- 7.39 (m, 1H), 7.36 - 7.20 (m, 6H), 7.16 (d, J = 8.0 Hz, 2H), 6.02 - 4.95 (m, 1H), 4.58 - 4.51 (m, 1H), 4.40 - 4.32 (m, 4H), 3.39 (s, 3H), 2, 40 - 2.33 (m, 1H), 2.24 - 2.03 (m, 3H). LCMS RT = 0.831 min., m/z = 418.0 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 0.831 min., ESI+ found [M+H] = 418.0. Example 554

[01840] WX 119 Method 8 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 5 ,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide Step 1: 8 -phenyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carbonitrile

[01841] A mixture of 8-phenyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (500 mg, 2.38 mmol) and cupric cyanide (234 mg, 2.62 mmol) in acetonitrile (30 mL) was added isopentyl nitrite (0.45 mL, 3.33 mmol) under 0oC. The mixture was stirred at 0°C for 30 min. and then heated under 80oC for 4 h. After cooling to 0oC, aqueous sodium hydroxide (2N, 8 mL), saturated sodium bicarbonate (120 mL) and dichloromethane (150 mL) were added to the mixture. The mixture was filtered and the organic layer phase was washed with brine (50 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 15% ethyl acetate in petroleum ether) to provide 8-phenyl-[1,2,4] triazolo[1,5 -a] pyridine -2 -carbonitrile (50 mg, 10%) as a white solid. LCMS RT = 1.053 min., m/z = 221.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.053 min., ESI+ found [M+H] = 221.1. Step 2: methyl 8 -phenyl -[1,2,4] triazolo [1,5 - a] pyridine -2 -carboxylate

[01842] The solution of 8-phenyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carbonitrile carbonitrile (50 mg, 0.22 mmol) in HCl (2N in methanol, 4.0 mL, 8.0 mmol) was stirred at 20oC for 20 h and concentrated under reduced pressure to provide crude methyl 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (30 mg, 52%) as a white solid. LCMS RT = 0.778 & 0.844 min., m/z = 253.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.778min., ESI+ found [M+H] = 253.9; retention time 0.844 min., ESI+ found [M+H] = 253.9. 0 Step 3: methyl 8 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylate

[01843] A mixture of methyl 8 -phenyl -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxylate (30 mg, 0.12 mmol) and Pd/C (10%, 126 mg , 0.12 mmol) in methanol (10 mL) was hydrogenated (50 psi) for 1 h and filtered. The filtrate was concentrated under reduced pressure to give crude methyl 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (20 mg , 66%) in the form of a white solid. LCMS RT = 0.729 min., m/z = 257.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.729 min., ESI+ found [M+H] = 257.9. Step 4: 8-Phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[01844] A mixture of methyl 8 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxylate (20 mg, 0.08 mmol) and hydrated lithium hydroxide (16 mg, 0.39 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred under 25oC for 4 h. The solution was diluted with water (20 mL) and adjusted to pH = 4 by adding 2N HCl. The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a] acid crude pyridine-2-carboxylic acid (10 mg, 53%), which was used in the next step as it was. Step 5: 8 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ] - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide

[01845] A mixture of 8-phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxylic acid (10 mg, 0.04 mmol) , 1 -hydroxybenzotriazole (7 mg, 0.05 mmol), (6s) -6 -amino -2,4 -dimethyl -7,8 -dihydro - 6 h -pyrazole [1,5 -a][1,3] diazepin-5-one (9 mg, 0.05 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9 mg, 0.05 mmol) in N,N-dimethylformamide (5 mL) was submitted stirring at 25oC for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (36% acetonitrile/0.05% ammonium hydroxide in water) to give 8-phenyl -N -[(6S)-2.4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -5,6,7,8 -tetrahydro - [1,2, 4] triazolo [1,5 -a] pyridine -2 -carboxamide (4.5 mg, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.39 - 7.23 (m, 3H), 7.20 - 7.08 (m, 2H), 6.10 (s, 1H), 4.53 - 4.47 (m, 1H), 4.38 - 4.12 (m, 5H), 3.34 - 3.31 (m, 3H), 2.83 - 2.72 (m, 1H), 2.40 - 2 .32 (m, 1H), 2.31 - 1.99 (m, 7H). LCMS RT = 0.769 min., m/z = 420.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.769 min., ESI+ found [M+H] = 420.1. Example 555

[01846] Method WX 056 1 -[(3,3-dimethylcyclobutyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: (3,3-dimethylcyclobutyl)methanol

[01847] To a solution of 3,3-dimethyl cyclobutane carboxylic acid (300 mg, 2.34 mmol) in tetrahydrofuran (10 mL) was added LiAlH4 (178 mg, 4.68 mmol) under 0oC. The mixture was stirred at 25°C for 16 h and then finalized by adding water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.3 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude (3,3-dimethylcyclobutyl) methanol (100 mg, 86%) as a colorless oil, which was used in the next step in the form in which was found. Step 2: (3,3-dimethylcyclobutyl)methyl 4-methylbenzene sulfonate

[01848] To a solution of p - toluenesulfonyl chloride (521 mg, 2.73 mmol) in dichloromethane (10 mL) was added (3,3-dimethylcyclobutyl) methanol (260 mg, 2.28 mmol) and 4-dimethylamino pyridine (556 mg, 4.55 mmol). The reaction mixture was stirred at 20oC for 16 h and then finished by adding water (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide (3,3-dimethyl cyclobutyl) methyl 4-methylbenzene sulfonate (350 mg, 57%) in the form of a colorless oil, which was used in the next step as is. Step 3: 3-(bromomethyl)-1,1-dimethylcyclobutane

[01849] To a solution of (3,3-dimethyl cyclobutyl) methyl 4-methylbenzene sulfonate (350 mg, 1.30 mmol) in acetone (20 mL) was added lithium bromide (566 mg, 6.52 mmol) . The reaction mixture was heated at 70°C for 2 h and then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated to provide crude 3-(bromomethyl)-1,1-dimethyl cyclobutane (150 mg , 65%) in the form of a colorless oil, which was used in the next stage as it was. Step 4: 1 -[(3,3-dimethylcyclobutyl) methyl] -N - (6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01850] A mixture of 3 -(bromomethyl) -1,1 - dimethyl -cyclobutane (37 mg, 0.21 mmol), N -[(6S) -2,4 - dimethyl -5 -oxo -7.8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1H -1,2,4 -triazole -3 -carboxamide (50 mg, 0.17 mmol) and potassium carbonate (72 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20°C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (40-70% acetonitrile/0.05% ammonium hydroxide in water) to give 1-[(3,3-dimethylcyclobutyl)methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 - triazole -3 - carboxamide (17.2 mg, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.46 (s, 1H), 6.12 (s, 1H), 4.57 — 4.52 (m, 1H), 4.32 — 4.24 (m, 4H ), 3.34 (s, 3H), 2.86 - 2.79 (m, 2H), 2.29 - 2.23 (m, 4H), 1.87 - 1.82 (m, 2H), 1.67 - 1.61 (m, 2H), 1.16 (s, 3H), 1.08 (s, 3H). LCMS RT = 0.810 min.; m/z = 386.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.810 min., ESI+ found [M+H] = 386.1. Example 556

[01851] WX Method 169 7,7 -dimethyl -6,6 -dioxo -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5H -thiene [3, 4 -d] pyrimidine -2 -carboxamide Step1: 2-chloro-7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine

[01852] A mixture of 2,4-dichloro-7,7-dimethyl-5,7-dihydrothiene [3,4-d] pyrimidine (1.0 g, 4.25 mmol) and zinc (834 mg, 12, 76 mmol) in water (20 mL) was heated at 100oC for 12 h. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide 2-chloro-7,7-dimethyl-5,7-dihydrothiene[ 3,4 -d] pyrimidine (400 mg, 47%) as a white solid. 1H NMR (400MHz, CD3OD) δ8.60 (s, 1H), 4.18 (s, 2H), 1.69 (s, 6H). Step 2: 7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine-2-carbonitrile

[01853] To a solution of 2-chloro-7,7-dimethyl-5H-thieno[3,4-d] pyrimidine (250 mg, 1.25 mmol) in dimethyl sulfoxide (10 mL) and water (10 mL ) sodium cyanide (122 mg, 2.49 mmol) and 1,4-diazabicyclo[2,2,2] octane (28 mg, 0.25 mmol) were added. The reaction mixture was stirred at 30oC for 12 h and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 7,7-dimethyl-5H-thieno[3,4-d] pyrimidine-2-carbonitrile (150 mg, 63%) as a white solid. Step 3: methyl 7,7 -dimethyl -5,7 -dihydrothieno[3,4 -d] pyrimidine -2 -carboxylate

[01854] To a solution of 7,7-dimethyl -5H - thieno[3,4 -d] pyrimidine -2 -carbonitrile (110 mg, 0.58 mmol) in methanol (5 mL) was added HCl (4N in methanol , 5 mL). The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 - 200 mesh, 0% to 60% ethyl acetate in petroleum ether) to give methyl 7,7 -dimethyl -5,7 - dihydrothieno[3,4 -d] pyrimidine -2-carboxylate (120 mg, 93%) as a white solid. LCMS RT = 0.600 min., m/z = 224.9 [M + H]+. LCMS (5 - 95% acetonitrile in water + 0.1% trifluoroacetic over 1.5 min.) retention time 0.600 min., ESI+ found [M + H]+ = 224.9. Step 4: methyl 7,7 -dimethyl -5,7 -dihydrothieno[3,4 -d] pyrimidine -2 -carboxylate 6,6 -dioxide

[01855] A mixture of oxone (658 mg, 1.07 mmol) and methyl 7,7-dimethyl-5,7-dihydrothiene [3,4-d] pyrimidine-2-carboxylate (120 mg, 0.54 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred at 20oC for 12 h and finalized by the addition of saturated sodium hydrogen sulfite (5 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 - 200 mesh, 0% to 60% ethyl acetate in petroleum ether) to provide methyl 7,7-dimethyl-5,7-dihydrothiene [3,4 -d] pyrimidine -2 -carboxylate 6,6 - dioxide (120 mg, 88%) as a white solid. LCMS RT = 1.226 min., m/z = 257.1[M + H]+. LCMS (0 - 60% acetonitrile in water + 0.1% trifluoroacetic for 2.0 min.) retention time 1.226 min., ESI+ found [M + H]+ = 257.1. Step 5: 6,6-7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine-2-carboxylic acid dioxide

[01856] A mixture of methyl 7,7 -dimethyl -5,7 -dihydrothiene [3,4 -d] pyrimidine -2 -carboxylate 6,6 - dioxide (30 mg, 0.12 mmol) and lithium hydroxide (61 mg, 21.9 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred at 25oC for 16 h. The mixture was adjusted to pH 5 by adding hydrochloric acid (1.0 M). The resulting solution was concentrated to drying under reduced pressure to provide crude 7,7-dimethyl-5,7-dihydrothiene[3,4-d]pyrimidine-2-carboxylic acid 6,6-dioxide (28 mg, 97%) in the form of a white solid, which was used in the next step as it was. Step 6: 7,7 -dimethyl -6,6 -dioxo -N -[(3S)-5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -5H - thiene [3,4 -d] pyrimidine -2 -carboxamide

[01857] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (22 mg, 0.12 mmol), 7,7 -dimethyl acid - 6,6-dioxo -5H -thieno[3,4-d] pyrimidine -2 -carboxylic acid (28 mg, 0.12 mmol), 1H -benzo[d][1,2,3] triazole -1 -ol ( 17 mg, 0.13 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL ) was subjected to stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (28% to 58% acetonitrile/0.1% ammonium hydroxide in water) to give 7,7-dimethyl-6,6-dioxo -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -5H -thieno[3,4 -d] pyrimidine -2 -carboxamide (7 mg, 15%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.93 (s, 1H), 7.45- 7.43 (m, 1H), 7.36 - 7.22 (m, 3H), 6.06 - 6.02 (m, 1H), 4.87 - 4.86 (m, 2H), 4.66 - 4.58 (m, 1H), 4.47 - 4.42 (m, 1H), 3.43 (s , 3H), 1.68 (s, 6H). LCMS RT = 1.543 min.; m/z = 417.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.543 min., ESI+ found [M+H] = 417.1. Example 557

[01858] Method WX 085 1 -benzyl -N -(1,7 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo[1,5 -a][1,3] diazepin -3 -yl) -1,2,4 -triazole -3 -carboxamide Step 1: ethyl 4 -(5 -amino -1H -imidazol -1 -yl) butanoate

[01859] A solution of a mixture of ethyl 4 -(5 - nitroimidazol -1 -yl) butanoate (13.0 g, 57.21 mmol) and Pd/C (10%, 6.0 g, 4.7 mmol) in 1,4-dioxane (200 mL) was hydrogenated [2.73 bar (25 psi)] for 15 h and filtered. The filtrate was concentrated under reduced pressure to provide crude ethyl 4-(5-aminoimidazol-1-yl)butanoate (10 g, 88%) as a black oil, which was used in the next step as where he was. Step 2: 4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[01860] A mixture of ethyl 4-(5-aminoimidazol-1-yl) butanoate (10.0 g, 50.7 mmol) and potassium 2-methylpropan-2-oleate (11.38 g, 101.4 mmol) in dimethyl sulfoxide (20 mL) was stirred at 25°C for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 1,3,4,5 - tetrahydroimidazo [1,5 -a][1,3 ] diazepin -2 -one (8.0 g, 100%) in the form of a light yellow oil, which was used in the next step as it was. Step 3: 1 -methyl -4,5 -dihydro -1H -imidazo[1,5 - a][1,3] diazepin -2(3H) -one

[01861] To a solution of 1,3,4,5-tetra hydroimidazo[1,5-a][1,3] diazepin -2 -one (3.0 g, 19.85 mmol) in N,N - dimethylformamide (20 mL) was added cesium carbonate (6.5 g, 19.85 mmol) and iodomethane (2.8 g, 19.85 mmol). The reaction mixture was stirred at 25°C for 15 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 1-methyl -4,5 -dihydro -3H - imidazo [1,5 - a][1,3] diazepin -2 -one (2.5 g, 76%) in the form of a light yellow oil, which was used in the next step as it was . Step 4: 9 -chloro -1 -methyl -4,5 -dihydro -1H - imidazo [1,5 -a][1,3] diazepine -2(3H) -one

[01862] To a solution of 1 -methyl -4,5 -dihydro -3H -imidazo[1,5 -a][1,3] diazepin -2 -one (1.0 g, 6.05 mmol) in chloroform (20 mL) 1-chloropyrrolidine-2,5-dione (0.73 g, 6.45 mmol) was added. The reaction mixture was heated at 60°C for 1 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 9-chloro-1-methyl-4,5-dihydro-3H- imidazo[1,5 -a][1,3] diazepin -2 -one (1.0 g, 83%) as a light yellow solid, which was used in the next step as it was . Step 5: 7 -bromo -9 -chloro -1 -methyl -4,5 - dihydro -1H -imidazo[1,5 -a] [1,3] diazepin -2(3H) -one

[01863] To a solution of 9 -chloro -1 -methyl - 4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -2 -one (500 mg, 2.5 mmol) in chloroform (20 mL) 1-bromo-2,5-pyrrolidinedione (446 mg, 2.5 mmol) was added. The reaction mixture was heated at 60°C for 4 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 60% ethyl acetate in petroleum ether) to provide 7-bromo-9-chloro-1-methyl-4,5- dihydro - 3H -imidazo[1,5 -a][1,3] diazepin -2 -one (650 mg, 93%) in the form of a yellow solid, which was used in the next step in the form in which it was found. Step 6: 9 -chloro -1,7 -dimethyl -4,5 -dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[01864] A mixture of 2,4,6-trimethyl - 1,3,5,2,4,6 -trioxatriborinane (496 mg, 3.95 mmol) cesium carbonate (1287 mg, 3.95 mmol), PdCl2 (dppf) (144 mg, 0.20 mmol) and 7 -bromo -9 -chloro -1 -methyl -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -2 - one (550 mg, 1.97 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 110oC for 4 h under nitrogen protection. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 9-chloro-1,7-dimethyl-4, 5 -dihydro -3H - imidazo [1,5 -a][1,3] diazepin -2 -one (300 mg, 71%) in the form of a yellow solid, which was used in the next step in the form in which was found. Step 7: 9 -chloro -3 -iodo -1,7 -dimethyl -4,5 - dihydro -1H -imidazo [1,5 -a] [1,3] diazepin -2(3H) -one

[01865] To a solution of 9 -chloro -1,7 -dimethyl -4,5 -dihydro -3H -imidazo[1,5 -a] [1,3] diazepin -2 -one (250 mg, 1.17 mmol) in dichloromethane (20 mL) was added N1,N1,N3,N3 -tetramethylpropane -1,3 -diamine (816 mg, 7.02 mmol) and trimethylsilane iodine (1.4 g, 7.02 mmol) under - 15oC. The reaction mixture was stirred at -15°C for 2 h and iodine (3.56 g, 14.04 mmol) was added. The mixture was stirred at -15oC for another 2 h and then finalized by adding 5% aqueous sodium thiosulfate (10 mL). The solution was extracted with dichloromethane (3 x 20 mL).

[01866] The combined organic layers were washed with water (10 mL), saline solution (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 9-chloro-3-iodo-1,7-dimethyl-4, 5 -dihydro - 3H -imidazo[1,5 -a][1,3] diazepin -2 -one (300 mg, 75%) in the form of a colorless solid, which was used in the next step in the form in which it was found. Step 8: 3 -azide -9 -chloro -1,7 -dimethyl -4,5 - dihydro -1H -imidazo[1,5 -a][1,3] diazepin -2(3H) -one

[01867] A mixture of 9 -chloro -3 -iodo -1,7 - dimethyl -4,5 -dihydro -3H -imidazo [1,5 -a] [1,3] diazepin -2 -one (300 mg, 0.88 mmol) and sodium azide (500 mg, 7.69 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 2 h and then poured into ice water (5 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated and the residue was purified by prep TIC (50% ethyl acetate in petroleum ether, Rf = 0.6) to give 3-azide-9-chloro-1,7-dimethyl -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -2 -one (250 mg, 100%) in the form of a yellow oil, which was used in the next step the way it was. Step 9: 3 -amino -1,7 -dimethyl -4,5 -dihydro -1H -imidazo[1,5 -a][1,3] diazepin -2(3H) -one

[01868] A mixture of 3-azide -9 -chloro -1,7 -dimethyl -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin - 2 -one (50 mg, 0.20 mmol) and Pd/C (10%, 208 mg, 0.20 mmol) in 1,4-dioxane (5 mL) was hydrogenated [2.04 bar (15 psi)] for 5 h and filtered. The filtrate was concentrated under reduced pressure to provide 3-amino-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (10 mg, 26%) in the form of a colorless oil, which was used in the next stage as it was. Step 10: 1 -benzyl -N -(1,7 -dimethyl -2 -oxo - 2,3,4,5 -tetrahydro -1H -imidazo[1,5 -a][1,3] diazepin -3 - yl ) -1H -1,2,4 -triazole -3 -carboxamide

[01869] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (10.0 mg, 0.05 mmol) 3-amino-1,7-dimethyl-4,5-dihydro-3H -imidazo [1,5 -a] [1,3] diazepin - 2 -one (10.0 mg, 0.05 mmol), 1 -benzo [d][1,2,3] triazol -1 -ol ( 7.0 mg, 0.05 mmol) and 3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (9.9 mg, 0.050 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring at 25oC for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13% to 43% acetonitrile, 0.05% ammonium hydroxide in water) to give 1-benzyl-N -(1,7 - dimethyl -2 -oxo -4,5 - dihydro -3H -imidazo[1,5 -a][1,3] diazepin -3 -yl) -1,2,4 - triazole -3 -carboxamide (6.9 mg , 37%) in the form of white solids. 1H NMR (400 MHz, DMSO -d6) δ8.82 (s, 1H), 8.49 (d, J= 7.6 Hz, 1H), 7.41 - 7.27 (m, 5H), 6, 80 (s, 1H), 6.48 (s, 2H), 4.40 - 4.32 (m, 1H), 4.22 - 4.16 (m, 1H), 3.73 - 3.71 ( m, 1H), 3.24 - 3.16 (m, 3H), 2.47 - 2.41 (m, 1H), 2.29 (s, 3H), 2.23 - 2.20 (m, 1H). LCMS RT = 1.705 min., m/z = 380.2 (M + H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.705 ESI+ found [M+H] =380.2. Example 558

[01870] WX 151 Method N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -1 -tetrahydropyran -4 -yl -pyrazolo [3,4 -d] pyrimidine -6 -carboxamide Step 1: 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

[01871] A mixture of 6-chloro-1H-pyrazolo[3,4-d] pyrimidine (2.0 g, 12.9 mmol), cesium carbonate (8.4 g, 25.9 mmol), 4 - bromotetrahydro-2H-pyran (3.2 g, 19.4 mmol) and sodium iodide (193 mg, 1.3 mmol) in N,N-dimethylformamide (40mL) was heated under 50°C for 20h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-chloro-1- ( tetrahydro -2H -pyran -4 -yl) -1H -pyrazolo [3,4 -d] pyrimidine (300 mg, 10%) as a white solid. LCMS RT = 1.024 min.; m/z = 239.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.024 min., ESI+ found [M+H] = 239.1. Step 2: 1 -(tetrahydro -2H -pyran -4 -yl) -1H - pyrazole [3,4 -d] pyrimidine -6 -carbonitrile

[01872] To a solution of 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.26 mmol) in dimethyl sulfoxide ( 10 mL) 1,4-diazabicyclo[2,2,2] octane (14 mg, 0.13 mmol) and sodium cyanide (180 mg, 3.67 mmol) in water (1 mL) were added. The mixture was stirred at 25°C for 3 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep TLC (40% ethyl acetate in petroleum ether) to provide 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine- 6-carbonitrile (100 mg, 35%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 3: methyl 1 -(tetrahydro -2H -pyran -4 -yl) - 1H -pyrazolo [3,4 -d] pyrimidine -6 -carboxylate

[01873] To a solution of 1 -(tetrahydro -2H - pyran -4 -yl) -1H -pyrazolo [3,4 -d] pyrimidine -6 - carbonitrile (100 mg, 0.44 mmol) in methanol (5 mL ) HCl (4N in methanol, 1.5 mL) was added. The mixture was subjected to stirring at 20oC for 20h and 50oC for 3 h. The reaction solution was concentrated under reduced pressure to provide crude methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (100 mg, 87% ) in the form of a yellow solid. LCMS RT = 0.930 min.; m/z = 263.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.930 min., ESI+ found [M+H] = 263.2. Step 4: 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[01874] A mixture of methyl 1 -(tetrahydro -2H -pyran -4 -yl) -1H -pyrazole [3,4 -d] pyrimidine -6 - carboxylate (100 mg, 0.38 mmol) and hydrated lithium hydroxide (80 mg, 1.91 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25oC for 2 h. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH = 4 by adding 2N HCl. The mixture was extracted with ethyl acetate (3 x 20mL). The combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure to provide 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid crude (60 mg, 63%) as a yellow solid. LCMS RT = 0.788 min.; m/z = 249.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.788 min., ESI+ found [M+H] = 249.2. Step 5: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -1 -tetrahydropyran -4 -yl - pyrazole [3,4 - d] pyrimidine -6 -carboxamide

[01875] A mixture of (3S) -3 -amino -5 -methyl - 2,3 -dihydro -1,5 -benzoxazepin -4 -one (33 mg, 0.17 mmol), 1 -tetrahydropyran acid -4 -ylpyrazole [3,4 -d] pyrimidine -6 -carboxylic acid (30 mg, 0.12 mmol), N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (36 mg, 0.19 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (25mg, 0.19 mmol) in N,N -dimethylformamide (3 mL) was subjected to stirring at 25oC for 16 H. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonium hydroxide in water) to give N -[(3S)-5-methyl - 4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] - 1 -tetrahydropyran -4 -yl -pyrazolo [3,4 -d] pyrimidine -6 -carboxamide (37.61 mg, 73 %) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ9.48 (s, 1H), 9.14 (d, J = 6.4 Hz, 1H), 8.54 (s, 1H), 7.54 - 7, 52 (m, 1H), 7.35 - 7.28 (m, 3H), 5.17 - 5.10 (m, 1H), 4.90 - 4.79 (m, 1H), 4.62 - 4.50 (m, 2H), 4.03 - 4.00 (m, 2H), 3.62 - 3.56 (m, 2H), 3.34 (s, 3H), 2.24 - 2, 15 (m, 2H), 1.94 - 1.91 (m, 2H). LCMS RT = 0.762 min.; m/z = 423.1 (M+H)+. LCMS (5 - 95% acetonitrile in water + 0.05% trifluoroacetic acid for 1.5 min.) retention time 0.762 min., ESI+ found [M+H] = 423.1. Example 559 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -tetrahydropyran - 4 -yl -pyrazole [3,4 -d] pyrimidine -6 - carboxamide

[01876] Amide coupling prepared in a manner similar to Method WX 149. The crude product was purified via RP-HPLC (17% to 47% acetonitrile/0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -tetrahydropyran -4 -yl - pyrazolo [3,4 -d] pyrimidine -6 -carboxamide (38.5 mg, 74%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ9.47 (s, 1H), 9.16 (d, J = 8.0 Hz, 1H), 8.53 (s, 1H), 6.16 (s, 1H), 5.19 - 5.15 (m, 1H), 4.43 - 4.40(m, 1H), 4.29 - 4.25(m, 1H), 4.21 - 4.11 ( m, 1H), 4.04 - 3.99 (m, 2H), 3.63 - 3.56 (m, 2H), 3.25(s, 3H), 2.74 - 2.69 (m, 1H), 2.50 - 2.49 (m, 1H), 2.22 - 2.18 (m, 5H), 1.94 - 1.91 (m, 2H). LCMS RT = 0.705 min.; m/z = 425.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.792 min., ESI+ found [M+H] =425.1. Example 560

[01877] WX Method 057 1 -[(1-methylcyclobutyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: (1-methylcyclobutyl)methanol

[01878] To a solution of 1-methylcyclobutane carboxylic acid (300 mg, 2.63 mmol) in tetrahydrofuran (10 mL) was added LiAlH4 (249 mg, 6.57 mmol) under 0oC. The reaction mixture was stirred at 25oC for 16 h and then finished by adding water (1.0 mL) and 15% aqueous sodium hydroxide (0.3 mL). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude (1-methylcyclobutyl)methanol (260 mg, 99%) as a colorless oil, which was used in the next step in its present form. . Step 2: (1-Methylcyclobutyl)methyl 4-methylbenzene Sulfonate

[01879] To a solution of 4-dimethylamino pyridine (634 mg, 5.19 mmol) in dichloromethane (10 mL) was added p-toluene sulfonyl chloride (594 mg, 3.12 mmol) and (1-methylcyclobutyl) methanol (260 mg, 2.60 mmol). The reaction mixture was stirred at 20oC for 16 h and then finished by adding water (10 mL). The mixture was extracted with ethyl acetate (3 x 20mL). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide methyl (1-methylcyclobutyl)4-methylbenzene sulfonate (500 mg, 76 %) in the form of a colorless oil, which was used in the next step as it was. Step 3: 1-(bromomethyl)-1-methylcyclobutane

[01880] A mixture of lithium bromide (598 mg, 6.88 mmol) and methyl (1-methylcyclobutyl)4-methylbenzene sulfonate (350 mg, 1.38 mmol) in acetone (15 mL) was heated at 70oC for 4 h. After cooling, the mixture was diluted with water (20mL) and extracted with ethyl acetate (3 x 20mL). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 1-(bromomethyl)-1-methyl-cyclobutane ( 120mg, 54%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 4: 1 -[(1-methylcyclobutyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01881] A mixture of N -[(6S) -2,4 -dimethyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1H -1,2,4 -triazole -3 -carboxamide (30 mg, 0.10 mmol), 1 -(bromomethyl) -1 -methyl -cyclobutane (25 mg, 0.16 mmol) and potassium carbonate (43 mg , 0.31 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20°C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to give 1-[(1-methylcyclobutyl)methyl]-N - (6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole - 3-carboxamide (7.5 mg, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.47 (s, 1H), 6.12 (s, 1H), 4.57 - 4.52 (m, 1H), 4.35 - 4.23 (m, 4H ), 3.34 (s, 3H), 2.91 - 2.87 (m, 1H), 2.29 - 2.26 (m, 4H), 2.13 - 2.08 (m, 2H), 1.96 - 1.92 (m, 1H), 1.87 - 1.83 (m, 1H), 1.77 - 1.72 (m, 2H), 1.10 (s, 3H). LCMS RT = 0.637 min.; m/z = 372.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.637 min., ESI+ found [M+H] = 372.0. Example 561 1 -[(1-methylcyclobutyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01882] N -Alkylation prepared in a similar manner to Method WX 057. The crude product was purified via RP-HPLC (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(1-methylcyclobutyl) methyl] -N -(6S) -2 -cyclopropyl -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6-yl -1,2,4 -triazole -3 -carboxamide (12 mg, 17%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.49 (s, 1H), 6.01 (s, 1H), 4.56 - 4.51 (m, 1H), 4.32 - 4.21 (m, 4H ), 3.32 (s, 3H), 2.89 - 2.83 (m, 1H), 2.28 - 2.24 (m, 1H), 2.12 - 2.08 (m, 2H), 1.95 - 1.90 (m, 3H), 1.77 - 1.73 (m, 2H), 1.10 (s, 3H), 0.95 - 0.93 (m, 2H), 0, 74 - 0.72 (m, 2H). LCMS RT = 0.727 min.; m/z = 398.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.727 min., ESI+ found [M+H] = 398.0. Example 562

[01883] WX Method 136 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl]spiro[5,6 -dihydro -[1,2,4] triazole [5, 1 -c][1,4] oxazine -8,1' -cyclopentane] -2 -carboxamide Step 1: 1-[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]cyclopentanol

[01884] To a solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2 g, 5.6 mmol) in tetrahydrofuran (10 mL) was added n - butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) under -78oC. The mixture was stirred at -78°C for 1 h, then a solution of cyclopentanone (1.2 g, 14.3 mmol) in tetrahydrofuran (2 mL) was added dropwise. After addition, the reaction mixture was stirred at -78oC for 1 h and finalized by addition of saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 1 - [5 -bromo -2 -(2 -tetra hydropyran -2 -yloxyethyl)-1,2,4-triazol-3-yl]cyclopentanol (1.5 g, 72%) as a colorless oil. LCMS RT = 0.790 min., m/z = 361.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.790 min., ESI+ found [M+H] = 361.8. Step 2: 1-[5-bromo-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopentanol

[01885] To a solution of 1 - [5 - bromo -2 - (2 - tetrahydropyran -2 -yloxyethyl) -1,2,4 - triazol -3 -yl] cyclopentanol (200 mg, 0.56 mmol) in methanol (10 mL) was added p -toluenes sulfonic acid (191 mg, 1.11 mmol). The mixture was stirred at 20°C for 2 h and concentrated under reduced pressure to provide crude 1-[5-bromo-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopentanol (250 mg, 110%) in the form of a colorless oil. LCMS RT = 0.423 min., m/z = 275.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.423 min., ESI+ found [M+H] =275.9. Step 3: 2-[3-bromo-5-(1-hydroxycyclopentyl)-1,2,4-triazol-1-yl]ethyl 4-methyl benzene sulfonate

[01886] A mixture of 1-[5-bromo-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl] cyclopentanol (250 mg, 0.91 mmol), 4-dimethylaminopyridine (11 mg , 0.09 mmol), trimethylamine (0.63 mL, 4.53 mmol) and p -toluene sulfonyl chloride (190 mg, 1 mmol) in dichloromethane (5 mL) was stirred under 19oC for 4 h. The mixture was concentrated under reduced pressure and the residue was purified by prep TLC (ethyl acetate:petroleum ether = 1:3, Rf = 0.6) to give 2-[3-bromo-5-( 1-hydroxycyclopentyl)-1,2,4-triazol-1-yl] ethyl 4-methylbenzene sulfonate (180 mg, 46%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 4: 2 -bromospiro [5,6 -dihydro -[1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' -cyclopentane]

[01887] To a solution of 2-[3-bromo-5-(1-hydroxycyclopentyl)-1,2,4-triazol-1-yl]ethyl 4-methylbenzene sulfonate (180 mg, 0.420 mmol) in tetrahydrofuran ( 40mL) lithium bis(trimethylsilyl) amide (1.0N in tetrahedron, 0.84mL, 0.84mmol) was added under -70oC. The mixture was stirred at -70°C for 1 h and then allowed to warm to 20°C for 12 h. The reaction mixture was finished by adding water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep TLC (33% ethyl acetate in petroleum ether, Rf = 0.5) to give 2-bromospiro[5,6-dihydro-[1,2,4]triazole[5 ,1-c][1,4] oxazine -8,1'-cyclopentane] (70mg, 65%) as a yellow solid. LCMS RT = 0.646 min., m/z = 257.7 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.646 min., ESI+ found [M+H] =257.7. Step 5:

[01888] ethyl spiro [5,6 -dihydro -[1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' -cyclopentane] -2 - carboxylate

[01889] A mixture of 2-bromospiro [5,6 - dihydro -[1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' - cyclopentane] (60 mg, 0 .23 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (17 mg, 0.02 mmol) and triethylamine (0.26 mL, 2.32 mmol) in methanol (20 mL) was heated under 70oC under CO [3.42 bar (35 psi)] for 20 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep TLC (ethyl acetate:petroleum ether = 1:2, Rf = 0.3) to give methyl spiro[5,6-dihydro-[ 1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' -cyclopentane] -2 -carboxylate (52 mg, 89%) in the form of a yellow oil. 1H NMR (400 MHz, CD3OD) δ4.30 - 4.25(m, 2 H), 4.16 - 4.10 (m, 2 H), 3.94 (s, 3 H), 2.19 - 2.07 (m, 4 H) 1.95 - 1.84 (m, 4 H). LCMS RT = 0.602 min., m/z = 237.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 0.602 min., ESI+ found [M+H] = 237.8. Step 6: spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1'-cyclopentane]-2-carboxylic acid

[01870] A mixture of methyl spiro [5,6 -dihydro - [1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' -cyclopentane] -2 -carboxylate (52 mg, 0.22 mmol) and lithium hydroxide (16 mg, 0.66 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was stirred under 18oC for 2 h. The mixture was adjusted to pH = 3 by adding 1N HCl. The mixture was concentrated under reduced pressure to provide spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1'-cyclopentane]-2 acid. -crude carboxylic acid (48 mg, 98%) in the form of a colorless oil. LCMS RT = 0.514 min., m/z = 223.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.514 min., ESI+ found [M+H] =223.8. Step 7: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] spiro [5,6 -dihydro -[1,2,4] triazole [5,1 -c][1,4] oxazine -8,1' -cyclopentane] -2 -carboxamide

[01871] A mixture of spiro [5,6 -dihydro - [1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' -cyclopentane] -2 -carboxylic acid (24 mg, 0.11 mmol), 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.22 mmol), (3S)-3-amino-5-methyl-2,3-dihydro- 1,5-Benzoxazepin-4-one (21 mg, 0.11 mmol) and 1-hydroxybenzotriazole (29 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL) was stirred at 20oC for 12 H. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (40% to 70% acetonitrile/0.05% ammonium hydroxide in water) to give N - [(3S) -5 -methyl - 4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]spiro[5,6 -dihydro -[1,2,4] triazolo [5,1 -c][1,4] oxazine - 8,1'-cyclopentane]-2-carboxamide (24.2 mg, 57%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.45 - 7.42 (m, 1H), 7.32 - 7.30 (m, 2H), 7.257.23 (m, 1H), 5.02 - 5.00 (m, 1H), 4.62 - 4.58 (m, 1H), 4.45 - 4.41 (m, 1H), 4.27 - 4.25(m, 2H), 4.13 - 4 .11 (m, 2H), 3.42 (s, 3H), 2.16 - 2.14 (m, 4H), 1.91 - 1.90 (m, 4H). LCMS RT = 0.807 min., m/z = 398.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.807 min., ESI+ found [M+H] =398.1. Example 563

[01872] WX Method 146 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -1 -tetrahydropyran -3 -yl -pyrazolo [3,4 -d] pyrimidine -6 -carboxamide Step 1: 6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine

[01873] To a solution of 6-chloro-1H-pyrazolo [3,4-d] pyrimidine (1.0 g, 6.47 mmol), triphenylphosphine (2.5 g, 9.7 mmol) and tetrahydro -2h -pyran-3-ol (661 mg, 6.47 mmol) in tetrahydrofuran (5 ml) was added diisopropyl azodicarboxylate (1.9 g, 9.7 mmol). The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 6-chloro-1-(tetrahydro-2H-pyran-3-yl ) - 1H -pyrazole [3,4-d] pyrimidine (1.5 g, 97%) as a white solid. LCMS RT = 1.07 min., m/z = 239.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 1.07 min., ESI+ found [M+H] = 239.2. Step 2: 1 -(tetrahydro -2H -pyran -3 -yl) -1H - pyrazole [3,4 -d] pyrimidine -6 -carbonitrile

[01874] To a solution of 6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.09 mmol) in dimethyl sulfoxide ( 20mL) sodium cyanide (205 mg, 4.19 mmol) in water (10 mL) was added. The mixture was heated at 40°C for 3 h and diluted with water (100 ml). The solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 1 -(tetrahydro -2H -pyran -3 -yl) -1H - pyrazole [3,4-d] pyrimidine-6-carbonitrile (120mg, 25%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 3: methyl 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

[01875] To a solution of 1 -(tetrahydro -2H -pyran - 3 -yl) -1H -pyrazolo [3,4 -d] pyrimidine -6 -carbonitrile (120 mg, 0.52 mmol) in methanol (10 mL ) HCl (4N in methanol, 3 mL) was added. The mixture was stirred at 50°C for 24 h and concentrated under reduced pressure to provide methyl 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (110 mg, 80%) as a yellow solid. LCMS RT = 0.97 min., m/z = 263.3 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.97 min., ESI+ found [M+H] = 263.3. Step 4: 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[01876] A mixture of methyl 1 -(tetrahydro -2H - pyran -3 -yl) -1H -pyrazolo [3,4 -d] pyrimidine -6 - carboxylate (100 mg, 0.38 mmol) and lithium hydroxide ( 46 mg, 1.91 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25oC for 4 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH = 2 by addition of 1N HCl. The mixture was extracted with ethyl acetate (2 x 20mL). The combined organics were concentrated under reduced pressure to provide crude 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (70mg, 74%) in form of a white solid, which was used in the next step in the form in which it was. LCMS RT = 0.85 min., m/z = 249.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.85 min., ESI+ found [M+H] = 249.2. Step 5: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 -tetrahydropyran -3 -yl - pyrazole [3,4 - d] pyrimidine -6 -carboxamide

[01877] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (23 mg, 0.12 mmol), 1 -tetrahydropyran acid -3 -ylpyrazole [3,4 -d] pyrimidine -6 -carboxylic acid (30 mg, 0.12 mmol), N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (35 mg, 0.18 mmol), 1H -benzo [d][1,2,3] triazol -1 -ol (25mg, 0.19 mmol) in N,N -dimethylformamide (3 mL) was subjected to stirring at 25oC for 16 H. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (50% to 80% acetonitrile/0.05% ammonium hydroxide in water) to give N -[(3S)-5-methyl - 4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] - 1 -tetrahydropyran -3 -yl -pyrazolo [3,4 -d] pyrimidine -6 -carboxamide (14.0 mg, 27 %) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 9.36 (s, 1H), 8.38 (s, 1H), 7.47 - 7.44 (m, 1H), 7.34 - 7.27 (m, 3H), 5.17 - 5.11 (m, 2H), 4.75 - 4.65 (m, 1H), 4.58 - 4.40 (m, 1H), 4.15 - 3.85 ( m, 3H), 3.65 - 3.53 (m, 1H), 3.45 (s, 3H), 2.40- 2.33 (m, 1H), 2.25- 2.21 (m, 1H), 1.98 - 1.91 (m, 2H). LCMS RT = 0.70min., m/z = 423.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.70min., ESI+ found [M+H] = 423.0. Example 564 7 -methyl -7 -propyl -N -[(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 - il] -5H -furo[3,4 -d] pyrimidine -2 -carboxamide

[01878] Amide coupling prepared in a manner similar to WX Method N. The crude product was purified via RP-HPLC (26% to 56% acetonitrile/0.05% ammonium hydroxide in water) 7-methyl - 7 -propyl -N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5H -furo[3,4 -d] pyrimidine -2 - carboxamide (43 mg .41%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.82 (s, 1H), 6.13 (s, 1H), 5.20- 5.12 (m, 2H), 4.62 - 4.55 (m, 1H ), 4.37 - 4.21 (m, 2H), 3.36 (s, 3H), 3.00 - 2.90 (m, 1H), 2.31 - 2.25(m, 4H), 1.95 - 1.79 (m, 2H), 1.49 - 1.40(m, 4H), 1.08 - 0.95 (m, 1H), 0.87 (t, J = 6.8 Hz, 3H). LC -MS RT = 1.546 min., m/z = 395.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide for 3.0 min.) retention time 1.546 min., ESI+ found [M+H] = 395.2. Example 565 N -[(6S)-4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] spiro [5H -furo [3, 4 -d] pyrimidine -7,1' -cyclopentane] -2 -carboxamide

[01879] Amide coupling prepared in a similar manner to Method WX 136, The crude product was purified via RP-HPLC (17% to 47% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7,1'-cyclopentane] -2-carboxamide (35.6 mg, 41%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.79 (s, 1H), 7.54 (s, 1H), 6.32 (s, 1H), 5.11 (s, 2H), 4.59 - 4, 57 (m, 1H), 4.55 - 4.43 (m, 1H), 4.33 - 4.31 (m, 1H), 3.38 (s, 3H), 3.00 - 2.95 ( m, 1H), 2.33 - 2.28(m, 1H), 2.07 - 2.03 (m, 4H), 1.94 - 1.92 (m, 4H). LC -MS RT = 0.720min., m/z = 383.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.720min., ESI+ found [M+H] = 383.1. Example 566 7 -methyl -7 -propyl -N -[(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 5H -furo[3,4 -d] pyrimidine -2 -carboxamide

[01880] Amide coupling prepared in a manner similar to Method WX N. The crude product was purified via RP-HPLC (19% to 49% acetonitrile / 0.05% ammonium hydroxide in water) to provide 7 - methyl -7 -propyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 5H -furo[3,4 - d] pyrimidine -2 -carboxamide (32.6 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.82 (s, 1H), 7.55 (d, J = 2.4 Hz,1H), 6.33 (s, 1H), 5.20- 5.12 ( m, 2H), 4.60 - 4.55 (m, 1H), 4.49 - 4.43 (m, 1H), 4.36 - 4.28 (m, 1H), 3.39 (s, 3H), 3.03 - 2.92 (m, 1H), 2.35 - 2.28 (m, 1H), 1.96 - 1.79 (m, 2H), 1.49 - 1.40( m, 4H), 1.08 - 0.95 (m, 1H), 0.87 (t, J = 6.8 Hz, 3H). LC -MS RT = 1.473 min., m/z = 385.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide for 3.0 min.) retention time 1.473 min., ESI+ found [M+H] = 385.2. Example 567 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] spiro [5,6 - dihydro -[1,2,4] triazolo [5,1 -c][1,4] oxazine -8,1' - cyclopentane] -2 -carboxamide

[01881] Amide coupling prepared in a manner similar to Method WX 136. The crude product was purified via RP-HPLC (13% to 43% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl]spiro[5,6 -dihydro -[1,2,4] triazolo [5,1 -c][1,4]oxazine -8,1' -cyclopentane] -2 - carboxamide (32.9 mg, 77%), in the form of a colorless oil . 1H NMR (400 MHz, DMSO -d6) δ8.46 (d, J = 7.2 Hz, 1H), 6.13 (s, 1H), 4.40- 4.20(m, 4H), 4, 16 - 4.03 (m, 3H), 3.22 (s, 3H), 2.63 - 2.54 (m, 1H), 2.39 - 2.30 (m, 1H), 2.17 ( s, 3H), 2.11 - 1.96 (m, 4H), 1.87 - 1.43 (m, 4H). LCMS RT = 0.724 min., m/z = 400.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 0.724 min., ESI+ found [M+H] = 400.1. Example 568

[01882] WX 118 Method 8 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -[1,2,4] triazolo [1,5 -a ] pyridine -2 -carboxamide Step 1: ethyl N -[(3-bromo-2-pyridyl) carbamothioyl] carbamate

[01883] To a solution of 3-bromo-2-pyridinamine (10.0 g, 57.8 mmol) in 1,4-dioxane (50 mL) was added ethoxycarbonyl isothiocyanate (9.1 g, 69.4 mmol) . The reaction mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The resulting solid was triturated in ether, filtered and dried to provide crude ethyl N -[(3-bromo-2-pyridyl) carbamothioyl] carbamate (10.6 g, 60%) as a solid colored light yellow. LCMS RT = 0.728 min., m/z = 305.7 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.728 min., ESI+ found [M+H] = 305.7. Step 2: 8 -bromo -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01884] To a solution of N,N-diisopropylethylamine (13.51 g, 104.53 mmol) in methanol (300 mL) and ethanol (30 mL) was added hydroxylamine hydrochloride (12.11 g, 174.27 mmol ). The mixture was stirred at 25oC for 30 min. and then ethyl N -[(3-bromo-2-pyridyl) carbamothioyl] carbamate (10.6 g, 34.85 mmol) was added. The resulting mixture was heated at 65°C for 16 h and concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (30 ml) and filtered. The filtrate was washed with water (30 mL), dried over sodium sulfate and concentrated to provide crude 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine ( 4.1 g, 55%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: 8 -phenyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine

[01885] A mixture of 8-bromo-[1,2,4] triazolo [1,5-a] pyridin-2-amine (4.1 g, 19.25 mmol), phenylboronicated (3.52 g, 28 .87 mmol), tetrakis (triphenylphosphine) palladium(0) (2.22 g, 1.92 mmol) and sodium bicarbonate (4.85 g, 57.73 mmol) in 1,4-dioxane (35 mL) and water (7 mL) was heated under 150oC for 10 min. under microwave conditions. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (300 mL) and filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 60% ethyl acetate in petroleum ether) to provide 8-phenyl-[1,2,4]triazole[1,5 -a] pyridin-2-amine (3.0 g, 74%) in the form of a yellow solid, which was used in the next step in the form in which it was. LCMS RT = 0.593min., m/z = 210.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.593 min., ESI+ found [M+H] = 210.9. Step 4: 2 -iodine -8 -phenyl -[1,2,4] triazole [1,5 -a] pyridine

[01886] To a suspension of 8 -phenyl -[1,2,4] triazolo [1,5 -a] pyridin -2 -amine (100 mg, 0.48 mmol) and p -toluenesulfonic acid monohydrate (343 mg , 1.81 mmol) in acetonitrile (8 mL) was added a solution of potassium iodide (261 mg, 1.57 mmol) and sodium nitrite (82 mg, 1.19 mmol) in water (2 mL) under 13oC . After addition, the reaction mixture was stirred at 13°C for 10 h and then diluted with ethyl acetate (20 mL). The separated organic layer was washed with water (2 x 10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -30% ethyl acetate in petroleum ether) to give 2 -iodine -8 - phenyl -[1,2,4] triazolo [1,5 -a] pyridine (100 mg, 65%) in the form of a yellow solid, was used in the next step in the form in which it was. LCMS RT = 0.845 min., m/z = 321.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.845 min., ESI+ found [M+H] = 321.8. Step: 5: 8 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -[1,2,4] triazole [1 ,5 -a] pyridine -2 -carboxamide

[01887] A mixture of 2 -iodo -8 -phenyl -[1,2,4] triazolo [1,5 -a] pyridine (30 mg, 0.09 mmol), (3s) -3 - amino -5 - methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (18 mg, 0.09 mmol), 4,5 -bis(diphenylphosphine) -9,9 - dimethylxanthenone (8 mg, 0.01 mmol) , triethylamine (61 mg, 0.61 mmol) and palladium diacetate (2 mg, 0.01 mmol) in toluene (2 mL) was heated at 80°C under CO atmosphere [2.05 bar (15 psi)] for 5 H. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RR-HPLC (40% to 70% acetonitrile/0.05% ammonium hydroxide in water) to provide 8-phenyl-N-[(3S)-5-methyl-4-oxo- 2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (5.7 mg, 9%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.83 - 8.77 (m, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.94 - 7.88 (m, 1H), 7.57 - 7.51 (m, 2H), 7.50 - 7.42 (m, 2H), 7.40- 7.28 (m, 3H), 7.27 - 7.21 (m, 1H) ), 5.12 - 5.04 (m, 1H), 4.67 - 4.62 (m, 1H), 4.52 - 4.46 (m, 1H), 3.43 (s, 3H). LCMS RT = 0.851 min., m/z = 414.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.851 min., ESI+ found [M+H] = 414.1. Example 569

[01888] Method WX 041 1 -[(3,3-difluorocyclopentyl) methyl] -N -(6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: (3,3-difluorocyclopentyl)methanol

[01889] To a mixture of LiAlH4 (253 mg, 6.66 mmol) in tetrahydrofuran (10 mL) was added 3,3-difluorocyclopentane carboxylic acid (500 mg, 3.33 mmol) in tetrahydrofuran (4 mL) under 0oC. the reaction mixture was subjected to stirring at 25oC for 18 h and then finished by adding water (0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.3 mL). The resulting mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude (3,3-difluorocyclopentyl)methanol (320 mg, 71%) as an oil. colorless, which was used in the next step as it was. Step 2: (3,3-difluorocyclopentyl)methyl 4-methylbenzene sulfonate

[01890] To a solution of (3,3-difluorocyclopentyl) methanol (300 mg, 2.20 mmol) in dichloromethane (10 mL) was added 4-dimethyl aminopyridine (323 mg, 2.64 mmol) and 4 - methyl benzene-1-sulfonyl (504 mg, 2.64 mmol) under 0oC. After addition, the reaction mixture was stirred at 25°C for 18 h and finalized by adding water (10 mL). The mixture was extracted with dichloromethane (2 x 20 ml). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide (3,3-difluorocyclopentyl)methyl 4-methylbenzene sulfonate (300 mg, 47 %) in the form of a colorless oil, which was used in the next step as it was. Step 3: 1,1-difluoro-3-(iodomethyl)cyclopentane

[01891] A mixture of (3,3-difluorocyclopentyl) methyl 4-methylbenzene sulfonate (100 mg, 0.34 mmol) and sodium iodide (154 mg, 1.03 mmol) in acetone (5 mL) was heated at 40oC for 18 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL) and washed with water (3 x 20 mL), saline (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated to provide 1,1-difluoro- 3 - crude (iodomethyl) cyclopentane (84 mg, 99%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 4: 1 -[(3,3-difluorocyclopentyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[01892] A mixture of 1,1-difluoro-3-(iodomethyl)cyclopentane (76 mg, 0.31 mmol), N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - il] -1H -1,2,4 -triazole -3 -carboxamide (45 mg, 0.16 mmol) and potassium carbonate ( 64 mg, 0.47 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (0-40% acetonitrile/0.05% ammonium hydroxide in water) to give 1-[(3,3-difluorocyclopentyl)methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 - triazole -3 - carboxamide (14 mg, 22%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.50 (s, 1H), 6.11 (s, 1H), 4.59 - 4.51 (m, 2H), 4.31 - 4.27 (m, 2H ), 4.26 - 4.18 (m, 1H), 3.33 (s, 3H), 2.94 - 2.69 (m, 3H), 2.25(s, 3H), 2.22 - 1.84 (m, 5H), 1.63 - 1.53 (m, 1H). LC -MS RT = 1.512 min., m/z = 408.2 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.512 min., ESI+ found [M+H] = 408.2. Example 570

[01893] Method WX 083 1 -benzyl -N -(6S) -2 -(1 -fluorocyclopropyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: Butyl 1-fluorocyclopropane carboxylate

[01894] To a solution of 1-fluorocyclopropane carboxylic acid (6.00 g, 57.65 mmol) in acetonitrile (60 mL) was added DBU (9.65 g, 63.41 mmol) and 1-iodobutane (11. 67 g, 63.41 mmol) dropwise under 0oC. The resulting mixture was stirred at 25°C for 12 h and finalized by adding water (100 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude butyl 1-fluorocyclopropane carboxylate (7.5 g, 81%) as a yellow oil, which was used in the step next in the form in which it was. Step 2: 3-(1-fluorocyclopropyl)-3-oxopropane nitrile

[01895] To a solution of acetonitrile (3.0 mL, 51.5 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexane, 21.0 mL, 51.5 mmol) dropwise the drop under -78oC. The resulting mixture was stirred at the same temperature for 30 minutes and butyl 1-fluorocyclopropane carboxylate (7.5 g, 46.8 mmol) was added. After addition, the reaction mixture was stirred at room temperature for 2 h and then quenched by addition of saturated ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude 3-(1-fluorocyclopropyl)-3-oxopropanenitrile (3.7 g, 62%) as a yellow oil. , which was used in the next stage as it was. Step 3: 5-(1-fluorocyclopropyl)-1H-pyrazole 3-amine

[01896] A mixture of 3-(1-fluorocyclopropyl)-3-oxopropanenitrile (3.7 g, 29.11 mmol) and hydrazine hydrate (50 mL) in propan-2-ol (30 mL) was heated at 80oC for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to give 5-(1-fluorocyclopropyl)-1H-pyrazol-3-amine (0.75 g , 18%) in the form of a yellow oil. LCMS RT = 0.95 min., m/z = 142.1 [M + H]+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 minutes) retention time 0.95 min., ESI+ found [M+H] = 142.1. Step 4: N -(5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl)formamide

[01897] A mixture of 5-(1-fluorocyclopropyl)-1H-pyrazole-3-amine (750 mg, 5.31 mmol) and formic acid (15 mL) was heated at 110oC for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide N -[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]formamide (600 mg, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO -d6) δ12.69 (br. s, 1H), 10.56 (br. s, 1H), 8.15 (s, 1H), 6.46 (s, 1H), 1.45 - 1.36 (m, 2H), 1.09 - 1.07 (m, 2H). Step 5: 5-(1-fluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine

[01898] To a stirred solution of N -[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]formamide (600 mg, 3.55 mmol) in tetrahydrofuran (10 mL) was added borane (10 M in Me2S, 1.8 mL, 18.0 mmol) under 0oC. After addition, the mixture was stirred for 2 h at 0°C and then finalized by adding methanol (10 mL). The mixture was stirred for 30 min. and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to obtain 5-(1-fluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine ( 380 mg, 69%) in the form of a yellow oil. LCMS RT = 1.44 min., m/z = 156.1 [M + H]+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3.0 min.) retention time 1.44 min., ESI+found [M+H] = 156.1. Step 6: 4-chloro-N-(5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

[01899] A mixture of 5-(1-fluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (380 mg, 2.45 mmol) and 4-chlorobutanoyl chloride (2 mL) was heated at 60oC for 2 .5 h and then finished by adding methanol (10 mL). The mixture was stirred for 30 min. and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 4-chloro-N-[5-(1-fluorocyclopropyl)-1H-pyrazole-3 -yl]-N-methyl-butanamide (450 mg, 70%) as a yellow oil. LCMS RT = 0.75 min., m/z = 259.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.75 min., ESI+found [M+H] = 259.9. Step 7: 2 -(1-fluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[01900] A mixture of 4-chloro-N-[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (400 mg, 1.54 mmol) and cesium carbonate (1 .0 g, 3.08 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to give 2-(1-fluorocyclopropyl)-4-methyl - 7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (180 mg, 52%) in the form of a yellow oil. 1H NMR (400 MHz, CDCI3) δ6.09 (s, 1H), 4.19 - 4.15 (m, 2H), 3.24 (s, 3H), 2.42 - 2.35 (m, 2H) ), 2.34 - 2.25(m, 2H), 1.41 - 1.31 (m, 2H), 1.12 - 1.04 (m, 2H). Step 8: 2 -(1-fluorocyclopropyl) -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5a][1,3] diazepin -5(6H) –one

[01901] To a stirred solution of 2 -(1-fluorocyclopropyl) -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (180 mg, 0.81 mmol) in dichloromethane (15 mL) was added N1,N1,N2,N2 - tetramethylethane -1,2 -diamine (937 mg, 8.06 mmol) and iodotrimethylsilane (1.6 g, 8.06 mmol) under -15oC. The mixture was stirred at -15°C for 1.5 h, then iodine (614 mg, 2.42 mmol) was added. The mixture was stirred for another 3 h and then finalized by the addition of 50% aqueous sodium thiosulfate (10 mL). The mixture was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine (2 x 20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 2 -(1-fluorocyclopropyl) -6 -iodo -4 -methyl - 7.8 - dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (150 mg, 53%) in the form of a light yellow oil. 1H NMR (400 MHz, CDCl3) δ6.13 (s, 1H), 4.58 - 4.54 (m, 1H), 4.19 - 4.10 (m, 2H), 3.29 (s, 3H ), 2.94 - 2.83 (m, 1H), 2.75 - 2.65 (m, 1H), 1.39 - 1.32 (m, 2H), 1.12 - 1.02 (m , 2H). LCMS RT = 2.07 min., m/z = 350.0 [M + H]+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 2.07 min., ESI+ found [M+H] = 350.0. Step 9: 6 -azide -2 -(1-fluorocyclopropyl) -4 - methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin - 5(6H) -one

[01902] A mixture of 2 -(1-fluorocyclopropyl) -6 -iodo -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (150 mg, 0.43 mmol) and sodium azide (57 mg, 0.87 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 12 h. The reaction mixture was finished by adding 20% aqueous sodium hypochlorite (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 20mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-azide-2-(1-fluorocyclopropyl)-4-methyl-7.8- crude dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (105 mg, 93%) as a yellow oil. Step 10: 6 -amino -2 -(1-fluorocyclopropyl) -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin - 5(6H) -one

[01903] To a solution of 6 -azide -2 -(1 - fluorocyclopropyl) -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one ( 60 mg, 0.23 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 80% polymer-binding triphenylphosphine (357 mg). The reaction mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 6-amino-2-(1-fluorocyclopropyl)- 4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (50 mg, 92%) in the form of a light yellow oil. LCMS RT = 1.48 min., m/z = 239.1 [M + H]+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.48 min., ESI+ found [M+H] = 239.1. Step 11: 1 -benzyl -N -(6S) -2 -(1 - fluorocyclopropyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01904] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (51 mg, 0.25 mmol), 6-amino-2-(1-fluorocyclopropyl)-4-methyl-7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg, 0.21 mmol), N,N -dimethyl -3(methylimino ethylmino methylene acetate) hydrochloride propan -1-amine (56 mg, 0.31 mmol) and 1-hydroxybenzotrizole (43 mg, 0.31 mmol) in N,N-dimethylformamide (3 mL) were stirred at 25oC for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (0% to 40% acetonitrile, 0.05% ammonium hydroxide in water) to give 1 -benzyl -N -2 -(1 - fluorocyclopropyl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide ( 60 mg, 67%) as a white solid. This material was separated using chiral SFC to provide:

[01905] 1 -benzyl -N -(6S) -2 -(1 - fluorocyclopropyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazol -3 - carboxamide (Peak 1, retention time 3.77 min.) (8 mg, 13%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.56 (s, 1H), 7.41 - 7.28 (m, 5H), 6.37 (s, 1H), 5.46 (s, 2H), 4, 56 - 4.53 (m, 1H), 4.39 - 4.31 (m, 1H), 4.29 - 4.20(m, 1H), 3.34 (s, 3H), 2.84 ( m, 1H), 2.26 (m, 1H), 1.42 - 1.34 (m, 2H), 1.18 - 1.07 (m, 2H). LCMS RT = 1.672 min., m/z = 424.2 (M + H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.672 min., ESI+ found [M+H] = 424.2.

