BR112018015410B1 - KINASE INHIBITOR COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND USES THEREOF - Google Patents

Abstract

THE PRESENT INVENTION GENERALLY REFERS TO COMPOUNDS AND COMPOSITIONS AND THEIR USE AS KINASE INHIBITORS.

Description

CROSS REFERENCE TO RELATED ORDERS

[001] This application claims, under 35 U.S.C. 119(e), the priority of U.S. Provisional Patent Applications numbers 62/292,202, filed February 5, 2016, 62/341,019, filed May 24, 2016, 62 /363,775, filed July 18, 2016, 62/385,217, filed September 8, 2016, and 62/417,219, filed November 3, 2016. The entire contents of these applications are incorporated by reference into this application.

FIELD OF INVENTION

[002] The present invention relates, in general, to kinase inhibitors, therapeutic modes of use, and manufacturing thereof.

BACKGROUND OF THE INVENTION

[003] Although inflammation may be a protective mechanism in response to harmful stimuli, such as pathogen invasion and tissue damage, chronic inflammation is an important underlying factor in many human diseases, such as neurodegeneration, rheumatoid arthritis, autoimmune diseases and inflammatory, and cancer. Likewise, activation of cell death pathways such as necrosis and apoptosis, which are useful in eliminating infected or damaged cells, is also an important underlying mechanism for human diseases, including acute and chronic neurodegenerative diseases.

[004] Receptor-interacting protein kinase 1 is a key regulator of inflammation, apoptosis and necroptosis. Receptor-interacting protein kinase 1 has an important role in modulating inflammatory responses mediated by nuclear factor kappa light chain enhancing activated B cells (NF-KB). More recent research has shown that its kinase activity controls necroptosis, a form of necrotic cell death, which was traditionally considered passive and unregulated, and is characterized by a unique morphology. Furthermore, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex that indicates its activity in regulating apoptosis.

[005] Receptor-interacting protein kinase 1 is subject to complex and elaborate regulatory mechanisms, including ubiquitylation, de-ubiquitylation and phosphorylation. These regulatory events collectively determine whether a cell will survive and activate an inflammatory response or die through apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death and, conversely, research has shown that inhibition of receptor-interacting protein kinase 1 can be effective therapy for diseases involving inflammation or cell death. .

DESCRIPTION

[006] Compounds that are useful as receptor-interacting protein kinase 1 inhibitors are provided herein. The description also provides compositions, including pharmaceutical compositions, kits including the compounds, and methods of using (or administering) and preparing the compounds. The disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder or condition that is mediated by receptor-interacting protein kinase 1. Furthermore, the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by (or mediated at least in part by) receptor-interacting protein kinase 1.

[007] In certain embodiments, a compound of Formula I is provided. In certain embodiments, a compound of Formula IIc is provided. In certain embodiments, a compound of Formula IIe is provided. In certain embodiments, a compound of Formula IIf is provided. In certain embodiments, a compound of Formula V is provided. In certain embodiments, a compound of Formula Va is provided. In certain embodiments, a compound of Formula VI is provided. In certain embodiments, there is provided a compound as in Table 1, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. In certain embodiments, there is provided a compound as in Table 2, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. In certain embodiments, there is provided a compound as in Table 3, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. In certain embodiments, there is provided a compound as in Table 4, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[008] Provided herein is a pharmaceutical composition comprising a compound, including those of any Formula described herein, and an excipient.

[009] Compounds and compositions for use in medicine are provided in this document. In certain embodiments, the compounds and compositions are for use in treating a disease or disorder mediated by receptor-interacting protein kinase 1.

[0010] Provided herein is a method for treating a disease or disorder mediated by a receptor-interacting protein kinase 1 comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need.

[0011] In certain embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, lupus systemic erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection , solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, stroke, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, diabetes type I, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, fever syndrome associated with interleukin-1 conversion, chronic obstructive pulmonary disease, periodic syndrome associated with tumor necrosis factor receptor or peridontitis. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, sepsis, Parkinson's disease, Alzheimer's disease , amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease. In certain embodiments, the disease or disorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, dementia with Lewy bodies, Parkinson's disease, or spinal muscular atrophy. In certain embodiments, the disease or disorder is brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, ALS, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, accident stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, or a prion disorder.

1. Definitions

[0012] The following description presents exemplary modalities of the present technology. It should be recognized, however, that such description is not intended to be a limitation of the scope of the present invention, but rather is provided as a description of exemplary embodiments.

[0013] As used in the present description, the following words, phrases and symbols are generally intended to have the meanings as defined below, unless the context in which they are used indicates otherwise.

[0014] A dash ("-") that is not between two letters or symbols is used to indicate an attachment point for a substituent. For example, -C(O)NH2 is bonded through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; Chemical groups can be represented with or without one or more dashes without losing their common meaning. A wavy line drawn through a line in a structure indicates a point of connection for a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0015] The prefix "Cu-v" indicates that the following group has u to v carbon atoms. For example, "C1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0016] Reference to "about" a value or parameter in this document includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount ± 10%. In certain embodiments, the term "about" includes the indicated amount ± 5%. In certain embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, the term "about X" includes the description of "X". Additionally, the singular forms "a/an" and "a/o" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., alkyl C1-6), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). In certain embodiments, the alkyl has 1 to 12 carbon atoms (i.e., C1-12 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl . When an alkyl residue with a specific number of carbons is called by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be covered; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert-butyl (i.e. - C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0018] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e. , C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes those groups that have a triple bond and a double bond.

[0020] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0021] "Alkylthio" refers to the group "alkyl-S-".

[0022] "Acyl" refers to a -C(O)R group, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0023] "Starch" refers to a "C-starch" group that refers to the -C(O)NRyRz group and a "N-starch" group that refers to the - NRyC(O)Rz group, where Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which can be optionally replaced.

[0024] "Amino" refers to the group -NRyRz in which Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl or heteroaryl; each of which can be optionally replaced.

[0025] "Amidino" refers to -C(NH)(NH2). In certain embodiments, "Amidino" refers to -C(NR)(NR2), wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0026] "Aryl" refers to an aromatic carbocyclic group with a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 ring carbon atoms (i.e., C6-12 aryl), or 6 to 10 carbon atoms ( i.e. aryl C6-10). In certain embodiments, the aryl has 6 to 18 carbon atoms in the ring (i.e., C6-18 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Arium, however, does not encompass or overlap in any way with the heteroaryl defined below. If one or more aryl groups are fused to a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused to a heterocyclyl, the resulting ring system is heterocyclyl.

[0027] "Azido" refers to -N3.

[0028] "Arylalkyl" or "Aralkyl" refers to the group "aryl-alkyl-".

[0029] "Carbamoyl" refers to both an "O-carbamoyl" group that refers to the -O-C(O)NRyRz group and an "N-carbamoyl" group that refers to the -NRyC(O)ORz group, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which can be optionally replaced.

[0030] "Carboxyl" refers to -C(O)OH.

[0031] "Carboxyl ester" or "ester" refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0032] "Cyano" or "carbonitrile" refers to the -CN group.

[0033] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 carbon atoms. carbon in the ring (i.e., C3-10 cycloalkyl, 3 to 8 carbon atoms in the ring (i.e., C3-8 cycloalkyl), or 3 to 6 carbon atoms in the ring (i.e., C3-6 cycloalkyl). In certain embodiments, cycloalkyl has 3 to 15 carbon atoms in the ring (i.e., C3-15 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. non-aromatic that can be fused to an aryl ring, independently of bonding to the rest of the molecule.

[0034] In certain embodiments, cycloalkyl also includes "spiro cycloalkyl" when there are two positions for substitution on the same carbon atom. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0035] "Guanidino" refers to -NHC(NH)(NH2). In certain embodiments, "guanidino" refers to -NRC(NR)(NR2), wherein each R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0036] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0037] "Hydrazine" refers to -NHNH2.

[0038] "Imino" refers to a group -C(NR)R, in which each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0039] "Imido" refers to a group -C(O)NRC(O)R, in which each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0040] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0041] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, it may be referred to using a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to alkyl substituted by two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3). In certain embodiments, examples of haloalkyl include difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0042] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by a halogen.

[0043] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by a hydroxy group.

[0044] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same heteroatomic group or a different heteroatomic group. The term "heteroalkyl" includes an unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms can be independently replaced by the same heteroatomic group or a different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of a heteroalkyl group include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which may be optionally substituted. In certain embodiments, examples of heteroalkyl groups include -CH2OCH3, -CH2SCH3, and -CH2NRCH3, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally overridden as defined in this document. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In certain embodiments, the term "heteroalkyl" requires that the point of attachment to the remainder of the molecule is through a carbon atom.

[0045] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon atoms. (i.e. C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen and sulfur. In certain embodiments, the term "heteroaryl" refers to a 5-14 membered ring system. In certain embodiments, the heteroaryl includes 1 to 13 ring carbon atoms (i.e., C3-12 heteroaryl). In certain embodiments, the heteroaryl includes 1 to 6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1 ,5-a]pyridinyl, in which the heteroaryl can be linked through any ring of the fused system. In certain embodiments, examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl , imidazolyl, indazolyl, indole, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxoazepinyl-2, oxazolyl, oxiranyl, oxidopyridinyl-1, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1 - phenyl-1h-pyrrolila, phenazinyl, phenotiazinyl, phenofinyl, pteridinyl pteridinyl, pyrolylilla, pyzolila, pyridinyl, pyrimidinilla, pyridazinyl, quinoxalinyl, quinolinyl, rfshr, isoquinolinyl, tetra-tetra Nolinila, Tiazoila, Tiadiazolila, Triazolila , tetrazolyl, triazinyl and thiophenyl (i.e., thienyl). Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of bonding to the remainder of the molecule (i.e., through any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0046] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0047] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocyclyl groups (i.e., the heterocyclyl group having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl can be a single ring or multiple rings where the multiple rings can be fused, bridged or spiro-linked. In certain embodiments, the heterocyclyl may comprise one or more oxo (C=O) or N-oxide (NO-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of bond (i.e., it can be bonded through a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of bonding to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 carbon atoms in the ring (i.e., C2-10 heterocyclyl), 2 to 8 carbon atoms in the ring (i.e., C2-8 heterocyclyl heterocyclyl), 3 to 12 carbon atoms in the ring (i.e., C3-12 heterocyclyl heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. In certain embodiments, examples of such heterocyclyl groups include dioxolanyl, thienyl[1,3]dithyanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxopyrrolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.Also used Herein, the term "spiroheterocyclyl" refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional rings, wherein the additional ring or rings is a three- to ten-membered cycloalkyl or heterocyclyl of three to ten members, wherein a single atom of the one or more additional rings is also an atom of the three to ten member heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3 ]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, in that the heterocyclyl can be linked through any ring of the fused system.

[0048] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0049] "Oxo" refers to the group (=O) or (O).

[0050] "Nitro" refers to the -NO2 group.

[0051] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0052] "Oxime" refers to the group -CR(=NOH), where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0053] "Sulfonyl" refers to the group -S (O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0054] "Sulfinyl" refers to the group -S(O)R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0055] "Sulfonamido" refers to the groups -SO2NRR and -NRSO2R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0056] "Alkylsulfonyl" refers to the group -S(O)2R, where R is alkyl.

[0057] "Alkylsulfinyl" refers to the group -S(O)R, where R is alkyl.

[0058] "Thiocyanate" refers to the -SCN group.

[0059] "Thiol" refers to the -SH group.

[0060] "Thioxo" or "thiona" refers to the group (=S) or (S).

[0061] In certain embodiments of any of the terms defined above, Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document.

[0062] In certain embodiments of any of the terms defined above, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally overridden as defined in this document. Certain commonly used alternative chemical names may be employed. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group or an "alkylenyl" group, an "arylene" group or an "arylenyl", respectively. Also, unless explicitly stated otherwise, where combinations of groups are referred to herein as a moiety, for example arylalkyl, the last mentioned group contains the atom by which the moiety is bonded to the rest of the molecule.

[0063] The terms "optional" or "optionally" mean that the event or circumstance described below may or may not occur and the description includes cases where said event or circumstance occurs and cases where it does not occur. Furthermore, the term "optionally substituted" refers to any one or more hydrogen atoms in the designated atom or group that may or may not be replaced by a different moiety of hydrogen.

[0064] The term "substituted" means that any one or more hydrogen atoms in the designated atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylic ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione or combinations thereof.

[0065] In certain embodiments, the term "substituted" used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and/or heteroalkyl ) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro , sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo, N-oxide or -Si(R100)3 wherein each R100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl , aryl, heteroaryl or heterocyclyl.

[0066] In certain embodiments, the term "substituted" used herein means any of the above groups (i.e., alkyl, alkylene, alkoxy, haloalkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl, heteroaryl, hydroxyalkyl and/or alkoxyalkyl) in that at least one hydrogen atom is replaced by a bond to a different hydrogen atom such as, but not limited to: an alkyl group, a haloalkyl group, a halogen atom such as F, Cl, Br and I; an alkenyl, haloalkenyl, alkynyl, haloalkynyl group, a cyclic group, such as an aryl, heteroaryl, cycloalkyl or heterocyclyl group, an oxygen atom in groups, such as hydroxy groups, alkoxy groups and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, thiohaloalkyl groups, sulfone groups, sulfonyl groups and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; and other heteroatoms in several other groups. "Substituted" also means any of the foregoing groups in which one or more hydrogen atoms are replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, formyl, carboxyl , carbonate and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.

[0067] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more hydrogen atoms are independently substituted with deuterium, halo, cyano, nitro, azido , oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, - NRgC(=O)ORh, -NRgS(= O)1-2Rh, -C(=O)Rg, -C(=O)ORg, -OC(=O)ORg, - OC(=O)Rg, -C(=O)NRgRh, -OC(= O)NRgRh, -ORg, -SRg, -S(=O)Rg, - S(=O)2Rg, -OS(=O)1-2Rg, -S(=O)1-2ORg, -NRgS(= O)1-2NRgRh, =NSO2Rg, =NORg, -S(=O)1-2NRgRh, -SF5, -SCF3 or -OCF3. In certain embodiments, "substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)Rg, - C(=O)ORg, -C(=O)NRgRh, - CH2SO2Rg, -CH2SO2NRgRh. In certain embodiments, "substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by -NRgS(O)1-2NRgRh, -CH2S(O)Rg, -CH2S(O)NRgRh, -OC (=O)ORg, -SF5, -SCF3 or -OCF3. In some embodiments, "substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In the foregoing, Rg and Rh and Ri are the same or different and independently hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and/or heteroarylalkyl, or two of Rg and Rh and Ri are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, amino, hydroxy or alkoxy. In one embodiment, each of said alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and/or heteroarylalkyl are independently optionally substituted with one or more oxo, alkyl, halo , amino, hydroxy or alkoxy. Furthermore, each of the above substituents may also be optionally substituted with one or more of the above-mentioned substituents.

[0068] Polymers or similar undefined structures obtained by defining substituents with other substituents attached ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted arium group, which is further substituted by a heteroalkyl group replaced, etc.) are not intended to be included in this document. Unless otherwise noted, the maximum number of tandem substitutions in the compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include disallowed substitution patterns (e.g., methyl substituted with 5 fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in certain embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is unsubstituted.

[0069] Any compound or formula provided in this document is also intended to represent unlabeled forms, as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of the description include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C , 14C, 15N, 18F, 31P, 32P, 35S, 36CI, and 125I. Various isotopically labeled compounds of the present invention, such as those in which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetics studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue delivery of substrate or drug, or in the radioactive treatment of patients.

[0070] The description also includes "deuterated analogues" of compounds of formula I in which 1 to n hydrogens attached to a carbon atom are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0071] The labeled or substituted deuterium compounds of the description may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and/or an increased therapeutic index. A compound labeled 18F, 3H, 11C may be useful for PET or SPECT or other imaging studies. The isotopically labeled compounds of this disclosure and their prodrugs can generally be prepared by carrying out the procedures described in the schemes or in the examples and preparations described below, substituting a readily available isotopically labeled reagent for an unlabeled isotopically labeled reagent. It is understood that deuterium, in this context, is considered as a substituent in the compound of Formula I.

[0072] The concentration of such a heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a specific isotope is intended to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in its naturally abundant isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0073] In many cases, the compounds of this description are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or groups similar to these.

[0074] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, stereoisomers and prodrugs of the compounds described in this document are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0075] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological efficacy and properties of the given compound, and that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with an organic acid. Furthermore, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basification of a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from organic and inorganic acids. Salts derived from inorganic acids include hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzonic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from organic and inorganic bases. Salts derived from inorganic bases include, by way of example, salts of sodium, potassium, lithium, ammonia, calcium and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialenylamines (i.e., HN(alkenyl)2), trialkylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2 (substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tricycloalkylamines (i.e. NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or triarylamines (i.e. NH2(aryl), HN(aryl)2, N(aryl) 3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

[0076] The term "hydrate" refers to the complex formed by the combination of a compound of Formula I and water.

[0077] A "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, dimethyl sulfoxide, ethyl acetate, acetic acid and ethanolamine.

[0078] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, the compounds are understood by one ordinarily skilled in the art to comprise tautomers of amide and imidic acid. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic acid-containing compounds are understood to include their amide tautomers.

[0079] The compounds described in this document, or the pharmaceutically acceptable salts thereof, include an asymmetric center and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as ( R)- or (S)- or, as (D)- or (L)- for amino acids. The description is intended to include all possible isomers as well as their racemic and optically pure forms. Optically active isomers (+) and (-), (R)- and (S)-, or (D)- and (L)- can be prepared using chiral synthons or chiral reagents, or determined using conventional techniques, e.g. chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate from a salt or derivative) using, for example, phase high-pressure liquid chromatography. chiral (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both Z and E geometric isomers. Likewise, all tautomeric forms must also be included.

[0080] "Stereoisomers" are isomers that differ only in the way the atoms are organized in space and include enantiomers and diastereoisomers. In certain embodiments, a "stereoisomer" refers to a compound consisting of the same atoms linked by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers, the molecules of which are mirror images not superimposed on each other.

[0081] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture.

[0082] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0083] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Determined compounds whose absolute configuration is unknown are designated by (+) or (-) depending on the direction (dextro- or levorotatory ) in which they rotate the plane of polarized light into the sodium D-line wavelength.

[0084] "Prodrugs" means any compound that releases an active parent drug according to Formula I or any other formula described herein in vivo when that prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I or any other formula described herein are prepared by modifying functional groups present in the compound of Formula I or any other formula described herein so that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compounds in such a way that the modifications are cleaved, both in routine manipulation and in vivo, to the parent compounds. Prodrugs include compounds of Formula I or any other formula described herein in which a hydroxy, amino, carboxyl or sulfhydryl group in a compound of Formula I or any other formula described herein is attached to any group that can be cleaved in vivo to regenerate the free hydroxy, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I or any other formula described in this document and the like. The preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series; "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated by reference herein.

[0085] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents and similar. The use of such media and agents for pharmaceutically active substances is well known in the art. Except to the extent that any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplemental active ingredients may also be incorporated into the compositions.2. List of Abbreviations and Acronyms

3. Compounds

[0086] Compounds that are useful as receptor-interacting protein kinase 1 inhibitors are provided herein. In certain embodiments, a compound of Formula I is provided:

[0087] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; on what

[0088] Y1 is O or NR2;

[0089] X1 and X2 are each independently nitrogen or carbon and

[0090] X1 or , then R2 and R1, together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, or

[0091] X1 and R1, together with the atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[0092] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[0093] R5 is H or optionally substituted C1-C6 alkyl;

[0094] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[0095] R5 is H or optionally substituted C1-C6 alkyl;

[0096] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[0097] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[0098] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[0099] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00100] R7 is H or optionally substituted C1-C6 alkyl;

[00101] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00102] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that when the fraction and the aromatic ring is optionally substituted, then at least one of the following occurs:

[00103] (1) L is absent or -C(R8)2- and each R8 is optionally substituted C1-C6 alkyl or halo, or two R8, together with the carbon atom to which they are attached, form an optionally cycloalkyl substituted or an optionally substituted heterocyclyl ring;

[00104] (2) Y2 is -C(R6)2- and at least one R6 is different from hydrogen;

[00105] (3) Y2 is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;

[00106] (4) Y2 is -S-, -S(O)- or -S(O)2-; and A is different from isoxazole and phenyl or Y2 is -S(O)(NH)-;

[00107] (5) Y2 is -NR5- and A is different from isoxazole, pyrazole and triazole;

[00108] (6) the carbonyl moiety and L are substituted other than 1,3- in the A ring; or

[00109] (7) R9 is substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, wherein at least one substituent is cyano;

[00110] (8) R1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or

[00111] (9) when X1 and X2 form an optionally substituted phenyl ring as in the fraction , at least one substituent is in the 1 or 4 position and is (a) other than fluorine, chlorine or methyl in the 1 position and/or (b) other than fluorine or methyl for the 4 position; and, additionally, provided that the fraction

[00112] wherein the nitrogen-containing aromatic ring is optionally substituted;

[00113] and with the additional provision that the compound is not: 5- (difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3- carboxamide; 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H- 1-benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]- 1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin- 3-yl]-1-piperazinecarboxamide.

[00114] In certain embodiments, a compound of Formula I is provided, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00115] where

[00116] Y1 is O or NR2;

[00117] X1 and X2 are each independently nitrogen or carbon and

[00118] X1 or , then R2 and R1, together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, or

[00119] X1 and R1, together with the atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[00120] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00121] R5 is H or optionally substituted C1-C6 alkyl;

[00122] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00123] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00124] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00125] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00126] R7 is H or optionally substituted C1-C6 alkyl;

[00127] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00128] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00129] provided that when the portion aromatic ring is optionally substituted, then at least one of the following occurs:

[00130] (1) L is absent or -C(R8)2- and each R8 is optionally substituted C1-C6 alkyl or halo, or two R8, together with the carbon atom to which they are attached, optionally form a cycloalkyl substituted or an optionally substituted heterocyclyl ring;

[00131] (2) Y2 is -C(R6)2- and at least one R6 is different from hydrogen;

[00132] (3) Y2 is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;

[00133] (4) Y2 is -S-, -S(O)- or -S(O)2-; and A is different from isoxazole and phenyl or Y2 is -S(O)(NH)-;

[00134] (5) Y2 is -NR5- and A is different from isoxazole, pyrazole and triazole;

[00135] (6) the carbonyl moiety and L are substituted other than 1,3- in the A ring;

[00136] (7) R1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or

[00137] (8) when X1 and X2 form an optionally substituted phenyl ring as in the fraction , at least one substituent is in the 1 or 4 position and is (a) other than fluorine, chlorine or methyl in the 1 position and/or (b) other than fluorine or methyl for the 4 position; and, additionally, provided that the fraction

[00138] wherein the nitrogen-containing aromatic ring is optionally substituted;

[00139] and with the additional provision that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3- carboxamide; 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H- 1-benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]- 1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin- 3-yl]-1-piperazinecarboxamide.

[00140] In certain embodiments, at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring. substituted, or R3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring.

[00141] In certain embodiments L is absent or -C(R8)2- and each R8 is optionally substituted C1-C6 alkyl or halo, or two R8, together with the carbon atom to which they are attached, optionally form a cycloalkyl substituted or an optionally substituted heterocyclyl ring.

[00142] In certain embodiments, Y1 is NR2.

[00143] In certain embodiments, X1 and X2 are each independently nitrogen or carbon and together form an optionally substituted 5-membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

[00144] In certain embodiments, X1 and R1 together with the atoms to which they are attached, form an optionally substituted 5- or 6-membered heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-.

[00145] In certain embodiments, Y2 is -C(R6)2-; and one R6 is hydrogen, halo or optionally substituted C1-C6 alkyl, and the other R6 is halo or optionally substituted C1-C6 alkyl; or two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[00146] In certain embodiments, Y2 is -O- and A is replaced with halo or cyan; or A is thiazolyl or a 3- or 4-membered ring.

[00147] In certain embodiments, Y2 is -S-, -S(O) - or -S(O)2-; and A is different from isoxazole and phenyl or Y2 is -S(O)(NH) -.

[00148] In certain embodiments, Y2 is -NR5-; X1 and X2 together form an optionally substituted phenyl, and A is different from isoxazole, pyrazole and triazole; X1 and X2 together form an optionally substituted pyridyl, and A is different from triazole; or X1 and X2 are optionally substituted pyrimidyl, and A is different from pyrazole and triazole.

[00149] In certain embodiments, the carbonyl moiety and L are substituted differently than 1,3- in the A ring.

[00150] In certain embodiments, a compound of Formula I is provided, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00151] where

[00152] Y1 is O or NR2;

[00153] X1 and X2 are each independently nitrogen or carbon and

[00154] X1 or , then R2 and R1, together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, or

[00155] X1 and R1, together with the atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[00156] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00157] R5 is H or optionally substituted C1-C6 alkyl;

[00158] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00159] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00160] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00161] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00162] R7 is H or optionally substituted C1-C6 alkyl;

[00163] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00164] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00165] provided that at least one of the following occurs:

[00166] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00167] (2) L is absent or -C(R8)2- and each R8 is optionally substituted C1-C6 alkyl or halo, or two R8, together with the carbon atom to which they are attached, optionally form a cycloalkyl substituted or an optionally substituted heterocyclyl ring;

[00168] (3) Y1 is NR2;

[00169] (4) X1 and X2 are each independently nitrogen or carbon and together form an optionally substituted 5-membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00170] (5) X1 and R1, together with the atoms to which they are attached, form an optionally substituted 5- or 6-membered heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[00171] (6) Y2 is -C(R6)2-; and one R6 is hydrogen, halo or optionally substituted C1-C6 alkyl, and the other R6 is halo or optionally substituted C1-C6 alkyl; or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00172] (7) Y2 is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;

[00173] (8) Y2 is -S-, -S(O)- or -S(O)2-; and A is different from isoxazole and phenyl or Y2 is -S(O)(NH)-;

[00174] (9) Y2 is -NR5-; X1 and X2 together form an optionally substituted phenyl, and A is different from isoxazole, pyrazole and triazole; X1 and X2 together form an optionally substituted pyridyl, and A is different from triazole; or X1 and X2 are optionally substituted pyrimidyl, and A is different from pyrazole and triazole;

[00175] (10) the carbonyl moiety and L are substituted differently from 1,3- in ring A;

[00176] (11) Y2 is -O-; X1 and X2 together form an optionally substituted pyridyl, and A is different from isoxazole;

[00177] (12) R1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or

[00178] (13) when X1 and X2 form an optionally substituted phenyl ring as in the at least one substituent is in the 1 or 4 position and is (a) other than fluorine, chlorine or methyl in the 1 position and/or (b) other than fluorine or methyl in the 4 position;

[00179] and with the additional provision that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2345-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide; 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H- 1-benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]- 1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin- 3-yl]-1-piperazinecarboxamide.

[00180] In certain embodiments, the compound is not 5-(difluorophenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-5-methyl-4-oxo-1,5-benzoxazepin- 3-yl]-3-isoxazolecarboxamide or 5-(difluorophenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxo-1,5-benzoxazepin-3-yl]-3 - isoxazolecarboxamide.

[00181] Also provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. In certain embodiments, a compound of Formula I is provided in which

[00182] R1 is H or optionally substituted C1-C6 alkyl;

[00183] (a) X1 and X2 are each independently nitrogen or carbon and together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; or

[00184] (b) X1 and R1, together with the atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[00185] Y1 is O or NR2, where R2 and R1, together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally heteroaryl ring;

[00186] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00187] R5 is H or optionally substituted C1-C6 alkyl;

[00188] each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00189] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00190] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00191] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00192] R7 is H or optionally substituted C1-C6 alkyl;

[00193] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00194] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00195] provided that at least one of the following occurs:

[00196] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00197] (2) L is absent or -C(R8)2-, and each R8 is optionally substituted C1-C6 alkyl or halo, as long as the compound is not 5- (difluoro(phenyl)methyl)-N-( 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide or 5-(difluoro(phenyl)methyl)-N-(5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide or two R8, together with the carbon atom to which they are attached linked, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00198] (3) Y1 is NR2;

[00199] (4) X1 and X2 are each independently nitrogen or carbon and together form an optionally substituted 5-membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00200] (5) X1 and R1, together with the atoms to which they are attached, form an optionally substituted 5- or 6-membered heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[00201] (6) Y2 is -C(R6)2-; and one R6 is hydrogen, halo or optionally substituted C1-C6 alkyl, and the other R6 is halo or optionally substituted C1-C6 alkyl; or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00202] (7) Y2 is -O-; and A is replaced with halo or cyano; or A is thiazolyl or a 3- or 4-membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-l) thiazol-4-carboxamide or 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4- carboxamide;

[00203] (8) Y2 is -S-, -S(O)- or -S(O)2-; and A is other than 1,3-isoxazole or Y2 is -S(O)N(H)-;

[00204] (9) Y2 is -NR5-; X1 and X2 together form an optionally substituted phenyl, and A is different from isoxazole, pyrazole and triazole; X1 and X2 together form an optionally substituted pyridyl, and A is different from triazole; or X1 and X2 are optionally substituted pyrimidyl, and A is different from pyrazole and triazole; or

[00205] (10) the carbonyl moiety and L are substituted other than 1,3- in the A ring;

[00206] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00207] In certain embodiments, R1 is C1-C6 alkyl. In certain embodiments, R1 is methyl.

[00208] In certain embodiments, the portion: on what

[00209] X3, X4 and X5 are each S, O, N, NH or CH;

[00210] X6, X7, X8 and X9 are each N or CH;

[00211] q is 0, 1, or 2;

[00212] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2-Ci-C6 alkyl.

[00213] In certain embodiments, the fraction: on what

[00214] X3, X4 and X5 are each S, O, N, NH or CH;

[00215] X6, X7, X8 and X9 are each N or CH;

[00216] q is 0, 1, or 2;

[00217] each R10 is independently cyano, halo or optionally substituted alkyl.

[00218] In certain embodiments, the portion: on what

[00219] X3, X4 and X5 are each S, O, N, NH or CH;

[00220] X6, X7, X8 and X9 are each N or CH;

[00221] q is 0, 1, or 2;

[00222] each R10 is independently halo or optionally substituted alkyl.

[00223] In certain embodiments, the portion:

[00224] In certain embodiments, the fraction

[00225] In certain embodiments, the portion

[00226] In certain embodiments, the portion

[00227] In certain embodiments, Y1 is O.

[00228] In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl.

[00229] In certain embodiments, Y2 is where n is 1, 2, 3 or 4,

[00230] In certain embodiments, Y2 is -O-; and A is replaced with halo or cyano; or A is thiazolyl or a 3- or 4-membered cycloalkyl or a 3- or 4-membered heterocycloalkyl ring.

[00231] In certain embodiments, both R3 and R4 are fluorine or R3 or R4 are fluorine and the other is hydrogen, or R3 and R4 form a cyclopropyl or R3 joins with R6 to form a cyclopropyl. In certain embodiments, R3 or R4 is methyl.

[00232] In certain embodiments, A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl , thiadiazolyl, cyclobutyl, cyclopropyl or azetidinyl.

[00233] In certain embodiments, A is isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b] pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl or azetidinyl .

[00234] In certain embodiments, A is phenyl.

[00235] In certain embodiments, L is absent, -S(O)2- or -C(R8)2-.

[00236] In certain embodiments, two R8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring.

[00237] In certain embodiments, R9 is phenyl or 2,3-dihydro-1H-indenyl. In certain embodiments, R9 is phenyl. In certain embodiments, R9 is 2-F-phenyl. In certain embodiments, R9 is pyridyl. In certain embodiments, R9 is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl.

[00238] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, R10 is methyl.

[00239] In one aspect, a compound of Formula Ia is provided:

[00240] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00241] where

[00242] Y1 is O or NR2;

[00243] X1 and X2 are each independently nitrogen or carbon and

[00244] X1 or , then R2 and R1, together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, or

[00245] X1 and R1, together with the atoms to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring; and X2 is -CH2-;

[00246] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00247] R5 is H or optionally substituted C1-C6 alkyl;

[00248] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00249] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00250] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00251] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00252] R7 is H or optionally substituted C1-C6 alkyl;

[00253] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00254] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

[00255] In certain embodiments, the portion In certain embodiments, when the portion q is 0 or R10 is halo or alkyl, and L is absent, then ring A is a 3-, 4-, or 5-membered monocyclic ring. In certain embodiments, the portion and when contribution , q is 0 or R10 is halo or alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring.

[00256] In certain embodiments, in any Formula described here, R9 is replaced with at least one cyano.

[00257] In certain embodiments, the compound is of Formula II:

[00258] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00259] where

[00260] q is 0, 1, or 2;

[00261] X6, X7, X8 and X9 are each N or CH;

[00262] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00263] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00264] R5 is H or optionally substituted C1-C6 alkyl; each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00265] R3 and R4 are independently H, halo, or optionally substituted C1-C6 alkyl, or R3 and R4 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00266] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00267] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00268] R7 is H or optionally substituted C1-C6 alkyl;

[00269] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00270] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00271] each R10 is independently cyano, halo or optionally substituted alkyl;

[00272] provided that at least one of the following occurs:

[00273] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00274] (2) L is absent or -C(R8)2- and each R8 is optionally substituted C1-C6 alkyl or halo, or two R8, together with the carbon atom to which they are attached, optionally form a cycloalkyl substituted or an optionally substituted heterocyclyl ring;

[00275] (3) Y2 is -C(R6)2-; and one R6 is hydrogen, halo, or optionally substituted C1-C6 alkyl, and the other R6 is halo or optionally substituted C1-C6 alkyl; or two R6 together with the carbon atom to which they are attached form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00276] (4) Y2 is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;

[00277] (5) Y2 is -S-, -S(O)-, or -S(O)2-; and A is different from isoxazole or Y2 is -S(O)(NH)-;

[00278] (6) Y2 is -NR5-; X6, X7, X8 and X9 together form an optionally substituted phenyl, and A is different from isoxazole, pyrazole and triazole; X6, X7, X8 and rX9 together form an optionally substituted pyridyl and A is different from triazole; or X6, X7, X8 and X9 are optionally substituted pyrimidyl, and A is different from pyrazole and triazole; or

[00279] (7) Y2 is -O-; X1 and X2 together form an optionally substituted pyridyl, and A is different from isoxazole;

[00280] (8) R1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or

[00281] (9) when X1 and X2 form an optionally substituted phenyl ring as in the at least one substituent is in the 1 or 4 position and is (a) other than fluorine, chlorine or methyl in the 1 position and/or (b) other than fluorine or methyl in the 4 position;

[00282] and with the additional provision that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3- carboxamide; 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H- 1-benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]- 1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin- 3-yl]-1-piperazinecarboxamide.