[01906] SFC Conditions: Column: Chiralcel AD -3 50 x 4.6 mm I.D., 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min. and held at 40% for 2.5 min., then 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 4.0 mL/min. Column temperature: 40oC). Examples 571, 572 and 573

[01907] WX 115 Method

[01908] 7-phenyl -N -[(3S) -5 -methyl -4 -oxo - 2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H - pyrrole [1 ,2 -b][1,2,4] triazole -2 -carboxamide and

[01909] (7S) -7 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide and

[01910] (7R) -7 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01911] Amide coupling prepared in a manner similar to Method WX 113 (RIP1K_experimental_3rd_WX.doc). The crude product was purified by PR-HPLC (22% to 52% acetonitrile, 0.05% ammonium hydroxide in water) to provide 7-phenyl-N-[(3S)-5-methyl-4- oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide (5, 5 mg, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.45 - 7.41 (m, 1H), 7.39 - 7.26 (m, 7H), 7.25 - 7.21 (m, 1H), 5.02 - 4.97 (m, 1H), 4.60 - 4.52 (m, 2H), 4.45 - 4.35 (m, 2H), 4.32 - 4.22 (m, 1H), 3 .40(s, 3H), 3.28 - 3.23 (m, 1H), 2.76 - 2.67 (m, 1H). LCMS RT = 1.017 min., m/z = 404.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.017 min., ESI+ found [M+H] = 404.3.

[01912] Another batch of racemic material (60 mg) was separated using chiral SFC to provide:

[01913] (7S) -7 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (Peak 1, retention time = 3.325min.) (18.3 mg, 30%) as white solids. 1H NMR (400 MHz, CD3OD) δ7.42 - 7.22 (m, 9H), 5.00 - 4.87 (m, 1H), 4.61 - 4.53 (m, 2H), 4.42 - 4.39 (m, 2H), 4.37 - 4.28 (m, 1H), 3.40(s, 3H), 3.28 - 3.25(m, 1H), 2.76 - 2 .70(m, 1H). LCMS RT = 1.011 min., m/z = 404.4 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.011 min., ESI+ found [M+H] = 404.4.

[01914] (7R) -7 -phenyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2-b][1,2,4] triazole -2 -carboxamide (Peak 2, retention time = 3.439 min.) (16.1 mg, 27%) as a white solid . 1H NMR (400 MHz, CD3OD) δ7.41 - 7.24 (m, 9H), 5.00 - 4.97 (m, 1H), 4.60 - 4.54 (m, 2H), 4.42 - 4.39 (m, 2H), 4.37 - 4.28 (m, 1H), 3.41 (s, 3H), 3.28 - 3.25(m, 1H), 2.76 - 2 .69 (m, 1H). LCMS RT = 1.006 min., m/z = 404.4 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.006 min., ESI+ found [M+H] = 404.4.

[01915] SFC Condition: Column: Chiralcel IC - 3 150x4.6 mm ID, 3 µm Mobile phase: 40% iso-propanol (0.05% DEA) in CO2 Flow rate: 2.5 mL / min. Column temperature: 40oC. Examples 574 and 575 7 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6 ,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide and (7S) -7 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H -pyrrole [1,2 -b][1, 2,4] triazole -2 - carboxamide

[01916] Amide coupling prepared in a manner similar to Method WX 113 (RIP1K_experimental_3rd_WX.doc). The crude product was purified by PR-HPLC (22% to 52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 7 - phenyl -N -[(6S) -2,4 -dimethyl - 5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 -dihydro -5H - pyrrole [1,2 -b][1 ,2,4] triazole-2-carboxamide (6.2 mg, 29%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.39 - 7.25 (m, 5H), 6.11 (s, 1H), 4.57 - 4.49 (m, 2H), 4.45 - 4.36 (m, 1H), 4.35 - 4.15 (m,3H), 3.32(s, 3H), 3.30 - 3.24 (m,1H), 2.90 - 2.66 (m , 2H), 2.33 - 2.14 (m, 4H). LCMS RT = 0.920 min., m/z = 406.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.920min., ESI+ found [M+H] = 406.3.

[01917] Another batch of racemic material (50 mg) was separated using chiral SFC to provide:

[01918] (7S) -7 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine - 6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (Peak 1, retention time 3.64 min.) (22 mg , yield 44%) as a white solid. 1H NMR (400 MHz, CD3OD) δ9.35 (s, 1H), 8.38 (s, 1H), 7.05 - 7.00 (m, 2H), 5.45 - 5.40(m, 1H ), 4.69 - 4.64 (m, 1H), 3.05 - 3.02 (m, 1H), 2.89 - 2.76 (m, 2H), 2.32 - 2.26 (m , 1H), 1.60 (d, J = 6.8 Hz, 6H). LCMS RT = 1.95 min., m/z = 406.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.95 min., ESI+ found [M+H] = 406.2.

[01919] SFC Conditions: Column: Chiralcel AD -3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate),Gradient: from 5% to 40% from B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature:40oC. Example 576 1 -[(2-fluorophenyl) methyl] -N -(3R) -1,7 - dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin - 3 -yl -1,2,4 -triazole -3 -carboxamide

[01920] Amide coupling prepared in a manner similar to Method WX 085. The crude product was purified via RP-HPLC (15% to 45% acetonitrile, 0.05% ammonium hydroxide in water) to provide 1 - [(2-fluorophenyl) methyl] -N -1,7 -dimethyl -2 -oxo -4,5 - dihydro -3H -imidazo [1,5 -a] [1,3] diazepin -3 -yl -1 ,2,4 - triazole -3 -carboxamide (50 mg, 54%) as a white solid. The racemic compound was separated using chiral SFC to provide:

[01921] 1 -[(2-fluorophenyl) methyl] -N -(3R) - 1,7 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 - a][1,3 ] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.788 min.) (23 mg, 25%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.81 (s, 1H), 8.48 (d, J = 8.0Hz, 1H), 7.46 - 7.39 (m, 1H), 7.38 - 7.31 (m, 1H), 7.28 - 7.19 (m, 2H), 6.80 (s, 1H), 5.55 (s, 2H), 4.38 - 4.33 (m , 1H), 4.23 - 4.17 (m, 1H), 3.75 - 3.71 (m, 1H), 3.23 - 3.17 (m, 3H), 2.47 - 2.41 (m, 1H), 2.29 (s, 3H), 2.25- 2.17 (m, 1H). LCMS RT = 1.77 min.; m/z = 398.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.77 min., ESI+ found [M+H] = 398.1.

[01922] SFC Conditions: Column: Chiralcel OJ -3 150x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35oC. Example 577 1 -[(2,5-difluorophenyl) methyl] -N -(3R) -1,7 - dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide

[01923] Amide coupling prepared in a manner similar to Method WX 085. The crude product was purified via RP-HPLC (18% to 48% acetonitrile, 0.05% ammonium hydroxide in water) to provide 1 - [(2,5-difluorophenyl) methyl] -N -1,7 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 -yl -1,2,4 - triazole -3 -carboxamide (50 mg, 52%) as white solids. The racemic compound was separated using chiral SFC to provide:

[01924] 1 -[(2,5-difluorophenyl) methyl] -N - (3R) -1,7 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 - a][1 ,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.857 min.) (17 mg, 17.5%). 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.37 - 7.22 (m, 3H), 6 .80 (s, 1H), 5.54 (s, 2H), 4.40- 4.32 (m, 1H), 4.22 - 4.16 (m, 1H), 3.75 - 3.69 (m, 1H), 3.21 (s, 3H), 2.47 - 2.41 (m, 1H), 2.29 (s, 3H), 2.25-2.17 (m, 1H). LCMS RT = 1.796 min., m/z = 416.1 (M + H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.796 min., ESI+ found [M+H] = 416.1.

[01925] SFC Conditions: Column: Chiralcel OJ -3 150x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35oC. Example 578 1 -[(2,6-difluorophenyl) methyl] -N -[(3R) -1,7 - dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3 ] diazepin -3 -yl] -1,2,4 -triazole -3 -carboxamide

[01926] Amide coupling prepared in a manner similar to Method WX 085. The crude product was purified by RP-HPLC (20% to 50% acetonitrile, 0.05% ammonium hydroxide in water) to provide 1 - [(2,6-difluorophenyl) methyl] -N -(1,7 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 - il) -1,2,4 -triazole -3 -carboxamide (50 mg, 47%) as white solids. The racemic compound was separated using chiral SFC to provide:

[01927] 1 -[(2,6-difluorophenyl) methyl] -N - [(3R) -1,7 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][ 1,3] diazepin -3 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.519 min.) (21 mg, 42%) as a white solid. 1H NMR (400 MHz, DMSO - d 6)δ8.83 (s, 1H), 8.46 (d, J = 8.0 Hz,1H), 7.54 - 7.46 (m, 1H), 7 .19 - 7.15 (m, 2H), 6.80 (s, 1H), 5.55 (s, 2H), 4.37 - 4.30 (m, 1H), 4.21 - 4.16 (m, 1H), 3.75 - 3.67 (m, 1H), 3.20(s, 3H), 2.46 - 2.40(m, 1H), 2.29 (s, 3H), 2.24 - 2.16 (m, 1H). LCMS RT = 1.762 min.; m/z = 416.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.762 min., ESI+ found [M+H] = 416.2.

[01928] SFC Conditions: Chiralcel OJ Column - 3 150 x 4.6 mm ID, 3 µm, Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5.0 min. and held 40% for 2.5 min., then 5% B for 2.5 min., Flow rate: 2.5 mL/min. Column temperature: 35oC. Example 579 7 -phenyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[01929] Amide coupling prepared in a manner similar to Method WX 113 (RIP1K_experimental_3rd_WX.doc). The crude product was purified via PR-HPLC (22% to 52% acetonitrile/0.05% ammonium hydroxide in water) to provide 7-phenyl-N-[(6S)-4-methyl-5- oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2 ,4] triazole-2-carboxamide (14.5 mg, 45%) as white solids. 1H NMR (400 MHz, CD3OD) δ7.52 (s,1H), 7.39 - 7.32 (m, 2H), 7.32 -7.25 (m, 3H), 6.30 (s, 1H ), 4.57 -4.46 (m, 2H), 4.45 - 4.35 (m, 2H), 4.33 - 4.20(m, 2H), 3.35 (s, 3H), 3.30 - 3.24 (m, 1H), 2.91 -2.79 (m, 1H), 2.76 -2.66 (m, 1H), 2.32 -2.21 (m, 1H ). LCMS RT = 0.889 min., m/z = 392.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.889 min., ESI+ found [M+H] = 392.3. Example 580 1 -[(2-fluorophenyl) methyl] -N -[(3R) -1,9 - dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepine -3 -yl] -1,2,4 -triazole -3 -carboxamide

[01930] Amide coupling prepared in a manner similar to Method WX 043. The crude product was purified via RP-HPLC (5% to 35% acetonitrile, 0.05% HCl in water) to provide N -( 1,9 -dimethyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a][1,3] diazepin -3 -yl) -1 -(2 -fluorobenzyl) - 1H -1,2,4 -triazole -3 -carboxamide (70mg, 68%) as a white solid. This racemic material was separated using chiral SFC to provide:

[01931] 1 -[(2-fluorophenyl) methyl] -N -[(3R) - 1,9 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 - a][1, 3] diazepin -3 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 3.642 min.) (47 mg, 33%). 1H NMR (400 MHz, CD3OD) δ8.59 (s, 1H), 7.56 (s, 1H), 7.41 - 7.38 (m, 2H), 7.22 - 7.15 (m, 2H ), 5.55 (s, 2H), 4.57 - 4.52 (m, 1H), 4.37 - 4.31 (m, 1H), 3.96 - 3.93 (m, 1H), 3.31 (s, 3H), 2.72 - 2.63 (m, 1H), 2.22 (s, 3H), 2.15 - 2.09 (m, 1H). LCMS RT = 0.447 min.; m/z = 398.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.447 min., ESI+ found [M+H] =398.0.

[01932] SFC Conditions: Column: Chiralpak OJ -3 150 x 4.6 mm ID, 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% from B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 581 1 -[(2,6-difluorophenyl) methyl] -N -(3R) -1,9 - dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide

[01933] Amide coupling prepared in a manner similar to Method WX 100 (RIP1K_experimental_3rd_WX.doc). The crude product was purified by RP-HPLC (5% to 35% acetonitrile, 0.05% HCl in water) to provide 1-(2,6-difluorobenzyl)-N-(1,9-dimethyl- 2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a][1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide ( 70 mg, 65%) as a white solid. The racemic material was separated using chiral SFC to provide:

[01934] 1 -[(2,6-difluorophenyl) methyl] -N - (3R) -1,9 -dimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 - a][1 ,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 3.397 min.) (26 mg, 37%) as a white solid. H NMR (400 MHz, CD3OD) δ8.65 (s, 1H), 8.33 (s, 1H), 7.50 - 7.44 (m, 1H), 7.09 - 7.02 (m, 2H ), 5.62 (s, 2H), 4.65 - 4.60 (m, 1H), 4.50 - 4.46 (m, 1H), 4.13 - 4.08 (m, 1H), 3.32 (s, 3H), 2.73 - 2.65 (m, 1H), 2.32 (s, 3H), 2.26 - 2.15 (m, 1H). LCMS RT = 0.549 min.; m/z = 416.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.549 min., ESI+ found [M+H] =416.0.

[01935] SFC Conditions: Column: Chiralpak OJ -3 150 x 4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 582 1 -[(2-chlorophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -1,2,4 -triazole -3 -carboxamide

[01936] Amide coupling prepared in a manner similar to Method WX 073 (RIP1K_experimental_3rd_WX.doc). The crude product was purified by RP-HPLC (20% to 50% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2-chlorophenyl) methyl] - N - (6S) - 4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 - triazole -3 -carboxamide (42.7 mg, 48%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.37 - 7.32 (m, 3H), 6.30 (s, 1H), 5.61 (s, 2H), 4.50 - 4.41 (m, 2H), 4.30 - 4.27 (m, 1H), 3.35 (s, 3H), 2.88 - 2.82 (m, 1H), 2.29 - 2.23 (m, 1H). LC -MS RT =0.633 min., m/z = 400.0 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.633 min., ESI+ found [M+H] = 400.0. Example 583

[01937] Method WX 052 N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -[[2 - (trifluoromethyl ) phenyl) methyl -1,2,4 -triazole -3 - carboxamide Step 1: methyl 1 -[[2 -(trifluoromethyl) phenyl] methyl] - 1,2,4 -triazole -3 -carboxylate

[01938] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (50 mg, 0.39 mmol) in N,N - dimethylformamide (3 mL) was added 2 - (trifluoromethyl) benzyl bromide (112 mg, 0.47 mmol) and potassium carbonate (81 mg, 0.59 mmol). The mixture was stirred at 40°C for 2 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep TLC (50% ethyl acetate in petroleum ether, Rf = 0.3) to give methyl 1-[[2-(trifluoromethyl)phenyl ] methyl] -1,2,4 -triazole -3 - carboxylate (100 mg, 89%) in the form of a colorless oil. LCMS RT = 0.690 min., m/z = 286.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.690 min., ESI+ found [M+H] = 286.0. Step 2: 1-[[2-(trifluoromethyl)phenyl)methyl]-1,2,4-triazole-3-carboxylic acid

[01939] A mixture of methyl 1 - [[2 - (trifluoromethyl) phenyl] methyl] -1,2,4 -triazole -3 - carboxylate (100 mg, 0.35 mmol) and lithium hydroxide (42 mg, 1 .75 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 15oC for 2 h. The mixture was filtered and the filtrate was adjusted to pH = 6 by addition of 1N HCl. The solution was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 1-[[2-(trifluoromethyl)phenyl)methyl]-1,2,4-triazole-3-carboxylic acid (86 mg , 90%) in the form of a colorless oil, which was used in the next step as it was. Step 3: N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -[[2 - (trifluoromethyl) phenyl] methyl -1,2,4 -triazole -3 - carboxamide

[01940] To a stirred solution of (6S) -6 -amino -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (25mg , 0.14 mmol) in N,N-dimethylformamide (6 mL) was added 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylic acid (45 mg, 0. 17 mmol), 1-hydroxybenzotriazole (28 mg, 0.21 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol). The mixture was stirred at 20°C for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (17 -47% acetonitrile / 0.05% ammonium hydroxide in water) to provide N -(6S) -4 -methyl -5 -oxo -7,8 - dihydro - 6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 -[[2 -(trifluoromethyl) phenyl] methyl] -1,2,4 -triazol -3 - carboxamide (17 mg, 28%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.55 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.57 - 7.49 (m, 2H), 7.28 (d, J = 8.0Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.70(s, 2H), 4 .51 - 4.49 (m, 1H), 4.45 - 4.37 (m, 1H), 4.32 - 4.21 (m, 1H), 3.34 (s, 3H), 2.89 - 2.83 (m, 1H), 2.32 - 2.26 (m, 1H). LCMS RT = 0.935 min., m/z = 434.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.935 min., ESI+ found [M+H] = 434.3. Example 584 N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1 -[[2 - ( trifluoromethyl) phenyl] methyl] -1,2,4 -triazole -3 - carboxamide

[01941] Amide coupling prepared in a manner similar to Method WX 052. The crude product was purified via RP-HPLC (17 -47% acetonitrile / 0.05 ammonium hydroxide in water) to provide N -( 6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl -1 -[[2 -(trifluoromethyl) phenyl )methyl]-1,2,4-triazole-3-carboxamide (32 mg, 55%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.56 (s, 1H), 7.78(d, J = 8.0 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.58 - 7.52 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 5.71 (s, 2H), 4.56 - 4.51 (m, 1H), 4.35 - 4.27 (m, 1H), 4.26 - 4.15 (m, 1H), 3.32 (s, 3H), 2.87 - 2.80 (m , 1H), 2.30 - 2.21 (m, 4H). LCMS RT = 0.971 min., m/z = 448.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.971 min., ESI+ found [M+H] = 448.3 Example 585

[01942] Method WX 055 1 -benzyl -N -(6S) -2 -cyclopropyl -5 -oxo - 4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl - 1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -(6R) -2 -cyclopropyl -5 -oxo - 4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 - yl - 1,2,4 -triazole -3 -carboxamide Step 1: 5-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-1H-pyrazol-3-amine

[01943] To a solution of 2,4-dimethoxybenzaldehyde (29.7 g, 178.6 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (20.0 g, 162.4 mmol) in 1.2 - dichloroethane (400 mL) acetic acid (9.75 g, 162.4 mmol) was added. The reaction solution was stirred under 25°C for 12 h, then sodium triacetoxyborohydride (51.6 g, 243.6 mmol) was added to the mixture. Stirring was continued for another 24 h and the reaction was terminated by adding water (300 mL). The resulting mixture was extracted with dichloromethane (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide 5-cyclopropyl -N -[(2,4-dimethoxyphenyl) methyl] -1H -pyrazole -3 -amine (8.0 g, 18%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 2: 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]butanamide

[01944] To a mixture of 5-cyclopropyl-N-[(2,4-dimethoxyphenyl) methyl]-1H-pyrazol-3-amine (8.00 g, 29.3 mmol) and 4-dimethylamino pyridine (0. 18 g, 1.5 mmol) in dichloromethane (400 mL) was added N,N - diisopropylethyl amine (29.02 mL, 176.0 mmol) and 4-chlorobutanoyl chloride (19.65 mL, 176.0 mmol) under 25oC. The resulting mixture was stirred at 25°C for 12 h and then finalized by addition of methanol (5 ml). The mixture was stirred for 0.5 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 4-chloro-N-(5-cyclopropyl-1H-pyrazole - 3 - il) -N -[(2,4-dimethoxyphenyl) methyl] butanamide (4.00 g, 36.2% yield) as a yellow oil. LCMS RT = 1.07 min., m/z = 378.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 1.07 min., ESI+found [M+H] = 378.2. Step 3: 2 -cyclopropyl -4 -[(3,5-dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[01945] A mixture of 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]butanamide (4.0 g, 10.59 mmol) and potassium carbonate (4.4 g, 31.76 mmol) in N,N-dimethylformamide (80 mL) was stirred at 70°C for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 60% ethyl acetate in petroleum ether) to provide 2-cyclopropyl-4-[(3,5-dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (2.0 g, 55.3% yield) as a yellow oil. LCMS RT = 0.816 min., m/z = 342.3[M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.816 min., ESI+ found [M+H] = 342.3. Step 4: 2 -cyclopropyl -4 -[(2,4-dimethoxyphenyl) methyl] -6 -iodo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one

[01946] 2 -cyclopropyl -4 -[(2,4 - dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (2.0 gg, 5.86 mmol) in dichloromethane (200 mL) was treated with N1,N1,N2,N2 - tetramethylethane -1,2 -diamine (6.8 g, 58.58 mmol) at - 15oC, followed by iodotrimethylsilane ( 11.7 g, 58.58 mmol). Stirring was continued at -15°C for 1.5 h, and then iodine (4.46 g, 17.57 mmol) was added. The mixture was stirred for another 3 h and then finalized by the addition of saturated sodium sulfite (3 ml) and water (15 ml). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether) to provide 2-cyclopropyl-4-[(2,4-dimethoxyphenyl) methyl] -6 -iodo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (1.0 g, 36.5% yield) light yellow solid. LCMS RT = 0.865 min., m/z = 468.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.865 min., ESI+ found [M+H] = 468.0. Step 5: 6 -azide -2 -cyclopropyl -4 -[(2,4 - dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one

[01947] To a solution of 2-cyclopropyl -4 - [(2,4-dimethoxyphenyl) methyl] - 6 -iodo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepine -5-one (1.0 g, 2.14 mmol) in N,N-dimethylformamide (20 mL) was added sodium azide (0.3 g, 4.28 mmol). The reaction mixture was stirred at 25oC for 12 h and diluted with water (15 mL). The solution was extracted with ethyl acetate (3 x 20mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 6-azide -2-cyclopropyl -4 - [(2,4 - dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (600 mg, 73%) in the form of a colorless oil. LCMS RT = 0.0.853 min., m/z = 383.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.853 min., ESI+ found [M+H] = 383.1. Step 6: 6 -amino -2 -cyclopropyl -4 -[(2,4 - dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one

[01948] To a solution of 80% polymer-binding triphenylphosphine (5.1 g) in tetrahydrofuran (25mL) was added water (5 mL) followed by 6-azide -2 - cyclopropyl -4 -[(2.4 -dimethoxyphenyl) methyl] -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (600 mg, 1.57 mmol). The mixture was subjected to stirring at 20oC for 16 h. The mixture was filtered through Celite and concentrated to dryness. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to provide 6-amino-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl ] -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (400 mg, 72%) in the form of a yellow colored oil, which was used in the next step in the form it was in. Step 7: 1-benzyl-N-[2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a][1, 3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide

[01949] A mixture of 6-amino -2 -cyclopropyl -4 -[(2,4-dimethoxyphenyl) methyl] -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5-one (200.0 mg, 0.56 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (136.8 mg, 0.67 mmol), 1-hydroxybenzotriazole (91.0 mg, 0.67 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (129.1 mg, 0.67 mmol).in N,N-dimethylformamide (6 mL) was stirred for 2 h under 20oC. This reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: 100 -200 mesh, eluting with 5% methanol in dichloromethane) to give 1-benzyl-N-[2- cyclopropyl -4 -[(2,4 - dimethoxyphenyl) methyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2 ,4-triazole-3-carboxamide (150 mg, 49.4% yield) in the form of a colorless oil. LCMS RT = 1.098 min., m/z = 542.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 1.098 min., ESI+ found [M+H] = 542.3. Step 8: 1 -benzyl -N -(6S) -2 -cyclopropyl -5 -oxo - 4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl - 1, 2,4-triazole -3 -carboxamide and 1 -benzyl -N -(6R) -2 -cyclopropyl -5 -oxo - 4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepine -6 -yl - 1,2,4 -triazole -3 -carboxamide

[01950] A mixture of 1 -benzyl -N -[2 - cyclopropyl -4 - [(2,4 -dimethoxyphenyl) methyl] -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (150.0 mg, 0.28 mmol) in trifluoroacetic acid (3.0 mL, 40 mmol) was subjected to stirring at 60oC for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (17-47% acetonitrile/0.05%HCl in water) to provide 1-benzyl-N-(6S)-2-cyclopropyl-5-oxo-4.6, 7,8-tetrahydropyrazole[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (80 mg, 73.8% yield) in the form of a white solid. The racemic material was separated using chiral SFC to provide:

[01951] 1 -benzyl -N -[(6S) -2 -cyclopropyl -5 -oxo -4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4-Triazole-3-carboxamide (Peak 1, retention time 3.786 min.) (39.2 mg, 48.5% yield) as white solids. 1H NMR (400 MHz, DMSO -d6) δ10.32 (s, 1H), 8.82 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.41 - 7, 26 (m, 5H), 5.66 (s, 1H), 5.48 (s, 2H), 4.38 - 4.35 (m, 1H), 4.28 - 4.20(m, 1H) , 4.13 - 4.02 (m, 1H), 2.59 - 2.54 (m, 1H), 2.34 - 2.25(m, 1H), 1.84 - 1.75 (m, 1H), 0.85 - 0.79 (m, 2H), 0.65 - 0.59 (m, 2H). LCMS RT = 0.869min., m/z = 392.0 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.869 min., ESI+ found [M+H] = 392.0.

[01952] 1 -benzyl -N -[(6R) -2 -cyclopropyl -5 -oxo -4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4-triazole-3-carboxamide (Peak 2, retention time 4,390 min.) (40.0 mg, 50% yield) as white solids. 1H NMR (400 MHz, DMSO -d6) δ10.32 (s., 1H), 8.82 (s., 1H), 8.48 (d, J=7.9 Hz, 1H), 7.41 - 7 .26 (m, 5H), 5.66 (s, 1H), 5.48 (s, 2H), 4.37 (m, 1H), 4.28 - 4.20(m, 1H), 4, 13 - 4.02 (m, 1H), 2.59 - 2.54 (m, 1H), 2.34 - 2.25(m, 1H), 1.84 - 1.75 (m, 1H), 0.85 - 0.79 (m, 2H), 0.65 - 0.59 (m, 2H). LCMS RT = 0.737 min., m/z = 392.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.737 min., ESI+ found [M+H] = 392.0.

[01953] SFC Condition: Column: Chiralpak AS - 3 150 x 4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: methanol (0.05% DEA) Gradient: from 5% to 40% from B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35 o Example 586

[01954] Method WX 054 1 -benzyl -N -(6S) -2 -methyl -5 -oxo -4,6,7,8 - tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 - triazole -3 -carboxamide e -benzyl -N -(6R) -2 -methyl -5 -oxo -4,6,7,8 - tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 - triazole -3 -carboxamide Step 1: N -[(2,4-dimethoxyphenyl) methyl] -5 - methyl -1H -pyrazol -3 -amine

[01955] To a solution of 2,4-dimethoxy benzaldehyde (18.8 g, 113.2 mmol) and 5-methyl-1H-pyrazol-3-amine (10.0 g, 102.9 mmol) in 1, 2-Dichloroethane (100 mL) was added acetic acid (6.1 g, 102.9 mmol). The reaction solution was stirred at 25°C for 12 h, then sodium triacetoxyborohydride (32.7 g, 154.4 mmol) was added to the mixture. Stirring was continued for another 24 h and the reaction was terminated by adding water (200 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 40 to 100% ethyl acetate in petroleum ether) to give N -[(2,4-dimethoxyphenyl)methyl]-5-methyl - 1H -pyrazole -3 -amine (3.0 g, 12%) in the form of a brown oil, which was used in the next step in the form in which it was. LCMS RT = 0.617 min., m/z = 248.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.617 min., ESI+ found [M+H] = 248.1. Step 2: 4-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(5-methyl-1H-pyrazol-3-yl)butanamide

[01956] To a solution of N -[(2,4 - dimethoxyphenyl) methyl] -5 -methyl -1H -pyrazol -3 -amine (7.00 g, 28.31 mmol) and N,N -diisopropyl ethylamine ( 17.42 mL, 169.84 mmol) in dichloromethane (150 mL) was added 4-dimethylamino pyridine (0.35 g, 2.83 mmol) and 4-chlorobutanoyl chloride (11.97 g, 84.92 mmol) under 0oC. After addition, the mixture was stirred at 20°C for 12 h and then finalized by addition of methanol (10 ml). The mixture was stirred for 0.5 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 4-chloro-N-[(2,4-dimethoxyphenyl)methyl ] -N -(5-methyl -1H -pyrazol -3 -yl) butanamide (2.5 g, 25.1% yield) in the form of a slightly yellow oil. LCMS RT = 0.875 min., m/z = 352.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.875 min., ESI+ found [M+H] = 352.1. Step 3: 4 -[(3,5-dimethoxyphenyl) methyl] -2 - methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[01957] A mixture of 4 -chloro -N -[(2,4 - dimethoxyphenyl) methyl] -N -(5 -methyl -1H -pyrazol -3 - yl)butanamide (800 mg, 2.27 mmol) and carbonate of cesium (1482 mg, 4.55 mmol) in N,N-dimethylformamide (10 mL) was stirred at 20°C for 3 h and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 ml), dried and concentrated. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 4-[(3,5-dimethoxyphenyl)methyl]-2-methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (400 mg, 55.8%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ7.00 (d, J = 8 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.48 - 6.41 (m, 1H) , 5.77 (s, 1H), 4.69 (s, 2H), 4.01 - 3.98 (m, 2H), 3.69 (d, J = 8.8 Hz, 6H), 2, 26 - 2.14 (m, 4H), 2.04 (s, 3H). Step 4: 4 -[(2,4-dimethoxyphenyl) methyl] -6 -iodo -2 - methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[01958] To a solution of 4 -[(2,4 - dimethoxyphenyl) methyl] -2 -methyl -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg, 0.16 mmol) in dichloromethane (20 mL) was treated with N1,N1,N2,N2 - tetramethylethane -1,2 -diamine (184 mg, 1.59 mmol) at - 15oC, followed by trimethyl iodine silane (317 mg, 1.59 mmol). Stirring was continued at -15°C for 1.5 h, and then iodine (120 mg, 0.48 mmol) was added. The mixture was stirred for another 3 h and then finalized by the addition of saturated sodium sulfite (3 ml) and water (15 ml). The resulting mixture was extracted with ethyl acetate (3 x 20mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep TLC (50% ethyl acetate in petroleum ether, Rf = 0.5) to give 4 -[(2,4 - dimethoxyphenyl) methyl] -6 -iodo -2 - methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg, 72%) as a yellow solid, which was used in the next step in the form it was in. Step 5: 6 -azide -4 -[(2,4-dimethoxyphenyl) methyl] -2 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[01959] To a solution of 4 -[(2,4 - dimethoxyphenyl) methyl] -6 -iodo -2 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -5-one (40 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL) was added sodium azide (147 mg, 2.27 mmol). The reaction mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf = 0.5) to provide 6-azide -4 -[(2,4-dimethoxyphenyl)methyl]-2- methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (25mg, 77%) as a white solid, which was used in the next step in form in which it was found. Step 6: 6 -amino -4 -[(2,4 -dimethoxyphenyl) methyl] -2 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one

[01960] A mixture of 6 -azide -4 - [(2,4 - dimethoxyphenyl) methyl] -2 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin - 5-one (30 mg, 0.08 mmol) and palladium (10% on carbon, 22 mg, 0.02 mmol) in methanol (15 mL) was hydrogenated [2.04 bar (15 psi)] under 25°C for 2 it is then filtered. The filtrate was concentrated under reduced pressure to provide 6-amino-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazole[1,5-a][1, 3] diazepin -5 -one (25mg, 90%) in the form of a colorless oil. LCMS RT = 0.618 min., m/z = 331.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.618min., ESI+ found [M+H] = 331.0. Step 7: 1 -benzyl -N -[4 -[(2,4-dimethoxyphenyl) methyl] -2 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1, 3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[01961] A mixture of 6 -amino -4 - [(2,4 - dimethoxyphenyl) methyl] -2 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin - 5-one (20 mg, 0.06 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (16 mg, 0.08 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol) and 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (17 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL) was stirred for 40 min. under 40oC. This reaction mixture was concentrated under reduced pressure and the residue was purified by prep TLC (10% methanol in dichloromethane, Rf = 0.3) to give 1-benzyl-N-[4-[(2.4 -dimethoxyphenyl) methyl] -2 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole - 3-carboxamide (20 mg, 64%) as a white solid. LCMS RT = 1.068 min., m/z = 515.9 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 1.068 min., ESI+ found [M+H] = 515.9. Step 8: 1 -benzyl -N -(6S) -2 -methyl -5 -oxo -4,6,7,8 - tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl -1, 2,4 - triazole -3 -carboxamide and 1 -benzyl -N -(6R) -2 -methyl -5 -oxo -4,6,7,8 - tetrahydropyrazole [1,5 -a][1,3] diazepine -6 -yl -1,2,4 - triazole -3 -carboxamide

[01962] A mixture of 1-benzyl -N -[4 -[(2,4-dimethoxyphenyl) methyl] -2 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (60.0 mg, 0.12 mmol) in trifluoroacetic acid (1.5 mL, 20 mmol) was subjected to stirring at 60oC for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (18 -48% acetonitrile / 0.05% FA in water) to provide 1-benzyl -N -(2-methyl -5 -oxo -4,6,7,8 -tetrahydropyrazole [1,5-a][1,3] diazepin -6 -yl) -1,2,4 -triazole -3 -carboxamide (40 mg, 94.1% yield) in the form of a solid White color. The racemic material was separated using chiral SFC to provide:

[01963] 1 -benzyl -N -(6S) -2 -methyl -5 -oxo - 4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl - 1, 2,4-Triazole-3-carboxamide (Peak 1, retention time 4.974 min.) (7 mg, 17%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ8.80 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.38 - 7.25 (m, 5H), 5, 72 (s, 1H), 5.46 (s, 2H), 4.39 - 4.34 (m, 1H), 4.28 - 4.19 (m, 1H), 4.13 - 4.01 ( m, 1H), 2.64 (s, 1H), 2.30 (s, 1H), 2.09 (s, 3H). LCMS RT = 0.689 min., m/z = 366.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.689 min., ESI+ found [M+H] = 366.0

[01964] 1 -benzyl -N -(6R) -2 -methyl -5 -oxo - 4,6,7,8 -tetrahydropyrazole [1,5 -a][1,3] diazepin -6 -yl -1 ,2,4-triazole-3-carboxamide (Peak 2, retention time 5.659 min.) (8.9 mg, 22%) as white solids. 1H NMR (400MHz, DMSO -d6) δ 8.80 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 7.38 - 7.25(m, 5H), 5, 72 (s, 1H), 5.46 (s, 2H), 4.36 (m, 1H), 4.28 - 4.19 (m, 1H), 4.13 - 4.01 (m, 1H) , 2.64 (s., 1H), 2.30 (s., 1H), 2.09 (s., 3H). LCMS RT = 0.684 min., m/z = 366.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.684 min., ESI+ found [M+H] = 366.1.

[01965] SFC Conditions: Column: Chiralpak AS -H 250x4.6 mm I.D., 5 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5.0 min. and held 40% for 2.5 min., then 5% B for 2.5 min., Flow rate: 2.5 mL/min. Column temperature: 35 oC. Example 587

[01966] Method WX 034 1 -[(2-methoxyphenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -1,2,4 -triazole -3 -carboxamide Step 1: 1-(bromomethyl)-2-methoxybenzene

[01967] A mixture of 2-methylanisole (2.0 g, 16.37 mmol), NBS (2.91 g, 16.37 mmol) and AIBN (0.05 g, 0.28 mmol) in 1.2 -dichloroethane (30 mL) was stirred for 3 h at 88oC. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 1 -(bromomethyl) -2 - methoxy-benzene (1.2 g, 37%) as a white solid. 1H NMR (400 MHz, CDCI3) δ7.33 - 7.25 (m, 2H), 6.94 - 6.87 (m, 2H), 4.57 (s, 2H), 3.90 (s, 3H) ). Step 2: methyl 1 -(2-methoxybenzyl) -1H -1,2,4 - triazole -3 -carboxylate

[01968] A mixture of methyl 1H -1,2,4 -triazole -3 -carboxylate (395 mg, 3.11 mmol), potassium carbonate (859 mg, 6.22 mmol) and 1 -(bromomethyl) -2 -methoxybenzene (750 mg, 3.73 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 40% ethyl acetate in petroleum ether) to give methyl 1-[(2-methoxyphenyl )methyl]-1,2,4-triazole-3-carboxylate (400 mg, 52%) as a white solid. 1H NMR (400 MHz, CDCI3) δ8.10 (s, 1H), 7.38 - 7.29 (m, 2H), 6.98 - 6.90 (m, 2H), 5.40(s, 2H ), 3.97 (s, 3H), 3.84 (s, 3H). Step 3: 1-(2-methoxybenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01969] A mixture of methyl 1 -[(2 - methoxyphenyl) methyl] -1,2,4 -triazole -3 -carboxylate (230 mg, 0.93 mmol) and lithium hydroxide (111 mg, 4.65 mmol ) in tetrahydrofuran (4 mL) and water (1 mL) was stirred for 3 h at 25oC and the organic solvent was evaporated under reduced pressure. The aqueous residue was adjusted to pH = 1~2 by adding 20% aqueous HCl. The resulting solid was collected through filtration and dried to provide crude 1-[(2-methoxyphenyl) methyl]-1,2,4-triazole-3-carboxylic acid (150 mg, 69%) in the form of a white solid, which was used in the next step as it was. Step 4: 1 -[(2-methoxyphenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -6 -yl -1,2,4 -triazole -3 -carboxamide

[01970] To a stirred solution of 1-[(2-methoxyphenyl) methyl]-1,2,4-triazole-3-carboxylic acid (49 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was added (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (32 mg, 0.18 mmol ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (51 mg, 0.27 mmol) and 1-hydroxybenzotriazole (36 mg, 0.27 mmol). The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -[(2-methoxyphenyl) methyl] -N -(6S) - 4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (36 mg, 50%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.44 (s, 1H), 7.51 (s, 1H), 7.36 - 7.32(m, 1H), 7.28 - 7.26(m, 1H ), 7.00 (d, J = 8.0 Hz, 1H), 6.96 -6.93 (m, 1H), 6.29 (s, 1H), 5.42 (s, 2H), 4 .51 - 4.46 (m, 1H), 4.44 - 4.38 (m, 1H), 4.30 - 4.22 (m, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 2.89 - 2.79 (m, 1H), 2.29 - 2.21 (m, 1H). LCMS RT = 1.48 min., m/z = 396.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.48 min., ESI+found [M+H] = 396.1. Example 588

[01971] Method WX 062 1 -(o -tolylmethyl) -N -(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl - 1 ,2,4-triazole-3-carboxamide Step 1: methyl 1 -(2-methylbenzyl) -1H -1,2,4 - triazole -3 -carboxylate

[01972] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (200 mg, 1.57 mmol) in N,N - dimethylformamide (6 mL) was added potassium carbonate (435 mg, 3 .14 mmol) and 1-(bromomethyl)-2-methylbenzene (349 mg, 1.89 mmol). The mixture was stirred at 25°C for 2 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 80% ethyl acetate in petroleum ether) to provide methyl 1-(2-methylbenzyl) -1H -1,2,4 - triazole -3 -carboxylate (240 mg, 66%) in the form of a white solid, which was used in the next step in the form in which it was. Step 2: 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01973] A mixture of methyl 1 -(2 - methylbenzyl) -1H -1,2,4 -triazole -3 -carboxylate (240 mg, 1.03 mmol) and potassium hydroxide (124 mg, 5.19 mmol) in tetrahydrofuran / methanol / water (5 mL, 2:2:1) was subjected to stirring at 25oC for 2 h. The organic solvents were evaporated under reduced pressure and the mixture was diluted with water (20 ml). The solution was adjusted to pH = 4 by adding 2N HCl. The resulting solid was collected through filtration and dried to provide crude 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylic acid (180 mg, 80%) in the form of a white solid, which was used in the next step as it was. Step 3: 1 -(o -tolylmethyl) -N -(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl - 1,2,4 -triazole -3 -carboxamide

[01974] A mixture of (6S) -6 -amino -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (40 mg, 0. 22 mmol), 1-(o-tolylmethyl)-1,2,4-triazole-3-carboxylic acid (51 mg, 0.23 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and 1-hydrochloride -(3-dimethylamino propyl)-3-ethylcarbodiimide (64 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20°C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -(o -tolylmethyl) -N -(6S) -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazol -3 -carboxamide (44 mg, 51%) in the form of a white solid. H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.52 - 7.51 (m, 1H), 7.26 - 7.15 (m, 4H), 6.31 - 6, 30 (m, 1H), 5.50 (s, 2H), 4.53 - 4.40 (m, 2H), 4.30 - 4.25(m, 1H), 3.35 (s, 3H) , 2.89 - 2.83 (m, 1H), 2.34 (s, 3H), 2.31 - 2.23 (m, 1H). LCMS RT = 1.48 min.; m/z = 380.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide acid for 3 min.) retention time 1.48 min., ESI+ found [M+H] =380.2. Example 589 1 -[(2-methoxyphenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide

[01975] Amide coupling prepared in a similar manner to Method WX 034, The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2-methoxyphenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl - 1,2,4 -triazole -3 -carboxamide (47 mg, 60%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.44 (s, 1H), 7.36 - 7.32 (m, 1H), 7.30 - 7.26 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.96 -6.92 (m, 1H), 6.09 (s, 1H), 5.42 (s, 2H), 4.53 - 4.48 (m, 1H), 4.32 - 4.26 (m, 1H), 4.23 - 4.15 (m, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 2.87 - 2.76 (m, 1H), 2.24 (s, 3H), 2.26 - 2.18 (m, 1H). LCMS RT = 1.55 min., m/z = 410.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.55 min., ESI+found [M+H] = 410.1. Example 590 1 -[(2-cyanophenyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl -1,2,4 -triazole -3 -carboxamide

[01976] Amide coupling prepared in a similar manner to Method WX 059. The crude product was purified via RP-HPLC (20-50% acetonitrile/HCl in water) to provide 1-[(2-cyanophenyl) methyl] -N - (6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2, 4-triazole-3-carboxamide (26 mg, 36%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.79 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.59 - 7.53 (m, 1H), 7.51 - 7.49 (m, 1H), 6.44 (s, 1H), 5.74 (s, 2H), 4.73 - 4.68 (m, 1H), 4.51 - 4.44 (m, 1H), 4.42 - 4.33 (m, 1H), 3.37 (s, 3H), 2.94 - 2.82 (m, 1H) , 2.46 - 2.35 (m, 4H). LCMS RT = 1.544 min.; m/z = 405.3 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.544 min., ESI+ found [M+H] = 405.3. Example 591 1 -(o -tolylmethyl) -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl - 1,2,4 -triazole -3 -carboxamide

[01977] Amide coupling prepared in a manner similar to Method WX 062. The crude product was purified via RP-HPLC (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - ( o -tolylmethyl) -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1, 2,4-triazole-3-carboxamide (20 mg, 25%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.45 (s, 1H), 7.26 - 7.22 (m, 2H), 7.20- 7.15 (m, 2H), 6.11 (s, 1H ), 5.50 (s, 2H), 4.55 - 4.50 (m, 1H), 4.30 - 4.28 (m, 1H), 4.23 - 4.20(m, 1H), 3.32 (s, 3H), 2.87 - 2.81 (m, 1H), 2.34 (s, 3H), 2.28 - 2.20(m, 4H). LCMS RT = 1.565 min.; m/z = 394.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide acid for 3 min.) retention time 1.565 min., ESI+ found [M+H] = 394.2. Example 592 1 -[(2-methoxyphenyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01978] Amide coupling prepared in a similar manner to Method WX 034. The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2-methoxyphenyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6-yl -1,2,4 -triazole -3 -carboxamide (42 mg, 53%) as a white solid. H NMR (400 MHz, CD3OD) δ8.44 (s, 1H), 7.36 - 7.32 (m, 1H), 7.30 - 7.26 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.96 -6.92 (m, 1H), 5.98 (s, 1H), 5.42 (s, 2H), 4.53 - 4.48 (m, 1H), 4.32 - 4.26 (m, 1H), 4.23 - 4.15 (m, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 2.83 - 2.78(m, 1H), 2.22 - 2.20(m, 1H), 1.91 - 1.86 (m, 1H), 0.93 - 0.91 (m, 2H), 0 .73 - 0.71 (m, 2H). LCMS RT = 1.68 min., m/z = 436.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.68 min., ESI+found [M+H] = 436.1. Example 593

[01979] Method WX 059 1 -[(2-cyanophenyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: methyl 1 -(2-cyanobenzyl) -1H -1,2,4 - triazole -3 -carboxylate

[01980] To a solution of 2-(bromomethyl)benzonitrile (386 mg, 1.97 mmol) in N,N-dimethylformamide (3 mL) was added methyl 1H-1,2,4-triazole-3-carboxylate ( 250 mg, 1.97 mmol) and potassium carbonate (408 mg, 2.95 mmol). The mixture was stirred at 25°C for 2 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% petroleum ether) to give methyl 1 - [(2 -cyanophenyl) methyl] - 1,2,4-triazole-3-carboxylate (240 mg, 50%) in the form of a white solid, which was used in the next step in the form in which it was. Step 2: 1-(2-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

[01981] A mixture of methyl 1 -[(2 - cyanophenyl) methyl] -1,2,4 -triazole -3 -carboxylate (150 mg, 0.62 mmol) and lithium hydroxide (74 mg, 3.1 mmol ) in tetrahydrofuran (5 mL) and water (2 mL) was stirred for 2 h. The organic solvent was evaporated under reduced pressure and the aqueous solution was adjusted to pH = 5 by adding 1N HCl. The resulting mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were concentrated under reduced pressure to provide crude methyl 1-[(2-cyanophenyl)methyl]-1,2,4-triazol-3-carboxylate (150 mg, 85%) as a solid. white color, which was used in the next stage as it was. Step 3: 1 -[(2-cyanophenyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01982] A mixture of (6S) -6 -amino -2 - cyclopropyl -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (38 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and 1-[(2) -cyanophenyl) methyl] -1,2,4 -triazole -3 - carboxylic acid (40 mg, 0.18 mmol) in N,N -dimethylformamide (5 mL) was stirred at 20°C for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (22-52% acetonitrile/HCl in water) to provide 1-[(2-cyanophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide (46 mg, 61%) in the form of white solids. 1H NMR (400 MHz, CD3OD) δ8.84 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.59 - 7.48 (m, 2H), 6.38 (s, 1H), 5.75 (s, 2H), 4.75 - 4.70(m, 1H), 4.54 - 4.45 (m, 1H), 4.42 - 4.33 (m, 1H), 3.36 (s, 3H), 2.94 - 2.83 (m, 1H), 2.46 - 2.36 (m, 1H) , 2.09 - 2.01 (m, 1H), 1.20- 1.17 (m, 2H), 1.00 - 0.91 (m, 2H). LCMS RT = 1.65 min.; m/z = 431.3 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 1.65 min., ESI+ found [M+H] = 431.3. Example 594 1 -[(3,3-difluoro cyclopentyl) methyl] -N -(6S) - 2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[01983] N -Alkylation prepared in a similar manner to Method WX 041. The crude product was purified via RP-HPLC (0 -40% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3,3-difluorocyclopentyl) methyl] -N -(6S) -2 -cyclopropyl -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (9.1 mg, 32%). 1H NMR (400 MHz, CD3OD) δ8.51 (s, 1H), 6.01 (s, 1H), 4.57 - 4.50 (m, 1H), 4.35 - 4.27 (m, 3H ), 4.24 - 4.16 (m, 1H), 3.32 (s, 3H), 2.92 - 2.70(m, 3H), 2.29 - 2.11 (m, 3H), 1.97 - 1.83 (m, 3H), 1.63 - 1.55 (m, 1H), 0.99 - 0.91 (m, 2H), 0.79 - 0.69 (m, 2H ). LC -MS RT = 0.945 min., m/z = 434.3 (M+H) +. LCMS (10 to 80% acetonitrile in water + 0.03% TFA over 2.0 min.) retention time 0.945 min., ESI+ found [M+H] = 434.3. Example 595 1 -(2,6 -difluorophenyl) -N -[(6S) -2,4 -dimethyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide

[01984] Amide coupling prepared in a manner similar to Method WX 140. The crude product was purified via RP-HPLC (35% to 65% acetonitrile / 0.05% HCl in water) to provide 1 -( 2,6 - difluorophenyl) - N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl ] pyrazole [3,4-d] pyrimidine-6-carboxamide (19 mg, 27%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 9.53 (s, 1H), 9.23 (d, J = 7.2 Hz, 1H), 8.70(s, 1H), 7.74 — 7.67 (m, 1H), 7.46 — 7.40(m, 1H), 7.34 — 7.28 (m, 3H), 7.26 - 7.21 (m, 1H), 5.06 - 5 .01 (m, 1H), 4.69 - 4.65 (m, 1H), 4.45 - 4.38 (m, 1H), 3.42 (s, 3H). LCMS RT = 1.851 min.; m/z = 451.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.851 min., ESI+ found [M+H] =451.2. Example 596 1 -[(2-fluorophenyl) methyl] -N -(3R) -1,7,9 - trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide

[01985] Amide coupling prepared in a manner similar to Method WX 096. The crude product was purified via RP-HPLC (18% to 48% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - (2-fluorobenzyl) -N -(1,7,9 -trimethyl -2 -oxo -2,3,4,5 - tetrahydro -1H -imidazo [1,5 -a][1,3] diazepin -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide (70 mg, 71%) as a white solid. The racemic compound was separated using chiral SFC to provide:

[01986] 1 -[(2-fluorophenyl) methyl] -N -(3R) - 1,7,9 -trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 - a][1 ,3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.147 min.) (18.9 mg, 31.2%) as a white solid . 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 7.43 - 7.36 (m, 2H), 7.22 - 7.12 (m, 2H), 5.48 (s, 2H ), 4.57 - 4.52 (m, 1H), 4.25- 4.19 (m, 1H), 3.83 - 3.79 (m, 1H), 3.30 (s, 3H), 2.68 - 2.62 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 2.09 - 2.05 (m, 1H). LCMS RT = 0.724 min., m/z = 412.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.724 min., ESI+ found [M+H] =412.0.

[01987] SFC Conditions: Column: Chiralpak OJ -3 150 x 4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 597 1 -[(2,6-difluorophenyl) methyl] -N -(3R) -1,7,9 - trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1, 3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide

[01988] Amide coupling prepared in a manner similar to Method WX 096. The crude product was purified via RP-HPLC (18% to 48% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - (2,6 -difluorobenzyl) -N -(1,7,9 -trimethyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a][1,3] diazepine -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide (70 mg, 71%) as a white solid. The racemic material was separated using chiral SFC to provide:

[01989] 1 -[(2,6-difluorophenyl) methyl] -N - (3R) -1,7,9 -trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a] [1,3] diazepin -3 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 3.054 min.) (25.1 mg, 41.4%) as a solid White color. 1H NMR (400 MHz, CD3OD) δ8.61 (s, 1H), 7.50 -7.42 (m, 1H), 7.08 -7.03 (m, 2H), 5.48 (s, 2H ), 4.57 -4.52 (m, 1H), 4.25-4.19 (m, 1H), 3.83 -3.79 (m, 1H), 3.30 (s, 3H), 2.68 -2.62 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 2.09 -2.05 (m, 1H). LCMS RT = 0.544 min.; m/z = 430.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.544 min., ESI+ found [M+H] =430.1.

[01990] SFC Condition Column: Chiralpak OJ -3 150 x 4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 598 1 -[(2,5-difluorophenyl) methyl] -N -(3R) -1,7,9 - trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1, 3] diazepin -3 -yl -1,2,4 -triazole -3 -carboxamide

[01991] Amide coupling prepared in a manner similar to Method WX 096. The crude product was purified via RP-HPLC (18% to 48% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - (2,5-difluorobenzyl) -N -(1,7,9 -trimethyl -2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a] [1,3] diazepine -3 -yl) -1H -1,2,4 -triazole -3 -carboxamide (70 mg, 71%) as a white solid. The racemic material was separated using chiral SFC to provide:

[01992] 1 -[(2,5-difluorophenyl) methyl] -N - (3R) -1,7,9 -trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a] [1,3] diazepin -3 -yl -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 3,240 min.) (21.7 mg, 36%). 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 7.19 - 7.13 (m, 3H), 5.54 (s, 2H), 4.57 - 4.52 (m, 1H), 4.25- 4.19 (m, 1H), 3.83 - 3.79 (m, 1H), 3.30 (s, 3H), 2.68 - 2.62 (m, 1H) , 2.34 (s, 3H), 2.16 (s, 3H), 2.09 - 2.05 (m, 1H). LCMS RT = 0.540 min.; m/z = 430.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.540min., ESI+ found [M+H] =430.0.

[01993] SFC Condition: Column: Chiralpak OJ - 3 150 x 4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 599 1 -[(2-fluorophenyl) methyl] -N -(3R) -1 -methyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 - yl -1,2,4 -triazole -3 -carboxamide

[01994] Amide coupling prepared in a similar manner to Method WX 043. The racemic compound obtained was separated by means of chiral SFC to provide:

[01995] 1 -[(2-fluorophenyl) methyl] -N -(3R) -1 -methyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepine -3 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time = 3.432 min.) (17.3 mg, 34%) as white solids. H NMR (400 MHz, DMSO -d6) δ8.81 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.44 — 7, 33 (m, 2H), 7.27 - 7.19 (m, 2H), 6.95 (s, 1H), 5.55 (s, 2H), 4.38 - 4.31 (m, 2H) , 3.88 - 3.81 (m, 1H), 3.23 (s, 3H), 2.44 (s, 1H), 2.27 - 2.21 (m, 1H). LCMS RT = 1.693 min., m/z = 384.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.693 min., ESI+ found [M+H] = 384.2.

[01996] SFC Conditions: Column: Chiralcel OJ -3 100x4.6 mm ID, 3 um Mobile phase: A: CO2 B: methanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40oC. Example 600 1 -[(2,6-difluorophenyl) methyl] -N -[(3R) -1 -methyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepine -3 -yl] -1,2,4 -triazole -3 -carboxamide

[01997] Amide coupling prepared in a similar manner to Method WX 096. The racemic compound obtained was separated by means of chiral SFC to provide:

[01998] 1 -[(2,6-difluorophenyl) methyl] -N - [(3R) -1 -methyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 - a][1, 3] diazepin -3 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.941 min.) (49.1 mg 49%). H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.61 - 7.43 (m, 2H), 7 .20 - 7.16 (m, 2H), 6.95 (s, 1H), 5.56 (s, 2H), 4.39 - 4.25(m, 2H), 3.88 - 3.78 (m, 1H), 3.22 (s, 3H), 2.48 - 2.39 (m, 1H), 2.27 - 2.20(m, 1H). LCMS RT = 1.681 min.; m/z = 402.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.681 min., ESI+ found [M+H] = 402.1.

[01999] SFC Condition: Column: Chiralpak AD - 3 100x4.6 mm ID, 3 um Mobile phase: A: CO2 B: Methanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40oC. Example 601 1 -[(2-fluorophenyl) methyl] -N -(7R) -9 -methyl -8-oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -7 - yl -1,2,4 -triazole -3 -carboxamide

[02000] Amide coupling prepared in a similar manner to Method WX 043. The racemic compound obtained was separated by means of chiral SFC to provide:

[02001] 1 -[(2-fluorophenyl) methyl] -N -(7R) -9-methyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepine -7 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.621 min.) (19 mg, 47.5%): 1H NMR (400 MHz, CD3OD) δ 8.58 ( s, 1H), 7.42 – 7.34 (m, 2H), 7.21 – 7.11 (m, 2H), 7.08 (s, 1H), 6.95 (s, 1H), 5 .54 (s, 2H), 4.54 - 4.47 (m, 1H), 4.32 - 4.25 (m, 1H), 4.09 — 4.02 (m, 1H), 3.38 (s, 3H), 2.87 - 2.79 (m, 1H), 2.28 - 2.23 (m, 1H). LCMS RT = 1.293 min., m/z = 384.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.293, ESI+ found [M+H] = 384.2.

[02002] SFC Conditions: Column: Chiralcel OJ -3 250x30 mm ID, 10 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 25% to 25%, Flow rate: 60 mL/min., Column temperature: 40oC. Example 602 1 -[(2,6-difluorophenyl) methyl] -N -[(7R) -9 - methyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepine -7 -yl] -1,2,4 -triazole -3 -carboxamide

[02003] Amide coupling prepared in a similar manner to Method WX 096. The racemic compound obtained was separated by means of chiral SFC to provide:

[02004] 1 -[(2,6-difluorophenyl) methyl] -N - [(7R) -9 -methyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 - a][1, 3] diazepin -7 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.289 min.) (19 mg, 47.5%) as white solids. 1H NMR (400 MHz, DMSO -d6) δ 8.84 (s, 1H), 8.53 (d, J = 7.6 Hz, 1H), 7.55 - 7.46 (m, 1H), 7 .17 (t, J = 8.0 Hz, 2H), 7.12 (s, 1H), 6.87 (s, 1H), 5.56 (s, 2H), 4.29 - 4.23 ( m, 2H), 3.95 - 3.87 (m, 1H), 3.24 (s, 3H), 3.51 - 3.50 (m, 1H), 2.38 - 2.34 (m, 1H). LCMS RT = 1.293 min.; m/z = 402.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.293, ESI+ found [M+H] = 402.1.

[02005] SFC Condition: Column: Chiralcel OJ - 3 250x30 mm ID, 10 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 25% to 25%, Flow rate: 60 mL/min., Column temperature: 40oC. Example 603 1 -[(2-cyanophenyl) methyl] -N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -1,2,4 -triazole -3 -carboxamide

[02006] Amide coupling prepared in a similar manner to Method WX 059. The crude product was purified via RP-HPLC (14-44% acetonitrile/HCl in water) to provide 1-[(2-cyanophenyl) methyl ] -N - (6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3-carboxamide (12 mg, 17%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.80 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.66 ( d, J = 2.0 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 2 .0 Hz, 1H), 5.74 (s, 2H), 4.57 - 4.52 (m, 1H), 4.50 - 4.44 (m, 1H), 4.38 - 4.27 ( m, 1H), 3.36 (s, 3H), 2.91 - 2.81 (m, 1H), 2.35 - 2.28 (m, 1H). LCMS RT = 1.732 min.; m/z = 391.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium hydroxide acid for 3 min.) retention time 1.732 min., ESI+ found [M+H] = 391.1. Example 604 1 -(o -tolylmethyl) -N -(6S) -2 -cyclopropyl -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02007] Amide coupling prepared in a similar manner to Method WX 062. The crude product was purified via RP-HPLC (30 -60% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - ( o -tolylmethyl) -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl - 1,2,4-Triazole-3-carboxamide (38 mg, 49%) as white solids. 1H NMR (400 MHz, CD3OD) δ8.44 (s, 1H), 7.26 - 7.15 (m, 4H), 6.00 (s, 1H), 5.50 (s, 2H), 4, 45 - 4.49 (m, 1H), 4.28 - 4.23 (m, 1H), 4.20- 4.18 (m, 1H), 3.35 (s, 3H), 2.85 - 2.80 (m, 1H), 2.34 (s, 3H), 2.24 - 2.22 (m, 1H), 1.92 - 1.88 (m, 1H), 0.95 - 0, 92 (m, 2H), 0.75 - 0.72 (m, 2H). LCMS RT = 1.69 min.; m/z = 420.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium hydroxide acid for 3 min.) retention time 1.69 min., ESI+ found [M+H] = 420.2. Example 605 1 -isopropyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] pyrazole [3,4 - d] pyrimidine -6 -carboxamide

[02008] Amide coupling prepared in a manner similar to Method WX 142. The crude product was purified via RP-HPLC (32% to 62% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - isopropyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] pyrazole [3,4 -d] pyrimidine -6 - carboxamide (14.7 mg, 26%) as a white solid. H NMR (400 MHz, CD3OD) δ9.36 (s, 1H), 8.39 (s, 1H), 6.98 - 6.88 (m, 2H), 5.46 - 5.42 (m, 1H ), 5.16 - 5.13 (m, 1H), 4.80 - 4.76 (m, 1H), 4.58 (t, J = 10.4 Hz, 1H), 1.60 (d, J = 6.4 Hz, 6H). LCMS RT = 0.787 min., m/z = 403.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.787 min., ESI+ found [M+H] =403.0. Example 606 1 -isopropyl -N -[(3S)-6 -fluoro -8 -methyl -4 - oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide

[02009] Amide coupling prepared in a manner similar to Method WX 142. The crude product was purified via RP-HPLC (32% to 62% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - isopropyl -N -[(3S)-6-fluoro -8 -methyl -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] pyrazole [3,4 -d] pyrimidine - 6-carboxamide (19.4 mg, 33%) as a white solid. H NMR (400 MHz, CD3OD) δ9.36 (s, 1H), 8.39 (s, 1H), 6.91 - 6.88 (m, 2H), 5.47 - 5.42 (m, 1H ), 5.12 - 5.09 (m, 1H), 4.76 - 4.72 (m, 1H), 4.51 (t, J = 10.4 Hz, 1H), 2.36 (s, 3H), 1.60 (d, J = 6.4 Hz, 6H). LCMS RT = 0.787 min., m/z = 399.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.787 min., ESI+ found [M+H] =399.0. Example 607 1 -isopropyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] pyrazole [3,4 - d] pyrimidine -6 -carboxamide

[02010] Amide coupling prepared in a manner similar to Method WX 142. The crude product was purified via RP-HPLC (35% to 65% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -isopropyl -N -[(3S)-7,9 -difluoro -2 -oxo -1,3,4,5 - tetrahydro -1 -benzazepin -3 -yl] pyrazole [3,4 -d] pyrimidine -6 - carboxamide (34.7 mg, 60%) as a white solid. 1H NMR (400 MHz, CD3OD) δ9.35 (s, 1H), 8.38 (s, 1H), 7.05 - 7.00 (m, 2H), 5.45 - 5.40(m, 1H ), 4.69 - 4.64 (m, 1H), 3.05 - 3.02 (m, 1H), 2.89 - 2.76 (m, 2H), 2.32 - 2.26 (m , 1H), 1.60 (d, J = 6.8 Hz, 6H). LCMS RT = 0.770min., m/z = 401.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.770min., ESI+ found [M+H] =401.0. Example 608

[02011] Method WX 096 1 -benzyl -N -(3R) -1,7,9 -trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 -yl -1 ,2,4 - triazole -3 -carboxamide Step1: 7 -bromo -1,9 -dimethyl -4,5 -dihydro -1H - imidazo [1,5 -a][1,3] diazepine -2(3H) -one

[02012] To a solution of 1,9 -dimethyl -4,5 - dihydro -3H -imidazo [1,5 -a][1,3] diazepin -2 -one (500 mg, 2.79 mmol) in chloroform (20 mL) 1-bromo-2,5-pyrrolidinedione (596 mg, 3.35 mmol) was added. The reaction mixture was heated at 70°C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 7-bromo-1,9-dimethyl-4,5-dihydro-3H-imidazo [ 1,5 -a][1,3] diazepin -2 -one (720mg, 100%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 2: 1,7,9 -trimethyl -4,5 -dihydro -3H - imidazo [1,5 -a][1,3] diazepin -2 -one

[02013] A mixture of 7-bromo-1,9-dimethyl - 4,5-dihydro -3H -imidazo [1,5-a] [1,3] diazepin -2 -one (600 mg, 2.32 mmol ), trimethylboroxine (584 mg, 4.65 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (170 mg, 0.23 mmol) and cesium carbonate (1.51 g, 4.65 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 95°C for 3 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (5% to 35% acetonitrile, 0.05% ammonium hydroxide in water) to provide 1,7,9-trimethyl-4,5-dihydro-3H-imidazo [1 ,5 -a][1,3] diazepin -2 -one (220 mg, 49%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: 3 -iodo -1,7,9 -trimethyl -4,5 -dihydro 3H -imidazo [1,5 -a][1,3] diazepin -2 -one

[02014] To a solution of 1,7,9 -trimethyl -4,5 - dihydro -3H -imidazo [1,5 -a] [1,3] diazepin -2 -one (220mg, 1.14 mmol) in dichloromethane (15 mL) was added N1,N1,N3,N3 -tetramethylpropane -1,3 -diamine (1.06 g, 9.11 mmol) and trimethylsilane iodine (1.82 g, 9.11 mmol) under -15oC . The reaction mixture was stirred at -15°C for 2 h and iodine (867 mg, 3.42 mmol) was added. The mixture was stirred at -15°C for another 2 h and finalized by the addition of saturated aqueous sodium sulfite (20 ml). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 3-iodo-1,7,9-trimethyl-4,5-dihydro-3H -imidazo [1,5 -a][1,3] diazepin - 2 -one (350 mg, 96%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: 3 -azide -1,9 -dimethyl -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -2 -one

[02015] A mixture of 3 -iodo -1,9 -dimethyl - 4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -2 -one (350 mg, 1.15 mmol ) and sodium azide (500 mg, 7.69 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 3 h and then diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide azide-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepine -2-one crude (250 mg, 99%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 4: 3 -amino -1,7,9 -trimethyl -4,5 -dihydro - 3H -imidazo [1,5 -a][1,3] diazepin -2 -one

[02016] A mixture of 3-azide -1,7,9 - trimethyl -4,5 -dihydro -3H -imidazo [1,5 -a] [1,3] diazepin -2 -one (250 mg, 1, 07 mmol) and Pd/C (10%, 114 mg, 0.11 mmol) in methanol (30 mL) was hydrogenated [2.04 bar (15 psi)] for 2 h and filtered. The filtrate was concentrated under reduced pressure to provide crude 3-amino-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (200 mg, 90%) in the form of a white solid, which was used in the next step in the form in which it was found . Step 5: 1 -benzyl -N -(3R) -1,7,9 -trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 - yl -1,2,4 - triazole -3 -carboxamide

[02017] A mixture of 3-amino -1,7,9 - trimethyl -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin - 2 -one (30 mg, 0. 14 mmol), 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol), 1-hydroxybenzotriazole (19 mg, 0.14 mmol) and 1-benzyl-1,2 acid, 4-Triazole-3-carboxylic acid (29 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (18% to 48% acetonitrile/0.05% ammonium hydroxide in water) to provide 1-benzyl-N-(1.7, 9 -trimethyl - 2 -oxo -2,3,4,5 -tetrahydro -1H -imidazo [1,5 -a][1,3] diazepin -3 -yl) -1H -1,2,4 -triazole - 3-carboxamide (40 mg, 71%) as a white solid. The racemic compound was separated using chiral SFC to provide:

[02018] 1 -benzyl -N -(3R) -1,7,9 -trimethyl -2 -oxo -4,5 -dihydro -3H -imidazo [1,5 -a][1,3] diazepin -3 - yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.482 min.) (12.1 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1H), 7.39 - 7.35 (m, 5H), 5.48 (s, 2H), 4.57 - 4.52 (m, 1H ), 4,254.19 (m, 1H), 3.83 - 3.79 (m, 1H), 3.30 (s, 3H), 2.68 - 2.62 (m, 1H), 2.34 ( s, 3H), 2.16 (s, 3H), 2.09 - 2.05 (m, 1H). LCMS RT = 1.332 min.; m/z = 394.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.332 min., ESI+ found [M+H] = 394.2.

[02019] SFC Conditions: Column: Chiralpak OJ -3 150 x 4.6 mm I.D., 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 609

[02020] WX 140 Method 1 -(2,6 -difluorophenyl) -N -[(6S) -2,4 -dimethyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide Step 1: (Z) -2,4,6 -trichloro -5 -((2 -(2,6 - difluorophenyl) hydrazono) methyl) pyrimidine

[02021] To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.0 g, 4.73 mmol) in tetrahydrofuran (400 mL) was added (2,6-difluorophenyl) hydrazine (682 mg, 4 .7 3 mmol) under 0oC. The mixture was stirred at 20°C for 1.5 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to provide (Z) -2,4,6 -trichloro -5 -( (2 - (2,6 - difluorophenyl) hydrazono) methyl) pyrimidine (1.2 g, 75%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 2: 4,6-dichloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine

[02022] A solution of 2,6-difluoro-N-[(Z)-(2,4,6-trichloropyrimidin-5-yl) methyleneamino] aniline (600 mg, 1.78 mmol) in acetonitrile (4 mL) was heated under 150oC for 1.5 h under microwave conditions. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide 4,6-dichloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (500 mg, 93%) as a white solid, which was used in the next step as it was. Step 3: 6-chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine

[02023] A mixture of 4,6-dichloro-1-(2,6-difluorophenyl)pyrazolo [3,4-d] pyrimidine (500 mg, 1.66 mmol), zinc (326 mg, 4.98 mmol) in water (10 mL) and tetrahydrofuran (10 mL) was heated under 100oC for 1 h. After cooling, the reaction was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (1 x 10 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 -200 mesh, 0 -20% ethyl acetate in petroleum ether) to provide 6-chloro-1-(2,6-difluorophenyl) pyrazole [3, 4 -d] pyrimidine (350 mg, 79%) in the form of a white solid, which was used in the next step in the form in which it was. Step 4: 1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

[02024] A solution of 1,4-diazabicyclo [2,2,2] octane (63 mg, 0.56 mmol) and sodium cyanide (110 mg, 2.25 mmol) in dimethyl sulfoxide (8 mL) 6-chloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (300 mg, 1.13 mmol) in water (4 mL) was added. The reaction mixture was stirred at 25oC for 12 h and extracted with ethyl acetate (3 x 20ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 1 -(2,6 - difluorophenyl)pyrazole [3,4 -d ] pyrimidine-6-carbonitrile (100 mg, 35%) in the form of a yellow solid, used in the next step in the form in which it was. Step 5: methyl 1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

[02025] To a solution of 1 -(2,6 difluorophenyl)pyrazolo [3,4 -d] pyrimidine-6-carbonitrile (100 mg, 0.39 mmol) in methanol (5 mL) was added HCl (4 N in methanol, 5 mL). The reaction mixture was stirred at 20°C for 3 h and concentrated under reduced pressure to provide crude methyl 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carboxylate (50 mg, 44 %) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 6: 1-(2,6-difluorophenyl)-1H-pyrazole[3,4-d]pyrimidine-6-carboxylic acid

[02026] A mixture of methyl 1 -(2,6 - difluorophenyl)2 pyrazole [3,4 -d] pyrimidine -6 - carboxylate (40 mg, 0.14 mmol) and lithium hydroxide (23 mg, 0.55 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 20oC for 2 h. The organic solvent was concentrated under reduced pressure and the aqueous solution was adjusted to pH = 3 by adding 1N HCl. The mixture was extracted with dichloromethane (2 x 10 mL). The combined organic layers were concentrated under reduced pressure to provide crude 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 78%) as a solid. yellow color, which was used in the next stage as it was. Step 6: 1 -(2,6-difluorophenyl) -N -[(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] pyrazole [3,4 -d] pyrimidine -6 - carboxamide

[02027] A mixture of (6S) -6 -amino -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (21 mg, 0.11 mmol), 1-hydroxy benzotriazole (35 mg, 0.26 mmol), 1-(2,6-difluorophenyl) pyrazolo[3,4-d] pyrimidine-6-carboxylic acid (30 mg, 0.11 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20oC for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (30% to 60% acetonitrile/0.05% HCl in water) to give 1-(2,6-difluorophenyl)-N-[ (6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole [3,4 -d] pyrimidine -6 - carboxamide (25mg, 48%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ9.58 (s, 1H), 8.76 (s, 1H), 7.77 - 7.68 (m, 1H), 7.35 - 7.31 (m, 2H ), 6.35 (s, 1H), 4.73 - 4.71 (m, 1H), 4.47 - 4.40(m, 1H), 4.38 - 4.31 (m, 1H), 3.38 (s, 3H), 3.00 - 2.92 (m, 1H), 2.42 - 2.30 (m, 4H). LCMS RT = 0.934 min.; m/z = 453.3 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.934 min., ESI+ found [M+H] =453.3. Example 610

[02028] WX 103 Method (S) -N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) -5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide Step 1: 1 -amino -5 -phenyl -pyrrolidin -2 -one

[02029] To a solution of tert-butyl N -(2-oxo-5-phenyl-pyrrolidin-1-yl)carbamate (350 mg, 1.3 mmol) in ethyl acetate (3 mL) was added HCl (4N in ethyl acetate, 3.0 mL, 12.0 mmol). The mixture was stirred at 20°C for 1 h and concentrated under reduced pressure. The residue was finished by adding saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (3 x 20 mL), brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 1-amino-5-phenyl-pyrrolidin-2 -one crude (190 mg, 85%) as a white solid. 1H NMR (400 MHz, CDCI3): δ7.42 - 7.32 (m, 3H), 7.24 (d, J = 7.6 Hz, 2H), 4.66 - 4.62 (m, 1H) , 3.95 (br. s., 2H), 2.63 - 2.45 (m, 3H), 1.91 - 1.88 (m, 1H). Step 2: ethyl (2Z) -2 -amino -2 -(2 -oxo -5 - phenyl -pyrrolidin -1 -yl) imino -acetate

[02030] To a stirred solution of 1-amino-5-phenyl-pyrrolidin-2-one (270 mg, 1.53 mmol) in ethanol (8.0 mL) was added ethyl amino (thioxo) acetate (224 mg, 1.69 mmol). The mixture was stirred at 90oC for 4 h and cooled to room temperature. The solution was diluted with ethyl acetate (15 mL), washed with water (2 x 5 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to provide ethyl (2Z) - Crude 2-amino-2-(2-oxo-5-phenyl-pyrrolidin-1-yl)imino-acetate (400 mg, 95%) as a yellow-colored oil. LCMS RT = 0.581 min., m/z = 275.9 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.581 min., ESI+ found [M+H] = 275.9. Step 3: (S) -ethyl 5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate and (R) -ethyl 5 -phenyl - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate

[02031] A solution of ethyl (2Z) -2 -amino -2 - (2 -oxo -5 -phenyl -pyrrolidin -1 -yl) imino -acetate (400 mg, 1.45 mmol) in POCl3 (2 mL) was subjected to stirring at 120oC for 1 h. After cooling, the mixture was finished by adding saturated sodium bicarbonate (15 mL). The resulting solution was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 70% ethyl acetate in petroleum) to give ethyl 5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate (310 mg, 81%) as a yellow oil. The racemic material was separated using chiral SFC to provide:

[02032] (S) -ethyl 5 -phenyl -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate (Peak 1, retention time = 4.063 min .) (130 mg, 42%) in the form of a yellow colored oil. LCMS RT = 0.629 min., m/z = 257.8 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.629 min., ESI+ found [M+H] = 257.8.

[02033] (R) -ethyl 5 -phenyl -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate (Peak 1, retention time = 5.844 min .) (135 mg, 43%) in the form of a yellow colored oil. LCMS RT = 0.631 min., m/z = 257.8 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.631 min., ESI+ found [M+H] = 257.8.

[02034] SFC condition: column: Lux Cellulose -2 150x4.6 mm ID, 3 μm mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 5 to 40 B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Step 4: (S)-5-phenyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole-2-carboxylic acid

[02035] To a solution of ethyl (5S) -5 -phenyl - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole - 2 - carboxylate (130 mg, 0. 51 mmol) in tetrahydrofuran (2 mL)/methanol (2 mL)/water (1 mL) hydrated lithium hydroxide (127.2 mg, 3.03 mmol) was added. The mixture was stirred at 25oC for 1 h and diluted with water (10 ml). The solution was adjusted to pH = 4 -5 by adding 1N HCl. The mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide (S)-5-phenyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2, 4] crude -2-carboxylic triazole (105 mg, 90%) in the form of a light yellow solid, which was used in the next step in the form in which it was. Step 5: (S) -N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepine -6 -yl) -5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02036] A mixture of (6S) -6 -amino -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (30 mg , 0.15 mmol), (S) -5 -phenyl -6,7 - dihydro -5H -pyrrole [1,2 -b] [1,2,4] triazole -2 - carboxylic acid (35 mg, 0. 15 mmol), N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (44 mg, 0.23 mmol) and 1H -benzo[d] [1,2,3] triazol-1-ol (31 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25°C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (26% to 56% acetonitrile / 0.05% ammonium hydroxide in water) to give (S) -N -((S) - 2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -phenyl -6,7 - dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide (48.3 mg, 76%) as a white solid. 1HNMR (400 MHz, CD3OD) δ7.38 - 7.34 (m, 3H), 7.21 - 7.20(m, 2H), 6.10 (s, 1H), 5.55 - 5.52 ( m, 1H), 4.53 - 4.48 (m, 1H), 4.28 - 4.26 (m, 1H), 4.21 - 4.18 (m, 1H), 3.31 (s, 3H), 3.26 - 3.24 (m, 1H), 3.14 - 3.12 (m, 1H), 3.06 - 3.04 (m, 1H), 2.91 - 2.80 ( m, 1H), 2.66 - 2.64 (m, 1H), 2.24 - 2.20(m, 4H). LCMS RT =0.752 min., m/z = 406.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.752 min., ESI+ found [M+H] = 406.1. Example 611 (5S) -5 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02037] Amide coupling prepared in a manner similar to Method WX 103. The crude product was purified via RP-HPLC (35% to 65% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5S) -5 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (21.9 mg, 34%) as a white solid. 1HNMR (400 MHz, CD3OD) δ7.38 - 7.34 (m, 3H), 7.22 - 7.20(m, 2H), 6.94 - 6.84 (m, 2H), 5.57 - 5.53 (m, 1H), 5.07 - 5.02 (m, 1H), 4.66 - 4.62 (m, 1H), 4.50 - 4.47 (m, 1H), 3, 25- 3.15 (m, 1H), 3.13 - 3.03 (m, 2H), 2.69 - 2.66 (m, 1H). LCMS RT =0.800 min., m/z = 426.0 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.800 min., ESI+ found [M+H] = 426.0. Example 612 (5S) -5 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02038] Amide coupling prepared in a manner similar to Method WX 103. The crude product was purified via RP-HPLC (40% to 70% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5S) -5 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 - tetrahydro -1 -benzazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (36.7 mg, 57%) as a white solid. 1HNMR (400 MHz, CD3OD) δ7.40- 7.33 (m, 3H), 7.21 - 7.20(m, 2H), 7.01 - 6.97 (m, 2H), 5.55 - 5.52 (m, 1H), 4.57 - 4.52 (m, 1H), 3.24 - 2.95 (m, 4H), 2.82 - 2.81 (m, 1H), 2, 67 - 2.62 (m, 2H), 2.23 - 2.17 (m, 1H). LCMS RT =0.798 min., m/z = 424.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.798 min., ESI+ found [M+H] = 424.1. Example 613 (5S) -5 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [ 1,2 -b][1,2,4] triazole -2 -carboxamide

[02039] Amide coupling prepared in a manner similar to Method WX 103. The crude product was purified via RP-HPLC (38% to 68% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5S) -5 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1 ,2 - b][1,2,4] triazole -2 -carboxamide (22.5 mg, 39%) as a white solid. 1HNMR (400 MHz, CD3OD) δ7.40- 7.30 (m, 6H), 7.29 - 7.20(m, 3H), 5.54 (t, J = 6.8 Hz, 1H), 4 .98 - 4.95 (m, 1H), 4.58 - 4.54 (m, 1H), 4.40- 4.35 (m, 1H), 3.39 (s, 3H), 3.27 - 3.24 (m, 1H), 3.14 - 3.04 (m, 2H), 2.67 - 2.65 (m, 1H). LCMS RT =0.823 min., m/z = 404.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.823 min., ESI+ found [M+H] = 404.1Example 614 . (5S) -5 -phenyl -N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02040] Amide coupling prepared in a manner similar to Method WX 103. The crude product was purified via RP-HPLC (22% to 52% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5S) -5 -phenyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (27.6 mg, 47%) as a white solid. 1HNMR (400 MHz, CD3OD) δ7.51 (s, 1H), 7.38 - 7.34 (m, 3H), 7.22 - 7.20 (m, 2H), 6.29 (s, 1H) , 5.55 (t, J = 6.8 Hz, 1H), 4.51 - 4.38 (m, 2H), 4.26 - 4.25(m, 1H), 3.34 (s, 3H ), 3.26 - 3.24 (m, 1H), 3.14 - 3.04 (m, 2H), 2.88 - 2.83 (m, 1H), 2.67 - 2.65 (m , 1H), 2.28 - 2.23 (m, 1H). LCMS RT =0.753 min., m/z = 392.0 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.753 min., ESI+ found [M+H] = 392.0. Example 615 (5R) -5 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - il] - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide

[02041] Amide coupling prepared in a manner similar to Method WX 108. The crude product was purified via RP-HPLC (23% to 53% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5R) -5 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (16 mg, 26%) as a white solid. H NMR (400 MHz, CD3OD) δ7.41 - 7.23 (m, 3H), 7.23 - 7.21 (m, 2H), 6.10 (s, 1H), 5.56 - 5.52 (m, 1H), 4.53 - 4.48 (m, 1H), 4.29 - 4.19 (m, 2H), 3.31 (s, 3H), 3.26 - 3.24 (m , 1H), 3.15 - 3.05 (m, 2H), 2.85 - 2.81 (m, 1H), 2.67 - 2.60 (m, 1H), 2.25 - 2.21 (m, 4H). LCMS RT = 0.759 min.; m/z = 406.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.759 min., ESI+ found [M+H] = 406.1. Example 616

[02042] WX 155 Method N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] spiro [5H –furo [3,4 -d] pyrimidine - 7,1' - cyclobutane ] -2 –carboxamide Step 1: 2' -chloro -5'H -spiro[cyclobutane -1,7' -furo[3,4 -d] pyrimidin] -5' -one

[02043] under a solution of 2,2,6,6 - tetramethylpiperidine (26.7 g, 189.2 mmol) in tetrahydrofuran (300 mL) n-butyl lithium (2.5 M in hexanes, 76.0 mL, 189.2 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (10.0 g, 63.1 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and cyclobutanone (13.2 g, 189.2 mmol) was added. After addition, the reaction mixture was stirred at 25°C for 16 h and finalized by addition of saturated ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 5% ethyl acetate in petroleum ether) to provide 2'-chlorospiro [cyclobutane -1,7' - fur [3,4 -d] pyrimidine] -5'-one (4.2 g, 32%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ8.97 (s, 1H), 2.84 - 2.72 (m, 2H), 2.66 - 2.57 (m, 2H), 2.29 - 2.16 ( m, 1H), 2.15 - 2.03 (m, 1H). Step 2: 2' -chloro -5'H -spiro[cyclobutane -1,7' -furo[3,4 -d] pyrimidin] -5' -ol

[02044] To a solution of 2'-chlorospiro [cyclobutane -1,7'-furo[3,4-d] pyrimidine]-5'-one (1.0 g, 4.75 mmol) in toluene (5 mL ) diisobutyl aluminum hydride (14.2 mL, 14.2 mmol, 1.0 M in toluene) was added under -70°C. The resulting solution was stirred at -70oC for 0.5 h and finalized by adding saturated ammonium chloride (20 mL). The mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate to provide 2'-chloro-5'H-spiro[cyclobutane-1,7'-furo[3,4-d]pyrimidin]-5'-ol in crude (850 mg, 84%) as a yellow oil. LCMS RT = 1.58 min., m/z = 213.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.58 min., ESI+found [M+H] = 213.1. Step 3: 2' -chloro -5'H -spiro[cyclobutane -1,7' -furo[3,4 -d] pyrimidine]

[02045] To a solution of 2' -chloro -5'H -spiro [cyclobutane -1,7' -furo [3,4 -d] pyrimidin] -5' -ol (850 mg, 4.0 mol) in dichloromethane (10 mL) was added trifluoroacetic acid (4.6 g, 40.0 mmol) under 0°C. The mixture was stirred for 30 min. under 0°C and triethylsilane (4.6 g, 39.98 mmol) was added. After addition, the mixture was stirred for 12 h at 25°C and finalized by addition of saturated sodium bicarbonate (20 mL). The resulting solution was extracted with dichloromethane (3 x 20mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 35% ethyl acetate in petroleum ether to give 2'-chloro-5'H-spiro [cyclobutane -1,7' - hole [3,4 -d] pyrimidine] (200 mg, 32%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ8.37 (s, 1H), 5.00 (s, 2H), 2.50 - 2.40 (m, 4H), 2.14 - 2.00 (m, 1H), 1.91 - 1.79 (m, 1H). LCMS RT = 1.94 min. , m/z = 197.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.94 min., ESI+found [ M+H] = 197.1. Step 4: 5'H -spiro[cyclobutane -1,7' -furo[3,4 -d] pyrimidine] -2' -carbonitrile

[02046] To a solution of 2' -chloro -5'H - spiro[cyclobutane -1,7' -furo[3,4 -d] pyrimidine] (200 mg, 1.02 mmol) in dimethyl sulfoxide (2 mL) and water (1 mL) 1,4-diazabicyclo[2,2,2] octane (143 mg, 1.27 mmol) and sodium cyanide (150 mg, 3.06 mmol) were added. The reaction mixture was stirred at 25oC for 16 h and diluted with water (15 mL). The mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 5'H-spiro[cyclobutane-1,7'-furo[3,4-d] pyrimidine] -2' - crude carbonitrile (200 mg, 94%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 5: methyl 5'H -spiro[cyclobutane -1,7'-furo[3,4-d]pyrimidine]-2'-carboxylate

[02047] A mixture of 5'H -spiro[cyclobutane -1,7'-furo[3,4-d]pyrimidine]-2'-carbonitrile (200 mg, 1.07 mmol) in methanol (5 mL) was HCl (4N in methanol, 5 mL) was added. The mixture was heated at 70oC for 12 h and concentrated under reduced pressure to obtain methyl 5'H-spiro[cyclobutane-1,7'-furo[3,4-d]pyrimidine] -2'-carboxylate crude (225 mg, 98%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 6: 5'H -spiro[cyclobutane -1,7'-furo[3,4-d]pyrimidine]-2'-carboxylic acid

[02048] A mixture of methyl 5'H - spiro[cyclobutane -1,7' - furo[3,4 -d] pyrimidine] -2' - carboxylate (220 mg, 1 mmol) and lithium hydroxyl hydrate (419 mg, 10 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 20oC for 12 h. The organic solvent was evaporated under reduced pressure and the aqueous layer was adjusted to pH = 2 -3 by adding 1N HCl. The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 5'H-spiro[cyclobutane-1,7'-furo[3,4-d]pyrimidine]-2'-carboxylic acid in crude (150 mg, 73%) as a yellow solid. LCMS RT = 0.40 min., m/z = 207.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 0.40 min., ESI+found [M+H] = 207.1. Step 7: N -[(3S)-5-methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7, 1'-cyclobutane ]-2-carboxamide

[02049] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (30 mg, 0.16 mmol), spiro acid [5H -furo[ 3,4 -d] pyrimidine -7,1' - cyclobutane ] -2 -carboxylic acid (35 mg, 0.17 mmol), N1 -((ethylimino)methylene) -N3,N3 - dimethylpropane -1,3 - hydrochloride diamine (45 mg, 0.23 mmol) and 1H -benzo [d][1,2,3] triazol -1 -ol (32 mg, 0.23 mmol) in N,N - dimethylformamide (3 mL) was subjected stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25% to 55% acetonitrile/0.05% ammonium hydroxide in water) to give N -[(3S)-5-methyl - 4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] spiro [5H -furo [3,4 - d] pyrimidine -7,1' -cyclobutane ] -2 -carboxamide (25.1 mg , 41.9%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ8.78(s, 1H), 7.43 (m, 1H), 7.35 - 7.20(m, 3H), 5.13 (s, 2H), 5, 08 - 4.99 (m, 1H), 4.71 (m, 1H), 4.43 (m, 1H), 3.44 (s, 3H), 2.59 - 2.47 (m, 4H) , 2.35 - 2.20(m, 1H), 1.92 (m, 1H). LCMS RT = 1.65 min., m/z = 381.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.65 min., ESI+found [M+H] = 381.1. Example 617 N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl]spiro[5H -furo[3,4 -d] pyrimidine -7 ,1'-cyclobutane]-2-carboxamide

[02050] Amide coupling prepared in a manner similar to Method WX 155. The crude product was purified via RP-HPLC (25% to 55% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 - benzoxazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine - 7, 1'-cyclobutane]-2-carboxamide (22 mg, 38%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.79 (s, 1H), 6.99 - 6.80 (m, 2H), 5.22 - 5.06 (m, 3H), 4.81 - 4.75 (m, 1H), 4.59 - 4.47 (m, 1H), 2.61 - 2.45 (m, 4H), 2.35 - 2.21 (m, 1H), 1.92 (m , 1H). LCMS RT = 1.62 min., m/z = 403.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.62 min., ESI+found [M+H] = 403.1. Example 618 N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 - tetrahydro -1 -benzazepin -3 -yl]spiro[5H -furo[3,4 -d] pyrimidine -7 ,1'-cyclobutane]-2-carboxamide

[02051] Amide coupling prepared in a manner similar to Method WX 155. The crude product was purified via RP-HPLC (22% to 52% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 - benzazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine - 7, 1'-cyclobutane]-2-carboxamide (17 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78(s, 1H), 7.07 - 6.98 (m, 2H), 5.13 (s, 2H), 4.70- 4.57 (m, 1H), 3.08 - 2.96 (m, 1H), 2.89 - 2.75 (m, 2H), 2.59 - 2.47 (m, 4H), 2.33 - 2.19 ( m, 2H), 1.97 - 1.87 (m, 1H). LCMS RT = 1.60 min., m/z = 401.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.60 min., ESI+found [M+H] = 401.1. Examples 619 and 620 (7S)-7-methyl -7 -propyl -N -[(3S) -6,8 - difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 - yl] -5H - furo[3,4 -d] pyrimidine -2 -carboxamide and (7R) -7 -methyl -7 -propyl -N -[(3S) -6,8 - difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 - yl] -5H -furo[3,4 -d] pyrimidine -2 -carboxamide

[02052] Amide coupling prepared in a similar manner to Method WX N. The racemic compound obtained was separated using chiral SFC to provide:

[02053] (7S) -7 -methyl -7 -propyl -N -[(3S) - 6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin - 3 -yl] -5H -furo[3,4-d] pyrimidine -2 -carboxamide (Peak 1, retention time 2.196 min.) (11.7 mg, 39%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.83 (s, 1H), 6.97 — 6.88 (m, 2H), 5.17 -5.07 (m, 3H), 4.79 - 4.74 (m, 1H), 4.58 - 4.52 (m, 1H), 1.93 - 1.83 (m, 2H), 1.50 - 1.40(m, 4H), 1.07 - 1 .01 (m, 1H), 0.90 - 0.86 (m, 3H). LCMS RT = 0.815 min.; m/z = 419.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.815 min., ESI+ found [M+H] = 419.0.

[02054] (7R) -7 -methyl -7 -propyl -N -[(3S) - 6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin - 3 -yl] -5H -furo[3,4-d] pyrimidine -2 -carboxamide (Peak 2, retention time 2.316 min.), (8.7 mg, 29%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.83 (s, 1H), 6.97 - 6.88 (m, 2H), 5.17 - 5.07 (m, 3H), 4.79 - 4.74 (m, 1H), 4.58 - 4.52 (m, 1H), 1.93 - 1.83 (m, 2H), 1.50 - 1.40 (m, 4H), 1.07 - 1 .01 (m, 1H), 0.89 - 0.86 (m, 3H). LCMS RT = 0.997 min.; m/z = 419.3 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.997 min., ESI+ found [M+H] = 419.3.

[02055] SFC Conditions: Column: Chiralcel OJ -3 100 x 4.6 mm ID, 3 µm Mobile phase: A: CO2 B: methanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40oC. Example 621 (5R) -5 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02056] Amide coupling prepared in a manner similar to Method WX 108. The crude product was purified via RP-HPLC (30% to 60% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5R) -5 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 - dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (18 mg, 27%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.41 - 7.35 (m, 3H), 7.23 - 7.21 (m, 2H), 6.92 - 6.84 (m, 2H), 5.57 - 5.53 (m, 1H), 5.07 - 5.03 (m, 1H), 4.67 - 4.65 (m, 1H), 4.63 - 4.48 (m, 1H), 3 .27 - 3.25(m, 1H), 3.14 - 3.13 (m, 1H), 3.08 - 3.06 (m, 1H), 2.70- 2.67 (m, 1H) . LCMS RT = 0.796 min.; m/z = 426.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.796 min., ESI+ found [M+H] = 426.0. Example 622 (5R) -5 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02057] Amide coupling prepared in a manner similar to Method WX 108. The crude product was purified via RP-HPLC (26% to 56% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5R) -5 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 - tetrahydro -1 -benzazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (29 mg, 44%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.40 - 7.34 (m, 3H), 7.22 - 7.21 (m, 2H), 7.00 - 6.98 (m, 2H), 5.56 - 5.52 (m, 1H), 4.60 - 4.53 (m, 1H), 3.27 - 3.25(m, 1H), 3.12 - 3.10 (m, 1H), 3 .07 - 3.05 (m, 1H), 2.96 - 2.93 (m, 1H), 2.85 - 2.82 (m, 1H), 2.66 - 2.63 (m, 2H) , 2.21 - 2.16 (m, 1H). LCMS RT = 0.797 min.; m/z = 424.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.797 min., ESI+ found [M+H] = 424.0. Example 623

[02058] WX 108 Method (5R) -5 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [ 1,2 -b][1,2,4] triazole -2 -carboxamide Step 1: (5R) -5 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylic acid

[02059] To a solution of ethyl (5R) -5 -phenyl - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole - 2 - carboxylate (130 mg, 0. 51 mmol) in tetrahydrofuran (2 mL)/methanol (2 mL)/water (1 mL) hydrated lithium hydroxide (127.2 mg, 3.03 mmol) was added. The mixture was stirred at 25oC for 1 h and diluted with water (10 ml). The solution was adjusted to pH = 4 -5 by adding 1N HCl. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide (5S)-5-phenyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2, 4] crude -2-carboxylic triazole (110 mg, 95%) in the form of a light yellow solid, which was used in the next step in the form in which it was. Step 2: (5R) -5 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02060] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (30 mg, 0.16 mmol), acid (5R) -5 - phenyl -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxylic acid (30 mg, 0.16 mmol), N1 -((ethylimino) methyl ene hydrochloride ) -N3,N3 -dimethylpropane -1,3 -diamine (30 mg, 0.15 mmol) and 1H -benzo [d] [1,2,3] triazol -1 -ol (21 mg, 0.16 mmol ) in N,N - dimethylformamide (5 mL) was stirred at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile, 0.05% ammonium hydroxide in water) to provide (5R)-5-phenyl-N-[ (3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2 -b][1,2, 4] triazole -2 -carboxamide (29 mg, 55%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.41 - 7.21 (m, 9H), 5.54 (t, J = 6.8 Hz, 1H), 5.00 - 4.96 (m, 1H), 4.59 - 4.56 (m, 1H), 4.41 - 4.36 (m, 1H), 3.40(s, 3H), 3.27 - 3.24 (m, 1H), 3, 15 - 3.04 (m, 2H), 2.67 - 2.65 (m, 1H). LCMS RT = 0.801 min.; m/z = 404.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.801 min., ESI+ found [M+H] =404.1. Example 624 (5R) -5 -phenyl -N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4]

[02061] Amide coupling prepared in a manner similar to Method WX 108. The crude product was purified via RP-HPLC (28% to 58% acetonitrile / 0.05% ammonium hydroxide in water) to provide ( 5R) -5 -phenyl -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 6,7 -dihydro -5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (17.4 mg, 34%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.51 (s, 1H), 7.38 - 7.34 (m, 3H), 7.22 - 7.20 (m, 2H), 6.29 (s, 1H ), 5.55 (t, J = 6.8 Hz, 1H), 4.51 - 4.38 (m, 2H), 4.26 - 4.25(m, 1H), 3.34 (s, 3H), 3.26 - 3.24 (m, 1H), 3.14 - 3.04 (m, 2H), 2.88 -2.83 (m, 1H), 2.67 - 2.65 ( m, 1H), 2.28 - 2.23 (m, 1H). LCMS RT = 0.727 min.; m/z = 392.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.727 min., ESI+ found [M+H] =392.0. Examples 625 and 626

[02062] WX 113 Method (7S) -7 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2-b][1,2,4] triazole -2 -carboxamide and (7R) -7 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3, 5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 –carboxamide Step 1: 1 -amino -3 -phenylpyrrolidin -2 -one

[02063] To a solution of tert-butyl N -(2-oxo-3-phenyl-pyrrolidin-1-yl)carbamate (1.4 g, 5.1 mmol) in ethyl acetate (20 mL) was added HCl (4N in ethyl acetate, 12.0 mL, 48.0 mmol). The mixture was stirred at 20°C for 3 h and concentrated under reduced pressure. The residue was slowly quenched by adding saturated sodium bicarbonate (30 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide crude 1-amino-3-phenyl-pyrrolidin-2-one (590 mg, 66%) as a white solid, which was used in the next step in the form in which it was . Step 2: Ethyl acetate 2 -imino -2 -((2 -oxo -3 -phenylpyrrolidin -1 -yl)amino)

[02064] To a solution of 1-amino-3-phenyl-pyrrolidin-2-one (590 mg, 3.35 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (1458 mg , 10.04 mmol). The mixture was stirred at 40°C for 12 h and concentrated under reduced pressure to obtain crude ethyl (2Z)-2-amino-2-(2-oxo-3-phenyl-pyrrolidin-1-yl) imino-acetate ( 1370 mg, 100%), which was used in the next step as it was. Step 3: ethyl 7 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxylate

[02065] A solution of ethyl (2Z) -2 -amino -2 - (2 -oxo -3 -phenyl -pyrrolidin -1 -yl) imino -acetate (1370 mg, 4.98 mmol) in phosphorus oxychloride (5 mL) was subjected to stirring at 120oC for 1 h. After cooling, the mixture was slowly quenched by adding saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide ethyl 7-phenyl-6,7-dihydro-5H-pyrrole [1 ,2 - b][1,2,4] triazole -2 -carboxylate (390 mg, 31%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ7.40- 7.14 (m, 5H), 4.45 (q, J = 8.0 Hz, 4H), 4.40- 4.36 (m, 1H), 4.26 - 4.23 (m, 1H), 3.29 - 3.22 (m, 1H), 2.78- 2.70(m, 1H), 1.40(t, J = 7.2 Hz, 3H). LCMS RT = 1.95 min., m/z = 258.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.95 min., ESI+found [M+H] = 258.1. Step 4: 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

[02066] A mixture of ethyl (7S) -7 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxylate (340 mg, 1.32 mmol) and hydrated lithium hydroxide (555 mg, 13.22 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred under 20oC for 12 h. The organic solvent was evaporated under reduced pressure and the aqueous residue was adjusted to pH = 2 -3 by adding 20% HCl. The mixture was extracted with dichloromethane (5 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 7-phenyl-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole acid -2 - crude carboxylic acid (260 mg, 85%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 5: (7S)-7-phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide and (7R) -7 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02067] A mixture of 7-phenyl-6,7-dihydro-5H-pyrrole [1,2-b][1,2,4] triazole-2-carboxylic acid (33 mg, 0.14 mmol), hydrochloride of 1-(3-dimethylamino propyl)-3-ethylcarbodiimide (33 mg, 0.17 mmol), 1-hydroxy benzotriazole (29 mg, 0.21 mmol) and (3s)-3-amino-6,8-difluoro -3,5-dihydro -2H -1,5 -benzoxazepin -4 -one (28 mg, 0.13 mmol) in N,N -dimethylformamide (3 mL) was stirred at 25oC for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (22% to 52% acetonitrile / 0.05% ammonium hydroxide in water) to give N -[(3S) -6.8 - difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -7 -phenyl -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2, 4] triazole -2 -carboxamide (40 mg, 72%) as a white solid.

[02068] The racemic material was separated using chiral SFC to provide: (7S) -7 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H - 1,5 - benzoxazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazol -2 -carboxamide (Peak 1, retention time 6.694 min.) (20 mg, 50%) as white solids. 1H NMR (400 MHz, CD3OD) δ7.38 - 7.33 (m, 2H), 7.31 - 7.26 (m, 3H), 6.96 - 6.89 (m, 1H), 6.88 - 685 (m, 1H), 5.08 - 5.04 (m, 1H), 4.68 - 4.64 (m, 1H), 4.56 - 4.37 (m, 3H), 4.32 - 4.23 (m, 1H), 3.26 - 3.25(m, 1H), 2,782.66 (m, 1H). LCMS RT = 2.22 min., m/z = 426.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 2.22 min., ESI+ found [M+H] = 426.1.

[02069] (7R) -7 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,7 - dihydro -5H -pyrrole [1,2-b][1,2,4] triazole -2 -carboxamide (Peak 2, retention time 7.313 min.) (19 mg, 48%) as a colored solid white. 1H NMR (400 MHz, CD3OD) δ7.29 - 7.22 (m, 2H), 7.21 - 7.14 (m, 3H), 6.87 - 6.79 (m, 1H), 6.78 - 6.75 (m, 1H), 4.98 - 4.94 (m, 1H), 4.58 - 4.56 (m, 1H), 4.48 - 4.27 (m, 3H), 4 .32 - 4.19 (m, 1H), 3.18 - 3.14 (m, 1H), 2.67 - 2.56 (m, 1H). LCMS RT = 2.23 min., m/z = 426.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 2.23 min., ESI+ found [M+H] = 426.2.

[02070] SFC Conditions: Column: Chiralcel AD -3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate), Gradient: from 5% to 40 % B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature: 40oC. Examples 627 and 628 (7S)-7-phenyl -N -[(3S)-7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,7 -dihydro - 5H -pyrrole [1,2-b][1,2,4] triazole -2 -carboxamide and (7R) -7 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1, 3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02071] Amide coupling prepared in a manner similar to Method WX 113. Racemic material (70 mg) was separated using chiral SFC to provide:

[02072] (7S) -7 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (Peak 1, retention time = 6.794 min.) (34.1 mg, 48.2%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ7.37 - 7.26 (m, 5H), 7.02 - 6.98 (m, 2H), 4.60 - 4.51 (m, 2H), 4.43 - 4.40(m, 1H), 4.30 - 4.27 (m, 1H), 3.30 - 3.27 (m, 1H), 2.98 - 2.96 (m, 1H), 2 .83 - 2.81 (m, 1H), 2.71 - 2.63 (m, 2H), 2.21 - 2.19 (m, 1H). LCMS RT = 1,730 min., m/z = 424.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.730 min., ESI+ found [M+H] = 424.1.

[02073] (7R) -7 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,7 - dihydro -5H -pyrrole [1,2-b][1,2,4] triazole -2 -carboxamide (Peak 2, retention time = 7.082 min.) (32.5 mg, 46%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ7.37 - 7.33 (m, 2H), 7.32 - 7.26 (m, 3H), 7.01 - 6.98 (m, 2H), 4.59 - 4.50 (m, 2H), 4.45 - 4.40(m, 1H), 4.27 - 4.25(m, 1H), 3.30 - 3.27 (m, 1H), 2 .98 - 2.96 (m, 1H), 2.83 - 2.81 (m, 1H), 2.71 - 2.63 (m, 2H), 2.22 - 2.19 (m, 1H) . LCMS RT = 1,730 min., m/z = 424.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.730 min., ESI+ found [M+H] = 424.1,

[02074] SFC condition: column: Chiralpak AD - 3 (250 mm*30 mm, 5 um), 3 um mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: from 5 to 40 B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 629

[02075] WX 125 Method (8R) -8 -(2-fluorophenyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 -carboxamide Step 1: (3 -bromo -1 -(2 -((tetrahydro -2H - pyran -2 -yl)oxy) ethyl) -1H -1,2,4 -triazol -5 -yl)(2 - fluorophenyl) methanol

[02076] A solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2.0 g, 5.6 mmol) in tetrahydrofuran (20mL) was n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) added under -78°C. The mixture was stirred at -78°C for 1 h and then a solution of 2-fluorobenzaldehyde (1.4 g, 11.27 mmol) in THF (2 mL) was added. After addition, the mixture was stirred at -78°C for another 1 h and then finalized by addition of saturated ammonium chloride (10 mL). The resulting mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl )-1,2,4-triazol-3-yl]-(2-fluorophenyl) methanol (1.0 g, 44%) as a light yellow oil. LCMS RT = 0.64 min., m/z = 401.7 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.64 min., ESI+ found [M+H] = 401.7. Step 2: 2 -bromo -8 -(2-fluorophenyl) -6,8 -dihydro -5H - [1,2,4] triazolo [5,1 -c][1,4] oxazine

[02077] A mixture of [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-(2-fluorophenyl) methanol (1000 mg, 2.5 mmol) and p -toluenesulfonic acid (546 mg, 3.17 mmol) in toluene (20 mL) was heated under reflux for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to provide 2-bromo-8-( 2 - fluorophenyl) -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c] [1,4]oxazine (300 mg, 40.3%) in the form of a colored solid yellow, which was used in the next stage as it was. Step 3: Methyl 8 -(2-fluorophenyl) -6,8 -dihydro -5H - [1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxylate

[02078] A mixture of 2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4] triazolo [5,1-c][1,4] oxazine (290 mg , 0.97 mmol), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (13 mg, 0.02 mmol). and triethylamine (1.31 mL, 9.73 mmol) in methanol (10 mL) was heated at 80oC for 16 h under CO (25psi) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 100% dichloromethane) to give methyl 8-(2-fluorophenyl)-6,8-dihydro-5H - [1,2,4] triazolo [5,1 -c][1,4]oxazine -2 -carboxylate (200 mg, 74%) in the form of a colorless oil. LCMS RT = 0.59 min., m/z = 277.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.59 min., ESI+ found [M+H] = 277.8. Step 4: 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid

[02079] A mixture of methyl 8 -(2 - fluorophenyl) -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 - c][1,4] oxazine -2 -carboxylate (200 mg, 0.72 mmol) and potassium hydroxide (80 mg, 1.44 mml) in ethanol (20 mL) and water (5 mL) were stirred under 25oC for 1 h. The ethanol was evaporated under reduced pressure and the aqueous residue was adjusted to pH = 3 by adding 2N HCl. The solution was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated to provide 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-acid crude carboxylic acid (180 mg, 94%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 5: (8R)-8-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6.8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 - carboxamide

[02080] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (50 mg, 0.26 mmol), 8 -(2-fluorophenyl) acid ) -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 - carboxylic acid (102 mg, 0.39 mmol), 1 -( hydrochloride 3-dimethylaminopropyl)-3-ethyl carbodiimide (49 mg, 0.26 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) in N,N-dimethylformamide (10 mL) were subjected to stirring at 25oC for 16 h . The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (36% to 66% acetonitrile/0.05% ammonium hydroxide in water) to give 8-(2-fluorophenyl)-N-[ (3S)-5-methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 - c][1,4]oxazine -2 - carboxamide (60 mg, 53%) as a white solid. The racemic material was separated using chiral SFC to provide:

[02081] (8R) -8 -(2-fluorophenyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 - carboxamide (Peak 2, retention time 1.825 min.) (33 mg, 54.3%) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ8.43 (d, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.45 - 7.39 (m, 1H ), 7.34 - 7.20(m, 5H), 6.18 (s, 1H), 4.86 - 4.77 (m, 1H), 4.61 - 4.55 (m, 1H), 4.45 - 4.32 (m, 4H), 4.25- 4.17 (m, 1H), 3.29 (s, 3H). LCMS RT = 0.80 min., m/z = 438.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.80 min., ESI+ found [M+H] = 438.1.

[02082] SFC: Column: Chiralcel AD -3 50x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min . and held at 5% for 0.2 min., then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Column temperature: 40oC. Example 630 (8S)-8-(2-fluorophenyl)-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6, 8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 -carboxamide

[02083] Amide coupling prepared in a manner similar to Method WX 125. The crude product was purified via RP-HPLC (35% to 75% acetonitrile / 0.05% ammonium hydroxide in water) to provide N -((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-8-(2-fluorophenyl)-6,8 -dihydro -5H - [1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide (60 mg, 53%) as a white solid. The racemic material (30 mg) was separated by chiral SFC to give: (8S) -8 -(2-fluorophenyl) -N -[(3S) -7,9 - difluoro -2 -oxo -1,3 ,4,5-tetrahydro -1 -benzazepin -3 - yl] -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 -carboxamide ( Peak 2, retention time 1.588 min.) (30 mg, 49.5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.47 - 7.41 (m, 1H), 7.37 - 7.32 (m, 1H), 7.23 - 7.12 (m, 2H), 7.01 - 6.94 (m, 3H), 6.13 (s, 1H), 4.57 - 4.33 (m, 4H), 4.27 - 4.18 (m, 1H), 3.00 - 2 .89 (m, 1H), 2.72 - 2.75 (m, 1H), 2.64 - 2.53 (m, 1H), 2.23 - 2.15 (m, 1H). LCMS RT = 0.79 min., m/z = 458.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.79 min., ESI+ found [M+H] = 458.1.

[02084] SFC Conditions: Column: Chiralcel AD -3 50x4.6 mm I.D., 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min. and held at 5% for 0.2 min., then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Column temperature: 40oC. Example 631

[02085] WX Method 138 1 -(2 -pyridyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide Step 1: N -[(Z) -(2,4,6 -trichloropyrimidin -5 - yl) methyleneamino] pyridin -2 –amine

[02086] To a solution of 2,4,6-trichloro-5-pyrimidine carboxaldehyde (1.0 g, 4.73 mmol) in N,N-dimethylformamide (5 mL) was added 2-hydrazino pyridine (530 mg, 4.86 mmol). The mixture was stirred at 20°C for 12 h and water (20 ml), saturated sodium bicarbonate (10 ml) were added. The resulting solid was collected by filtration and dried under reduced pressure to provide N -[(Z)-(2,4,6-trichloropyrimidin-5-yl)methyleneamino]pyridin-2-amine (900 mg, 63%) in the form of a brown solid, which was used in the next step as it was. Step 2: 4,6-dichloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine

[02087] A solution of N -[(Z) -(2,4,6 - trichloropyrimidin -5 -yl) methylene amino] pyridin -2 -amine (820 mg, 2.71 mmol) in acetonitrile (30 mL) was subjected to stirring at 110oC for 6 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to provide 4,6-dichloro- 1 -(2-pyridyl) pyrazolo [3,4 -d] pyrimidine (550 mg, 76%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: 6-chloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine

[02088] A mixture of 4,6-dichloro-1-(2-pyridyl) pyrazolo [3,4-d] pyrimidine (550 mg, 2.07 mmol) and zinc (418 mg, 6.39 mmol) in Tetrahydrofuran (20mL) was added to ammonium hydroxide (20mL) under 0oC. The reaction mixture was stirred for 1.5 h and adjusted to pH = 9 by addition of saturated sodium bicarbonate. The mixture was filtered and the filtrate was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.2) to give 6-chloro-1-(2-pyridyl)pyrazole[3,4-d ] pyrimidine (270 mg, 56%) light yellow solid, which was used in the next step in the form in which it was. Step 4: methyl 1 -(2-pyridyl) pyrazole [3,4 -d] pyrimidine-6 -carboxylate

[02089] A mixture of 6-chloro-1-(2-pyridyl) pyrazole [3,4-d] pyrimidine (180 mg, 0.78 mmol), triethylamine (0.88 mL, 6.32 mmol), dichloride of 1,1'-bis(diphenylphosphine) ferrocene palladium (57 mg, 0.08 mmol) in methanol (20 mL) was heated at 70oC under CO [3.42 bar (35 psi)] for 20h and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by prep TLC (ethyl acetate, Rf = 0.2) to give methyl 1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine - 6-carboxylate (120mg, 61%) in the form of a brown-colored oil, which was used in the next step in the form in which it was. Step 6: 1 -(2 -pyridyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [3,4 - d] pyrimidine -6 -carboxamide

[02090] To a solution of (3S) -3 -amino -5 - methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (23 mg, 0.12 mmol), methyl 1 -(2 - pyridyl) pyrazole [3,4-d] pyrimidine - 6 -carboxylate (30 mg, 0.12 mmol) in toluene (10 mL) trimethyl aluminum (0.2 mL, 0.40 mol) in toluene (10 mL) was added ). The mixture was heated at 110°C for 12 h and then finalized by addition of methanol (5 mL). The mixture was concentrated under reduced pressure and the residue was purified by prep TLC (dichloromethane:methane = 10:1, Rf = 0.5) to give 1-(2-pyridyl)-N-[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] pyrazole [3,4 -d] pyrimidine -6 - carboxamide (5 mg, 9.8%) in the form of a yellow colored oil. 1H NMR (400 MHz, CD3OD) δ 9.53 (s, 1H), 8.68 (s, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.19 - 8.12 (m, 1H), 7.54 - 7.50 (m, 1H), 7.48 - 7.44 (m, 1H), 7, 36 - 7.30 (m, 2H), 7.28 - 7.25(m, 1H), 5.12 - 5.07 (m, 1H), 4.73 - 4.69 (m, 1H), 4.55 - 4.47 (m, 1H), 3.45 (s, 3H). LC -MS RT = 0.757 min., m/z = 416.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.757 min., ESI+ found [M+H] =416.0. Examples 632 and 633 1 -(2 -pyridyl) -N -[(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide and 1 -(2 -pyridyl) -N -[(6R) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide

[02091] Ester-amide exchange prepared in a manner similar to Method WX 138. The racemic compound was separated using chiral SFC to provide arbitrarily assigned enantiomers:

[02092] 1 -(2-pyridyl) -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine - 6 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide (Peak 1, retention time 1.70 min.) (14.5 mg, 47%) as a light yellow oil. 1H NMR (400 MHz, CD3OD) δ9.53 (s, 1H), 8.68 (s, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.18 - 8.11 (m, 1H), 7.55 - 7.50 (m, 1H), 6.14 (s, 1H), 4.66 - 4.59 (m, 1H), 4.36 - 4.27 (m, 2H), 3.37 (s, 3H), 3.02 - 2.92 (m, 1H), 2.39 - 2.31 (m , 1H), 2.27 (s, 3H). LC -MS RT = 0.712 min., m/z = 418.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.712 min., ESI+ found [M+H] = 418.0.

[02093] 1 -(2-pyridyl) -N -[(6R) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine - 6 -yl] pyrazole [3,4 -d] pyrimidine -6 -carboxamide (Peak 2, retention time 2.07 min.) (5.0 mg, 16%) as a yellow oil. 1H NMR (400 MHz, CD3OD) δ9.52 (s, 1H), 8.68 (s, 1H), 8.64 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H) , 8.14 (t, J = 7.2 Hz, 1H), 7.56 - 7.49 (m, 1H), 6.14 (s, 1H), 4.67 - 4.59 (m, 1H ), 4.41 - 4.25(m, 2H), 3.37 (s, 3H), 3.01 - 2.93 (m, 1H), 2.38 - 2.29 (m, 1H), 2.27 (s, 3H). LC -MS RT = 0.709 min., m/z = 418.0 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.709 min., ESI+ found [M+H] = 418.0.