[00283] In certain embodiments, the compound is of Formula II in which

[00284] q is 0, 1, or 2;

[00285] X6, X7, X8 and X9 are each N or CH;

[00286] R1 is H or optionally substituted C1-C6 alkyl;

[00287] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00288] R5 is H or optionally substituted C1-C6 alkyl;

[00289] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00290] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6 in together with the carbon atoms to which they are attached, they form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00291] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00292] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00293] R7 is H or optionally substituted C1-C6 alkyl;

[00294] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00295] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00296] each R10 is independently halo or optionally substituted alkyl;

[00297] provided that at least one of the following occurs:

[00298] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, R3 and R4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00299] (2) L is absent or -C(R8)2-, and each R8 is optionally substituted C1-C6 alkyl or halo, as long as the compound is not 5- (difluoro(phenyl)methyl)-N-( 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide or 5-(difluoro(phenyl)methyl)-N-(5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3-carboxamide or two R8, together with the carbon atom to which they are attached linked, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00300] (3) Y2 is -C(R6)2-; and one R6 is hydrogen, halo, or optionally substituted C1-C6 alkyl, and the other R6 is halo or optionally substituted C1-C6 alkyl; or two R6 together with the carbon atom to which they are attached form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00301] (4) Y2 is -O-; and A is replaced with halo or cyano; or A is thiazolyl or a 3- or 4-membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-l) thiazol-4-carboxamide or 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4- carboxamide;

[00302] (5) Y2 is -S-, -S(O)- or -S(O)2-; and A is other than 1,3-isoxazole or Y2 is -S(O)N(H)-;

[00303] (6) Y2 is -NR5-; X6, X7, X8 and X9 together form an optionally substituted phenyl, and A is different from isoxazole, pyrazole and triazole; X6, X7, X8 and rX9 together form an optionally substituted pyridyl and A is different from triazole; or X6, X7, X8 and X9 are optionally substituted pyrimidyl, and A is different from pyrazole and triazole; or

[00304] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00305] In certain embodiments, the compound is of Formula II and L is absent or -C(R8)2-, and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted.

[00306] In any of the embodiments of Formula II (or sub-formula thereof), R1 is H or optionally substituted C1-C6 alkyl. In any of the embodiments of Formula II (or sub-formula thereof), R1 is H or C1-C6 alkyl.

[00307] In any of the embodiments of Formula II (or sub-formula thereof), q is 0, 1 or 2 and when present, each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O) 2- C1-C6 alkyl. In any of the embodiments of Formula II (or sub-formula thereof), q is 0, 1 or 2 and when present, each R10 is independently cyano, halo or optionally substituted alkyl. In any of the embodiments of Formula II (or sub-formula thereof), each R10 is independently haloed. In certain embodiments, each R10 is independently fluorine. In any of the modalities of Formula II (or sub-formula thereof), q is 0. In any of the modalities of Formula II (or sub-formula thereof), q is 1. In any of the modalities of Formula II ( or sub-formula thereof), q is 2.

[00308] In certain embodiments, the compound is of Formula IIa:

[00309] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; on what

[00310] q is 0, 1, or 2;

[00311] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00312] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00313] R5 is H or optionally substituted C1-C6 alkyl;

[00314] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00315] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R3 and R6 , together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00316] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00317] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00318] R7 is H or optionally substituted C1-C6 alkyl;

[00319] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00320] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00321] each R10 is independently cyano, halo or optionally substituted alkyl;

[00322] provided that at least one of the following occurs:

[00323] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00324] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00325] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00326] (4) R1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or

[00327] (5) when X1 and X2 form an optionally substituted phenyl ring as in the fraction at least one substituent is in the 1 or 4 position and is (a) other than fluorine, chlorine or methyl in the 1 position and/or (b) other than fluorine or methyl in the 4 position; and with the further provision that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin- 3-yl)isoxazol-3-carboxamide; 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazol-3- carboxamide; 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-4-carboxamide; 4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H- 1-benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]- 1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin- 3-yl]-1-piperazinecarboxamide.

[00328] In certain embodiments, the compound is of Formula IIa in which

[00329] R1 is H or optionally substituted C1-C6 alkyl;

[00330] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00331] R5 is H or optionally substituted C1-C6 alkyl;

[00332] each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00333] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, they form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00334] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00335] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00336] R7 is H or optionally substituted C1-C6 alkyl;

[00337] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring; It is

[00338] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00339] provided that at least one of the following occurs:

[00340] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00341] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring; or

[00342] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00343] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00344] In certain embodiments, the compound is of Formula IIa-1: wherein one of R11 or R12 is halo and the other is C1-6 alkyl or C16 cycloalkyl and the remaining variables are as defined throughout the document.

[00345] In certain embodiments, the compound is of Formula IIa-2:

[00346] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00347] in which

[00348] q is 0, 1, or 2;

[00349] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00350] R4 is H, halo or optionally substituted C1-C6 alkyl;

[00351] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00352] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00353] R7 is H or optionally substituted C1-C6 alkyl;

[00354] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00355] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00356] each R10 is independently cyano, halo or optionally substituted alkyl.

[00357] In certain embodiments, the compound is of Formula IIa-2a. In certain embodiments, the compound is of Formula IIa-2b. In certain embodiments, the compound is of Formula IIa-3. In certain embodiments, the compound is of Formula IIa-4. In certain embodiments, the compound is of Formula IIa-5.

[00358] In certain embodiments, the compound is of Formula IIb:

[00359] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; on what

[00360] q is 0, 1, or 2;

[00361] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00362] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00363] R5 is H or optionally substituted C1-C6 alkyl;

[00364] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00365] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00366] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00367] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00368] R7 is H or optionally substituted C1-C6 alkyl;

[00369] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00370] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00371] each R10 is independently cyano, halo or optionally substituted alkyl;

[00372] provided that at least one of the following occurs:

[00373] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00374] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00375] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or

[00376] (4) the compound is not 5-(phenylmethyl)-N-[(3S)-1,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b][ 1,4]oxazepin-3-yl]-3-isoxazolecarboxamide; N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo- 1H-pyrido[2,3-b][1,4]diazepin-3- yl]-3-(phenylmethyl)-1H-1,2,4-triazol-5-carboxamide; 5-(phenylmethyl)-N-[(3S)-1,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b][1,4]oxazepin-3-yl] -3-isoxazolecarboxamide; or N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-pyrido[2,3-b][1,4]diazepin-3 -yl]-3-(phenylmethyl)-1H-1,2,4-triazol-5-carboxamide.

[00377] In certain embodiments, the compound is of Formula IIb in which

[00378] R1 is H or optionally substituted C1-C6 alkyl;

[00379] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00380] R5 is H or optionally substituted C1-C6 alkyl;

[00381] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00382] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00383] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00384] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00385] R7 is H or optionally substituted C1-C6 alkyl;

[00386] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00387] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00388] provided that at least one of the following occurs:

[00389] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00390] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring; or

[00391] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00392] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00393] In certain embodiments, the compound is of Formula IIb-1:

[00394] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00395] in which

[00396] q is 0, 1, or 2;

[00397] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00398] R4 is H, halo or optionally substituted C1-C6 alkyl;

[00399] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00400] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00401] R7 is H or optionally substituted C1-C6 alkyl;

[00402] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00403] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00404] each R10 is independently cyano, halo or optionally substituted alkyl.

[00405] In certain embodiments, the compound is of Formula IIb-2. In certain embodiments, the compound is of Formula IIb-3. In certain embodiments, the compound is of Formula IIb-4. In certain embodiments, the compound is of Formula IIb-5. In certain embodiments, the compound is of Formula IIb-6.

[00406] In certain embodiments, the compound is of Formula IIc:

[00407] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00408] where

[00409] q is 0, 1, or 2;

[00410] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00411] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00412] R5 is H or optionally substituted C1-C6 alkyl;

[00413] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00414] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00415] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring, optionally substituted aryl or optionally substituted heteroaryl ring;

[00416] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00417] R7 is H or optionally substituted C1-C6 alkyl;

[00418] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00419] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00420] each R10 is independently cyano, halo or optionally substituted alkyl.

[00421] In certain embodiments, the compound is of Formula IIc in which

[00422] R1 is H or optionally substituted C1-C6 alkyl;

[00423] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00424] R5 is H or optionally substituted C1-C6 alkyl;

[00425] each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00426] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00427] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00428] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00429] R7 is H or optionally substituted C1-C6 alkyl;

[00430] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00431] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00432] provided that at least one of the following occurs:

[00433] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00434] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring; or

[00435] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00436] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00437] In certain embodiments, a compound of Formula IIc, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof is provided;

[00438] in which

[00439] q is 0, 1, or 2;

[00440] R1 is H or C1-C6 alkyl;

[00441] Y2 is -O- or -C(R6)2-;

[00442] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00443] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00444] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00445] L is absent, -O- or -C(R8)2-;

[00446] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00447] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00448] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2- C1-C6 alkyl.

[00449] In certain embodiments, the compound is of Formula IIc-1:

[00450] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00451] where

[00452] q is 0, 1, or 2;

[00453] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00454] R4 is H, halo or optionally substituted C1-C6 alkyl;

[00455] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00456] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00457] R7 is H or optionally substituted C1-C6 alkyl;

[00458] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00459] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00460] each R10 is independently cyano, halo or optionally substituted alkyl.

[00461] In certain embodiments, the compound is of Formula IIc-2. In certain embodiments, the compound is of Formula IIc-3. In certain embodiments, the compound is of Formula IIc-4. In certain embodiments, the compound is of Formula IIc-5. In certain embodiments, the compound is of Formula IIc-6.

[00462] In certain embodiments, a compound of Formula IIc-4 is provided:

[00463] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00464] where

[00465] q is 0, 1, or 2;

[00466] R1 is H or C1-C6 alkyl;

[00467] Y2 is -O- or -C(R6)2-;

[00468] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00469] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00470] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00471] L is absent, -O- or -C(R8)2-; each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00472] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00473] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2- C1-C6 alkyl.

[00474] In certain embodiments, the compound is of Formula IId:

[00475] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00476] where

[00477] q is 0, 1, or 2;

[00478] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00479] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00480] R5 is H or optionally substituted C1-C6 alkyl;

[00481] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00482] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00483] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00484] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00485] R7 is H or optionally substituted C1-C6 alkyl;

[00486] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00487] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00488] each R10 is independently cyano, halo or optionally substituted alkyl;

[00489] provided that at least one of the following occurs:

[00490] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00491] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00492] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or

[00493] (4) the compound is not 5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3-b][1,4] oxazepin-3-yl]-3-isoxazolecarboxamide; or

[00494] 5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3- b][1,4]oxazepin-3-yl]- 3-isoxazolecarboxamide.

[00495] In certain embodiments, the compound is of Formula IId in which

[00496] R1 is H or optionally substituted C1-C6 alkyl;

[00497] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00498] R5 is H or optionally substituted C1-C6 alkyl;

[00499] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00500] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00501] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00502] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00503] R7 is H or optionally substituted C1-C6 alkyl;

[00504] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00505] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00506] provided that at least one of the following occurs:

[00507] (1) at least one of R3 and R4 is halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00508] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring; or

[00509] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00510] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00511] In certain embodiments, the compound is of Formula IId-1:

[00512] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00513] in which

[00514] q is 0, 1, or 2;

[00515] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00516] R4 is H, halo or optionally substituted C1-C6 alkyl;

[00517] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00518] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00519] R7 is H or optionally substituted C1-C6 alkyl;

[00520] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00521] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00522] each R10 is independently cyano, halo or optionally substituted alkyl.

[00523] In certain embodiments, the compound is of Formula IId-2. In certain embodiments, the compound is of Formula IId-3. In certain embodiments, the compound is of Formula IId-4. In certain embodiments, the compound is of Formula IId-5. In certain embodiments, the compound is of Formula IId-6.

[00524] In certain embodiments, a compound of Formula IIe is provided:

[00525] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00526] in which

[00527] q is 0, 1, or 2;

[00528] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00529] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00530] R5 is H or optionally substituted C1-C6 alkyl;

[00531] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00532] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00533] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00534] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00535] R7 is H or optionally substituted C1-C6 alkyl;

[00536] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00537] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00538] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2- C1-C6 alkyl.

[00539] In certain embodiments, the compound is of Formula IIe or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00540] where

[00541] q is 0, 1, or 2;

[00542] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00543] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00544] R5 is H or optionally substituted C1-C6 alkyl;

[00545] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00546] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00547] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00548] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00549] R7 is H or optionally substituted C1-C6 alkyl;

[00550] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00551] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00552] each R10 is independently cyano, halo or optionally substituted alkyl.

[00553] In certain embodiments, the compound is of Formula IIe in which

[00554] R1 is H or optionally substituted C1-C6 alkyl;

[00555] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00556] R5 is H or optionally substituted C1-C6 alkyl;

[00557] each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00558] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00559] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00560] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00561] R7 is H or optionally substituted C1-C6 alkyl;

[00562] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00563] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs:

[00564] (1) at least one of R3 and R4 is optionally substituted halo or C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00565] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring; or

[00566] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00567] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00568] In certain embodiments, a compound of Formula IIe, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof is provided;

[00569] where

[00570] q is 0, 1, or 2;

[00571] R1 is H or C1-C6 alkyl;

[00572] Y2 is -O- or -C(R6)2-;

[00573] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00574] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00575] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00576] L is absent, -O- or -C(R8)2-;

[00577] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00578] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00579] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2- C1-C6 alkyl.

[00580] In certain embodiments, the compound is of Formula IIe-1:

[00581] in which

[00582] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00583] q is 0, 1, or 2;

[00584] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00585] R4 is H, halo or optionally substituted C1-C6 alkyl;

[00586] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00587] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00588] R7 is H or optionally substituted C1-C6 alkyl;

[00589] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00590] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00591] each R10 is independently cyano, halo or optionally substituted alkyl.

[00592] In certain embodiments, the compound is of Formula IIe-2. In certain embodiments, the compound is of Formula IIe-3. In certain embodiments, the compound is of Formula IIe-4. In certain embodiments, the compound is of Formula IIe-5. In certain embodiments, the compound is of Formula IIe-6.

[00593] In certain embodiments, a compound of Formula IIe-4, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof is provided;

[00594] in which

[00595] q is 0, 1, or 2;

[00596] R1 is H or C1-C6 alkyl;

[00597] Y2 is -O- or -C(R6)2-;

[00598] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00599] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00600] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00601] L is absent, -O- or -C(R8)2-;

[00602] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00603] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00604] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2- C1-C6 alkyl.

[00605] In certain embodiments, a compound of Formula IIf is provided:

[00606] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00607] where

[00608] q is 0, 1, or 2;

[00609] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00610] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00611] R5 is H or optionally substituted C1-C6 alkyl;

[00612] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00613] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00614] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00615] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00616] R7 is H or optionally substituted C1-C6 alkyl;

[00617] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00618] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00619] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2-C1-C6 alkyl.

[00620] In certain embodiments, the compound is of Formula IIf or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00621] where

[00622] q is 0, 1, or 2;

[00623] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00624] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00625] R5 is H or optionally substituted C1-C6 alkyl;

[00626] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00627] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00628] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00629] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00630] R7 is H or optionally substituted C1-C6 alkyl;

[00631] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00632] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00633] each R10 is independently cyano, halo or optionally substituted alkyl.

[00634] In certain embodiments, the compound is of Formula IIf in which

[00635] R1 is H or optionally substituted C1-C6 alkyl;

[00636] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00637] R5 is H or optionally substituted C1-C6 alkyl;

[00638] each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00639] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00640] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00641] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00642] R7 is H or optionally substituted C1-C6 alkyl;

[00643] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00644] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs:

[00645] (1) at least one of R3 and R4 is optionally substituted halo or C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring , or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00646] (2) L is absent or -C(R8)2- and two R8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring; or

[00647] (3) Y2 is -C(R6)2-; and two R6 together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00648] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00649] In certain embodiments, a compound of Formula IIf, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof is provided;

[00650] where

[00651] q is 0, 1, or 2;

[00652] R1 is H or C1-C6 alkyl;

[00653] Y2 is -O- or -C(R6)2-;

[00654] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00655] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00656] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00657] L is absent, -O- or -C(R8)2-;

[00658] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00659] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00660] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2-C1-C6 alkyl.

[00661] In certain embodiments, the compound is of Formula IIf-1:

[00662] in which

[00663] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00664] q is 0, 1, or 2;

[00665] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00666] R4 is H, optionally substituted halo or C1-C6 alkyl;

[00667] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00668] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00669] R7 is H or optionally substituted C1-C6 alkyl;

[00670] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring;

[00671] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00672] each R10 is independently cyano, halo or optionally substituted alkyl.

[00673] In certain embodiments, the compound is of Formula IIf-2. In certain embodiments, the compound is of Formula IIf-3. In certain embodiments, the compound is of Formula IIf-4. In certain embodiments, the compound is of Formula IIf-5. In certain embodiments, the compound is of Formula IIf-6.

[00674] In certain embodiments, a compound of Formula IIf-4, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof is provided;

[00675] in which

[00676] q is 0, 1, or 2;

[00677] R1 is H or C1-C6 alkyl;

[00678] Y2 is -O- or -C(R6)2-;

[00679] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00680] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00681] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00682] L is absent, -O- or -C(R8)2-;

[00683] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00684] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00685] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl or -S(O)2- C1-C6 alkyl.

[00686] In certain embodiments of compounds of Formula I (or sub-formulas thereof), R3 is H. In certain embodiments of compounds of Formula I (or sub-formulas thereof), R4 is optionally substituted C1-C6 alkyl. In certain embodiments of the compounds of Formula I (or subformulas thereof), R3 is H and R4 is optionally substituted C1-C6 alkyl. In certain embodiments of compounds of Formula I (or subformulas thereof), R3 is H and R4 is methyl.

[00687] In certain embodiments of compounds of Formula I (or subformulas thereof), R3 is H and R4 is H.

[00688] In certain embodiments of compounds of Formula II (or sub-formulas thereof), R3 H. In certain embodiments of compounds of Formula II (or sub-formulas thereof), R4 is optionally substituted C1-C6 alkyl. In certain embodiments of compounds of Formula II (or subformulas thereof), R3 is H and R4 is optionally substituted C1-C6 alkyl. In certain embodiments of compounds of Formula II (or subformulas thereof), R3 is H and alkyl R4 is C1-C6. In certain embodiments of compounds of Formula II (or subformulas thereof), R3 is H and R4 is methyl.

[00689] In certain embodiments of compounds of Formula IIa, IIb, IIc, IId, IIe and IIf (or sub-formulas thereof), R3 is H and R4 is H. In certain embodiments of compounds of Formula IIe-4 and IIe- 5, R3 is H and R4 is H.

[00690] In certain embodiments of compounds of Formula I (or subformulas thereof), ring A is an optionally substituted heteroaryl ring. In certain embodiments of compounds of Formula I (or subformulas thereof), ring A is an unsubstituted heteroaryl ring. In certain embodiments of compounds of Formula I (or subformulas thereof), ring A is a pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of Formula I (or subformulas thereof), ring A is an oxadiazolyl. In certain embodiments of compounds of Formula I (or subformulas thereof), ring A is a triazolyl.

[00691] In certain embodiments of compounds of Formula II (or sub-formulas thereof), ring A is an optionally substituted heteroaryl ring. In certain embodiments of compounds of Formula II (or subformulas thereof), ring A is an unsubstituted heteroaryl ring. In certain embodiments of the compounds of Formula II (or subformulas thereof), ring A is an optionally substituted 5-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformulas thereof), ring A is an unsubstituted 5-membered heteroaryl ring. In certain embodiments of the compounds of Formula II (or subformulas thereof), ring A is an optionally substituted 6-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformulas thereof), ring A is a substituted heteroaryl ring with at least one halo. In certain embodiments of the compounds of Formula II (or subformulas thereof), ring A is a 5-membered heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of Formula II (or subformulas thereof), ring A is a pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of Formula II (or subformulas thereof), ring A is oxadiazolyl. In certain embodiments of compounds of Formula II (or subformulas thereof), ring A is a triazolyl.

[00692] In certain embodiments of compounds of Formula II (or sub-formulas thereof), ring A is of the formula:

[00693] in which

[00694] X10, X11 and X12 are each S, O, N, CR13 or NR13, and X13 is C or N; It is

[00695] each R13 is independently optionally substituted H, halo, cyano or C1C6 alkyl.

[00696] In certain embodiments, at least one of X10X11 and X12 is CR13 or NR13 and at least one R13 is optionally substituted halo, cyano or C1-C6 alkyl. In certain embodiments, at least one of X10X11 and X12 is CR13 or NR13 and at least one R13 is halo. In certain embodiments, each R13 is independently H, fluorine, chlorine, cyano or methyl.

[00697] In certain embodiments of compounds of Formula II (or sub-formulas thereof), ring A is one of the following: wherein each ring may be optionally substituted with one or more halo, cyano or C1-C6 alkyl.

[00698] In certain embodiments of compounds of Formula II (or sub-formulas thereof), ring A is one of the following:

[00699] In certain embodiments of compounds of Formula I (or sub-formulas thereof), L is absent, -O- or -C(R8)2-; and each R8 is independently H or C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments of the compounds of Formula I (or subformulas thereof), L is -C(R8)2- and each R8 is taken together with the carbon atom to which they are attached to form cyclopropyl.

[00700] In certain embodiments of compounds of Formula I (or sub-formulas thereof), L is absent, -O- or -C(R8)2-; and each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring. In certain embodiments of compounds of Formula II (or subformulas thereof), L is absent, -O- or -C(R8)2-; and each R8 is independently H or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl.

[00701] In certain embodiments of compounds of Formula II (or sub-formulas thereof), L is absent. In certain embodiments of compounds of Formula II (or subformulas thereof), L is -O-. In certain embodiments of compounds of Formula I (or subformulas thereof), L is -O- or -C(R8)2-; and each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring. In certain embodiments of compounds of Formula II (or subformulas thereof), L is -O- or -C(R8)2-; and each R8 is independently H, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments of the compounds of Formula II (or sub-formulas thereof), L is -C(R8)2- and each R8 is taken together with the carbon atom to which they are attached to form cyclopropyl.

[00702] In certain embodiments of compounds of Formula I (or subformulas thereof), R9 is optionally substituted aryl. In certain embodiments of the compounds of Formula I (or subformulas thereof), R9 is phenyl optionally substituted with one or more halo, cyano or C1-C6 alkyl optionally substituted with halo. In certain embodiments of compounds of Formula I (or subformulas thereof), R9 is phenyl.

[00703] In certain embodiments of compounds of Formula II (or sub-formulas thereof), R9 is optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments of the compounds of Formula II (or subformulas thereof), R9 is phenyl, dihydroindenyl, pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl , 2,4-difluorophenyl, 3-cyano-4-fluorophenyl or 5-fluoropyridin-3-yl.

[00704] In certain embodiments of compounds of Formula II (or sub-formulas thereof), q is 0. In certain embodiments of compounds of Formula II (or sub-formulas thereof), q is 1 or 2; and each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl, or -S(O)2-C1-C6 alkyl. In certain embodiments of compounds of formula II (or subformulas thereof), q is 1 or 2; and each R10 is independently cyano, halo, methyl or -S(O)2-methyl.

[00705] In certain embodiments, the compound is of Formula III:

[00706] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00707] where

[00708] q is 0, 1, or 2;

[00709] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00710] X1 and X2 are each N or CH;

[00711] X3, X4 and X5 are each S, O, N, NH or CH

[00712] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00713] R5 is H or optionally substituted C1-C6 alkyl; each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00714] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00715] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00716] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00717] R7 is H or optionally substituted C1-C6 alkyl;

[00718] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00719] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00720] each R10 is independently cyano, halo or optionally substituted alkyl.

[00721] In certain embodiments, at least one of the following occurs:

[00722] (1) at least one of R3 and R4 is optionally substituted halo or C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally heterocyclyl ring substituted, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00723] (2) L is absent or -C(R8)2- and each R8 is optionally substituted C1-C6 alkyl or halo, or two R8, together with the carbon atom to which they are attached, optionally form a cycloalkyl substituted or an optionally substituted heterocyclyl ring; or

[00724] (3) Y2 is -C(R6)2-; and one R6 is hydrogen, halo, or optionally substituted C1-C6 alkyl, and the other R6 is optionally substituted halo or C1-C6 alkyl; or two R6, together with the carbon atom to which they are attached, form C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[00725] In certain embodiments, the compound is of Formula III in which

[00726] X1 and X2 are each N or CH;

[00727] X3, X4 and X5 are each S, O, N, NH or CH

[00728] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00729] R5 is H or optionally substituted C1-C6 alkyl; each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00730] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00731] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00732] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00733] R7 is H or optionally substituted C1-C6 alkyl;

[00734] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00735] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00736] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00737] In certain embodiments, the compound is of Formula IIIa, IIIb or IIIc:

[00738] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00739] in which

[00740] q is 0, 1, or 2;

[00741] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00742] X3, X4 and X5 are each S, O, N, NH or CH

[00743] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00744] R1 is H or C1-C6 alkyl;

[00745] R5 is H or optionally substituted C1-C6 alkyl;

[00746] each R6 is independently H, halo or optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00747] R3 and R4 are independently H, halo or optionally substituted C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00748] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00749] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00750] R7 is H or optionally substituted C1-C6 alkyl;

[00751] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00752] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00753] each R10 is independently cyano, halo or optionally substituted alkyl.

[00754] In certain embodiments, the compound is of Formula IIIa-1, IIIb-1 or IIIc-1:

[00755] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00756] where

[00757] q is 0, 1, or 2;

[00758] R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy or cyano;

[00759] X3, X4 and X5 are each S, O, N, NH, or CH;

[00760] R1 is H or C1-C6 alkyl;

[00761] R4 is H, optionally substituted halo or C1-C6 alkyl;

[00762] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00763] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00764] R7 is H or optionally substituted C1-C6 alkyl;

[00765] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00766] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00767] each R10 is independently cyano, halo or optionally substituted alkyl.

[00768] In certain embodiments, the compound is of Formula IIIa, IIIb or IIIc:

[00769] where

[00770] X3, X4 and X5 are each S, O, N, NH or CH

[00771] Y2 is -O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -NR5- or -C(R6)2-;

[00772] R5 is H or optionally substituted C1-C6 alkyl;

[00773] each R6 is independently H, halo, optionally substituted C1-C6 alkyl, or two R6, together with the carbon atom to which they are attached, form a C1-C6 alken-1-yl, optionally substituted cycloalkyl or heterocyclyl ring optionally substituted;

[00774] R3 and R4 are independently H, halo, optionally substituted C1-C6 alkyl, R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00775] A is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

[00776] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-;

[00777] R7 is H or optionally substituted C1-C6 alkyl;

[00778] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; It is

[00779] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[00780] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[00781] In certain embodiments, the compound is of Formula IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8 or IIIa-9:

[00782] in which the variables of Formula IIIa-1 to IIIa-9 are defined throughout the document.

[00783] In certain embodiments, the compound is of Formula IVa, IVb, IVc, IVd, IVe, IVf or IVg:

[00784] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;

[00785] where

[00786] q is 0, 1, or 2;

[00787] R4 is H, optionally substituted halo or C1-C6 alkyl;

[00788] A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;

[00789] L is absent, -O-, -S-, -S(O)-, -S(O)2-, -NR7- or -C(R8)2-; R7 is H or optionally substituted C1-C6 alkyl;

[00790] each R8 is independently H, halo or optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00791] R9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; It is

[00792] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl, or -S(O)2-C1-C6 alkyl.

[00793] In certain embodiments, a compound of Formula V is provided:

[00794] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized by the fact that

[00795] q is 0, 1, or 2;

[00796] X6 and X9 are independently N or CR14;

[00797] R1 is H or optionally substituted C1-C6 alkyl;

[00798] Y2 is -O- or -C(R6)2-;

[00799] each R6 is independently optionally substituted H, halo, C1-C6 alkyl;

[00800] R3 is H, halo, optionally substituted C1-C6 alkyl, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00801] L is -C(R8)2-;

[00802] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00803] R9 is optionally substituted aryl or optionally substituted heteroaryl;

[00804] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted C1-C6 alkoxy or -S(O)2-C1- C6 alkyl; It is

[00805] each R14 is independently hydrogen, cyano, halo, C1C3 alkyl optionally substituted with halo, or C1-C3 alkoxy optionally substituted with halo;

[00806] provided that, when both X6 and X9 are CR14, one or more of (i), (ii), (iii), (iv) and (v) is true: (i) R3 and R6, together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring, (ii) L is -C(R8)2- and each R8 is taken together with the carbon atom to which they are attached to form cyclopropyl, (iii) R9 is substituted with at least one cyano, (iv) X9 is different from C-H, C-F, C-Cl or C-CH3 and/or (v) X6 is different from C-H, C-F or C-CH3 .

[00807] In certain embodiments of compounds of Formula V (or sub-formulas thereof), X9 is N. In certain embodiments, X9 is N and X6 is CR14. In certain embodiments, X9 and X6 are N.

[00808] In certain embodiments of compounds of Formula V (or sub-formulas thereof), Y2 is O. In certain embodiments, R3 is H. In certain embodiments, R3 is methyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cyclopropyl ring.

[00809] In certain embodiments of compounds of Formula V (or sub-formulas thereof), X6 and X9 are CR14 and R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cyclopropyl ring. In certain embodiments, X9 is CH. In certain embodiments, X9 is CF.

[00810] In certain embodiments of compounds of Formula V (or sub-formulas thereof), X6 and X9 are CR14 and L is -C(R8)2- and each R8 is taken together with the carbon atom to which they are attached linked to form cyclopropyl.

[00811] In certain embodiments of compounds of Formula V (or sub-formulas thereof), X6 and X9 are CR14, L is -C(R8)2- and each R8 is taken together with the carbon atom to which they are attached bonded to form cyclopropyl and R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cyclopropyl ring.

[00812] In certain embodiments of compounds of formula Va (or sub-formulas thereof), each R10 is independently cyano, halo or -S(O)2-C1-C6 alkyl. In certain embodiments, q is 1 or 2 and each R10 is independently cyano, halo or -S(O)2-C1-C6 alkyl. In certain embodiments, q is two and both R10 are halo. In certain embodiments, q is two and both R10 are fluorine. In certain embodiments, q is two and at least one R10 is fluorine.

[00813] In certain embodiments of compounds of Formula V (or sub-formulas thereof), R1 is H or methyl. In certain embodiments of compounds of Formula V (or subformulas thereof), R1 is H.

[00814] In certain embodiments of compounds of Formula V (or sub-formulas thereof), R1 is methyl.

[00815] In certain embodiments of compounds of Formula V (or sub-formulas thereof), L is CH2 or two R8 together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments, L is CH2. In certain embodiments, R9 is optionally substituted phenyl. In certain embodiments, R9 is phenyl. In certain embodiments, R9 is phenyl substituted by one to two substituents independently selected from the group consisting of cyano and halo. In certain embodiments R9 is phenyl substituted by cyano.

[00816] In certain embodiments of compounds of Formula V (or sub-formulas thereof), R14 is hydrogen, halo or methyl optionally substituted with 1-3 fluorine. In certain embodiments, R14 is hydrogen or halo. In certain embodiments, R14 is hydrogen. In certain embodiments, R14 is halo. In certain embodiments, R14 is fluorine.

[00817] In certain embodiments, a compound of Formula Va is provided:

[00818] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein

[00819] q is 0, 1, or 2;

[00820] X6 is N or CR14;

[00821] R1 is H or optionally substituted C1-C6 alkyl;

[00822] Y2 is -O- or -C(R6)2-;

[00823] each R6 is independently optionally substituted H, halo, C1-C6 alkyl;

[00824] R3 is H, halo, optionally substituted C1-C6 alkyl, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00825] L is -C(R8)2-;

[00826] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00827] R9 is optionally substituted aryl or optionally substituted heteroaryl;

[00828] each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted C1-C6 alkoxy or -S(O)2-C1 alkyl -C6; It is

[00829] R14 is hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo or oxo, or C1-C3 alkoxy optionally substituted with halo or oxo.

[00830] In certain embodiments of compounds of formula Va, X6 is CR14. In certain embodiments, X6 is N.

[00831] In certain embodiments of compounds of formula Va, each R10 is independently cyano, halo or -S(O)2-C1-C6 alkyl. In certain embodiments, q is at least one and at least one R10 is halo. In certain embodiments, q is at least one and at least one R10 is fluorine. In certain embodiments, q is at least one and at least one R10 is cyan.

[00832] In certain embodiments of the compounds of Formula Va, q is 0.

[00833] In certain embodiments of compounds of formula Va, Y2 is O. In certain embodiments, R3 is H. In certain embodiments, R3 is methyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cyclopropyl ring.

[00834] In certain embodiments of compounds of Formula Va, R1 is H or methyl.

[00835] In certain embodiments of compounds of Formula Va, R1 is methyl.

[00836] In certain embodiments of compounds of Formula Va, L is CH2 or two R8 together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments, L is CH2.

[00837] In certain embodiments of compounds of Formula Va, R9 is optionally substituted phenyl. In certain embodiments, R9 is phenyl. In certain embodiments, R9 is phenyl substituted by one to two substituents independently selected from the group consisting of cyano and halo. In certain embodiments R9 is phenyl substituted by cyano.

[00838] In certain embodiments of compounds of Formula Va (or sub-formulas thereof), R14 is hydrogen, cyano, halo or methyl optionally substituted with 1-3 fluorine or oxo. In certain embodiments, R14 is hydrogen or halo. In certain embodiments, R14 is hydrogen. In certain embodiments, R14 is cyan.

[00839] In certain embodiments, compounds of Formula V and Va do not easily cross the blood-brain barrier. In certain embodiments, compounds of Formula V and Va have an MDCKII-MDR1 efflux ratio greater than 2.5. In certain embodiments, compounds of Formula II, Va and V, wherein at least one of X6 and X9 are N, have a hepatic clearance of less than 5, 4, 3, 2 or 1 mL/min/kg when tested in accordance with with the human liver stability assay described below.

[00840] In certain embodiments, the compound is of Formula VI:

[00841] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein

[00842] q is 0, 1, or 2;

[00843] X6 is N or CR14;

[00844] R1 is H or optionally substituted C1-C6 alkyl;

[00845] Y2 is -O- or -C(R6)2-;

[00846] each R6 is independently H, halo, optionally substituted C1-C6 alkyl;

[00847] R3 is H, halo, optionally substituted C1-C6 alkyl, or R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl ring;

[00848] L is -C(R8)2-;

[00849] each R8 is independently H, halo, optionally substituted C1-C6 alkyl, or two R8, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;

[00850] R9 is optionally substituted aryl; each R10 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, or optionally substituted C1-C6 alkoxy; and R14 is hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo or oxo, or C1-C3 alkoxy optionally substituted with halo or oxo.

[00851] In certain embodiments of compounds of formula VI, X6 is CR14. In certain embodiments, X6 is N.

[00852] In certain embodiments of the compounds of Formula VI, each R10 is independently halo. In certain embodiments, q is a and R10 is fluorine.

[00853] In certain embodiments of the compounds of Formula VI, Y2 is O. In certain embodiments, R3 is H. In embodiments, R3 is methyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl. In certain embodiments, R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cyclopropyl ring.

[00854] In certain embodiments of compounds of Formula VI, R1 is H or methyl. In certain embodiments of the compounds of Formula VI, R1 is methyl.

[00855] In certain embodiments of the compounds of Formula VI, L is CH2 or two R8 together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments, L is CH2.

[00856] In certain embodiments of compounds of Formula VI, R9 is phenyl. In certain embodiments, R9 is optionally substituted phenyl. In certain embodiments, R9 is phenyl substituted with one to two halo.

[00857] In certain embodiments of compounds of Formula VI, R14 is hydrogen, halo or methyl optionally substituted with 1-3 fluorine or oxo. In certain embodiments, R14 is hydrogen or halo. In certain embodiments, R14 is hydrogen.

[00858] In certain embodiments, compounds of Formula VI easily cross the blood-brain barrier. In certain embodiments, compounds of Formula VI have an MDCKII-MDR1 efflux ratio of 2.5 or less. In certain embodiments, compounds of Formula VI have a hepatic clearance of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 μL/min/kg when tested in accordance with the human liver stability assay. Described below.

[00859] In any of the embodiments described throughout the document, q is 0, 1 or 2; and each R10 is independently cyano, halo or optionally substituted alkyl. In any of the embodiments described throughout the document, q is 0, 1 or 2; and each R10 is independently cyano, halo or alkyl optionally substituted with 1-3 halo or oxo.

[00860] In any of the embodiments described throughout the document, q is 0, 1 or 2; and each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl, or -S(O)2-C1-C6 alkyl. In any of the embodiments described throughout the document, q is 1 or 2; and each R10 is independently cyano, halo, optionally substituted C1-C6 alkyl, or -S(O)2-C1-C6 alkyl. In any of the embodiments described throughout the document, q is 0, 1 or 2; and each R10 is independently cyano, fluorine, chlorine, bromine, methyl, trifluoromethyl or -S(O)2-methyl. In any of the embodiments described throughout the document, q is 1 or 2; and each R10 is independently cyano, fluorine, chlorine, bromine, methyl, trifluoromethyl or -S(O)2-methyl.

[00861] In any of the embodiments described throughout the document, ring A is an optionally substituted heteroaryl ring. In any of the embodiments described throughout the document, ring A is an unsubstituted heteroaryl ring. In any of the embodiments described throughout the document, ring A is an optionally substituted 5-membered heteroaryl ring. In any of the embodiments described throughout the document, ring A is an unsubstituted 5-membered heteroaryl ring. In any of the embodiments described throughout the document, ring A is an optionally substituted 6-membered heteroaryl ring. In any of the embodiments described throughout the document, ring A is a substituted heteroaryl ring with at least one halo. In any of the embodiments described throughout the text, ring A is a 5-membered heteroaryl ring substituted with at least one halo.

[00862] In any of the embodiments described throughout the document, ring A is optionally substituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and L is -C(R8)2- and each R8 is taken together with the carbon atom to which they are attached to form cyclopropyl.

[00863] In any of the embodiments described throughout the document, ring A is optionally substituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolium; and R3 and R6, together with the carbon atoms to which they are attached, form an optionally substituted cyclopropyl ring.

[00864] In any of the embodiments described throughout the document, ring A is of the formula:

[00865] in which

[00866] X10, X11 and X12 are each S, O, N, CR13 or NR13, and X13 is C or N; It is

[00867] each R13 is independently optionally substituted H, halo, cyano or C1C6 alkyl.

[00868] In certain embodiments, at least one of X10X11 and X12 is CR13 or NR13 and at least one R13 is optionally substituted halo, cyano or C1-C6 alkyl. In certain embodiments, at least one of X10X11 and X12 is CR13 or NR13 and at least one R13 is halo.

[00869] In any of the embodiments described throughout the document, ring A is one of the following:

[00870] wherein each ring can be optionally replaced.

[00871] In any of the embodiments described throughout the document, ring A is one of the following:

[00872] In any of the embodiments described throughout the document, ring A is one of the following:

[00873] In any of the embodiments described throughout the document, ring A is one of the following:

[00874] It is recognized that certain features described herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. On the other hand, various features described herein that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments belonging to the chemical groups represented by the variables contained in Formula I (and all other Formulas described herein), are specifically covered by this document as if each combination were individual and explicitly recited, to the extent that such combinations encompass compounds that result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Additionally, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of medical uses and indications described herein, such as conditions or disorders mediated by receptor-interacting protein kinase 1, are also specifically covered in this document as if each and every subcombination of chemical groups and subcombination of medical uses and indications were individually and explicitly recited in this document. Furthermore, some embodiments include each combination of one or more additional agents described herein, as if each and every combination were recited individually and explicitly.

[00875] In certain embodiments, a compound may be selected from the compounds of Table 1, 2, 3 or 4. Also included in the description are stereoisomers and mixtures of their stereoisomers. Also included in the description is a compound selected from Table 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof. Table 1

4. Treatment Methods and Uses

[00876] "Treatment" or "treat" is an approach to obtaining beneficial or desired results, including clinical results. The beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or decreasing the extent of the disease or condition); b) delay or stop the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilize the disease or condition, prevent or delay the worsening or progression of the disease or condition, and/or prevent or delay the spread (e.g. example, metastasis) of the disease or condition); and/or c) alleviating the disease, that is, causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of other medication, slowing the progression of the disease , increasing quality of life and/or prolonging survival.

[00877] "Prevention" or "prevent" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. The compounds may, in some embodiments, be administered to a subject (including a human) who is at risk for or has a family history of the disease or condition.

[00878] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation or experiment. The methods described herein may be useful for human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human being.

[00879] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof means an amount sufficient to effect treatment when administered to a subject so as to provide a therapeutic benefit such as improvement of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to lessen a symptom of a disease or condition as described herein. The therapeutically effective amount may vary depending on the subject, disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administration, which can be readily determined by one ordinarily skilled in the art.

[00880] The term "trauma", as used herein, refers to any physical damage to the body caused by violence, accident, fracture, etc. The term "ischemia" refers to a cardiovascular disorder characterized by a low oxygen status, usually due to obstruction of the arterial blood supply or inadequate blood flow, leading to tissue hypoxia. The term "stroke" refers to cardiovascular disorders caused by a blood clot or bleeding in the brain, most commonly caused by an interruption in blood flow to the brain from the clot blocking a blood vessel, and in certain embodiments of the description , stroke refers to ischemic stroke or hemorrhagic stroke. The term "myocardial infarction" refers to a cardiovascular disorder characterized by localized necrosis resulting from obstruction of the blood supply.

[00881] The methods described in this document can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described in this document can be used therapeutically in an individual. "Ex vivo means outside of a living individual. Examples of ex vivo cell populations include, in vitro cell cultures and biological samples, including, but not limited to, fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. The compounds and compositions described herein can be used ex vivo to determine the optimal schedule and/or dosage of administration of a compound of the present invention for a given indication, cell type, individual and other parameters. use can be used for experimental purposes or in the clinic to define protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to examine dosage safety or tolerability in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art.

[00882] Experiments with knockout animal models and Necrostatin 1, an inhibitor of receptor-interacting protein kinase 1, demonstrated the effectiveness of inhibiting receptor-interacting protein kinase 1 in protecting tissues against inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), psoriasis, photoreceptor necrosis induced by retinal detachment, retinitis pigmentosa, caerulein-induced acute pancreatitis, and sepsis/systemic inflammatory response syndrome (SIRS), and in the relief of ischemic brain injury, retinal ischemia/reperfusion, Huntington's disease, renal ischemia reperfusion injury, cisplatin-induced renal injury, traumatic brain injury, hematologic and solid organ malignancies, bacterial infections and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases .

[00883] The receptor-interacting protein kinase 1 inhibitors of the present invention are therefore useful for treating diseases and conditions mediated by receptor-interacting protein kinase 1, including, but not limited to, inflammatory diseases or disorders, cellular necrotic diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ocular diseases, infections and malignancies. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can inhibit inflammation, protect the tissue or cell from damage or unwanted cell death (e.g., necrosis or apoptosis), improve symptoms, and improve response. immune or neuronal function in a patient suffering from any of the prescribed diseases or conditions. Furthermore, the compounds may be suitable for the treatment of immune-mediated diseases, such as, but not limited to, allergic diseases, autoimmune diseases and prevention of transplant rejection.

[00884] Compounds and compositions for use in medicine are provided in this document. In certain embodiments, the compounds and compositions are for use in treating a disease or disorder mediated by receptor-interacting protein kinase 1. Also provided is a method for treating a disease or disorder mediated by a receptor-interacting protein kinase 1 comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In certain embodiments, the disease or disorder is an inflammatory disease associated with A20 SNPs.

[00885] Various specific diseases and disorders are described below. In certain embodiments, the disease or disorder is necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wohlman syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g. , acute pancreatitis), atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, diseases autoimmune hepatobiliary disorders, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, stroke, myocardial infarction, Huntington's disease, Alzheimer's, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, fever syndrome associated with interleukin-1 conversion, chronic obstructive pulmonary disease, associated periodic syndrome to tumor necrosis factor recipient, peridontitis, bacterial infection, staphylococcal infection, microbacterial infection, retinitis pigmentosa, influenza, transplant rejection, burns or hypoxia. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease , amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Huntington's disease, HIV-associated dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease. In certain embodiments, the disease or disorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, dementia with Lewy bodies, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, accident stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, lysosomal storage disease, or a prion disorder. In certain embodiments, the disease is ALS. In certain embodiments, the disease is Alzheimer's disease. In certain embodiments, the disease is lysosomal storage disease. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disorder is an ischemic disease of organs including, but not limited to, the brain, heart, kidney, and liver. In some different embodiments, the disorder is an eye disorder such as retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder.

[00886] In certain embodiments, the compounds and compositions are useful for treating psoriasis.

[00887] In certain embodiments, the disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis (both commonly known together as inflammatory bowel disease). In certain embodiments, the mammal is a primate, canine or feline subject. In certain embodiments, the mammal is a human subject. Without wishing to be limited to any theory, it is believed that the inhibition of receptor-interacting protein kinase 1 by the compounds presently described is responsible, at least in part, for its anti-inflammatory activity. Accordingly, embodiments of the disclosure also include methods for inhibiting receptor-interacting protein kinase 1, either in vitro or in a subject in need thereof, the method comprising contacting a receptor-interacting protein kinase 1 with a compound described in this document. In some of these modalities, inhibition of receptor-interacting protein kinase 1 is effective to block (partially or completely) the release of inflammatory mediators, such as TNF and/or IL6.

[00888] In certain embodiments, there is provided a method of treating a disease or disorder selected from the group consisting of rheumatoid arthritis, systemic juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, psoriasis, Crohn's disease, ulcerative colitis, and multiple sclerosis , comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, there is provided a method for treating a disease or disorder selected from the group consisting of autoimmune hepatitis, atherosclerosis, neutrophilic dermatoses, or a rare disease induced by A20, NEMO and/or LUBAC mutations, comprising administering a therapeutically effective amount of a compound as provided herein to a subject in need thereof. In certain embodiments, the compound is of Formula I (or any Formula described herein or tautomer thereof), where A is triazole. In certain embodiments, the compound is of Formula V or Va. In certain embodiments, the method comprises administering Compound 42 or tautomer thereof.

Inflammatory Diseases or Disorders

[00889] The receptor-interacting protein kinase 1 inhibitors described herein can be used to treat diseases and inflammatory disorders. Inflammatory diseases and disorders typically exhibit elevated levels of inflammation in connective tissues or degeneration of these tissues.

[00890] Non-limiting examples of inflammatory diseases and disorders include Alzheimer's, ankylosing spondylitis, arthritis including osteoarthritis, rheumatoid arthritis (RA), psoriasis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, bowel syndrome irritable bowel disease (IBS), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease and ulcerative colitis.

[00891] In certain embodiments, the compounds and compositions of the present invention are useful for treating rheumatoid arthritis (RA). In certain embodiments, the compounds and compositions of the present invention are useful for treating ulcerative colitis. In certain embodiments, the compounds and compositions of the present invention are useful for treating psoriasis. In certain embodiments, the compounds and compositions of the present invention are useful for treating psoriasis or psoriatic arthritis. In certain embodiments, the disease is spondyloarthritis.

Necrotic Cellular Diseases

[00892] The compounds described in this document can be used for the treatment of diseases/disorders caused by or associated in some way with necrosis. The term "necrotic cellular disease" refers to diseases associated with or caused by cellular necrosis, e.g. trauma, ischemia, stroke, infarction, infection, Gaucher disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-associated dementia, retinal degenerative diseases, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

[00893] Cellular necrotic diseases can be acute diseases, such as trauma, ischemia, stroke, cardiac infarction, septic shock induced by lethal anthrax toxin, sepsis, LPS-induced cell death and HIV-induced T cell death that leads to immunodeficiency. Cellular necrotic diseases also include chronic neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, infectious encellopathies, and dementia, such as HIV-associated dementia.

Neurodegenerative and CNS Diseases

[00894] The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many of the body's activities, such as balance, movement, speech, breathing and heart function. Neurodegenerative diseases can be genetic or caused by medical conditions such as alcoholism, tumors, strokes, toxins, chemicals and viruses.

[00895] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Dementia with Lewy bodies, Parkinson's disease and spinal muscular atrophy. In certain embodiments, neurodegenerative diseases and CNS diseases include Niemann-Pick disease, type C1 (NPC1), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, dementia with Lewy bodies, Parkinson's, and spinal muscular atrophy.

[00896] In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat NPC1 by inhibiting necroptosis that causes neuronal loss. In certain embodiments, the compounds and compositions of the present invention are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present invention are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present invention are useful for treating amyotrophic lateral sclerosis (ALS).

[00897] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve the viability of neurons and promote axon growth and nerve functions in the central nervous system (CNS). Consequently, the compounds can be used to reduce or even reverse the loss of cognitive, motor and sensory functions associated with a CNS disease or disorder, preserving the viability of neurons and/or promoting the regeneration of axons and/or nerve functions.

[00898] The receptor-interacting protein kinase 1 inhibitors described herein can be used in a method to promote regeneration of axons in a CNS neuron, such as a CNS sensory neuron, a motor neuron, a cortical neuron , a cerebellar neuron, a hippocampal neuron, and a midbrain neuron. The receptor-interacting protein kinase 1 inhibitors described herein can be used in a method to promote nerve function or preserve viability after injury to a CNS neuron. In other embodiments, these compounds can be used to promote regeneration of an axon in a CNS neuron that is degenerated in CNS disease or disorder. RIP receptor-interacting protein kinase 1 inhibitors can be administered by any conventional means, such as local application to the neuron or ex vivo application prior to reimplantation.

[00899] Thus, in one aspect, the disclosure provides a method of treating a CNS disorder in an individual in need thereof, wherein a symptom of the CNS disorder is degeneration or injury of axon within a CNS neuron. The method comprises administering to the subject an effective amount of a compound or composition described herein to thereby promote the regeneration of an axon in a CNS neuron affected by the CNS disorder. After administration, neural functions can be measured, for example, as an indication of axon regeneration. It is also contemplated that, after administration of the compound or composition, the neuronal function of the CNS neuron is preserved or improved relative to the neuronal function before administration.

[00900] Non-limiting examples of CNS diseases or disorders include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson's disease, Huntington's disease , multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, and a prion disorder.

[00901] In exemplary embodiments, the CNS disorder is brain injury or spinal cord injury.

[00902] Also provided herein are methods for promoting the survival of neurons and the regeneration of axons in the CNS. CNS disorders characterized by impaired or insufficient axon growth or axonal degeneration may arise from CNS injury (e.g., trauma, surgery, nerve compression, nerve contusion, nerve transection, neurotoxicity, or other physical injury to the brain or spinal cord) or neurodegenerative disease of the CNS, in which a symptom of the disorder is axonal degeneration (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine diseases (polyQ ), stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorder (e.g., Creutzfeldt-Jakob disease). In certain embodiments, the CNS disorder is brain injury (e.g., brain injury). , traumatic brain injury) or spinal cord injury (e.g., chronic, acute, or traumatic spinal cord injury). In certain embodiments, the CNS disorder affects a subject's basic life functions, such as breathing, heart rate, and blood pressure. , for example, a lesion or aneurysm in the brain stem.

[00903] In certain embodiments, the CNS disease or disorder affects a subject's cognitive ability. In certain embodiments, the CNS disease or disorder affects a subject's movement and/or strength. In certain embodiments, the CNS disease or disorder affects a subject's coordination.

[00904] In certain embodiments, CNS disease affects a subject's cognitive ability, such as brain damage to the cerebral cortex or a neurodegenerative disease of the CNS, such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration , progressive supranuclear palsy, and prion disorders.

[00905] In certain embodiments, the CNS disorder affects the subject's movement and/or strength, such as brain or spinal cord injury or a neurodegenerative disorder of the CNS such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy and prion disorders.

[00906] In certain embodiments, CNS disease affects a subject's coordination, such as brain damage to the cerebellum or a neurodegenerative disease of the CNS such as spinocerebellar atrophies, Friedreich's ataxia, and prion disorders.

[00907] In each of the foregoing methods, the CNS disorder includes, but is not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorders (e.g. Creutzfeldt-Jakob disease), dementia (e.g. , frontotemporal dementia, dementia with Lewy bodies), corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, hereditary spastic paraparesis, and spinocerebellar atrophies.

[00908] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, lysosomal storage diseases, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Dementia with Lewy bodies, Parkinson's disease and spinal muscular atrophy.

[00909] In certain embodiments, the compounds and compositions of the present invention are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present invention are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present invention are useful for treating amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the present invention are useful for treating lysosomal storage diseases.

[00910] In certain embodiments, the disorder is a brain disorder, such as, but not limited to, Alzheimer's disease, ALS, frontotemporal dementias, vascular dementia, Huntington's disease, Parkinson's disease, Lewy body dementia, Supranuclear Palsy Progressive, multiple sclerosis, neuromyelitis optica, ischemic brain injury (stroke), hypoxic brain damage, traumatic brain injury, spinal cord injury, sepsis-induced brain damage, CNS infections, CNS abscesses, glioblastoma multiforme, epilepsy, neuropathic pain , acute depression, bipolar depression, schizophrenia, autism, Niemann-Pick disease, Neuro-Behçet disease.

[00911] In certain embodiments, there is provided a method of treating a disease or disorder of the CNS, comprising administering a therapeutically effective amount of a compound as provided herein to an individual in need thereof. In certain embodiments, the disease or disorder is Alzheimer's disease or amyotrophic lateral sclerosis (ALS). In certain embodiments, the compound is of Formula I (or any Formula described herein), wherein A is other than triazole. In certain embodiments, the compound is of Formula VI.

Eye Conditions

[00912] The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat ocular conditions, for example, to reduce or prevent the loss of photoreceptors and/or retinal pigment epithelial cell viability.

[00913] In certain embodiments, the description provides a method for preserving the visual function of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of photoreceptor cell viability in the retina of the eye with the condition. The method comprises administering to the subject's eye an effective amount of a compound or composition described herein, thereby preserving the viability of photoreceptor cells disposed within the retina of the eye. After administration, the visual function (e.g., visual acuity) of the eye may be preserved or improved relative to the visual function of the eye before administration.

[00914] The ocular condition may be a condition selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central areola choroidal dystrophy, BEST disease, adult vitelliform disease, standard dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, Cone-Rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, and light-induced toxicity. AMD can be the neovascular or dry form of AMD. Retinal detachment can be rhegmatogenous, serous and tractional retinal detachment. In certain embodiments, the ocular condition may be a condition selected from the group consisting of geographic atrophy, glaucoma, and other ischemic ocular diseases.

[00915] In certain embodiments, the disclosure provides a method for preserving the viability of retinal pigment epithelial (RPE) cells within the retina of a subject with an ocular condition with the administration of a compound of the present invention. The subject to be treated may have a loss of retinal pigment epithelial cells in the retina of the eye with the condition and the eye condition may be selected from the group consisting of age-related macular degeneration (AMD), BEST disease, myopic degeneration, Stargardt syndrome, uveitis, adult foveomacular dystrophy, fundus falvimaculatus, multiple evanescent white dot syndrome, serpiginous choroidopathy, acute multifocal posterior placoid epitheliopathy (AMPPE), and other uveitis disorders. In certain embodiments, the method comprises administering to the subject's eye an effective amount of a compound or composition described herein, thereby preserving the viability of retinal pigment epithelial cells.

[00916] Provided in another embodiment is a method for preserving the viability of photoreceptor cells disposed within the retina of an individual with an ocular condition selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa (RP), edema macular, diabetic retinopathy, central areola choroidal dystrophy, BEST disease, adult vitelliform disease, standard dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, Cone-Rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity. Thus, in certain embodiments, the method comprises administering to the eye an effective amount of a compound or composition described herein, thereby preserving the viability of photoreceptor cells disposed within the retina of the subject with a condition.

[00917] In another embodiment, a method is provided for preserving the viability of photoreceptor cells disposed within a retina of a mammalian eye after retinal detachment. Retinal detachment can be a rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment. In other embodiments, retinal detachment may occur as a result of a retinal tear, retinoblastoma, melanoma or other cancers, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. In certain embodiments, the method comprises administering a compound or composition described herein to the eye in which a region of the retina has been detached in quantities sufficient to preserve the viability of photoreceptor cells disposed within the region of the detached retina.

[00918] In another embodiment, a method is provided for preserving the visual function of an eye of a subject with an ocular condition selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, central areola choroidal dystrophy, retinal detachment, diabetic retinopathy, BEST disease, adult vitelliform disease, standard dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, Cone-Rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity, wherein a symptom of the ocular condition is the loss of viability of photoreceptor cells in the retina of the eye, wherein the method comprises treating the subject with a compound or composition described herein to the subject.

[00919] In another aspect, the disclosure provides a way of preserving the visual function of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is loss of photoreceptor cell viability and/or RPE viability in the retina of the subject. eye, wherein the method comprises treating the subject with a compound or composition described herein for the subject.

[00920] In certain embodiments, a method is provided for preserving the visual function of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of viability of retinal ganglion cells in the retina of the eye with the condition. The method comprises administering to the subject's eye an effective amount of a compound or composition, thereby preserving the viability of retinal ganglion cells disposed within the retina of the eye. After administration of the compound or composition, the visual function of the eye may be preserved or improved relative to the visual function of the eye before administration. Furthermore, after administration, the preserved retinal ganglion cell is capable of stimulating axonal regeneration.

[00921] Non-limiting examples of symptoms associated with ocular conditions include loss of viability of retinal ganglion cells in the retina of the eye, glaucoma, optic nerve damage, optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artery occlusion, and occlusion of the central retinal vein.

[00922] The compounds described herein can also be used for the treatment of optic neuropathies such as ischemic optic neuropathy (e.g., arteritic or non-arteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy (e.g., Leber optic neuropathy, dominant optic atrophy, Behr syndrome).

[00923] Also described is a method for preserving the visual function of an eye of a subject with an ocular condition selected from the group consisting of glaucoma, optic nerve damage, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and occlusion. of the central retinal vein. The method comprises administering to the subject's eye an effective amount of a compound or composition described herein, thereby preserving the viability of retinal ganglion cells disposed within the retina of the eye and the visual function of the eye.

[00924] In another aspect, described herein is a method for preserving the viability of retinal ganglion cells disposed within a retina of a mammalian eye affected by, for example, glaucoma, optic nerve damage, optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. The method comprises administering a compound or composition described herein to the eye in which a region of the retina has been affected in amounts sufficient to preserve the viability of retinal ganglion cells disposed in the affected region of the retina. The preserved retinal ganglion cell is capable of stimulating axonal regeneration.

[00925] Also described is a method for promoting the regeneration of axons in an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of retinal ganglion viability in the retina of the eye with the condition. The method comprises administering to the subject's eye an effective amount of a compound or composition described herein, thereby promoting the regeneration of retinal ganglion cell axons within the retina of the eye.

[00926] In each of the foregoing embodiments, it is understood that the methods and compositions described herein may be utilized to preserve the viability and/or promote axon regeneration of retinal ganglion cells during the treatment of underlying conditions including, but not limited to, limiting to, glaucoma, optic nerve damage, optic neuritis, optic neuropathies, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion.

Injury or tissue damage

[00927] The ability of the compounds described herein to inhibit inflammation and cell death makes them suitable for improving tissue injury or damage. Tissue injuries or damage can be the result of any of the diseases or conditions described above. For example, the compounds may be used to ameliorate brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or to ameliorate cardiac tissue injury or damage following myocardial infarction, or to ameliorate brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease, or Parkinson's disease, or to improve liver tissue lesions or damage associated with nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, or primary sclerosing cholangitis or to improve lesions or damage in liver tissue associated with acetaminophen overdose, or to improve renal tissue injury or damage following kidney transplantation or administration of nephrotoxic drugs or substances. In certain embodiments, the compounds can, for example, be used to improve brain tissue injury or damage resulting from lung injury or damage.

[00928] Non-limiting examples of brain injury or damage include stroke (e.g., hemorrhagic and non-hemorrhagic), traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage secondary to cerebral arterial malformation, cerebral infarction, brain injury perinatal, non-traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, cerebral hemorrhage, brain infections, brain tumor, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia focal, global cerebral ischemia and hypoxic hypoxia.

[00929] In one embodiment, the compounds and compositions of the present invention can be used to treat peritoneal tissue injury. Non-limiting examples of peritoneal tissue injury include peritoneal deterioration, peritoneal sclerosis, and peritoneal cancer. For example, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects.

Liver Injuries and Diseases

[00930] In one embodiment, the compounds and compositions of the present invention can be used to treat liver injuries and diseases. Non-limiting examples of liver injury or damage include not only degeneration or necrosis of hepatic parenchymal cells that results from injury caused by a given factor, but also undesirable phenomena caused by biological reactions to injury, such as mobilization, infiltration, activation of Kupffer cells , leukocytes and the like, liver tissue fibrosis, etc., the reactions of which occur alone or in combination. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat steatohepatitis and hepatocellular carcinoma by inhibiting activity-dependent apoptosis of hepatocytes and receptor-interacting protein kinase 1-dependent hepatocarcinogenesis. receiver. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat alcoholic hepatitis, autoimmune hepatitis, fulminant hepatic failure, acute cholestasis, and liver injury.

Kidney Injury and Disease

[00931] In one embodiment, the compounds and compositions of the present invention can be used to treat kidney injuries and diseases. Non-limiting examples of kidney diseases include chronic kidney disease (CKD) (e.g., glomerular diseases, tubulointerstitial diseases, obstruction, polycystic kidney disease), acute kidney injury (AKI), diabetic nephropathy, fibrosis, glomerulonephritis, focal glomerulosclerosis, immune complex nephropathy crystalline nephropathy or lupus nephritis. Kidney disease can be caused by drug-induced kidney injury or kidney graft rejection. Kidney disease can be characterized as nephrotic syndrome or kidney failure. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat kidney diseases (e.g., AKI) by inhibiting the cell death pathway in kidney diseases. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat patients with kidney stones and to prevent crystal-induced cytotoxicity and acute kidney injury by inhibiting the protein kinase that interacts with receptor-mediated necroptosis. 3-MLKL protein kinase that interacts with the receptor.

Skin diseases

[00932] In one embodiment, the compounds and compositions of the present invention can be used to treat dermal (or skin) diseases, including, but not limited to, inflammatory skin diseases or neutrophilic dermatoses.

Malignancies

[00933] In one embodiment, the compounds and compositions of the present invention are useful for treating malignancies/cancers such as carcinoma, sarcoma, melanoma, lymphoma or leukemia. Non-limiting examples of malignancies adequately treated by the receptor-interacting protein kinase 1 inhibitors described herein include lung cancer (e.g., non-small cell lung cancer), hepatocellular cancer, melanoma, pancreatic cancer, urological cancer, bladder cancer , colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and anaplastic astrocytoma in adults), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions , mesotheliomas, Wilms' tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancer of the vulva, cancers of the adrenal cortex, tumors producing ACTH, lymphoma and leukemia.

Infectious diseases

[00934] In one embodiment, the compounds and compositions of the present invention are useful for treating infectious diseases resulting from the presence of pathogenic agents, including pathogenic viruses, pathogenic bacteria, fungi, protozoa, multicellular parasites and aberrant proteins known as prions. Non-limiting examples of infectious diseases suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein include viral infectious diseases and bacterial infectious diseases. Viral infectious disease is not particularly limited and includes, for example, infectious diseases with respiratory infectious viruses (e.g., infectious diseases due to respiratory infectious viruses such as influenza virus, rhinovirus, corona virus, parainfluenza virus, RS virus, adenovirus, rhinovirus, viruses and the like), Staphylococcus aureus (MRSA) pneumonia, Serratia marcescens hemorrhagic pneumonia, herpes zoster caused by herpesvirus, diarrhea caused by rotavirus, viral hepatitis, AIDS and the like. Infectious bacterial disease is not particularly limited and includes, for example, infectious diseases caused by Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA, Salmonella, Botulinus, Candida and the like.

Bone Diseases

[00935] In one embodiment, the compounds and compositions of the present invention are useful for treating bone diseases that may result from a bone remodeling disorder, in which the balance between bone formation and bone resorption is displaced. Non-limiting examples of bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, achondroplasia, osteocoditis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease, and periodontal. Additional examples of bone diseases adequately treated by the receptor-interacting protein kinase 1 inhibitors described herein include bone fracture, bone trauma, or a bone deficit condition associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-traumatic bone surgery. plastic surgery, post-dental surgery, bone chemotherapy treatment or bone radiotherapy treatment. Additional examples of diseases affecting bony joints or bones adequately treated by the receptor-interacting protein kinase 1 inhibitors described herein include metastatic bone cancer, rheumatic diseases such as rheumatoid arthritis, osteoarthritis and other inflammatory arthropathies. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat postmenopausal osteoporosis by inhibiting osteocyte necrosis and trabecular deterioration.

Cardiovascular diseases

[00936] In one embodiment, the compounds and compositions of the present invention are useful for the treatment of cardiovascular diseases that may be related to the cardiovascular disorders of brittle plaque disorder, occlusive disorder and stenosis. Non-limiting cardiovascular diseases include coronary artery disorders and peripheral arterial disorders, including, but not limited to, atherosclerosis, arterial occlusion, aneurysm formation, thrombosis, post-traumatic aneurysm formation, restenosis, and postoperative graft occlusion. Atherosclerosis is believed to result from maladaptive inflammation caused primarily by macrophages. Thus, the compounds and compositions of the present invention can be used to treat atherosclerosis by inhibiting macrophage necroptosis.

Transplant

[00937] In one embodiment, the compounds and compositions of the present invention are useful for treating transplant patients. Non-limiting examples of transplant patients appropriately treated by the receptor-interacting protein kinase 1 inhibitors described herein include patients with solid and non-solid tissue and organ transplants and transplants, such as liver, heart, kidney and marrow transplants. heterologous and autologous bone. Typically, immunosuppressive therapy is used to prevent graft rejection in solid organ transplant recipients. Bone marrow transplant recipients generally undergo extensive irradiation and chemotherapy prior to transplantation. It is believed that protein kinase 1 and NF-KB signaling interacting with the receptor on dead cells determines the cross-priming of CD8+ T Cells. Thus, protein kinase 1 inhibitors that interact with the receptor described here can be used to treat transplant patients and prevent graft rejection through modulation of CD8+ T Cell cross-priming.