[02094] SFC Condition: Column: Chiralpak AD-3 50*4.6 mm ID, 3 µm Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: maintained 5% for 0.2 min. ,then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 4 mL/min. Column temperature: 40oC. Example 634 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl]spiro[5,6 -dihydropyrrole [1,2 - b][1,2, 4] triazole -7,4' -tetrahydropyran] -2 -carboxamide

[02095] Amide coupling prepared in a manner similar to Method WX 129. The crude product was purified via RP-HPLC (22% to 52% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]spiro[5,6 -dihydropyrrole [1,2 -b][1,2,4 ]triazol-7,4'-tetrahydropyran]-2-carboxamide (15 mg, 56%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.46 - 7.40(m, 1H), 7.36 - 7.27 (m, 2H), 7.25- 7.21 (m, 1H), 5.03 - 4.98 (m, 1H), 4.62 - 4.58 (m, 1H), 4.45 - 4.39 (m, 1H), 4.27 - 4.23 (m, 2H), 4 .08 - 4.00 (m, 2H), 3.79 - 3.70(m, 2H), 3.42 (s, 3H), 2.71 - 2.67 (m, 2H), 1.97 - 1.87 (m, 2H), 1.82 - 1.70(m, 2H). LCMS RT = 1.58 min., m/z = 398.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.58 min., ESI+found [M+H] = 398.3. Example 635

[02096] WX Method 131 N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro[5,6 - dihydropyrrole [1,2 -b][1,2,4] triazole -7,4' -tetrahydropyran] -2 -carboxamide Step 1: ethyl 4 -allyltetra hydropyran -4 - carboxylate

[02097] To a solution of ethyl tetrahydropyran-4-carboxylate (10.0 g, 63.22 mmol) in tetrahydrofuran (200 mL) was added lithium diisopropylzanide (2N in Tetrahedron, 32.91 mL, 65.81 mmol ) under -78oC. The reaction mixture was stirred at -78oC for 30 min. and then allyl bromide (9.2 g, 75.86 mmol) was added. The reaction mixture was stirred at 20oC for 16 h and finalized by the addition of saturated ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude ethyl 4-allyltetrahydropyran-4-carboxylate (9.0 g, 72%) in the form of a yellow oil, which was used in the next step in the form in which it was. -oxoethyl)tetra hydropyran -4 -carboxylate

[02098] A mixture of ethyl 4-allyl tetrahydropyran-4-carboxylate (9.0 g, 45.39 mmol), osmium tetra oxide (500 mg, 1.97 mmol) and sodium periodate (14.5 g , 68.09 mmol) in tetrahydrofuran (100 mL) and water (100 mL) was stirred at 20oC for 2 h. The mixture was finished by adding water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide ethyl 4-(2-oxoethyl) tetrahydropyran-4-carboxylate (4 .0 g, 44%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 3: tert-butyl N -(1 -oxo -8 -oxa -2 -aza spiro [4,5] decan -2 -yl)carbamate

[02099] To a solution of ethyl 4-(2-oxoethyl) tetrahydropyran-4-carboxylate (4.0 g, 19.98 mmol) in acetic acid (20 mL) and tetrahydrofuran (40 mL) was added tert-butyl hydrazine carboxylate (3.17 g, 23.97 mmol). The reaction mixture was stirred at 20°C for 2 h and then sodium cyanoborohydride (3.77 g, 59.93 mmol) was added. The reaction mixture was heated at 50°C for 6 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (17% to 47% acetonitrile / 0.05% ammonium hydroxide in water) to provide tert-butyl N -(1 -oxo -8 -oxa -2 - azaaspiro [4 .5] decan-2-yl)carbamate (1.0 g, 18%) in the form of a white solid, which was used in the next step in the form in which it was. Step 4: 2-amino-8-oxa-2-azaspiro[4,5]decan-1-one hydrochloride

[02100] To a solution of tert-butyl N -(1 -oxo -8 -oxa -2 -azaaspiro [4.5] decan -2 -yl) carbamate (200 mg, 0.74 mmol) in ethyl acetate ( 5 mL) HCl (4N in ethyl acetate, 10.0 mL, 40.0 mmol) was added. The mixture was stirred at 35°C for 12 h and concentrated under reduced pressure to provide crude 2-amino-8-oxa-2-azaspiro[4.5]decan-1-one (120 mg, 95%) in the form of a yellow oil, which was used in the next stage as it was. Step 5: (Z)-ethyl 2-amino -2 -((2 -oxo -8 -oxa -1 - azaaspiro [4,5] decan -1 -yl) imino) acetate

[02101] To a solution of 2-amino-8-oxa-2-azaaspiro [4.5]decan-1-one hydrochloride (100 mg, 0.59 mmol) in ethanol (10 mL) was added ethyl 2 - ethoxy-2-imino-acetate (256 mg, 1.76 mmol). The mixture was stirred at 30°C for 12 h and concentrated under reduced pressure to provide ethyl (2Z)-2-amino-2-[(2-oxo-8-oxa-1-azaaspiro[4.5]decan-1 -yl)imino] crude acetate (130 mg, 82%) as a yellow oil. LCMS RT = 1.43 min., m/z = 270.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.43 min., ESI+found [M+H] = 270.1. Step 6: ethyl 2,3,5,5',6,6'-hexahydrospiro[pyran-4,7'-pyrrole[1,2-b][1,2,4]triazole]-2'-carboxylate

[02102] A mixture of (Z) -2 -amino -2 - [(2 - oxo -8 -oxa -1 -azaaspiro [4.5] decan -1 -yl)imino] acetate (180 mg, 0.67 mmol) and phosphorus oxychloride (5 mL, 53.28 mmol) in ethyl acetate (10 mL) was heated under 120oC for 1 h and cooled. The mixture was slowly quenched by adding water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 20% sodium bicarbonate (20 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 60% ethyl acetate in petroleum ether) to give ethyl spiro [5,6 - dihydropyrrole [1,2 -b][ 1,2,4] triazol -7,4' -tetrahydropyran] -2 -carboxylate (85 mg, 51%) in the form of a light yellow oil, which was used in the next step in the form in which it was. Step 7: 2,3,5,5',6,6'-hexahydrospiro[pyran-4,7'-pyrrole[1,2-b][1,2,4]triazole]-2'-carboxylic acid

[02103] A mixture of ethyl spiro [5,6 - dihydropyrrole [1,2 -b][1,2,4] triazole -7,4' -tetrahydropyran] -2 -carboxylate (80 mg, 0.32 mmol ) and lithium hydroxide (153 mg, 6.37 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred under 20oC for 12 h. After evaporation of the organic solvent, the mixture was adjusted to pH = 6 by adding 1N HCl. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure to provide crude spiro[5,6-dihydropyrrole[1,2-b][1,2,4]triazol-7,4'-tetrahydropyran]-2-carboxylic acid. (60 mg, 84%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 8: N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 - yl]spiro[5 ,6 -dihydropyrrole [1,2 -b][1,2,4] triazole -7,4' -tetrahydropyran] -2 -carboxamide

[02104] Amide coupling prepared in a manner similar to Method WX 129. The crude product was purified via RP-HPLC (22% to 52% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] spiro [5,6 -dihydropyrrole [1,2 - b][1,2,4] triazole -7,3' -tetrahydrofuran] -2 -carboxamide (6.7 mg, 18.5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ6.11 (s, 1H), 4.59 — 4.49 (m, 1H), 4.37 - 4.16 (m, 4H), 4.06 - 4.02 (m, 2H), 3.80 - 3.68 (m, 2H), 3.33 (s, 3H), 2.86 - 2.84 (m, 1H), 2.74 - 2.65 (m , 2H), 2.30 - 2.21 (m, 4H), 1.99 - 1.88 (m, 2H), 1.82 - 1.71 (m, 2H). LCMS RT = 1.13 min., m/z = 400.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.13 min., ESI+found [M+H] = 400.2. Example 636

[02105] WX Method 134 4 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5 ,6 - dihydroimidazo [1,2 -b][1,2,4] triazole -2 -carboxamide Step 1: 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole-5-amine

[02106] To a solution of aniline (329 mg, 3.54 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl) amide (1N in tetrahedron, 12.86 mL, 12.86 mmol), and then 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (500 mg, 1.61 mmol) under 0oC. The reaction mixture was stirred at 0oC for 15 h and finalized by the addition of saturated ammonium hydroxide (10 mL). The mixture was extracted with dichloromethane (2 x 20mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -20% ethyl acetate in petroleum ether) to give 3-bromo -N - phenyl -1 - (tetrahydro -2H -pyran -2 -yl) -1H -1,2,4 -triazol -5 - amine (500 mg, 96%) in the form of a yellow solid, which was used in step next in the form in which it was. Step 2: 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1 ,2,4-triazole-5-amine

[02107] To a solution of sodium iodide (232 mg, 1.55 mmol) and 3-bromo-N-phenyl -1 -(tetrahydro -2H - pyran -2 -yl) -1H -1,2,4 - triazol-5-amine (500 mg, 1.55 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 62 mg, 1.55 mmol). The reaction mixture was stirred under 50°C for 0.5 hour, then 2-(2-bromoethoxy) tetrahydro-2H-pyran (408 mg, 1.95 mmol) was added. After addition, the mixture was stirred at 50°C for another 15 h and then diluted with ice-cold water (5 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 20% ethyl acetate in petroleum ether) to give 3-bromo -N - phenyl -1 -(tetrahydro -2H -pyran -2 -yl) -N -(2 -((tetrahydro -2H -pyran -2 -yl)oxy)ethyl) - 1H -1,2,4 -triazole -5 - amine (500 mg, 72%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 3: 2 -((3 -bromo -1H -1,2,4 -triazol -5 - yl)(phenyl) amino) ethanol

[02108] A mixture of 3-bromo -N -phenyl -1 - (tetrahydro -2H -pyran -2 -yl) -N -(2 -((tetrahydro -2H - pyran -2 -yl)oxy)ethyl) - 1H-1,2,4-triazol-5-amine (500 mg, 1.11 mmol) and 2,2,2-trifluoroacetic acid (126 mg, 1.11 mmol) in dichloromethane (10 mL) was subjected to Stirring at 15oC for 15 h and concentrating under reduced pressure to provide crude 2-(N-(3-bromo-1H-1,2,4-triazol-5-yl)-2,6-difluoro-aniline) ethanol ( 200 mg, 64%) in the form of a brown-colored oil. LCMS RT = 1.315 min., m/z = 283.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.315 min., ESI+ found [M+H] = 283.2. Step 4: 3-bromo-N-(2-bromoethyl)-N-phenyl-1H-1,2,4-triazole-5-amine

[02109] A mixture of 2 -(N -(3 -bromo -1H - 1,2,4 -triazol -5 -yl) -2,6 -difluoro -aniline) ethanol (100 mg, 0.35 mmol) and Phosphoryl tribromide (101 mg, 0.35 mmol) in acetonitrile (5 mL) was heated at 50°C for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -20% ethyl acetate in petroleum ether) to give 3-bromo -N -(2-bromoethyl) -N -(2 ,6-difluorophenyl)-1H-1,2,4-triazole-5-amine (100 mg, 82%) as a brown oil. LCMS RT = 0.719 min., m/z = 346.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.719 min., ESI+ found [M+H] = 346.8. Step 5: 2 -bromo -4 -phenyl -5,6 -dihydro -4H - imidazo [1,2 -b][1,2,4] triazole

[02110] A mixture of 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-5-amine (90 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20°C for 15 h and then diluted with ice water (3 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 50% 0-ethyl acetate in petroleum ether) to give 2-bromo-4 -phenyl -5,6 - dihydro -4H -imidazo [1,2 -b] [1,2,4] triazole (50 mg, 73%) as a white solid, which was used in the next step in form in which it was found. Step 6: methyl 4 -phenyl -5,6 -dihydro -4H -imidazo [1,2 -b][1,2,4] triazole -2 -carboxylate

[02111] A mixture of 2-bromo-4-phenyl-5,6-dihydro-4H-imidazo [1,2-b][1,2,4] triazole (50 mg, 0.19 mmol), sodium dichloride 1,1'-bis(diphenylphosphine) ferrocene palladium (13 mg, 0.02 mmol) and triethylamine (191 mg, 1.88 mmol) in methanol (40 mL) was heated at 70oC for 12 h under CO [3.77 bar (40 psi)] and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give methyl 4-phenyl-5,6 -dihydro -4H -imidazo [1,2 -b][1,2,4] triazole -2 -carboxylate (45 mg, 98%) as a yellow solid. LCMS RT = 1.535 min., m/z = 245.3 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 1.535 min., ESI+ found [M+H] = 245.3. Step 7: 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylic acid

[02112] A mixture of methyl 4 -phenyl -5,6 - dihydro -4H -imidazo [1,2 -b][1,2,4] triazole -2 -carboxylate (40 mg, 0.16 mmol) and hydroxide lithium (20 mg, 0.82 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred at 25oC for 15 h. The reaction mixture was adjusted to pH = 3 by addition of 1N HCl and concentrated under reduced pressure to provide 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2] acid ,4] crude -2-carboxylic triazole (40 mg, 93%) yellow in color. LCMS RT = 1.309 min., LCMS (0 to 60% acetonitrile in water + acetic for 3.0 min.) ESI+ time found [M+H] = 230.9. Step 8: 4 -phenyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ] - 5,6 -dihydroimidazo [1,2 -b][1,2,4] triazole -2 -carboxamide

[02113] A mixture of 4-phenyl -5,6 - dihydroimidazo [1,2 -b][1,2,4] triazole -2 -carboxylic acid (40 mg, 0.17 mmol), (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (33 mg, 0.17 mmol), 1 -hydroxybenzotriazole (56 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring at 20oC for 2 h . The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile/0.05% HCl in water) to give 4-phenyl-N-[(6S)-2, 4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -5,6 -dihydroimidazo [1,2 -b][1 ,2,4] triazole-2-carboxamide (3.5 mg, 5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.58 (d, J = 8.0 Hz, 2H), 7.41 - 7.37 (m, 2H), 7.06 - 7.02 (m, 1H), 6.15 (s, 1H), 4.63 — 4.51 (m, 3H), 4.48 — 4.41 (m, 2H), 4.33 (s, 1H), 4.29 - 4, 23 (m, 1H), 3.35 (s, 3H), 2.91 - 2.84 (m, 1H), 2.38 - 2.21 (m, 4H). LCMS RT = 0.752 min., m/z = 407.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.752 min., ESI+ found [M+H] = 407.1. Example 637 N -[(3S)-7,9 -difluoro -2 -oxo -1,3,4,5 - tetrahydro -1 -benzazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine -7 ,1'-cyclopentane]-2-carboxamide

[02114] Amide coupling prepared in a manner similar to Method WX 164. The crude product was purified via RP-HPLC (38% to 68% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 - benzazepin -3 -yl] spiro [5H -furo [3,4 -d] pyrimidine - 7, 1'-cyclopentane]-2-carboxamide (30.3 mg, 51%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 7.06 - 7.00 (m, 2H), 5.11 (s, 2H), 4.65 - 4.60 (m, 1H), 3.07 - 2.98 (m, 1H), 2.86 - 2.76 (m, 2H), 2.27 - 2.22 (m, 1H), 2.10 - 2.00 ( m, 4H), 1.98 - 1.87 (m, 4H). LCMS RT = 0.714 min., m/z = 414.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.05% ammonium hydroxide for 1.5 min.) retention time 0.714 min., ESI+found [M+H] = 414.9. Examples 638 and 639 (8S) -8 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide and (8R) -8 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide

[02115] Amide coupling prepared in a similar manner to Method WX 121. Racemic material (30 mg) was separated using chiral SFC to provide:

[02116] (8S) -8 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 - carboxamide (Peak 1, retention time 4.962 min.) (9.4 mg, 31%) in the form of a light yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.34 (m, 5H), 7.04 - 6.96 (m, 2H), 5.94 (s, 1H), 4.59 - 4, 52 (m, 1H), 4.50 - 4.43 (m, 1H), 4.40- 4.33 (m, 2H), 4.25- 4.17 (m, 1H), 3.01 - 2.91 (m, 1H), 2.84 - 2.76 (m, 1H), 2.66 - 2.55 (m, 1H), 2.26 - 2.14 (m, 1H). LCMS RT = 0.955 min., m/z = 440.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.955 min., ESI+ found [M+H] = 440.2.

[02117] (8R) -8 -phenyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 - carboxamide (Peak 2, retention time 5.392 min.) (8.8 mg, 29%) in the form of a yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.34 (m, 5H), 7.03 - 6.95 (m, 2H), 5.94 (s, 1H), 4.60 - 4, 52 (m, 1H), 4.50 - 4.43 (m, 1H), 4.40- 4.32 (m, 2H), 4.25- 4.16 (m, 1H), 3.01 - 2.91 (m, 1H), 2.84 - 2.76 (m, 1H), 2.66 - 2.54 (m, 1H), 2.24 - 2.13 (m, 1H). LCMS RT = 0.955 min., m/z = 440.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.955 min., ESI+ found [M+H] = 440.2.

[02118] SFC Condition: Column: Chiralpak AD - 3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Examples 640 and 641 (8S) -8 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro - 5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 -carboxamide and (8R) -8 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo - 3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,8 -dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide

[02119] Amide coupling prepared in a manner similar to Method WX 121. The crude product was purified via RP-HPLC (17% to 47% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - ((S) -6,8 -difluoro -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl -6,8 -dihydro - 5H - [1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide (40 mg, 42%). The racemic material was separated using chiral SFC to provide:

[02120] (8S) -8 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 - carboxamide (Peak 1, retention time 4.810 min.) (7.7 mg, 19%) in the form of a light yellow oil. 1H NMR (400 MHz, CD3OD) δ7.45 - 7.35 (m, 5H), 6.96 - 6.89 (m, 1H), 6.88 - 6.82 (m, 1H), 5.95 (s, 1H), 5.09 - 5.01 (m, 1H), 4.68 - 4.60 (m, 1H), 4.51 - 4.46 (m, 2H), 4.42 - 4 .33 (m, 2H), 4.26 - 4.17 (m, 1H). LCMS RT = 0.956 min., m/z = 442.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.956 min., ESI+ found [M+H] = 442.1.

[02121] (8R) -8 -phenyl -N -[(3S) -6,8 -difluoro -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 - carboxamide (Peak 2, retention time 5.392 min.) (7.9 mg, 19%) in the form of a yellow oil. 1H NMR (400 MHz, CD3OD) δ7.47 - 7.33 (m, 5H), 6.97 - 6.89 (m, 1H), 6.85 (d, J = 9.6 Hz, 1H), 5.95 (s, 1H), 5.09 - 5.01 (m, 1H), 4.66 - 4.59 (m, 1H), 4.52 - 4.44 (m, 2H), 4, 40- 4.33 (m, 2H), 4.26 - 4.17 (m, 1H). LCMS RT = 0.961 min., m/z = 442.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.961 min., ESI+ found [M+H] = 442.1.

[02122] SFC Condition: Column: Chiralpak AD - 3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Examples 642 and 643 (8S)-8-phenyl -N -[(3S)-6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 - carboxamide and (8R) -8 -phenyl -N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6,8 - dihydro -5H -[1,2,4] triazolo [5,1 -c][ 1,4]oxazine -2 - carboxamide

[02123] Amide coupling prepared in a manner similar to Method WX 121. Racemic material (30 mg) was separated using chiral SFC to provide:

[02124] (8S) -8 -phenyl -N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6 ,8-dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4]oxazine -2 -carboxamide (Peak 1, retention time 5.076 min.) (10.9 mg, 36 %) in the form of a light yellow oil. H NMR (400 MHz, CD3OD) δ7.44 - 7.36 (m, 5H), 6.89 - 6.83 (m, 2H), 5.94 (s, 1H), 5.06 - 4.98 (m, 1H), 4.63 - 4.56 (m, 1H), 4.52 - 4.33 (m, 5H), 4.25- 4.17 (m, 1H), 2.33 (s , 3H). LCMS RT = 0.988 min., m/z = 438.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.988 min., ESI+ found [M+H] = 438.2.

[02125] (8R) -8 -phenyl -N -[(3S) -6 -fluoro -8 -methyl -4 -oxo -3,5 -dihydro -2H -1,5 -benzoxazepin -3 -yl] -6 ,8-dihydro -5H -[1,2,4] triazolo [5,1 -c][1,4] oxazine -2 -carboxamide (Peak 2, retention time 5.374 min.) (11 mg, 37%) in the form of a yellow oil. 1H NMR (400 MHz, CD3OD) δ7.44 -7.36 (m, 5H), 6.90 - 6.82 (m, 2H), 5.95 (s, 1H), 5.06 - 4.98 (m, 1H), 4.62 - 4.55 (m, 1H), 4.52 - 4.33 (m, 5H), 4.25- 4.17 (m, 1H), 2.33 (s , 3H). LCMS RT = 0.994 min., m/z = 438.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.994 min., ESI+ found [M+H] = 438.1.

[02126] SFC Condition: Column: Chiralpak AD - 3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 644 dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02127] Amide coupling prepared in a similar manner to Method WX 019. The crude product was purified via RP-HPLC (13 -43% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3 -methyl -2 -pyridyl) methyl] -N -(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - il -1,2,4 -triazole -3 -carboxamide (8.0 mg, 15%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1H), 8.32 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.28 - 7.27 ( m, 1H), 6.10 (s, 1H), 5.63 (s, 2H), 4.54 - 4.49 (m, 1H), 4.33 - 4.20(m, 2H), 3 .30 (s, 3H), 2.85 - 2.83 (m, 1H), 2.46 (s, 3H), 2.25- 2.23 (m, 4H). LC -MS RT =1.258 min., m/z = 395.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.258 min., ESI+ found [M+H] = 395.1, Example 645

[02128] WX Method 129 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl]spiro[5,6 -dihydropyrrole [1,2 - b][1,2, 4] triazole -7,3' -tetrahydrofuran] -2 -carboxamide Step 1: Methyl 3-allyltetrahydrofuran -3 -carboxylate

[02129] To a solution of methyl tetrahydrofuran-3-carboxylate (2.6 g, 19.98 mmol) in tetrahydrofuran (10 mL) was added sodium bis(trimethylsilyl) azanide (1N in tetrahydrofuran, 20.0 mL, 20 .0 mmol) under -78oC. The reaction mixture was stirred at -78oC for 30 min. and then allyl iodide (5.0 g, 29.77 mmol) was added. The reaction mixture was stirred at -78oC for another 15 min. and then finished by adding saturated ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide methyl 3-allyltetrahydrofuran-3-carboxylate (1.9 g, 56 %) in the form of a yellow oil, which was used in the next stage as it was. Step 2: methyl 3-(2-oxoethyl)tetrahydrofuran-3-carboxylate

[02130] A mixture of methyl 3-allyltetrahydrofuran-3-carboxylate (1.9 g, 11.16 mmol), osmium tetroxide (100 mg, 0.39 mmol) and sodium periodate (4.77 g, 22. 33 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was stirred at 20oC for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide methyl 3-(2-oxoethyl) tetrahydrofuran-3-carboxylate (1. 0 g, 57%) in the form of a yellow oil, which was used in the next step as it was. Step 3: tert-butyl (6 -oxo -2 -oxa -7 - azaespiro[4,4]nonan -7 -yl) carbamate

[02131] To a solution of methyl 3-(2-oxoethyl) tetrahydrofuran-3-carboxylate (1.1 g, 6.39 mmol) in acetic acid (7.5 mL) and tetrahydrofuran (15 mL) was added methyl carboxylate tert-butyl hydrazine (1.01 g, 7.67 mmol). The reaction mixture was stirred at 20°C for 2 h and sodium cyanoborohydride (1.2 g, 19.17 mmol) was added. The reaction mixture was heated at 50°C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (17 -47% acetonitrile / 0.05% ammonium hydroxide in water) to provide tert-butyl N -(1 -oxo -7 -oxa -2 - azaaspiro [4, 4] nonan -2 -yl)carbamate (500 mg, 31%) in the form of white solids, which was used in the next step as it was. Step 4: 7 -amino -2 -oxa -7 -azaespiro [4,4] nonan -6 -one

[02132] To a solution of tert-butyl N -(1 -oxo -7 -oxa -2 -azaaspiro [4,4] nonan -2 -yl) carbamate (500 mg, 1.95 mmol) in ethyl acetate ( 10 mL) HCl (4N in ethyl acetate, 5.0 mL, 20 mmol) was added. The reaction mixture was stirred at 15°C for 4 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and adjusted to pH = 10 by addition of saturated sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (8 x 20mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 2-amino-7-oxa-2-azaspiro [4.4 ] nonan -1 -one (200 mg, 66%) in the form of a yellow oil, which was used in the next step as it was. Step 5: (Z)-ethyl 2-amino -2 -((6 -oxo -2 -oxa -7 -azaaspiro [4,4] nonan -7 -yl)imino) acetate

[02133] To a solution of 2-amino-7-oxa-2-azaspiro [4,4] nonan-1-one (200 mg, 1.28 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy - 2-imino-acetate (929 mg, 6.40 mmol). The mixture was heated at 40°C for 12 h and concentrated under reduced pressure to provide ethyl (2Z)-2-amino-2-[(2-oxo-7-oxa-1-azaspiro[4,4]nonan-1-yl ) imino] crude acetate (150 mg, 46%) in the form of a yellow oil, which was used in the next step as it was. Step 6: ethyl spiro[5,6-dihydropyrrole [1,2-b][1,2,4] triazole -7,3' -tetrahydrofuran] -2 -carboxylate

[02134] A solution of ethyl (2Z) -2 -amino -2 - [(2 -oxo -7 -oxa -1 -azaaspiro [4,4] nonan -1 -yl) imino] acetate (150 mg, 0. 59 mmol) in phosphorus oxychloride (5 mL, 56.09 mmol) was heated at 120°C for 1 h and cooled. The mixture was slowly quenched by adding water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 20% sodium bicarbonate (20 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 60% ethyl acetate in petroleum ether) to give ethyl spiro[5,6-dihydropyrrole[1,2-b][ 1,2,4] triazole -7,3' -tetrahydrofuran] -2 -carboxylate (80 mg, 57%) in the form of a light yellow oil, which was used in the next step as it was . Step 7: spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3'-tetrahydrofuran]-2-carboxylic acid

[02135] A mixture of ethyl spiro [5,6 - dihydropyrrole [1,2 -b][1,2,4] triazole -7,3' - tetrahydrofuran] -2 -carboxylate (80 mg, 0.34 mmol) and lithium hydroxide monohydrate (141 mg, 3.37 mmol) in tetrahydrofuran (5 mL) and water (3 mL) was stirred under 20oC for 2 h. The mixture was concentrated under reduced pressure and diluted with water (10 mL). The solution was adjusted to pH = 5 by adding 1N HCl (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure to provide crude spiro[5,6-dihydropyrrole[1,2-b][1,2,4]triazol-7,3'-tetrahydrofuran]-2-carboxylic acid ( 40 mg, 57%) in the form of a yellow solid, which was used in the next step as it was. Step 8: N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl]spiro[5,6 -dihydropyrrole [1,2 - b][1 ,2,4] triazole -7,3' -tetrahydrofuran] -2 -carboxamide

[02136] A mixture of spiro [5,6 - dihydropyrrole [1,2 -b][1,2,4] triazole -7,3' - tetrahydrofuran] -2 -carboxylic acid (20 mg, 0.10 mmol) , 1-hydroxybenzotriazole (25 mg, 0.19 mmol), 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol), and (3S)-3-amino-5-methyl -2,3-dihydro -1,5 - benzoxazepin -4 -one (18 mg, 0.10 mmol) in N,N - dimethylformamide (5 mL) was stirred at 15°C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (32-62% acetonitrile/0.05% ammonium hydroxide in water) to give N -[(3S)-5-methyl-4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] spiro [5,6 - dihydropyrrole [1,2 -b][1,2,4] triazol -7,3' - tetrahydrofuran] - 2-carboxamide (8.6 mg, 23%) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.43 (d, J = 6.8 Hz, 1H), 7.33 - 7.30 (m, 2H), 7.23 (d, J = 6.0 Hz, 1H), 5.00 - 4.84 (m, 1H), 4.61 - 4.57 (m, 1H), 4.43 - 4.40(m, 1H), 4.26 (t, J = 6.8 Hz, 2H), 4.13 - 4.09 (m, 1H), 4.03 - 4.00 (m, 1H), 3.95 - 3.91 (m, 1H), 3.88 - 3.85 (m, 1H), 3.42 (s, 3H), 2.85 - 2.79 (m, 2H), 2.40- 2.35 (m, 1H), 2.21 - 2 .18 (m, 1H). LCMS RT = 0.713 min.; m/z = 384.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.713 min., ESI+ found [M+H] =384.0, N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]spiro[5,6 - dihydropyrrole [1,2 -b][1,2,4] triazole -7,3' - tetrahydrofuran] -2 -carboxamide

[02137] Amide coupling prepared in a manner similar to Method WX 129. The crude product was purified via RP-HPLC (28% to 58% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] spiro [5,6 -dihydropyrrole [1,2 - b][1,2,4] triazol -7,3' -tetrahydrofuran] -2 -carboxamide (5.9 mg, 16%) as a white solid. 1H NMR (400 MHz, CD3OD) δ6.11 (s, 1H), 4.54 — 4.52 (m, 1H), 4.53 - 4.24 (m, 4H), 4.15 - 4.10 (m, 1H), 4.05 - 4.01 (m, 1H), 3.94 - 3.92 (m, 1H), 3.89 - 3.86 (m, 1H), 3.33 (s , 3H), 2.85 - 2.79 (m, 3H), 2.40- 2.35 (m, 1H), 2.26 (s, 3H), 2.24 - 2.19 (m, 2H ). LCMS RT = 0.626 min.; m/z = 386.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.626 min., ESI+ found [M+H] =386.0. Example 647

[02138] WX Method 019 1 -[(3 -methyl -2 -pyridyl) methyl] -N -(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: methyl 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate

[02139] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (200 mg, 1.57 mmol) in N,N - dimethylformamide (4 mL) was added potassium carbonate (435 mg, 3 .15 mmol) and 2-(chloromethyl)-3-methylpyridine (223 mg, 1.57 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 1-[(3-methyl -2 - pyridyl) methyl] -1,2,4 -triazole -3 - carboxylate (150 mg, 41%) in the form of a colorless oil. LC -MS RT =0.302 min., m/z = 232.9 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.302 min., ESI+ found [M+H] = 232.9. Step 2: 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid

[02140] A mixture of methyl 1 -[(3-methyl -2 - pyridyl) methyl] -1,2,4 -triazole -3 -carboxylate (100 mg, 0.43 mmol) and hydrated lithium hydroxide (90 mg , 2.15 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25oC for 2 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 by adding 1M HCl. The resulting solid was collected by filtration and dried under reduced pressure to provide crude 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (90 mg, 96%) light yellow solid, which was used in the next step as it was. Step 3: 1 -[(3 -methyl -2 -pyridyl) methyl] -N -(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02141] To a stirred solution of (6S) -6 -amino -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3] diazepin -5 -one (25mg , 0.14 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxy benzotriazole (29 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39 mg, 0.21 mmol) and 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (30 mg, 0.14 mmol). The mixture was stirred at 20°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (10 -40% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - [(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl] -1 - [(3 -methyl -2 -pyridyl) methyl] -1,2,4 -triazole -3 -carboxamide ( 7 mg, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1H), 8.32 (d, J = 4.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7 .52 (d, J = 2.0 Hz, 1H), 7.30 - 7.26 (m, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.63 (s, 2H), 4.52 - 4.39 (m, 2H), 4.32 - 4.28 (m, 1H), 3.35 (s, 3H), 2.89 - 2.84 (m, 1H) , 2.45 (s, 3H), 2.28 - 2.24 (m, 1H). LC -MS RT =1.135 min., m/z = 381.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.135 min., ESI+ found [M+H] = 381.2. Example 648 1 -[(3 -methyl -2 -pyridyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[02142] Amide coupling prepared in a manner similar to Method WX 019. The crude product was purified via RP-HPLC (18 -48% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3 -methyl -2 -pyridyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (7.4 mg, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7 .30 - 7.27 (m, 1H), 6.00 (s, 1H), 5.63 (s, 2H), 4.53 - 4.48 (m, 1H), 4.31 - 4.26 (m, 1H), 4.24 - 4.20(m, 1H), 3.32 (s, 3H), 2.86 - 2.80 (m, 1H), 2.46 (s, 3H), 2.25 - 2.21 (m, 1H), 1.91 - 1.87 (m, 1H), 0.94 - 0.92 (m, 2H), 0.75 - 0.73 (m, 2H ). LC -MS RT =1.357 min., m/z = 421.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.357 min., ESI+ found [M+H] = 421.2. Example 649

[02143] WX Method 133 4 -(2,6 -difluorophenyl) -N -[(6S) -2,4 -dimethyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -5,6 -dihydroimidazo [1,2 -b][1,2,4] triazol -2 – carboxamide Step 1: 3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

[02144] A mixture of 3,4-dihydro-2H-pyran (13.19 g, 156.85 mmol), 4-methylbenzene sulfonic acid (1.35 g, 7.84 mmol) and 3,5-dibromo-1H -1,2,4-triazole (10.0 g, 44.08 mmol) in tetrahydrofuran (50 mL) was heated under 25°C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (11g, 80%) as a solid colored white, which was used in the next stage as it was. Step 2: 3-bromo-N-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole-5-amine

[02145] To a solution of 2,6-difluoroaniline (1.83 g, 14.15 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl) amide (1N in tetrahedron, 12.86 mL, 12. 86 mmol), then 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (2.0 g, 6.43 mmol) under 0oC. The mixture was stirred at 0oC for 15 h and finalized by the addition of saturated ammonium chloride (10 mL). The resulting mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -20% ethyl acetate in petroleum ether) to provide 5-bromo-N- (2,6-difluorophenyl)-2-tetrahydropyran-2-yl-1,2,4-triazol-3-amine (1.2 g, 52%) as a yellow solid, which was used in the next stage of the form in which he found himself. Step 3: 3-bromo-N-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy) ethyl) -1H -1,2,4 -triazole -5 -amine

[02146] To a solution of e-5-bromo-N-(2,6-difluorophenyl)-2-tetrahydropyran-2-yl-1,2,4-triazol-3-amine (700 mg, 1.95 mmol ) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 78 mg, 1.95 mmol). The reaction mixture was stirred at 50°C for 0.5 h, then 2-(2-bromoethoxy)tetrahydro-2H-pyran (408 mg, 1.95 mmol) and sodium iodide (292 mg, 1.95 mmol) were added. 95 mmol). The reaction mixture was stirred at 50oC for 15 h and poured into ice water (5 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -20% ethyl acetate in petroleum ether) to provide 5-bromo-N-(2,6-difluorophenyl)-2- tetrahydropyran-2-yl-N-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-amine (800 mg, 84%) as a yellow oil. LCMS RT = 0.893 min., m/z = 508.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.893 min., ESI+ found [M+H] = 508.9. Step 4: 2 -((3 -bromo -1H -1,2,4 -triazol -5 -yl)(2,6 - difluorophenyl) amino) ethanol

[02147] A mixture of 5-bromo-N-(2,6-difluorophenyl)-2-tetrahydropyran-2-yl-N-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole 3-amine (300 mg, 0.62 mmol) and 2,2,2-trifluoroacetic acid (70 mg, 0.62 mmol) in dichloromethane (10 mL) was stirred at 15°C for 15 h and then concentrated under pressure reduced to give crude 2-(N-(3-bromo-1H-1,2,4-triazol-5-yl)-2,6-difluoro-anilino) ethanol (160 mg, 81%) as a brown colored oil without any further purification. LCMS RT = 0.551 min., m/z = 318.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.551 min., ESI+ found [M+H]+ = 318.9. Step 5: 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-5-amine

[02148] A mixture of 2 -(N -(3 -bromo -1H - 1,2,4 -triazol -5 -yl) -2,6 -difluoro -anilino) ethanol (160 mg, 0.50 mmol) and Phosphoryl tribromide (144 mg, 0.50 mmol) in acetonitrile (5 mL) was heated at 50°C for 15 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 -20% ethyl acetate in petroleum ether) to provide 3-bromo -N - (2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-5-amine (100 mg, 52%) as a brown oil. LCMS RT = 1.149 min., m/z = 382.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 1.149 min., ESI+ found [M+H] = 382.9. Step 6: 2 -bromo -4 -(2,6 -difluorophenyl) -5,6 - dihydro -4H -imidazo [1,2 -b][1,2,4] triazole

[02149] A mixture of 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-5-amine (100 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20oC for 15 hours. The reaction mixture was diluted with ice water (3 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2-bromo-4-(2, 6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4] triazole (65 mg, 83%) as a white solid. LCMS RT = 0.612 min., m/z = 300.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.612 min., ESI+ found [M+H] = 300.1. Step 7: methyl 4 -(2,6-difluorophenyl) -5,6 -dihydro -4H - imidazo [1,2 -b][1,2,4] triazole -2 -carboxylate

[02150] A mixture of 2-bromo-4-(2,6-difluorophenyl)-5,6-dihydroimidazo [1,2-b] [1,2,4] triazole (60.0 mg, 0.20 mmol ), 1,1'-bis(diphenylphosphine) ferrocene palladium dichloride (13 mg, 0.02 mmol) and triethylamine (0.27 mL, 1.99 mmol) in methanol (40 mL) was heated under 70oC for 12 h under CO [3.77 bar (40psi)] and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 4 - (2,6 - difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 53%) as a yellow solid. LCMS RT = 0.566 min., m/z = 280.8 [M + H]+, LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.566 min. ., ESI+ found [M+H] = 280.8. Step 8: 4-(2,6-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylic acid

[02151] A mixture of methyl 4 -(2,6 - difluorophenyl) -5,6 -dihydroimidazo [1,2 -b][1,2,4] triazole -2 -carboxylate (30 mg, 0.11 mmol) and lithium hydroxide (13 mg, 0.54 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred under 25oC for 15 h. The reaction mixture was adjusted to pH = 3 by addition of 1N HCl and concentrated under reduced pressure to provide methyl 4-(2,6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1 ,2,4] crude triazole-2-carboxylate (30 mg, 100%) as a yellow solid. LCMS RT = 0.263 min., m/z = 267.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.263 min., ESI+ found [M+H] = 267.0. Step 9: 4 -(2,6-difluorophenyl) -N -[(6S) -2,4 -dimethyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -5,6 -dihydroimidazo [1,2 -b][1,2,4] triazol -2 - carboxamide

[02152] A mixture of 4 -(2,6 difluorophenyl) -5,6 -dihydroimidazo [1,2 -b][1,2,4] triazole -2 -carboxylic acid (25 mg, 0.09 mmol), (6S) -6 -amino -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (17 mg, 0.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and 1-hydroxybenzotriazole (28 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) stirred under 20oC for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile/0.05% HCl in water acetonitrile) to give 4-(2,6-difluorophenyl)-N- [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -5,6 -dihydroimidazo [1 ,2-b][1,2,4] triazole-2-carboxamide (6.5 mg, 18% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ7.52 - 7.43 (m, 1H), 7.21 - 7.17 (m, 2H), 6.46 (s, 1H), 4.72 - 4.60 (m, 3H), 4.60 - 4.53 (m, 2H), 4.51 - 4.45 (m, 1H), 4.43 - 4.35 (m, 1H), 3.38 (s , 3H), 2.91 - 2.82 (m, 1H), 2.45 - 2.35 (m, 4H). LCMS RT = 0.745 min., m/z = 443.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.745 min., ESI+ found [M+H] = 443.0. Example 650

[02153] WX Method 028 1 -(2-pyridylmethyl) -N -(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl - 1 ,2,4-triazole-3-carboxamide Step 1: methyl 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylate

[02154] A mixture of methyl 1H -1,2,4 -triazole -3 -carboxylate (2.0 g, 15.7 mmol), potassium carbonate (4.35 g, 31.5 mmol) and 2 -( bromomethyl) pyridine (2.71 g, 15.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 1-(2-pyridylmethyl) -1,2,4 -triazole -3 -carboxylate (1.6 g, 47%) as a light yellow solid. 1H NMR (400 MHz, DMSO -d6) δ 8.85 (s, 1H), 8.52 (br. s., 1H), 7.83 (t, J = 7.3 Hz, 1H), 7, 38 - 7.31 (m, 2H), 5.62 (s, 2H), 3.82 (s, 3H). Step 2: 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylic acid

[02155] A mixture of methyl 1 -(2 - pyridylmethyl) -1,2,4 -triazole -3 -carboxylate (500 mg, 2.29 mmol) and potassium hydroxide (0.26 g, 4.58 mmol) in ethanol (8 mL) and water (2 mL) was stirred for 2 h at 25oC. The solvent was removed under reduced pressure. The residue was dissolved in water (5 mL) and adjusted to pH = 6 by addition of 2 N HCl and concentrated under reduced pressure to provide 1-(2-pyridylmethyl)-1,2,4-triazol-3 acid -raw carboxylic acid (0.70g, 149%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 3: 1 -(2-pyridylmethyl) -N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 - yl -1,2,4 -triazole -3 -carboxamide

[02156] To a solution of 1-hydroxybenzotriazole (7.5 mg, 0.06 mmol) in N,N-dimethylformamide (2.5 mL) was added 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride ( 79 mg, 0.42 mmol), (6S)-6 -amino -4 - methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg , 0.28 mmol) and 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylic acid (56 mg, 0.28 mmol). The mixture was stirred at 20°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17 -47 / 0.05% ammonium hydroxide in water) to provide N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5-a][1,3] diazepin -6 -yl] -1 -(2-pyridylmethyl) -1,2,4 -triazole -3 -carboxamide (95.6 mg, 89.9 %) in the form of white solids. H NMR (400 MHz, CD3OD) δ8.66 (s, 1H), 8.55 (d, J = 4.4 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7 .54 (s, 1H), 7.42 - 7.38 (m, 2H), 6.32 (s, 1H), 5.62 (s, 2H), 4.55 - 4.42 (m, 2H ), 4.31 - 4.29 (m, 1H), 3.38 (s, 3H), 2.91 - 2.81 (m, 1H), 2.36 - 2.28 (m, 1H). LCMS RT = 1.25min., m/z = 367.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.25 min., ESI+ found [M+H] =367.2. Example 651 1 -(2-pyridylmethyl) -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 - yl -1,2,4 -triazole -3 -carboxamide

[02157] Amide coupling prepared in a manner similar to Method WX 028. The crude product was purified via RP-HPLC (17 -47% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - (2-pyridylmethyl) -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1 ,2,4-triazole-3-carboxamide (64.3 mg, 63%) in the form of a light yellow semi-solid. H NMR (400MHz, CD3OD) δ8.64 (s, 1H), 8.52 (d, J = 4.4 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.43 - 7 .32 (m, 2H), 6.10 (s, 1H), 5.60 (s, 2H), 4.57 - 4.48 (m, 1H), 4.36 - 4.27 (m, 1H) ), 4.26 - 4.14 (m, 1H), 3.32 (s, 3H), 2.90 - 2.77 (m, 1H), 2.30 - 2.20(m, 4H). LCMS RT = 0.652 min., m/z = 381.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.652 min., ESI+ found [M+H] =381.2. Example 652 1 -(2-pyridylmethyl) -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02158] Amide coupling prepared in a manner similar to Method WX 028. The crude product was purified via RP-HPLC (17 -47% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - (2 -pyridylmethyl) -N -(6S) -2 -cyclopropyl -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (70.3 mg, 75%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.65 (s, 1H), 8.53 (d, J = 4.8 Hz, 1H), 7.87 - 7.84 (m, 1H), 7.40- 7.37 (m, 2H), 6.00 (s, 1H), 5.60 (s, 2H), 4.56 - 4.51 (m, 1H), 4.30 - 4.28 (m, 1H), 4.23 - 4.18 (m, 1H), 3.32 (s, 3H), 2.88 - 2.81 (m, 1H), 2.29 - 2.24 (m, 1H) , 1.93 - 1.90 (m, 1H), 0.96 - 0.93 (m, 2H), 0.76 - 0.74 (m, 2H). LCMS RT = 0.747 min., m/z = 407.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min.) retention time 0.747 min., ESI+ found [M+H] =407.2. Example 653 1 -[(3 -fluoro -2 -pyridyl) methyl] -N -(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02159] Amide coupling prepared in a manner similar to Method WX 025. The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3-fluoro-2-pyridyl) methyl] -N -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6-yl - 1,2,4 -triazole -3 -carboxamide (16 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.65 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.71 - 7.60 (m, 1H), 7.51 ( s, 1H), 7.46 - 7.43 (m, 1H), 6.29 (s, 1H), 5.70(s, 2H), 4.52 - 4.38 (m, 2H), 4 .29 - 4.26 (m, 1H), 3.34 (s, 3H), 2.87 - 2.81 (m, 1H), 2.36 - 2.21 (m, 1H). LCMS RT = 1.05 min., m/z = 385.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.05 min., ESI+found [M+H] = 385.1. Example 654 Method WX 025 1 -[(3-fluoro-2-pyridyl) methyl] -N -(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: methyl 1 -((3 -fluoropyridin -2 -yl) methyl) -1H -1,2,4 -triazole -3 -carboxylate

[02160] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (128 mg, 1.01 mmol) in N,N - dimethylformamide (5 mL) was added potassium carbonate (1746 mg, 12 .63 mmol) and 2-(bromomethyl)-3-fluoro-pyridine (240 mg, 1.26 mmol). The reaction mixture was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 1-[(3-fluoro -2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (120mg, 40% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.32 (s, 2H), 7.42 - 7.38 (m, 1H), 7.28 - 7.26 (m, 1H), 5.58 (s, 2H ), 3.91 (s, 3H). Step 2: 1-((3-fluoropyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

[02161] A mixture of methyl 1 -[(3-fluoro-2-pyridyl) methyl]-1,2,4-triazole-3-carboxylate (120 mg, 0.51 mmol) and lithium hydroxide (114 mg, 4.75 mmol) in tetrahydrofuran (8 mL) and water (4 mL) was stirred at 25oC for 16 h. The mixture was adjusted to pH = 6 by adding 1N hydrochloric acid. The solid was collected by filtration and dried to provide crude 1-[(3-fluoro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (80 mg, 71% ) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: 1-[(3-fluoro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02162] A stirred solution of (6S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (26 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxy benzotriazole (27 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) and 1-[(3-fluoro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (30 mg, 0.14 mmol). The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (22-52% acetonitrile/0.05% ammonium hydroxide in water) to provide 1-[(3-fluoro-2-pyridyl)methyl]-N-(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide ( 31 mg, 56%) as a white solid. H NMR (400 MHz, CD3OD) δ8.65 (s, 1H), 8.35 (d, J = 4.8 Hz, 1H), 7.70- 7.62 (m, 1H), 7.46 - 7.42 (m, 1H), 6.09 (s, 1H), 5.70(s, 2H), 4.53 - 4.49 (m, 1H), 4.34 - 4.26 (m, 1H), 4.24 - 4.12 (m, 1H), 3.31 (s, 3H), 2.87 - 2.77 (m, 1H), 2.27 - 2.18 (m, 1H) , 2.24 (s, 3H). LCMS RT = 1.17 min., m/z = 399.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.17 min., ESI+found [M+H] = 399.2. Example 655 1 -[(3 -fluoro -2 -pyridyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[02163] Amide coupling prepared in a manner similar to Method WX 025. The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3-fluoro-2-pyridyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (38 mg, 65%) as a white solid. H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.45 - 7.43 (m, 1H), 5.99 (s, 1H), 5.70(s, 2H), 4.52 - 4.47 (m, 1H), 4.33 - 4.24 (m , 1H), 4.23 - 4.12 (m, 1H), 3.29 (s, 3H), 2.85 - 2.78(m, 1H), 2.28 - 2.17 (m, 1H) ), 1.94 - 1.85 (m, 1H), 0.97 - 0.88 (m, 2H), 0.75 - 0.69 (m, 2H). LCMS RT = 1.35 min., m/z = 425.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.35 min., ESI+found [M+H] = 425.2. Example 656 1 -[(3 -chloro -2 -pyridyl) methyl] -N -[rac -(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02164] Amide coupling prepared in a manner similar to Method WX 022. The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3 -chloro -2 -pyridyl) methyl] -N -(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6-yl - 1,2,4 -triazole -3 -carboxamide (44 mg, 73%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.62 (s, 1H), 8.43 – 8.41 (m, 1H), 7.91 – 7.89 (m, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.39 – 7.35 (m, 1H), 6.29 (d, J = 1.8 Hz, 1H), 5.78(s, 2H), 4.52 — 4.47 (m,1H), 4.46 — 4.38 (m, 1H), 4.31 - 4.22 (m, 1H), 3.34 (s, 3H), 2.81 - 2 .80 (m, 1H), 2.30 - 2.22 (m, 1H). LCMS RT = 1.21 min., m/z = 401.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.21 min., ESI+found [M+H] = 401.1. Example 657

[02165] WX Method 022 1 - [(3 -chloro -2 -pyridyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: 3-chloro-2-(chloromethyl)pyridine

[02166] To a stirred solution of (3-chloro-2-pyridyl) methanol (120mg, 0.84 mmol) in dichloromethane (15 mL) was added thionylchloride (497 mg, 4.18 mmol) at 25oC. After addition, the mixture was stirred for 2 h and then finalized by addition of water (10 mL). The solution was adjusted to pH = 11 by adding saturated aqueous sodium bicarbonate and then extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 3-chloro-2-(chloromethyl)pyridine (130 mg, 96%) in form of a yellow oil, which was used in the next stage in the form in which it was. Step 2: methyl 1 -((3 -chloropyridin -2 -yl) methyl) -1H -1,2,4 -triazole -3 -carboxylate

[02167] To a solution of methyl 1H -1,2,4 - triazole -3 -carboxylate (102 mg, 0.80 mmol) in N,N -dimethyl formamide (5 mL) was added 3-chloro -2 -( chloromethyl) pyridine (130 mg, 0.80 mmol) and potassium carbonate (333 mg, 2.41 mmol). The reaction mixture was stirred at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give methyl 1-[(3-chloro -2-pyridyl) methyl] - 1,2,4 -triazole -3 -carboxylate (125 mg, 62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.38 (dd, J = 1.4, 4.5 Hz, 1H), 8.26 (s, 1H), 7.68 (dd, J = 1.3, 8 .2Hz, 1H), 7.22 - 7.18 (m, 1H), 5.65 (s, 2H), 3.92 (s, 3H). Step 3: 1-((3-chloropyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

[02168] A mixture of methyl 1 -[(3-chloro-2-pyridyl) methyl]-1,2,4-triazole-3-carboxylate (125 mg, 0.50 mmol) and lithium hydroxide (104 mg, 4.35 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred for 16 h at 25oC. The mixture was adjusted to pH = 6 by adding 1N HCl. The resulting solid was collected by filtration and dried under reduced pressure to provide crude 1-[(3-chloro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (110 mg, 87%) in the form of a white solid, which was used in the next step in the form in which it was. Step 4: 1 -[(3-chloro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a] [1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02169] To a stirred solution of 1-[(3-chloro-2-pyridyl) methyl]-1,2,4-triazole-3-carboxylic acid (35 mg, 0.15 mmol) in N,N -dimethylformamide (3 mL) was added 1-hydroxybenzotriazole hydrochloride (29 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (42 mg, 0.22 mmol) and (6S)-6 -amino -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (31 mg, 0.16 mmol). The mixture was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (22-52% acetonitrile/0.05% ammonium hydroxide in water) to provide 1-[(3-chloro-2-pyridyl)methyl]-N-(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide ( 45 mg, 72%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.62 (s, 1H), 8.43 - 8.41 (m, 1H), 7.91 - 7.89 (m, 1H), 7.39 - 7.35 (m, 1H), 6.09 (s, 1H), 5.78(s, 2H), 4.54 - 4.50 (m, 1H), 4.35 - 4.27 (m, 1H), 4.25- 4.14 (m, 1H), 3.31 (s, 3H), 2.88 - 2.78(m, 1H), 2.29 - 2.18 (m, 1H), 2, 24 (s, 3H). LCMS RT = 1.26 min., m/z = 415.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.26 min., ESI+found [M+H] = 415.1. 1 -[(3 -chloro -2 -pyridyl) methyl] -N -(6S) -2 - cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[02170] Amide coupling prepared in a manner similar to Method WX 022. The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(3-chloro-2-pyridyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (37 mg, 56%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.62 (s, 1H), 8.43 - 8.41 (m, 1H), 7.91 - 7.89 (m, 1H), 7.51 (s, 1H ), 7.39 - 7.35 (m, 1H), 6.29 (s, 1H), 5.78(s, 2H), 4.52 - 4.47 (m,1H), 4.46 - 4.38 (m, 1H), 4.31 - 4.22 (m, 1H), 3.34 (s, 3H), 2.81 - 2.80 (m, 1H), 2.30 - 2, 22 (m, 1H). LCMS RT = 1.44 min., m/z = 441.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.44 min., ESI+found [M+H] = 441.1 . 1 -[(2-fluorophenyl) methyl] -N -(7R) -2,9 - dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin - 7 -yl -1,2,4 -triazole -3 -carboxamide

[02171] Amide coupling prepared in a manner similar to Method WX 091. The crude product was purified via RP-HPLC (20% to 50% acetonitrile / 0.05% ammonium hydroxide in water) to provide N - (2,9 -dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 - a][1,3] diazepin -7 -yl) -1 - [(2 -fluorophenyl) methyl] - 1,2,4-triazole-3-carboxamide (35 mg, 52% yield) as a white solid. The racemic material was separated using chiral SFC to provide:

[02172] 1 -[(2-fluorophenyl) methyl] -N -(7R) - 2,9 -dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 - a][1,3 ] diazepin -7 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 3.433 min.) (15.5 mg, 22%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.57 (s, 1H), 7.45 - 7.33 (m, 2H), 7.24 - 7.11 (m, 2H), 6.77 (s, 1H ), 5.55 (s, 2H), 4.54 - 4.49 (m, 1H), 4.21 - 4.15 (m, 1H), 4.04 - 3.95 (m, 1H), 3.36 (s, 3H), 2.87 - 2.78(m, 1H), 2.28 - 2.14 (m, 4H). LCMS RT = 1.819 min.; m/z = 398.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.819 min., ESI+ found [M+H] = 398.1.

[02173] SFC Conditions: Column: Chiralpak AD -3 150 x 4.6 mm ID, 3 µm Mobile phase: 40% ethanol (0.05% DEA) in CO2 Flow rate: 2.5 mL / min. Column temperature: 35 oC. Example 660 1 -[(2,6-difluorophenyl) methyl] -N -(7R) -2,9 - dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -7 -yl -1,2,4 -triazole -3 -carboxamide

[02174] Amide coupling prepared in a manner similar to Method WX 091. The crude product was purified via RP-HPLC (20% to 50% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 -[(2,6-difluorophenyl) methyl] -N -(2,9 -dimethyl -8 -oxo - 6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -7 - il) - 1,2,4 -triazole -3 -carboxamide (35 mg, 50%) as a white solid. The racemic material was separated using chiral SFC to provide:

[02175] 1 -[(2,6-difluorophenyl) methyl] -N -(7R) - 2,9 -dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 - a][1 ,3] diazepin -7 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.195 min.) (18.7 mg, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.60 (s, 1H), 7.50 - 7.42 (m, 1H), 7.07 - 7.03 (m, 2H), 6.77 (s, 1H) ), 5.60 (s, 2H), 4.53 - 4.48 (m, 1H), 4.21 - 4.15 (m, 1H), 4.03 - 3.95 (m, 1H), 3.36 (s, 3H), 2.84 - 2.76 (m, 1H), 2.26 - 2.16 (m, 4H). LCMS RT = 1.817 min.; m/z = 416.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.817 min., ESI+ found [M+H] = 416.2.

[02176] SFC Conditions: Column: Chiralcel OJ -3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40oC. Example 661 1 -[(2,5-difluorophenyl) methyl] -N -(7R) -2,9 - dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -7 -yl -1,2,4 -triazole -3 -carboxamide

[02177] Amide coupling prepared in a manner similar to Method WX 091. The crude product was purified via RP-HPLC (20% to 50% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2,5-difluorophenyl) methyl] -N -(2,9 -dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 -a][1,3] diazepin -7 - il) -1,2,4 -triazole -3 -carboxamide (50 mg, 71%) as a white solid. The racemic mixture was separated using chiral SFC to give:

[02178] 1 -[(2,5-difluorophenyl) methyl] -N - (7R) -2,9 -dimethyl -8 -oxo -6,7 -dihydro -5H -imidazo [1,2 - a][1 ,3] diazepin -7 -yl -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.786 min.) (21.5 mg, 47%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.61 (s, 1H), 7.22 - 7.11 (m, 3H), 6.78(s, 1H), 5.54 (s, 2H), 4, 55 - 4.48 (m, 1H), 4.21 - 4.16 (m, 1H), 4.05 - 3.98 (m, 1H), 3.36 (s, 3H), 2.86 - 2.76 (m, 1H), 2.31 - 2.15 (m, 4H). LCMS RT = 1.852 min.; m/z = 416.1 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 1.852 min., ESI+ found [M+H] = 416.1.