Other Diseases and Conditions

[00938] Additional examples of diseases and disorders adequately treated by the receptor-interacting protein kinase 1 inhibitors described herein include pancreatitis, atopic dermatitis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), systemic lupus erythematosus (SLE) , Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, primary sclerosing cholangitis (PSC), acetaminophen toxicity, renal damage/injury (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, e.g., cisplatin, injury acute renal disease (AKI), celiac disease, idiopathic autoimmune thrombocytopenic purpura (autoimmune ITP), cerebrovascular accident (CVA), myocardial infarction (MI), allergic diseases (including asthma), diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, disease Behçet's disease, interleukin-1 associated febrile syndrome (ICE/caspase-1), chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), peridontitis, NEMO deficiency syndrome ( essential modulator gene deficiency F-kappa-B (also known as IKK gamma or IKKG), HOIL-1 deficiency (also known as RBCKl) heme-oxidized IRP2 ligase 1 deficiency), ubiquitin linear chain complex (LUBAC ), hematologic and solid organ malignancies, bacterial infections and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases. Additional examples of diseases and disorders adequately treated by the receptor-interacting protein kinase 1 inhibitors described herein include Gaucher disease or organ failure.

[00939] Non-limiting examples of lysosomal storage diseases include Gaucher disease, GM2, Gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon's disease, Fabry disease, Farber's disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick, neuronal ceroidal lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, sialic acid storage disease, Tay-Sachs and Wolman disease.

5. Kits

[00940] Also provided here are kits that include a compound of the description, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound of the description, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue, and a package insert and/or instructions for use of the compounds in treating the indications, including the diseases or conditions described here.

[00941] Also provided here are articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue in a suitable container. The container can be a vial, vial, ampoule, pre-filled syringe and intravenous bag.

6. Pharmaceutical Compositions and Modes of Administration

[00942] The compounds provided here are usually administered in the form of pharmaceutical compositions. Thus, also provided herein are pharmaceutical compositions containing one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue and one or more pharmaceutically acceptable carriers selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable carriers may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17a. Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3a. ed. (GS Banker and CT Rhodes, Eds.).

[00943] Pharmaceutical compositions can be administered in single or multiple doses. The pharmaceutical composition can be administered by various methods including, for example, rectally, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical injection or as an inhalant.

[00944] One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs. , mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical carriers.

[00945] Oral administration can be another route for administering the compounds described here. Administration can be done, for example, by enteric-coated capsules or tablets. In making pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue, the active ingredient is typically diluted by an excipient and/or enclosed within a carrier that It may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[00946] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulations may include lubricating agents such as talc, magnesium stearate and mineral oil; humidifying agents; suspending agents and emulsifiers; preserving agents, such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[00947] Compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or polymer matrix drug formulations. Another formulation for use in the methods described herein employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts and can be constructed for continuous, pulsatile or on-demand administration of pharmaceutical agents.

[00948] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or pharmaceutically acceptable deuterated analogue. By referring to these preformulation compositions as homogeneous, the active ingredient can be dispersed evenly throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.

[00949] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action, or to protect from acidic conditions of the stomach. For example, the tablet or pill may include an internal dosage component and an external dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or have a delayed release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol and cellulose acetate.

[00950] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. In other embodiments, pharmaceutically acceptable solvent compositions can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizer device or the nebulizer device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may also be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

7. Combination Therapy

[00951] In certain embodiments, the compounds described herein can be administered in combination with at least one other therapeutically active agent. The two or more agents may be co-administered, co-formulated, or administered separately. In certain embodiments, the other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, a platelet aggregation inhibitor, an antimicrobial agent (antibiotic, a broad-spectrum antibiotic, a lactam, an antimycobacterial agent, a bactericidal antibiotic, anti-MRSA therapy), a long-acting beta-agonist, a combination of an inhaled corticosteroid and a long-acting beta-agonist, a short-acting beta-agonist, a leukotriene modifier, an anti-IgE, a bronchodilator of methylxanthine, a mast cell inhibitor, a protein tyrosine kinase inhibitor, a CRTH2/Dprostanoid receptor antagonist, an epinephrine inhalation aerosol, a phosphodiesterase inhibitor, a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4, a long-acting inhaled anticholinergic, a muscarinic antagonist, a long-acting muscarinic antagonist, a low-dose steroid, an inhaled corticosteroid, an oral corticosteroid, a topical corticosteroid, thymocyte antiglobulin, thalidomide, chlorambucil, a blocker of calcium channels, a topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, an antifibrotic agent, a proton pump inhibitor, a cystic fibrosis transmembrane conductance regulator enhancer , a mucolytic agent, pancreatic enzymes, a bronchodilator, an ophthalmic intravitreal injection, an antivascular endothelial growth factor inhibitor, a ciliary neurotrophic factor growth agent, trivalent inactivated influenza vaccine (IIV3), trivalent inactivated influenza vaccine (IIV4 ), a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, inactivated influenza vaccine, a ciliary neurotrophic growth factor, a gene transfer agent, a topical immunomodulator, calcineurin inhibitor, an interferon gamma globulin, an antihistamine, a monoclonal antibody, a polyclonal anti-T cell antibody, equine antithymocyte gammaglobulin antibodies, a rabbit antithymocyte globulin antibody, an anti-CD40 antagonist, a JAK inhibitor, and a murine anti- -TCR.

[00952] Other exemplary therapeutically active agents include heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatidz, aspirin, vacomycin, cefeprima, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, hydrocortisone , vedolizumab, alicaforsen, remestemcel-L, ixekizumab, tildrakizumab, secukinumab, chlorhexidine, doxycycline, minocycline, fluticasone (fluticasone proprionate, fluticasone furoate), beclomethasone dipropionate, budesonide, trimcinolone acetonine, flunisolide, mometasone furoate, ciclesonide, formoterol tartrate, formoterol fumarate, salmeterol xinafoate, albuterol (albuterol sulfate), levalbuterol tartrate, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab, theophylline, cromulin sodium, nedocromil sodium, masitinib, AMG 853, indacaterol, E004, reslizumab, salbutamol, tiotropium bromide, VR506, lebrikizumabRPL554, afibercept, umeclidinium, indacterol maleate, aclidinium bromide, roflumilast, SCH527123, glycopyrronium bromide, olodaterol, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol , a combination of fluticasone furoate and fluticasone proprionate, a combination of fluticasone propionate and eformoterol fumarate dihydrate, a combination of formoterol and budesonide, a combination of beclomethasone dipropionate and formoterol, a combination of mometasone furoate and formoterol fumarate dihydrate, a combination of umeclidinium and vilanterol, a combination of ipratropium bromide and albuterol sulfate, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, a combination of ehambutol aclidinium and formoterol, isoniazid, rifampicin, pyrazinamide, rifabutin, rifapentine , capreomycin, levofloxacin, moxifloxacin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, Bedaquiline fumarate, PNU-100480, delamanid, imatinib, ARG201, tocilizumab, Muromonab-CD3, basiliximab, daclizumab, rituximab, prednisolone, antiglobulin - thymocyte, FK506 (tacrolimus), methotrexate, cyclosporine, sirolimus, everolimus, mycophenolate sodium, mycophenolate mofetil, cyclophosphamide, azathioprine, thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicine, acid para-aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, Lansoprazole, Esomeprazole, Pantoprazole, rabeprazole, imatinib, belimumab, ARG201, tocilizumab, ivacftor, dornase alfa, pancrelipase, Tobramycin, Aztreonam, colistics sodium, monohydrate cefadroxyl, cefazoline, cefalexin, cefazoline, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamycin, ceftazidima, a combination of trimetoprims and sulfametoxazole, chloranphenicol, a combination of ivacphtor and lumacaf TOR, ATALERENO, NT-501- CNTF, a gene transfer agent encoding myosin VIIA (MY07A), ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, bevacizumab, oseltamivir, zanamivir, rimantadine, amantadine, nafcillin, sulfamethoxazolem, trimethoprim, sulfasalazine, acetylsulfisoxazole, vancomycin, muromonab -CD3, ASKP-1240, ASP015K, TOL101, pimecrolimus, hydrocortizone, betamethasone, flurandrenolide, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, a recombinant synthetic interferon type I, interferon alfa-2a, interferon alfa-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin and erythromycin.

[00953] A compound described herein can be administered in combination with other anti-inflammatory agents for any of the above indications, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine preparations, hydroxychloroquine, thiopurines, methotrexate , cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologics, including anti-IL6 biologics, anti-IL1 biologics, anti-IL17 biologics, anti-CD22 , anti-integrins, anti-IFNa, anti-CD20 or CD4 biologics, and other cytokine inhibitors or biologics for T-cell or B-cell receptors or interleukins.

[00954] In the treatment of ALS, a compound described herein can be administered in combination with riluzole.

[00955] In the treatment of Parkinson's disease, a compound described herein can be administered in combination with levodopa, carbodopa or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl or amantadine.

[00956] In the treatment of Alzheimer's disease, a compound described herein can be administered in combination with donepezil, galantamine, memantine, rivastigmine, anti-ABeta (beta amyloid) including aducanumab, crenezumab, solanezumab and gantenerumab, small molecule inhibitors of BACE1 including verubecestat, AZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or anti-tau therapies such as LMTM (leuko- inium- bis(hydromethanesulfonate)).

[00957] In the treatment of rheumatoid arthritis, a compound described herein can be administered in combination with ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept, adalimumab, anakinra, pegal, etanercept, golimumab, infliximab, rituximab, tocilizumab or tofacitinib.

[00958] In the treatment of CVA, a compound described herein can be administered in combination with a thrombolytic agent (such as tissue plasminogen activator (TPA®), Activase®, Lanoteplase®, Reteplase®, Staphylokinase®, Streptokinase®, Tenecteplase ®, Urokinase®), an anticoagulant (such as heparin, coumadin, clopidrogel (Plavix®)) and a platelet aggregation inhibitor (such as dipyridamole (Persantine®), ticlopidine HCL (Ticlid®), eptifibatide (Integrillin®) and/or aspirin).

[00959] In the treatment of SIRS, a compound described herein can be administered in combination with a broad-spectrum antibiotic (such as vacomycin) or other anti-MRSA therapy (cefeprima (Maxipime®), piperacillin/tazobactam (Zosyn®), carbapenem (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.) and low-dose steroids, such as hydrocortisones.

[00960] In the treatment of inflammatory bowel disease (particularly Crohn's disease and/or ulcerative colitis), a compound of any formula described herein may be administered in combination with vedolizumab (Entyvio®), alicaforsen, or remestemcel-L ( Prochymal®). Specifically, in the treatment of inflammatory bowel disease (particularly Crohn's disease and/or ulcerative colitis), a compound described herein can be administered in combination with alicaforsen, or remestemcel-L (Prochymal®). In the treatment of psoriasis, a compound described herein can be administered in combination with ixekizumab, tildrakizumab (MK-3222) or secukinumab (AIN457).

[00961] Specifically, in the treatment of psoriasis, a compound described herein can be administered in combination with ixekizumab or tildrakizumab (MK-3222). In the treatment of periodontitis, a compound of any formula described herein can be administered in combination with an antimicrobial agent (such as chlorhexidine (Peridex®, PerioCard®, PerioGard®, etc.)) or an antibiotic (such as doxycycline (Vibrox®) , Periostat®, Monodox®, Oracea®, Doryx®, etc.) or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).

[00962] In the treatment of asthma, a compound of any formula described herein can be administered in combination with an inhaled corticosteroid ((ICS) such as fluticasone propionate (Flovent®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort) , triamcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone phosphate (Asmanex® Twisthaler®) or Ciclesonide (Alvesco®)), a long-acting beta-agonist ((LABA), such as formoterol fumarate (Foradil ®), salmeterol xinafoate (Serevent®)), a combination of an ICS and LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®), formoterol/budesonide inhalation (Symbicort®), beclomethasone/formoterol dipropionate (Inuvair® ) and fluticasone propionate/salmeterol (Advair®), a short-acting beta agonist (SABA) such as albuterol sulfate (ProAir®, Proventil HFA®, Ventolin HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate ( Xopenex® HFA), ipratropium bromide/albuterol (Combivent® Respimat®), ipratropium bromide (Atrovent® HFA), a leukotriene modifier (such as montelukast sodium (Singulair®), zafirlukast (Accolate®) or zileuton (Zyflo®) and anti-IgE (such as omalizumab (Xolair®)), a methylxanthine bronchodilator (such as theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid® , Lanophyllin®, Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear ®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Uniphyl®), a mast cell inhibitor (such as cromulin sodium (Nasalcrom®) and nedocromil sodium (Tilade®)), a muscarinic antagonist of long-acting ((LAMA), such as mometasone furoate/formoterol fumarate dihydrate (Dulera®)).

[00963] Other agents that may be suitable for use in combination therapy in the treatment of asthma include a protein tyrosine kinase inhibitor (masitinib), CRTH2/D-prostand receptor antagonist (AMG 853), indacaterol (Arcapta® Neohaler® ), an epinephrine inhalation aerosol (E004), fluticasone furoate/fluticasone propionate, vilanterol/fluticasone furoate inhalation powder (Relovair™), fluticasone propionate/eformoterol fumarate dihydrate (Flutiform®), reslizumab , salbutamol dry powder inhalation, tiotropium bromide (Spiriva®HandiHaler®), formoterol/budesonide (Symbicort®SMART®), fluticasone furoate (Veramyst®), Vectura's VR506, lebrikizumab (RG3637), a combination inhibitor of phosphodiesterase (PDE)-3 and (PDE-4 (RPL554).

[00964] In the treatment of COPD, a compound of any formula described herein can be administered in combination with a LABA (such as salmeterol xinafoate (Serevent), umeclidinium/vilanterol (Anuro Ellipta®), umeclidinium (Incruse Ellipta®), arformoterol tartrate (Brovana®), inhalation powder formoterol fumarate (Foradil®), indacterol maleate (Arcapta Neohaler®), or fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®)), a long-acting anticholinergic (or muscarinic antagonist, such as tiotropium bromide (Spiriva®) and aclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r) inhibitor (as organic intermediates, Daliresp®), an ICS/LABA combination (as fluticasone furoate and vilanterol (Breo Ellipta®), fluticasone propionate/salmeterol (Advair®), budesonide/formoterol (Symbicort®), mometasone/formoterol (Dulera®), albuterol sulfate/ipratropium bromide (Duoneb®, Atrovent®), albuterol/ipratropium (Combivent Respimat ®)), a SABA (such as Atrovent® ipratropium bromide) and albuterol sulfate (ProAir®, Proventil®)) and an ICS (such as budesonide (Pulmicort®) and fluticasone propionate (Flovent®), beclomethasone dipropionate (QVAR®).

[00965] Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (a CXCR2 antagonist), glycoproronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide and indacaterol maleate ((QVA149 ) Ultibro® Breezhaler®), glycopyrrolate formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®)/olodaterol (Striverdi® Respimat®) and aclidinium/formoterol inhalation .

[00966] In the treatment of a mycobacterial infection (tuberculosis), a compound of any formula described herein can be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®) and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (capreomycin), a fluoroquinolone (levofloxacin, moxifloxacin, ofloxacin), thioamide (eionamide), cyclosporine (Sandimmune®), para-aminosalicylic acid (Paser®), cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®) or delamanid (OPC- 67683).

[00967] Specifically, in the treatment of a mycobacterial infection (tuberculosis), a compound described herein can be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®) and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (Capreomycin®), a fluoroquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (eionamide), cycloserine (Seromycin®) , kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®) or delamanid (OPC-67683).

[00968] In the treatment of systemic scleroderma, a compound of any formula described herein may be administered in combination with an oral corticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent ( such as methotrexate (Rhumatrex®, Trexall®), cyclosporine (Sandimmune®), anti-thymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide (Thalomid® ), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)), a calcium channel blocker (such as nifedipine (Procardia®, Adalat®) or nicardipine (Cardene®), a topical emollient (nitroglycerin ointment) , an ACE inhibitor (e.g., lisinopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), a serotonin reuptake inhibitor (such as fluoxetine (Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)) an antifibrotic agent (such as colchicine (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (KMSO) and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), a proton pump inhibitor (such as omeprazole (Prilosec®) , metoclopramide (Reglan®), Lansoprazole (Prevacid®), esomeprazole (Nexium®), Pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentis pharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).

[00969] Specifically, in the treatment of systemic scleroderma, a compound of any formula described herein may be administered in combination with an oral corticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), antithymocyte globulin (Atgam®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), a calcium channel blocker (such as nifedipine (Procardia®, Adalat®) or nicardipine (Cardene®), a topical emollient (ointment of nitroglycerin), an ACE inhibitor (such as lisinopril (Zestril®, Prinivil®), diltaxem (Cardizem®, Cardizem®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), a serotonin reuptake inhibitor ( such as fluoxetine (Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)), an anti-fibrotic agent (such as colchicines (Colcrys®) , para-aminobenzoic acid (PABA), dimethyl sulfoxide (KMSO) and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), a proton pump inhibitor (such as omeprazole (Prilosec®) , metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical) or tocilizumab (Actema®).

[00970] In the treatment of cystic fibrosis, a compound as described herein can be administered in combination with a cystic fibrosis transmembrane conductance regulator (CFTR) enhancer (ivacftor (Kalydeco®)), a mucolytic agent (such as dornase alfa (Pulmozyme®)), pancreatic enzymes (such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), a bronchodilator (such as salbutamol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®)), an antibiotic (including inhaled, oral, or parenteral, such as tobramycin inhalation solution (TOBI®, Bethkis®, TOBI Podhaler®), aztreonam inhalation (Azactam®, Cayston®), colistimethate sodium (Coly Mycin ®), cephalosporins (cefadroxil monohydrate (Duricef®), cefazolin (Kefzol®), Cephalexin (Keflex®), cefazolin (Ancef®, etc.), fluoroquinolones (moxifloxacin, levofloxacin, gemifloxacin, etc.), azithromycin (Zithromax®), gentamicin (Garamycin®), piperacillin/tazobacam (Zosyn®), Cephalexin (Keflex), Ceftazidime (Fortaz, Tazicef), ciprofloxin (Cipro XR, Proquin XR), trimethoprim/sulfamethoxazole (Bactrim DS, DS Septra), chloramphenicol)), or ivacftor (Kalydeco®)/lumacaftor (VX-809), ataluren (Translarna®), or with tiopropium bromide (Spiriva Handihaler®) as an additive to standard therapy.

[00971] In the treatment of retinitis pigmentosa, a compound as described herein can be administered in combination with a ciliary neurotrophic growth factor (NT-501-CNTF) or gene transfer agent, UshStat®.

[00972] In the treatment of macular degeneration, a compound of any formula described herein can be administered in combination with ophthalmic intravitreal injections (afibercept (Eylea®)) or with an anti-vascular endothelial growth factor (VEGF) inhibitor (such as ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophic growth factor agent (NT501), iSONEP® or bevacizumab (Avastin®).

[00973] In the treatment of influenza, a compound as described herein can be administered in combination with a trivalent inactivated influenza vaccine (IIV3) (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®) , an inactivated quadrivalent (IIV4) influenza vaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), a trivalent recombinant influenza vaccine (such as FluBlok®), a live attenuated quadrivalent influenza vaccine (such as FluMist® Quadrivalent) , an antiviral agent (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®) or amantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®, Preflucel or VaxiGrip®

[00974] In the treatment of a staphylococcal infection, a compound of any formula described herein may be administered in combination with an antibiotic (such as a-lactase cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef® etc.), nafcillin (Unipen®), a sulfonamide (sulfamethoxazole and trimethoprim (Bacrim®, Septra®), sulfasalazine (Azulfidine®), acetylsulfisoxazole (Gantrisin®), etc.) or vancomycin (Vancocin®)).

[00975] In the treatment of transplant rejection, a compound of any formula described herein can be administered in combination with a high dose corticosteroid (such as prednisone (Deltasone®), methylprednisolone (SoluMedrol®) etc.) a calcineurin inhibitor ( such as cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), an mTor inhibitor (such as sirolimus (Rapamune®) or everolimus (Afinitor®)), an antiproliferative agent (such as azathioprine (Imuran®, Azasan®), mycophenolate mofetil (CellCept®) or mycophenolate sodium (Myfortic®)), a monoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)), an interleukin-2 receptor antagonist ( (Basiliximab®, Simulect®), daclizumab (Zenapax®) or rituximab (Rituxan®)), a polyclonal anti-T cell antibody (such as equine anti-thymocyte gamma globulin (Atgam®) or rabbit anti-thymocyte globulin (Thymoglobulin®) ) an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K) or a murine anti-TCR mAb (TO L101).

[00976] Specifically, in the treatment of transplant rejection, a compound of any formula described herein can be administered in combination with a monoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)), an anti-T cell polyclonal antibody (such such as anti-thymocyte equine gamma globulin (Atgam®) or anti-thymocyte rabbit globulin (Thymoglobulin®)), an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K) or a murine anti-TCR mAb (TOL101) .

[00977] In the treatment of atopic dermatitis, a compound of any formula described herein can be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), a oral corticosteroid (such as hydrocortisone (Cortef®), methylprednisolone (Medrol®) or prednisolone (Pediapred®, Prelone®), an immunosuppressant (such as cyclosporine (Neoral®) or interferon-gamma (Alferon N®, Infergen® , Intron A, Roferon-A®)), an antihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), an antibiotic (such as the penicillin derivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), nonsteroidal immunosuppressive agent (such as azathioprine (Imuran®, Azasan®), methotrexate (Rhumatrex®, Trexall®), cyclosporine (Sandimmune®), or mycophenolate mofetil (CellCept®)).

[00978] Specifically, in the treatment of atopic dermatitis, a compound of any formula described herein can be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a corticosteroid topical (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), fluorandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®) and clobetasol (Temovate®)), oral corticosteroids (such as hydrocortisone (Cortef®), methylprednisolone (Medrol®) or prednisolone (Pediapred®, Prelone®), a gamma interferon (Alferon N®, Infergen®, Intron A, Roferon A®)), an antihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), or an antibiotic (such as flucloxacillin), penicillin derivatives (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm ®, etc.)).

[00979] In the treatment of burns, e.g., a burn or burn shock, a compound of any formula described herein may be administered alone, or in combination with an antimicrobial agent, typically a topical antibiotic (mafenide acetate cream, of silver sulfadiazine) and/or an analgesic (opioid analgesics, e.g. morphine, oxycodone). Other therapeutic agents that may be useful for treating burns include retinoids and pirfenidone.

[00980] In certain embodiments, at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, and a platelet aggregation inhibitor. In certain embodiments, at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a cerebrovascular accident.

[00981] In certain embodiments, at least one other therapeutically active agent is selected from a broad-spectrum antibiotic, anti-MRSA therapy, and a low dose steroid. In certain embodiments, at least one other therapeutically active agent is selected from vacomycin, cefeprima, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone. In certain embodiments, the disease or disorder treated with these agents is systemic inflammatory response syndrome.

[00982] In certain embodiments, at least one other therapeutically active agent is alicaforsen or remestemcel-L. In certain embodiments, the disease or disorder treated with these agents is Crohn's disease or ulcerative colitis.

[00983] In certain embodiments, at least one other therapeutically active agent is ixekizumab or tildrakizumab. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is psoriasis.

[00984] In certain embodiments, at least one other therapeutically active agent is an antimicrobial agent or an antibiotic. In certain embodiments, at least one other therapeutically active agent is selected from chlorhexidine, doxycycline, and minocycline. In certain embodiments, the disease or disorder treated with these agents is periodontitis.

[00985] In certain embodiments, at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long-acting beta-agonist, a combination of an inhaled corticosteroid and a long-acting beta-agonist, a short-acting beta-agonist , a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. In certain embodiments, at least one other therapeutically active agent is selected from fluticasone propionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone phosphate or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate. and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide , montelukast sodium, zafirlukast, zileuton, omalizumab theophylline, cromulin sodium, nedocromil sodium and a combination of mometasone furoate and formoterol fumarate dihydrate. In certain embodiments, at least one other therapeutically active agent is selected from a protein tyrosine kinase inhibitor, a CRTH2/D-prostanoid receptor antagonist, an epinephrine inhalation aerosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor. In certain embodiments, at least one other therapeutically active agent is selected from masitinib, AMG 853, indacaterol, E004, a combination of fluticasone furoate and fluticasone propionate, a combination of vinanterol fluticasone furoate, a combination of fluticasone propionate and fumarate of formoterol dihydrate, reslizumab, salbutamol, tiotropium bromide, a combination of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab and RPL554. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is asthma.

[00986] In certain embodiments, at least one other therapeutically active agent is selected from a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, a combination of a long-acting beta agonist and corticosteroid inhaled, a short-acting beta-agonist and an inhaled corticosteroid. In certain embodiments, at least one other therapeutically active agent selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, arformoterol tartrate, formoterol fumarate, indacterol maleate, a combination of fluticasone propionate and formoterol fumarate di- hydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate and beclomethasone dipropionate. In certain embodiments, at least one other therapeutically active agent is selected from SCH527123, glycopyrronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol and a combination of aclidinium and formoterol. In certain embodiments, the disease or disorder treated with these agents is COPD.

[00987] In certain embodiments, at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic. In certain embodiments, at least one other therapeutically active agent is selected from isoniazid, embutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxfloxicin, ofloxacin, eionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU- 100480 and delamanid. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a mycobacterial infection.

[00988] In certain embodiments, at least one other therapeutically active agent is selected from an oral corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, a reuptake inhibitor serotonin, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton pump inhibitor or imatinib, ARG201 and tocilizumab. In certain embodiments, at least one active agent is selected from prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicines, acid para. -aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, alpha interferon, gamma interferon (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201 and tocilizumab. In certain embodiments, the disease or disorder treated with these agents is systemic scleroderma.

[00989] In certain embodiments, at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulatory enhancer, amucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic or ivactor/lumacaftor, ataluren and bromide. tiopropium. In certain embodiments, at least one other therapeutically active agent is selected from ivacftor, dornase alfa, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin. , piperacillin/tazobacam, ceftazidime, ciprofloxin, sulfamethoxazole/trimethoprim, chloramphenicol or ivactor/lumacaftor, ataluren and tiopropium bromide. In certain embodiments, the disease or disorder treated with these agents is cystic fibrosis.

[00990] In certain embodiments, at least one other therapeutically active agent is a ciliary neurotrophic growth factor or a gene transfer agent. In certain embodiments, at least one other therapeutically active agent is NT-501-CNTF or a gene transfer agent encoding myosin VIIA (MY07A). In certain embodiments, the disease or disorder treated with these agents is retinitis pigmentosa.

[00991] In certain embodiments, at least one other therapeutically active agent is selected from ophthalmic intravitreal injections, an antivascular endothelial growth factor inhibitor and a ciliary neurotrophic growth factor agent. In certain embodiments, at least one other therapeutically active agent is selected from afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab. In certain embodiments, the disease or disorder treated with these agents is macular degeneration.

[00992] In certain embodiments, at least one other therapeutically active agent is selected from a trivalent inactivated influenza vaccine (IIV3), a quadrivalent inactivated influenza vaccine (IIV4), a trivalent recombinant influenza vaccine, a quadrivalent attenuated influenza vaccine live, an antiviral agent, or inactivated flu vaccine. In certain embodiments, at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is influenza.

[00993] In certain embodiments, at least one other therapeutically active agent is selected from a beta-lactam, nafcillin, sulfamethoxazolem, trimethoprim, sulfasalazine, acetylsulfisoxazole and vancomycin. In certain embodiments, the disease or disorder treated with these agents is a staphylococcal infection.

[00994] In certain embodiments, at least one other therapeutically active agent is selected from a monoclonal antibody, an anti-T cell polyclonal antibody, an anti-thymocyte equine gamma globulin antibody, an anti-thymocyte rabbit globulin antibody, an anti-T cell antagonist. -CD40, a JAK inhibitor and a murine anti-TCR mAb.

[00995] In certain embodiments, at least one other therapeutically active agent is selected from muromonabCD3, ASKP-1240, ASP015K and TOL101. In certain embodiments, the disease or disorder treated with these agents is transplant rejection.

[00996] In certain embodiments, at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, a gamma interferon, an antihistamine or an antibiotic. In certain embodiments, at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortisone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, an alpha interferon protein, a recombinant synthetic type I interferon , interferon alfa-2a, interferon alfa-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin and erythromycin. In certain embodiments, the disease or disorder treated with these agents is atopic dermatitis.

8. Dosage

[00997] The specific dose level of a compound of the present application for any particular individual will depend on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration and excretion rate, combination of medications and the severity of the particular disease in the subject being treated. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Dosages between about 0.1 and 150 mg/kg may be appropriate. In certain embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments, a dosage between 0.5 and 60 mg/kg may be appropriate. Normalization according to the subject's body weight is particularly useful when adjusting dosages between individuals of very different sizes, as occurs when using the drug in human children and adults or when converting an effective dosage in a non-human subject, such as as a dog to a dosage suitable for a human subject.

[00998] Daily dosage can also be described as a total amount of a compound described herein administered per dose or per day. The daily dosage of a compound described herein may be between about 1 mg and 4000 mg, between about 2000 and 4000 mg/day, between about 1 to 2000 mg/day, between about 1 to 1000 mg/day, between about 10 to 500 mg/day, from about 20 to 500 mg/day, from about 50 to 300 mg/day, from about 75 to 200 mg/day, or from about 15 to 150 mg/day.

[00999] When administered orally, the total daily dosage for a human can be between 1 mg and 1,000 mg, between about 1,0002,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.

[001000] The compounds of the present application or their compositions can be administered once, twice, three or four times a day, using any suitable method described above. Furthermore, administration or treatment with the compounds can be continued for several days; for example, treatment would generally continue for at least 7 days, 14 days, or 28 days, for a treatment cycle. Treatment cycles are well known in cancer chemotherapy and are often alternated with rest periods of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. Treatment cycles, in other modalities, can also be continuous.

[001001] In certain embodiments, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week or once a week.

9. Synthesis of compounds

[001002] Compounds can be prepared using the methods described herein and their routine modifications, which will be evident given the present invention and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings described herein. The synthesis of typical compounds described herein can be carried out as described in the following examples. If available, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers.

[001003] The compounds of the description can be prepared using the methods described herein and their routine modifications, which will be evident given the present invention and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings described herein. The synthesis of typical compounds described herein, for example, compounds having structures described by one or more formulas or compounds described herein, can be carried out as described in the following examples. If available, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers.

[001004] The compounds of this description can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that, where typical or preferred process conditions are given (i.e. reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.), other process conditions may also be used unless otherwise stated. . Optimal reaction conditions may vary with the specific reagents or solvents used, but such conditions can be determined by a person skilled in the art through routine optimization procedures.

[001005] Additionally, as will be evident to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from being subjected to undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protective groups are described in Wuts, PGM, Greene, TW, and Greene, TW (2006). Greene’s Protective Groups in Organic Synthesis. Hoboken, NJ, Wiley-Interscience and references cited therein.

[001006] Furthermore, the compounds of this description may contain one or more chiral centers. In this sense, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All of these stereoisomers (and enriched mixtures) are included within the scope of this description unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[001007] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof described in standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1 -5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[001008] The terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent that is inert under the conditions of the reaction being described together therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like, the solvents used in the reactions of the present invention are solvents. inert organics, and the reactions are carried out under an inert gas, preferably nitrogen.

[001009] The term "qs" means adding an amount sufficient to achieve a stated function, for example, to bring a solution to the desired volume (i.e. 100%).

[001010] Scheme 1 shows the synthesis of compounds of Formula I, where LG is a leaving group and X1X2Y1Y2, A, L, R2, R3, R4 and R9 are as defined here. Scheme 1

[001011] As represented in Scheme 1, compounds of Formula I can be prepared by contacting a 1-a with compound 1-b, under standard amide bonding forming condition reactions. As is typical in peptide coupling reactions, an activating agent may be used to facilitate the reaction. Suitable coupling agents (or activating agents) are known in the art and include, for example, carbodiimides (e.g. N,N'-dicyclohexylcarbodiimide (DCC), N,N'-dicyclopentylcarbodiimide, N,N'-diisopropylcarbodiimide (DIC ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-butyl-N-methylcarbodiimide (BMC), N-butyl-N-ethylcarbodiimide (BEC), 1,3-bis(2,2- dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC), etc.), anhydrides (e.g. symmetric, mixed or cyclic anhydrides), activated esters (e.g. phenyl-activated ester derivatives, p-activated ester -hydroxamic, hexafluoroacetone (HFA), acylazoles (acylimidazoles using CDI, acylbenzotriazoles, etc.), acylazides, acid halides, phosphonium salts (HOBt, PyBOP, HOAt, etc.), ammonium/uronium salts (e.g. tetramethyl aminium, bispirolidine aminium salts, bispiperidino aminium salts, imidazolium uronium salts, pyrimidine uronium salts, uronium salts derived from N, N, N'-trimethyl-N'-phenylurea, ammonium/uronium based coupling reagents morpholino, uranium antimoniate salts, etc.), organophosphate reagents (e.g. phosphinic and phosphoric acid derivatives), organosulfur reagents (e.g. sulfonic acid derivatives), triazine coupling reagents (e.g. 2-chloro -4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphonium chloride, 4-(4, 6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium, etc.), pyridinium coupling reagents (e.g., Mukaiyama reagent, pyridinium tetrafluoroborate coupling reagents, etc.), polymer-supported reagents (e.g., polymer-bound carbodiimide, polymer-bound TBTU 2, 4, 6-trichloro-1,3, 5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ to polymer, etc.) and the like (see, for example, El-Faham et al. Chem. Rev., 2011, 111(11): 6557-6602; Han, et al. Tetrahedron, 2004, 60:2447-2467). Compounds of formula 1-a and 1-b for use in Scheme 1 can be obtained as described in the schemes and Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials.

[001012] Scheme 2 shows an exemplary synthesis for compounds that contain a 6,7-fused ring and where Y1 is O. In Scheme 2, PG is a protecting group (e.g., BOC) and X6X7X8X9Y2q R1, R3, R4, and R10 are as defined here. Scheme 2

[001013] In Scheme 2, appropriately substituted 2-a can be cyclized under standard amide bonds forming reaction conditions (e.g., as described above). Compounds of formula 2-a can be obtained from commercial sources, or prepared as described in the Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials. Furthermore, the desired functional groups at Y2, R1, R3, R4 and R10 can be installed before or after cyclization, employing conventional synthetic methods known in the art (e.g., halogenation, reduction, oxidation, olefination, alkylation, etc.) .

[001014] Scheme 3 shows an exemplary synthesis for compounds that contain a fused ring with 5.7 and where Y1 is O. In Scheme 3, Z is halo and X1X2X3X4X5Y2q R1, R3, R4 and R10 are as defined here. Scheme 3

[001015] In Scheme 3, appropriately substituted 3-a can be contacted with hydroxylamine hydrochloride under reaction conditions sufficient for 3-b. Ring expansion of 3-b to provide lactam 3-c can be accomplished by contacting oxime 3-b with phosphorus pentoxide. Alternatively, lactam 3-c can be provided by contacting 3-a with sodium azide in the presence of sulfuric acid. α- Halogenation of 3-c using a suitable reagent (e.g. NBS, iodotrimethylsilane, etc.) and optional N-alkylation of the azapanone nitrogen with a compound of formula R1-LG, where LG is a suitable leaving group (e.g. , halo) provides 3-d. Contacting 3-d with sodium azide yields 3-e. Reduction of the azide to 3-e (e.g. hydrogenation, triphenylphosphine, etc.) gives 3-f. Compounds of formula 3-a can be obtained from commercial sources, or prepared as described in the Examples provided herein or from conventional synthetic methods known in the art using appropriate starting materials. Furthermore, alternative functional groups can be installed at any point before, during or after the steps shown in Scheme 3 employing conventional synthetic methods known in the art (e.g., halogenation, reduction, oxidation, olefination, alkylation, etc.).

[001016] Also provided here is a process for preparing a compound of Formula II:

[001017] or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, comprising the contact of a compound of formula XVI or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof:

[001018] and contact a compound of Formula XVI or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, with a compound of Formula XVII:

[001019] under reaction conditions sufficient to provide the compound of Formula II or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein

[001020] Y2 is -O-, -S- or -NR5-;

[001021] R5 is H or optionally substituted C1-C6 alkyl; It is

[001022] L, ring A, q, R1, R3, R4, R9, R10X6X7X8 and X9 are as defined here.

[001023] In certain embodiments, a process for preparing a compound of Formula II is provided:

[001024] or a respective salt, tautomer, stereoisomer or mixture of stereoisomers, comprising:

[001025] (a) contacting a compound of Formula X:

[001026] or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, with a compound of formula XI:

[001027] under reaction conditions sufficient to provide the compound of Formula II or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof:

[001028] (b) contacting a compound of Formula XII or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, under reaction conditions sufficient to provide the compound of Formula (XIII) or a salt, tautomer, stereoisomer or mixture thereof its stereoisomers:

[001029] (c) contacting a compound of Formula XIII or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, under reaction conditions sufficient to provide the compound of Formula XIV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof :

[001030] (d) optionally contacting a compound of Formula XIV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, with an alkylating agent, under reaction conditions sufficient to provide the compound of Formula XV or a salt, tautomer, stereoisomer or mixture of its stereoisomers:

[001031] (e) deprotect the compound of Formula XV or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, under reaction conditions sufficient to provide the compound of Formula XVI or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof:

[001032] and contact a compound of Formula XVI or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, with a compound of Formula XVII:

[001033] under reaction conditions sufficient to provide the compound of Formula II or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein

[001034] P is a protecting group;

[001035] Y2 is -O-, -S- or -NR5-;

[001036] R5 is H or optionally substituted C1-C6 alkyl; and L, ring A, q, R1, R3, R4, R9, R10X6X7X8 and X9 are as defined herein.

[001037] In certain embodiments of the processes described above, at least one of X7 or X9 is N. In certain embodiments of the processes described above, X7 is N and X6X8 and X9 are CH. In certain embodiments of the processes described above, X9 is N and X6X7 and X8 are CH. In certain embodiments of the processes described above, R1 is methyl. In certain embodiments of the processes described above, Y2 is -O-.

[001038] In certain embodiments of the processes described above, P is tert-butoxycarbonyl. In certain embodiments of the processes described above, the reaction conditions of step (b) comprise hydrogen gas. In certain embodiments of the processes described above, the reaction conditions of step (c) comprise a peptide coupling agent. In certain embodiments of the processes described above, the alkylating agent of step (d) is methyl iodide.

[001039] It will also be appreciated that in each of the above schemes, the addition of any substituent may result in the production of a number of isomeric products (including, but not limited to, enantiomers or one or more diastereomers) any or all of which can be isolated and purified using conventional techniques. When enantiomerically pure or enriched compounds are desired, chiral chromatographies and/or enantiomerically pure or enriched starting materials may be employed, as conventionally used in the art or as described in the Examples.

EXAMPLES

[001040] The following examples are included to demonstrate specific embodiments of the description. It should be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques for operation as well as the practice of description and thus may be considered to constitute specific modes for their practice. However, those skilled in the art should, in light of the present invention, appreciate that many changes can be made to the specific embodiments that are disclosed and still obtain the same or similar result without departing from the spirit and scope of the description.

General Procedures

[001041] Liquid Chromatography-Mass Spectrometry Method A: Total chromatographic total ion current (TIC) and DAD UV traces, along with MS and UV spectra associated with the peaks, were obtained on an AcquityTM UPLC/MS system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in positive and negative alternating electrospray ionization mode. [LC/MS-ES (+/-): analyzes performed using an Acquity UPLCTM CSH, C18 column (50 x 2.1 mm, 1.7 μm particle size), column temperature 40 °C, mobile phase: A-water + 0.1% HCOOH/B-CH3CN + 0.1% HCOOH, flow rate: 1.0 mL/min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, dwell time 2.0 min. Positive ES 100-1000, Negative ES 100-1000, UV DAD Detection 210-350 nm.

[001042] Liquid Chromatography-Mass Spectrometry Method B: Total chromatographic total ion current (TIC) and DAD UV traces, along with MS and UV spectra associated with the peaks, were obtained on an AcquityTM UPLC/MS system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in positive and negative alternating electrospray ionization mode. [LC/MS-ES (+/-): analyzes performed using an Acquity UPLCTM BEH, C18 column (50 x 2.1 mm, 1.7 particle size), column temperature 40, mobile phase: A- 0 .1% v/v aqueous ammonia solution pH 10/B- CH3CN, flow rate: 1.0 mL/min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, stopping time 2.0 min. Positive ES 100-1000, Negative ES 100-1000, UV DAD Detection 210-350 nm.

[001043] Liquid Chromatography-Mass Spectrometry Method C: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B : 0.05% TFA in MeCN) 2.2 min with a total run time of 2.6 min. The column temperature was 40 oC with a flow rate of 1.0 mL/min.

[001044] Liquid Chromatography-Mass Spectrometry Method D: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) 3.2 min with a total run time of 3.6 min. The column temperature was 40 oC with a flow rate of 1.0 mL/min.

[001045] Liquid Chromatography-Mass Spectrometry Method E: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a 2.7 μm, 3.0 x 50 mm Ascentis Express C18. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a total time of run of 20.0 min. The column temperature was 45 oC with a flow rate of 1.5 mL/min.

[001046] Liquid Chromatography-Mass Spectrometry Method F: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a 2.7 μm, 3.0 x 50 mm Ascentis Express C18. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.8 min with a total run time of 3.0 min. The column temperature was 45 oC with a flow rate of 1.5 mL/min.

[001047] Liquid Chromatography-Mass Spectrometry Method G: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: MeCN) over 1.7 min with a total run time of 2.0 min. The column temperature was 40 oC with a flow rate of 1.3 mL/min.

[001048] Liquid Chromatography-H Mass Spectrometry Method: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: MeCN) over 2.7 min with a total run time of 3.0 min. The column temperature was 40 oC with a flow rate of 1.3 mL/min.

[001049] Liquid Chromatography-Mass Spectrometry Method I: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 2.1 x 50 mm. A linear gradient was applied, starting at 90% A (A: 0.10% formic acid in water) and ending at 100% B (B: 0.10% formic acid in MeCN) over 1.70 min with a total running time of 2.0 min. The column temperature was 45 oC with a flow rate of 1.0 mL/min.

[001050] Liquid Chromatography-Mass Spectrometry Method J: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 2.1 x 50 mm. A linear gradient was applied, starting at 90% A (A: 0.10% formic acid in water) and ending at 95% B (B: 0.10% formic acid in MeCN) 2.70 min with a total run time of 3 ,0 min. The column temperature was 45 oC with a flow rate of 1.0 mL/min.

[001051] Liquid Chromatography-K Mass Spectrometry Method: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a 2.7 μm, 3.0 x 50 mm Ascentis Express C18. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.6 min with a total time running time of 2.0 min. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001052] Liquid Chromatography-Mass Spectrometry Method L: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a 2.7 μm, 3.0 x 50 mm Ascentis Express C18. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.6 min with a total time running time of 3.0 min. The column temperature was 40 °C with a flow rate of 1.5 mL/min.

[001053] Liquid Chromatography-Mass Spectrometry Method M: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a Kinetex XB-C18, 2.6 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.8 min with a total time running time of 3.0 min. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001054] Liquid Chromatography-Mass Spectrometry Method N: LCMS analyzes were performed on a SHIMADZU LCMS consisting of a UFLC 20-AD detector and LCMS 2020 MS. The diode array detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.5 to 1.0 s. The column used was a 2.7 μm, 3.0 x 50 mm Ascentis Express C18. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.7 min with a total time of 2.0 min run. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001055] Liquid Chromatography-Mass Spectrometry Method O: The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 2.7 min with a total time 3 min execution time. The column temperature was 45 oC with a flow rate of 1.5 mL/min.

[001056] Liquid Chromatography-Mass Spectrometry Method P: The column used was an Ascentis Express C18, 3.5 μm, 4.6 x 50 mm. A linear gradient was applied, starting at 90% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 5.2 min with a dwell time total run time of 5.6 min. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001057] Liquid Chromatography-Mass Spectrometry Method Q: The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) over 4.7 min with a total time of 5.0 min run. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001058] Liquid Chromatography-Mass Spectrometry Method R: The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) for 1.8 min with a total run time of 2.0 min. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001059] Liquid Chromatography-Mass Spectrometry Method S: The column used was a 2.7 μm Ascentis Express C18, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a total time of 2.0 min run. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001060] Liquid Chromatography-Mass Spectrometry Method T: The column used was a 2.7 μm Ascentis Express C18, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.7 min with a total dwell time of 3.0 min run. The column temperature was 40 oC with a flow rate of 1.5 mL/min.

[001061] Liquid Chromatography-Mass Spectrometry Method U: The column used was an Acquity UPLCTM BEH column, C18 (50 x 2.1 mm, particle size 1.7), column temperature 40 oC, mobile phase: A - 10 mM ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia/B-CH3CN aqueous solution, flow rate: 1.0 mL/min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, dwell time 2.0 min. Positive ES 100-1000, Negative ES 100-1000, UV DAD Detection 210-350 nm.

[001062] Liquid Chromatography-Mass Spectrometry Method V: The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total time of 5.3 min. The column temperature was 40 oC with a flow rate of 1.0 mL/min.

[001063] Liquid Chromatography-Mass Spectrometry Method W: The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total time of 5.3 min. The column temperature was 40 oC with a flow rate of 1.0 mL/min.

[001064] Liquid Chromatography-Mass Spectrometry Method X: The column used was an Ascentis Express C18, 2.7 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) 4.1 min with a total run time of 5.3 min. The column temperature was 40 oC with the flow rate of 1.5 mL/min.

[001065] Liquid Chromatography-Mass Spectrometry Method Y: The column used was a Poroshell HPH-C18, 2.7 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% NH4HCO3 in water) and ending at 95% B (B: 0.05% NH4HCO3 in MeCN) for 1.8 min with a total run time 2 min. The column temperature was 45 oC with a flow rate of 1.5 mL/min.

[001066] HPLC analyzes were performed on a SHIMADZU UFLC with two LC20 AD pumps and an SPD-M20A Photodiiode Array Detector. The column used was an XBridge C18, 3.5 μm, 4.6 x 100 mm. A linear gradient was applied, starting at 90% A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) over 10 min with a total dwell time of 15 min. The column temperature was 40 °C with a flow rate of 1.5 mL/min. The diode array detector was scanned from 200-400 nm.

[001067] Thin layer chromatography (TLC) was performed on Alugram® (silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional visualization methods were also employed in some cases. In these cases, the TLC plate was developed with iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing well), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g ( NH4)6Mo7O24.4H2O, 5 g (NH4)2Ce (IV) (N]O3)6 in 450 mL of water and 50 mL of concentrated H2SO4) to visualize the compound. Flash chromatography was performed using 40-63 μm silica gel (230-400 mesh) from Silicycle following techniques analogous to those described in Still, WC; Kahn, M; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents used for flash chromatography or thin layer chromatography were mixtures of chloroform/methanol, dichloromethane/methanol, ethyl acetate/methanol, and hexanes/ethyl acetate.

Analytical Methods

[001068] 1H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with a DUAL 400MHz S1 probe, a Bruker Avance 400 instrument equipped with a 6 S1 400 MHz 5mm 1H-13C ID probe, a Bruker Avance III 400 nanobay instrument equipped with a direct 5mm BBFO broadband probe, a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker probe 400 BBO operating at 400 MHz. Spectra were acquired in the indicated solvent at about room temperature unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Flash chromatography was performed using 40-63 μm silica gel (230-400 mesh) from Silicycle following techniques analogous to those described in Still, WC; Kahn, M; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923.

Compost Preparation

[001069] When the preparation of the starting materials is not described, they are commercially available, are known in the literature, or are readily obtained by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to previous examples or intermediates, it will be appreciated by one skilled in the art that the reaction time, number of reagent equivalents and temperature may be modified for each specific reaction and that it may be necessary or desirable to employ different processing or purification techniques. When reactions are carried out using microwave irradiation, the microwave used is a Biotage Initiator. The actual power delivered varies during the course of the reaction in order to maintain a constant temperature.Example 1: 5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H,6H,7H,8H - thieno[3,2-b]azepin-6-yl)-1,2-oxazol-3-carboxamide Step 1: Preparation of N-[4,5,6,7-tetrahydro-1-benzothiophen-4-ylidene]hydroxylamine

[001070] A solution of hydroxylamine hydrochloride (4.56 g, 65.7 mmol) in 5N sodium acetate solution (120 mL) was added to a solution of 6,7-dihydro-1- benzothiophen-4(5H)-one (2.00 g, 13.1 mmol) in EtOH (200 mL). The reaction mixture was heated to 100 °C and stirred for 2 h. The volatiles were removed under reduced pressure and the crude product was dissolved in water and extracted with EtOAc. The organic portion was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 50:50) to give the title compound (1.10 g, 51%). 1H NMR (400 MHz, CDCI3) δ 7.76-7.42 (m, 1H), 7.30 (d, J=5.3 Hz, 1H), 7.09 (d, J=5.3 Hz , 1H), 2.89 (t, J=6.1 Hz, 2H), 2.82-2.77 (m, 2H), 2.02 (quin, J=6.3 Hz, 2H). LC-MS (Method A): m/z = 168.0 [M+H]+, 0.83 min. Step 2: Preparation of 4H,5H,6H,7H,8H-Thieno[3,2-b]azepin-5-one

[001071] Phosphorus pentoxide (11.3 g, 79.5 mmol) was added to methanesulfonic acid (10.9 g, 113.6 mmol) and the mixture was stirred for 2 hours. N-[4,5,6,7-Tetrahydro-1-benzothiophen-4-ylidene]hydroxylamine (1.10 g, 6.58 mmol) was then added to the above stirred solution, which had previously been heated to 100 °C. After stirring for 4 h at 110 °C, the reaction was cooled and quenched carefully by addition of saturated NaHCO3 solution. The mixture was extracted with chloroform. The combined organic portions were washed with saturated NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 80:20 to 0:100) to give the desired compound (450 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.90-7.69 (m, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.64 (d, J=5.3 Hz , 1H), 3.00 (t, J=6.9 Hz, 2H), 2.67-2.60 (m, 2H), 2.26-2.14 (m, 2H). Step 3: Preparation of 2-Chloro-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

[001072] N-chlorosuccinimide (356 mg, 2.68 mmol) was added to a solution of 4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (450 mg, 2. 69 mmol) in DMF (10 mL). The reaction was heated to 50 °C and stirred at that temperature for 16 h. The reaction was diluted with EtOAc, washed twice with saturated NH4Cl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 100:0 to 0:100) to give the title compound (190 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 7.73 (br.s, 1H), 6.50 (s, 1H), 2.89 (t, J=6.9 Hz, 2H), 2.66-2 .59 (m, 2H), 2.23- 2.13 (m, 2H). LC-MS (Method A): m/z = 202.1 [M+H]+0.84 min. Step 4: Preparation of 2-Chloro-6-iodo-4H,5H,6H,7H,8H-thieno[3,2- b]azepin-5-one

[001073] Iodotrimethylsilane (264 μL, 0.189 mmol) was added to a solution of 2-chloro-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (190 mg, 0.945 mmol ) and TMEDA (430 μL, 22.8 mmol) in CH2Cl2 (3 mL) which had been pre-cooled to -10 °C. The reaction was stirred at -10 °C for 30 min. Iodine powder (360 mg, 1.42 mmol) was added. The mixture was stirred at -10 °C for 1 h, allowed to reach room temperature over 1.5 h, stirred for a further 30 min and quenched with 1 M Na2S2O3 solution. The layers were separated and the aqueous portion was extracted twice with CH2Cl2. The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with CH2Cl2 to give the title compound (135 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 6.69 (s, 1H), 4.99-4.91 (m, 1H), 3.15-3.06 ( m, 1H), 2.95 (ddd, J=17.4, 11.9, 5.5 Hz, 1H), 2.19-208 (m, 1H), 1.88 (dddd, J=14, 9, 11.9, 5.1, 2.0 Hz, 1H). Step 5: Preparation of 2-Chloro-6-iodo-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

[001074] Iodomethane (29 μL, 0.460 mmol) was added to a mixture of 2-chloro-6-iodo-4H, 5H, 6H, 7H, 8H-thieno[3,2-b]azepin-5-one (135 mg, 0.418 mmol) and Cs2CO3 (205 mg, 0.627 mmol) in DMF (6 mL). The reaction was stirred at room temperature for 4 h, cooled to 4°C and stirred at that temperature for 36 h. More iodomethane (29 μL, 0.460 mmol) was added and the mixture was stirred at room temperature for 5 h. EtOAc was added and the organic portion was washed twice with 0.5 M HCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 50:50) to give the title compound (72 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 4.82 (dd, J=9.2, 6.7 Hz, 1H), 3.17 (s, 3H), 2 .90-2.56 (m, 4H). LC-MS (Method A): m/z = 342.0 [M+H]+, 1.10 min. Step 6: Preparation of 6-Azido-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

[001075] A mixture of 2-chloro-6-iodo-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (70 mg, 0.205 mmol) and NaN3 (20 mg, 0.307 mmol) in DMF (2 mL) was stirred at 33°C for 2 h. EtOAc was added and the organic portion was washed twice with 0.5 M HCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (52 mg), which was directly progressed to the next step. . 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 4.11 (dd, J=11.7, 7.4 Hz, 1H), 3.20 (s, 3H), 2 .88-2.77 (m, 2H), 2.53-2.40 (m, 1H), 2.28-2.13 (m, 1H). LC-MS (Method A): m/z = 257.1 [M+H]+1.04 min. Step 7: Preparation of 6-Amino-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

[001076] A mixture of 6-azido-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (52 mg) and triphenylphosphine (60 mg , 0.229 mg) in 3:1 THF-H2O (2 mL) was stirred at room temperature for 18 h. The reaction was diluted with EtOAc and washed twice with water. The organic portion was washed over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 60:40) to give the title compound (37 mg, 85% purity). 1H NMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 3.37-3.28 (m, 1H), 3.16 (s, 3H), 2.71-2.64 ( m, 2H), 2.37-2.26 (m, 1H), 1.90-1.77 (m, 1H), 1.66 (br. s, 2H). LC-MS (Method A): m/z = 231.1 [M+H]+0.41 min. Amide Coupling Procedure Step 8: Preparation and Separation of 5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H,6H,7H,8H-thieno[3,2-b] azepin-6-yl)-1,2-oxazol-3-carboxamide

[001077] A solution of 6-amino-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (27 mg, ~85% purity ), HBTU (39.6 mg, 0.104 mmol), 1-hydroxybenzotriazole (14 mg, 0.104 mmol), DIPEA (45 μL, 0.261 mmol), and 5-benzyl-1,2-oxazol-3-carboxylic acid (19 mg , 0.092 mmol) in DMF (3.5 mL) was stirred at room temperature for 4 h. EtOAc was added and the organic portion was washed twice with saturated NH4Cl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/EtOAc, 100:0 to 50:50) to give the title compound as a mixture of enantiomers. This mixture was determined by chiral HPLC on a Whelk O-1 (R,R) column (25 x 2.0 cm), 10 μm, using a mobile phase of n-hexane/(EtOH/MeOH/CH2Cl2 45/45/ 10 +0.1% isopropylamine) 20/80% v/v to give the two title compounds as separate enantiomers.

[001078] First elution enantiomer, Enantiomer 1: 1H NMR (400 MHz, CDCI3) δ 7.76 (d, J=7.5 Hz, 1H), 7.42-7.20 (m, 5H), 6 .80 (s, 1H), 6.34 (s, 1H), 4.81 (dt, J=11.2, 7.2 Hz, 1H), 4.13 (s, 2H), 3.31 ( s, 3H), 3.02-2.78 (m, 2H), 2.77-2.66 (m, 1H), 2.23-2.09 (m, 1H). LC-MS (Method A): m/z = 416.2 [M+H]+1.16 min. e.e. > 99.5% as determined on a 10 μm Whelk O-1 (R, R) (25 x 2.0 cm) column using a mobile phase of n-hexane/(EtOH/MeOH/CH2Cl2 45/45/ 10 + +0.1% isopropylamine) 20/80% v/v.

[001079] Second elution enantiomer, Enantiomer 2: 1H NMR (400 MHz, CDCl3) δ 7.82-7.71 (m, 1H), 7.39-7.23 (m, 5H), 6.80 ( s, 1H), 6.34 (s, 1H), 4.81 (dt, J=11.2, 7.1 Hz, 1H), 4.13 (s, 2H), 3.31 (s, 3H ), 3.00-2.78 (m, 2H), 2.76-2.66 (m, 1H), 2.21-2.10 (m, 1H). LC-MS (Method A): m/z = 416.2 [M+H]+1.16 min. ee = 98.4% as determined on a Whelk O-1 (R, R) (25 x 2.0 cm), 10 μm column using a mobile phase of n-hexane/(EtOH/MeOH/CH2Cl2 45/45 /10 + +0.1% isopropylamine) 20/80% v/v. Example 2: 5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetra - hydro-1H-benzo[b]azepin-3-yl)isoxazol-3-carboxamide Scheme caption: rt to ta Step 1: Preparation of (2R)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid

[001080] Di-tert-butyl dicarbonate (7.19 g, 32.9 mmol) was added to a solution of (2R) 2-Amino-4-(2-aminophenyl)-4-oxobutanoic acid sulfate (9 .18 g, 29.9 mmol) and triethylamine (12.1 g, 119.6 mmol) in dioxane (50 mL) under a nitrogen atmosphere with stirring. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to provide the title compound (9.18 g crude). LC-MS (Method C): m/z = 309.1 [M+H]+, 1.307 min. Step 2: Preparation of (R)-tert-butyl (2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

[001081] 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (13.6 g, 35.9 mmol) and ethyldiisopropylamine (11.6 g, 89 .7 mmol) were added to a stirred solution of (2R)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid (9.21 g, 29.8 mmol) in N,N-dimethylformamide (50 mL). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether1/6) to give the title compound (2.2 g25%). LC-MS (Method C): m/z = 291.1 [M+H]+, 1.298 min. Step 3: Preparation of tert-butyl (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

[001082] Iodomethane (1.08 g, 7.60 mmol) was added dropwise to a stirred solution of (2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b] (R)-tert-butyl azepin-3-yl)carbamate (2.01 g, 6.89 mmol) and cesium carbonate (2.47 g, 7.58 mmol) in N,N-dimethylformamide (20 mL ) with agitation. The resulting solution was stirred for 3 hours at room temperature. Water (10 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether 1/10) to give the title compound (1.20 g 57%). LC-MS (Method G): m/z = 305.0 [M+H]+, 1.004 min. Step 4: Preparation of tert-butyl (5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

[001083] tert-butyl (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (506.0 mg, 1 .66 mmol) in methanol (20 mL) was hydrogenated in the presence of 10% palladium on carbon (50.0 mg) under a hydrogen atmosphere (2-3 atmospheres). The resulting solution was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was evaporated in vacuo to give the title compound (0.5 g crude). LC-MS (Method C): m/z = 307.2 [M+H]+, 1.273 min. Step 5: Preparation of tert-butyl N-[5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

[001084] Diethylaminosulfur trifluoride (40.3 mg, 0.25 mmol) was added to a solution of (5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H- tert-butyl benzo[b]azepin-3-yl)carbamate (30.6 mg, 0.10 mmol) in dichloromethane (2 mL) under nitrogen atmosphere at 0 oC. The resulting solution was stirred for 3 hours at 0°C. The reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to give the title compound (25 mg81%). LC-MS (Method K): m/z = 208.9 [M-Boc+H]+, 0.946 min. Step 6: Preparation of 3-amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one hydrochloride

[001085] A solution of tert-butyl N-[5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate (25 .0 mg, 0.08 mmol) in 4N hydrogen chloride in dioxane (2 mL) was stirred for 0.5 hours at room temperature. The resulting mixture was concentrated in vacuo to provide the title compound (20 mg crude). LC-MS (Method K): m/z = 208.9 [M+H]+, 0.555 min Step 7: Preparation of 5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2, 3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazol-3-carboxamide

[001086] A solution of 5-benzyl-1,2-oxazol-3-carboxylic acid (16.0 mg, 0.08 mmol) in N,N-dimethylformamide (2 mL) was added to a stirred solution of hexafluorophosphate. 2-(7-aza-1H-benzotriazol- 1-yl)-1,1,3,3-tetramethyluronium (45.6 mg, 0.12 mmol), ethyldiisopropylamine (38.7 mg, 0.30 mmol), 3-amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one hydrochloride (20.0 mg, 0.08 mmol) in N,N - dimethylformamide (10 mL). The resulting solution was stirred for 2 hours at room temperature and then diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reversed-phase chromatography using an Xbridge Phenyl OBD 5 μm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 7.6 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.44 - 7.26 (m, 7H), 6.54 (s, 1H), 5.76 (dd, J = 4.4, 48.8 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.22 (s , 2H), 3.25 (s, 3H), 2.74 - 2.71 (m, 1H), 2.66 - 2.61 (m, 1H). LC-MS (Method L): m/z = 394.1 [M+H]+, 1.482 min. Amide Coupling Procedure B Step 8: Preparation of 5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin- 3-yl)isoxazol-3-carboxamide (first elution isomer, example 2A) and 5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b]azepin-3-yl)isoxazol-3-carboxamide (second example of elution isomer 2B)

[001087] 3-Amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30 mg, 0.140 mmol) was added to a solution in stirring of 5-benzyl-1, 2-oxazol-3-carboxylic acid (32.3 mg, 0.159 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate )uronium (65.7 mg, 0.173 mmol) and N,N-diisopropylethylamine (55.7 mg, 0.432 mmol) in N,N-dimethylformamide (5 mL). After stirring for 3 hours at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5.19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (45.0% ACN to 70.0% for 7 min); Detector, UV 254/220 nm to produce the title compounds:

[001088] Example 2A, first elution isomer: 1H NMR (300 MHz, CD3OD) δ 8.53 (d, J = 6.9 Hz, 1H), 7.55-7.50 (m, 1H), 7 .50-7.42 (m, 1H), 7.40-7.14 (m, 7H), 6.36 (s, 1H), 5.79-5.28 (m, 1H), 4.73 -4.48 (m, 1H), 4.13 (s, 2H), 3.32 (s, 3H), 2.91-2.72 (m, 1H), 2.64-2.40 (m , 1H). LC-MS (Method D): m/z = 394.1 [M+H]+, 2.075 min.

[001089] Example 2B, second elution isomer: 1H NMR (300 MHz, DMSO-d6) δ 8.84 (d, J = 7.5 Hz, 1H), 7.51-7.39 (m, 4H) , 7.38-7.25 (m, 5H), 6.52 (s, 1H), 5.98-5.28 (m, 1H), 4.34-4.25 (m, 1H), 4 .21 (s, 2H), 3.29 (s, 3H), 2.91-2.83 (m, 1H), 2.42-2.32 (m, 1H). LC-MS (Method D): m/z = 394.1 [M+H]+2.164 min. Example 3: (S)-5-benzyl-N-(1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) isoxazol-3-carboxamide Caption: Rt - ta Step 1: Preparation of (2S)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid

[001090] Di-tert-butyl dicarbonate (0.96 g, 4.39 mmol) was added to a solution of (2S)-2-amino-4-(2-aminophenyl)-4-oxobutanoic acid sulfate ( 1.22 g, 4.00 mmol) and triethylamine (1.21 g, 11.98 mmol) in dioxane (10 mL) under nitrogen atmosphere with stirring. The resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated in vacuo to provide the title compound (1.22 g crude). LC-MS (Method K): m/z = 309.1 [M+H]+, 1.549 min. Step 2: Preparation of tert-butyl N-[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

[001091] 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.82 g, 4.80 mmol) and ethyldiisopropylamine (1.55 g, 11 .99 mmol) were added to a stirred solution of (2S)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoic acid (1.23 g, 4.00 mmol) in N,N-dimethylformamide (10 mL). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3 X 20 ml). The combined organic portions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (850 mg). LC-MS (Method K): m/z = 291.1 [M+H]+, 0.850 min. Step 3: Preparation of tert-butyl N-[(3S)-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

[001092] Iodomethane (118 mg, 0.83 mmol) was added dropwise to a mixture of N-[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-1H-1 - stirred tert-butyl benzazepin-3-yl]carbamate (220.0 mg, 0.76 mmol) and cesium carbonate (272 mg, 0.83 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred for 6 hours at room temperature before adding water (10 mL) to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (130 mg, 56%). LC-MS (Method K): m/z = 305.0 [M+H]+, 0.907 min. Step 4: Preparation of tert-N-[(3S)-1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate butyl

[001093] A suspension of methyltriphenylphosphonium bromide (382 mg, 1.07 mmol) and sodium hydride (20.0 mg, 0.83 mmol) in tetrahydrofuran (2 mL) was stirred for 1 h at 50 oC under atmospheric of nitrogen. Then, a solution of tert-butyl N-[(3S)-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate ( 101.0 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction mixture with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (5 mL). The resulting solution was extracted with ethyl acetate (3 x 10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether1/10) to provide the title compound (75 mg, 75%). LC-MS (Method C): m/z = 303.2 [M+H]+, 1.531 min. Step 5: Preparation of (S)-3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one hydrochloride

[001094] A solution of tert N-[(3S)-1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate -butyl (40.0 mg, 0.13 mmol) in hydrogen chloride in dioxane (4 N, 6 mL) was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to provide the title compound (25.2 mg crude). LC-MS (Method C): m/z = 203.2 [M+H]+, 0.635 min. Amide C Coupling Procedure Step 6: Preparation of (S)-5-benzyl-N-(1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[ b]azepin-3-yl)isoxazol-3-carboxamide

[001095] A solution of (S)-3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one hydrochloride (25.4 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was added to a stirred solution of 5-benzyl-1,2-oxazol-3-carboxylic acid (20 mg, 0.10 mmol), 1- hydroxybenzotriazole (16 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (23 mg, 0.12 mmol), ethyldiisopropylamine (39 mg, 0.30 mmol) in N,N-dimethylformamide (8 mL). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse phase chromatography using an Xbridge Phenyl OBD 5 column, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to provide the title compound (17.8 mg44%) as a white solid. This compound was subsequently purified by chiral HPLC on a Chiralpak AS-H column (25 x 2.0 cm), 5 μm, using a mobile phase of n-hexane/(2-propanol/MeOH 1/1 +0.1% isopropylamine) 60/40% v/v to provide the title compound. 1H NMR (400MHz, CDCl3) δ 7.87 (d, J=6.8 Hz, 1H), 7.44-7.22 (m, 8H), 7.18 (d, J=7.8 Hz, 1H), 6.33 (s, 1H), 5.25-5.20 (m, 1H), 5.14-5.08 (m, 1H), 4.91 (td, J=6.9, 12.1 Hz, 1H), 4.13 (s, 2H), 3.55 (tdd, J=2.9, 6.5, 15.7 Hz, 1H), 3.39 (s, 3H), 2.84 (dd, J=12.0, 15.6 Hz, 1H). LC-MS (Method A): m/z = 388.1 [M+H]+1.21 min. ee > 99.5% as determined on a Chiralpak AS-H Column (25 x 0.46 cm), 5 μm using a mobile phase of n-hexane/(2-propanol/MeOH 1/1 +0.1% isopropylamine ) 60/40% v/v. Example 4: (S)-1-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepine -3-yl)-1H-pyrazol-3-carboxamide Step 1: Preparation of ethyl 4-chloro-5-methyl--1H-pyrazol-3-carboxylate

[001096] N-chlorosuccinimide (0.81 g, 5.99 mmol) was added to a solution of ethyl 5-methyl-1H-pyrazol-3-carboxylate (1.01 g, 6.49 mmol) in N, N-dimethylformamide (5 mL). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (0.81 g, 65%). LC-MS (Method C): m/z = 230.1 [M+CH3CN+H]+, 1.240 min. Step 2: Preparation of ethyl 1-benzyl-4-chloro-5-methyl-1H-pyrazol-3-carboxylate