[02179] SFC Conditions: Column: Chiralcel OD -3 100 x 4.6 mm I.D., 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40oC. Example 662

[02180] Method WX 082 1 -benzyl -N -(6S) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazol -3 -carboxamide and 1 -benzyl -N -(6R) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazol -3 –carboxamide Step 1: N -(5-bromo-1H-pyrazol-3-yl)formamide

[02181] A solution of the compound 5-bromo-1H-pyrazol-3-amine (500 g, 3.1 mol) in formic acid (1.5 L) was refluxed at 110°C for 3 h. TLC (dichloromethane: methanol = 10: 1, Rf = 0.35) showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residue was washed with 2-methoxy-2-methylpropane (1 L) twice to provide N -(5-bromo-1H-pyrazol-3-yl)formamide (538 g , 92% yield) in the form of a white solid, which was used in the next step in the form in which it was. Step 2: 5-bromo-N-methyl-1H-pyrazole-3-amine

[02182] With two reactions carried out in parallel, the compound N -(5-bromo-1H-pyrazole) was added to a solution of lithium aluminum hydride (105 g, 2.8 mol) in tetrahydrofuran (2.6 L). -3-yl)formamide (265 g, 1.4 mol) under 0°C and the reaction mixture was subjected to stirring under 10°C for 16 h. The two reactions were combined and the reaction mixture was finished with water (106 mL) and 15% NaOH solution (106 mL). The resulting solid was filtered and washed with tetrahydrofuran (2 x 2L). The filtrate was concentrated under reduced pressure and the crude product was purified by silica column chromatography (petroleum ether:ethyl acetate = 50:1~3:1) to give 5-bromo-N-methyl- 1H - pyrazole -3 -amine (200 g, 41% yield) in the form of a yellow oil. 1H NMR (400MHz, CD3OD) δ 4.85 (s, 2 H), 2.70 -2.79 (m, 3 H). Step 3: N -(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide

[02183] A solution of the compound 5-bromo-N-methyl-1H-pyrazol-3-amine (175 g, 1.0 mol) and 4-chlorobutanoyl chloride compound (661 g, 4.7 mol) was subjected to stirring under 60°C for 1 h. The reaction mixture was quenched with methanol (800 mL) at -30oC and allowed to warm to 0oC and stir for 1 h. Then the mixture was neutralized with aq. NaOH. (10M) to pH 6, the mixture was concentrated, extracted with dichloromethane (3 x 300 mL) and the combined filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 1:0 ~ 30:1) to give N -(3-bromo-1H-pyrazol-5-yl)-4-chloro-N - methylbutanamide (180 g, 64% yield) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 4: 2 -bromo -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one

[02184] With two reactions carried out in parallel, a solution of the compound N -(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide (100 g, 356 mmol) in acetonitrile (1 L) was Cesium carbonate (232 g, 713 mmol) was added and stirred at 30°C for 16 h. The two reactions were combined for processing, filtered off the Cs2CO3 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50: 1~1: 1) to give 2-bromo-4-methyl-7,8-dihydro-4H-pyrazole [1, 5 -a][1,3] diazepin -5(6H) -one (110 g, 63% yield) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 5: 2 -bromo -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepine -5(6H) -

[02185] To a solution of the compound 2 -bromo -4 - methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin - 5(6H) -one (100 g, 410 mmol) in dichloromethane (2 L) was added N,N,N',N'-tetramethylethane-1,2-diamine (143 g, 1.23 mol), stirred at -15°C for 0.5 h , followed by adding iodine (trimethyl) silane (246 g, 1.23 mol) dropwise under -15°C for 1.5 h. Subsequently, iodine (312 g, 1.23 mol) was added and the reaction mixture was stirred at -15°C for 3 h. The reaction mixture was finished with aq. Na2SO3. (10M, 1L), filtered, washed with brine (1L), extracted with dichloromethane (2 x 3L), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide the compound 2-bromo -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (170g, crude) as a solid brown color, which was used in the next step without any further purification. Step 6: 6 -azide -2 -bromo -4 -methyl -7,8 - dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[02186] To a solution of the compound 2 -bromo -6 - iodo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one ( 170 g, 460 mmol) in dimethylformamide (500 mL) was added sodium azide (45 g, 670 mol) and stirred at 30°C for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (2 x 2 L), the combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 6-azide-2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 g, crude) in the form of a yellow oil, which was used in the next step without any further purification. Step 7: 6 -amino -2 -bromo -4 -methyl -7,8 - dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[02187] To a solution of the compound 6 -azide -2 - bromo -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one ( 100 g, 350 mmol) in methanol (1 L) Pd/C (15 g) was added, the mixture was stirred at 30°C for 16 h under H2 [3.08 bar (30 psi)]. Pd/C was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using a flash silica column (petroleum ether: ethyl acetate = 50:1 ~ 0:1) to provide 6-amino -2 -bromo -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one (50 g, yield: 54%) as a white solid. 1H NMR (400MHz, DMSO -d6) δ 6.43 (s, 1 H), 4.17 -4.27 (m, 1 H), 4.05 (ddd, J= 14.6, 12.7, 6.7 Hz, 1 H), 3.19 (s, 3 H), 3.13 -3.17 (m, 1 H), 2.44 -2.50 (m, 1 H), 1.73 -1.83 (m, 1 H). Step 8: 1 -benzyl -N -(2 -bromo -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02188] A mixture of 6-amino -2 -bromo -4 - methyl -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one (4.0 g, 15.44 mmol), 1-hydroxybenzotriazole (3.1 g, 23.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.4 g, 23.16 mmol) and 1-benzyl acid - 1,2,4-triazole -3-carboxylic acid (3.8 g, 18.53 mmol) in N,N - dimethylformamide (20 mL) was stirred at 20oC for 16 h. The reaction mixture was poured into water (100 mL) and stirred for 20 min. The resulting solid was collected through filtration and dried to provide 1-benzyl-N-(2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1 ,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (6.8 g, 99% yield) in the form of white solids, which it was used in the next stage as it was. Step 9: 1 -benzyl -N -[4 -methyl -5 -oxo -2 -(3 - oxopropyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazol -3 -carboxamide and (E) -1 -benzyl -N -(2 -(3 -hydroxyprop -1 -en -1 -yl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02189] A mixture of 1-benzyl -N -(2-bromo -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 - yl) -1,2,4 -triazole -3 -carboxamide (300 mg, 0.68 mmol), N,N -diisopropylethylamine (262 mg, 2.03 mmol), allyl alcohol (118 mg, 2.03 mmol) and bis(tri-tert-butylphosphine) palladium (34 mg, 0.07 mmol) in 1,4-dioxane (10 mL) was subjected to stirring at 80oC for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give a mixture of 1-benzyl-N-[ 4 -methyl - 5 -oxo -2 -(3 - oxopropyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide, and (E) -1 -benzyl -N -(2 -(3 -hydroxyprop -1 -en -1 -yl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (250 mg, 88%, ratio 3:7) in form of a yellow solid, which was used in the next step in the form in which it was. Step 10: [(E)-3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H- pyrazole [1,5 -a][1,3] diazepin -2 -yl] allyl] methanesulfonate

[02190] To a solution of (E) -1 -benzyl -N -(2 -(3 -hydroxyprop -1 -en -1 -yl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5-a][1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide (40 mg, 0.09 mmol) in dichloromethane (5 mL) triethylamine (38 mg, 0.30 mmol) and methanesulfonyl chloride (16 mg, 0.14 mmol) were added. The reaction mixture was subjected to stirring at 15oC for 12 h. The mixture was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide [(E)-3-[6-[(1-benzyl-1,2,4- crude triazol -3 -carbonyl)amino] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -2 -yl] allyl] methanesulfonate ( 35 mg, 74%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 11: 1-benzyl-N-[4-methyl-2-[(E)-3-morpholino prop-1-enyl]-5-oxo-7,8-dihydro-6H-pyrazole[1,5-a ][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02191] To a solution of [(E) -3 - [6 - [(1 - benzyl -1,2,4 -triazol -3 -carbonyl) amino] -4 -methyl -5 - oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -2 - yl] allyl] methane sulfonate (35 mg, 0.07 mmol) in N,N - dimethylformamide (3 mL) was added carbonate potassium (48 mg, 0.35 mmol) and morpholine (18 mg, 0.21 mmol). The reaction mixture was stirred at 35°C for 1 h and then poured into water (15 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide 1-benzyl-N-[4-methyl-2-[(E)-3-morpholino prop -1 -enyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide crude (30 mg, 87%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 12: 1 -benzyl -N -(6S) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -(6R) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02192] A mixture of 1-benzyl -N -[4-methyl -2 -[(E) -3 -morpholino prop -1 -enyl] -5 -oxo -7,8 - dihydro -6H -pyrazole [1, 5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (30 mg, 0.06 mmol) and Pd/C (10%, 19 mg, 0.02 mmol) in ethyl acetate (10 mL) was hydrogenated [2.04 bar (15 psi)] for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC ((20-50% acetonitrile / 0.05% NH3,H2O in water)) to give 1-benzyl-N-[4-methyl -2 -(3 -morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (15 mg, 50%) as a white solid.

[02193] Two batches of racemic material (40 mg) were separated using chiral SFC to provide:

[02194] 1 -benzyl -N -(6S) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, Retention time = 4.402 min.) (18.3 mg, 44%) as a white solid. 1H NMR (400MHz, CD3OD) δ8.57 (s, 1H), 7.38 - 7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.54 - 4.49 (m, 1H), 4.33 - 4.30 (m, 1H), 4.27 - 4.23 (m, 1H), 3.72 (t, J = 4.4 Hz, 4H ), 3.32 (s, 3H), 2.83 - 2.80 (m, 1H), 2.66 - 2.48 (m, 8H), 2.26 - 2.24 (m, 1H), 1.92 - 1.88 (m, 2H). LC -MS RT = 1.449 min., m/z = 493.3 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.449 min., ESI+ found [M+H] = 493.3.

[02195] 1 -benzyl -N -(6R) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, Retention time = 4.483 min.) (18.8 mg, 45%) as a white solid. 1H NMR (400MHz, CD3OD) δ8.56 (s, 1H), 7.38 - 7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.54 - 4.49 (m, 1H), 4.33 - 4.30 (m, 1H), 4.27 - 4.21 (m, 1H), 3.69 (t, J = 4.8 Hz, 4H ), 3.33 (s, 3H), 2.83 - 2.80 (m, 1H), 2.66 - 2.62 (m, 2H), 2.48 - 2.40(m, 6H), 2.26 - 2.24 (m, 1H), 1.89 - 1.86 (m, 2H). LC -MS RT = 1.449 min., m/z = 493.3 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.449 min., ESI+ found [M+H] = 493.3.

[02196] SFC condition: column: Chiralpak AD - 3 (100x4.6 mm), 3 um mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 5 to 40 B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 663

[02197] Method WX 031 1 -[(2 -methyl -3 -pyridyl) methyl] -N -(6S) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide Step 1: 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid

[02198] A mixture of methyl 1H -1,2,4 -triazole -3 -carboxylate (239 mg, 1.88 mmol), potassium carbonate (520 mg, 3.76 mmol) and 3 -(bromomethyl) -2 -methyl-pyridine (350 mg, 1.88 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to provide crude methyl 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazol-3-carboxylate (0.30 g, 69%) as of a yellow oil.

[02199] The aforementioned crude product was diluted with water (5 mL) and stirred for 10 min. under 25oC. The mixture was adjusted to pH = 6 by adding 2N HCl. The resulting mixture was concentrated under reduced pressure to provide crude 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazol-3-carboxylic acid (260 mg, 92%) as a yellow solid, which was used in the next step as it was. Step 2: 1 -[(2 -methyl -3 -pyridyl) methyl] -N - (6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1 ,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide

[02200] A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol), (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazole [1,5 -a][1,3] diazepin -5 -one (49 mg, 0.27 mmol), 1 - hydroxybenzotriazole (7 mg, 0.05 mmol) and 1 -[(2 -methyl -3) acid -pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (60 mg, 0.27 mmol) in N,N-dimethylformamide (2.5 mL) was stirred at 20°C for 12 h and concentrated under pressure reduced. The residue was purified by RP-HPLC (acetonitrile 17 -47 / 0.05% ammonium hydroxide in water to give 1 - [(2 -methyl -3 -pyridyl) methyl] - N - (6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (36.1 mg , 34%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.63 (s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 7.60 ( d, J = 7.6 Hz, 1H), 7.56-7.52 (m, 1H), 7.32 - 7.29 (m, 1H), 6.33-6.31 (m, 1H) , 5.60 (s, 2H), 4.55 - 4.42 (m, 2H), 4.35 - 4.24 (m, 1H), 3.37 (s, 3H), 2.95 - 2 .82 (m, 1H), 2.61 (s, 3H), 2.35 - 2.25(m, 1H). LCMS RT = 1.068 min., m/z = 381.2 [M + H]+ LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.068 min., ESI+ found [M+H] =381.2. Example 664 1 -[(2 -methyl -3 -pyridyl) methyl] -N -(6S) -2,4 - dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 –carboxamide

[02201] Amide coupling prepared in a manner similar to Method WX 031. The crude product was purified via RP-HPLC (17 -47% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2 -methyl -3 -pyridyl) methyl] -N -(6S) -2,4 -dimethyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl -1,2,4 -triazole -3 -carboxamide (28.6 mg, 26%) in the form of a light yellow semi-solid. H NMR (400 MHz, CD3OD) δ8.61 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7 .30 - 7.27 (m, 1H), 6.11 (s, 1H), 5.58 (s, 2H), 4.55 - 4.50 (m, 1H), 4.35 - 4.27 (m, 1H), 4.26 - 4.16 (m, 1H), 3.32 (s., 3H), 2.90 - 2.78(m, 1H), 2.59 (s., 3H) , 2.30 - 2.20(m, 4H). LCMS RT = 1.165 min., m/z = 395.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.165 min., ESI+ found [M+H] =395.2. [1,5 -a][1,3] diazepin -6 -yl -1,2,4 -triazole -3 - carboxamide

[02202] Amide coupling prepared in a manner similar to Method WX 031. The crude product was purified via RP-HPLC (17 -47% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - [(2-methyl -3 -pyridyl) methyl] -N -(6S) -2 -cyclopropyl -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl -1,2,4 -triazole -3 -carboxamide (37 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.62 (s, 1H), 8.40(d, J = 4.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7 .31 - 7.28 (m, 1H), 6.01 (s, 1H), 5.59 (s, 2H), 4.55 - 4.50 (m, 1H), 4.35 - 4.27 (m, 1H), 4.25- 4.15 (m, 1H), 3.33 - 3.32 (m, 3H), 2.90 - 2.78(m, 1H), 2.60 (s , 3H), 2.33 - 2.19 (m, 1H), 1.96 - 1.87 (m, 1H), 0.98 - 0.91 (m, 2H), 0.78- 0.70 (m, 2H). LCMS RT = 1.287 min., m/z = 421.3 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min.) retention time 1.287 min., ESI+ found [M+H] =421.3. Examples 666 and 667

[02203] WX Method 127 (5R) -5 -(2-fluorophenyl) -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide and (5S) -5 -(2 -fluorophenyl) -N - [(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 –carboxamide Step 1: methyl 4-(4-bromo-2-fluorophenyl)-4-oxobutanoate

[02204] To a solution of 1-bromo-3-fluorobenzene (5.0 g, 28.57 mmol) in 1,2-dichloroethane (100 mL) was added aluminum chloride (15.2 g, 114.29 mmol ) and methyl 4-chloro-4-oxobutyrate (8.6 g, 57.14 mmol). The mixture was heated at 70°C for 12 h and cooled. The reaction was finished slowly by adding water (20 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide methyl 4 -(4 - bromo-2-fluoro-phenyl)-4-oxo-butanoate (2.0 g, 24%) as a yellow solid. LCMS RT = 0.995 min., m/z = 291.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.995 min., ESI+ found [M+H] = 291.1. Step 2: tert-butyl(2-(4-bromo-2-fluorophenyl)-5-oxopyrrolidin-1-yl) carbamate

[02205] To a solution of methyl 4 -(4-bromo-2-fluoro-phenyl)-4-oxo-butanoate (2.0 g, 6.91 mmol) in tetrahydrofuran (10 mL) and acetic acid (5 mL ) tert-butyl hydrazine carboxylate (1.3 g, 10.38 mmol) was added. The mixture was stirred at 40°C for 12 h and then sodium cyanoborohydride (652 mg, 10.38 mmol) was added. Stirring was continued for another 6 h and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (2 x 20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide N-[2-(2-fluorophenyl)-5 tert-butyl -oxo -pyrrolidin -1 -yl]carbamate (800 mg, 78%) in the form of a yellow oil. LCMS RT = 1.067 min., m/z = 319.0 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 1.067 min., ESI+ found [M -55] = 319.0. Step 3: tert-butyl(2-(2-fluorophenyl)-5-oxopyrrolidin-1-yl) carbamate

[02206] A mixture of tert-butyl N -[2 -(4 - bromo -2 -fluoro -phenyl) -5 -oxo -pyrrolidin -1 -yl] carbamate (800 mg, 2.14 mmol) and Pd/C (10%, 228 mg, 0.21 mmol) in methanol (10 mL) was hydrogenated [2.04 bar (15 psi)] under 25°C for 4 h and then filtered. The filtrate was concentrated under reduced pressure to provide crude tert-butyl N-[2-(2-fluorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (500 mg, 79%) as a solid. White color. LCMS RT = 0.972 min., m/z = 239.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min.) retention time 0.972 min., ESI+ found [M -55] = 239.1. Step 4: 1 -amino -5 -(2 - fluorophenyl) pyrrolidin -2 -one hydrochloride

[02207] A solution of tert-butyl (2-(2-fluorophenyl)-5-oxopyrrolidin-1-yl) carbamate (400 mg, 1.36 mmol) in ethyl acetate (5 mL) was added HCl (4N in ethyl acetate, 1.0 mL, 4.0 mmol). The mixture was stirred at 25°C for 4 h and then concentrated under reduced pressure to provide crude 1-amino-5-(2-fluorophenyl)pyrrolidin-2-one hydrochloride (400 mg, 100%) as a white solid, which was used in the next step as it was. Step 5: (Z)-ethyl 2-amino -2 -((2 -(2 - fluorophenyl) -5 -oxopyrrolidin -1 -yl) imino) acetate

[02208] To a solution of 1-amino-5-(2-fluorophenyl)pyrrolidin-2-one hydrochloride (400 mg, 2.06 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino - acetate (1.8 g, 12.36 mmol). The mixture was stirred at 40°C for 12 h and concentrated under reduced pressure to provide ethyl (2Z)-2-amino-2-[2-(2-fluorophenyl)-5-oxo-pyrrolidin-1-yl]imino- crude acetate (500 mg, 82%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 6: methyl 7 -methyl -5,6,7,8 - tetrahydroimidazo [1,5 -a] pyridine -1 -carboxylate

[02209] A solution of ethyl (2Z) -2 -amino -2 - [2 - (2 -fluorophenyl) -5 -oxo -pyrrolidin -1 -yl] imino - acetate (500 mg, 1.7 mmol) in oxychloride of phosphorus (5.0 mL, 135.9 mmol) was heated under 120oC for 1 h. After cooling, the mixture was slowly quenched by adding water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 20% sodium bicarbonate (20 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 60% ethyl acetate in petroleum ether) to give ethyl 5-(2-fluorophenyl)-6,7-dihydro-5H - pyrrole [1,2 -b][1,2,4] triazole -2 -carboxylate (400 mg, 85%) in the form of a light yellow oil. LCMS RT = 0.760 min., m/z = 275.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.760 min., ESI+ found [M+H] = 275.9. Step 7: 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole-2-carboxylic acid

[02210] A mixture of ethyl 5 -(2-fluorophenyl) -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxylate (400 mg, 1.45 mmol) and potassium hydroxide in ethanol (20mL) and water (5mL) was stirred at 25oC for 12 h. Ethanol was removed under reduced pressure. The residue was diluted with water (20 mL) and adjusted to pH = 4 by adding 2N HCl. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure to provide 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrole[1,2-b][1,2,4]triazole-2-carboxylic acid in crude (200 mg, 55%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 8: (5R) -5 -(2-fluorophenyl) -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin - 6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide and (5S) -5 -(2 -fluorophenyl) -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl] -6,7 - dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide

[02211] A mixture of (6S) -6 -amino -2,4 - dimethyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 5 -one (40 mg, 0.21 mmol), 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol), 1-hydroxy benzotriazole (31 mg, 0.21 mmol). and 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (50 mg, 0.21 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by prep TLC (0 -2% methanol in dichloromethane, Rf = 0.5) to give N -((S) -2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -5 -(2-fluorophenyl) -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (60 mg, 69%) as a white solid. The racemic material was separated using chiral SFC to provide:

[02212] (5R) -5 -(2-fluorophenyl) -N -[(6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1 ,3] diazepin -6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide (Peak 1, retention time 2.561 min.) ( 25 mg, 41.7%) as white solids. 1H NMR (400 MHz, CD3OD) δ7.45 - 7.38 (m, 1H), 7.24 - 7.14 (m, 3H), 6.12 (s, 1H), 5.79 - 5.75 (m, 1H), 4.53 - 4.49(m, 1H), 4.35 - 4.28 (m, 1H), 4.26 - 4.16 (m, 1H), 3.37 - 3 .33 (m, 3H), 3.32 - 3.27 (m, 1H), 3.19 - 3.05 (m, 2H), 2.88 - 2.79 (m, 1H), 2.78 - 2.68 (m, 1H), 2.26 (s, 3H), 2.25- 2.17 (m, 1H). LCMS RT = 0.91 min., m/z = 424.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1% trifluoroacetic acid for 2.0 min.) retention time 0.91 min., ESI+ found [M+H] = 424.2.

[02213] (5S) -5 -(2-fluorophenyl) -N -[(6S) - 2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1 ,3] diazepin -6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 - b][1,2,4] triazole -2 -carboxamide (Peak 2, retention time 2.779 min.) ( 25 mg, 41.7%) white solids. 1H NMR (400 MHz, CD3OD) δ7.45 - 7.38 (m, 1H), 7.24 - 7.14 (m, 3H), 6.12 (s, 1H), 5.80 - 5.76 (m, 1H), 4.54 - 4.49 (m, 1H), 4.35 - 4.28 (m, 1H), 4.26 - 4.16 (m, 1H), 3.37 - 3 .33 (m, 3H), 3.32 - 3.27 (m, 1H), 3.19 - 3.05 (m, 2H), 2.88 - 2.79 (m, 1H), 2.78 - 2.68 (m, 1H), 2.26 (s, 3H), 2.25- 2.17 (m, 1H). LCMS RT = 0.92 min., m/z = 424.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1% trifluoroacetic acid for 2.0 min.) retention time 0.92 min., ESI+ found [M+H] = 424.2.

[02214] SFC Conditions: Column: Chiralcel OJ -3 100x4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min., Column temperature: 40oC. Examples 668 and 669 (5R) -5 -(2 -fluorophenyl) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 - yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide and (5S) -5 -(2 -fluorophenyl) -N -[( 6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 - yl] -6,7 -dihydro -5H -pyrrole [1 ,2 -b][1,2,4] triazole -2 - carboxamide

[02215] Amide coupling prepared in a manner similar to Method WX 127. The crude product was purified via RP-HPLC (22 -52% acetonitrile / 0.05% ammonium hydroxide in water) to provide 5 - (2-fluorophenyl) -N -((S) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) - 6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 - carboxamide (60 mg, 66%). The racemic material was separated using chiral SFC to provide:

[02216] (5R) -5 -(2-fluorophenyl) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (Peak 1, retention time 2.784 min.) (25mg, 41.2%) 1H NMR (400 MHz, CD3OD) δ7.51 (d, J = 2.0 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.22 - 7.13 ( m, 3H), 6.29 (d, J = 2.0 Hz, 1H), 5.77 (dd, J = 8.0, 12.0 Hz, 1H), 4.52 - 4.38 (m , 2H), 4.30 - 4.22 (m, 1H), 3.34 (s, 3H), 3.30 - 3.25(m, 1H), 3.19 - 3.03 (m, 2H ), 2.88 - 2.80 (m, 1H), 2.74 - 2.68 (m, 1H), 2.30 - 2.21 (m, 1H). LCMS RT = 0.76 min., m/z = 410.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.76 min., ESI+ found [M+H] = 410.0.

[02217] (5S) -5 -(2-fluorophenyl) -N -[(6S) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -6,7 -dihydro -5H -pyrrole [1,2 -b][1,2,4] triazole -2 -carboxamide (Peak 2, retention time 2,950 min.) (24 mg , 39.6%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ7.52 (s, 1H), 7.43 - 7.37 (m, 1H), 7.22 - 7.12 (m, 3H), 6.30 (s, 1H ), 5.80 - 5.76 (m, 1H), 4.53 - 4.38 (m, 2H), 4.30 - 4.22 (m, 1H), 3.35 (s, 3H), 3.30 - 3.25(m, 1H), 3.19 - 3.03 (m, 2H), 2.90 - 2.79 (m, 1H), 2.76 - 2.67 (m, 1H) ), 2.30 - 2.21 (m, 1H). LCMS RT = 0.75 min., m/z = 410.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% trifluoroacetic acid for 1.5 min.) retention time 0.75 min., ESI+ found [M+H] = 410.0.

[02218] SFC Conditions: Column: Chiralcel OJ -3 100x4.6 mm I.D., 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min., Column temperature: 40oC. Examples 670-697 (“Chiral Table 1”):

[02219] In each example set out below, Solvent A is comprised of CO2 and Solvent B is comprised of 0.1% NH4OH/ Methanol. The column temperature is 40°C in each example. Example 698

[02220] Suzuki Method 1 1 -benzyl -N -[2 -(1-ethylpyrazol -4 -yl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide

[02221] A microwave flask was charged with 1-benzyl-N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazole [1,5-a] [1,3] diazepin -6 -yl) -1,2,4 - triazole -3 -carboxamide (100 mg, 0.2251 mmol), 1 -ethyl -4 - (4,4,5,5 -tetramethyl -1,3,2 -dioxaborolan -2 -yl) -1H - pyrazole, (61.21 mg, 0.27 mmol), and [1,1' - bis(diphenylphosphine) ferrocene] dichloro palladium (II) (1:1) (17, 34 mg, 0.023 mmol). The solids were dissolved in a mixture of acetonitrile (0.6431 mL) and 1N potassium carbonate (0.6431 mL, 0.6431 mmol), the vial was sealed and irradiated in a microwave at 110°C for 10 min. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 5 mL), saline and dried over sodium sulfate. The filtrate was concentrated to drying in vacuo and the residue was purified by reverse phase HPLC to provide 1-benzyl-N-[2-(1-ethylpyrazol-4-yl)-4-methyl-5-oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide in the form of a white solid (30 mg, 29% yield). 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 0.7 Hz, 1H ), 7.72 (d, J = 0.7 Hz, 1H), 7.55 - 7.21 (m, 5H), 6.50 (s, 1H), 5.48 (s, 2H), 4 .45 - 4.28 (m, 2H), 4.24 - 4.09 (m, 3H), 3.26 (s, 3H), 2.69 - 2.57 (m, 1H), 2.43 - 2.30 (m, 1H), 1.39 (t, J = 7.3 Hz, 3H). LC -MS RT = 4.04 min., m/z = 460.2 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.04 min., ESI+ found [M+H] = 460.2.

[02222] SFC Condition: Column: Cellulose -1 150 x 21.2 mm., 3 μm Mobile phase: A: CO2 B: Methanol (0.1% NH4OH)., Isocratic Gradient: 40% B for 37.5 min. Flow rate: 70 mL/min. Column temperature: 40°C, BPR: 120 bar. Example 699 1 -benzyl -N -[2 -(1 -isobutylpyrazol -4 -yl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide

[02223] Suzuki Method 1, (20 mg, 41% yield), 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 0.7 Hz, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.44 - 7.23 (m, 5H), 6, 51 (s, 1H), 5.48 (s, 2H), 4.46 - 4.29 (m, 2H), 4.25- 4.11 (m, 1H), 3.93 (d, J = 7.2 Hz, 2H), 3.26 (s, 3H), 2.71 - 2.58 (m, 1H), 2.43 - 2.32 (m, 1H), 2.19 - 2.05 (m, 1H), 0.85 (d, J = 6.7 Hz, 6H). LC -MS RT = 4.51 min., m/z = 488.2 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.51 min., ESI+ found [M+H] = 488.2. Example 700 5 -bromo -N -[rac -(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 - yl]isoquinoline - 3 - carboxamide

[02224] Method B. (74 mg, 90% yield), 1H NMR (400 MHz, DMSO -d6) δ 9.49 (d, J = 0.8 Hz, 1H), 9.13 (d, J = 7.7 Hz, 1H), 8.58 (t, J = 0.9 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (dd, J = 7 .5, 1.0 Hz, 1H), 7.77 (dd, J = 8.2, 7.5 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 4.50 - 4.37 (m, 2H), 4.33 - 4.19 (m, 1H), 3.29 (s, 3H), 2, 81 - 2.71 (m, 1H), 2.46 - 2.35 (m, 1H). LC -MS RT = 5.10 min., m/z = 414.0 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.10 min., ESI+ found [M+H] = 414.0. Example 701 5 -bromo -N -[rac -(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] isoquinoline -3 -carboxamide

[02225] Method B. (74 mg, 88% yield), 1H NMR (400 MHz, DMSO -d6) δ 9.49 (d, J = 0.9 Hz, 1H), 9.11 (d, J = 7.8 Hz, 1H), 8.58 (t, J = 0.9 Hz, 1H), 8.40- 8.31 (m, 1H), 8.26 (dd, J = 7.5, 1.0 Hz, 1H), 7.77 (dd, J = 8.2, 7.5 Hz, 1H), 6.15 (s, 1H), 4.54 - 4.38 (m, 1H), 4.38 - 4.25(m, 1H), 4.24 - 4.08 (m, 1H), 3.26 (s, 3H), 2.89 (d, J = 0.4 Hz, 1H) , 2.80 - 2.66 (m, 2H), 2.42 - 2.31 (m, 1H), 2.19 (d, J = 0.5 Hz, 3H). LC -MS RT = 5.32 min., m/z = 428.0 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.32 min., ESI+ found [M+H] = 428.0. 5 -phenyl -N -[rac -(6S) -2,4 -dimethyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] isoquinoline -3 -carboxamide

[02226] Method B and subsequently Suzuki Method 1, (32 mg, 36% yield), 1H NMR (400 MHz, DMSO -d6) δ 9.50 (d, J = 0.9 Hz, 1H), 9, 06 (d, J = 7.7 Hz, 1H), 8.44 - 8.18 (m, 2H), 7.97 - 7.79 (m, 2H), 7.66 - 7.46 (m, 5H), 6.12 (s, 1H), 4.45 - 4.34 (m, 1H), 4.34 - 4.22 (m, 1H), 4.22 - 4.08 (m, 1H) , 3.24 (s, 3H), 2.75 - 2.62 (m, 1H), 2.39 - 2.27 (m, 1H), 2.17 (s, 3H). LC -MS RT = 7.20min., m/z = 426.1 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 7.20 min., ESI+ found [M+H] = 426.1. Example 703 5 -phenyl -N -[rac -(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 - yl]isoquinoline - 3-carboxamide

[02227] Method B and subsequently Suzuki Method 1, (18 mg, 21% yield), 1H NMR (400 MHz, DMSO -d6) δ 9.51 (d, J = 0.9 Hz, 1H), 9, 08 (d, J = 7.7 Hz, 1H), 8.40- 8.25(m, 2H), 7.97 - 7.79 (m, 2H), 7.66 - 7.46 (m, 6H), 6.33 (d, J = 2.0 Hz, 1H), 4.45 - 4.32 (m, 2H), 4.32 - 4.17 (m, 1H), 3.27 (s , 3H), 2.78- 2.64 (m, 1H), 2.44 - 2.31 (m, 1H). LC -MS RT = 6.97 min., m/z = 412.1 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.97 min., ESI+ found [M+H] = 412.1. Example 704 1 -benzyl -N -[2 -(1-ethylpyrazol -3 -yl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide

[02228] Suzuki Method 1 (38 mg, 61% yield), 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H ), 7.75 (d, J = 2.3 Hz, 1H), 7.46 - 7.25(m, 5H), 6.59 (s, 1H), 6.50 (d, J = 2, 2 Hz, 1H), 5.48 (s, 2H), 4.44 - 4.33 (m, 2H), 4.28 - 4.19 (m, 1H), 4.15 (q, J = 7 .2Hz, 2H), 3.28 (s, 3H), 2.69 - 2.60 (m, 1H), 2.42 - 2.33 (m, 1H), 1.39 (t, J = 7.3Hz, 3H). LC -MS RT = 5.45 min., m/z = 460.2 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.45 min., ESI+ found [M+H] = 460.2. Example 705

[02229] GH5 METHOD 1 -benzyl -N -[4 -methyl -5 -oxo -2 -(pyrazol -1 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - il] -1,2,4 -triazole -3 -carboxamide Step 1: 1 -benzyl -N -(2 -(hydroxymethyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepine -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02230] To a solution of 1 -benzyl -N -(2 - formyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (678 mg, 1.725 mmol, 1.0 equiv.) in methanol (15 mL) cooled to 0°C sodium borohydride was added (131 mg, 3.45 mmol, 2.0 equiv.). The reaction mixture was heated to RT and stirred for 2 h. The reaction was terminated with 5% aqueous citric acid (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated until dry in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 15% methanol in dichloromethane) to provide 1-benzyl-N-[2-(hydroxymethyl)-4-methyl-5-oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (350 mg, 51% yield). LCMS RT = 0.97 min. [2 min. method], m/z = 396 [M + H]+. Step 2: (6 -(1 -benzyl -1H -1,2,4 -triazol -3 carboxamido) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1.5 -a][1,3] diazepin -2 -yl) methyl methanesulfonate

[02231] To a solution of 1 -benzyl -N -[2 -(hydroxymethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -6-yl] -1,2,4 -triazole -3 - carboxamide (350 mg, 0.885 mmol, 1.0 equiv.) in dichloromethane (10 mL) cooled to 0°C was added triethylamine (0.370 mL, 2.0 equiv.) 66 mmol, 3.0 equiv.) and methanesulfonyl chloride (0.137 mL, 1.77 mmol, 2.0 equiv.). The reaction mixture was allowed to warm slowly to RT for 1 h. The reaction was terminated with saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated to dryness in vacuo to provide (6-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)- 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -2 -yl) methyl methanesulfonate (405 mg, 97% yield) which was used without any further purification. LCMS RT = 1.13 min. [method 2 min.], m/z = 474 [M + H]+. (pyrazole -1 -ylmethyl) -7,8 -dihydro -6H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02232] To a solution of (6 -(1-benzyl -1H - 1,2,4 -triazole -3 -carboxamido) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -2 -yl) methyl methanesulfonate (60 mg, 0.126 mmol, 1.0 equiv.) in acetonitrile (1 mL) was added pyrazole (17 mg, 0.252 mmol, 2.0 equiv.) and cesium carbonate (82 mg, 0.252 mmol, 2.0 equiv.). The resulting mixture was subjected to stirring for 16 h at RT. The mixture was then filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% methanol in dichloromethane) to provide 1-benzyl -N -[4-methyl -5 -oxo -2 -(pyrazole - 1 -ylmethyl) -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (31 mg, 55% yield) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 7.78(dd, J = 2.3, 0, 7 Hz, 1H), 7.44 (dd, J = 1.9, 0.7 Hz, 1H), 7.41 — 7.27 (m, 5H), 6.25(dd, J = 2.3 , 1.8 Hz, 1H), 6.21 (s, 1H), 5.48 (s, 2H), 5.32 - 5.20 (m, 2H), 4.38 - 4.25 (m, 2H), 4.16 (ddd, J = 14.5, 12.6, 6.6 Hz, 1H), 3.20(s, 3H), 2.65 - 2.53 (m, 1H), 2 .42 - 2.30 (m, 1H). LCMS RT = 3.70min. [10 min. method], m/z = 446.2 [M + H]+. Example 706 1 -benzyl -N -[4 -methyl -2 -[(2 -methylimidazol -1 -yl) methyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02233] The title compound was prepared from 2-methylimidazole according to the GH5 METHOD. Yield of the final stage: 37 mg, 64%, obtained as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 7.44 - 7.25(m, 5H), 7 .08 (d, J = 1.3 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 6.23 (s, 1H), 5.48 (s, 2H), 5 .12 - 4.96 (m, 2H), 4.39 - 4.23 (m, 2H), 4.16 (ddd, J = 14.5, 12.6, 6.6 Hz, 1H), 3 .20(s, 3H), 2.68 - 2.52 (m, 1H), 2.44 - 2.34 (m, 1H), 2.31 (s, 3H). LCMS RT = 2.66 min. [10 min. method], m/z = 460.2 [M + H]+. Example 707 (S) -1 -benzyl -N -[2 -(imidazol -1 -ylmethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02234] The title compound was prepared from imidazole according to the GH5 METHOD and chiral separation of the resulting racemate. Final step yield: 12 mg, 22% (including chiral separation), obtained as a white solid. SFC Conditions: Column: Phenomenex Lux Amylose -1, 50x4.6 mm ID, 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 35% B in 2.5 min. Flow rate: 4 mL/min. Column temperature: 40 °C, BPR: 120 bar. Analytical SFC RT (Amylose -1 column, 35% methanol + 0.1% ammonium hydroxide isocratic elution, method 2.5 min.): 0.63 min., 100% ee (First enantiomer elution). 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 7.70(t, J = 1.1 Hz, 1H ), 7.42 - 7.26 (m, 5H), 7.19 (t, J = 1.2 Hz, 1H), 6.89 (t, J = 1.1 Hz, 1H), 6.29 (s, 1H), 5.48 (s, 2H), 5.20- 5.07 (m, 2H), 4.37 - 4.25(m, 2H), 4.17 (ddd, J = 14 .6, 12.7, 6.7 Hz, 1H), 3.22 — 3.19 (m, 3H), 2.65 - 2.54 (m, 1H), 2.42 - 2.31 (m , 1H). LCMS RT = 2.58 min. [10 min. method], m/z = 446.1 [M + H]+. Example 708 4 -(2-fluorophenyl) -N -[(3S) -5 -methyl -4 -oxo - 2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [1,5 -a] pyridine -2 -carboxamide

[02235] The title compound was prepared from 2-fluorophenyl boronic acid, according to METHOD GH6. Final step yield: 95 mg, 69%. 1H NMR (400 MHz, DMSO -d6) δ 8.83 (dt, J = 7.0, 1.0 Hz, 1H), 8.52 (d, J = 8.1 Hz, 1H), 7.64 (td, J = 7.6, 1.8 Hz, 1H), 7.56 (dddd, J = 8.4, 7.2, 5.3, 1.8 Hz, 1H), 7.53 - 7 .48 (m, 1H), 7.46 - 7.36 (m, 3H), 7.36 - 7.26 (m, 2H), 7.26 - 7.23 (m, 1H), 7.19 (t, J = 7.0 Hz, 1H), 6.80 (dd, J = 2.0, 1.0 Hz, 1H), 4.91 (dt, J = 11.6, 7.9 Hz, 1H), 4.59 (dd, J = 11.6, 9.9 Hz, 1H), 4.44 (dd, J = 9.9, 7.7 Hz, 1H), 3.33 (s, 3H ). LCMS RT = 5.64 min. [method 10 min.], m/z = 431.1 [M + H]+. Examples 709 and 710

[02236] GH8 METHOD (4R)-4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5,6, 7 - tetrahydropyrazole [1,5 -a] pyridine -2 -carboxamide and (4S) -4 -(2 -fluorophenyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1 ,5-benzoxazepin -3 -yl] -4,5,6,7 - tetrahydropyrazole [1,5 -a] pyridine -2 -carboxamide

[02237] To a solution of 4 -(2-fluorophenyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [1, 5-a] pyridine-2-carboxamide (88 mg, 0.20 mmol, 1.0 equiv.) in acetic acid (2 mL) was added platinum (IV) oxide (5 mg, 0.020 mmol, 0.10 equiv. .). The reaction mixture was subjected to stirring under a hydrogen balloon for 48 h. After this period of time, the mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified using chiral SFC (SFC Conditions: Column: CHIRALPAK IC 50x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 45% B in 2 .5 min. Flow rate: 4 mL/min. Column temperature: 40oC, BPR: 120 bar) to provide arbitrarily assigned diastereomers (4R) -4 -(2-fluorophenyl) -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] - 4,5,6,7 -tetrahydropyrazole [1,5 -a] pyridine -2 - carboxamide (23 mg, 26% ) and (4S)-4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5, 6,7 -tetrahydropyrazole [1,5 -a] pyridine -2 - carboxamide (17 mg, 19%).

[02238] Analytical data for the first eluting diastereomer (arbitrarily assigned S, R configuration): SFC RT (CHIRALPAK IC column, 45% methanol + 0.1% ammonium hydroxide isocratic elution, 2.5 min. method) : 0.96 min., 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.08 (d, J = 8.1 Hz, 1H), 7.51 - 7.46 (m, 1H) , 7.37 - 7.24 (m, 3H), 7.24 - 7.11 (m, 4H), 6.03 (d, J = 1.0 Hz, 1H), 4.81 (dt, J = 11.5, 7.9 Hz, 1H), 4.53 (dd, J = 11.6, 9.9 Hz, 1H), 4.42 (dd, J = 9.5, 4.7 Hz, 1H), 4.36 (dd, J = 9.9, 7.7 Hz, 1H), 4.32 - 4.14 (m, 2H), 3.30 (s, 3H), 2.20 - 1 .99 (m, 3H), 1.99 - 1.84 (m, 1H). LCMS RT = 5.70min. [10 min. method], m/z = 435.1 [M + H]+.

[02239] Analytical data for the second elution diastereomer (S, S configuration arbitrarily assigned): SFC RT 1.18 min., 99% ee. 1H NMR (400 MHz, DMSO -d6) δ 8.06 (d, J = 8.1 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.38 - 7.24 (m, 3H), 7.24 - 7.12 (m, 4H), 6.04 (d, J = 0.9 Hz, 1H), 4.81 (dt, J = 11.5, 7.9 Hz, 1H ), 4.51 (dd, J = 11.5, 9.9 Hz, 1H), 4.42 (dd, J = 9.6, 4.8 Hz, 1H), 4.36 (dd, J = 9.9, 7.7 Hz, 1H), 4.33 - 4.14 (m, 2H), 3.30 (s, 3H), 2.19 - 2.00 (m, 3H), 1.90 (q, J = 10.1 Hz, 1H). LCMS RT = 5.70min. [method 10 min.], m/z = 435.1 [M + H]+. Example 711 1 -(3,3 -difluoropropyl) -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [4,3 - c] pyridine -6 -carboxamide

[02240] The title compound was prepared according to the GH7 METHOD carrying the isopropyl isomer 1 -(3,3-difluoroallyl)pyrazolo [4,3-c] pyridine -6 - carboxylate obtained in Step 2. Step yield final: 59 mg, 70%. 1H NMR (400 MHz, DMSO -d6) δ 9.20(d, J = 1.1 Hz, 1H), 9.03 (d, J = 7.8 Hz, 1H), 8.48 (d, J = 1.0 Hz, 1H), 8.34 (t, J = 1.1 Hz, 1H), 7.55 — 7.50 (m, 1H), 7.40-7.24 (m, 3H) , 6.15 (tt, J = 56.2, 4.4 Hz, 1H), 4.93 (dt, J = 10.5, 8.2 Hz, 1H), 4.70(t, J = 6 .8Hz, 2H), 4.60 - 4.49 (m, 2H), 3.35 (s, 3H), 2.47 - 2.36 (m, 2H). LCMS RT = 5.00 min. [method 10 min.], m/z = 416.1 [M + H]+. Example 712 1 -(1,1 -difluoropropyl) -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazolo [4,3 - c] pyridine -6 -carboxamide Step 1: isopropyl 1H -pyrazolo[4,3-c]pyridine-6-carboxylate

[02241] To a solution of 6-bromo-1H-pyrazolo [4,3-c] pyridine (3000 mg, 15.150 mmol, 1.0 equiv.) in 2-propanol (20mL) was added triethylamine (6.33 mL , 45 mmol, 3.0 equiv.) and [1,1'-bis(diphenylphosphine) ferrocene] palladium (II) dichloro (1131 mg, 1.51 mmol, 0.10 equiv.). The reaction vessel was pressurized with carbon monoxide to 9.28 bar (120 psi). The reaction mixture was then heated at 80°C for 16 h with stirring. After this time, the mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 10% isopropyl alcohol in dichloromethane) to provide isopropyl 1H -pyrazolo[4,3-c]pyridine-6-carboxylate (1250 mg , 40% yield) as a red solid. LCMS RT = 0.79 min. [method 2 min.], m/z = 206 [M + H]+. Step 2: isopropyl 1 -(1,1-difluoroallyl) -1H - pyrazole [4,3 -c] pyridine -6 -carboxylate and isopropyl 1 - (3,3 -difluoroallyl) -1H -pyrazole [4,3 -c ] pyridine -6 - carboxylate

[02242] To a solution of isopropyl 1H -pyrazolo [4,3-c] pyridine-6-carboxylate (1250 mg, 6.09 mmol, 1.0 equiv.) in acetonitrile (20 mL) was added cesium carbonate ( 3970mg, 12.2 mmol, 2.0 equiv.) and 3-bromo-3,3-difluoropropene (0.6481 mL, 1000 mg, 6.37117 mmol, 1.05 equiv.). A reaction vessel was sealed and stirred at RT for 72 h. The mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 100% isopropyl acetate in heptane) to provide isopropyl 1-(1,1-difluoroallyl)pyrazolo[4,3-c]pyridine -6 -carboxylate (first elution time, 170 mg, 10% yield) (LCMS RT = 1.37 min. [method 2 min.], m/z = 282 [M + H]+) and isopropyl 1 - (3,3-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate (second elution time, 300 mg, 18% yield) (LCMS RT = 1.19 min. [method 2 min.], m/z = 282 [M + H]+) in the form of white solids. Step 3: isopropyl 1 -(1,1-difluoropropyl) -1H - pyrazole [4,3 -c] pyridine -6 -carboxylate

[02243] To a solution of isopropyl 1 -(1,1 - difluoroallyl)pyrazole [4,3 -c] pyridine -6 -carboxylate (170 mg, 0.6043 mmol, 1.0 equiv.) in ethanol (3 mL ) 10% palladium on carbon (64 mg, 0.06043 mmol, 0.10 equiv.) was added. A reaction vessel was placed under a hydrogen balloon for 16 h with stirring. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 60% isopropyl acetate in heptane) to provide isopropyl 1 -(1,1-difluoropropyl)-1H - pyrazole [4,3 - c] pyridine-6-carboxylate (109 mg, 64% yield) as a colorless oil. LCMS RT = 1.44 min. [2 min. method], m/z = 284 [M + H]+. Step 4: sodium 1 -(1,1-difluoropropyl) -1H - pyrazole [4,3 -c] pyridine -6 -carboxylate

[02244] To a solution of isopropyl 1 -(1,1 - difluoropropyl) -1H -pyrazolo [4,3 -c] pyridine -6 - carboxylate (109 mg, 0.385 mmol, 1.0 equiv.) in tetrahydrofuran (2 mL) 1M sodium hydroxide (0.42 mL, 0.42 mmol, 1.1 equiv.) was added. The reaction mixture was stirred for 2 h under 50°C. After this time, the mixture was concentrated to dryness in vacuo to provide sodium 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate as a brown residue. which was used directly in the next reaction. LCMS RT = 0.94 min. [method 2 min.], m/z = 242 [M + H]+. Step 5: 1 -(1,1-difluoropropyl) -N -[(3S) -5 - methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [4,3 - c] pyridine -6 -carboxamide

[02245] To a solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] ammonium chloride (88 mg, 0.385 mmol, 1.0 equiv .) in N,N - dimethylformamide (2 ml) was added 1 - (1,1 - difluoropropyl) - 1H - pyrazolo [4,3 - c ] pyridine -6 - sodium carboxylate (101 mg, 0.385 mmol, 1. 0 equiv.), N,N -diisopropyl ethylamine (0.201 mL, 1.15 mmol, 3.0 equiv.), and (7-Azabenzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate (251 mg, 0.46 mmol, 1.2 equiv.). The reaction mixture was subjected to stirring for 16 h under RT. After this time, the crude mixture was loaded directly onto a silica column and purified via chromatography (silica gel, 100 -200 mesh, 0 to 80% isopropyl acetate in heptane) to provide 1 -(1,1 - difluoropropyl) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] pyrazolo [4,3 -c] pyridine -6 - carboxamide (101 mg , yield 63%). 1H NMR (400 MHz, DMSO -d6) δ 9.35 (d, J = 1.1 Hz, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.74 (d, J = 0.9 Hz, 1H), 8.25(p, J = 1.3 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.38 - 7.25 (m, 3H) , 4.92 (dt, J = 11.2, 7.8 Hz, 1H), 4.65 - 4.46 (m, 2H), 3.35 (s, 3H), 2.86 - 2.70 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). LCMS RT = 5.75 min. [10 min. method], m/z = 416.1 [M + H]+. Example 713

[02246] GH6 METHOD 4 -phenyl -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazolo [1,5 -a] pyridine -2 – carboxamide Step 1: ethyl 4-phenylpyrazole[1,5-a]pyridine-2-carboxylate

[02247] To a solution of ethyl 4-bromopyrazole [1,5-a] pyridine-2-carboxylate (200 mg, 0.74 mmol, 1.0 equiv.) in toluene (8 ml) was added phenylboronic acid (136 mg, 1.11 mmol, 1.5 equiv.), tribasic potassium phosphate (483 mg, 2.23 mmol, 3.0 equiv.), and 2-(dicyclohexylphosphine)-2',4',6' -triisopropylbiphenyl (22 mg, 0.045 mmol, 0.06 equiv.). The mixture was degassed for 15 min. with a stream of nitrogen, then chlorine (2-dicyclohexylphosphine - 2',4',6' -triisopropyl -1,1' -biphenyl) [2 -(2' -amino -1,1' -biphenyl) )] palladium (II) (18 mg, 0.022 mmol, 0.03 equiv.). The reaction vessel was sealed and heated to 80°C with vigorous stirring for 1 h. The mixture was cooled to RT, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100 -200 mesh, 0 to 70% isopropyl acetate in heptane) to provide ethyl 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate (187 mg , 95% yield) as an off-white solid. LCMS RT = 1.53 min. [method 2 min.], m/z = 267 [M + H]+. Step 2: sodium 4-phenylpyrazole[1,5-a]pyridine-2-carboxylate

[02248] To a solution of ethyl 4-phenylpyrazole [1,5-a] pyridine-2-carboxylate (187 mg, 0.70 mmol, 1.0 equiv.) in tetrahydrofuran (4 mL) was added 1M sodium hydroxide (0.8427 mL, 0.8427 mmol, 1.2 equiv.). The reaction mixture was stirred overnight at RT, then concentrated to dryness in vacuo to provide sodium 4-phenylpyrazole[1,5-a]pyridine-2-carboxylate as a white solid. which was used directly in the next step. LCMS RT = 1.22 min. [2 min. method], m/z = 239 [M + H]+. Step 3: 4-phenyl -N -[(3S)-5 -methyl -4 -oxo - 2,3 -dihydro -1,5 -benzoxazepin -3 -yl] pyrazole [1,5 -a] pyridine -2 - carboxamide

[02249] To a solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl] ammonium chloride (80 mg, 0.35 mmol, 1, 0 equiv.) in DMF (2 mL) was added 4-phenylpyrazole [1,5-a]pyridine-2-sodium carboxylate (91 mg, 0.35 mmol, 1.0 equiv.), N,N - diisopropyl ethylamine (0.18 mL, 1.1 mmol, 3.0 equiv.), and tripyrrolidine phosphonium hexafluorophosphate (7-Azabenzotriazol-1-yloxy) (230 mg, 0.42 mmol, 1.2 equiv.). The reaction mixture was subjected to stirring for 16 h under RT. After this time, the crude mixture was loaded directly onto a silica column and purified via chromatography (silica gel, 100 -200 mesh, 0 to 80% isopropyl acetate in heptane) to provide 4-phenyl-N-[ (3S)-5-methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] pyrazolo [1,5 -a] pyridine -2 - carboxamide (76 mg, 53% yield) . 1H NMR (400 MHz, DMSO -d6) δ 8.77 (dt, J = 7.0, 1.0 Hz, 1H), 8.53 (d, J = 8.1 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.61 - 7.45 (m, 4H), 7.41 (dd, J = 7.1, 0.9 Hz, 1H), 7.38 - 7.22 (m, 3H), 7.22 - 7.13 (m, 1H), 7.07 (d, J = 1.0 Hz, 1H), 4.92 (dt, J = 11.4, 7.9 Hz, 1H), 4.59 (dd, J = 11.6, 9.9 Hz, 1H), 4.45 (dd, J = 9.9, 7.7 Hz, 1H), 3.33 (s , 3H). LCMS RT = 5.70min. [10 min. method], m/z = 413.1 [M + H]+. Example 714 (S) -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -4 -phenylpyrazole [1,5 -a] pyridine -2 -carboxamide

[02250] The title compound was prepared from (S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5 (6H)-one according to METHOD GH6. Final stage yield: 94%. 1H NMR (400 MHz, DMSO -d6) δ 8.76 (dt, J = 7.0, 1.0 Hz, 1H), 8.58 (d, J = 7.9 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.62 - 7.53 (m, 2H), 7.53 - 7.45 (m, 1H), 7.40(dd, J = 7.1, 1, 0 Hz, 1H), 7.17 (t, J = 7.0 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 6.14 (s, 1H), 4.41 (dt, J = 11.6, 7.9 Hz, 1H), 4.29 (dd, J = 14.5, 7.9 Hz, 1H), 4.20- 4.05 (m, 1H), 3.23 (s, 3H), 2.68 - 2.56 (m, 1H), 2.41 - 2.30 (m, 1H), 2.18 (s, 3H). LCMS RT = 4.86 min. [method 10 min.], m/z = 415.1 [M + H]+. Examples 715 - 718 prepared according to the GH_chiral_1 method (see, for example, Examples 352 and 354). Examples 719 - 722 prepared according to the GZ9 method (see, for example, Example 391). Example 723 N -[(3S)-5 -methyl -4 -oxo -2,3 -dihydro -1,5 - benzoxazepin -3 -yl] -8 -phenyl -5,6,7,8 -tetrahydro - [1,2 ,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[02251] GZ6 Method. 1H NMR (400 MHz, DMSO -d6) δ 8.34 (dd, J = 8.1, 1.9 Hz, 1H), 7.49 (dt, J = 7.5, 1.5 Hz, 1H) , 7.44 - 7.11 (m, 9H), 5.20(t, J = 5.0 Hz, 1H), 4.91 - 4.75 (m, 1H), 4.56 (ddd, J = 11.5, 9.9, 4.1 Hz, 1H), 4.37 (ddd, J = 9.9, 7.6, 6.0 Hz, 1H), 4.32 - 4.15 (m , 2H), 3.37 (q, J = 5.3 Hz, 1H), 3.32 - 3.11 (m, 4H). LCMS RT = 3.26 min. [method 10 min.], m/z = 419.1 [M + H]+. 1 -benzyl -N -[2 -[(2-methoxyethylamino) methyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02252] GZ9 method. 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.43 - 7.26 (m, 5H), 6 .26 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.21 - 4.07 (m, 1H), 3.66 (d, J = 2.1 Hz, 2H), 3.46 - 3.31 (m, 2H), 3.23 (s, 6H), 2.72 (t, J = 5.7 Hz, 2H), 2.58 (m, 1H ), 2.41 - 2.28 (m, 1H). LCMS: m/z = 419.1 [M + H]+. Example 725 (S) -1 -benzyl -N -(2 -((3 -methoxyazetidin -1 - yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1, 5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02253] GZ9 method. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.51 (d, J = 7.7 Hz, 1H), 7.42 - 7.26 (m, 5H), 6 .21 (s, 1H), 5.48 (s, 2H), 4.35 - 4.23 (m, 2H), 4.13 (m, 1H), 3.94 (p, J = 5.8 Hz, 1H), 3.57 - 3.32 (m, 4H), 3.18 (ds, 6H), 2.86 (m, 2H), 2.58 (m, 1H), 2.41 - 2 .28 (m, 1H). LCMS: m/z = 465.2. Example 726 (S) -1 -benzyl -N -(2 -((3 -fluoroazetidin -1 - yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1, 5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02254] GZ9 method. 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 5H), 6 .23 (s, 1H), 5.48 (s, 2H), 5.26 - 5.01 (m, 1H), 4.35 - 4.23 (m, 2H), 4.14 (m, 1H ), 3.63 - 3.50 (m, 4H), 3.27 - 3.06 (m, 5H), 2.58 (m, 1H), 2.41 - 2.28 (m, 1H). LCMS: m/z = 453.2. Example 727 (S) -1 -benzyl -N -(2 -((3,3 -difluoropyrrolidin -1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [ 1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02255] 1-benzyl -N -(2 -((3,3 - difluoropyrrolidin -1 -yl) methyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide was further purified using chiral SFC (Cellulose -1; 150 x21.2 mm, 5 a; isocratic elution of 35% methanol with carbon dioxide) to provide (S)-1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide assigned arbitrarily (25.2 mg, 34.7%) as a white solid:

[02256] Analytical data for (S) -1 -benzyl -N -(2 -((3,3 -difluoropyrrolidin -1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide: SFC RT (Cellulose -1, 25% methanol + elution isocratic with 0.1% ammonium hydroxide with carbon dioxide, method 2.5 min.): 0.876 min., purity 100%, 100% ee: . 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 5H), 6 .28 (s, 1H), 5.48 (s, 2H), 4.31 (qd, J = 7.9, 2.4 Hz, 2H), 4.15 (ddd, J = 14.5, 12 .6, 6.6H, 1H), 3.57 (q, J = 13.4 Hz, 2H), 3.23 (s, 3H), 2.91 (t, J = 13.4 Hz, 2H ), 2.73 (t, J = 7.0 Hz, 2H), 2.67 - 2.54 (m, 1H), 2.43 - 2.10 (m, 3H). LC -MS RT = 2.86 min., m/z = 485.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.86 min., ESI+ found [M+H] = 485.2. Example 728 (S) -1 -benzyl -N -(2 -(((2 -methoxyethyl) amino) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1.5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02257] 1-benzyl -N -(2 -(((2-methoxyethyl) amino) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide was further purified by means of chiral SFC (Cellulose -1; 150 x21.2 mm, 5 µm; elution isocratic mixture of 30% methanol with carbon dioxide) to give (S) -1 -benzyl -N -(2 -(((2 -methoxyethyl) amino) methyl) -4 - methyl -5 -oxo -5.6 ,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (7.4 mg, 18, 5%) in the form of a white solid:

[02258] Analytical data for (S) -1 -benzyl -N -(2 -(((2-methoxyethyl)amino) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide: SFC RT (Cellulose -1, 25% methanol + isocratic hydroxide elution 0.1% ammonium with Carbon Dioxide, method 2.5 min.): 0.805 min., 99.7% purity, 99.4% ee: 1H NMR (400 MHz, DMSO -d6) δ 8, 82 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.43 - 7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s , 2H), 4.31 (m, 2H), 4.21 - 4.07 (m, 1H), 3.66 (d, J = 2.1 Hz, 2H), 3.46 - 3.31 ( m, 2H), 3.23 (s, 6H), 2.72 (t, J = 5.7 Hz, 2H), 2.58 (m, 1H), 2.41 - 2.28 (m, 1H ). LC -MS RT = 2.65 min., m/z = 453.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.65 min., ESI+ found [M+H] = 453.2. Example 729 (8R) -N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro - 1,5 -benzoxazepin -3 -yl] -8 -phenyl -5,6,7,8 -tetrahydro - [1,2,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[02257] Further purification of Example 723, 1H NMR (400 MHz, DMSO -d6) δ 8.34 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 7.6, 1, 9 Hz, 1H), 7.42 - 7.18 (m, 9H), 5.20(d, J = 5.3 Hz, 1H), 4.81 (dt, J = 11.4, 7.8 Hz, 1H), 4.56 (dd, J = 11.6, 9.8 Hz, 1H), 4.36 (dd, J = 9.9, 7.7 Hz, 1H), 4.32 - 4 .15 (m, 2H), 3.37 (q, J = 5.1 Hz, 1H), 3.32 - 3.11 (m, 4H). LCMS: m/z=419.1 (3.26 min.). Example 730

[02258] GZ17 METHOD 7 -methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -8 -phenyl -5,6 ,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 - carboxamide Step 1: (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -8 -phenyl -[1,2 ,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[02259] (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 -phenyl - [1,2 ,4] triazolo [1,5 -a] pyrazine -2 -carboxamide was prepared from (S) -3 -amino -5 -methyl -2,3 - dihydrobenzo [b] [1,4] oxazepin -4( 5H)-one and 3-phenylpyrazin-2-amine according to Method GZ5. The residue was purified using RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid). Final step yield: 35.5 mg, 22.9%. 1H NMR (400 MHz, DMSO -d6) δ 9.15 - 9.03 (m, 2H), 8.84 - 8.75 (m, 2H), 8.47 (d, J = 4.5 Hz, 1H), 7.70- 7.58 (m, 3H), 7.55 (dd, J = 7.6, 1.9 Hz, 1H), 7.40- 7.23 (m, 3H), 4 .98 (dt, J = 11.5, 7.8 Hz, 1H), 4.73 (dd, J = 11.6, 9.8 Hz, 1H), 4.51 (dd, J = 9.8 , 7.7 Hz, 1H), 3.35 (s, 3H). LC -MS RT = 5.04 min., m/z = 415.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 5.04 min., ESI+ found [M+H] = 415.1. Step 2: N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -8 -phenyl -5,6, 7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 - carboxamide

[02260] To a solution of (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -8 - phenyl - [1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (368 mg, 0.88 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added platinum(iv) oxide ( 20.2 mg, 0.088 mmol). The reaction mixture was stirred under a balloon of hydrogen gas for 16 h at RT, then filtered through Celite and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% methanol in dichloromethane) to provide N -((S) -5 - methyl -4 -oxo -2,3,4, 5 -tetrahydrobenzo [b][1,4] oxazepin - 3 -yl) -8 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 -carboxamide (216 mg, 52% yield) as a bronze-colored solid: 1H NMR (400 MHz, DMSO -d6) δ 8.34 (dd, J = 8.1, 1.9 Hz, 1H) , 7.49 (dt, J = 7.5, 1.5 Hz, 1H), 7.44 - 7.11 (m, 9H), 5.20(t, J = 5.0 Hz, 1H), 4.91 - 4.75 (m, 1H), 4.56 (ddd, J = 11.5, 9.9, 4.1 Hz, 1H), 4.37 (ddd, J = 9.9, 7 .6, 6.0 Hz, 1H), 4.32 - 4.15 (m, 2H), 3.37 (q, J = 5.3 Hz, 1H), 3.32 - 3.11 (m, 4H). LC -MS RT = 3.26 min., m/z = 419.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.26 min., ESI+ found [M+H] = 419.1. 9 Step 3: 7 -methyl -N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -8 - phenyl - 5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[02261] To a solution of N -((S) -5 -methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 - phenyl - 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (83 mg, 0.198 mmol) in dichloroethane (1.5 mL) was added formaldehyde (13 .31 mol/L) in water (0.05 mL, 0.595 mmol), then acetic acid (0.04 mL, 0.595 mmol) was added, then sodium triacetoxy borohydride (168 mg, 0.793 mmol) was added and left. if under agitation at night. The reaction mixture was brought to basic condition by adding saturated aqueous NaHCO3 solution (10 mL) and stirring for 20 min. Extracted with DCM (3 x 30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude residue was further purified by prep RP-HPLC (20 -60% acetonitrile in water + 0 formic acid .1%, column: Gemini -NX C18 10 µm, 50 x 30 mm) to give 7 - methyl -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[ b][1,4]oxazepin -3 -yl) -8 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 - carboxamide (14 .7 mg, 17%) as a bronze-colored solid. 1H NMR (400 MHz, DMSO -d6) δ 8.28 (dd, J = 8.0, 5.5 Hz, 1H), 7.48 (dt, J = 7.6, 2.0 Hz, 1H) , 7.42 - 7.17 (m, 9H), 4.85 - 4.72 (m, 1H), 4.61 - 4.49 (m, 2H), 4.45 - 4.27 (m, 3H), 3.28 (d, J = 1.9 Hz, 4H), 3.00 - 2.87 (m, 1H), 2.21 (s, 3H). LC -MS RT = 4.29 min., m/z = 433.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.29 min., ESI+ found [M+H] = 433.2. Example 731 N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -8 - (trifluoromethyl) -5,6,7 ,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyrazine -2 -carboxamide

[02262] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 - (trifluoromethyl) -5, 6,7,8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide was prepared from 3-(trifluoromethyl)pyrazin-2-amine according to Method GZ6. Final step yield: 6 mg, 86%, isolated as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.44 (dd, J = 7.9, 2.3 Hz, 1H), 7.57 - 7.45 (m, 1H), 7.39 - 7, 16 (m, 4H), 5.16 - 4.99 (m, 1H), 4.85 (dtd, J = 11.5, 7.8, 3.8 Hz, 1H), 4.60 (dt, J = 11.5, 9.7 Hz, 1H), 4.43 (ddd, J = 9.9, 7.6, 6.8 Hz, 1H), 4.25(m, 1H), 4.21 - 4.04 (m, 1H), 3.68 (m, 1H), 3.31 (s, 3H), 3.27 - 3.19 (m, 1H). LC -MS RT = 3.87 min., m/z = 411.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.87 min., ESI+ found [M+H] = 411.1. Example 732 (S) -1 -benzyl -N -(2 -(hydroxymethyl) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02263] 1 -benzyl -N -(2 -(hydroxymethyl) -4 -methyl - 5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepine -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide was further purified by means of chiral SFC (Chiralpak AD, 150 x 21.2 mm, isocratic elution of 30% methanol with Carbon dioxide) to provide (S) -1 -benzyl -N -(2 - (hydroxymethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (11.6 mg, 46%) as a white solid.