[001097] Sodium hydride (108 mg, 4.50 mmol) was added to a solution of ethyl 4-chloro-5-methyl-1H-pyrazol-3-carboxylate (600 mg, 3.18 mmol) in tetra- hydrofuran (3 mL). After stirring for 1 h at 0°C, benzyl bromide (550 mg, 3.22 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature. After quenching with water (3 mL), the reaction mixture was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (500 mg, 56%). LC-MS (Method E): m/z =278.9 [M+H]+, 0.986 min. Step 3: Preparation of 1-benzyl-4-chloro-5-methyl-1H-pyrazol-3-carboxylic acid

[001098] Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl 1-benzyl-4-chloro-5-methyl-1H-pyrazol-3-carboxylate (120 mg, 0.43 mmol ) in methanol (1.5 mL) and water (0.5 mL). The resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and diluted with water (5 mL). 3N Hydrochloric acid was added to adjust the pH to 3. The resulting solid was collected by filtration to yield the title compound (110 mg). LC-MS (Method F): m/z = 251.0 [M+H]+, 1.323 min. Step 4: Preparation of (S)-1-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepine-3-yl)-1H-pyrazol-3-carboxamide

[001099] The crude material obtained using the Amide B coupling procedure was purified by reversed phase chromatography using a 5 μm, 19 x 150 mm Xbridge Prep C18 column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to provide the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=7.9 Hz, 1H), 7.50 (dd, J=7.6, 1.9 Hz, 1H), 7, 43 - 7.14 (m, 8H), 5.46 (s, 2H), 4.83 (dt, J=11.5, 7.8 Hz, 1H), 4.56 (dd, J=11, 5, 9.8 Hz, 1H), 4.42 (dd, J=9.8, 7.7 Hz, 1H), 3.32 (s, 3H), 2.20 (s, 3H). LC-MS (Method E): m/z = 425.0 [M+H]+, 1.488 min. Example 5: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-2-carboxamide Schematic caption: rt to ta Step 1: Preparation of ethyl 5-methylthiazol-2-carboxylate

[001100] Oxalyl chloride (5 mL, 50.0 mmol) was added to a stirring solution of 5-methylthiazol-2-carboxylic acid (1.43 g, 10.0 mmol) in dichloromethane (10 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was quenched by addition of ethanol (50 mL) and concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (1.6 g, 90%) as a white solid. LC-MS (Method E): m/z = 172 [M+H]+, 0.607 min. Step 2: Preparation of Ethyl 5-(bromomethyl)thiazol-2-carboxylate

[001101] N-Bromosuccinimide (900 mg, 5.0 mmol) was added to a solution of ethyl 5-methylthiazol-2-carboxylate (850 mg, 5.0 mmol) in carbon tetrachloride (20 mL). The reaction was initiated by benzolyl peroxide (1 mg) and then heated to 75 oC and stirred for 16 hours. The reaction mixture was cooled to 0°C and the solid was removed by filtration. The filtrate was diluted with water (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/20) to provide the title compound (1.0 g, 80%). LC-MS (Method F): m/z = 250, 252 [M+H]+, 1.490 min. Step 3: Preparation of Ethyl 5-Benzylthiazol-2-carboxylate

[001102] A 50 mL round bottom flask was filled with ethyl 5-(bromomethyl)thiazol-2-carboxylate (300 mg, 1.38 mmol), toluene (10 mL), ethanol (5 mL), phenylboronic acid (100 mg, 2.00 mmol) and sodium carbonate (372 mg, 5.52 mmol). The reaction mixture was placed under a nitrogen atmosphere and tetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) was added. The resulting solution was stirred at 85oC overnight under a nitrogen atmosphere and was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/15) to provide the title compound (250 mg, 56%). LC-MS (Method C): m/z = 248 [M+H]+, 1.971min. Step 4: Preparation of 5-Benzylthiazol-2-carboxylic acid

[001103] A solution of lithium hydroxide (5.4 mg, 2.02 mmol) in water (3 mL) was added to a solution of ethyl 5-benzylthiazol-2-carboxylate (100 mg, 0.405 mmol) in tetra -hydrofuran (9 mL). The resulting solution was stirred for 2 hours at room temperature and diluted with water (10 mL). The pH value of the solution was adjusted to 3-4 with 1N aqueous hydrogen chloride. The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (80 mg, 76%). LC-MS (Method F): m/z =220 [M+H]+, 0.790 min. Step 5: Preparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)thiazole -2-carboxamide

[001104] The crude material obtained using the Amide Coupling Procedure C was purified by reversed phase chromatography using a 5 μm, 19 x 150 mm Xbridge Prep C18 column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to yield the title compound. 1H NMR (300 MHz, Chloroform-d) δ 8.12 (d, J = 7.3 Hz, 1H), 7.62 (s, 1H), 7.41-7.16 (m, 9H), 5 .12-4.95 (m, 1H), 4.81-4.69 (m, 1H), 4.37-4.21 (m, 1H), 4.19 (s, 2H), 3.46 (s, 3H). LC-MS (Method D): m/z = 394 [M+H]+2.232 min. Example 6: (S)-1-benzyl-4-chloro-5-methyl-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt to ta Step 1: Preparation of ethyl 4-fluoro-5-methyl-1H-pyrazol-3-carboxylate

[001105] Selectfluor (3.5 g, 9.9 mmol) was added to a solution of ethyl 5-methyl-1H-pyrazol-3-carboxylate (1.01 g, 6.49 mmol) in acetonitrile (10 mL). The resulting solution was stirred overnight at 65 oC in an oil bath. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (660 mg, 59%). LC-MS (Method E): m/z = 172.9 [M+H]+, 0.607 min. Step 2: Preparation of ethyl 1-benzyl-4-fluoro-5-methyl-1H-pyrazol-3-carboxylate

[001106] Sodium hydride (118 mg, 4.92 mmol) was added to a solution of ethyl 4-fluoro-5-methyl-1H-pyrazol-3-carboxylate (600 mg, 3.49 mmol) in tetra- hydrofuran (3 mL). After stirring for 1 hour at 0oC, benzyl bromide (595 mg, 3.48 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (240 mg, 26%). LC-MS (Method C): m/z =263.1 [M+H]+.1.490 min. Step 3: Preparation of 1-benzyl-4-fluoro-5-methyl-1H-pyrazol-3-carboxylic acid

[001107] Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl 1-benzyl-4-fluoro-5-methyl-1H-pyrazol-3-carboxylate (113 mg, 0.43 mmol ) in methanol (1.5 mL), and water (0.5 mL). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated in vacuo and the residue was diluted with water (1.5 ml). Hydrochloric acid (3N) was added to adjust the pH to 3. The resulting solid was collected by filtration to yield the title compound (110 mg). LC-MS (Method E): m/z = 235.1 [M+H]+, 1.257 min. Step 4: Preparation of (S)-1-benzyl-4-fluoro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ] oxazepin-3-yl) -1H-pyrazol-3- carboxamide

[001108] The crude material obtained using the Amide B coupling procedure was purified by reversed phase chromatography using an Xbridge Prep C18 5 μm 19 x 150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to provide the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.6, 2.0 Hz, 1H), 7, 43 - 7.20 (m, 6H), 7.20 - 7.13 (m, 2H), 5.39 (s, 2H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.56 (dd, J = 11.5, 9.8 Hz, 1H), 4.42 (dd, J = 9.8, 7.7 Hz, 1H), 3.32 (s, 3H ), 2.16 (d, J = 1.4 Hz, 3H). LC-MS (Method F): m/z = 409.1 [M+H]+.1.412 min. Example 7: 5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl) isoxazol-3-carboxamide Step 1: Preparation of (Z)-tert-butyl (1-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepin-3-yl)carbamate

[001109] To a solution of tert-butyl (5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate ( 918.0 mg, 3.00 mmol) and triethylamine (909.0 mg, 9.00 mmol) in dichloromethane (20 mL) was added dropwise to a solution of methanesulfonyl chloride (687 mg, 6.00 mmol) in dichloromethane (2 mL) at 0 oC. After stirring overnight at room temperature the reaction mixture was quenched by addition of water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. 1,8-diazabicyclo[5,4,0]undec-7-ene was added to the crude solid with stirring. The resulting solution was stirred for 1 hour at 90°C. Water (20 mL) was added to quench the reaction. The stock mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (0.3 g crude). LC-MS (Method C): m/z = 289.0 [M+H]+, 1.494 min. Step 2: Preparation of tert N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate -butyl

[001110] A solution of 1-methyl-1-nitrosourea (1.073 g, 10.41 mmol) in ether (10 mL) was added to a solution of potassium hydroxide (1.166 g, 20.78 mmol) in water (1 .75 mL) dropwise with stirring at 0oC. After stirring for 1 hour at 0 oC, the organic phase was separated to provide a diazomethane solution (10 mL). To a solution of (Z)-tert-butyl (1-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepin-3-yl)carbamate (300.0 mg, 1. 04 mmol) in tetrahydrofuran (4 ml) was added to diazomethane solution (10 ml) with stirring at 0 oC. To this mixture was added a solution of palladium diacetate (23.3 mg, 0.10 mmol) in tetrahydrofuran (1 mL) dropwise with stirring at 0 oC. The resulting mixture was stirred at room temperature overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (50 mg, 16%). LC-MS (Method N): m/z = 303.1 [M+H]+, 1.043 min. Step 3: Preparation of 5-amino-7-methyl-7-azatricyclo [6.4.0.0-[2, 4]]dodeca-1(8),9,11-trien-6-one hydrochloride

[001111] A solution of N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0- [2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate tert-butyl (151.0 mg, 0.50 mmol) was treated with 4N hydrogen chloride in dioxane (10 mL) for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to provide the title compound (50 mg crude). LC-MS (Method C): m/z = 203.1 [M+H]+, 1.043 min. Step 4: Preparation of 5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b- hexahydrobenzo[b]cyclopropa[d]azepin-2- il)isoxazole-3-carboxamide

[001112] The crude product obtained using the Amide C Coupling Procedure was purified by reversed phase chromatography using an Xbridge Phenyl OBD 5 μm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.39-7.20 (m, 8H), 6.60 (s, 1H), 4.45 (d, J = 7.5 Hz, 1H), 4.22 (s, 2H), 3.22 (s, 3H), 2 .30-2.21 (m, 1H), 1.92-1.84 (m, 1H), 1.08-1.01 (m, 2H). LC-MS (Method H): m/z = 388.1 [M+H]+, 1,700 min.

[001113] This mixture was determined by chiral HPLC on a Chiralpak IB column (25 x 2.0 cm), 5 μm, using a mobile phase of n-hexane/(ethanol/methanol/dichloromethane 45/45/10 + 0. 1% isopropylamine) 60/40% v/v with a flow rate of 18 mL/min to provide the two separate enantiomers.

[001114] First elution enantiomer (6.3 min), Enantiomer 1: 1H NMR (400 MHz, CDCfe) δ 8.13 (d, J=7.0 Hz, 1H), 7.40-7.16 ( m, 8H), 7.10 (dd, J=7.8, 1.4 Hz, 1H), 6.35 (s, 1H), 4.76 (d, J=7.2 Hz, 1H), 4.12 (s, 2H), 3.35 (s, 3H), 2.17-2.08 (m, 1H), 2.02 (td, J=8.7, 4.9 Hz, 1H) , 1.22 (q, J=5.3 Hz, 1H), 1.05 (td, J=8.5, 6.5 Hz, 1H). LC-MS (Method A): mz = 388.3 [M+H]+1.17 min. ee > 99.9% as determined on a Chiralpak IB column (25 x 0.46 cm), 5 μm column using a mobile phase of n-hexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1 % isopropylamine) 60/40% v/v with a flow rate of 1 mL/min.

[001115] Second elution enantiomer (7.9 min), Enantiomer 2: 1H NMR (400 MHz, CDCb) δ 8.14 (d, J=7.3 Hz, 1H), 7.41-7.17 ( m, 8H), 7.12 (dd, J=7.7, 1.6 Hz, 1H), 6.37 (s, 1H), 4.78 (d, J=7.0 Hz, 1H), 4.14 (s, 2H), 3.36 (s, 3H), 2.14 (td, J=9.2, 5.4 Hz, 1H), 2.03 (td, J=8.7, 5.0 Hz, 1H), 1.23 (q, J=5.3 Hz, 1H), 1.07 (td, J=8.5, 6.3 Hz, 1H). LC-MS (Method A): mz = 388.3 [M+H]+1.17 min. ee > 99.9% as determined on a Chiralpak IB column (25 x 0.46 cm), 5 μm column using a mobile phase of n-hexane/(ethanol/methanol/dichloromethane 45/45/10 + 0.1 % isopropylamine) 60/40% v/v with a flow rate of 1 mL/min. Example 8: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl )isoxazole-3-carboxamide Step 1: Preparation of Methyl 5-(1-phenylcyclopropyl)-1,2-oxazol-3-carboxylate

[001116] A solution of 1-methyl-1-nitrosourea (449.8 mg, 4.36 mmol) in ether (10 mL) was added dropwise to a solution of potassium hydroxide (359.1 mg, 6. 40 mmol) in water (0.54 mL) with stirring at 0 oC. After stirring for 0.5 hours at 0 oC, the organic phase was separated to provide a diazomethane solution (10 mL). To a solution of ethyl 5-(1-phenylethenyl)-1,2-oxazol-3-carboxylate (50.0 mg, 0.21 mmol) in tetrahydrofuran (3 mL) was added diazomethane solution (10 mL) with stirring at 0 oC followed by the addition of a solution of palladium diacetate (4.7 mg, 0.02 mmol) in tetrahydrofuran (1 mL) dropwise with stirring at 0 oC. The resulting solution was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether 1/5) to provide the title compound (30 mg, 57%) as a yellow solid. LC-MS (Method C): m/z = 244.0 [M+H]+, 1.519 min. Step 2: Preparation of 5-(1-phenylcyclopropyl)-1,2-oxazol-3-carboxylic acid

[001117] A solution of methyl 5-(1-phenylcyclopropyl)-1,2-oxazol-3-carboxylate (25.0 mg, 0.10 mmol) and lithium hydroxide (4.8 mg, 0.20 mmol ) in methanol/water = 3/1 (2 mL) was stirred for 2 hours at room temperature. The pH value of the solution was adjusted to 6-7 with 1N hydrochloric acid. The resulting solution was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (20 mg crude). LC-MS (Method G): m/z = 230 [M+H]+, 0.700 min. Step 3: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[3,2-b][1,4]oxazepin-3-yl-5 -(1-phenylcyclopropyl)isoxazole-3-carboxamide

[001118] The crude product obtained using Amide Coupling Procedure B was purified by reversed-phase chromatography using an Xbridge Phenyl OBD 5 μm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 8.1 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.38 - 7.25 (m, 7H), 7.24 - 7.20 (m, 1H), 6.36 (s, 1H), 4.87 - 4.77 (m, 1H), 4.55 (dd, J = 9.9, 11.7 Hz, 1H), 4.38 (dd, J = 8.1, 9.9 Hz, 1H), 3.30 (s, 3H), 1.57 - 1.52 (m, 2H), 1.45 - 1.41 (m, 2H). LC-MS (Method H): m/z = 404.2 [M+H]+, 1.766 min. Example 9: (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropan]-3- il)isoxazol-3-carboxamide Step 1: Preparation of tert N-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-3-yl]carbamate - butyl

[001119] A solution of 1-methyl-1-nitrosourea (255.8 mg, 2.48 mmol) in ether (10 mL) was added dropwise to a solution of potassium hydroxide (278 mg, 4.96 mmol ) in water (0.4 mL) with stirring at 0 oC. After stirring for 0.5 hour at 0 oC, the organic phase was separated to provide a diazomethane solution (10 mL). To a solution of tert-butyl N-[(3R)-1-methyl-2-oxo-2,3-dihydro-1H-1-benzazepin-3-yl]carbamate (75.0 mg, 0. 25 mmol) in tetrahydrofuran (1.5 mL) was added to diazomethane solution (10 mL) dropwise followed by the addition of a solution of palladium diacetate (5.5 mg, 0.02 mmol) in tetrahydrofuran. hydrofuran (0.5 mL) dropwise with stirring at 0 oC. The resulting solution was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (55 mg, 70%). LC-MS (Method C): m/z = 317.2 [M+H]+, 1.531 min. Step 2: Preparation of (3S)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-one hydrochloride

[001120] tert N-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydro-spiro[1-benzazepine-5,1-cyclopropane]-3-yl]carbamate -butyl (40.0 mg, 0.13 mmol) was treated with 4N hydrogen chloride in dioxane (6 mL) for 1 hour at room temperature. The resulting mixture was concentrated in vacuo to provide the title compound (25.2 mg) as a yellow solid. LC-MS (Method K): m/z = 217.2 [M+H]+, 0.635 min. Step 3: Preparation of (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropane]- 3-yl)isoxazol-3-carboxamide

[001121] The crude product obtained using the Amide C coupling procedure was purified by reversed-phase chromatography using an Xbridge Phenyl OBD 5 μm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50% to 70% in 7 min) to provide the title compound (17.8 mg44%) as a white solid. This compound was subsequently purified by chiral HPLC on a Chiralpak AS-H column (25 x 2.0 cm), 5 μm, using a mobile phase of n-hexane/(2-propanol/MeOH 1/1 +0.1% isopropylamine) 60/40% v/v to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=7.0 Hz, 1H), 7.39-7.19 (m, 9H), 6.31 (s, 1H), 4.69 (td, J=7.6, 10.9 Hz, 1H), 4.11 (s, 2H), 3.43 (s, 3H), 3.13 (dd, J=12.3, 8.3 Hz, 1H), 1.33 (dd, J=12.5, 11.0 Hz, 1H), 1.16-1.08 (m, 1H), 0.88 (ddd, J=9.3, 5.5, 4.3 Hz, 1H), 0.71 (td, J=5.5, 9.3 Hz, 1H), 0.51-0.42 (m, 1H). LC-MS (Method A): m/z = 402.2 [M+H]+1.21 min. ee > 99.5% as determined on a Chiralpak AS-H Column (25 x 0.46 cm), 5 μm using a mobile phase of n-hexane/(2-propanol/MeOH 1/1 +0.1% isopropylamine ) 60/40% v/v. Example 10: 5-benzyl-N-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H -1,2,4-triazol-3-carboxamide Step 1: Preparation of tert-butyl (5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate

[001122] A solution of tert-butyl (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) (200 mg, 0.658 mmol) in bis(2-methoxyethyl)aminosulfur trifluoride (6 mL) was heated to 65 oC and stirred overnight. The reaction mixture was allowed to cool to room temperature, quenched with water (30 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (60 mg/30%). LC-MS (Method E): m/z = 327 [M+H]+, 1.035 min. Step 2: Preparation of 3-amino-5,5-difluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

[001123] tert-butyl 5,5-Difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (40 mg, 0.184 mmol) was added to a solution of hydrogen chloride (4N) in 1,4-dioxane (30 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated in vacuo to provide the title compound (50 mg crude) as a yellow solid. LC-MS (Method N): m/z =227 [M+H]+, 0.995 min. Step 3: Preparation of 5-benzyl-N-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) -4H-1,2,4-triazole-3-carboxamide

[001124] The crude product obtained using the Amide Coupling Procedure C was purified by reversed phase chromatography using a 5 μm, 19 x 150 mm Xbridge Prep C18 column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.25 (s, 1H), 8.59 (s, 1H), 7.63 (m 3H), 7.44 (t, J = 7.5 Hz, 1H), 7.35 — 7.18 (m, 5H), 4.52 (dt, J = 11.8, 7.8 Hz, 1H), 4.10 (s, 2H), 3.26 (s , 3H), 3.15 - 2.81 (m, 2H). LC-MS (Method L): m/z = 412.1 [M+H]+, 1.309 min. Example 11 and 12: 5-benzyl-N-((3S, 5R)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin- 3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-benzyl-N-((3R,5S)-5-fluoro-1-methyl-2-oxo-2,3,4, 5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazol-3-carboxamide (Example 11) and 5-benzyl-N-((3S,5S)- 5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-benzyl-N- ((3R,5R)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) -4H-1,2,4-triazol-3-carboxamide (Example 12)

[001125] The crude product obtained using the Amide Coupling Procedure A was purified by reversed-phase column chromatography using an Xbridge Phenyl OBD 5 μm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (25.0% to 55.0% in 7 min) to provide the title compounds:

[001126] Example 11, first elution isomer: 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 8.41 (s, 1H), 7.65-7.49 (m, 2H), 7.45 (dt, J = 7.7, 1.7 Hz, 1H), 7.40 - 7.20 (m, 6H), 5.76 (dd, J = 47.0, 4, 8 Hz, 1H), 4.47 (dt, J = 11.4, 7.5 Hz, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 2.94 - 2, 56 (m, 2H). LC-MS (Method F): m/z = 394.1 [M+H]+, 1.085 min.

[001127] Example 12, second elution isomer: 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 8.41 (s, 1H), 7.58 - 7.38 (m, 4H), 7.38 - 7.20 (m, 5H), 5.92 (ddd, J = 46.6, 10.5, 8.1 Hz, 1H), 4.30 (dt, J = 11, 4, 7.9 Hz, 1H), 4.12 (s, 2H), 3.31 (s, 3H), 2.96-2.78 (m, 1H), 2.41 - 2.30 (m , 1H). LC-MS (Method F): m/z = 394.1 [M+H]+, 1.156 min. Example 11: Chiral Separation

[001128] This mixture was determined by chiral HPLC on a Whelk O-1 (R,R) column (25 x 2.0 cm), 10 μm using a mobile phase of n-hexane/(ethanol + 0.1% isopropylamine ) 30/70% v/v with a flow rate of 18 mL/min to provide the two separate enantiomers.

[001129] First elution enantiomer (6.8 min), Enantiomer 1: 1H NMR (400 MHz, CDCb) δ 8.27 (d, J=6.8 Hz, 1H), 7.35 (m, 9H) , 5.51 (m, 1H), 4.74 (dt, J=11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3, 07 (m, 1H), 2.44 (m, 1H). LC-MS (Method A): mz = 394.3 [M+H]+0.87 min. ee > 99.9% as determined on a Whelk O-1 (R, R) (25 x 0.46 cm), 5 μm column using an n-hexane/(ethanol + 0.1% isopropylamine) mobile phase 30/70% v/v with a flow rate of 1 mL/min.

[001130] Second elution enantiomer (8.9 min), Enantiomer 2: 1H NMR (400 MHz, CDCb) δ 8.27 (d, J=6.8 Hz, 1H), 7.35 (m, 9H) , 5.51 (m, 1H), 4.74 (dt, J=11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3, 07 (m, 1H), 2.44 (m, 1H). LC-MS (Method A): mz = 394.3 [M+H]+0.86 min. ee > 99.9% as determined on a Whelk O-1 (R, R) (25 x 0.46 cm), 5 μm column using an n-hexane/(ethanol + 0.1% isopropylamine) mobile phase 30/70% v/v with a flow rate of 1 mL/min. Example 12: Chiral Separation

[001131] This mixture was determined by chiral HPLC on a Chiralcel OJ-H (25 x 2.0 cm), 5 μm column using a mobile phase of n-hexane/(ethanol/methanol 1/1 + 0.1% isopropylamine) 30/70% v/v with a flow rate of 18 mL/min to provide the two separate enantiomers.

[001132] First elution enantiomer (4.8 min), Enantiomer 1: 1H NMR (400 MHz, CDCI3) δ 8.14 (d, J=6.1 Hz, 1H), 7.62-7.14 ( m, 9H), 5.87-5.64 (m, 1H), 4.67-4.54 (m, 1H), 4.17 (s, 2H), 3.44 (s, 3H), 3.032 .85 (m, 1H), 2.66-2.53 (m, 1H). LC-MS (Method U): m/z = 394.2 [M+H]+0.75 min. ee > 99.9% as determined on a Chiralcel OJ-H (25 x 0.46 cm), 5 μm column using an n-hexane/(ethanol/methanol 1/1 + 0.1% isopropylamine) mobile phase 50/50% v/v with a flow rate of 1 mL/min.

[001133] Second elution enantiomer (7.0 min), Enantiomer 2: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=6.3 Hz, 1H), 7.62-7.15 ( m, 10H), 5.86-5.63 (m, 1H), 4.66-4.53 (m, 1H), 4.12 (s, 2H), 3.42 (s, 3H), 3.002 .82 (m, 1H), 2.64-2.52 (m, 1H). LC-MS (Method U): m/z = 394.2 [M+H]+0.74 min. ee > 99.9% as determined on a Chiralcel OJ-H (25 x 0.46 cm), 5 μm column using an n-hexane/(ethanol/methanol 1/1 + 0.1% isopropylamine) mobile phase 50/50% v/v with a flow rate of 1 mL/min. Example 13: (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4- phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-carboxamide SCHEME LEGEND :rt – ta Step 1: Preparation of (2S,3R)-1-nitroso-3-phenylpyrrolidine-2-carboxylic acid Step 1: Preparation of (2S,3R)-1-nitroso-3-phenylpyrrolidine- acid 2- carboxylic

[001134] (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid (1.01 g, 5.23 mmol) was added to a solution of sodium nitrite (800 mg, 11.59 mmol) in water (5 mL). Concentrated hydrochloric acid (5 mL) was added at 0 oC. The reaction mixture was stirred overnight at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (700 mg crude). LC-MS (Method I): m/z = 220.95[M+H]+, 0.741 min. Step 2: Preparation of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2c][1,2,3]oxadiazol-7-io-3a-ide

[001135] To a solution of (2S,3R)-1-nitroso-3-phenylpyrrolidine-2-carboxylic acid (700 mg, 3.18 mmol) in ether (7 mL) at 0 oC was added trifluoroacetic anhydride (1. 01 g, 4.76 mmol) dropwise. The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under vacuum and diluted with water (50 mL). The pH of the solution was adjusted to 8 with potassium carbonate (0.5 M). The resulting solution was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1:1) to provide the title compound (380 mg, 59%) d. LC-MS (Method I): m/z = 202.9 [M+H]+0.725 min. Step 3: Preparation of (4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazol-3-ethyl carboxylate

[001136] To a solution of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxadiazol-7-io- 3a-ida (380 mg, 1.88 mmol) in o-xylene (6 mL), purged and maintained in an inert nitrogen atmosphere, ethyl prop-2-inoate (240 mg, 2.45 mmol) was added dropwise. the drop. The resulting solution was stirred overnight at 125 oC in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1:1) to provide the title compound (100 mg, 21%). LC-MS (Method J): m/z = 257.1 [M+H]+, 1.367 min. Step 4: Preparation of (4R)-4-phenyl-4H,5H,6H-pyrrol[1,2-b]pyrazol-2-carboxylic acid

[001137] To a solution of (4R)-4-phenyl-4H,5H,6H-pyrrol[1,2-b]pyrazol-ethyl 2-carboxylate (100 mg, 0.39 mmol) in methanol (2, 1 mL) and water (0.7 mL) were added potassium hydroxide (67 mg, 1.19 mmol). The resulting solution was stirred overnight at room temperature, concentrated in vacuo and the resulting residue was diluted with water. The pH value of the solution was adjusted to 3 with 3N hydrochloric acid. The resulting solid was collected by filtration to give the title compound (80 mg, 90%). LC-MS (Method I): m/z = 228.9 [M+H]+, 0.804 min. Step 5: Preparation of (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 4-phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-carboxamide

[001138] The crude product obtained using the Amide B coupling procedure was purified by reversed phase chromatography using an Xbridge Phenyl OBD 5 μm, 19 x 150 mm column; mobile phase, water (10 mmol/L NH4HCO3) and ACN (250.0% to 550.0% in 7 min) to provide the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=8.1 Hz, 1H), 7.51 (dd, J=7.5, 1.9 Hz, 1H), 7, 39 - 7.20 (m, 8H), 6.32 (d, J=0.9 Hz, 1H), 4.84 (dt, J=11.5, 7.9 Hz, 1H), 4.61 - 4.48 (m, 2H), 4.45 - 4.31 (m, 2H), 4.22 (dt, J=11.0, 7.7 Hz, 1H), 3.32 (s, 3H ), 3.09 (dtd, J=12.7, 8.3, 4.2 Hz, 1H), 2.51 - 2.41 (m, 1H). LC-MS (Method J): m/z = 403.2 [M+H]+, 1.499 min. Example 14: (S)-N-(5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4] oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)isoxazole-3-carboxamide Schematic legend: rt - ta Step 1: Preparation of methyl 5-(bromomethyl)isoxazole-3-carboxylate

[001139] To a solution of methyl 5-methylisoxazole-3-carboxylate (4.65 g, 30 mmol) and N-bromosuccinimide in carbon tetrachloride (250 mL) was added benzoyl peroxide (2 mg, 0.1 mol %). The resulting mixture was refluxed at 80 oC for 24 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane, 1/5) to provide the title compound (1.6 g, 23%) as a white solid. LC-MS (Method C): m/z = 221.7 [M+H]+, 0.746 min. Step 2: Preparation of methyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate

[001140] For a mixture of methyl 5-(bromomethyl)isoxazole-3-carboxylate (350 mg, 1.59 mmol) and cuprous iodide (570 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL) Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.44 g, 7.50 mmol) was added. The resulting mixture was heated at 100 oC for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (125 mg, 37%) as a yellow solid. LC-MS (Method C): m/z = 209.9 [M+H]+, 0.788 min. Step 3: Preparation of 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid

[001141] To a solution of methyl 5-(2,2,2-trifluoroethyl)isoxazol-3-carboxylate (90 mg, 0.43 mmol) in 4:1 THF:H2O (2.5 mL) was added hydroxide lithium (72 mg, 3 mmol). The resulting solution was stirred at room temperature for 40 min. After completion of the reaction, the solvent was evaporated under reduced pressure and water (25 mL) was added to the resulting residue. This solution was washed with ethyl acetate (3 x 50 mL). The aqueous layer was acidified with 1N hydrochloric acid to pH~3-4 and extracted with ethyl acetate (3 x 20 mL). The combined organic phases from this extraction were dried with sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (43 mg crude), which was used directly in the next step without further purification. LC-MS (Method D): m/z = 196.9 [M+H]+, 0.290 min. Step 4: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2 ,2,2-trifluoroethyl)isoxazole-3-carboxamide

[001142] The crude product obtained using Amide Coupling Procedure C was purified by crystallization (ethanol/n-hexane) to provide the title compound. 1H NMR (300 MHz, Chloroform-d) δ 7.80 (d, J = 7.0 Hz, 1H), 7.26 - 7.19 (m, 4H), 6.71 (s, 1H), 5 .04 (dt, J = 11.1, 7.1 Hz, 1H), 4.76 (dd, J = 9.8, 7.4 Hz, 1H), 4.28 (dd, J = 11.1 , 9.7 Hz, 1H), 3.69 (q, J = 9.7 Hz, 2H), 3.46 (s, 3H). LC-MS (Method E): m/z = 370.2 [M+H]+, 2.462 min. Example 15: 5-benzyl-N-(6,7,8,9-tetrahydro-5H-benzo[7]-annulen-7-yl)isoxazol-3-carboxamide

[001143] The crude product obtained using the Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV 254 and 220 nm to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 8.4 Hz, 1H), 7.25-7.14 (m, 5H), 7.15-7.07 (m, 4H), 6.52 (s, 1H), 4.19 (s, 2H), 4.17-4.04 (m, 1H), 2.89-2.69 (m, 4H), 2.02 -1.97 (m, 2H), 1.43-1.23 (m, 2H). LC-MS (Method F): m/z = 347.1 [M+H]+, 1.652 min. Example 16: (S)-1-benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl )-1H-pyrazole-5-carboxamide Schematic legend: rt - ta Step 1: Preparation of ethyl 1-benzyl-3-methyl-1H-pyrazol-5-carboxylate

[001144] To a solution of ethyl 2,4-dioxopentanoate (0.5 g, 3.20 mmol) and benzylhydrazine hydrochloride (0.75 g, 3.84 mmol) in ethanol (10 mL) was added N,N-diisopropylethylamine (1.2 g, 9.60 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (0.5 g, 65%) as a yellow oil. LC-MS (Method S): m/z = 245.2 [M+H]+, 1.070 min. Step 2: Preparation of 1-benzyl-3-methyl-1H-pyrazol-5-carboxylic acid

[001145] A solution of sodium hydroxide (0.25 g, 6.02 mol) in water (1 mL) was added to a stirred solution of ethyl 1-benzyl-3-methyl-1H-pyrazol-5-carboxylate (0.5 g, 2.01 mmol) in ethanol (2 mL). The resulting mixture was stirred overnight at 80°C. After cooling to room temperature, the reaction mixture was adjusted to pH = 3-4 with aqueous hydrochloric acid (1N, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (0.4 g, 90%) as a white solid, which was used directly in the next step without additional purification. LC-MS (Method C): m/z = 217.2 [M+H]+, 1.219 min. Step 3: Preparation of (S)-1-benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)-1H-pyrazol-5-carboxamide

[001146] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.4 Hz, 1H), 7.53-7.47 (m, 1H), 7.35-7.19 (m, 6H), 7.11-7.07 (m, 2H), 6.82 (s, 1H), 5.64-5.51 (m, 2H), 4.88-4.81 (m, 1H) , 4.55-4.49 (m, 1H), 4.40-4.35 (m, 1H), 3.30 (s, 3H), 2.20 (s, 3H). LC-MS (Method L): m/z = 391.1 [M+H]+, 1.437 min. Example 17: (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4- phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-carboxamide Schematic legend: rt - ta Step 1: Preparation of (4R)-4-phenyl-4H,5H, 6H-pyrrol[1,2-b]pyrazol-3-ethyl carboxylate

[001147] To a stirring solution of (R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxadiazol-7- io-3a-ide (380 mg, 1.88 mmol) in o-xylene (6 mL) under nitrogen atmosphere was added ethyl-propane-2-anoate (240 mg, 2.45 mmol). The resulting mixture was heated to 125oC and stirred overnight in an oil bath. The reaction mixture was cooled to RT, concentrated under reduced pressure and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (120 mg, 25%) as a light yellow oil. LC-MS (Method J): m/z = 257.0 [M+H]+, 1.323 min. Step 2: Preparation of (4R)-4-phenyl-4H,5H,6H-pyrrol[1,2-b]pyrazol-3-carboxylic acid

[001148] A solution of potassium hydroxide (67 mg, 1.19 mmol) in water (7 mL) was added to a solution of (4R)-4-phenyl-4H,5H,6H-pyrrole[1,2- b]ethyl pyrazol-3-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure and diluted with water. The pH value of the solution was adjusted to 3 with hydrochloric acid (3 N, 20 mL). The precipitate was collected by filtration to provide the title compound (50 mg, 47%) as a yellow solid. LC-MS (Method I): m/z = 228.9 [M+H]+, 0.738 min. Step 3: Preparation of (R)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 4-phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-carboxamide

[001149] The crude product obtained using the Amide B coupling procedure was purified by preparative HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (25.0% ACN to 55.0% over 7 min); Detector, UV 254 and 220 nm to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 7.6, 2, 0 Hz, 1H), 7.34-7.14 (m, 6H), 7.10-7.02 (m, 2H), 4.77-4.58 (m, 2H), 4.35-4 .23 (m, 1H), 4.22-4.03 (m, 3H), 3.26 (s, 3H), 3.19-3.05 (m, 1H), 2.39 (dq, J = 8.8, 4.3 Hz, 1H). LC-MS (Method O): m/z = 403.0 [M+H]+, 1.334 min. Example 18: (S)-N-benzyl-2-((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)amino) acetamide

[001150] A mixture of (3S)-3-amino-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride (40 mg, 0.175 mmol, ee = 90%), N-benzyl-2-chloroacetamide (18 mg, 0.097 mmol), K2CO3 (27 mg, 0.195 mmol) and KI (32 mg, 0.195 mmol) in DMF (3 mL) was stirred at 30 oC for 16 h . The mixture was diluted with EtOAc and washed twice with saturated NH4Cl solution. The aqueous portion was extracted with EtOAc. The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 80:20 to 0:100) to provide the title compound. 1H NMR (400 MHz, CDCI3) δ 7,467.08 (m, 10H), 4.51-4.37 (m, 2H), 4.33 (dd, J=10.2, 7.4 Hz, 1H) , 4.12 (t, J=10.8 Hz, 1H), 3.61-3.43 (m, 3H), 3.41 (s, 3H), 3.06-2.97 (m, 1H ). LC-MS (Method A): m/z = 340.0 [M+H]+0.70 min. ee = 88% as determined on a Chiralcel OD-H column (25 x 0.46 cm), 5 μm using a mobile phase of n-hexane/(ethanol +0.1% isopropylamine) 35/65% v/v. Example 19: (S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3 -carboxamide Step 1: Preparation of tert-butyl N-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate

[001151] Sodium hydride (8.64 mg, 0.22 mmol) was added to a stirred solution of N-((3S)-4-oxo-2,3,4,5-tetrahydro-1,5 tert-butyl-benzoxazepin-3-yl)carbamate (50 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was stirred for 1 hour at room temperature. Iodoethane (33.7 mg, 0.21 mmol) was added dropwise. After stirring for 3 hours at room temperature, the action mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether 1/3) to provide the title compound (40 mg, 73%) as a yellow solid. LC-MS (Method S): m/z = 307.2 [M+H]+, 1.021 min. Step 2: Preparation of (3S)-3-amino-5-ethyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride

[001152] Tert-butyl N-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (40 mg, 0 .13 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 mL). The reaction mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure to yield the title compound (30 mg) as a white solid, which was used directly in the next step without further purification. LC-MS (Method D): m/z = 207.1 [M+H]+, 0.930 min. Step 3: Preparation of (S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole -3 -carboxamide

[001153] The crude product obtained using the Amide Coupling Procedure B was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (45.0% ACN to 70.0% for 7 min); Detector, UV 254 and 220 nm to yield the title compounds. 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 7.8 Hz, 1H), 7.547.51 (m, 1H), 7.38-7.21 (m, 8H), 6 .54 (s, 1H), 4.84-4.75 (m, 1H), 4.56 (t, J = 11.4 Hz, 1H), 4.39-4.33 (m, 1H), 4.21 (s, 2H), 4.10-4.03 (m, 1H), 3.67-3.60 (m, 1H), 1.02 (t, J = 7.2 Hz, 3H) . LC-MS (Method D): m/z = 392.2 [M+H]+2.181 min.Example 20: 5-benzyl-N-(1-methyl-2,3,4,5-tetrahydro- 1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001154] Borane tetrahydrofuran complex (1 M solution in THF, 570, 0.570 mmol) was added dropwise to a solution of 3-amino-1-methyl-2,3,4,5-tetrahydro -1H-1-benzazepin-2-one (50 mg, 0.26 mmol) in THF (1 mL) which had been pre-cooled to 0 °C. The reaction was allowed to gradually warm to room temperature and stirred for 18 h before being quenched with 1M HCl solution. The resulting mixture was stirred at room temperature for 3 h. Volatiles were removed under reduced pressure. The crude product was purified by ion exchange chromatography on an SCX cartridge (MeOH and then 7M NH3 in MeOH) to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.14-7.02 (m, 2H), 6.93-6.85 (m, 1H), 6.84-6.74 (m, 1H), 3.10-2.85 (m, 2H), 2.84-2.68 (m, 4H), 2.66-2.54 (m, 1H), 2.48-2.36 (m, 1H ), 1.89-1.77 (m, 1H), 1.75-1.55 (m, 2H), 1,331.06 (m, 1H). LC-MS (Method A): m/z = 177.2 [M+H]+, 0.40 min.

[001155] The crude product obtained using the Amide Coupling Procedure C was purified by column chromatography (CH2Cl2-MeOH, 95:5 to 80:20) and then by reversed phase chromatography (water-CH3CN, 100:0 to 50:50) to provide the title compound as a mixture of enantiomers. 1H NMR (400 MHz, DMSO-d6) δ 14.61-14.37 (m, 1H), 8.37-8.25 (m, 1H), 7.35-7.10 (m, 7H), 6,996.93 (m, 1H), 6.85 (td, J=7.3, 1.1 Hz, 1H), 4.19-4.11 (m, 1H), 4.08 (s, 2H) , 3.05-2.98 (m, 1H), 2.84 (s, 3H), 2.81-2.73 (m, 2H), 2.65-2.58 (m, 1H), 1 .89-1.78 (m, 1H), 1.68-1.55 (m, 1H). LC-MS (Method A): m/z = 362.4 [M+H]+, 1.02 min. Example 21: 5-benzyl-N-((4S,9aR)-5-oxohexahydro -1H,3H-pyrrole[2,1-c][1,4]oxazepin-4-yl)isoxazol-3-carboxamide Example 22: 5-benzyl-N-((4S, 9aS)-5-oxo-hexahydro-1H,3H-pyrrole[2,1-c][1,4]oxazepin-4-yl)isoxazole-3 -carboxamide Example 23: (S)-5-benzyl-N-(1-methyl-2-oxoazepan-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001156] The crude product obtained using the Amide Coupling Procedure C was purified by column chromatography (CH2Cl2/MeOH 9: 1), then by column chromatography on silica gel modified with KP-NH (EtOAc/MeOH 9: 1 ) and then by reverse phase chromatography (water-CH3CN, 70:30) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.44 (s, 1H), 8.34 (d, J=6.2 Hz, 1H), 7.37-7.20 (m, 5H), 4 .75-4.65 (m, 1H), 4.11 (s, 2H), 3.68 (dd, J=15.4, 11.4 Hz, 1H), 3.23 (dd, J=15 .3, 5.2 Hz, 1H), 2.94 (s, 3H), 2.01-1.93 (m, 1H), 1.92-1.82 (m, 1H), 1.81- 1.67 (m, 2H), 1.45-1.28 (m, 2H). LC-MS (Method A): m/z = 328.3 [M+H]+, 0.74 min. Example 24: (S)-5-cyano-1-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl )-1H-pyrrole-2-carboxamide

[001157] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 70:30) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 4H), 7.11 (d, J=6.6 Hz, 1H), 6.77 (d, J=4.3 Hz , 1H), 6.69 (d, J=4.3 Hz, 1H), 5.00 (dt, J=11.2, 6.9 Hz, 1H), 4.77 (dd, J=9, 7, 7.4 Hz, 1H), 4.25 (dd, J=11.1, 9.7 Hz, 1H), 4.00 (s, 3H), 3.47 (s, 3H). LC-MS (Method A): m/z = 325.0 [M+H]+0.93 min. Example 25: (S)-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H- 1,2,4-triazol-3-carboxamide

[001158] The crude product obtained using the Amide C coupling procedure was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV 254 and 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.2 (br. s, 1H), 8.43 (d, J = 6.8 Hz, 1H), 7.54-7.45 (m, 1H) , 7.22-7.18 (m, 3H), 4.90-4.75 (m, 1H), 4.58 (t, J = 10.0 Hz, 1H), 4.47-4.35 (m, 1H), 4.39 (s, 3H), 2.39 (s, 3H). LC-MS (Method L): m/z = 302.0 [M+H]+, 0.885 min. Example 26: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]oxazepin-3-yl)acetamide

[001159] Acetic anhydride (20.5 mg, 0.20 mmol) was added to a solution of (3S)-3-amino-5-methyl-2,3,4,5-tetrahydro-1 hydrochloride, 5-benzoxazepin-4-one (45.6 mg, 0.20 mmol) and triethylamine (40 mg, 0.40 mmol) in dichloromethane (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC-Prep, with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV 254 & 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.4 Hz, 1H), 7.50-7.45 (m, 1H), 7.36-7.15 (m, 3H), 4.76-4.65 (m, 1H), 4.38-4.15 (m, 2H), 3.29 (s, 3H), 1.84 (s, 3H). LC-MS (Method D): m/z = 235.1 [M+H]+, 1,340 min. Example 27: 5-benzyl-N-((4S,9aS)-5-oxo-hexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4-yl)-4H- 1,2,4-triazol-3-carboxamide Step 1: Preparation of tert-butyl (2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropoxy]methyl}pyrrolidine-1-carboxylate

[001160] Boron trifluoride diethyl etherate (0.52 mL, 4.25 mmol) was added to a solution of 1-benzyl 2-methyl(2S)-aziridine-1,2-dicarboxylate (2.00 g, 8.50 mmol) and N-Boc-L-prolinol (6.85 g, 34.03 mmol) in dry CHCl3 (20 mL) at -30 °C under a nitrogen atmosphere. The solution was left to stir overnight at room temperature, then diluted with CH2Cl2 (20 mL) and washed with water (3 x 10 mL) with back extraction. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-diethyl ether, 50:50) to provide the title product (3.30 g, 89%) as a colorless oil. 1H NMR (400MHz, CDCI3) δ 7.47-7.30 (m, 5H), 5.97-5.50 (m, 1H), 5.23-5.08 (m, 2H), 4.49 (br. s., 1H), 4.07-3.21 (m, 10H), 1.97-1.73 (m, 4H), 1.49-1.38 (m, 9H). LC-MS (Method A): m/z = 437.5 [M+H]+, 1.18 min. Step 2: Preparation of Methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-pyrrolidin-2-ylmethoxy]propanoate

[001161] A solution of (2S)-2-{[(2S)-2- {[(benzyloxy)carbonyl](methyl)amino}-3-methoxy-3-oxopropoxy]methyl}tert pyrrolidine-1-carboxylate -butyl (450 mg, 1.03 mmol) in CH2Cl2 (5 mL) and TFA (5 mL) were stirred at 0 oC for 3 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography on KP-NH modified silica (cyclohexane-EtOAc, 80:20 to 60:40 then pure MeOH) to provide the compound of titer (313 mg, 90%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ 7.48-7.29 (m, 5H), 6.23 (br. s., 1H), 5.22-5.10 (m, 2H), 4.50 ( br. s., 1H), 3.96 (dd, J=9.9, 3.1 Hz, 1H), 3.78 (s, 3H), 3.72 (dd, J=9.8, 3 .3 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.32 (m, 1H), 3.25 (dq, J=4.5, 7.0 Hz, 1H), 3.02-2.93 (m, 1H), 2.91-2.81 (m, 1H), 1.87-1.63 (m, 3H), 1.44-1.32 ( m, 1H). LC-MS (Method A): m/z = 337.3 [M+H]+0.49 min. Step 3: Preparation of Benzyl N-[(4S,9aS)-5-oxo-octahydropyrrole[2,1- c][1,4]oxazepin-4-yl]carbamate

[001162] Trimethylaluminum solution (2M in heptane, 0.56 mL, 1.12 mmol) was added dropwise to a stirred solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[ Methyl (2S)-pyrrolidin-2-ylmethoxy]propanoate (313 mg, 0.93 mmol) in CH2Cl2 (5 mL) at -30°C. The solution was allowed to warm to room temperature and allowed to stir at room temperature for 1 h. The reaction mixture was cooled to 0°C and an aqueous solution of 1N HCl (4.63 mL, 4.63 mmol) and water (5 mL) were added. The phases were separated and the aqueous fraction was extracted twice with CH2Cl2, filtered through a hydrophobic frit (Phase Separator) and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2-MeOH, 95:5) to give the title compound (217 mg, 77%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ 7.45-7.29 (m, 5H), 5.73 (br. s., 1H), 5.14 (br. s., 2H), 4.41 (br. s., 1H), 4.18-3.89 (m, 3H), 3.82-3.58 (m, 2H), 3.54-3.19 (m, 2H), 2.18- 2.04 (m, 1H), 1.97-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.56 - 1.39 (m, 1H). LC-MS (Method A): m/z = 305.3 [M+H]+, 0.74 min. Step 4: Preparation of (4S,9aS)-4-amino-octahydropyrrolo[2,1- c][1,4]oxazepin-5-one

[001163] Palladium on carbon (10%, 75 mg) was added to a solution of N-[(4S,9aS)-5-oxo-octahydropyrrole[2,1-c][1,4]oxazepin- Benzyl 4-yl]carbamate (215 mg, 0.71 mmol) in MeOH (5 mL) under a nitrogen atmosphere. The nitrogen atmosphere was replaced by a hydrogen atmosphere and the reaction was stirred for 15 hours. The reaction was quenched by filtration through a Celite buffer, washing with copious MeOH. The filtrate was concentrated under reduced pressure to give the title compound (116 mg, 96%) which was used directly in the next step. 1H NMR (400MHz, CDCI3) δ 4.23-4.11 (m, 1H), 4.02 (dd, J=12.5, 1.3 Hz, 1H), 3.93 (dd, J=12 .8, 4.5 Hz, 1H), 3.80-3.68 (m, 2H), 3.64 (dd, J=4.4, 0.9 Hz, 1H), 3.41 (ddd, J=11.9, 10.4, 6.8Hz, 1H), 3.23 (dd, J=12.7, 9.4Hz, 1H), 2.18-2.08 (m, 1H) , 2.00-1.87 (m, 1H), 1.86-1.68 (m, 1H), 1.57-1.44 (m, 1H). LC-MS (Method B): m/z = 171.1 [M+H]+, 0.35 min. Step 5: Preparation of 5-benzyl-N-((4S,9aS)-5-oxo-hexahydro-1H,3H- pyrrolo[2,1-c][1,4]oxazepin-4-yl)- 4H-1,2,4-triazol-3-carboxamide

[001164] To a suspension of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (50 mg, 0.246 mmol) and (4S,9aS)-4-amino-octa-hydropyrrole[2.1 -c][1,4]oxazepin-5-one (42 mg, 0.246 mmol), in CH2Cl2 (2 mL) was added N,N-diisopropylethylamine (0.107 mL, 0.49 mmol). The reaction mixture was stirred for 10 minutes and then T3P solution (50 wt% in EtOAc, 0.22 mL, 0.37 mmol) was added. After 40 minutes the reaction mixture was quenched by adding water and the two phases were separated. The organic phase was washed with 0.5N HCl solution, saturated NaHCO3 solution and brine and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2-MeOH, 90:10 to 70:30) to provide the title compound. 1H NMR (400MHz, CDCl3) δ 8.05 (d, J=6.3 Hz, 1H), 7.40-7.17 (m, 5H), 4.72 (dd, J=6.9, 4 .9 Hz, 1H), 4.33-4.03 (m, 5H), 3.84 (d, J=12.8 Hz, 1H), 3.75-3.62 (m, 1H), 3 .43 (dt, J=6.8, 11.2 Hz, 1H), 3.31 (dd, J=12.8, 9.5 Hz, 1H), 2.21-2.08 (m, 1H ), 1.95-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.58-1.43 (m, 1H). LC-MS (Method A): m/z = 356.3 [M+H]+0.67 min. Example 28 and 29: 5-benzyl-N-((3R,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin- 3-yl)isoxazol-3-carboxamide and 5-benzyl-N-((3S,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b]azepine-3-yl)isoxazol-3-carboxamide (28); and 5-benzyl-N- ((3R,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) isoxazol-3-carboxamide and 5-benzyl-N-((3S,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)isoxazol-3-carboxamide (29) Example 30: (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazol-3-carboxamide Schematic legend: rt - ta Step 1: Preparation of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[001165] To a solution of 3-iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4.50 g, 15.7 mmol) in N,N-dimethylformamide ( 20 mL) sodium azide (1.23 g, 18.8 mmol) was added and the reaction mixture was stirred at room temperature. Precipitate was formed after 30 minutes. The reaction mixture was diluted with water (300 mL). More solids precipitated and the mixture was stirred for a further 10 minutes. The solid was collected by filtration, washed with water (20 ml) and dried in vacuo. The crude product was dissolved in tetrahydrofuran (30 ml) and water (0.5 ml). Triphenylphosphine (4.50 g, 17.2 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Solids were removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.00 g, 72%) as a white solid. LC-MS (Method E): m/z= 177.0 [M+H]+, 0.413 min. Step 2: Preparation of (3S)-3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[001166] To a solution of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (1.85 g, 11.0 mmol) in isopropanol (200 mL) at At 70°C L-pyroglutamic acid (1.42 g, 11.0 mmol) was added followed by 2-hydroxy-5-nitrobenzaldehyde (0.06 g, 0.33 mmol). The reaction mixture was stirred at 70°C for 4 days. After cooling to room temperature, the solid was collected by filtration, rinsed with isopropanol and the filtrate was basified with ammonium hydroxide (28%, 10 mL). The resulting solution was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (0.91 g, 49%) as a white solid. LC-MS (Method E): m/z = 177.0 [M+H]+, 0.421 min. Step 3: Preparation of Benzyl N-((3S)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate

[001167] A solution of potassium carbonate (2.00 g, 15 mmol) in water (4 mL) was added to a solution of (3S)-3-amino-2,3,4,5-tetrahydro -1H-1-benzazepin-2-one (0.5 g, 3 mmol) in dichloromethane (30 mL) and then benzyl chloroformate (0.77 g, 4.5 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (0.87 g, 99%) as a white solid. LC-MS (Method E): m/z = 311.0 [M+H]+, 0.838 min. Step 4: Preparation of Benzyl N-((3S)-2-sulfanilidene-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate

[001168] Lawesson's reagent (1.05 g, 2.6 mmol) was added to a solution of N-((3S)-2-oxo-2,3,4,5-tetrahydro-1H-1 Benzyl-benzazepin-3-yl)carbamate (0.80 g, 2.6 mmol) in tetrahydrofuran (40 mL) and the reaction mixture was stirred under a nitrogen atmosphere for 16 hours at room temperature. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (0.82 g, 98%) as a white solid. LC-MS (Method E): m/z = 349.1 [M+Na]+, 0.946 min. Step 5: Preparation of Benzyl N-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-1-benzazepin-3-yl)carbamate

[001169] 2,2-Dimethoxyethaneamine (1.06 g, 10.1 mmol) was added to a mixture of N-((3S)-2-sulfanilidene-2,3,4,5-tetrahydro-1H -1- benzazepin-3-yl) benzyl carbamate (0.81 g, 2.5 mmol) and mercury dichloride (0.89 g, 3.3 mmol) in tetrahydrofuran (25 mL). The resulting mixture was heated for 20 minutes at 55°C. After cooling to room temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (20 ml) and extracted with dichloromethane (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.89 g, 90%) as a pale yellow solid. LC-MS (Method C): m/z = 398.2 [M + H]+, 1.182 min. Step 6: Preparation of benzyl (S)-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)carbamate

[001170] A solution of benzyl N-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-1-benzazepin-3-yl)carbamate (0, 85 g, 3 mmol) in formic acid (8 mL, 96%) was heated for 2 hours at 100°C. The black sediment was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL), basified with aqueous sodium hydroxide (1 N, 30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (0.68 g, 95%) as a white solid. LC-MS (Method E): m/z = 334.0 [M+H]+, 0.671 min. Step 7: Preparation of (S)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-amine

[001171] A solution of (S)-benzyl (5,6-dihydro-4H-benzo[f]imidazo[1,2-a] azepin-4-yl)carbamate (0.68 g, 2 mmol) in ethanol (20 mL) was aged overnight in the presence of palladium on carbon (10%, 0.5 g) under a hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound (0.40 g, 99%) as a yellow oil. LC-MS (Method C): m/z = 200.1 [M + H]+, 0.915 min. Step 8: Preparation of (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo [1,2-a]azepin-4-yl)isoxazol-3-carboxamide

[001172] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; mobile phase, water (0.1% formic acid) and ACN (45.0% ACN to 70.0% over 7 min); Detector, 254/220 nm UV to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 7.46-7.41 (m, 3H), 7.40-7.21 (m, 6H), 6.96 (d, J = 1.5 Hz, 1H), 6.53 (s, 1H), 4.80 (dd, J = 10.2, 7.5 Hz, 1H), 4.18 (s, 2H), 2.72 (dd, J = 11.7, 6.0 Hz, 1H), 2.45-2.27 (m, 3H). LC-MS (Method O): m/z = 385.0 [M + H]+1.587 min. Examples 31 and 34: 5-benzyl-N-((3R,4R)-4-fluoro-1-methyl- 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-benzyl-N-( (3S,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4H-1,2,4 -triazol-3-carboxamide (31); and 5-benzyl-N-((3R,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) -4H-1,2,4-triazol-3-carboxamide and 5-benzyl-N-((3S, 4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetra- hydro-1H-benzo [b]azepin-3-yl)-4H-1,2,4-triazol-3-carboxamide (34) Example 32: (S)-5-benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl )-4H-1,2,4-triazole-3-carboxamide Step 1: Preparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-(2-chloro-6-nitrophenoxy)propanoic acid

[001173] Sodium hydride (60%, 0.39 g, 97.6 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (10.0 g, 48. 8 mmol) in N,N-dimethylformamide (50 mL) under nitrogen atmosphere. After stirring for 2 hours at 0°C, 1-chloro-2-fluoro-3-nitrobenzene (8.6 g, 48.8 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with hydrochloric acid (0.5 M, 50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography using an RP-C18 column (acetonitrile/water 7/3) to provide the title compound (5.5 g, 31%) as a yellow solid. LC-MS (Method G): m/z = 361.0 [M+H]+, 0.665 min. Step 2: Preparation of (2S)-3-(2-amino-6-chlorophenoxy)-2-((tert-butoxy)carbonyl)amino)propanoic acid

[001174] Zinc (8.13 g, 125 mmol) and ammonium chloride (6.70 g, 125 mmol) were added to a stirred solution of (2S)-2-(((tert-butoxy)carbonyl) acid amino)-3-(2-chloro-6-nitrophenoxy)propanoic acid (4.5 g, 12.5 mmol) in methanol/tetrahydrofuran (100 mL, 1/1). The resulting mixture was stirred for 2 hours at 25°C. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to provide the title compound (4 g crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method G): m/z = 331.0 [M+H]+, 0.704 min. Step 3: Preparation of tert-butyl N-((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate

[001175] 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 g, 2.91 mmol) and ethyldiisopropylamine (0.94 g, 7 .26 mmol) were added to a stirred solution of (2S)-3-(2-amino-6-chlorophenoxy)-2-((tert-butoxy)carbonyl)amino)propanoic acid; (0.80 g, 2.42 mmol) in N,N-dimethylformamide (10 mL). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to provide the title compound (0.18 g, 24%) as a yellow solid. LC-MS (Method G): m/z = 313.0 [M+H]+, 1.006 min. Step 4: Preparation of tert-N-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate butyl

[001176] Iodomethane (82 mg, 0.58 mmol) was added dropwise to a stirred mixture of N-((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro- tert-butyl 1,5-benzoxazepin-3-yl)carbamate (180 mg, 0.58 mmol) and cesium carbonate (188 mg, 0.58 mmol) in N,N-dimethylformamide (10 mL). After stirring for 2 hours at room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to provide the title compound (120 mg 64%) as a white solid. LC-MS (Method G): m/z = 327.0 [M+H]+, 1.045 min. Step 5: Preparation of (3S)-3-amino-9-chloro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride

[001177] Tert-butyl N-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate ( 120 mg, 0.37 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 mL). The reaction mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure to provide the title compound (83 mg crude) as a white solid. LC-MS (Method G): m/z = 227.0 [M+H]+, 0.772 min. Step 6: Preparation of (S)-5-benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)-4H-1,2,4-triazol-3-carboxamide

[001178] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 7.44-7.20 (m, 8H), 4.98 (dd, J = 15.2, 10.0 Hz, 1H), 4.68 (dd, J = 13.2, 10.0 Hz, 1H), 4.46 (dd, J = 15.2, 13.2 Hz, 1H), 4.17 (s, 2H), 3.42 (s, 3H). LC-MS (Q Method): m/z = 412.2 [M + H]+, 1.336 min.Example 33: (S)-1-benzyl-N-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)azetidine-3-carboxamide

[001179] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 4H), 7.19 (m, 4H), 7.06 (d, J = 6.9 Hz, 1H), 4.95-4.80 (m, 1H), 4.67 (dd, J = 9.6, 7.5 Hz, 1H), 4.14 (dd, J = 11.1, 9.6 Hz, 1H), 3.65 ( s, 2H), 3.57 (s, 2H), 3.51 (s, 3H), 3.34 (m, 2H), 3.22-3.02 (m, 1H). LC-MS (Method O): m/z = 365.9 [M + H]+1.215 min. Example 35: (S)-N- (5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[3,2-b] [1,4]oxazepin-3-yl)- 5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: rt - taStep 1: Preparation of 1-phenylcyclopropane-1-carbohydrazide

[001180] A solution of hydrazine in tetrahydrofuran (1 M, 30 mL) was added to a solution of 1-phenylcyclopropane-1-carboxylic acid (0.48 g, 3.00 mmol), 2-(7-aza) hexafluorophosphate -1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium (1.37 g, 3.60 mmol) and ethyldiisopropylamine (1.16 g, 8.98 mmol) in N,N-dimethylformamide ( 10 mL). After stirring for 1 hour at room temperature, the stock mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to give the title compound (0.53 g, 98%) as a yellow oil. LC-MS (Method R: m/z = 177.2 [M+H]+, 0.670 min. Step 2: Preparation of ethyl 2-amino-2-(((1-phenylcyclopropyl)formamido)imino)acetate

[001181] Ethyl 2-ethoxy-2-iminoacetate (452 mg, 3.11 mmol) was added to a stirred solution of 1-phenylcyclopropane-1-carbohydrazide (528 mg, 3.00 mmol) in ethanol/ether ( 12 mL, 1/3). The reaction mixture was stirred for 2 hours at room temperature. The yellow solid was collected by filtration to provide the title compound (300 mg, 36%). LC-MS (Method S: m/z = 276.2 [M+H]+, 0.663 min. Step 3: Preparation of 5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxylate ethyl

[001182] A solution of ethyl 2-amino-2-(((1-phenylcyclopropyl)formamido)imino)acetate (275 mg, 1.00 mmol) in xylene (10 mL) was irradiated with microwave radiation for 10 hours at 170°C. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (100 mg, 39%) as a yellow solid. LC-MS (Method C): m/z = 258.1 [M+H]+, 1.641 min. Step 4: Preparation of 5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxylic acid

[001183] A solution of lithium hydroxide (28 mg, 1.17 mmol) in water (1 mL) was added to a solution of 5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3- ethyl carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (3 mL) and the resulting mixture was stirred overnight at room temperature. After adjusting the pH to 6-7 with aqueous hydrochloric acid (1N, 20 mL), the reaction mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (90 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method R): m/z = 230.2 [M+H]+, 0.530 min. Step 5: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[3,2-b][1,4]oxazepin-3-yl )-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide

[001184] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV at 254 and 220 nm to generate the title compound. 1H NMR (400 MHz, CD3OD) δ 7.44-7.20 (m, 9H), 4.99 (dd, J = 11.6, 7.6 Hz, 1H), 4.58 (dd, J = 9.6, 7.6 Hz, 1H), 4.39 (dd, J = 11.6, 10.0 Hz, 1H), 3.57 (s, 3H), 1.67-1.56 (m , 2H), 1.46-1.29 (m, 2H). LC-MS (Method D): m/z = 404.1 [M + H]+1.966 min. Example 36: 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)isoxazol-3-carboxamide Example 37: (R)-5-benzyl-N-(4,4-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3- il)-4H-1,2,4-triazol-3-carboxamide Example 38A and 38B: (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6 -yl)-4H-1,2,4-triazol-3-carboxamide and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro -4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide Step 1: Preparation of azepane-2,7-dione

[001185] A stirring solution of azepan-2-one (11.3 g, 100 mmol) 2-hydroxyisoindoline-1,3-dione (1.63 g, 10 mmol) and cobalt acetate (88.5 mg, 0.5 mmol) in acetonitrile (100 mL) was washed with oxygen (flask). The reaction mixture was heated overnight at 85°C under an oxygen atmosphere. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give a title compound (3.70 g, 29.1 %) as a white solid. LC-MS (Method C): m/z = 128.2 [M+H]+, 0.683 min.Step 2: Preparation of 1-methylazepane-2,7-dione

[001186] Iodomethane (1.68 g, 11.8 mmol) was added dropwise to a stirred mixture of azepane-2,7-dione (1.50 g, 11.8 mmol) and cesium carbonate (3. 85 g, 5.0 mmol) in N,N-dimethylformamide (25 mL) at 0oC. The reaction mixture was stirred overnight at room temperature, quenched by addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (1.1 g, 66.1%) as a yellow oil. LC-MS (Method C): m/z = 142.1 [M+H]+, 0.863 min. Step 3: Preparation of 3-bromo-1-methylazepane-2,7-dione

[001187] Bromine (632 mg, 4.00 mmol) was added to a stirred solution of 1-methylazepane-2,7-dione (564 mg, 4.0 mmol) in chloroform (10 mL). The reaction mixture was stirred at 110°C for 1.5 hours in a sealed tube. The reaction mixture was concentrated in high vacuum to provide the title compound (600 mg crude) as a brown oil. LC-MS (Method C): m/z = 220.1 [M+H]+, 0.940 min. Step 4: Preparation of 2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

[001188] Ethanylethioamide (300 mg, 4.0 mmol) was added to a solution of 3-bromo-1-methylazepane-2,7-dione (600 mg, 4.0 mmol) in pyridine (10 mL). The reaction mixture was stirred at 50°C for 16 hours, quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (70 mg, 9%) as a yellow solid. LC-MS (Method C): m/z = 197.1 [M+H]+, 0.981min. Step 5: Preparation of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

[001189] N1, N1, N2, N2-tetramethylethane-1,2-diamine (124 mg, 1.07 mmol) was added to a stirred solution of 2,4-dimethyl-7,8-dihydro-4H- thiazolo[4,5-b]azepin-5(6H)-one (70 mg, 0.36 mmol) in dichloromethane (5 mL) at 0°C, followed by addition of iodotrimethylsilane (214 mg, 1.07 mmol) . The reaction mixture was stirred for 1 hour at 0°C. After adding iodine (137.2 mg, 0.54 mmol), the reaction mixture was stirred for an additional 2 hours at 0°C and quenched with aqueous sodium thiosulfate (5%, 15 mL). The resulting solution was stirred for an additional 15 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (61 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method R): m/z = 323.2[M+H]+, 0.820 min. Step 6: Preparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

[001190] To a solution of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one (61 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) azide (37.1 mg, 0.57 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) and water (1 mL) and Tripenylphosphine (149.3 mg, 0.57 mmol) was added in one portion. The reaction mixture was stirred at 50°C overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (33 mg, 83%) as a yellow solid. LC-MS (Method C): m/z = 212.1 [M+H]+, 0.735min. Step 7: Preparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl) -4H-1,2,4-triazole-3-carboxamide

[001191] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L of NH4HCO3); Phase B: ACN (20% to 80% over 12 min); Detector, 220 & 254 nm UV to generate the title compound. LC-MS (Method R): m/z = 397.1[M+H]+, 1.095 min. Step 8: Preparation of (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin- 6-yl)-4H-1,2,4-triazol-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6, 7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)- 4H-1,2,4-triazol-3-carboxamide (second elution isomer)

[001192] The enantiomers of 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl )-4H-1,2,4-triazol-3-carboxamide (24 mg, 0.06 mmol) were separated by prechiral HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 μm; Mobile phase A: hexanes, mobile phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B over 17.5 min; UV 220 and 254 nm; RT 1: 10.18 min; RT 2: 15.13 min to generate the title compounds:

[001193] Example 38B (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.25 (m, 5H), 4.73-4.69 (m, 1H), 4 .18 (s, 2H), 3.39 (s, 3H), 3.05-2.88 (m, 2H), 2.73-2.64 (m, 4H), 2.36-2.27 (m, 1H). LC-MS (Method D): mz = 397.1 [M + H]+1.623 min.