[02264] Analytical data (S) -1 -benzyl -N -(2 - (hydroxymethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a] [1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide: SFC RT (Chiralpak AD, 30% methanol + 0.1% isocratic ammonium hydroxide elution with carbon dioxide , 2.5 min method): 0.824 min, 99.8% purity, 99.6% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.51 ( d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 5.10 (t, J = 5.8 Hz, 1H), 4.45 - 4.24 (m, 4H), 4.15 (m, 1H), 3.24 (s, 3H), 2.58 (m, 1H), 2 .41 - 2.28 (m, 1H). LC -MS RT = 3.14 min., m/z = 396.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.14 min., ESI+ found [M+H] = 396.1. Example 733 (S) -1 -benzyl -N -(4 -methyl -5 -oxo -2 -(((2,2,2 -trifluoroethyl)amino) methyl) -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02265] 1-benzyl -N -(4-methyl -5 -oxo -2 -(((2,2,2-trifluoroethyl) amino) methyl) -5,6,7,8 -tetrahydro -4H - pyrazole [ 1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 1-benzyl-N-(2-formyl-4-methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide and 2,2,2-trifluoroethanamine hydrochloride; according to Method GZ8. The crude residue was further purified by means of chiral SFC (Chiralpak OX; 150 x 21.2 mm, 5 µm; isocratic elution of 40% methanol with Carbon dioxide) to provide (S)-1-benzyl-N- (4 - methyl -5 -oxo -2 -(((2,2,2 -trifluoroethyl) amino) methyl) - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1, 3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (5 mg, 8.3%) in the form of a white solid:

[02266] Analytical data for (S) -1 -benzyl -N -(4 -methyl -5 -oxo -2 -(((2,2,2 -trifluoroethyl) amino) methyl) - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide: SFC RT (Chiralpak OX, 35% methanol + elution isocratic 0.1% ammonium hydroxide with carbon dioxide, method 2.5 min.): 1.177 min., 100% purity, 100% ee. 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 5H), 6 .28 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.15 (m, 1H), 3.79 - 3.64 (m, 2H), 3, 33 - 3.15 (m, 4H), 2.77 (p, J = 6.9 Hz, 1H), 2.59 (m, 1H), 2.50 - 2.29 (m, 1H). LCMS RT = 3.18 min., m/z = 477.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.18 min., ESI+ found [M+H] = 477.2. Examples 734 and 735 (R) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -5 -phenyl -5,6 ,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide and (S) -N -((S) -5 -methyl -4 -oxo -2,3 ,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -5 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 - carboxamide (1:1)

[02267] N -((S) -5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 -phenyl - 5,6, 7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was further purified via chiral SFC (Cellulose -3; 151 x21.2 mm, 5 µm; isocratic elution of 15% methanol with carbon dioxide) to provide arbitrarily assigned diastereomers (R) -N -((S) -5 - methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b] [1, 4] oxazepin - 3 -yl) -5 -phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (14.7 mg, 9 .4%) and (S) -N -((S) -5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - phenyl -5,6,7,8 -tetrahydro -[1,2,4] triazolo [1,5 -a] pyridine -2 -carboxamide (10 mg, 6.4%) as white solids:

[02268] Analytical data for the first elution diastereomer (arbitrarily assigned R, S configuration): SFC RT (Cellulose -3, 15% methanol + isocratic elution of 0.1% ammonium hydroxide with Carbon dioxide, method 2, 5 min.): 0.603 min., 100% purity, 100% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.40(d, J = 7.9 Hz, 1H), 7.49 (dd , J = 7.6, 2.0 Hz, 1H), 7.40- 7.18 (m, 6H), 7.09 - 7.01 (m, 2H), 5.57 (t, J = 5 .9 Hz, 1H), 4.80 (dt, J = 11.5, 7.8 Hz, 1H), 4.57 (dd, J = 11.6, 9.9 Hz, 1H), 4.38 (dd, J = 9.9, 7.6 Hz, 1H), 3.30 (s, 3H), 3.11 - 2.89 (m, 2H), 2.49 - 2.32 (m, 1H ), 2.11 - 1.98 (m, 1H), 1.87 (h, J = 5.9, 5.4 Hz, 2H). LCMS RT = 11.60 min., m/z = 418.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 30 min.) retention time 11.60 min., ESI+ found [M+H] = 418.2.

[02267] Analytical data for the second elution diastereomer (arbitrarily assigned S, S configuration): SFC RT (Cellulose -3, 15% methanol + isocratic elution of 0.1% ammonium hydroxide with Carbon dioxide, method 2, 5 min.): 0.746 min., 99.4% purity, 98.8% ee: 1H NMR (400 MHz, DMSO -d6) δ 8.38 (d, J = 8.0 Hz, 1H), 7 .49 (dd, J = 7.5, 2.0 Hz, 1H), 7.40- 7.19 (m, 6H), 7.09 - 7.01 (m, 2H), 5.57 (t , J = 5.9 Hz, 1H), 4.80 (dt, J = 11.5, 7.8 Hz, 1H), 4.56 (dd, J = 11.5, 9.9 Hz, 1H) , 4.38 (dd, J = 9.9, 7.7 Hz, 1H), 3.44 - 3.20(s, 3H), 3.10 - 2.90 (m, 2H), 2.38 (dt, J = 11.5, 6.4 Hz, 1H), 2.10 - 1.98 (m, 1H), 1.86 (p, J = 6.3 Hz, 2H). LCMS RT = 11.72 min., m/z = 418.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 30 min.) retention time 11.72 min., ESI+ found [M+H] = 418.1. Example 736

[02268] GZ20 METHOD (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) imidazo [1,2 - a] pyridine -2 -carboxamide

[02269] To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (100 mg, 0.520 mmol) and 5-(trifluoromethyl) imidazo acid [1,2-a]pyridine-2-carboxylic acid (126 mg, 0.546 mmol) in N,N-dimethylformamide (2 mL) was added HATU (224 mg, 0.752 mmol), and N,N-diisopropyl ethylamine (0. 28 mL, 1.56 mmol The reaction mixture was stirred overnight at RT, then purified via prep RP-HPLC (20 -60% acetonitrile in water + 0.1% formic acid) to provide (S) -N -(5-methyl -4 -oxo - 2,3,4,5 -tetrahydrobenzo [b] [1,4] oxazepin -3 -yl) -5 - (trifluoromethyl) imidazo [1 ,2 -a] pyridine -2 -carboxamide (169 mg, 80%) as a tan solid. 1H NMR (400 MHz, DMSO -d6) δ 8.58 (d, J = 8.0 Hz, 1H), 8.30 (q, J = 1.8 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.70(d, J = 7.1 Hz, 1H) , 7.60 - 7.48 (m, 2H), 7.30 (m, 3H), 4.91 (dt, J = 11.4, 7.9 Hz, 1H), 4.60 (dd, J = 11.5, 9.9 Hz, 1H), 4.47 (dd, J = 9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LCMS RT = 6.00 min., m/z = 405.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 6.00 min., ESI+ found [M+H] = 405.0. Example 737 (S) -N -(5 -methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin -3 -yl) -8 - (trifluoromethyl)imidazo [1,2 - a] pyridine -2 -carboxamide

[02270] (S) -N -(5-methyl -4 -oxo -2,3,4,5 - tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -8 - (trifluoromethyl) imidazo [1 ,2 -a] pyridine -2 -carboxamide was prepared correspondingly to (S) - 3 -amino -5 -methyl -2,3 -dihydrobenzo hydrochloride [b] [1,4] oxazepin - 4(5H) - one, and 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid according to Method GZ20. The residue was purified using RP-HPLC preparation (20 -60% acetonitrile in water + 0.1% formic acid). Final step yield: 175 mg, 83%. 1H NMR (400 MHz, DMSO -d6) δ 8.82 (d, J = 6.8 Hz, 1H), 8.57 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H ), 7.86 (dt, J = 7.3, 1.2 Hz, 1H), 7.55 - 7.46 (m, 1H), 7.39 - 7.23 (m, 3H), 7, 14 (t, J = 7.0 Hz, 1H), 4.91 (dt, J = 11.3, 7.7 Hz, 1H), 4.64 - 4.45 (m, 2H), 3.35 (s, 3H). LC -MS RT = 4.81 min., m/z = 405.1 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 4.81 min., ESI+ found [M+H] = 405.1. Example 738 1 -benzyl -N -[(6R) -4 -methyl -2 -(3 - morpholinopropyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide

[02271] Further purification of Example 662. 1H NMR (400MHz, CD3OD) δ 8.56 (s, 1H), 7.38 - 7.32 (m, 5H), 6.17 (s, 1H), 5, 47 (s, 2H), 4.54 - 4.49 (m, 1H), 4.33 - 4.30 (m, 1H), 4.27 - 4.21 (m, 1H), 3.69 ( t, J = 4.8 Hz, 4H), 3.33 (s, 3H), 2.83 - 2.80 (m, 1H), 2.66 - 2.62 (m, 2H), 2.48 - 2.40(m, 6H), 2.26 - 2.24 (m, 1H), 1.89 - 1.86 (m, 2H). Example 739

[02272] WX 211 Method 1 -benzyl -N -[(6S) -2 -[3 -(3,3 - difluoropyrrolidin -1 -yl)propyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1, 5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[3 -(3,3 -difluoropyrrolidin -1 -yl)propyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 –carboxamide Step 1: 1-benzyl -N -[2 -[(E) -3 -(3,3 - difluoropyrrolidin -1 -yl)prop -1 -enyl] -4 -methyl -5 -oxo-7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4 -triazole -3 -carboxamide

[02273] To a solution of [(E) -3 -[6 -[(1 benzyl -1,2,4 -triazol -3 -carbonyl)amino] -4 -methyl -5 oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -2 - yl] allyl] methane sulfonate (20 mg, 0.04 mmol) in N,N - dimethylformamide (3 mL) was added potassium carbonate ( 28 mg, 0.20 mmol) and 3,3-difluoropyrrolidine hydrochloride (17 mg, 0.12 mmol). The reaction mixture was stirred at 35°C for 12 h and then poured into water (15 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 1-benzyl-N-[2-[(E)-3-(3, 3 - difluoropyrrolidin -1 -yl)prop -1 -enyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - crude 1,2,4-triazole-3-carboxamide (18 mg, 88%) as a yellow oil. LC -MS RT = 0.579 min., m/z = 511.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.579 min., ESI+ found [M+H] = 511.1. Step 2: 1 -benzyl -N pyrrolidin -1 -yl)propyl] 6H -pyrazole [1,5 -a][1,3] -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[ 3 -(3,3 -difluoropyrrolidin -1 -yl)propyl] -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazolo [1,5 -a][1,3] diazepin -6 - il] -1,2,4 -triazole -3 -carboxamide

[02274] A mixture of 1 -benzyl -N -[2 -[(E) - 3 -(3,3 -difluoropyrrolidin -1 -yl)prop -1 -enyl] -4 -methyl -5 -oxo -7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide (18 mg, 0.04 mmol) and Palladium on carbon (10%, 19 mg) in ethyl acetate (10 mL) was hydrogenated [2.04 bar (15 psi)] for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (30 -60% acetonitrile / 0.05% NH3,H2O in water) to give 1 - benzyl -N - [2 - [3 - (3,3 -difluoropyrrolidin -1 -yl)propyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4-triazole-3-carboxamide (13 mg, 72%) as a white solid. The racemic material (50 mg, from 2 batches) was further separated using chiral SFC to provide:

[02275] 1 -benzyl -N -[(6S) -2 -[3 -(3,3 - difluoro pyrrolidin -1 -yl) propyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, Retention time 4,500 min.) (8.1 mg, 16% ) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.58 (s, 1H), 7.39 - 7.33 (m, 5H), 6.17 (s, 1H), 5.48 (s, 2H), 4, 54 - 4.49 (m, 1H), 4.32 - 4.30 (m, 1H), 4.26 - 4.21 (m, 1H), 3.33 (s, 3H), 3.07 - 3.03 (m, 2H), 2.91 - 2.83 (m, 3H), 2.68 - 2.65 (m, 4H), 2.36 - 2.27 (m, 3H), 1, 91 - 1.87 (m, 2H). LC -MS RT = 1.639 min., m/z = 513.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.639 min., ESI+ found [M+H] = 513.2.

[02276] 1-benzyl -N -[(6R) -2 -[3 -(3,3 - difluoropyrrolidin -1 -yl)propyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, Retention time = 5.268 min.) (7.7 mg, 15% ) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.59 (br. s., 1H), 7.39 - 7.33 (m, 5H), 6.17 (s, 1H), 5.48 (s, 2H) , 4.54 - 4.49 (m, 1H), 4.32 - 4.30 (m, 1H), 4.25- 4.22 (m, 1H), 3.33 (s, 3H), 3 .23 - 3.20(m, 2H), 3.07 (br. s., 2H), 2.83 - 2.80 (m, 3H), 2.68 (t, J = 7.2 Hz, 2H), 2.40- 2.37 (m, 2H), 2.35 - 2.25(m, 1H), 1.95 - 1.91(m, 2H). LC -MS RT = 1.647 min., m/z = 513.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.647 min., ESI+ found [M+H] = 513.2.

[02277] SFC condition: column: Chiralcel OD - 3 (100x4.6 mm), 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 5 to 40 B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 740

[02278] WX Method 182 1 -benzyl -N -[(6S)-4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole -3 - carboxamide Step 1: methyl 1-benzylpyrazole-3-carboxylate

[02279] To a solution of methyl 1H -pyrazole -3 - carboxylate (200 mg, 1.59 mmol) in N,N -dimethylformamide (5 mL) was added potassium carbonate (658 mg, 4.76 mmol) and benzyl bromide (326 mg, 1.9 mmol). The mixture was stirred at 25°C for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 1-benzylpyrazole-3-carboxylate (240 mg, 70%) in the form of a white solid, which was used in the next step in the form in which it was. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.495 min., ESI+ found [M+H] = 217.1. Step 2: 1-benzylpyrazole-3-carboxylic acid

[02280] A mixture of methyl 1-benzylpyrazole-3-carboxylate (240 mg, 1.11 mmol) and lithium hydroxide hydrate (133 mg, 5.55 mmol) in ethanol / water (13 mL, 8:1) was subjected to stirring at 25oC for 12 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 by adding 2M HCl. The resulting solid was collected through filtration and dried under reduced pressure to provide crude 1-benzylpyrazole-3-carboxylic acid (170mg, 76%) as a white solid, which was used in the next step. without any further purification. Step 3: 1 -benzyl -N -[(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole -3 -carboxamide

[02281] A mixture of 1-benzylpyrazole-3-carboxylic acid (60 mg, 0.28 mmol), (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazole [1,5 - a][1,3] diazepin -5 -one (50 mg, 0.28 mmol), 1-hydroxy benzotriazole (56 mg, 0.42 mmol) and 1 -(3-dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride ( 80 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (27 -57% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - benzyl -N -[(6S) -4 -methyl -5 -oxo -7 ,8-dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole -3 - carboxamide (66.9 mg, 66%) as a white solid. H NMR (400 MHz, CD3OD) δ 7.71 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.35 - 7.26 (m , 5H), 6.74 (d, J = 2.8 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.40(s, 2H), 4.57 - 4 .52 (m, 1H), 4.46 - 4.44 (m, 1H), 4.34 - 4.31 (m, 1H), 3.36 (s, 3H), 2.89 - 2.82 (m, 1H), 2.34 - 2.28 (m, 1H). LC -MS RT = 0.755 min., m/z = 365.0 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.755 min., ESI+ found [M+H] =365.0. Example 741 -3 -carboxamide

[02282] Amide coupling prepared in a manner similar to Method WX 182. The crude product was purified via RP-HPLC (27 -57% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - benzyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] pyrazole -3 - carboxamide (66.6 mg, 68%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 7.36 - 7.25(m, 5H), 6.75 (s, 1H), 6.39 - 6.34 (m, 1H), 5.40(s, 2H), 4.66 - 4.65 (m, 1H), 4.44 - 4.34 (m, 2H), 3.36 (s, 3H), 2.92 - 2.81 (m, 1H), 2.39 - 2.37 (m, 4H). LC -MS RT =0.764 min., m/z = 379.0 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.764 min., ESI+ found [M+H] =379.0. Examples 742 and 744

[02283] WX Method 186 (1S) -1 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -1 -(trifluoromethyl) -3H -furo[ 3,4 -c] pyridine -6 -carboxamide and (1R) -1 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl ] -1 -(trifluoromethyl) -3H -furo[3,4 -c] pyridine -6 -carboxamide Step 1: 6-chloro-1-methyl-1-(trifluoromethyl)furo[3,4-c]pyridin-3(1H)-one

[02284] To a solution of 2,2,6,6-tetramethyl piperidine (13.5 g, 95.2 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in hexanes, 38, 0 mL, 95.0 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 6-chloronicotinic acid (5.0 g, 31.7 mmol) was added. The reaction mixture was stirred at -78°C for another 2 h and 1,1,1-trifluoroacetone (10.7 g, 95 mmol) was added. After addition, the reaction mixture was stirred at 25°C for 24 h and finalized by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 6-chloro-1-methyl-1-(trifluoromethyl)fur [3,4 -c] pyridin -3(1H) -one (6.0 g, 75%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 2: 2 -(2 -chloro -5 -(hydroxymethyl)pyridin - 4 -yl) -1,1,1 -trifluoropropan -2 -ol

[02285] To a solution of 6-chloro-1-methyl -1 -(trifluoromethyl) fur [3,4 -c] pyridin -3(1H) -one (3.0 g, 11.9 mmol) in tetrahydrofuran ( 60 mL) lithium aluminum hydride (881 mg, 24 mmol) was added portionwise under -78°C. After addition, the mixture was slowly heated to 0°C and stirred at 0°C for 30 min. The mixture was finished with the addition of water (0.05 mL), 10% NaOH (0.05 mL) and followed by water (0.15 mL). To the resulting mixture, anhydrous sodium sulfate (20 g) was added and stirred for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2 -(2 - chloro -5 - (hydroxymethyl) pyridin -4 -il) -1,1,1 - trifluoropropan -2 -ol (400 mg, 13%) in the form of a white solid, which was used in the next step in the form in which it was. Step 3: 6-chloro-1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine

[02286] To a solution of N1,N1,N2,N2 - tetramethyl diazene -1,2 -dicarboxamide (808 mg, 4.7 mmol) in toluene (40 mL) was added tri-n-butylphosphine (950 mg, 4 .7 mmol) and 2 -[2 -chloro -5 -(hydroxymethyl) -4 - pyridyl] -1,1,1 -trifluoro -propan -2 -ol (400 mg, 1.6 mmol) under nitrogen atmosphere. The mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 6-chloro-1-methyl -1 -(trifluoromethyl) - 1 ,3-dihydrofuro[3,4-c]pyridine (200 mg, 54%). LC -MS RT = 1.5 min., m/z = 238.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.98 min., ESI+ found [M+H] = 238.1. Step 4: methyl 1 -methyl -1 -(trifluoromethyl) -1,3 -dihydrofuro[3,4 -c] pyridine -6 -carboxylate

[02287] A mixture of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (55 mg, 0.08 mmol), 6-chloro-1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro [3 ,4-c] pyridine (180 mg, 0.76 mmol) and triethylamine (230 mg, 2.27 mmol) in methanol (50 mL) was heated to 70oC under CO atmosphere [3.42 bar (35 psi) ] for 15 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 1 -methyl -1 - (trifluoromethyl) -1,3 - dihydrofuro [3,4-c] pyridine-6-carboxylate (150 mg, 76%) in the form of a light yellow oil, which was used in the next step in the form in which it was. LC -MS RT = 0.78min., m/z = 261.9 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.78min., ESI+ found [M+H] = 261.9. Step 5: 1-Methyl-1-(trifluoromethyl)-1,3—dihydrofuro[3,4-c]pyridine-6-carboxylic acid

[02288] A mixture of methyl 1 -methyl -1 - (trifluoromethyl) -1,3 -dihydrofuro [3,4 -c] pyridine -6 - carboxylate (140 mg, 0.54 mmol) and potassium hydroxide (60 mg , 1.07 mmol) in ethanol (4 mL) and water (1 mL) was stirred at 25oC for 12 h. To the mixture was added 1N HCl (3 mL) and concentrated under reduced pressure. The crude product was dissolved in methanol (20 ml) and filtered. The filtrate was concentrated under reduced pressure to provide crude 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (120 mg, 91%) as of a yellow solid, which was used in the next step without any further purification. Step 6: (1S)-1-methyl -N -[(3S)-5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 - (trifluoromethyl) -3H -furo[3,4 -c] pyridine -6 -carboxamide and (1R) -1 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin - 3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide

[02289] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (40 mg, 0.21 mmol), 1H -benzo[d][ 1,2,3] triazol -1 -ol (5.6 mg, 0.04 mmol), 1 -methyl -1 -(trifluoromethyl) acid -1,3 -dihydrofuro[3,4 - c] pyridine -6 - carboxylic acid (51 mg, 0.21 mmol) and N1 -((ethylimino) methylene) -N3,N3 -dimethylpropane -1,3 -diamine hydrochloride (40 mg, 0.21 mmol) in N,N -dimethylformamide (5 mL) was subjected to stirring at 25oC for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (48% to 78% acetonitrile/0.05% ammonium hydroxide in water) to give 1-methyl-N-((S)- 5 -methyl -4 -oxo -2,3,4,5 -tetrahydrobenzo [b][1,4] oxazepin -3 -yl) -1 -(trifluoromethyl) -1,3 - dihydrofuro [3,4 -c] pyridine-6-carboxamide (55 mg, 63%) as a white solid. This racemic material was further separated using chiral SFC to provide:

[02290] (1S) -1 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 - (trifluoromethyl) -3H -hole [3,4 -c] pyridine -6 - carboxamide (Peak 1, retention time 4.376 min.) (17.9 mg, 31%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 8.0 Hz, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 7.27 - 7.26 (m, 3H), 5.31 (s, 2H), 5.14 - 5.05 (m, 1H), 4.79 (t, J = 8.0 Hz, 1H), 4.36 - 4, 27 (m, 1H), 3.46 (s, 3H), 1.71 (s, 3H). LC -MS RT = 1.084 min., m/z = 422.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 2 min.) retention time 1.084 min., ESI+ found [M+H] = 422.2.

[02291] (1R) -1 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -1 - (trifluoromethyl) -3H -hole [3,4 -c] pyridine -6 - carboxamide (Peak 2, retention time 5.736 min.) (19.1 mg, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 7.2 Hz, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 7.26 (s, 3H ), 5.31 (s, 2H), 5.15 - 5.05 (m, 1H), 4.79 (t, J = 8.0 Hz, 1H), 4.33 - 4.27 (m, 1H), 3.46 (s, 3H), 1.71 (s, 3H). LC -MS RT = 1.092 min., m/z = 422.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 2 min.) retention time 1.092 min., ESI+ found [M+H] = 422.2, SFC Condition: Column: Chiralpak AD ( 250mm*30mm,10um) Mobile phase: A: CO2 B: methanol (0.1%NH3H2O), supercritical CO2 / EtOH + NH3H2O = 45/ 45; 80 mL/min. Examples 743 and 745

[02292] WX Method 188 (7S) -7 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin -3 -yl] -7 -(trifluoromethyl) -5H -furo[ 3,4 -d] pyrimidine -2 -carboxamide and (7R) -7 -methyl - N -[(3S) -5 -methyl -4 -oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl ] -7 -(trifluoromethyl) -5H -furo[3,4 -d] pyrimidine - 2 –carboxamide Step 1: 2-chloro-7-methyl-7-(trifluoromethyl)furo[3,4-d]pyrimidin-5(7H)-one

[02293] To a solution of 2,2,6,6-tetramethyl piperidine (27.0 g, 190.4 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium (2.5 M in hexanes, 76, 0 mL, 190.0 mmol) under -78oC. The reaction mixture was stirred at -78°C for 1 h and 2-chloropyrimidine-5-carboxylic acid (10.0 g, 63.3 mmol) in THF (100 mL) was added. The reaction mixture was stirred at -78°C for another 2.5 h and 1,1,1-trifluoroacetone (21.4 g, 190.0 mmol) was added. After addition, the reaction mixture was stirred at 25°C for 24 h and finalized by addition of saturated ammonium chloride (100 mL). The mixture was adjusted to pH = 2 -3 by adding 2 M HCl (200 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 2-chloro-7-methyl-7-(trifluoromethyl)furo [3,4 -d] pyrimidin - 5(7H) -one (2.5 g, 16%) in the form of a yellow oil, which was used in the next step in the form in which it was. Step 2: 2-chloro-7-methyl-7-(trifluoromethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

[02294] To a solution of 2-chloro-7-methyl -7 -(trifluoromethyl)furo[3,4-d]pyrimidin-5(7H)-one (2.5 g, 9.9 mmol) in toluene ( 60 mL) diisobutyl aluminum hydride (1.0 M in toluene, 20.0 mL, 20.0 mmol) was added dropwise under -78°C. After addition, the mixture was stirred at -78oC for 2 h and then finished by adding water (0.05 mL), 10% NaOH (0.05 mL) and followed by H2O (0.15 mL). . The mixture was dried with Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2-chloro-7- methyl -7 - (trifluoromethyl) -5,7 -dihydrofuro[3,4 -d] pyrimidin -5 -ol (1.2 g, 48%) in the form of a yellow oil. LCMS RT = 0.622 min., m/z = 254.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.622 min., ESI+ found [M+H] = 254.9. 2-(2-chloro-5-(hydroxymethyl),1,1-trifluoropropan-2-ol

[02295] A mixture of 2-chloro-7-methyl -7 - (trifluoromethyl) -5H -furo[3,4 -d] pyrimidin -5 -ol (600 mg, 2.36 mmol) in trifluoroacetic acid (2 .69 g, 23.57 mmol) was stirred at 0°C for 30 min. and then triethylsilane (2.74 g, 23.57 mmol) was added. The reaction mixture was stirred at 50°C for 16 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide 2-[2-chloro-5-(hydroxymethyl)pyrimidin-4 -yl] -1,1,1 -trifluoro -propan -2 -ol (300 mg, 50%) as a yellow oil. Step 4: 2-chloro-7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine

[02296] To a solution of 2-[2-chloro-5-(hydroxymethyl)pyrimidin-4-yl]-1,1,1-trifluoro-propan-2-ol (300 mg, 1.17 mmol) in toluene (5 mL) tri-n-butylphosphine (355 mg, 1.75 mmol) and N1,N1,N2,N2 -tetramethyldiazene-1,2-dicarboxamide (302 mg, 1.75 mmol) were added. The reaction mixture was stirred at 20°C for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide 2-chloro-7-methyl-7-(trifluoromethyl)-5H -furo[3,4 -d] pyrimidine (120 mg, 43%). LCMS RT = 0.692 min., m/z = 239.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.692 min., ESI+ found [M+H] = 239.0. Step 5: methyl 7 -methyl -7 -(trifluoromethyl) -5H -furo[3,4 -d] pyrimidine -2 -carboxylate

[02297] A mixture of 2-chloro-7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine (100 mg, 0.42 mmol), 1,1'-bis(dichloride) diphenylphosphine) ferrocene palladium (31 mg, 0.04 mmol) and triethylamine (212 mg, 2.1 mmol) in methanol (20 mL) was heated at 80oC for 8 h under CO [4.11 bar (45 psi)]. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 100% ethyl acetate in petroleum ether) to provide methyl 7-methyl-7-(trifluoromethyl)-5H-furo [3,4-d] pyrimidine-2-carboxylate (80 mg, 73%) in the form of a light yellow oil, which was used in the next step in the form in which it was. Step 6: 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid

[02298] A mixture of methyl 7 -methyl -7 - (trifluoromethyl) -5H -furo[3,4 -d] pyrimidine -2 - carboxylate (80 mg, 0.31 mmol) and lithium hydroxide monohydrate (128 mg , 3.05 mmol) in tetrahydrofuran (5 mL)/water (3 mL) was stirred at 20°C for 2 h. The mixture was acidified by adding 1N HCl (3 mL) and concentrated under reduced pressure. The residue was dissolved in methanol (20 ml) and filtered. The filtrate was concentrated under reduced pressure to provide crude 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid (60 mg, 79%) as a yellow solid, which was used in the next step in the form in which it was. Step 7: (7S)-7-methyl -N -[(3S)-5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -7 - (trifluoromethyl) -5H -furo[3,4 -d] pyrimidine -2 - carboxamide and (7R) -7 -methyl -N -[(3S) -5 -methyl -4 -oxo -2,3 - dihydro -1,5 -benzoxazepin - 3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

[02299] A mixture of (3S) -3 -amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (28 mg, 0.15 mmol), 7 -methyl -7 - acid (trifluoromethyl)-5H-furo[3,4-d] pyrimidine-2-carboxylic acid (30 mg, 0.12 mmol), 1-hydroxybenzotriazole (20mg, 0.15 mmol) and 1-(3-dimethylaminopropyl) hydrochloride -3-ethylcarbodiimide (28 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20°C for 2 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (32% to 62% acetonitrile / 0.05% ammonium hydroxide in water) to provide 7 -methyl -N -((S) -5 -methyl - 4 -oxo - 2,3,4,5-tetrahydrobenzo[b] [1,4] oxazepin -3 -yl) -7 -(trifluoromethyl) -5,7 -dihydrofuro[3,4 -d] pyrimidine -2 -carboxamide (30 mg , 59%) in the form of a white solid. The racemic material was further separated using chiral SFC to provide:

[02300] (7S) -7 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -7 - (trifluoromethyl) -5H -furo[3,4 -d] pyrimidine -2 - carboxamide (Peak 1, retention time 5.298 min.) (10.7 mg, 36%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 7.46 - 7.43 (m, 1H), 7.34 - 7.24 (m, 3H), 5.32 (s, 2H), 5.04 - 4.96 (m, 1H), 4.72 - 4.67 (m, 1H), 4.48 - 4.42 (m, 1H), 3.44 (s, 3H) , 1.76 (s, 3H). LCMS RT = 0.817 min., m/z = 423.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.817 min., ESI+ found [M+H] = 423.0.

[02301] (7R) -7 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -7 - (trifluoromethyl) -5H -furo[3,4 -d] pyrimidine -2 - carboxamide (Peak 2, retention time 6.174 min.) (11.7 mg, 39%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 7.46 - 7.43 (m, 1H), 7.34 - 7.24 (m, 3H), 5.32 (s, 2H), 5.04 - 4.96 (m, 1H), 4.72 - 4.67 (m, 1H), 4.48 - 4.42 (m, 1H), 3.44 (s, 3H) , 1.76 (s, 3H). LCMS RT = 0.824 min., m/z = 423.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.824 min., ESI+ found [M+H] = 423.0.

[02302] SFC Condition: Column: ChiralCel (OD -H 150x4.6 mm ID, 5 µm) Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5.5 min. and held 40% for 3 min., then 5% B for 1.5 min., Flow rate: 2.5 mL/min. Column temperature: 40oC. Examples 746 and 748 (1S)-1-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-1-(trifluoromethyl)- 3H -furo[3,4-c] pyridine -6 -carboxamide and (1R) -1 -methyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -1 - (trifluoromethyl) -3H -furo[3,4 -c] pyridine -6 -carboxamide

[02303] Amide coupling prepared in a manner similar to Method WX 184. The crude product was purified via RP-HPLC (48 -78% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - methyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -1 -(trifluoromethyl) -3H -furo[3, 4 - c] pyridine -6 -carboxamide (55 mg, 63%) as a white solid. The racemate was further separated using chiral SFC to provide:

[02304] (1S) -1 -methyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -1 - ( trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide (Peak 1, retention time 3.756 min.) (18.7 mg, 34%) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.84 (d, J = 6.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.17 (s, 1H) , 6.91 - 6.82 (m, 2H), 5.31 (s, 2H), 4.79 - 4.70(m, 1H), 3.12 - 3.01 (m, 1H), 2 .96 - 2.85 (m, 1H), 2.80 - 2.72 (m, 1H), 2.21 - 2.10 (m, 1H), 1.72 (s, 3H). LC -MS RT = 1.056 min., m/z = 442.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 2 min.) retention time 1.056 min., ESI+ found [M+H] = 442.2.

[02305] (1R) -1 -methyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -1 - ( trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide (Peak 2, retention time 5.978 min.) (15.6 mg, 28%) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.84 (d, J = 7.2 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.17 (s, 1H) , 6.91 - 6.82 (m, 2H), 5.31 (s, 2H), 4.79 - 4.70(m, 1H), 3.12 - 3.01 (m, 1H), 2 .96 - 2.85 (m, 1H), 2.80 - 2.72 (m, 1H), 2.21 - 2.10 (m, 1H), 1.72 (s, 3H). LC -MS RT = 1.068 min., m/z = 442.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 2 min.) retention time 1.068 min., ESI+ found [M+H] = 442.2.

[02306] SFC Conditions: Column: Chiralpak AD 150x4.6 mm ID, 3 µm, Mobile phase: 25% methanol (0.05% DEA) in CO2, Flow rate: 2.4 mL/min., Cell temperature column: 40oC. Examples 747 and 749 (7S)-7-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-7-(trifluoromethyl)- 5H -furo[3,4-d] pyrimidine -2 - carboxamide and (7R) -7 -methyl -N -[(3S) -7,9 -difluoro -2 -oxo - 1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -7 - (trifluoromethyl) -5H -furo[3,4 -d] pyrimidine -2 - carboxamide

[02307] Amide coupling prepared in a manner similar to Method WX 188. The crude product was purified via RP-HPLC (32% to 62% acetonitrile / 0.05% ammonium hydroxide in water) to provide N -((S) -7,9 -difluoro -2 -oxo -2,3,4,5 -tetrahydro -1H - benzo [b]azepin -3 -yl) -7 -methyl -7 -(trifluoromethyl) - 5 ,7-dihydrofuro[3,4-d] pyrimidine-2-carboxamide (30 mg, 56%) as a white solid. The racemate was separated using chiral SFC to provide:

[02308] (7S) -7 -methyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -7 - ( trifluoromethyl) -5H -furo[3,4-d] pyrimidine -2 - carboxamide (Peak 1, retention time 3.801 min.) (9.1 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.04 - 6.99 (m, 2H), 5.32 (s, 2H), 4.66 - 4.61 (m, 1H), 3.04 - 2.98 (m, 1H), 2.87 - 2.75 (m, 2H), 2.28 - 2.23 (m, 1H), 1.76 (s, 3H) . LCMS RT = 0.799 min., m/z = 443.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.799 min., ESI+ found [M+H] = 443.0.

[02309] (7R) -7 -methyl -N -[(3S) -7,9 -difluoro -2 -oxo -1,3,4,5 -tetrahydro -1 -benzazepin -3 -yl] -7 - ( trifluoromethyl) -5H -furo[3,4-d] pyrimidine -2 - carboxamide (Peak 2, retention time 4.334 min.) (9.9 mg, 33%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.04 - 6.99 (m, 2H), 5.32 (s, 2H), 4.66 - 4.61 (m, 1H), 3.04 - 2.98 (m, 1H), 2.87 - 2.75 (m, 2H), 2.28 - 2.23 (m, 1H), 1.76 (s, 3H) . LCMS RT = 0.803 min., m/z = 443.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.803 min., ESI+ found [M+H] = 443.0, SFC Condition: Column: ChiralPak (AD -3 150x4.6 mm I.D., 3 µm) Mobile phase: A: CO2 B: Methanol (0.05% DEA) Gradient: from 5% to 40% B in 5.5 min. and held 40% for 3 min., then 5% B for 1.5 min., Flow rate: 2.5 mL/min. Column temperature: 40oC. Example 750

[02310] WX Method 184 ° 1 -benzyl -N -[(6S) -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] imidazole -4 -carboxamide , Step 1: methyl 1-benzylimidazole-4-carboxylate

[02311] To a solution of methyl 4-imidazole carboxylate (500 mg, 3.96 mmol) in acetonitrile (10 mL) was added triethylamine (482 mg, 4.76 mmol) and benzyl bromide (678 mg, 3.96 mmol) mmol). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (20-50% acetonitrile/0.05% ammonium hydroxide in water) to provide methyl 1-benzylimidazole-4-carboxylate (118 mg, 14%) as a solid white, which was used in the next stage as it was. LC -MS RT = 1.273 min., m/z = 217.1 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.273 min., ESI+ found [M+H] = 217.1. Step 2: 1-Benzylimidazole-4-carboxylic acid

[02312] A mixture of methyl 1-benzylimidazole-4-carboxylate (90 mg, 0.42 mmol) and hydrated lithium hydroxide (50 mg, 2.08 mmol) in ethanol / water (9 mL, 8:1) was subjected to stirring at 25oC for 12 h. The solution was diluted with water (10 mL) and adjusted to pH = 4 -5 by adding 2M HCl. The resulting solid was collected through filtration and subjected to drying under reduced pressure to provide crude 1-benzylimidazole-4-carboxylic acid (60 mg, 71%) as a white solid, which was used in the step next without any further purification. Step 3: 1 -benzyl -N -[(6S) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] imidazole -4 -carboxamide

[02313] The mixture of 1-benzylimidazole -4-carboxylic acid (34 mg, 0.17 mmol), (6S) -6 -amino -4 -methyl - 7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (30 mg, 0.17 mmol), 1 -hydroxy benzotriazole (34 mg, 0.25 mmol) and 1 -(3 -dimethyl aminopropyl) -3 - ethylcarbodiimide hydrochloride (48 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (7 -37% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - benzyl -N -[(6S) -4 -methyl -5 -oxo -7 ,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]imidazole -4 - carboxamide (14.5 mg, 24%) as a yellow solid. H NMR (400MHz, CD3OD) δ 9.16 (s, 1H), 8.10 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.42 - 7.41 ( m, 5H), 6.29 (d, J = 2.0 Hz, 1H), 5.44 (s, 2H), 4.44 - 4.37 (m, 2H), 4.25- 4.22 (m, 1H), 3.25(s, 3H), 2.70- 2.65 (m, 1H), 2.27 - 2.22 (m, 1H). LC -MS RT = 0.679 min., m/z = 365.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.679 min., ESI+ found [M+H] =365.1. Example 751

[02314] Amide coupling prepared in a manner similar to Method WX 184. The crude product was purified via RP-HPLC (10 -40% acetonitrile / 0.05% ammonium hydroxide in water) to provide 1 - benzyl -N -[(6S) -2,4 -dimethyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]imidazole -4 - carboxamide (21.5 mg, 37%) as a yellow solid. H NMR (400MHz, CD3OD) δ 9.21 (s, 1H), 8.16 (s, 1H), 7.47 — 7.42 (m, 5H), 6.28 (s, 1H), 5, 48 (s, 2H), 4.58 - 4.53 (m, 1H), 4.39 - 4.27 (m, 2H), 3.30 (s, 3H), 2.77 — 2.71 ( m, 1H), 2.32 - 2.28 (m, 4H). LC -MS RT =0.709 min., m/z = 379.1 [M+H] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.709 min., ESI+ found [M+H] =379.1. Example 752

[02315] WX Method 199 1 -benzyl -N -[(6S) -4 -methyl -2 -(2 -morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazol -3 -carboxamide and 1 -benzyl -N -[(6R) -4 -methyl -2 -(2 -morpholinoethyl) -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 –carboxamide Step 1: tert-butyl (4 -methyl -2 -(2 - morpholinoethyl) -5 -oxo -5,6,7,8 –tetrahydro -4H –pyrazole [1,5 -a][1,3] diazepin - 6-yl) carbamate

[02316] A mixture of 2 -[6 -(tert-butoxycarbonyl amino) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -2 -yl]ethyl methanesulfonate (200 mg, 0.50 mmol) and morpholino (216 mg, 2.48 mmol) in N,N-dimethylformamide (10 mL) was heated at 50°C for 6 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide tert-butyl N -[4 - methyl -2 -(2-morpholinoethyl) -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl]carbamate (150 mg, 77%) in the form of a colorless oil, which was used in the step next in the form in which it was. Step 2: 6-amino -4 -methyl -2 -(2-morpholinoethyl) -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one hydrochloride

[02317] To a solution of tert-butyl N -[4 - methyl -2 -(2-morpholinoethyl) -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin-6-yl]carbamate (150 mg, 0.38 mmol) in ethyl acetate (5 mL) was added hydrochloric acid (4.0 M in ethyl acetate, 4.0 mL, 16.0 mmol). The reaction mixture was stirred at 20°C for 2 h and concentrated under reduced pressure to provide 6-amino-4-methyl-2-(2-morpholinoethyl)-7,8-dihydro-4H-pyrazole hydrochloride [1, 5 -a][1,3] diazepin -5(6H) -one crude (120 mg, 96%) as a white solid, which was used in the next step without any further purification. Step 3: 1 -benzyl -N -[(6S) -4 -methyl -2 -(2 - morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -4 -methyl -2 -(2 - morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02318] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (40 mg, 0.20 mmol), 6-amino-4-methyl-2-(2-morpholinoethyl) hydrochloride 7,8 -dihydro -4H - pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (60 mg, 0.18 mmol), 1 -hydroxy benzotriazole (27 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15oC for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35-65% acetonitrile/0.05% NH4OH in water) to give 1-benzyl-N-[4-methyl-2-( 2 -morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide (70mg , 81%) in the form of a white solid. The racemic material was further separated using chiral SFC to provide:

[02319] 1 -benzyl -N -[(6S) -4 -methyl -2 -(2 - -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepine -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 5.064 min.) (23 mg, 32%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.37 - 7.34 (m, 5H), 6.20(s, 1H), 5.48 (s, 2H), 4.53 - 4.50 (m, 1H), 4.33 - 4.31 (m, 1H), 4.23 - 4.21 (m, 1H), 3.73 - 3.71 (m, 4H), 3.33 (s , 3H), 2.86 - 2.81 (m, 3H), 2.72 - 2.67 (m, 2H), 2.58 - 2.52 (m, 4H), 2.26 - 2.24 (m, 1H). LCMS RT = 0.653 min., m/z = 479.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min. ) retention time 0.653 min., ESI+ found [M+H] = 479.2.

[02320] 1 -benzyl -N -[(6R) -4 -methyl -2 -(2 - morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 6.035 min.) (22.7 mg, 32%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.37 - 7.34 (m, 5H), 6.20(s, 1H), 5.48 (s, 2H), 4 .53 - 4.50 (m, 1H), 4.34 - 4.31 (m, 1H), 4.24 - 4.21 (m, 1H), 3.73 (m, 4H), 3.33 (s, 3H), 2.86 - 2.80 (m, 3H), 2.72 - 2.67 (m, 2H),2.58 - 2.52 (m, 4H), 2.26 - 2 .24 (m, 1H). LCMS RT = 0.651 min., m/z = 479.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5min.) retention time 0.651 min., ESI+ found [M+H] = 479.2.

[02321] SFC Condition: Column: Chiralcel (OD -3 100x4.6 mm ID, 3 µm) Mobile phase: A:CO2 B:ethanol (0.05% DEA), Gradient: from 5% to 40% from B in 4.5 min. and maintained 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min., Column temperature: 40oC. Example 753 1 -[(2-fluorophenyl) methyl] -N -[(6S) -4 -methyl - 2 -(2 -morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[(6R) -4 -methyl - 2 -(2 -morpholinoethyl) -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide

[02322] Amide coupling prepared in a manner similar to Method WX 199. Racemic material was separated using chiral SFC to provide:

[02323] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 4 -methyl -2 -(2 -morpholinoethyl) -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.621 min.) (17.4 mg, 24%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.41 - 7.38 m, 2H), 7.22 - 7.15 (m, 2H), 6.19 (s, 1H ), 5.55 (s, 2H), 4.55 - 4.50 (m, 1H), 4.33 - 4.31 (m, 1H), 4.23 - 4.21 (m, 1H), 3.73 - 3.71 (m, 4H), 3.33 (s, 3H), 2.86 - 2.81 (m, 3H), 2.72 - 2.67 (m, 2H), 2, 58 - 2.52 (m, 4H), 2.26 - 2.23 (m, 1H). LCMS RT = 0.668 min., m/z = 497.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.668 min., ESI+ found [M+H] = 497.2.

[02324] 1 -[(2-fluorophenyl) methyl] -N -[(6R) - 4 -methyl -2 -(2 -morpholinoethyl) -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 6.349 min.) (19.8 mg, 27%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.42 - 7.38 (m, 2H), 7.22 - 7.15 (m, 2H), 6.19 (s, 1H), 5.55 (s, 2H), 4.54 - 4.52 (m, 1H), 4.33 - 4.30 (m, 1H), 4.24 - 4.21 (m, 1H) , 3.73 - 3.70(m, 4H), 3.33 (s, 3H), 2.86 - 2.81 (m, 3H), 2.72 - 2.68 (m, 2H), 2 .58 - 2.52 (m, 4H), 2.26 - 2.24 (m, 1H). LCMS RT = 0.665 min., m/z = 497.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.665 min., ESI+ found [M+H] = 497.2.

[02325] SFC Condition: Column: Chiralcel (OD -3 100x4.6 mm I.D., 3 um) Mobile phase: A:CO2 B:ethanol (0.05% DEA), Gradient: from 5% to 40% from B in 4.5 min. and maintained 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min., Column temperature: 40oC. Example 754

[02326] WX 213 Method 1 -benzyl -N -[(6S) -2 -(azetidin - 3 -yl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole hydrochloride [1,5 - a][1, 3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -(azetidin - 3 -yl) -4 -methyl -5 - hydrochloride oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02327] A solution of the stirred mixture of tert-butyl 3 -[6 -[(1-benzyl -1,2,4 -triazol - 3 -carbonyl)amino] -4 -methyl -5 -oxo -7 ,8-dihydro-6H-pyrazole[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate (60 mg, 0.12 mmol) in dichloromethane (5 mL) trifluoroacetic acid was added (120 mg, 1.05 mmol). The resulting mixture was stirred at 25°C for 12 h and then finalized by adding saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (5 -35% acetonitrile / 0.05% HCl in water) to give N -[2 -(azetidin -3 -yl) -4 - methyl -5 -oxo -7 ,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1 -benzyl -1,2,4 -triazole -3 -carboxamide (35 mg, 41%) in form a white solid.

[02328] The racemic material was separated using chiral SFC and then purified using RP-HPLC (5-35% acetonitrile / 0.05% HCl in water) to provide:

[02329] 1-Benzyl -N -[(6S) -2 - (azetidin -3 -yl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole hydrochloride [1,5 -a] [1,3]diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 2.254 min.) (11.0 mg, 31%) as a colored solid white. 1H NMR (400MHz, CD3OD) δ 8.90 (s, 1H), 7.41 - 7.30 (m, 5H), 6.36 (s, 1H), 5.52 (s, 2H), 4, 53 - 4.50 (m, 1H), 4.47 - 4.14 (m, 7H), 3.34 (s, 3H), 2.88 - 2.78(m, 1H), 2.35 - 2.27 (m, 1H). LCMS RT = 2.187 min.; m/z = 421.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water for 3.0 min.) retention time 2.187 min., ESI+ found [M+H] =421.2.

[02330] 1-Benzyl -N -[(6R) -2 - (azetidin -3 -yl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole hydrochloride [1,5 -a] [1,3]diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2 retention time 3.065 min.) (11.1 mg, 32%) as a white solid .

[02331] 1H NMR (400MHz, CD3OD) δ 8.82 (s, 1H), 7.43 - 7.30 (m, 5H), 6.37 (s, 1H), 5.53 (s, 2H) , 4.55 - 4.50 (m, 1H), 4.48 - 4.14 (m, 7H), 3.37 (s, 3H), 2.89 - 2.78(m, 1H), 2 .37 - 2.29 (m, 1H). LCMS RT = 2.195 min.; m/z = 421.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water for 3.0 min.) retention time 2.195 min., ESI+ found [M+H] = 421.2.

[02332] SFC Conditions: Column: Chiralcel OD -3 150x4.6 mm I.D., 3 µm Mobile phase: 40% methanol (0.1% ethanolamine) in CO2. Flow rate: 2.5 mL / min. Column temperature: 35 oC. Example 755

[02333] WX Method 192 1 -benzyl -N -[(6S) -2 -[2 -(2 -methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(2 -methoxyethoxy)ethyl] -4 -methyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide Step 1: (2-methoxyethoxy)ethane

[02334] A mixture of iodomethane (7.7 mL, 124.0 mmol), ethylene glycol monovinyl ether (5.0 g, 56.8 mmol) and potassium hydroxide (3.8 g, 68.1 mmol) was subjected to stirring at 0oC for 30 min. and then under 20oC for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude (2-methoxyethoxy)ethane (2 g, 35%) in the form of a colorless oil. 1H NMR (CDC13, 400 MHz) δ 6.52 - 6.47 (m, 1H), 4.19 - 4.02 (m, 1H), 4.01 - 3.99 (m, 1H), 3, 82 (t, J = 4.4 Hz, 2H), 3.62 (t, J = 2.4 Hz, 2H), 3.37 (s, 3H). Step 2: (E) -tert-butyl (2 -(2 -(2 - methoxyethoxy)vinyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl)carbamate.

[02335] A mixture of tert-butyl N -(2 -bromo -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl ) carbamate (500 mg, 1.39 mmol), N,N - diisopropyl ethylamine (540 mg, 4.18 mmol), 1 -methoxy -2 - vinyloxy -ethane (142 mg, 1.39 mmol) and bis(tri -tert-butylphosphine) palladium (0) (71 mg, 0.14 mmol) in 1,4-dioxane (15 mL) was heated at 80oC for 12 h under nitrogen protection. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide (E)-tert-butyl (2-( 2 -(2-methoxyethoxy) vinyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate (140 mg, 26%) in the form of a yellow solid, which was used in the next step in the form in which it was. LC -MS RT = 1.535 min., m/z = 381.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.535 min., ESI+ found [M+H] = 381.2. Step 3: tert-butyl (2 -(2 -(2 -methoxyethoxy)ethyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl)carbamate

[02336] A mixture of (E) -tert-butyl (2 -(2 - (2-methoxyethoxy) vinyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl) carbamate (140 mg, 0.37 mmol) and palladium on carbon (10%, 0.1 g) in methanol (10 mL) was hydrogenated [4, 46 bar (50 psi)] under 25oC for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide tert-butyl (2-( 2 - (2-methoxyethoxy)ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate (140 mg, 99%) in the form of a colorless oil. LC -MS RT = 1.39 min., m/z = 383.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.39 min., ESI+ found [M+H] = 383.2. Step 4: 6 -amino -2 -(2 -(2 -methoxyethoxy)ethyl) - 4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H ) -one

[02337] A stirred mixture solution of tert-butyl (2-(2-(2-methoxyethoxy)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1,5 - a][1,3] diazepin -6 -yl)carbamate (110 mg, 0.29 mmol) in dichloromethane (5 mL) trifluoroacetic acid (656 mg, 5.75 mmol) was added. The resulting mixture was stirred for 12 h at 25°C and then finalized by adding saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide 6-amino-2-[2-(2-methoxyethoxy)ethyl]-4-methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] crude diazepin -5 -one (80 mg, 98%) as a yellow oil. LC -MS RT = 1.256 min., m/z = 283.2 [M+H] +. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.256 min., ESI+ found [M+H] = 283.2 . Step 5: 1 -benzyl -N -[(6S) -2 -[2 -(2 -methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a ][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(2 -methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02338] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (17 mg, 0.09 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (27 mg , 0.14 mmol), 6 -amino -2 - [2 - (2 -methoxyethoxy) ethyl] -4 - methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -5-one (20 mg, 0.07 mmol) and 1-hydroxy benzotriazole (27 mg, 0.20 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20oC for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25-45% acetonitrile/0.05% NH3,H2O in water) to give 1-benzyl-N-[2-[2- (2-methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (20 mg, 60%) as a white solid. The racemic material was further separated using chiral SFC to provide:

[02339] 1 -benzyl -N -[(6S) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.593 min.) (6 mg, 30%) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.46 (s, 1H), 7.30 — 7.22 (m, 5H), 6.11 (s, 1H), 5.37 (s, 2H), 4, 44 - 4.40(m, 1H), 4.27 - 4.20 (m, 1H), 4.16 - 4.07 (m, 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.54 - 3.51 (m, 2H), 3.46 - 3.42 (m, 2H), 3.25(s, 3H), 3.23 (s, 3H), 2.79 - 2.71 (m, 3H), 2.16 - 2.13 (m, 1H). LC -MS RT = 1.355 min., m/z = 468.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.355 min., ESI+ found [M+H] = 468.2.

[02340] 1 -benzyl -N -[(6R) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 5.435 min.) (2 mg, 10%) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.46 (s, 1H), 7.30 - 7.23 (m, 5H), 6.11 (s, 1H), 5.38 (s, 2H), 4, 44 - 4.40 (m, 1H), 4.27 - 4.20 (m, 1H), 4.16 - 4.07 (m, 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.54 - 3.51 (m, 2H), 3.46 - 3.42 (m, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.79 - 2.73 (m, 3H), 2.18 - 2.14 (m, 1H). LC -MS RT = 1,400 min., m/z = 468.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1,400 min., ESI+ found [M+H] = 468.2.

[02341] SFC condition: column: Chiralcel OD - 3 100 x 4.6 mm I.D., 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: held at 5% for 1.0 min, then from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1.0 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 756

[02342] WX Method 198 1 -benzyl -N -[(6S) -2 -[2 -(azetidin -1 - yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(azetidin -1 -yl)ethyl] - 4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide Step 1: tert-butyl (2 -(2 -(azetidin -1 -yl)ethyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl)carbamate

[02343] To a solution of azetidine hydrochloride (186 mg, 1.99 mmol) in acetonitrile (5 mL) was added potassium carbonate (549 mg, 3.98 mmol). The mixture was subjected to stirring at 25°C for 3 h. Then the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was added to a mixture of 2-(6-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole[1,5-a] [1,3] diazepin -2 -yl) ethyl methanesulfonate (160 mg, 0.40 mmol), N,N -diisopropyl ethylamine (308 mg, 2.39 mmol) and sodium iodide (60 mg, 0.40 mmol ) in N,N-dimethylformamide (4 mL). The mixture was heated at 50°C for 16 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide tert-butyl (2 -(2 -(azetidin -1 -yl )ethyl) - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl)carbamate (110 mg, 76% ) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 2: 6 -amino -2 -(2 -(azetidin -1 -yl)ethyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 - a][1,3] diazepine hydrochloride -5(6H)-one

[02344] To a solution of tert-butyl (2 -(2 - (azetidin -1 -yl) ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1, 5 -a][1,3] diazepin -6 - yl)carbamate (110 mg, 0.30 mmol) in ethyl acetate (20 mL) was added hydrochloric acid (4M in ethyl acetate, 12.0 mL, 48 The reaction mixture was stirred at 25°C for 15 h and concentrated under reduced pressure to provide 6-amino-2-(2-(azetidin-1-yl)ethyl)-4-methyl-7 hydrochloride ,8-dihydro -4H - pyrazole [1,5 -a][1,3] crude diazepin -5(6H) -one (90 mg, 99%) as a white solid, which was used in the next step without any further purification. Step 3: 1 -benzyl -N -[(6S) -2 -[2 -(azetidin -1 - yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(azetidin -1 - yl) ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02345] A mixture of 6-amino hydrochloride - 2 - (2 - (azetidin -1 -yl) ethyl) -4 -methyl -7,8 -dihydro -4H - pyrazole [1,5 -a][1, 3] diazepin -5(6H) -one (60 mg, 0.20 mmol), 1 -benzyl -1,2,4 -triazole -3 -carboxylic acid (41 mg, 0.20 mmol), 1 -hydroxybenzotriazole ( 41 mg, 0.30 mmol) and 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15oC for 12 p.m. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (3 -33% acetonitrile in water and 0.05% hydrochloric acid) to give N -(2 -(2 -(azetidin -1 -yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1 -benzyl - 1H -1,2,4 -triazole -3 - carboxamide (40 mg, 45%) as a white solid. The racemic compound was further separated using chiral SFC to provide:

[02346] 1 -benzyl -N -[(6S) -2 -[2 -(azetidin - 1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time 4.941 min.) (4.2 mg, 5%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.39 - 7.31 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4 .57 - 4.52 (m, 1H), 4.33 - 4.31 (m, 1H), 4.24 - 4.21 (m, 1H), 3.36 - 3.34 (m, 2H) , 3.33 (s, 3H), 3.32 - 3.30 (m, 2H), 2.87 - 2.78(m, 3H), 2.67 - 2.63 (m, 2H), 2 .25 - 2.22 (m, 1H), 2.15 - 2.10 (m, 2H). LC -MS RT = 0.603 min., m/z = 449.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.603 min., ESI+ found [M+H] = 449.1.

[02347] 1 -benzyl -N -[(6R) -2 -[2 -(azetidin - 1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 5.372 min.) (4.1 mg, 5%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.40- 7.32 (m, 5H), 6.16 (s, 1H), 5.47 (s, 2H), 4 .57 - 4.51 (m, 1H), 4.33 - 4.31 (m, 1H), 4.25- 4.16 (m, 1H), 3.33 (s, 3H), 3.32 - 3.30 (m, 2H), 3.29 - 3.28 (m, 2H), 2.87 - 2.82 (m, 1H), 2.77 (t, J = 8.0 Hz, 2H ), 2.66 - 2.61 (m, 2H), 2.29 - 2.21 (m, 1H), 2.16 - 2.08 (m, 2H). LC -MS RT = 0.604 min., m/z = 449.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.604 min., ESI+ found [M+H] = 449.1.

[02348] SFC condition: chiralpak AD -3 column (100 mm*4.6 mm I.D), 3 um mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: from 5% to 40% B in 4.5 min. and maintained 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min., 40oC. Example 757

[02349] WX Method 194 1 -benzyl -N -[(6S) -2 -[2 -(3 -methoxyazetidin -1-yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(3 -methoxyazetidin -1 -yl )ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide Step 1: tert-butyl (2 -bromo -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate

[02350] To a solution of 6-amino -2 -bromo -4 -methyl -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -5 -one (9.0 g , 34.7 mmol) in dichloromethane (10 mL) was added triethylamine (14.5 mL, 104.2 mmol) and di-tert-butyldicarbonate (11.4 g, 52.1 mmol) under 0°C. The reaction mixture was stirred at 20°C for 16 h and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide tert-butyl (2-bromo-4-methyl-5- oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl)carbamate (10.5 g, 84%) as a colored solid white, which was used in the next stage as it was. Step 2: tert-butyl (4-methyl -5 -oxo -2 -vinyl - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate

[02351] A mixture of tert-butyl (2 -bromo -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl)carbamate (6.0 g, 16.70 mmol), cesium fluoride (7.6 g, 50.11 mmol), bis(di-tert-butyl(4-dimethyl aminophenyl) phosphine) dichloro palladium (II ) (1.2 g, 1.67 mmol) and potassium vinyl trifluoroborate (4.5 g, 33.40 mmol) in 1,4-dioxane (100 mL)/water (10 mL) was heated under 90°C for 16 h under nitrogen protection. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide tert-butyl (4-methyl -5 -oxo -2 -vinyl - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) carbamate (4.2 g , 82%) in the form of a yellow solid, which was used in the next step in the form in which it was. LC -MS RT = 0.687 min., m/z = 250.8 [M -56] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.687 min., ESI+ found [M -56] = 250.8. Step 3: tert-butyl (4 -methyl -2 -(oxiran -2 -yl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate

[02352] To a solution of tert-butyl (4-methyl - 5 -oxo -2 -vinyl -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin - 6-yl) carbamate (3.7 g, 12.08 mmol) in dichloromethane (15 mL) was added 3-chloroperoxybenzoic acid (2.1 g, 12.08 mmol) under 0°C. The reaction mixture was stirred at 0°C for 3 h and then quenched by addition of saturated aqueous sodium thiosulfate (5 mL). The organic layer was separated, washed with brine (5 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide tert-butyl (4-methyl -2 -(oxiran -2 - il) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) carbamate (1.1 g, 28%) in the form of a colorless solid. LC -MS RT = 0.704 min., m/z = 266.8 [M -56] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.704 min., ESI+ found [M -56] = 266.8. Step 4: tert-butyl (2 -(2-hydroxyethyl) -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin - 6-yl) carbamate

[02353] A mixture of tert-butyl (4-methyl -2 -(oxiran -2 -yl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1 ,3] diazepin -6 -yl) carbamate (1.6 g, 4.96 mmol), palladium on carbon (10%, 528 mg) and an ammonium formate (3.2 g, 49.63 mmol) in methanol (15 mL) was hydrogenated [2.04 bar (15 psi)] under 20°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure to provide tert-butyl (2-(2-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole[1,5-a] [1,3] diazepin -6 -yl) crude carbamate (1.4 g, 87%) as a white solid. LC -MS RT = 0.704 min., m/z = 268.9 [M -56]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.704 min., ESI+ found [M -56] = 268.9. Step 5: 2 -(6 -((tert-butoxycarbonyl)amino) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -2 -yl) ethyl methane sulfonate

[02354] To a solution of tert-butyl (2 -(2 - hydroxyethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1, 3] diazepin-6-yl) carbamate (600 mg, 1.85 mmol) in dichloromethane (20 mL) was added triethylamine (0.77 mL, 5.55 mmol) and methane sulfonyl chloride (600 mg, 5.24 mmol). The reaction mixture was stirred at 20°C for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 80% ethyl acetate in petroleum ether) to provide 2 -(6 -((tert-butoxycarbonyl)amino) - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -2 -yl) ethyl methane sulfonate (632 mg, 85%) in the form of a white solid, which was used in the next step as it was. Step 6: tert-butyl (2 -(2 -(3 -methoxyazetidin -1 -yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro - 4H - pyrazole [1,5 - a][1,3] diazepin -6 -yl)carbamate

[02355] To a solution of 3-methoxy azetidine hydrochloride (246 mg, 1.99 mmol) in acetonitrile (5 mL) was added potassium carbonate (549 mg, 3.98 mmol). The mixture was stirred at 25°C for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was added to a mixture of 2-(6-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole[1,5-a] [1,3] diazepin -2 -yl) ethyl methane sulfonate (160 mg, 0.40 mmol), N,N - diisopropylethyl amine (54 mg, 0.40 mmol) and sodium iodide (60 mg, 0.40 mmol) in N,N-dimethylformamide (4 mL) was heated at 50°C for 16 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to provide tert-butyl (2 -(2 -(3 -methoxyazetidin -1 - yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazolo [1,5 -a][1,3] diazepin -6 -yl) carbamate (150 mg, 96%) in the form of a yellow solid, which was used in the next step in the form in which it was. LC -MS RT = 0.551 min., m/z = 394.0 [M -56] +. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.551 min., ESI+ found [M -56] = 394.0. Step 7: 6 -Amino -2 -(2 -(3 - methoxyazetidin -1 -yl)ethyl) -4 -methyl -7,8 -dihydro -4H - pyrazole hydrochloride [1,5 -a][1,3 ] diazepin -5(6H) -one

[02356] To a solution of tert-butyl (2 -(2 -(3 -methoxyazetidin -1 -yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [ 1,5 -a][1,3] diazepin -6 -yl) carbamate (150 mg, 0.38 mmol) in ethyl acetate (20 mL) was added hydrochloric acid (4 M in ethyl acetate, 15.0 mL, 60.0 mmol). The reaction mixture was stirred at 25°C for 15 h and concentrated under reduced pressure to provide 6-amino-2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-7.8 hydrochloride -dihydro -4H -pyrazole [1,5 -a][1,3] crude diazepin -5(6H) -one (125mg, 99%) as a white solid, which was used in the next step without any other purification. Step 8: 1 -benzyl -N -[(6S) -2 -[2 -(3 - methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(3 -methoxyazetidin - 1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02357] A mixture of 6-amino hydrochloride - 2 - [2 - (3 -methoxyazetidin -1 -yl)ethyl] -4 -methyl -7,8 - dihydro -6H -pyrazole [1,5 -a][ 1,3] diazepin -5 -one (80 mg, 0.24 mmol), 1 -benzyl -1,2,4 -triazole -3 -carboxylic acid (49 mg, 0.24 mmol), 1 -hydroxy benzotriazole ( 49 mg, 0.36 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15oC for 12 p.m. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (5-35% acetonitrile in water and 0.05% hydrochloric acid) to give 1-benzyl-N-(2-(2-( 3 -methoxyazetidin -1 - yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (40 mg, 34%) as a white solid. The racemic compound was further separated using chiral SFC to provide:

[02358] 1 -benzyl -N -[(6S) -2 -[2 -(3 - methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time 1.696 min.) (3.5 mg, 3%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.35 (s, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.57 - 4 .52 (m, 1H), 4.37 - 4.31 (m, 1H), 4.26 - 4.19 (m, 1H), 4.06 - 4.00 (m, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.33 (s, 3H), 3.25(s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 2.84 - 2.80 (m, 3H), 2.67 (t, J = 7.2 Hz, 2H), 2.29 - 2.21 (m, 1H). LC -MS RT = 0.556 min., m/z = 479.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.556 min., ESI+ found [M+H] = 479.1.

[02359] 1 -benzyl -N -[(6R) -2 -[2 -(3 - methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 2, retention time 1.995 min.) (3.5 mg, 3%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.38 - 7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4 .57 - 4.52 (m, 1H), 4.36 - 4.31 (m, 1H), 4.26 - 4.17 (m, 1H), 4.06 - 4.02 (m, 1H) , 3.63 (t, J = 7.0 Hz, 2H), 3.33 (s, 3H), 3.25(s, 3H), 3.02 (t, J = 6.6 Hz, 2H) , 2.84 - 2.80 (m, 3H), 2.67 (t, J = 7.4 Hz, 2H), 2.29 - 2.21 (m, 1H). LC -MS RT = 0.550 min., m/z = 479.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.550min., ESI+ found [M+H] = 479.1.

[02360] SFC condition: Chiralpak AD -3 column (50 mm*4.6 mm I.D), 3 um mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: held 5% for 0.2 min, then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 4 mL/min. Column temperature: 40oC. Example 758

[02361] WX 190 Method 1 -benzyl -N -[(6S) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] - 1,2,4 -triazol -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 –carboxamide Step 1: tert-butyl N -[2 -[(E) -2 -ethoxyvinyl] - 4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] carbamate

[02362] A mixture of ethyl vinyl ether (40 mg, 0.56 mmol), N,N-diisopropylethyl amine (216 mg, 1.67 mmol), bis(tri-tert-butylphosphine) palladium (28 mg, 0. 06 mmol) and tert-butyl N -(2 -bromo -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate (200 mg, 0.56 mmol) in 1,4-dioxane (15 mL) was heated at 80oC for 12 h under nitrogen protection. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide tert-butyl N - [2 -[(E) -2 -ethoxyvinyl] -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] carbamate ( 100 mg, 51%) as a yellow solid. LCMS RT = 2.13 min., m/z = 351.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 2.13 min., ESI+ found [M+H] = 351.2. Step 2: tert-butyl (2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6-yl)carbamate

[02363] A mixture of tert-butyl N -[2 -[(E) - 2 -ethoxyvinyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1 .3] diazepin-6-yl]carbamate (100 mg, 0.29 mmol) and palladium on carbon (10%, 0.1 g) in methanol (50 mL) was hydrogenated [4.46 bar (50 psi)] under 25oC for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide tert-butyl(2-(2-ethoxyethyl)-4- methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate (60 mg, 60%) in the form of an oil yellow in color. LCMS RT = 0.779 min., m/z = 353.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.779 min., ESI+ found [M+H] = 353.1. Step 3: 6 -amino -2 -(2-ethoxyethyl) -4 -methyl - 7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) - one

[02364] To a solution of tert-butyl (2 -(2 - ethoxyethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1, 3] diazepin-6-yl) carbamate (90 mg, 0.26 mmol) in dichloromethane (5 mL) trifluoroacetic acid (874 mg, 7.66 mmol) was added. The resulting mixture was stirred at 25°C for 12 h and then finalized by addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-amino-2-(2-ethoxyethyl)-4-methyl-7,8- crude dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (50 mg, 78%) as a yellow colored oil, which was used in the next step without any further purification . LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.325min., ESI+ found [M+H] = 253.2. Step 4: 1 -benzyl -N -[(6S) -2 -(2 -ethoxyethyl) -4 -methyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide

[02365] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (24 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0 .20 mmol), 6 -amino -2 -(2-ethoxyethyl) -4 -methyl -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (25mg, 0.10 mmol) and 1-hydroxy benzotriazole (27 mg, 0.20 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20oC for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (22-52% acetonitrile / 0.05% NH3,H2O in water) to give 1-benzyl-N-[2-(2- ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide (25 mg, 58%) as a white solid. The racemic material was further separated using chiral SFC to provide:

[02366] 1 -benzyl -N -[(6S) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.421 min.) (4.3 mg, 17%) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.46 (s, 1H), 7.27 - 7.24 (m, 5H), 6.09 (s, 1H), 5.38 (s, 2H), 4, 44 - 4.41 (m, 1H), 4.36 - 4.30 (m, 1H), 4.24 - 4.19 (m, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.45 - 3.43 (m, 2H), 3.23 (s, 3H), 2.78- 2.74 (m, 3H), 2.17 - 2.13 (m, 1H) , 1.09 (t, J = 7.2 Hz, 3H). LC -MS RT = 1.482 min., m/z = 438.2 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.482 min., ESI+ found [M+H] = 438.2.

[02367] 1 -benzyl -N -[(6R) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 5.225min.) (7.5 mg, 30%) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.46 (s, 1H), 7.27 — 7.24 (m, 5H), 6.09 (s, 1H), 5.38 (s, 2H), 4, 44 - 4.41 (m, 1H), 4.30 - 4.20 (m, 1H), 4.19 - 4.10 (m, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.45 - 3.43 (m, 2H), 3.23 (s, 3H), 2.78- 2.74 (m, 3H), 2.19 - 2.13 (m, 1H) , 1.09 (t, J = 7.2 Hz, 3H). LC -MS RT = 1.483 min., m/z = 438.2 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.483 min., ESI+ found [M+H] = 438.2.

[02368] SFC condition: column: Chiralcel OD - 3 50x4.6 mm I.D., 3 μm mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: held at 5% for 0.2 min, then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 759

[02369] WX 212 Method tert-butyl 3 -[(6S) -6 -[(1 -benzyl -1,2,4 -triazol -3 - carbonyl)amino] -4 -methyl -5 -oxo - 7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -2 -yl]azetidine -1 - carboxylate and tert-butyl 3 -[(6R) -6 -[(1 -benzyl -1,2,4 - triazole - 3-carbonyl)amino] -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -2 -yl]azetidine -1 – carboxylate Step 1: (6 -(1-benzyl -1H -1,2,4 -triazole -3 -carboxamido) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole acid [1 ,5 -a][1,3] diazepin -2 -yl) boronic

[02370] A mixture of 1 -benzyl -N -(2 -bromo -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - il) -1,2,4 -triazole -3 -carboxamide (2.5 g, 5.63 mmol), 4,4,4',4',5,5,5',5' -octamethyl -2, 2'-bi(1,3,2-dioxaborolane) (2.1 g, 8.44 mmol), 1,1-bis(diphenylphosphine) ferrocene palladium dichloride (0.4 g, 0.56 mmol) and acetate of potassium (1.7 g, 16.88 mmol) in 1,4-dioxane (20 mL) was heated at 90°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 18 -28/0.05% ammonia in water) to give acid [6-[(1-benzyl-1,2,4 -triazol -3 -carbonyl) amino] -4 -methyl -5 - oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -2 - yl] boronic (1.0 g, 43%) as a white solid. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.687 min., ESI+ found [M+H] = 410.1. Step 2: tert-butyl 3 -[(6S) -6 -[(1 -benzyl -1,2,4 - triazol -3 -carbonyl)amino] -4 -methyl -5 -oxo - 7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -2 -yl]azetidine -1 - carboxylate and tert-butyl 3 -[(6R) -6 -[(1 -benzyl -1,2,4 - triazol -3 -carbonyl)amino] -4 -methyl -5 -oxo - 7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -2 -yl] azetidine -1 - carboxylate

[02371] A mixture of tert-butyl 3-iodine azetidine-1-carboxylate (276 mg, 0.98 mmol), [6-[(1-benzyl-1,2,4-triazol-3-carbonyl)amino acid ] -4 -methyl - 5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -2 -yl] boronic acid (200 mg, 0.49 mmol), carbonate cesium (159 mg, 0.49 mmol) and cyclopentyl(diphenyl) phosphane dichloromethane dichloro palladium iron (399 mg, 0.49 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was subjected to stirring under 90oC for 0.5 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide tert-butyl 3-[6-[ (1 - benzyl -1,2,4 -triazol -3 -carbonyl) amino] -4 -methyl -5 - oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -2 - il] azetidine -1 -carboxylate (60 mg, 24%) as a white solid. The racemic material (25 mg) was further separated using chiral SFC to provide:

[02372] tert-butyl 3 -[(6S) -6 -[(1-benzyl - 1,2,4 -triazol -3 -carbonyl) amino] -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5-a][1,3] diazepin -2 -yl] azetidine -1 -carboxylate (Peak 1 retention time 5.537 min.) (7.5 mg, 30%) as a solid white in color. 1H NMR (400MHz, CD3OD) δ 8.56 (s, 1H), 7.41 - 7.31 (m, 5H), 6.30 (s, 1H), 5.47 (s, 2H), 4, 58 - 4.49 (m, 1H), 4.44 - 4.19 (m, 4H), 4.09 - 3.98 (m, 2H), 3.85 - 3.76 (m, 1H), 3.39 (s, 3H), 2.92 - 2.79 (m, 1H), 2.32 - 2.22 (s, 1H), 1.46 (s, 9H). LCMS RT = 1.747 min.; m/z = 421.2 (M -100)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water for 3.0 min.) retention time 1.747 min., ESI+ found [M -100] =421.2.

[02373] tert-butyl 3 -[(6R) -6 -[(1-benzyl - 1,2,4 -triazol -3 -carbonyl) amino] -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5-a][1,3] diazepin -2 -yl] azetidine -1 -carboxylate (Peak 2 retention time 6,650 min.) (10.0 mg, 40%) as a solid white in color. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.41 - 7.31 (m, 5H), 6.30 (s, 1H), 5.47 (s, 2H), 4 .58 - 4.48 (m, 1H), 4.45 - 4.19 (m, 4H), 4.09 - 3.98 (m, 2H), 3.85 - 3.76 (m, 1H) , 3.39 (s, 3H), 2.92 - 2.79 (m, 1H), 2.32 - 2.22 (s, 1H), 1.46 (s, 9H). LCMS RT = 1.747 min.; m/z = 421.2 (M -100)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water for 3.0 min.) retention time 1.747 min., ESI+ found [M -100] = 421.2.

[02374] SFC Condition Column: ChiralPak AD -3 150x4.6 mm ID, 3 μ m Mobile phase: A: CO2 B: Ethanol (0.05% DEA). Gradient: from 5% to 40% B in 5.5 min. and held 40% for 3 min., then 5% B for 1.5 min. Flow rate: 2.5 mL/min. Column temperature:40oC. Example 760 1 -[(2-fluorophenyl) methyl] -N -[(6S) -2 -[2 -(2-methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[(6R) -2 -[ 2 -(2-methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2, 4 -triazole -3 -carboxamide

[02375] Amide coupling prepared in a manner similar to Method WX 192. Racemic material was separated using chiral SFC to provide:

[02376] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 2 -[2 -(2-methoxyethoxy)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time 4.167 min.) (17 mg, 56%) in form a white solid. 1H NMR (400MHz, CD3OD) δ 8.47 (s, 1H), 7.30 - 7.26 (m, 2H), 7.11 - 7.02 (m, 2H), 6.11 (s, 1H ), 5.45 (s, 2H), 4.43 - 4.40(m, 1H), 4.25- 4.22 (m, 1H), 4.15 - 4.10 (m, 1H), 3.64 (t, J = 6.8 Hz, 2H), 3.52 - 3.51 (m, 2H), 3.49 - 3.45 (m, 2H), 3.25(s, 3H) , 3.22 (s, 3H), 2.78- 2.75 (m, 3H), 2.19 - 2.14 (m, 1H). LC -MS RT = 0.748 min., m/z = 508.2.2 [M+Na]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.748 min., ESI+ found [M+Na] = 508.2.

[02377] 1 -[(2-fluorophenyl) methyl] -N -[(6R) - 2 -[2 -(2-methoxyethoxy) ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.878 min.) (11.4 mg, 38% ) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.47 (s, 1H), 7.30 - 7.26 (m, 2H), 7.11 - 7.02 (m, 2H), 6.11 (s, 1H ), 5.45 (s, 2H), 4.43 - 4.40(m, 1H), 4.26 - 4.22 (m, 1H), 4.16 - 4.10 (m, 1H), 3.64 (t, J = 6.8 Hz, 2H), 3.52 - 3.51 (m, 2H), 3.49 - 3.44 (m, 2H), 3.25(s, 3H) , 3.22 (s, 3H), 2.78- 2.75 (m, 3H), 2.19 - 2.14 (m, 1H). LC -MS RT = 0.744 min., m/z = 508.2 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.744 min., ESI+ found [M+Na] = 508.2.

[02378] SFC Conditions: (Column: Chiralcel OD -3 100x4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate),Gradient: from 5% to 40% B in 4.5 min and held at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40oC Example 761

[02379] WX 203 Method 1 -benzyl -N -[(6S)-4 -methyl -2 -[2 -(2 -oxa -5 - azabicyclo [2,2,1]heptan -5 -yl)ethyl] -5 -oxo -7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -4 -methyl -2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1]heptan -5 -yl)ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 –carboxamide Step 1: tert-butyl (2 -(2 -(2 -oxa -5 - azabicyclo [2,2,1]heptan -5 -yl)ethyl) -4 -methyl -5 -oxo - 5,6,7, 8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate

[02380] A mixture of 2 -[6 -(tert-butoxycarbonylamino) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -2 - yl] ethyl methane sulfonate (230 mg, 0.57 mmol), 2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (232 mg, 1.71 mmol) and potassium carbonate (237 mg, 1 .71 mmol) in N,N-dimethylformamide (10 mL) was heated at 50°C for 6 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (25-55% acetonitrile/0.05% NH4OH in water) to provide tert-butyl (2-(2-(2-oxa-5-azabicyclo[2,2, 1] heptan -5 -yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) carbamate (100 mg, 43%) in the form of a colorless oil, which was used in the next step in the form in which it was. Step 2: 2 -(2 -(2 -oxa -5 - azabicyclo [2,2,1]heptan -5 -yl)ethyl) -6 -amino -4 -methyl - 7,8 -dihydro -4H - hydrochloride pyrazole [1,5 -a][1,3] diazepine -5(6H) - one

[02381] To a solution of tert-butyl (2 -(2 -(2 -oxa -5 -azabicyclo [2,2,1] heptan -5 -yl)ethyl) -4 -methyl - 5 -oxo -5, 6,7,8-tetrahydro-4H-pyrazole[1,5-a][1,3]diazepin-6-yl) carbamate (100 mg, 0.25 mmol) in ethyl acetate (5 mL) acid was added hydrochloric acid (4 M in ethyl acetate, 4.0 mL, 16.0 mmol). The reaction mixture was stirred at 20°C for 2 h and concentrated under reduced pressure to provide 2-(2-(2-oxa-5-azabicyclo[2,2,1]heptan-5-yl)ethyl) hydrochloride -6 - amino -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one crude (80 mg, 95%) in the form of a white solid, which was used in the next step without any further purification. Step 3: 1 -benzyl -N -[(6S) -4 -methyl -2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1]heptan -5 -yl)ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide and 1 -benzyl -N -[(6R ) -4 -methyl -2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1]heptan -5 -yl)ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide

[02382] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (30 mg, 0.15 mmol), 2-(2-(2-oxa-5-azabicyclo [2,2, 1] heptan -5 -yl)ethyl) -6 -amino -4 - methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin - 5(6H) -one hydrochloride (40 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) and 1-hydroxybenzotriazole (16 mg, 0.12 mmol) in N, N-dimethylformamide (5 mL) was stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (18-48% acetonitrile/0.05% NH4OH in water) to give 1-benzyl-N-[4-methyl-2-[ 2 -(2 -oxa -5 - azabicyclo [2,2,1] heptan -5 -yl) ethyl] -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (30 mg, 52%) as a white solid. The racemic material was separated using chiral SFC to provide:

[02383] 1 -benzyl -N -[(6S) -4 -methyl -2 -[2 - (2 -oxa -5 -azabicyclo [2,2,1] heptan -5 -yl)ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4 -triazole -3 -carboxamide (Peaks 1 and 2, retention time 5.386 min., 5.502 min.) (10.7 mg, 36%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.39 - 7.33 (m, 5H), 6.20(s, 1H), 5.47 (s, 2H), 4 .55 - 4.52 (m, 1H), 4.33 - 4.31 (m, 1H), 4.30 - 4.25(m, 1H), 4.24 - 4.15 (m, 1H) , 4.06 - 4.03 (m, 1H), 3.64 - 3.61 (m, 2H), 3.33 (s, 3H), 2.93 - 2.77 (m, 6H), 2 .62 - 2.59 (m, 1H), 2.26 - 2.20(m, 1H), 1.92 - 1.89 (m, 1H), 1.78 - 1.75 (m, 1H) . LCMS RT = 0.670min., m/z = 491.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.670 min., ESI+ found [M+H] = 491.2.

[02384] 1 -benzyl -N -[(6R) -4 -methyl -2 -[2 - (2 -oxa -5 -azabicyclo [2,2,1] heptan -5 -yl)ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4 -triazole -3 -carboxamide (peak 3, retention time 6.674 min. ) (9.8 mg, 33%) as a white solid. 1H NMR (400 MHz, CD3OD) 8.57 (s, 1H), 7.39 - 7.33 (m, 5H), 6.20(s, 1H), 5.47 (s, 2H), 4, 55 - 4.52 (m, 1H), 4.34 - 4.30 (m, 1H), 4.30 - 4.24 (m, 1H), 4.25- 4.15 (m, 1H), 4.06 - 4.03 (m, 1H), 3.64 - 3.61 (m, 2H), 3.33 (s, 3H), 2.93 - 2.77 (m, 6H), 2, 62 -2.59 (m, 1H),2.26 - 2.20(m, 1H), 1.92 -1.89 (m, 1H), 1.78- 1.74 (m, 1H). LCMS RT = 0.669 min., m/z = 491.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5min.) retention time 0.669 min., ESI+ found [M+H] = 491.2.

[02385] SFC Condition: Column: Chiralcel (OD -3 100x4.6 mm ID, 3 µm) Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature:40oC. Example 762 1 -[(2-fluorophenyl) methyl] -N -[(6S) -4 -methyl -2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1]heptan -5 -yl)ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -[(2 -fluorophenyl) methyl] -N -[(6R) -4 -methyl - 2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1]heptan -5 -yl)ethyl] -5 -oxo - 7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide

[02386] Amide coupling prepared in a manner similar to Method WX 203. Racemic material was separated using chiral SFC to provide:

[02387] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 4 -methyl -2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1] heptan -5 - yl )ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peaks 1 and 2, retention time 4.939, 5.026 min.) (15.5 mg, 39%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.41 - 7.36 (m, 2H), 7.21 - 7.14 (m, 2H), 6.20(s, 1H), 5.47 (s, 2H), 4.55 - 4.52 (m, 1H), 4.33 - 4.31 (m, 1H), 4.30 - 4.25(m, 1H) , 4.24 - 4.15 (m, 1H), 4.06 - 4.03 (m, 1H), 3.64 - 3.61 (m, 2H), 3.33 (s, 3H), 2 .93 - 2.77 (m, 6H), 2.62 - 2.59 (m, 1H), 2.26 - 2.20(m, 1H), 1.92 - 1.89 (m, 1H) , 1.78- 1.75 (m, 1H). LCMS RT = 0.680 min., m/z = 509.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.05% ammonium hydroxide for 1.5 min.) retention time 0.680 min., ESI+ found [M+H] = 509.2.

[02388] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 4 -methyl -2 -[2 -(2 -oxa -5 -azabicyclo [2,2,1] heptan -5 - yl ) ethyl] -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peaks 3 , retention time 5.812 min.) (13.9 mg, 35%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.41 - 7.36 (m, 2H), 7.21 - 7.14 (m, 2H), 6.20(s, 1H), 5.55 (s, 2H), 4.55 - 4.52 (m, 1H), 4.33 - 4.31 (m, 1H), 4.30 - 4.25(m, 1H) , 4.24 - 4.15 (m, 1H), 4.06 - 4.03 (m, 1H), 3.64 - 3.61 (m, 2H), 3.33 (s, 3H), 2 .93 - 2.77 (m, 6H), 2.62 - 2.59 (m, 1H), 2.26 - 2.20(m, 1H), 1.92 - 1.89 (m, 1H) , 1.78- 1.75 (m, 1H). LCMS RT = 0.685 min., m/z = 509.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.685 min., ESI+ found [M+H] = 509.2.

[02389] SFC Condition: Column: Chiralcel (OD -3 100x4.6 mm ID, 3 μm) Mobile phase: A:CO2 B:ethanol (0.05% DEA), Gradient: from 5% to 40% from B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 763 1 -[(2-fluorophenyl) methyl] -N -[(6S) -2 -(2 -ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[(6R) -2 -(2-ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide

[02390] Amide coupling prepared in a manner similar to Method WX 190. Racemic material was separated using chiral SFC to provide:

[02391] 1 -[(2-fluorophenyl) methyl] -N -[(6S) 2 -(2-ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.003 min.) (6.8 mg, 26%) as a solid white in color. 1H NMR (400MHz, CD3OD) δ 8.47 (s, 1H), 7.34 — 7.22 (m, 2H), 7.12 - 7.00 (m, 2H), 6.08 (s, 1H ), 5.45 (s, 2H), 4.45 - 4.40 (m, 1H), 4.27 — 4.19 (m, 1H), 4.16 — 4.07 (m, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.43 (q, J = 6.8 Hz, 2H), 3.23 (s, 3H), 2.78- 2.70(m , 3H), 2.19 - 2.11 (m, 1H), 1.08 (t, J =7.2 Hz, 3H). LC -MS RT = 0.760 min., m/z = 456.1 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.760 min., ESI+ found [M+H] = 456.1.

[02392] 1 -[(2-fluorophenyl) methyl] -N -[(6R) - 2 -(2-ethoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.673 min.) (9.5 mg, 36%) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.47 (s, 1H), 7.33 - 7.22 (m, 2H), 7.13 - 7.00 (m, 2H), 6.08 (s, 1H ), 5.45 (s, 2H), 4.44 - 4.40(m, 1H), 4.27 - 4.19 (m, 1H), 4.16 - 4.07 (m, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.43 (q, J = 6.8 Hz, 2H), 3.23 (s, 3H), 2.78- 2.70(m , 3H), 2.19 - 2.11 (m, 1H), 1.09 (t, J =7.2 Hz, 3H). LC -MS RT = 0.760 min., m/z = 456.1 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.760 min., ESI+ found [M+H] = 456.1.

[02393] SFC Condition: (Column: Chiralcel OD -3 100x4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate), Gradient: from 5% to 40% B in 4.5 min and held at 40% for 2.5 min, then 5% B for 1.0 min, Flow rate: 2.8 mL/min Column temperature: 40oC. Example 764

[02394] WX Method 209 (1S) -1 -ethyl -1 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -3H -furo[3, 4 - c] pyridine -6 -carboxamide

[02395] A mixture of 1-hydroxybenzotriazole hydrochloride (35 mg, 0.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (374 mg, 1.95 mmol), (3S)-3- amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (250 mg, 1.30 mmol) and acid (1S) -1 -ethyl -1 -methyl -3H - furo[3, 4-c]pyridine-6-carboxylic acid (270 mg, 1.30 mmol) in N,N-dimethylformamide (10 mL) was stirred at 15oC for 12 h and poured into ice water (50 mL). The resulting solid was collected by filtration and dried under reduced pressure to provide (1S)-1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydro -1,5 -benzoxazepin -3 -yl] -3H -furo [3,4 -c] pyridine -6 -carboxamide (406 mg, 82%) as a white solid. 1H NMR (400MHz, DMSO -d6) δ 8.88 (d, J = 7.6 Hz, 1H), 8.64 (s, 1H), 7.88 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.36 - 7.24 (m, 3H), 5.15 (s, 2H), 4.91 - 4.85 (m, 1H), 4.59 - 4 .46 (m, 2H), 3.35 - 3.34 (m, 3H), 1.87 - 1.73 (m, 2H), 1.40(s, 3H), 0.68 (t, J = 7.2 Hz, 3H). LCMS RT = 0.841 min.; m/z = 382.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.841 min., ESI+ found [M+H] = 382.1.

[02396] Chiral HPLC retention time: 3.978 min. (Column: Chiralpak AD -3 100x4.6 mm I.D., 3 μ m. Mobile phase: A: CO2 B:ethanol (0.05% DEA). Gradient: from 5% to 40% B in 4.5 min and held 40% for 2.5 min, then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 765

[02397] WX 208 Method (1R) -1 -ethyl -1 -methyl -N -[(3S) -5 -methyl -4 - oxo -2,3 -dihydro -1,5 -benzoxazepin -3 -yl] -3H -furo[3, 4 - c] pyridine -6 -carboxamide

[02398] A mixture of 1-hydroxybenzotriazole hydrochloride (35 mg, 0.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (374 mg, 1.95 mmol), (3S)-3- amino -5 -methyl -2,3 -dihydro -1,5 -benzoxazepin -4 -one (250 mg, 1.30 mmol) and acid (1R) -1 -ethyl -1 -methyl -3H - fur [3, 4-c]pyridine-6-carboxylic acid (270 mg, 1.30 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25oC for 12 h and poured into ice water (100 mL). The resulting solid was collected by filtration and dried under reduced pressure to provide (1R)-1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydro -1,5 -benzoxazepin -3 -yl] -3H -furo[3,4 -c] pyridine -6 -carboxamide (404 mg, 81%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.85 (s, 1H), 7.45 - 7.42 (m, 1H), 7.33 - 7.31 (m, 2H), 7.30 - 7.23 (m, 1H), 5.16 (s, 2H), 5.15 - 5.12 (m, 1H), 4.66 — 4.62 (m, 1H) , 4.42 — 4.37 (m, 1H), 3.42 (s, 3H), 1.87 - 1.82 (m, 2H), 1.45 (s, 3H), 0.76 (t , J = 7.6 Hz, 3H). LCMS RT = 0.850 min.; m/z = 382.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 1.5 min.) retention time 0.850 min., ESI+ found [M+H] = 382.1.

[02399] Chiral HPLC retention time: 3.478 min. (Column: Chiralcel OD -3 100x4.6 mm I.D., 3 μ m. Mobile phase: A:CO2 B:ethanol (0.05% DEA). Gradient: from 5% to 40% B in 4.5 min and held 40% for 2.5 min, then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 766

[02400] WX Method 207 1 -benzyl -N -[(6S) -2 -(2 -hydroxyethyl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazol -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -(2 -hydroxyethyl) -4 - methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide Step 1: 6 -amino -2 -(2-hydroxyethyl) -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one

[02401] To a solution of tert-butyl N -[2 -(2 - hydroxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin-6-yl] carbamate (200 mg, 0.62 mmol) in dichloromethane (10 mL) trifluoroacetic acid (703 mg, 6.17 mmol) was added. The reaction mixture was stirred at 20°C for 3 h and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), potassium carbonate (1.38 g, 10 mmol) was added and stirred for 30 min. The solid was removed by filtration and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 50% methanol in dichloromethane) to give 6-amino-2-(2-hydroxyethyl ) -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (120mg, 87%) in the form of a yellow-colored oil, which was used in the next stage in the form in which it was found. Step 2:1 -benzyl -N -[(6S) -2 -(2 -hydroxyethyl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -(2 -hydroxyethyl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02402] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (63 mg, 0.31 mmol), 6-amino-2-(2-hydroxyethyl)-4-methyl-7, 8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (70mg, 0.31 mmol), 1 -hydroxy benzotriazole (42 mg, 0.31 mmol) and 1 -hydrochloride -(3-dimethylaminopropyl)-3-ethylcarbodiimide (60 mg, 0.31 mmol) in N,N-dimethylformamide (6 mL) was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (10-40 acetonitrile/0.05% HCl in water) to give 1-benzyl-N-[2-(2-hydroxyethyl ) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide ( 30 mg, 24%) as a white solid. The racemic material was further separated using chiral SFC to provide:

[02403] 1 -benzyl -N -[(6S) -2 -(2 - hydroxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (Peak 1, retention time 4,640 min.) (11.5 mg, 38%) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.57 (s, 1H), 7.41 - 7.29 (m, 5H), 6.19 (s, 1H), 5.48 (s, 2H), 4, 58 - 4.53 (m, 1H), 4.39 - 4.31 (m, 1H), 4.28 - 4.17 (m, 1H), 3.82 (t, J = 6.8 Hz, 2H), 3.35 - 3.33 (m, 3H), 2.92 - 2.77 (m, 3H), 2.29 - 2.21 (m, 1H). LCMS RT = 0.992 min.; m/z = 410.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% formic acid for 2.0 min.) retention time 0.992 min., ESI+ found [M+H] =410.2.

[02404] 1 -benzyl -N -[(6R) -2 -(2 - hydroxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (Peak 2, retention time 5.416 min.) (10.2 mg, 33%) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.57 (s, 1H), 7.41 - 7.29 (m, 5H), 6.19 (s, 1H), 5.47 (s, 2H), 4, 58 - 4.53 (m, 1H), 4.39 - 4.31 (m, 1H), 4.28 - 4.17 (m, 1H), 3.82 (t, J = 6.8 Hz, 2H), 3.37 - 3.33 (m, 3H), 2.92 - 2.76 (m, 3H), 2.29 - 2.20(m, 1H). LCMS RT = 0.992 min.; m/z = 410.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% formic acid for 2.0 min.) retention time 0.992 min., ESI+ found [M+H] = 410.2.

[02405] SFC Condition: Column: Chiralcel OD - 3 100x4.6 mm I.D., 3 μm Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature:40oC. Example 767

[02406] WX Method 196 1 -benzyl -N -[(6S) -2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazol -3 -carboxamide and 1 -benzyl -N - [(6R) -2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide sStep 1: tert-butyl (2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin - 6-yl)carbamate.

[02407] A mixture of tert-butyl N -[2 -(2 - hydroxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -6 -yl] carbamate (250 mg, 0.77 mmol), iodomethane (2 mL, 32.13 mmol) and silver (II) oxide (893 mg, 3.85 mmol) was subjected to stirring at 20oC for 14 it is then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 40% ethyl acetate in petroleum ether) to provide tert-butyl N -[2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] carbamate (200 mg, 77%) in the form of a white solid. 1H NMR (400 MHz, CDCl3) δ 5.93 (s, 1H), 5.39 (d, J = 7.8 Hz, 1H), 4.36 - 4.23 (m, 2H), 4.07 - 3.98 (m, 1H), 3.65 - 3.61 (m, 2H), 3.37 (s, 3H), 3.30 (s, 3H), 2.94 - 2.87 (m , 1H), 2.84 (d, J = 8.0 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.39 (s, 9H). LC -MS RT = 0.653 min., m/z = 338.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.653 min., ESI+ found [M+H] = 338.9. Step 2: 6 -amino -2 -(2-methoxyethyl) -4 -methyl -7,8 - dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one.

[02408] To the solution of a stirred mixture of tert-butyl N -[2 -(2-methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 - yl] carbamate (200 mg, 0.59 mmol) in dichloromethane (5 mL) trifluoroacetic acid (3 mL, 5.91 mmol) was added. The resulting mixture was stirred for 12 h at 25°C and then finalized by adding saturated aqueous sodium bicarbonate (10 mL). The resulting mixture was extracted with dichloromathane (5 x 20mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-amino-2-(2-methoxyethyl)-4-methyl-7,8- dihydro -6H - pyrazole [1,5 -a][1,3] crude diazepin -5 -one (120 mg, 85%) as a yellow oil. LC -MS RT = 1.147 min., m/z = 239.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.147 min., ESI+ found [M+H] = 239.2. Step 3: 1 -benzyl -N -[(6S) -2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin - 6 -yl] -1,2,4 -triazole -3 -carboxamide

[02409] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (23 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol), 6 -amino -2 -(2 -methoxyethyl) -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (25 mg, 0.10 mmol) and 1-hydroxybenzotriazole (28 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20oC for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (20-45% acetonitrile/0.225% formic acid in water) to give 1-benzyl-N-[2-(2-methoxyethyl ) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide ( 40 mg, 90%) as a white solid. The racemic material was separated by chiral SFC to provide: 1 -benzyl -N -[(6S) -2 -(2 -methoxyethyl) -4 - methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.453 min.) (11 mg, 27%) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.55 (s, 1H), 7.38 - 7.31 (m, 5H), 6.18 (s, 1H), 5.47 (s, 2H), 4, 58 - 4.52 (m, 1H), 4.34 - 4.30 (m, 1H), 4.25- 4.22 (m, 1H), 3.66 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 2.87 - 2.83 (m, 3H), 2.27 - 2.21 (m, 1H). LC -MS RT = 1.429 min., m/z = 424.2 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.429 min., ESI+ found [M+H] = 424.2.

[02410] 1 -benzyl -N -[(6R) -2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 5.281 min.) (19.2 mg, 47%) as a white solid. 1H NMR (400 MHz, CD3OD) δ8.47 (s, 1H), 7.31 - 7.20(m, 5H), 6.09 (s, 1H), 5.38 (s, 2H), 4, 45 - 4.41 (m, 1H), 4.26 - 4.21 (m, 1H), 4.15 - 4.09 (m, 1H), 3.57 (t, J = 6.8 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2,782.71 (m, 3H), 2.18 - 2.13 (m, 1H). LC -MS RT = 1.361 min., m/z = 424.2. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.361 min., ESI+ found [M+H] = 424.2.

[02411] SFC Condition: (Column: Chiralcel AD -3 100x4.6 mm ID, 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate), Gradient: from 5% to 40% B in 4.5 min and held at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 768 1 -[(2-fluorophenyl) methyl] -N -[(6S) -2 -(2 - methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[(6R) -2 -(2 -methoxyethyl) - 4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide

[02412] Amide coupling prepared in a manner similar to Method WX 196. Racemic material was separated using chiral SFC to provide:

[02413] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.028 min.) (11 mg, 27%) as a solid White color. 1H NMR (400MHz, CD3OD) δ 8.56 (s, 1H), 7.42 - 7.33 (m, 2H), 7.22 - 7.09 (m, 2H), 6.17 (s, 1H ), 5.54 (s, 2H), 4.58 - 4.51 (m, 1H), 4.36 - 4.29 (m, 1H), 4.26 - 4.16 (m, 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 2.86 - 2.77 (m, 3H), 2.28 - 2.20(m, 1H). LC -MS RT = 1.446 min., m/z = 442.2 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.446 min., ESI+ found [M+H] = 442.2.

[02414] 1 -[(2-fluorophenyl) methyl] -N -[(6R) - 2 -(2 -methoxyethyl) -4 -methyl -5 -oxo -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 4.447 min.) (25.1 mg, 61%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.44 - 7.35 (m, 2H), 7.22 - 7.11 (m, 2H), 6.17 (s, 1H), 5.54 (s, 2H), 4.54 - 4.50 (m, 1H), 4.36 - 4.30 (m, 1H), 4.25- 4.17 (m, 1H) , 3.66 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 3.32 (s, 3H), 2.85 (t, J = 6.6 Hz, 2H) , 2.83 - 2.77 (m, 1H), 2.26 - 2.20(m, 1H). LC -MS RT = 1.379 min., m/z = 442.2 [M+H] +. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min.) retention time 1.379 min., ESI+ found [M+H] = 442.2.

[02415] SFC Conditions: (Column: Chiralcel AD -3 100x4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% ethyl acetate),Gradient: from 5% to 40% B in 4.5 min and held at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 769

[02416] WX 201 Method 1 -benzyl -N -[(6S) -2 -[2 -(3 -fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(3 -fluoroazetidin -1 -yl )ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 – carboxamide Step 1: tert-butyl (2 -(2 -(3 -fluoroazetidin -1 -yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 - a][1,3] diazepin -6 -yl) carbamate

[02417] A mixture of 2 -[6 -(tert-butoxycarbonylamino) -4 -methyl -5 -oxo -7,8 -dihydro - 6H - pyrazole [1,5 -a][1,3] diazepin -2 - il] ethyl methane sulfonate (200 mg, 0.50 mmol), potassium carbonate (155 mg, 1.12 mmol), 3-fluoroazetidine (50 mg, 0.67 mmol) and sodium iodide (56 mg, 0. 37 mmol) in N,N-dimethylformamide (10 mL) was heated at 50°C for 6 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, solvent gradient: 0 -10% methanol in dichloromethane) to provide tert-butyl N -[2 -[2 - (3-fluoroazetidin - 1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] carbamate (120 mg, 63%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 2: 6 -amino -2 -[2 -(3 -fluoroazetidin -1 -yl)ethyl] -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepine -5 -one hydrochloride

[02418] To a solution of tert-butyl N -[2 -[2 - (3-fluoroazetidin -1 -yl) ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1, 5 -a][1,3] diazepin -6 -yl] carbamate (120 mg, 0.31 mmol) in ethyl acetate (10 mL) was added hydrochloric acid (4.0 M in ethyl acetate, 1.0 mL, 4.0 mmol). The mixture was stirred at 25°C for 4 h and concentrated under reduced pressure to provide 6-amino-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-7,8-dihydrohydrochloride -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (80 mg, 80%) as a white solid, which was used in the next step without any further purification. Step 3: 1 -benzyl -N -[(6S) -2 -[2 -(3 -fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(3 -fluoroazetidin - 1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02419] To a solution of A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (26 mg, 0.13 mmol), 6-amino hydrochloride -2 -[2 -(3 - fluoroazetidin -1 -yl) ethyl] -4 -methyl -7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] diazepin -5 -one (40 mg, 0.13 mmol), 1 -hydroxy benzotriazole (26 mg, 0.19 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was subjected to stirring at 15oC for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (3-33 acetonitrile/0.05% HCl in water) to give 1-benzyl-N-[2-[2-( 3 - fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2 ,4-triazole-3-carboxamide (15 mg, 26%) as a white solid. The racemic material was further separated using chiral SFC to provide:

[02420] 1 -benzyl -N -[(6S) -2 -[2 -(3 - fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time 4.263 min.) (3.6 mg, 23%) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.57 (s, 1H), 7.41 - 7.30 (m, 5H), 6.18 (s, 1H), 5.48 (s, 2H), 5, 24 - 5.18 (m, 0.5H), 5.09 - 5.04 (m, 0.5H), 4.57 - 4.52 (m, 1H), 4.38 - 4.30 (m , 1H), 4.26 - 4.17 (m, 1H), 3.76 - 3.66 (m, 2H), 3.39 - 3.32 (m, 5H), 2.91 - 2.81 (m, 3H), 2.71 - 2.64 (m, 2H), 2.30 - 2.21 (m, 1H). LCMS RT = 1.472 min.; m/z = 467.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water over 3.0 min.) retention time 1.472 min., ESI+ found [M+H] =467.2.

[02421] 1 -benzyl -N -[(6R) -2 -[2 -(3 - fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time 5.366 min.) (1.8 mg, 11%) in the form of a white solid. H NMR (400MHz, CD3OD) δ 8.57 (s, 1H), 7.41 - 7.30 (m, 5H), 6.18 (s, 1H), 5.48 (s, 2H), 5, 24 - 5.18 (m, 0.5H), 5.09 - 5.04 (m, 0.5H), 4.57 - 4.52 (m, 1H), 4.38 - 4.30 (m , 1H), 4.26 - 4.17 (m, 1H), 3.76 - 3.66 (m, 2H), 3.39 - 3.32 (m, 5H), 2.91 - 2.81 (m, 3H), 2.71 - 2.64 (m, 2H), 2.30 - 2.21 (m, 1H). LCMS RT = 1.466 min.; m/z = 467.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water for 3.0 min.) retention time 1.466 min., ESI+ found [M+H] = 467.2.

[02422] SFC Condition: Column: Chiralpak AD -3 100x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: iso-propanol (0.05% DEA), Gradient: from 5% to 40% from B in 4.5 min. and maintained 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature: 40oC. Example 770 1 -[(2-fluorophenyl) methyl] -N -[(6S) -2 -[2 -(3-fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[(6R) -2 -[2 -(3 -fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide

[02423] Amide coupling prepared in a manner similar to Method WX 201. Racemic material was separated using chiral SFC to provide:

[02424] 1 -benzyl -N -[(6S) -2 -[2 -(3 - fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 1, retention time 4.021 min.) (4.7 mg, 29%) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.59 (s, 1H), 7.40- 7.37 (m, 2H), 7.22 - 7.13 (m, 2H), 6.20(s, 1H) ), 5.56 (s, 2H), 5.33 - 5.25(m, 0.5H), 5.22 - 5.18 (m, 0.5H), 4.58 - 4.49 (m , 1H), 4.36 - 4.33 (m, 1H), 4.25- 4.22 (m, 1H), 4.15 - 4.06 (m, 2H), 3.85 - 3.76 (m, 2H), 3.33 (s, 3H), 3.21 - 3.18 (m, 2H), 2.86 - 2.79 (m, 3H), 2.29 - 2.25(m , 1H). LCMS RT = 1.486 min.; m/z = 485.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water for 3.0 min.) retention time 1.486 min., ESI+ found [M+H] =485.2.

[02425] 1 -benzyl -N -[(6R) -2 -[2 -(3 - fluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1 ,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide (Peak 2, retention time 5.051 min.) (3.3 mg, 21%) in the form of a white solid. 1H NMR (400MHz, CD3OD) δ 8.58 (s, 1H), 7.42 - 7.36 (m, 2H), 7.23 - 7.15 (m, 2H), 6.18 (s, 1H ), 5.56 (s, 2H), 5.22 - 5.19 (m, 0.5H), 5.08 - 5.04 (m, 0.5H), 4.56 - 4.51 (m , 1H), 4.35 - 4.31 (m, 1H), 4.25- 4.17 (m, 1H), 3.72 - 3.66 (m, 2H), 3.35 - 3.29 (m, 5H), 2.89 - 2.84 (m, 3H), 2.70 - 2.66 (m, 2H), 2.26 - 2.21 (m, 1H). LCMS RT = 1.482 min.; m/z = 485.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonia water over 3.0 min.) retention time 1.486 min., ESI+ found [M+H] =485.2.

[02426] SFC Condition: Column: Chiralpak AD - 3 100x4.6 mm ID, 3 μm Mobile phase: A: CO2 B: iso-propanol (0.05% DEA), Gradient: from 5% to 40% from B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature:40oC. Example 771 1 -[(2-fluorophenyl) methyl] -N -[(6S) -2 -[2 -(3 -methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[(6R) -2 -[2 -(3 -methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide

[02427] Amide coupling prepared in a manner similar to Method WX 194. The residue was purified via RP-HPLC (5 -35% acetonitrile in water and 0.05% hydrochloric acid) to provide 1 -(2 - fluorobenzyl) -N -(2 -(2 -(3 -methoxyazetidin -1 -yl)ethyl) - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a ][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (40 mg, 33%) as a white solid. The racemic compound was further separated using chiral SFC to provide:

[02428] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 2 -[2 -(3 -methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo - 7.8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 1.653 min.) (5.5 mg, 5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.40- 7.36 (m, 2H), 7.22 - 7.13 (m, 2H), 6.16 (s, 1H), 5.55 (s, 2H), 4.56 - 4.51 (m, 1H), 4.36 - 4.31 (m, 1H), 4.25 - 4.17 (m, 1H) , 4.06 - 4.04 (m, 1H), 3.65 - 3.61 (m, 2H), 3.32 (s, 3H), 3.25(s, 3H), 3.03 - 3 .00 (m, 2H), 2.87 - 2.80 (m, 3H), 2.68 - 2.66 (m, 2H), 2.28 - 2.20(m, 1H). LC -MS RT = 0.567 min., m/z = 497.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.567 min., ESI+ found [M+H] = 497.1.

[02429] 1 -[(2-fluorophenyl) methyl] -N -[(6R) - 2 -[2 -(3 -methoxyazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo - 7.8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] - 1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 1.912 min.) (4.5 mg, 4%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.43 - 7.36 (m, 2H), 7.22 - 7.12 (m, 2H), 6.16 (s, 1H), 5.55 (s, 2H), 4.56 - 4.51 (m, 1H), 4.34 - 4.30 (m, 1H), 4.25- 4.20 (m, 1H) , 4.05 - 4.02 (m, 1H), 3.64 - 3.60 (m, 2H), 3.32 (s, 3H), 3.25(s, 3H), 3.00 (t , J = 7.0 Hz, 2H), 2.87 - 2.78(m, 3H), 2.68 - 2.64 (m, 2H), 2.28 - 2.21 (m, 1H). LC -MS RT = 0.574 min., m/z = 497.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.574 min., ESI+ found [M+H] = 497.2.