[001194] Example 38A (second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.24 (m, 5H), 4.73-4.68 (m, 1H), 4 .18 (s, 2H), 3.39 (s, 3H), 3.06-2.87 (m, 2H), 2.73-2.63 (m, 4H), 2.36-2.27 (m, 1H). LC-MS (Method D): mz = 397.1 [M + H]+1.623 min. Example 39: (S)-5-benzyl-N-(1-methyl-2-oxo-8-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide Example 40: (S)-5-benzyl-N-(5-methyl-4-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)-4H-1,2,4-triazol-3-carboxamide Scheme legend: rt - taExample 41: (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,4-b][1 ,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: rt - taStep 1: Preparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoic acid

[001195] Sodium hydride (60%, 1.92 g, 80.1 (mmol) was added to a stirred solution of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (8.21 g, 40.0 mmol) in dimethyl formamide (30 mL) in a nitrogen atmosphere at 0°C. After stirring for 2 hours at 0°C, a solution of 3-fluoro-4-nitropyridine (5.52 g, 40. 0 mmol) in dimethylformamide (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature, quenched by addition of water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase CombiFlash using an RP-C18 column (acetonitrile/water, 1/4) to give. the title compound (2.41 g, 18%) as a yellow solid. LC-MS (Method S): m/z = 328.1 [M+H]+, 0.829 min. 2S)-3-((4-aminopyridin-3- yl)oxy)-2-((tert-butoxy)carbonyl)amino) propanoic acid

[001196] (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoic acid (2.41 g, 7.34 mmol) in Methanol (20 mL) was aged overnight at room temperature in the presence of palladium on carbon (10%, 345 mg) in a hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound (1.8 g, 83%) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method S): m/z = 298.1 [M+H]+, 0.601 min. Step 3: Preparation of tert-butyl N-((3S)-2-oxo-1H,2H,3H,4H-pyrido[3,4- b][1,4]oxazepin-3-yl)carbamate

[001197] 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.5 g, 4.04 mmol) and ethyldiisopropylamine (1.30 g, 10 .1 mmol) were added to a stirred solution of (2S)-3-((4-aminopyridin-3-yl)oxy)-2-((tert-butoxy)carbonyl)amino)propanoic acid (1.01 g, 3.37 mmol) in N,N-dimethylformamide (13 mL). After stirring for 3 hours at room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (0.4 g, 83%) as a yellow solid. LC-MS (Method S): m/z = 280.1 [M+H]+, 0.604 min. Step 4: Preparation of tert N-((3S)-1-methyl-2-oxo-1H,2H,3H,4H-pyrido[3,4- b][1,4]oxazepin-3-yl)carbamate -butyl

[001198] Iodomethane (203 mg, 1.43 mmol) was added dropwise to a mixture of N-((3S)-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][ tert-butyl 1,4]oxazepin-3-yl)carbamate (400 mg, 1.43 mmol) and cesium carbonate (467 mg, 1.43 mmol) in N,N-dimethylformamide (7 mL). After stirring for 10 minutes at 0°C, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether 1/3) to provide the title compound (300 mg, 72%) as a yellow solid. LC-MS (Method S): m/z = 294.1 [M+H]+, 0.650 min. Step 5: Preparation of (3S)-3-amino-1-methyl- 1H,2H,3H,4H- pyrido[3,4-b][1,4]oxazepin-2-one hydrochloride

[001199] A solution of hydrogen chloride in 1,4-dioxane (4 M 5 mL, 20 mmol) was added to a solution of N-((3S)-1-methyl-2-oxo- 1H,2H,3H, tert-Butyl 4H-pyrido[3,4-b][1,4] oxazepin-3-yl)carbamate (300 mg, 1.02 mmol) in 1,4-dioxane (7 mL). The reaction mixture was stirred for 1 hour at room temperature and concentrated to provide the title compound (215 mg, 92%) as a white solid. LC-MS (Method S): m/z = 194.1 [M+H]+, 0.184 min. Step 6: Preparation of (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,4-b][1,4]oxazepine -3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide

[001200] A solution of (3S)-3-amino-1-methyl-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-2-one hydrochloride (115 mg, 0.50 mmol) in N,N-dimethylformamide (1 mL) was added to a stirring solution of 5-benzyl-2H-1,2,4-triazol-3-carboxylic acid (102 mg, 0.50 mmol) , ethyldiisopropylamine (129 mg, 1.00 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (92 mg , 0.60 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: 19 x 150 mm, 5 μm XBridge Prep C18 OBD column; Mobile Phase A: water (10 mmol/L NH4HCO3; Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15% B to 45% B over 10 min; 254 nm. The fractions collected were combined and concentrated under reduced pressure to give the title compound 1H NMR (400 MHz, CDCl3) δ 12.34 (s, 1H), 8.54-8.46 (m, 2H), 8.06 ( d, J = 7.3 Hz, 1H), 7.36-7.29 (m, 5H), 7.16 (d, J = 5.2 Hz, 1H), 5.09 (m, 1H), 4.77 (dd, J = 10.0, 3.2 Hz, 1H), 4.41 (dd, J = 11.6, 10.0 Hz, 1H), 4.20 (s, 2H), 3 .46 (s, 3H). LC-MS (Method T): m/z = 379.2 [M+H]+, 0.888 min. Example 42: (S)-5-benzyl-N-(5-methyl). -4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4] oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: rt - taStep 1: Preparation of (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid

[001201] Sodium hydride (60%, 2 g, 50 mmol) was added to a stirring solution of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (5 g, 25.0 mmol) in N,N-dimethylformamide (100 mL). The resulting mixture was stirred at 0°C for 2 hours. 3-fluoro-2-nitropyridine (3.6 g, 25.3 mmol) was added and the action mixture was stirred at room temperature for a further 8 hours before being quenched with hydrochloric acid (3N, 5 mL). After adjusting the pH to 34 with hydrochloric acid (3N, 20 mL), the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography with an RP-C18 column (acetonitrile/water, 1/2) to provide the title compound (3.2 g, 39%) as a pale yellow oil. LC-MS (Method C): m/z = 272.1 [M+H-(t-BuO)]+, 1.269 min. Step 2: Preparation of (2S)-3-((2-aminopyridin-3-yl)oxy)-2-((tert-butoxy)carbonyl)amino) propanoic acid

[001202] (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid (0.45 g, 1.4 mmol) in methanol (20 mL) was aged overnight at room temperature in the presence of palladium on carbon (10%, 0.5 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound (0.32 g, 78%) as a yellow oil. LC-MS (Method C): mz = 298.1 [M + H]+, 0.982 min. Step 3: Preparation of tert-butyl N-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2- b][1,4]oxazepin-3-yl)carbamate

[001203] N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.73 g, 1.92 mmol) and N,N-diisopropylethylamine (0 .25 g, 1.93 mmol) to a stirred solution of (2S)-3-((2-aminopyridin-3-yl)oxy)-2-((tert-butoxy)carbonyl)amino)propanoic acid (0. 45 g, 1.51 mmol) in N,N-dimethylformamide (5 mL). After stirring for 6 hours at room temperature, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (0.11 mg, 26%) as a white solid. LC-MS (Method C): m/z = 280.1 [M + H]+, 1.248 min. Step 4: Preparation of tert N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2- b][1,4]oxazepin-3-yl)carbamate -butyl

[001204] Iodomethane (50 mg, 0.35 mmol) was added dropwise to a stirring solution of N-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2- b tert-butyl ][1,4]oxazepin-3-yl)carbamate (100 mg, 0.36 mmol) and cesium carbonate (120 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL). After stirring for 3 hours at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (90 mg, 86%) as a white solid. LC-MS (Method C): m/z = 294.1 [M+H]+, 1.333 min. Step 5: Preparation of (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-one hydrochloride

[001205] N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl) tert-butyl carbamate (90 mg, 0.31 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 mL). The reaction mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure to yield the title compound (65 mg, 93%) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 194.1 [M+H]+, 0.847 min. Step 6: Preparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepine -3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide

[001206] A solution of (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-one hydrochloride (55 mg , 0.24 mmol) in N,N-dimethylformamide (1 mL) was added to a stirring solution of 5-benzyl-2H-1,2,4-triazole-3-carboxylic acid (80 mg, 0.40 mmol ), 1-hydroxy-benzotrizole (70 mg, 0.53 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N,N-diisopropylethylamine (160 mg, 1.21 mmol) in N,N-dimethylformamide (2 mL). After stirring for 8 hours at room temperature, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC with the following conditions: Column, OBD XBridge Shield RP18 Column, 5.19 x 150 mm; mobile phase, water (0.1% formic acid) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 14.45 (s, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.37 (dd, J = 4.8, 1, 8 Hz, 1H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.37-7.21 (m, 6H), 4.92-4.82 (m, 1H ), 4.73 (dd, J = 11.4, 9.6 Hz, 1H), 4.53 (dd, J = 9.6, 7.5 Hz, 1H), 4.14 (s, 2H) , 3.37 (s, 3H). LC-MS (Method D): mz = 379.1 [M + H]+1.611 min. Example 43: 3-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclobutane-1 -carboxamide Schematic legend: rt - taStep 1: Preparation of ethyl 3-(phenylmethylidene)cyclobutane-1-carboxylate

[001207] A solution of n-butyllithium in hexane (2.5 M, 3.4 mL, 8.5 mmol) was added dropwise to a suspension of benzyltriphenylphosphinium chloride (3.3 g, 8.5 mmol) in anhydrous tetrahydrofuran (50 mL) at -60oC. The resulting mixture was stirred at -60°C for 0.5 hour and then allowed to warm to room temperature. Ethyl 3-oxocyclobutanecarboxylate (1.2 g, 8.5 mmol) was added and the reaction mixture was heated to reflux and stirred overnight. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to provide the title compound (0.14 g, 8%) as a pale yellow oil. LC-MS (Method S): m/z = 217.2 [M+H]+, 1.144 min. Step 2: Preparation of Ethyl 3-Benzylcyclobutane-1-carboxylate:

[001208] Ethyl 3-(phenylmethylidene)cyclobutane-1-carboxylate (130 mg, 0.6 mmol) in methanol (5 mL) was hydrogenated in the presence of palladium on carbon (10%, 15 mg) in a hydrogen atmosphere . After stirring for 2 hours at room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound (100 mg crude) as a yellow oil, which was used directly in the step following, without additional purification. LC-MS (Method S): m/z = 219.3 [M+H]+, 1.160 min. Step 3: Preparation of 3-benzylcyclobutane-1-carboxylic acid:

[001209] A solution of sodium hydroxide (60 mg, 1.5 mmol) in water (1 mL) was added to a solution of ethyl 3-benzylcyclobutane-1-carboxylate (100 mg, 0.5 mmol) in tetra -hydrofuran (3 mL). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water (10 mL), adjusted to pH = 3 with aqueous hydrochloric acid (3 N, 10 mL), and extracted with ethyl acetate (3 x 10 mL ). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude title compound (85 mg/97%) as a yellow oil. LC-MS (Method I): m/z = 190.9 [M+H]+, 0.954 min. Step 4: Preparation of 3-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclobutane -1-carboxamide

[001210] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD column, 5 μm, 19 x 150 mm; mobile phase, water (0.05% NH3H2O), ACN (25% ACN at 55% B over 7 min); detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.29-7.13 (m, 9H), 6.41 (d, J = 6.0 Hz, 1H), 4.93-4.86 (m, 1H) , 4.69 (t, J = 7.6 Hz, 1H), 4.12 (t, J = 10.0 Hz, 1H), 3.44 (s, 3H), 2.88-2.69 ( m, 3H), 2.48 (q, J = 7.6 Hz, 1H), 2,352.24 (m, 2H), 2.09-1.91 (m, 2H). LC-MS (Method O): m/z = 365.0 [M + H]+, 1.585 min. Example 44: (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropan]-3- il)-4H-1,2,4-triazol-3-carboxamide Step 1: Preparation of tert-butyl 1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate

[001211] To a mixture of methyltriphenyl phosphomonium bromide (4.4 g, 12.3 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 0.30 g, 12.3 mmol) . The resulting mixture was stirred for 1 hour at 50°C in a nitrogen atmosphere. To this mixture, a solution of tert-butyl 1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (1. 50 g, 4.93 mmol) in tetrahydrofuran (20 mL) dropwise at 50°C. After stirring overnight at 50°C, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (600 mg, 40%) as a yellow solid. LC-MS (Method C): m/z = 303.2 [M+H]+, 1.531 min. Step 2: Preparation of tert N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate -butyl

[001212] To a solution of potassium hydroxide (2.23 g, 39.7 mmol) in water (3.3 mL) was added a solution of 1-methyl-1-nitrosourea (2.05 g, 19.7 mmol) in ether (100 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to obtain the diazomethane solution (100 mL). To a solution of tert-butyl 1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (0.6 g, 1 .99 mmol) in tetrahydrofuran (5 mL) was added to diazomethane solution (100 mL) dropwise, followed by the addition of a mixture of palladium diacetate (45 mg, 0.20 mmol) in tetrahydrofuran ( 1 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (0.15 mg, 24%) as a yellow solid. LC-MS (Method C): m/z = 317.2 [M+H]+, 1.531 min. Step 3: Preparation of 3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-one hydrochloride

[001213] A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL) was added to a solution of N-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2, tert-butyl 4]]dodeca-1(8,9,11-trien-5-yl]carbamate (150 mg, 0.60 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to provide the title compound (95 mg crude) as a yellow solid. LC-MS (Method K): m/z = 217.2 [M+H]+, 0.635 min. Step 4: Preparation of (3S)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-one (first elution isomer) and (3R)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro-[1-benzazepine-5,1-cyclopropane]-2-one (second elution isomer)

[001214] 3-Amino-1-methyl-1,2,3,4-tetrahydrospiro-[1-benzazepine-5,1-cyclopropane]-2-one hydrochloride (90 mg crude) was separated by HPLC of Chiral Preparation with the following conditions: Column: Phenomenex Lux Cellulose-4, AXIA packed, 2.12 x 25 cm, 5 μm; Mobile phase A: hexanes (0.1% DEA), Mobile phase B: EtOH; Flow rate: 20 mL/min; Gradient: 35% B to 35% B over 17.5 min; 220/254nm; RT1: 11.24 min; RT2: 13.82 min to deliver the title compound.

[001215] First elution isomer: (36 mg, 38%) as a white solid. LC-MS (Method D): m/z = 217.2 [M+H]+, 1.096 min.

[001216] Second elution isomer: (46 mg, 48%) as a white solid. LC-MS (Method D): m/z = 217.2 [M+H]+, 1.089 min. Step 5: Preparation of (S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropan]- 3-yl)-4H-1,2,4-triazol-3-carboxamide

[001217] The crude product obtained using amide bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5.19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% in 7 min); Detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, J = 7.5 Hz, 1H), 7.457.32 (m, 2H), 7.35-7.20 (m, 7H), 4 .46-4.36 (m, 1H), 4.07 (s, 2H), 3.30 (s, 3H), 2.71-2.65 (m, 1H), 1.57 (t, J = 12.6 Hz, 1H), 1.10-1.07 (m, 1H), 0.750.63 (m, 2H), 0.42-0.37 (m, 1H). LC-MS (Method D): m/z = 402.2 [M + H]+, 1.871 min. Example 45: (S)-1-benzyl-4-fluoro-5-methyl-N-(4-oxo -2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Step 1: Preparation of (3S)-3-amino-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride

[001218] tert-Butyl N-((3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (100 mg, 0.36 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL). The reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to provide the title compound (100 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method E): m/z = 178.9 [M+H]+, 0.397 min. Step 2: Preparation of (S)-1-benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)-1H-pyrazol-3-carboxamide

[001219] The crude product obtained using Amide Binding Procedure B was purified by Prep-HPLC with the following conditions: Column: 19 x 150 mm, 5 μm XBridge Prep C18 OBD Column; Mobile Phase A: water (10 mmol/L NH4HCO3; Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15% B to 45% B in 10 min; 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7 .43-7.28 (m, 3H), 7.20-7.09 (m, 6H), 5.39 (s, 2H), 4.80 (dt, J = 10.0, 7.3 Hz , 1H), 4.53-4.39 (m, 2H), 2.17 (d, J = 1.4 Hz, 3H). + H]+, 2.860 min. Example 46: 5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[ d]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide

[001220] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep C18 OBD XBridge Column, 5 μm, 19 x 150 mm; Mobile phase A: water (0.05% TFA), mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to provide the title compound. LC-MS (Method J): m/z = 388.2 [M + H]+, 1.305 min.

[001221] The enantiomers of 5-benzyl-N-{7-methyl-6-oxo-7- azatricyclo[6.4.0.0A{2,4}]dodeca-1(8),9,11-trien-5- yl}-4H-1,2,4-triazol-3-carboxamides were separated by HPLC of chiral preparation with the following conditions: column: CHIRALPAK IC, 2.0 cm x 25 cm (5 μm); Mobile phase A: hexanes, Mobile phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B for 30 min; 254/220nm; RT1: min 10.478; Rt2: 13.826 min to generate the title compounds:

[001222] Example 46A (first elution isomer): 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 7.1 Hz, 1H), 7.39-7.17 (m, 8H ), 7.11 (d, J = 7.5 Hz, 1H), 4.80 (d, J = 7.0 Hz, 1H), 4.22 (s, 2H), 3.35 (s, 3H ), 2.28-1.80 (m, 2H), 1.21 (m, 1H), 1.04 (m, 1H). LC-MS (Method J): m/z = 388.2 [M + H] +, 1.302 min.

[001223] Example 46B (second elution isomer): 1H NMR (400 MHz, Chloroform-d) δ 8.53 (d, J = 7.1 Hz, 1H), 7.39-7.18 (m, 8H ), 7.12 (d, J = 7.7 Hz, 1H), 4.80 (d, J = 7.0 Hz, 1H), 4.23 (s, 2H), 3.35 (s, 3H ), 2.09 (m, 1H), 2.02 (m, 1H), 1.21 (m, 1H), 1.05 (m, 1H). LC-MS (Method J): m/z = 388.2 [M + H]+, 1.306 min. Example 47: (S)-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1- (1-phenylcyclopropyl)-1H-pyrazol-3-carboxamide Example 48: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(3-phenyloxane -3-yl)-4H-1,2,4-triazol-3-carboxamide Example 49: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(phenylsulfonyl)thiazol-2 -carboxamide Schematic legend: rt - taStep 1: Preparation of ethyl 5-(phenylthio)thiazol-2-carboxylate

[001224] To a stirred mixture of ethyl 5-iodo-1,3-thiazol-2-carboxylate (300 mg, 1.06 mmol), sodium benzeneethate (220 mg, 1.66 mmol) in 1-methyl- 2-pyrrolidinone (10 mL) was added to cuprous iodide (40 mg, 0.21 mmol) in an argon atmosphere. The resulting solution was stirred for 4 hours at 70°C, quenched with water (20 ml) and extracted with ethyl acetate (4 x 20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-TLC (ethyl acetate/petroleum ether, 5/1) to provide the title compound (120 mg, 43%) as a yellow oil. LC-MS (Method S): m/z = 266.0 [M+H]+, 1.040 min. Step 2: Preparation of Ethyl 5-(phenylsulfonyl)thiazol-2-carboxylate

[001225] To a stirred mixture of ethyl 5-(phenylthio)thiazol-2-carboxylate (100 mg, 0.38 mmol) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (167 mg, 0.97 mmol) . The reaction mixture was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (100 mg, 88%) as a yellow oil. LC-MS (Method S): m/z = 298.0 [M+H]+, 0.931 min. Step 3: Preparation of 5-(phenylsulfonyl)thiazol-2-carboxylic acid

[001226] To a stirred mixture of ethyl 5-(phenylsulfonyl)thiazol-2-carboxylate (100 mg, 0.34 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added to the lithium hydroxide (12 mg, 0.50 mmol). The resulting mixture was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was diluted with water (10 mL) and adjusted to pH = 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (90 mg crude) as a white oil, which was used directly in the next step without further purification. LC-MS (Method E): m/z = 270.0 [M+H]+, 0.635 min. Step 4: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(phenylsulfonyl )thiazol-2-carboxamide

[001227] The crude product obtained using Amide Bonding Procedure B was purified by Prep-HPLC with the following conditions: column: Xbridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (20% to 80% over 12 min); Detector, 220 & 254 nm UV to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (br. s, 1H), 8.76 (s, 1H), 8.10-8.01 (m, 2H), 7.82-7, 63 (m, 3H), 7.52-7.44 (m, 1H), 7.38-7.17 (m, 3H), 4.83-4.70 (m, 1H), 4.71- 4.59 (m, 1H), 4.45-4.32 (m, 1H), 3.30 (s, 3H). LC-MS (Method O): m/z = 443.9 [M + H]+1.594 min. Example 50: (1R,2S)-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)cyclopropane-1-carboxamide Step 1: Preparation of (±)-trans-2-benzylcyclopropanecarboxylic acid

[001228] Sodium hydroxide (60%, 74 mg, 1.84 mmol) was added to a solution of (±)-trans-ethyl 2-benzylcyclopropanecarboxylate (200 mg, 0.74 mmol) in methanol (12 mL ) and water (6 mL). The reaction mixture was then stirred at room temperature overnight. After removing methanol under reduced pressure, the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (95 mg, 73%) as a yellow oil. LC-MS (Method I): m/z = 177.0 [M+H]+, 0.877 min. Step 2: Preparation of trans-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl )cyclopropanecarboxamide

[001229] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (40.0% ACN to 65.0% for 8 min); Detector, 254 nm UV to provide the title compound. LC-MS (Method J): m/z = 351.1 [M+H]+, 2.116 min. Step 3: Preparation of (1R,2S)-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3 -yl)cyclopropanecarboxamide and (1S,2R)-2-benzyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]oxazepine-3-yl)cyclopropanecarboxamide

[001230] The diastereoisomers of trans-2-benzyl-N-((S)-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3- il) cyclopropanecarboxamide were separated by chiral HPLC preparation with the following conditions: Column: Phenomenex Lux Cellulose-4, AXIA packed, 2.12 x 25 cm, 5 μm; Mobile phase A: hexanes, mobile phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 12 min; 254/220nm; RT1: 7.474 min; RT2: 8.916 min to provide the title compounds:

[001231] Example 50A (first elution isomer): 1H NMR (400 MHz, Chloroform-d) δ 7.31-7.23 (m, 2H), 7.24-7.11 (m, 7H), 6 .65 (d, J = 6.4 Hz, 1H), 4.94-4.85 (m, 1H), 4.69-4.61 (m, 1H), 4.18-4.09 (m , 1H), 3.44 (s, 3H), 2.79-2.71 (m, 1H), 2.58-2.50 (m, 1H), 1.57 (s, 1H), 1.371, 33 (m, 1H), 1.20-1.16 (m, 1H), 0.80-0.75 (m, 1H). LC-MS (Method J): m/z = 351.1 [M + H]+, 2.116 min.

[001232] Example 50B (second elution isomer): 1H NMR (400 MHz, Chloroform-d) δ 7.31-7.26 (m, 2H), 7.21-7.13 (m, 7H), 6 .59 (d, J = 6.4 Hz, 1H), 4.95-4.84 (m, 1H), 4.69-4.58 (m, 1H), 4.16-4.09 (m , 1H), 3.43 (s, 3H), 2.79-2.70 (m, 1H), 2.63-2.54 (m, 1H), 1.67-1.57 (m, 1H ), 1.37-1.32 (m, 1H), 1.17-1.13 (m, 1H), 0.78-0.73 (m, 1H). LC-MS (Method J): m/z = 351.1 [M + H]+, 1.451 min. Example 51: 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4-oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide Step 1: Preparation of 2,3-dihydro-1H-indene-1-carbohydrazide

[001233] A solution of hydrazine in tetrahydrofuran (1 M31 mL, 31 mmol) was added to a solution of 2,3-dihydro-1H-indene-1-carboxylic acid (1.0 g, 6.2 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.8 g, 7.4 mmol) and ethyldiisopropylamine (2.4 g, 18. 6 mmol) in N,N-dimethylformamide (20 mL). After stirring for 1 hour at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (0.87 g, 80%) as a white solid. LC-MS (Method E): m/z = 177.0 [M+H]+, 0.506 min. Step 2: Preparation of ethyl 2-amino-2-(2-(2,3-dihydro-1H-indene-1-carbonyl)hydrazono)acetate

[001234] Ethyl 2-ethoxy-2-iminoacetate (412 mg, 2.8 mmol) was added to a solution of 2,3-dihydro-1H-indene-1-carbohydrazide (500 mg, 2 .8 mmol) in ethanol (5 mL) and diethyl ether (5 mL). The resulting suspension was stirred at room temperature for 2 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo to provide the title compound (600 mg78%) as a yellow solid. LC-MS (Method S): m/z = 276.2 [M+H]+, 0.709 min. Step 3: Preparation of ethyl 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylate

[001235] Ethyl 2-amino-2-(2-(2,3-dihydro-1H-indene-1-carbonyl)hydrazono)-ethyl acetate (600 mg, 2.2 mmol) was added to xylene ( 10 mL) in a sealed tube. The reaction mixture was heated for 5 hours at 170°C and irradiated by microwave. After concentration in high vacuum, the residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (340 mg, 60%) as a yellow oil. LC-MS (Method I): m/z = 258.1 [M+H]+, 0.848 min. Step 4: Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazol-3-carboxylic acid

[001236] Lithium hydroxide (95.3 mg, 4.0 mmol) was added to a solution of 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2, Ethyl 4-triazole-3-carboxylate (340 mg, 1.3 mmol) in tetrahydrofuran (6 mL) and water (3 mL). After stirring at room temperature for 4 hours and removing the tetrahydrofuran under reduced pressure, the reaction mixture was diluted with water (20 mL), the pH was adjusted to 2 with aqueous hydrochloric acid (1 N, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (140 mg, 47%) as a yellow solid. LC-MS (Method E): m/z = 229.9 [M+H]+, 0.642 min. Step 5: Preparation 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b][1,4-oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001237] The crude product obtained using Amide Binding Procedure B was purified by Prep-HPLC with the following conditions: Column: OBD XBridge Shield RP18 column, 5.19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 10 min; 254 nm to give the title compound. 1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.2, 1H), 7.29-7.19 ( m, 6H), 5.17-5.06 (m, 1H), 4.77-4.67 (m, 2H), 4.34-4.27 (m, 1H), 3.45 (s, 3H), 3.16-3.01 (m, 2H), 2.68-2.63 (m, 1H), 2.46-2.39 (m, 1H). LC-MS (Method J): m/z = 404.3 [M + H]+1.332 min. Example 52: (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-4H-1,2,4 -triazol-3-carboxamide

[001238] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, OBD XBridge Shield RP18 Column, 5.19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (10.0% ACN to 40.0% over 7 min); Detector, 220 & 254 nm UV to generate the title compound. 1H NMR (300 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.67 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.53-7 .47 (m, 3H), 7.46-7.22 (m, 6H), 7.04 (d, J = 1.5 Hz, 1H), 4.87-4.77 (m, 1H), 4.14 (s, 2H), 2.80-2.73 (m, 1H), 2.67-2.56 (m, 1H), 2.46-2.32 (m, 2H). LC-MS (Method O): m/z = 385.0 [M+H]+, 1.229 min. Example 53: 3-benzyl-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepine -3-yl)-1H-1,2,4-triazol-5-carboxamide Example 54A and 54B: 5-((R)-2,3-dihydro-1H-inden-1-yl)-N-((S)-4-oxo- 2,3,4,5-tetra- hydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-((S)-2,3-dihydro-1H -inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H -1,2,4-triazol-3-carboxamide Scheme caption: rt – ta Step 1: Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3 ,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001239] A solution of trimethylaluminum in toluene (2 M, 0.6 mL, 1.2 mmol) was added to a mixture of (S)-3-amino-5-methyl-2,3-di-hydrochloride hydropyrido[3,2-b][1,4]oxazepin-4(5H)-one (60 mg, 0.26 mmol) in toluene (2 mL) dropwise at 0°C. The resulting solution was warmed to room temperature and stirred for 30 minutes. A solution of ethyl 5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazol-3-carboxylate (108 mg, 0.42 mmol) was added in toluene (2 mL) dropwise to the resulting solution. The resulting solution was stirred overnight at room temperature. The solution was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: 19 x 150 mm, 5 mm XBridge Prep Phenyl OBD column; Mobile Phase A: water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; 254nm; RT: 6 min to provide the title compound (25 mg, 23.8%) as a white solid. LC-MS (Method D): m/z = 405.1 [M+H]+, 1.759 min. Step 2: Preparation of 5-((R)-2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4, 5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-((S)-2,3-di -hydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

[001240] A 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide (25 mg) was separated by chiral preparation HPLC with the following conditions: Column: CHIRALPAK IA, 2 x 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 40 min; 220/254nm; RT1: 9.716 min; RT2: 29.084 min to provide the title compounds.

[001241] 54A (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.36-8.35 (m, 1H), 7.70-7.68 (m, 1H), 7, 34-7.31 (m, 2H), 7.25-7.24 (m, 1H), 7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m, 2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3, 18-3.15 (m, 1H), 3.07-3.05 (m, 1H), 2.65-2.62 (m,1H), 2.43-2.38 (m, 1H). LC-MS (Method T): m/z = 405.3 [M+H]+, 1.296 min.

[001242] 54B (second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.36-8.35 (m, 1H), 7.70-7.68 (m, 1H), 7, 34-7.31 (m, 2H), 7.25-7.24 (m, 1H), 7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m, 2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3, 18-3.15 (m, 1H), 3.07-3.05 (m, 1H), 2.65-2.62 (m,1H), 2.43-2.38 (m, 1H). LC-MS (Method T): m/z = 405.3 [M+H]+, 1.301 min. Example 55: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1- (pyridine-2-ylmethyl)-1H-pyrazol-3-carboxamide Schematic legend: rt - ta Step 1: Preparation of ethyl 4-fluoro-1H-pyrazol-3-carboxylate

[001243] 1-(Chloromethyl)-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octane tetrafluoroborate (14 g, 39.5 mmol) was added to a mixture of 1H-pyrazol-3-carboxylate of ethyl (5 g, 35.7 mmol) in acetonitrile (50 mL). The resulting mixture was stirred for 48 hours at 100°C. After cooling to room temperature, the solids were removed by filtration and the filtrate was concentrated in vacuo to provide the title compound (2.4 g) as a yellow solid. LC-MS (Method S): m/z = 159.2 [M+H]+, 0.639 min. Step 2: Preparation of 4-fluoro-1-(pyridin-2-ylmethyl)-1H-pyrazol-3-carboxylic acid

[001244] Sodium hydride (60%, 506 mg, 12.7 mmol) was added to a solution of ethyl 4-fluoro-1H-pyrazol-3-carboxylate (500 mg, 3.2 mmol) in N,N- dimethylformamide (10 mL) at 0°C. The resulting mixture was stirred at room temperature for 0.5 hour before adding 2-(bromomethyl)pyridine (600 mg, 3.5 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and quenched by the addition of water (10 mL). The resulting solution was stirred at room temperature for 5 hours. The pH was adjusted to 7 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (360 mg, 72%). LC-MS (Method I): m/z = 221.9 [M+H]+, 0.320 min. Step 3: Preparation of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1-(pyridine2-ylmethyl)-1H-pyrazol-3-carboxamide

[001245] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD, 5 μm, 19 x 150 mm; Mobile phase A: water (10 mmol/L of 4HCO3), mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 45% B over 7 min; 254/220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.56-8.55 (m, 1H), 8.16-8.15 (d, J = 4.4 Hz, 1H), 8.11-8, 09 (m, 1H), 7.83-7.82 (m, 1H), 7.51-7.49 (m, 1H), 7.34-7.28 (m, 3H), 7.24- 7.20 (m, 2H), 5.46 (s, 2H), 4.91-4.78 (m, 1H), 4.58-4.53 (m, 1H), 4.41-4, 37 (m, 1H), 3.33 (s, 3H). LC-MS (Method F): m/z = 396.1 [M+H]+, 0.924 min. Example 56: (S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl )-4H-1 2,4-triazole-3-carboxamide Schematic legend: rt – ta Step 1: (S) 9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate -tert-butyl

[001246] A mixture of 9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate of (S)-tert- butyl (200 mg, 0.61 mmol) and zinc cyanide (300 mg, 2.59 mmol) in tetrahydrofuran (2 mL) and water (10 mL) were added to 3rd generation t-BuXPhos precatalyst (244 mg, 0.31 mmol) and t-BuXPhos (130 mg, 0.31 mmol) in a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to provide the title compound (150 mg, 78%) as a white solid. LC-MS (Method E): m/z = 262.0 [M+H-56]+, 0.853 min. Step 2: Preparation of (S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carbonitrile hydrochloride

[001247] A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL) was added to a solution of (S)-9-cyano-5-methyl-4-oxo-2,3,4, tert-Butyl 5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (90 mg, 0.28 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred for 1 hour at room temperature and concentrated in vacuo to provide the title compound (55 mg) as a white solid. LC-MS (Method E): m/z = 218.0 [M+H]+, 0.551 min. Step 3: Preparation of (S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)-4H-1 2,4-triazol-3-carboxamide

[001248] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5.19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1H), 8.55 (s, 1H), 7.81 (dd, J = 8.2, 1.5 Hz, 1H), 7 .72 (dd, J = 7.8, 1.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.35-7.14 (m, 5H), 4, 94-4.74 (m, 2H), 4.58-4.47 (m, 1H), 4.10 (s, 2H), 3.30 (s, 3H). LC-MS (Method F): m/z = 403.0 [M+H]+, 1.069 min. Example 57: (S)-1-benzyl-4-fluoro-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl )-1H-pyrazole-3-carboxamide

[001249] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: OBD Shield XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 60% B over 7 min; UV 254 & 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.17-8.13 (m, 2H), 7 .56 (dd, J = 7.6, 1.2 Hz, 1H), 7.41-7.31 (m, 3H), 7.30- 7.27 (m, 2H), 7.19-7 .15 (m, 1H), 5.35 (s, 2H), 4.83-4.77 (m, 1H), 4.53 4.42 (m, 2H). LC-MS (Method V): m/z = 382.1 [M+H]+, 2.321 min. Example 58: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl )-1,3,4-thiadiazol-2-carboxamide Step 1: Preparation of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-amine

[001250] A mixture of 1-phenylcyclopropanecarboxylic acid (1.6 g