[02430] SFC condition: Chiralpak AD -3 column (50 mm 4.6 mm I.D), 3 μ m mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: held 5% for 0.2 min, then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 4 mL/min. Column temperature: 40oC. Example 772

[02431] WX 205 Method 1 -benzyl -N -[(6S) -2 -[2 -(3,3 -difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1, 5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(3,3 - difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 - triazole -3 -carboxamide Step 1: tert-butyl (2 -(2 -(3,3 - difluoroazetidin -1 -yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1, 5 -a][1,3] diazepin -6 - yl)carbamate

[02432] To a solution of 3,3-difluoroazetidine hydrochloride (241 mg, 1.86 mmol) in acetonitrile (5 mL) was added potassium carbonate (513 mg, 3.72 mmol). The mixture was stirred at 25°C for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was added to a mixture of sodium iodide (59 mg, 0.37 mmol), 2-[6-(tert-butoxycarbonylamino)-4-methyl-5-oxo-7,8-dihydro-6H- pyrazole [1,5 - a][1,3] diazepin -2 -yl]ethyl methane sulfonate (150 mg, 0.37 mmol) and N,N -diisopropyl ethylamine (241 mg, 1.86 mmol) in N, N -dimethylformamide (2 mL). The reaction mixture was heated at 60°C for 4 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, solvent gradient: 0 -10% methanol in dichloromethane) to provide tert-butyl (2 -(2 -(3,3 - difluoroazetidin - 1-yl)ethyl) -4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) carbamate (100 mg , 67%). LCMS RT = 0.547 min., m/z = 400.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.547 min., ESI+ found [M+H] = 400.0. Step 2: 6-Amino-2-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazole hydrochloride [1,5-a][1 ,3] diazepin -5(6H) -one

[02433] To a solution of tert-butyl (2 -(2 - (3,3 -difluoroazetidin -1 -yl)ethyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H - pyrazole[1,5-a][1,3]diazepin-6-yl)carbamate (100 mg, 0.25 mmol) in ethyl acetate (5 mL) was added hydrochloric acid (4 M in ethyl acetate, 5 .0 mL, 20.0 mmol). The mixture was stirred at 25°C for 3 h and concentrated under reduced pressure to provide 6-amino-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-7 hydrochloride, 8 -dihydro -6H - pyrazole [1,5 -a][1,3] crude diazepin -5 -one (84 mg, 99.9%) as a white solid, which was used in the next step without any further purification. Step 3: 1 -benzyl -N -[(6S) -2 -[2 -(3,3 -difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -2 -[2 -(3, 3 - difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2 ,4-triazole-3-carboxamide

[02434] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (12 mg, 0.06 mmol), 6-amino-2-[2-(3,3-difluoroazetidin-1- yl)ethyl] -4 -methyl -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one hydrochloride (20 mg, 0.06 mmol), 1 -hydroxybenzo triazole (12 mg, 0.09 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (11 mg, 0.06 mmol) in N,N-Dimethylformamide (5 mL) was stirred under 25oC for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by PR-HPLC (5-30% acetonitrile/0.05% HCl in water) to give 1-benzyl-N-[(6S)-2-[ 2 -(3,3 -difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 - oxo - 7,8 -dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 - yl ]-1,2,4-triazole-3-carboxamide (10 mg, 7.5%) as a white solid. The racemic material was separated by means of chiral SFC (AD(250 mm 30 mm, 10 µm), 0.1% NH4OH in EtOH, 50%, 80 mL/min.), and further purified by means of RP-HPLC (acetonitrile 27 -57% / 0.05% ammonium hydroxide in water) to provide:

[02435] 1-benzyl -N -[(6S) -2 -[2 -(3,3 - difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.921 min.) (3.1 mg, 11%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.42 - 7.35 (m, 5H), 6.21(s, 1H), 5.50 (s, 2H), 4 .59 - 4.52 (m, 1H), 4.36 - 4.32 (m, 1H), 4.26 - 4.22 (m, 1H), 3.67 (t, J = 12.0 Hz , 4H), 3.35(s, 3H), 2.97 - 2.82 (m, 3H), 2.75 - 2.65 (m, 2H), 2.29 - 2.23 (m, 1H) ). LCMS RT = 0.660 min., m/z = 485.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.66 min., ESI+ found [M+H] = 485.2.

[02436] 1-benzyl -N -[(6R) -2 -[2 -(3,3 - difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 6.833 min.) (3.0 mg, 10%) in the form of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.42 - 7.35 (m, 5H), 6.20(s, 1H), 5.50 (s, 2H), 4 .58 - 4.52 (m, 1H), 4.36 - 4.32 (m, 1H), 4.26 - 4.21 (m, 1H), 3.67 (t, J = 12.0 Hz , 4H), 3.35(s, 3H), 2.97 - 2.82 (m, 3H), 2.75 - 2.65 (m, 2H), 2.30 - 2.23 (m, 1H) ). LCMS RT = 0.660 min., m/z = 485.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) min., ESI+ found [M+H] = 485.2.

[02437] SFC Condition: Column: Chiralpak AD - 3 100×4.6 mm ID, 3 µm Mobile phase: A: CO2 B: ethanol (0.05% DEA), Gradient: from 5% to 40% from B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min., Flow rate: 2.8 mL/min. Column temperature:40oC. Example 773 1 -[(2-fluorophenyl) methyl] -N -[(6S) -2 -[2 -(3,3 - difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 - dihydro -6H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -[(2-fluorophenyl) methyl] -N -[( 6R) -2 -[2 - (3,3 -difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 -oxo -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3 ] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02438] Amide coupling prepared in a manner similar to Method WX 205. Racemic material was separated using chiral SFC to provide:

[02439] 1 -[(2-fluorophenyl) methyl] -N -[(6S) - 2 -[2 -(3,3-difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 - oxo -7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 4.665 min.) (2 .2 mg, 22%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.42 - 7.35 (m, 2H), 7.20- 7.12 (m, 2H), 6.19 (s, 1H), 5.50 (s, 2H), 4.57 - 4.52 (m, 1H), 4.36 - 4.32 (m, 1H), 4.24 - 4.20(m, 1H) , 3.65 (t, J = 12.0 Hz, 3H), 3.30 (s, 3H), 2.97 - 2.82 (m, 3H), 2.75 - 2.67 (m, 2H ), 2.29 - 2.23 (m, 1H). LCMS RT = 0.670min., m/z = 503.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.67 min., ESI+ found [M+H] = 503.2.

[02440] 1 -[(2-fluorophenyl) methyl] -N -[(6R) - 2 -[2 -(3,3-difluoroazetidin -1 -yl)ethyl] -4 -methyl -5 - oxo -7, 8 -dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -6 - yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 6.242 min.) (3 .0 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7.42 - 7.35 (m, 2H), 7.20- 7.12 (m, 2H), 6.19 (s, 1H), 5.57 (s, 2H), 4.57 - 4.52 (m, 1H), 4.36 - 4.32 (m, 1H), 4.24 - 4.20(m, 1H) , 3.64 (t, J = 12.0 Hz, 3H), 3.30 (s, 3H), 2.93 - 2.82 (m, 3H), 2.75 - 2.67 (m, 2H ), 2.29 - 2.23 (m, 1H). LCMS RT = 0.675 min., m/z = 503.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.67 min., ESI+ found [M+H] = 503.2,

[02441] SFC Conditions: Column: Chiralpak AD -3 100x4.6 mm I.D., 3 μm Mobile phase: A: CO2 B: ethanol (0.05% DEA). Gradient: from 5% to 40% B in 4.5 min. and held 40% for 2.5 min., then 5% B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40oC. Example 774

[02442] WX 210 Method 1 -benzyl -N -[(6S) -4 -methyl -5 -oxo -2 -(tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3 ] diazepin -6 -yl] -1,2,4 -triazol -3 -carboxamide and 1 -benzyl -N -[(6R) -4 -methyl -5 -oxo -2 -(tetrahydropyran -4 -ylmethyl) - 7,8 -dihydro -6H -pyrazole [1,5 - a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide Step 1: ethyl 2 -tetra hydropyran -4 -yl-acetate

[02443] To a solution of 2-tetrahydropyran-4-yl acetic acid (5.0 g, 34.68 mmol) and cesium carbonate (22.6 g, 69.36 mmol) in N,N-dimethylformamide Ethane iodine (60 mL) was added (10.8 g, 69.36 mmol) over 10 min. under 0oC. The resulting mixture was stirred at 15oC for 60 h and finalized by adding water (100 ml). The mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide crude ethyl 2-tetrahydropyran-4-ylacetate (5.8 g, 97%) as a yellow oil. 1H NMR (400MHz, CDCl3) δ 4.21 - 4.08 (m, 2H), 4.00 - 3.90 (m, 2H), 3.47 - 3.35 (m, 2H), 2.24 (d, J = 8.0 Hz, 1H), 2.09 - 1.96 (m, 1H), 1.70- 1.58 (m, 2H), 1.42 - 1.31 (m, 2H ), 1.26 (t, J = 8.0 Hz, 3H). Step 2: 3 -oxo -4 -tetra hydropyran -4 -yl - butane nitrile

[02444] To a solution of acetonitrile (2 mL, 37.69 mmol) in tetrahydrofuran (60 mL) was added n - butyl lithium (2.5 M in hexanes, 15.1 mL, 37.69 mmol) dropwise drop under -78oC. After addition, the mixture was stirred at -78°C for 30 min., then ethyl 2-tetrahydropyran-4-ylacetate (5.8 g, 33.68 mmol) was added dropwise. The mixture was warmed to room temperature and stirred at 25°C for another 2 h. The reaction mixture was terminated by adding saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide 3-oxo-4-tetrahydropyran-4-yl-butane nitrile (4.4 g, 76%) as an oil. brown color, which was used in the next step without any further purification. Step 3: 5 -(tetrahydropyran -4 -ylmethyl) -1H - pyrazole -3 -amine

[02445] A mixture of 3-oxo-4-tetrahydropyran-4-yl-butane nitrile (4.4 g, 26.31 mmol) and hydrazine hydrate (30 mL) in propan-2-ol (30 mL) it was heated at 60°C for 12 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 7% methanol in dichloromethane) to provide 5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine ( 3.2 g, 67%) in the form of a yellow oil, which was used in the next step in the form in which it was. LCMS RT = 1.084 min.; m/z = 182.2 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium hydroxide for 3 minutes) retention time 1.084 min., ESI+ found [M+H] = 182.2. Step 4: N -[5 -(tetrahydropyran -4 -ylmethyl) - 1H -pyrazol -3 -yl]formamide

[02446] A mixture of 5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine (3.2 g, 17.66 mmol) and formic acid (30 mL) was heated at 110oC for 12 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide N - [5 - (tetrahydropyran -4 -ylmethyl) -1H - pyrazole -3 -yl]formamide (3.4 g, 92%) in the form of a yellow solid, which was used in the next step in the form in which it was. LCMS RT = 1.241 min.; m/z = 210.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3.0 min.) retention time 1.241 min., ESI+found [M+H] = 210.2. Step 5: N -methyl -5 -(tetrahydropyran -4 -ylmethyl) -1H -pyrazol -3 -amine

[02447] To a stirred solution of N -[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]formamide (3.4 g, 16.25 mmol) in tetrahydrofuran (100 mL) Borane (1M in tetrahedron, 49.0 mL, 49.0 mmol) was added dropwise under 0°C. After addition, the mixture was stirred for 2 h at 0°C and then finalized by adding methanol (10 mL). The resulting mixture was stirred for another 30 min. under 15oC and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to obtain N -methyl -5 - (tetrahydropyran -4 -ylmethyl) -1H - pyrazole - 3-amine (1.9 g, 60%) in the form of a light yellow oil, which was used in the next step in the form in which it was. LCMS RT = 1.316 min.; m/z = 196.2 (M+H)+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3.0 min.) retention time 1.316 min., ESI+found [M+H] = 196.2. Step 6: 4-chloro-N-methyl-N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]butanamide

[02448] A mixture of 4-chlorobutanoyl chloride (10 mL) and N-methyl-5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine (1.5 g, 7.68 mmol) was heated at 60oC for 1 h and finished by slowly adding methanol (10 mL). The resulting mixture was stirred for 15 min. and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 4-chloro-N-[5-(1-fluorocyclopropyl)-1H-pyrazole- 3-yl]-N-methyl-butanamide (1.72 g, 75%) in the form of a yellow oil, which was used in the next step in the form in which it was. LCMS RT = 0.633 min.; m/z = 299.8 (M+H)+ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.633 min., ESI+found [M+H] = 299.8. Step 7: 4 -methyl -2 -(tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[02449] A mixture of cesium carbonate (3.7 g, 11.4 mmol) and 4-chloro-N-methyl-N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl ]butanamide (1.72 g, 5.73 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25°C for 15 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 4-methyl-2-(tetrahydropyran-4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a][1,3] diazepin -5 -one (1.1 g, 52%) in the form of a yellow oil, which it was used in the next stage as it was. LCMS RT = 0.583 min.; m/z = 263.8 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.583 min., ESI+found [M+H] = 263.8. Step 8: 6 -iodo -4 -methyl -2 -(tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[02450] A stirred solution of 4-methyl -2 -(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazole [1,5-a] [1,3] diazepin -5 - one (200 mg, 0.76 mmol) in dichloromethane (60 mL) was slowly added N1,N1,N2,N2 -tetramethylethane -1,2 -diamine (1.14 mL, 7.59 mmol) and iodotrimethylsilane (1. 08 mL, 7.59 mmol) under -15oC under nitrogen protection. The mixture was stirred at -15°C for 1.5 h, and then iodine (578 mg, 2.28 mmol) was added. The reaction mixture was stirred for another 2 h, and then finished by adding 50% aqueous sodium thiosulfate (10 mL). The resulting mixture was extracted with dichloromethane (2 x 80 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-iodo-4-methyl-2-(tetrahydropyran-4-ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a][1,3] crude diazepin -5 -one (150 mg, 53%) in the form of a yellow colored oil, which was used in next step without any further purification. LCMS RT = 1.839 min., m/z = 390.0 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.839 min., ESI+ found [M+H] = 390.0. Step 9: 6 -azide -4 -methyl -2 -(tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one

[02451] A mixture of 6 -iodo -4 -methyl -2 - (tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 - one (295 mg, 0.76 mmol) and sodium azide (120 mg, 1.85 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The reaction mixture was finished by adding 20% aqueous sodium hypochlorite (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-azide-4-methyl-2-(tetrahydropyran-4-ylmethyl)- 7,8 -dihydro -6H - pyrazole [1,5 -a][1,3] crude diazepin -5 -one (230 mg, 99%) in the form of a yellow colored oil, which was used in the next step without any further purification. Step 10: 6 -amino -4 -methyl -2 -(tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a ] [1,3] diazepin -5 -one

[02452] A mixture of 6-azide -4 -methyl -2 - (tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 - one (230 mg, 0.76 mmol) and palladium on carbon (10%, 10 mg) in methanol (10 mL) was hydrogenated [2.04 bar (15 psi)] under 20°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep TLC (10% methanol in dichloromethane, Rf = 0.4) to give 6-amino-4-methyl-2-(tetrahydropyran-4- ylmethyl) -7,8 - dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -5 -one (140 mg, 66%) in the form of a yellow colored oil, which was used in the step next in the form in which it was. Step 11: 1 -benzyl -N -[(6S) -4 -methyl -5 -oxo -2 -(tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 - a] [ 1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide and 1 -benzyl -N -[(6R) -4 -methyl -5 -oxo -2 -(tetrahydropyran -4 - ylmethyl) -7,8 -dihydro -6H -pyrazolo [1,5 - a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide

[02453] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (102 mg, 0.5 mmol), 6-amino-4-methyl-2-(tetrahydropyran-4-ylmethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [1,3] diazepin -5 -one (140 mg, 0.5 mmol), N,N -dimethyl -3 hydrochloride (methylimino methyleneethyl acetatemino ) propan-1-amine (144 mg, 0.75 mmol) and 1-hydroxybenzotrizole (101 mg, 0.75 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25oC for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25% to 50% acetonitrile, 0.225% formic acid in water) to give 1-benzyl-N-[4-methyl-5- oxo -2 - (tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl] -1,2,4 -triazole -3 - carboxamide (130 mg, 55%) in the form of a white solid. The racemic material was further purified using chiral SFC to provide:

[02454] 1-benzyl -N - [ (6S) -4 -methyl -5 -oxo - 2 - (tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [ 1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 1, retention time 1.543 min.) (19.7 mg, 15.2%) in the form of a solid White color. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.40- 7.33 (m, 5H), 6.16 (s, 1H), 5.48 (s, 2H), 4 .54 - 4.48 (m, 1H), 4.37 - 4.30 (m, 1H), 4.27 - 4.17 (m, 1H), 3.96 - 3.90 (m, 2H) , 3.44 - 3.36 (m, 2H), 3.33 (s, 3H), 2.90 - 2.80 (m, 1H), 2.57 - 2.53 (m, 2H), 2 .30 - 2.22 (m, 1H), 1.92 - 1.82 (m, 1H), 1.68 - 1.62 (m, 2H), 1.35 - 1.31 (m, 2H) . LCMS RT = 0.754 min., m/z = 464.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.754 min., ESI+found [M+H] = 464.2.

[02455] 1-benzyl -N - [ (6S) -4 -methyl -5 -oxo - 2 - (tetrahydropyran -4 -ylmethyl) -7,8 -dihydro -6H - pyrazole [1,5 -a] [ 1,3] diazepin -6 -yl] -1,2,4 -triazole -3 -carboxamide (Peak 2, retention time 1.875 min.) (26.0 mg, 20.0%) in the form of a solid White color. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.40- 7.33 (m, 5H), 6.16 (s, 1H), 5.48 (s, 2H), 4 .54 - 4.48 (m, 1H), 4.38 - 4.30 (m, 1H), 4.27 - 4.17 (m, 1H), 3.96 - 3.90 (m, 2H) , 3.44 - 3.36 (m, 2H), 3.33 (s, 3H), 2.90 - 2.81 (m, 1H), 2.57 - 2.53 (m, 2H), 2 .30 - 2.22 (m, 1H), 1.93 - 1.82 (m, 1H), 1.69 - 1.62 (m, 2H), 1.35 - 1.31 (m, 2H) . LCMS RT = 0.752 min., m/z = 464.2 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min.) retention time 0.752 min., ESI+found [M+H] = 464.2.

[02456] SFC Condition: Column: Chiralpak AD - 3 50*4.6 mm I.D., 3 μ m Mobile phase: A:CO2 B:methanol (0.05% DEA) Gradient: maintained 5% for 0.2 min ., then from 5% to 40% B in 1.4 min. and held 40% for 1.05 min., then 5% B for 0.35 min. Flow rate: 4 mL/min. column temperature: 40oC. Example 775

[02457] Suzuki Method 2 1-benzyl -N -(2 -(1,2 -dimethyl -1H -imidazol -5 -yl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02458] In a microwave flask, 1-benzyl -N -(2-bromo -4 -methyl -5 -oxo -7,8 -dihydro - 6H -pyrazole [1,5 -a] [1,3 ] diazepin -6 -yl) -1,2,4 -triazole -3 -carboxamide (66 mg, 0.15 mmol), potassium acetate (30 mg, 0.31 mmol), 4,4,5,5 - tetramethyl -2 -(4,4,5,5 - tetramethyl -1,3,2 -dioxaborolan -2 -yl) -1,3,2 - dioxaborolane (72 mg, 0.28 mmol) and [1,1' - bis(diphenylphosphine) ferrocene] dichloropalladium (II) (1:1) (9.5 mg, 0.0129 mmol)

[02459] The solids were dissolved in anhydrous acetonitrile (2 mL) and the vial was sealed and irradiated in a microwave at 140°C for 15 min. To the reaction mixture was added 5-bromo-1,2-dimethyl-imidazole (57 mg, 0.257 mmol), an additional [1,1'-bis(diphenylphosphine) ferrocene] dichloro palladium (II) (1:1) (9.5 mg, 0.0129 mmol) and diluted with 1 M potassium carbonate (2 mL). The vial was sealed and irradiated in a microwave at 110°C for 10 min. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 5 mL), saline and dried over sodium sulfate. The filtrate was concentrated to dryness in vacuo and the residue was purified by reverse phase HPLC to provide 1-benzyl-N-(2-(1,2-dimethyl-1H-imidazol-5-yl)-4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide (8 mg, 12% yield) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.34 (s, 2H), 7.45 - 7 .24 (m, 5H), 7.05 (s, 1H), 6.60 (s, 1H), 5.49 (s, 2H), 3.76 (s, 3H), 3.27 (s, 3H), 2.81 (dd, J = 63.8, 0.6 Hz, 1H), 2.71 - 2.56 (m, 1H), 2.32 (s, 3H). LC -MS RT = 2.76 min., m/z = 460.2 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.76 min., ESI+ found [M+H] = 460.2. Example 776 1-benzyl -N -(2 -(1,2 -dimethyl -1H -imidazol -4 -yl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02460] Suzuki Method 2 (7 mg, 10%) in the form of a white solid. H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 8.32 (s, 2H), 7.46 - 7 .23 (m, 5H), 6.46 (s, 1H), 5.48 (s, 2H), 3.56 (s, 3H), 3.26 (s, 3H), 2.73 - 2, 57 (m, 1H), 2.29 (s, 3H). LC -MS RT = 2.27 min., m/z = 460.2 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.72 min., ESI+ found [M+H] = 460.2. Example 777 1 -benzyl -N -(4 -methyl -2 -(1 -methyl -1H -pyrazol -3 -yl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a ][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02461] Suzuki Method 2, (9 mg, 20%) in the form of a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.70(dd, J = 2.2, 0, 4 Hz, 1H), 7.45 – 7.20(m, 5H), 6.58 (s, 1H), 6.50 (d, J = 2.2 Hz, 1H), 5.48 (s, 2H), 4.37 (s, 1H), 4.11 – 3.98 (m, 1H), 3.86 (s, 3H), 3.17 (d, J = 5.2 Hz, 4H). LC -MS RT = 3.67 min., m/z = 446.2 [M+H] +. LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 3.67 min., ESI+ found [M+H] = 446.2. Example 778 1-benzyl -N -(4-methyl -2 -(1-methyl -1H - pyrazol -4 -yl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a ][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide

[02462] Suzuki Method 1 (13 mg, 29%). 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 0.9 Hz, 1H ), 7.70(d, J = 0.8 Hz, 1H), 7.47 - 7.19 (m, 4H), 6.50 (s, 1H), 5.48 (s, 2H), 4 .45 - 4.08 (m, 2H), 3.86 (s, 3H), 3.26 (s, 4H), 2.44 - 2.24 (m, 1H). LC -MS RT = 3.63 min., m/z = 446.2 [M+H] +. Example 779 (S) -1 -benzyl -N -(4 -methyl -2 -(morpholinomethyl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02463] 1 -benzyl -N -(4 -methyl -2 - (morpholinomethyl) -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepine -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (Example 443) was further purified by means of chiral SFC (Chiralpak AD; 150 x21.2 mm, 5 μ m; 30% methanol isocratic elution with Carbon dioxide) to give (S)-1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazole [1.5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (13.4 mg, 28.4%) in the form of a white solid:

[02464] Analytical data for (S) -1 -benzyl -N -(4 -methyl -2 -(morpholinomethyl) -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazole [1,5 -a ][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide: SFC RT (AD, 25% methanol + 0.1% isocratic elution of ammonium hydroxide with carbon dioxide , 2.5 min. method): 0.838 min., 100% purity, 100% ee: H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.51 (d, J = 7.7 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.36 - 4.24 (m, 2H ), 4.14 (m, 1H), 3.57 (m, 4H), 3.48 - 3.21 (m, 5H), 2.59 (m, 1H), 2.43 - 2.29 ( m, 5H). LCMS RT = 2.55 min., m/z = 465.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.55 min., ESI+ found [M+H] = 465.2. Example 780 1-benzyl -N -(2 -(((2-methoxyethyl)amino) methyl)-4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][ 1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02465] 1-benzyl -N -(2 -(((2-methoxyethyl)amino) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide was prepared from 1 -benzyl -N -(2 - formyl -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide and 2 -methoxyethane -1 -amine according to Method GZ7. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% DCM in MeOH) to provide 1-benzyl -N -(2 -(((2-methoxyethyl)amino) methyl) - 4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole - 3-carboxamide (49 mg, 85% Yield) as a bronze-colored solid: 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.51 (d, J = 7 .8Hz, 1H), 7.43 - 7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.21 - 4.07 (m, 1H), 3.66 (d, J = 2.1 Hz, 2H), 3.46 - 3.31 (m, 2H), 3.23 (s, 6H), 2, 72 (t, J = 5.7 Hz, 2H), 2.58 (m, 1H), 2.41 - 2.28 (m, 1H). LC -MS RT = 2.62 min., m/z = 453.2 (M+H) +. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.62 min., ESI+ found [M+H] = 453.2. Example 781 (S) -1 -benzyl -N -(2 -((3 -methoxyazetidin -1 - yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1, 5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02466] 1-benzyl -N -(2 -((3-methoxyazetidin -1 - yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide was further purified using chiral SFC (Cellulose -1; 150 x 21.2 mm, 5 μ m; isocratic elution of 25% methanol with Carbon dioxide) to provide (S)-1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 - a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 - carboxamide (12,7 mg, 34.7%) as a white solid:

[02467] Analytical data for (S) -1 -benzyl -N -(2 -((3 -methoxyazetidin -1 -yl) methyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide: SFC RT (Cellulose -1, 25% methanol + isocratic elution of 0.1% ammonium hydroxide with Carbon dioxide, method 2.5 min.): 0.883 min., 100% purity, 100% ee: 1H 1H NMR (400 MHz, DMSO - d6) δ 8.81 ( s, 1H), 8.51 (d, J = 7.7 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.21 (s, 1H), 5.48 (s, 2H) ), 4.35 - 4.23 (m, 2H), 4.13 (m, 1H), 3.94 (p, J = 5.8 Hz, 1H), 3.57 - 3.32 (m, 4H), 3.18 (ds, 6H), 2.86 (m, 2H), 2.58 (m, 1H), 2.41 - 2.28 (m, 1H). LCMS RT = 2.62 min., m/z = 465.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.62 min., ESI+ found [M+H] = 465.2. Example 782 (S) -1 -benzyl -N -(2 -((3 -fluoroazetidin -1 - yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1, 5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02468] 1-benzyl -N -(2 -((3-fluoroazetidin - 1 -yl) methyl) -4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide was prepared from 1 -benzyl -N -(2 -formyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H - pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide was further purified by means of chiral SFC (Cellulose -1; 150 x21.2 mm, 5 µm; isocratic elution of 35% methanol with Carbon dioxide) to provide (S) -1 -benzyl -N -(2 -((3 -fluoroazetidin -1 -yl) methyl) - 4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 - a][1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 - carboxamide (16.6 mg, 32.8%) as a white solid:

[02469] Analytical data for (S) -1 -benzyl -N -(2 -((3 -fluoroazetidin -1 -yl) methyl) -4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro - 4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide: SFC RT (Cellulose -1, 25% methanol + isocratic elution of 0.1% ammonium hydroxide with Carbon dioxide, method 2.5 min.): 0.879 min., 100% purity, 100% ee: . 1H NMR (400 MHz, DMSO -d6) δ 8.81 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 5H), 6 .23 (s, 1H), 5.48 (s, 2H), 5.26 - 5.01 (m, 1H), 4.35 - 4.23 (m, 2H), 4.14 (m, 1H ), 3.63 - 3.50 (m, 4H), 3.27 - 3.06 (m, 5H), 2.58 (m, 1H), 2.41 - 2.28 (m, 1H). LCMS RT = 2.59 min., m/z = 453.2 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min.) retention time 2.59 min., ESI+ found [M+H] = 453.2.

[02470] Examples 783 - 793 are comprised of chiral separations of the previous examples as previously provided in this context.

[02471] Example 794: RIP1 kinase inhibition assays (biochemical assay). The compounds of the present invention were tested for their ability to inhibit RIP1K activity as described below.

[02472] Enzyme assay: The ability of receptor-interacting protein kinase (RIPK1) to catalyze the hydrolysis of adenosine -5-triphosphate (ATP) is monitored using Transcreener's ADP (adenosine -5d-diphosphate) assay ( BellBrook Labs). The purified human RIP1 kinase domain (2 -375) (50 nM) derived from a baculovirus-infected insect cell expression system is incubated with test compounds for 2 hours in 50 m m Hepes buffer (pH 7.5) containing 30 g of 30 mm MgCl2, 1 mm dithiothreitol, 50 uM ATP, 0.002% Brij-35 and 0.5% dimethyl sulfoxide (DMSO). Reactions are quenched by the addition of 1X Bell Brooks Stop buffer B (20 mm Hepes (pH 7.5), 40 mm ethylene diamine tetraacetic acid and 0.02% Brij-35) containing 12 mm EDTA and 55 ug/mL ADP2 antibody and the 4 nM ADP-AlexaFluor™ 633 label. The antibody-bound label is displaced by the ADP generated during the RIP1K reaction, which causes a decrease in fluorescence polarization that is measured by laser excitation under 3 nm with an FP M1000 microplate reader. The fractional activity was plotted against the concentration of the test article. Using the Genedata Screener software (Genedata, Basel, Switzerland), the data were adjusted to the apparent inhibition constant (Kiapp) of the Morrison equation [Williams, JW and Morrison, JF (1979) The kinetics of reversible tight binding inhibition . Methods Enzymol 63: 437 -67]. The equation set out below was used to calculate the fractional activity and Kiapp: where [E]T and [I]T are the total concentrations of the active enzyme and test article, respectively.

[02473] In the Tables set out below, exemplary compounds of the present invention are set out together with their physicochemical characteristics and data on RIP1 kinase inhibitory activity in vitro. The “Method” in the first column of each table refers to the synthetic method(s) used to prepare each of the compounds as previously set out in the Examples. In certain examples, columns of chiral retention times (min.) for certain stereoisomers are provided.

[02474] TABLE 1

[02475] TABLE 2

[02476] The compounds of the following Tables 3, 4 and 5 were prepared according to the methods previously described in this context. References to specific methods in the report are provided as non-limiting examples of how these compounds were prepared.

[02477] TABLE 3

[02478] TABLE 4

[02479] TABLE 5 The following methods exemplify processes that have been scaled for the synthesis of the compounds provided in this context.

[02480] Example A: (S) -1 -benzyl -N -(2 -cyclopropyl -4 -methyl -5 - oxo -5,6,7,8 -tetrahydro -4H –pyrazole [1,5 -a][1,3] diazepin - 6 -yl) -1H -1,2,4 -triazole -3 -carboxamide Step 1: N -(3-cyclopropyl-1H-pyrazol-5-yl)formamide

[02481] 1H -1,2,4 -triazole -3 -carboxamide NH” N -(3 -cyclopropyl -1H -pyrazol -5 -yl) A mixture of 5 -cyclopropyl -1H - pyrazol -3 -amine (10, 0 g, 81.2 mmol) and formic acid (31 mL) was heated under 110°C for 12 h and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide N -(3-cyclopropyl-1H-pyrazol-5-yl)formamide (8.0 g, 65%) in the form of a yellow solid, which was used in the next step in the form in which it was. Step 2: 3-cyclopropyl-N-methyl-1H-pyrazol-5-amine

[02482] To a stirred solution of N -(3-cyclopropyl-1H-pyrazol-5-yl)formamide (8.0 g, 52.9 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride (4.0 g, 105.8 mmol) in small parts under 0oC. After addition, the mixture was stirred for 15 h at 25°C and subsequently quenched slowly by adding water (4 mL), aqueous sodium hydroxide (10%, 4 mL) and water (12 mL). To the mixture was added anhydrous sodium sulfate (50 g) and stirred for 30 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to provide 3-cyclopropyl-N-methyl-1H-pyrazole- Crude 5-amine (6.0 g, 83%) as a colorless oil, which was used in the next step without further purification. Step 3: 4 -chloro -N -(3 -cyclopropyl -1H -

[02483] A mixture of 3-cyclopropyl-N-methyl-1H-pyrazol-5-amine (6.0 g, 43.7 mmol) 4-chlorobutanoyl chloride (49 mL) was heated at 60oC for 5 h and cooled to at room temperature. The reaction was terminated by slow addition of methanol (100 mL). The resulting mixture was stirred for 30 min. and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 4-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)- N-methylbutanamide (6.5 g, 62%) in the form of a white solid, which was used in the next step as is. Step 4: 2 -cyclopropyl -4 -methyl -7,8 -dihydro - 4H -pyrazolo[1,5 -a][1,3]diazepin -5(6H) -one

[02484] A mixture of 4-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylbutanamide (6.0 g, 24.9 mmol) and cesium carbonate (16.2 g, 49.8 mmol) in N,N-dimethylformamide (100 mL) was stirred at 25°C for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 2-cyclopropyl-4-methyl-7,8- dihydro -4H -pyrazole [1,5 - a][1,3] diazepin -5(6H) -one (3.7 g, 72%) as a yellow oil, which was used in the next step the way it was. LCMS RT = 1.61 min., m/z = 206.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.61 min., ESI+ found [M+H] = 206.1. Step 5: 2 -cyclopropyl -6 -iodo -4 -methyl -7,8 -dihydro - 4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[02485] To a stirred solution of 2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo [1,5-a][1,3] diazepin -5(6H)-one (3, 7 g, 18.0 mmol) in dichloromethane (200 mL) was added N1,N1,N2,N2 - tetramethylethane -1,2 -diamine (16.8 g, 144.2 mmol) and trimethylsilane iodine (28.9 g , 144.2 mmol) under -15oC. The mixture was stirred at -15°C for 1.5 h and subsequently iodine (13.7 g, 54.0 mmol) was added. The mixture was stirred for another 3 h and finalized by addition of 50% aqueous sodium thiosulfate (50 ml). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 2-cyclopropyl-6-iodo-4-methyl-7,8-dihydro-4H- pyrazolo[1,5 -a][1,3]diazepin -5(6H) -one (4.5 g, 75%) in the form of a colorless oil, which was used in the next step as it was . Step 6: 6 -azide -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[02486] A mixture of 2-cyclopropyl -6 -iodo -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one (4, 5 g, 13.6 mmol) and sodium azide (1.3 g, 20.4 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25°C for 2 h. To the reaction mixture, ice-cold water (5 mL) was added and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-azide-2-cyclopropyl-4-methyl-7,8-dihydro-4H -pyrazolo [1,5 -a][1,3] diazepin - crude 5(6H)-one (3.0 g, 90%) as a yellow solid, which was used in the next step of the form in which it was found. LCMS RT = 1.84 min., m/z = 247.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.84 min., ESI+ found [M+H] = 247.1. Step 7: (S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1,3] diazepin -5(6H) -one

[02487] 6 -Azide -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one (3.0 g, 12.2 mmol) and palladium on carbon (10%, 1.3 g, 1.22 mmol) in methyl alcohol (100 mL) were hydrogenated [2.04 bar (15 psi)] under 25oC for 12 h and subsequently filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica (solvent gradient: 0-10% methanol in dichloromethane) to give 6-amino-2-cyclopropyl-4-methyl-7, 8 -dihydro -4H -pyrazole [1,5 - a][1,3] crude diazepin -5(6H) -one, which was further separated by means of chiral SFC (SFC80; Chiralpak OD (250 mm, 30 mm .5 μm); Supercritical CO2 / MeOH+NH3^H2O = 20/20; 50 mL / min. ) to provide:

[02488] Peak 1 (Rt = 3.113 min.): (S) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 - a][1,3] diazepin -5(6H) -one (600 mg, 22%) in the form of a colorless oil. LCMS RT = 1.65 min., m/z = 221.2 [M + H]+.

[02489] Peak 2 (Rt = 3.525 min.) (R) -6 -amino -2 -cyclopropyl -4 -methyl -7,8 -dihydro -4H -pyrazole [1,5 - a][1,3] diazepine -5(6H)-one (700 mg, 26%) as a colorless oil. LCMS RT = 1.65 min., m/z = 221.2 [M + H]+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.65 min., ESI+ found [M+H] = 221.2, Step 8: (S) -1 -benzyl -N -(2 -cyclopropyl -4 - methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo[1,5 - a][1,3 ]diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02490] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (185 mg, 0.91 mmol), (S)-6-amino-2-cyclopropyl-4-methyl-7, 8 -dihydro -4H -pyrazole [1,5 - a][1,3] diazepin -5(6H) -one (200 mg, 0.91 mmol), 1 -(3-dimethylamino propyl) -3 - hydrochloride ethylcarbodiimide (261 mg, 1.36 mmol) and 1 - hydroxybenzotrizole (184 mg, 1.36 mmol) in N,N - dimethylformamide (20 mL) were subjected to stirring at 25oC for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (30% to 60% acetonitrile, 0.05% HCl) to provide (S)-1-benzyl-N-(2-cyclopropyl- 4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole - 3-carboxamide (123 mg, 33%) as a white solid.

[02491] 1H NMR (400MHz, DMSO -d6) δ 8.83 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.40 - 7.28 (m, 5H) , 6.06 (s, 1H), 5.48 (s, 2H), 4.34 - 4.24 (m, 2H), 4.10 - 4.03 (m, 1H), 3.19 (s , 3H), 2.61 - 2.54 (m, 1H), 2.37 -2.29 (m, 1H), 1.87 -1.81 (m, 1H), 0.88 - 0.81 (m, 2H ), 0.70 - 0.61 (m, 2H) LCMS RT = 0.978 min., m/z = 406.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 0.978 min., ESI+ found [M+H] = 406.2.

[02492] SFC Conditions: Column: Chiralcel AD -3 100 x 4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% DEA), Gradient: from 5% to 40 % B in 4.5 min. and maintained 40% for 2.5 min., then 5% B for 1 min.. Flow rate: 2.8 mL/min.. Column temperature: 40oC.

[02493] Example B: (S) -1 -benzyl -N -(4 -methyl -5 -oxo -5,6,7,8 - tetrahydro -4H -pyrazolo[1,5 -a][1,3]diazepin -6 -yl) -1H - 1,2,4 -triazole -3 –carboxamide Step 1: (S) -6 -amino -4 -methyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[02495] A mixture of 6-amino -4 -methyl -7,8 - dihydro -6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (5.2 g, 29.0 mmol ), 2-hydroxy-5-nitrobenzaldehyde (146 mg, 0.87 mmol) and (2R,3R)-2,3-dihydroxybutanedioic acid (4.36 g, 29.0 mmol) in ethanol (162 mL) was heated at 60oC for 48 hours and cooled to room temperature. The solid was collected by filtration, washed with ethanol and dried under reduced pressure to provide (S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazole acid [1,5-a ][1,3] crude diazepin -5 -one (2R,3R) -2,3 - dihydroxybutanedioic acid in the form of a light yellow solid.

[02496] This crude product was recrystallized three times from ethanol / H2O (9:1, 50 mL/g) to provide fine needle crystals (7.0 g, 73%). The crystals (900 mg, 2.7 mmol) were added to a solution of concentrated aqueous ammonia (31 mL) and dichloromethane (75 mL), and subjected to stirring at 25oC for 30 min. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 25 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide (6S)-6-amino-4-methyl-7,8-dihydro-6H -pyrazole [1,5 -a] [1,3] crude diazepin -5 -one (400 mg, 82%) in the form of a colorless oil, which was used in the next step as is. Step 2: (S) -1 -benzyl -N -(4 -methyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02497] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (23 mg, 0.11 mmol), (S)-6-amino-4-methyl-7,8-dihydro- 6H -pyrazole [1,5 -a][1,3] diazepin -5 -one (20 mg, 0.11 mmol), 1 -hydroxy benzotriazole (15 mg, 0.11 mmol) and 1 -(3) hydrochloride -dimethylaminopropyl)-3-ethylcarbodiimide (32 mg, 0.17 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (12-42% acetonitrile/0.05% ammonium hydroxide in water) to give (S)-1-benzyl-N-(4 -methyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a] [1,3] diazepin -6 -yl) - 1H -1,2,4 -triazole -3 -carboxamide (23 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO -d6) δ 8.82 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H ), 7.40 - 7.27 (m, 5H), 6.34 (d, J = 1.6 Hz, 1H), 5.48 (s, 2H), 4.40 - 4.27 (m, 2H) , 4.23 - 4.14 (m, 1H), 3.24 (s, 3H), 2.64 - 2.55 (m, 1H), 2.43 - 2.31 (m, 1H). LC -MS RT = 0.702 min., m/z = 366.0 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 3.0 min.) retention time 0.702 min., ESI+ found [M+H] = 366.0.

[02498] SFC Conditions: Column: Chiralcel AD -3 150 x 4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% DEA), Gradient: from 5% to 40 % B in 5.0 min. and held 40% for 2.5 min., then 5% B for 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35oC.

[02499] Example C: (S) -1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazole [1,5 -a][1,3] diazepin -6 - il) - 1H -1,2,4 -triazole -3 -carboxamide Step 1: N -(3-methyl -1H -pyrazol -5 -yl)formamide

[02500] A mixture of 5-methyl-1H-pyrazole-3-amine (20.0 g, 206 mmol) and formic acid (100 mL) was heated at 110oC for 3 h in a sealed vessel and then concentrated under reduced pressure . The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide N -(3-methyl -1H -pyrazol-5 -yl)formamide (22.5 g, 87%) in the form of a yellow solid, which was used in the next step as it was. Step 2: N,3 -dimethyl -1H -pyrazole -5 –amine

[02501] To a stirred solution of N -(3-methyl-1H-pyrazol-5-yl)formamide (10.0 g, 80 mmol) in tetrahydrofuran (400 mL) was added lithium aluminum hydride (6, 0 g, 160 mmol) in small parts under 0oC. After addition, the mixture was stirred for 15 h at 25°C and subsequently quenched slowly by adding water (6 mL), aqueous sodium hydroxide (10%, 6 mL) and water (18 mL). To the mixture was added anhydrous sodium sulfate (60 g) and stirred for 30 min. The reaction mixture was filtered and the filtrate was concentrated to provide N,3-dimethyl-1H-pyrazol-5-amine in crude (8.0 g, 90%) in the form of a colorless oil, which was used in the next step without any further purification. Step 3: 4-chloro-N-methyl-N-(3-methyl-1H-pyrazol-5-yl)butanamide

[02502] A mixture of N,3-dimethyl-1H-pyrazol-5-amine (10.0 g, 90 mmol) and 4-chlorobutanoyl chloride (20 mL) was heated at 60oC for 5 h. After cooling to room temperature, the reaction mixture was quenched by addition of methanol (5 mL) and stirred for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by chromatography. column (silica gel, 100 - 200 mesh, 0 to 5% methanol in dichloromethane) to provide 4-chloro-N-methyl-N-(3-methyl-1H-pyrazol-5-yl)butanamide (6.0 g , 31%) in the form of a yellow oil, which was used in the next stage as it was. Step 4: 2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

[02503] A mixture of 4-chloro-N-methyl-N-(3-methyl-1H-pyrazol-5-yl) butanamide (6.0 g, 27.8 mmol) and cesium carbonate (18.1 g , 55.6 mmol) in N,N-dimethylformamide (100 mL) was stirred at 25°C for 15 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to give 2,4-dimethyl-7,8-dihydro- 4H -pyrazolo[1,5 -a][1,3] diazepin - 5(6H) -one (4.0 g, 80%) in the form of a yellow oil, which was used in the next step in the form where he was. Step 5: 6 -iodo -2,4 -dimethyl -7,8 -dihydro -4H - pyrazolo[1,5 -a][1,3]diazepin -5(6H) -one

[02504] To a stirred solution of 2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepin -5(6H)-one (2.7 g , 15.1 mmol) in dichloromethane (200 mL) was added N1,N1,N2,N2 -tetramethyl ethane -1,2 - diamine (14.0 g, 120.0 mmol) and trimethylsilane iodine (24.0 g, 120.0 mmol) under -15oC. The mixture was stirred at -15°C for 1.5 h and subsequently iodine (11.5 g, 41.2 mmol) was added. The reaction mixture was stirred for another 3 h and subsequently quenched by addition of 5% aqueous sodium thiosulfate (20 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 10% methanol in dichloromethane) to provide 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazole [ 1,5 -a][1,3] diazepin -5(6H) -one (3.0 g, 65%) in the form of a colorless oil, which was used in the next step as it was. Step 6: 6 -azide -2,4 -dimethyl -7,8 -dihydro -4H -pyrazolo [1,5 -a] [1,3] diazepin -5(6H) -one

[02505] A mixture of 6 -iodo -2,4 -dimethyl - 7,8 -dihydro -4H -pyrazolo[1m /,,1-*,-a][1,3] diazepin - 5(6H) -one (3.0 g, 9.8 mmol) and sodium azide (959 mg, 14.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 25°C for 2 h. To a reaction mixture was added ice water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to provide 6-azide-2,4-dimethyl-7,8-dihydro-4H-pyrazole Crude [1,5 -a][1,3]diazepin -5(6H) -one (2.0 g, 92%) as a yellow oil. LCMS RT = 1.85 min., m/z = 221.2 [M + H]+. LCMS (0 to 30% acetonitrile in water + 0.05% ammonium hydroxide for 3 min.) retention time 1.85 min., ESI+ found [M+H] = 221.2. Step 7: (S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -4H -pyrazolo [1,5 -a][1,3] diazepin -5(6H) -one

[02506] A mixture of 6-azide -2,4-dimethyl - 7,8 -dihydro -4H -pyrazole [1,5-a][1,3] diazepin -5(6H) -one (2.0 g , 9.1 mmol) and palladium on carbon (10%, 966 mg) in methyl alcohol (100 mL) was hydrogenated [(15 psi)] under 25oC for 12 h and filtered, concentrated and the residue was purified by means of chromatography. silica column (solvent gradient: 0 -10% methanol in dichloromethane) to provide the crude 6-amino - 2,4 -dimethyl -7,8 -dihydro -4H -pyrazole [1,5 -a] [1 .3] diazepin -5(6H) -one (1.5 g). The crude material was purified using SFC (SFC80; Quiralpak OD (250 mm*30 mm, 5 μ m); CO2Supercritical / MeOH+NH3^H2O= 20/20; 50 mL/min.) to provide:

[02507] Peak 1 (Rt = 2.516 min.): (S) -6 -amino -2,4 -dimethyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin - 5(6H)-one (400 mg, 27%) in the form of a yellow solid, which was used in the next step as is.

[02508] Peak 2 (Rt = 2.757 min.) (R) -6 -amino -2,4 -dimethyl -7,8 -dihydro -4H -pyrazole [1,5 -a][1,3] diazepin -5 (6H)-one (350 mg, 23%) as a yellow solid. Step 8: (S) -1 -benzyl -N -(2,4 -dimethyl -5 -oxo -5,6,7,8 -tetrahydro -4H -pyrazolo[1,5 -a][1,3]diazepine -6 -yl) -1H -1,2,4 -triazole -3 -carboxamide

[02509] A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (251 mg, 1.24 mmol), (S)-6-amino-2,4-dimethyl-7,8-dihydro- 4H -pyrazole [1,5 -a][1,3] diazepin -5(6H) -one (200 mg, 1.03 mmol), 1 - (3 -dimethylaminopropyl) -3 -ethylcarbodiimide hydrochloride (296 mg, 1.54 mmol ) and 1-hydroxy benzotriazole (209 mg, 1.54 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25oC for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (17-47 acetonitrile/0.05% HCl in water) to give (S)-1-benzyl-N-(2.4- dimethyl -5 -oxo - 5,6,7,8 -tetrahydro -4H -pyrazolo [1,5 -a][1,3] diazepin -6 -yl) -1H -1,2,4 -triazol -3 - carboxamide (221 mg, 56%) as a white solid.

[02510] 1H NMR (400 MHz, DMSO -d6) δ 8.83 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.39 - 7.29 (m, 5H ), 6.12 (s, 1H), 5.48 (s, 2H), 4.34 - 4.25 (m, 2H), 4.23 - 4.06 (m, 1H), 3.21 ( s, 3H), 2.59 - 2.54 (m, 1H), 2.36 - 2.33 (m, 1H), 2.16 (s, 3H). LCMS RT = 0.916 min., m/z = 380.4 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.05% ammonium bicarbonate for 3 min.) retention time 0.910 min., ESI+ found [M+H] = 380.4.

[02511] SFC Conditions: Column: Chiralcel AS -H 150 x 4.6 mm I.D., 3 μ m Mobile phase: A: CO2 B: ethanol (0.05% DEA), Gradient: maintained 5% for 0.5 min., then from 5% to 40% B in 3.5 min. and held 40% for 2.5 min., then 5% B for 1.5 min. Flow rate: 3 mL/min. Column temperature: 40oC.

[02512] Data based on previous climbing experiences:

[02513] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent application publications and non-patent publications referred to in this report are incorporated herein by reference in their entireties.

[02514] Although the invention set forth in this context was described in certain details to facilitate understanding, it will be evident that certain changes and modifications may be made within the scope of the attached claims. For this reason, the described embodiments should be considered as illustrative and not restrictive, and the invention should not be limited to the details set forth in this context, but may be modified within the scope and equivalents of the attached claims.

Claims (22)

1. Compound of formula I: characterized by the fact that it has the structure structure or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of H and unsubstituted C1-C4 alkyl; ring A is selected from the group consisting of 5-membered aryl and 5-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein ring A is optionally substituted by: (a) 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1 haloalkoxy -C6, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in ring A is substituted, the substituent is not halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl or cyano; (b) 1 substituent selected from the group consisting of C4-C6 heterocyclyl, C5C6 heteroaryl, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), CH2-(C5-C6 heteroaryl), CH2CH2- (C5-C6 heteroaryl); and optionally a second substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; or (c) two adjacent substituents that together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl; Z1 is selected from the group consisting of: (i) C and N when ring A is a 5-membered heteroaryl; and (ii) C when ring A is a 5-membered aryl; Z2, Z3, and Z4 are each independently selected from the group consisting of CRZ and NR8; each RZ is independently selected from the group consisting of H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, CH2(C3-C6 cycloalkyl), C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl, CH2( C4-C6 cycloalkoxy), CH2(C4-C6 thiocycloalkyl), phenyl, benzyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl; each R8 is either absent if the nitrogen atom to which it is attached has three bonds to the other atoms, or R8 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, CH2(C3-C6 cycloalkyl) , C1-C6 haloalkyl, CH2(C4-C6 cycloalkoxy), CH2(C4-C6 thiocycloalkyl), phenyl and benzyl; where Z1 is N only if X is CH2, CF2, CH(CH3), CH(CF3), C(CH3) or CH(OH); where if Z1 is N, at least one of Z2, Z3 or Z4 is CRZ; wherein, when Z2 and Z3 are each independently selected from CRZ and NR8, Z2 and Z3 together with their respective substituents RZ and R8 can form a 6-membered aryl, 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5 to 6-membered heterocyclyl group members; wherein, when Z3 and Z4 are each independently selected from CRZ and NR8, Z3 and Z4 together with their respective substituents RZ and R8 can form a 6-membered aryl, 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5 to 5-membered heterocyclyl group. 6 members; ring B is tetrazolyl or a 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein ring B is optionally substituted by 1 to 2 substituents selected from the group consisting of halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano; and wherein if a nitrogen atom in ring B is substituted, the substituent is not halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl or cyano; ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, 5-7 membered cycloalkyl and 5-7 membered heterocyclyl; wherein ring C is optionally substituted by: (a) 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1 haloalkoxy -C6, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2-(C3-C6 cycloalkyl) and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in ring C is substituted, the substituent is not halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl or cyano; (b) 1 to 2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4 heterocyclyl -C6) and unsubstituted C5-C6 heteroaryl; or (c) two adjacent substituents that together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl; L is selected from the group consisting of a bond, O, S, NH, NCH3, (CH2)m, CH(CH3), C(CH3)2, CF2, CH2O, CH2S, CH(OH), CH2NH and CH2N(CH3), or L is absent such that ring B and ring C are fused; X is selected from the group consisting of O, S, SO, SO2, CH2, C(CH3)2, CF2 and CHCF3; m is 1 or 4; en is 1 or 2; with the proviso that if ring A is a 5-membered heteroaryl having 3 heteroatoms, two of said heteroatoms must be nitrogen; and further with the proviso that if ring B is tetrazolyl, L is selected from the group consisting of CH2, CH(CH3), C(CH3)2, CF2; and ring C is phenyl. 2. Compound of formula I(a), according to claim 1, characterized by the fact that the compound is of a formula selected from the group consisting of: independently selected that consists of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms, C1-C6 haloalkyl, (C1-C4 alkoxy)-C1-C2 alkyl, phenyl, benzyl, C4-C6 heterocyclyl, CH2- (C3-C6 cycloalkyl), CH2-(C3-C6 cycloalkyl substituted by 1 to 2 fluorine atoms) and CH2-(C4-C6 heterocyclyl). 3. Compound according to claim 2, characterized in that each R9 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, CH2CH2OCH3, C3-C4 cycloalkyl, substituted C3-C4 cycloalkyl by 1 to 2 fluorine atoms, CH2-(C3-C4 cycloalkyl), CH2-(C3-C4 cycloalkyl substituted by 1 to 2 fluorine atoms) and CH2-(C4 heterocyclyl). 4. Compound according to any one of claims 1 to 3, characterized by the fact that: is selected from the group consisting of: ; where Y is selected from the group consisting of O, S, SO and SO2; X1, X2, and X3 are each independently N or CH, wherein 1 or 2 of X1, X2, and X3 are N; X4 and X5 are each independently N or CH; R5a and R5b are each selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, benzyl, -CH2(C3-cycloalkyl) C6) and 5- to 6-membered heteroaryl; wherein R5a and R5 together with the carbon atom to which they are attached can form a 4- to 4-membered cycloalkyl or a 4-membered cycloalkoxy; R6a and R6b are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, mono- or di-fluorophenyl , benzyl, -CH2(C3-C6 cycloalkyl) and 5- to 6-membered heteroaryl; wherein R6a and R6, together with the carbon atom to which they are attached, can form a 3- to 4-membered cycloalkyl or a 4-membered cycloalkoxy; wherein when R5a and R6a are each H, R5b and R6b can together form a 3 to 4 membered cycloalkyl; and wherein only two of R5a, R5b, R6a and R6b can be other than H in each case; R7 is selected from the group consisting of H and unsubstituted C1-C4 alkyl; R10 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl and benzyl; and R11 is selected from the group consisting of H, halogen, C1-C4 alkyl and C1-C4 haloalkyl. 5. Compound, according to claim 4, characterized by the fact that: R5a and R5b are each H; or cyclopropyl or cyclobutyl. 6. Compound according to claim 4 or 5, characterized by the fact that Y is O. 7. Compound according to any one of claims 4 to 6, characterized in that R5a and R5b are each H. 8. Compound, according to any of the characterized by the fact that is selected from the group consisting of: 9. Compound according to any one of claims 1 to 3, characterized by the fact that R12 is selected from the group consisting of halogen and methyl; et is 0, 1 or 2. 10. Compound according to any one of claims 1 to 9, characterized by the fact that n is 1. 11. Compound according to any one of claims 1 to 10, characterized by the fact that R1 is H or CH3. 12. Compound, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: 13. Compound, according to claim 12, characterized by the fact that it has, in the RIP1 kinase inhibition assay, a Ki less than or equal to 0.1 μM. 14. Compound according to any one of claims 1 to 13, characterized by the fact that it is for use as a therapeutically active substance. 15. Pharmaceutical composition characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 13, and a therapeutically inert carrier. 16. Compound according to any one of claims 1 to 13, characterized in that it is for use in the treatment or prophylaxis of an illness or disorder selected from the group consisting of irritable bowel disorders (IBD), irritable bowel (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemic-reperfusion injury of the kidneys, liver and lungs, cisplatin-induced renal injury, septicemia, inflammatory response syndrome systemic disease (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD). 17. Compound according to claim 16, characterized in that the disease or disorder is an irritable bowel disorder. 18. Compound according to claim 1, characterized by the fact that the compound is selected from the group consisting of: (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3] diazepin-6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxamide; (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin- 6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6- il)-1H-1,2,4-triazol-3-carboxamide; (S)-1-(2,6-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(2,6-difluorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(3,5-difluorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(2,5-difluorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-1-(2,5-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(2,3-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(2-isopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin- 6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-ethyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) 1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (R)-5-(2-fluorophenyl)-N-((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1, 3]diazepin-6-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxamide; (5R)-5-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6- yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxamide; It is (5R)-5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin- 6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxamide. 19. Compound according to claim 1, characterized by the fact that the compound is (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6- il)-1H-1,2,4-triazol-3-carboxamide. 20. Compound according to claim 1, characterized by the fact that the compound is selected from the group consisting of: (S)-1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl) -1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-acetyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-benzyl-1H-1,2,4-triazol-3-carboxamide; (S)-1-(2,6-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-1H-1,2,4-triazol-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol[1,5-a][1,3]diazepine -6-yl]-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(2,3-difluorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) -1-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3] diazepin-6-yl)-1H-1,2,4-triazol-3-carboxamide; N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5- a][1,3]diazepin-6-yl]-5-phenyl-[1, 2,4]triazolo[1,5-a]pyridine-2-carboxamide; 5-(2,5-difluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6- yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol[1,5-a][1,3]diazepin-6-yl] - [1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 5-(2,6-difluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol[1,5-a][1,3]diazepin-6- yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl -6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxamide; (S)-1-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6- il)-1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(2-cyclobutyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin- 6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(2-isopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin- 6-yl)-1H-1,2,4-triazol-3-carboxamide; (S)-1-benzyl-N-(2-(cyclopropylmethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3] diazepin-6-yl)-1H-1,2,4-triazol-3-carboxamide; 1-[(2,3-dichlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazol[1,5-a][1,3] diazepin-6-yl-1,2,4-triazol-3-carboxamide; It is (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin- 6-yl)-1H-1,2,4-triazol-3-carboxamide. 21. Compound, or a pharmaceutically acceptable salt thereof, characterized in that the compound is N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-( 3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-carboxamide. 22. Compound according to any one of claims 18 to 21, characterized in that it is for use in the treatment or prophylaxis of an illness or disorder selected from the group consisting of irritable bowel disorders (IBD), irritable bowel (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemic-reperfusion injury of the kidneys, liver and lungs, cisplatin-induced renal injury, septicemia, inflammatory response syndrome systemic disease (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD).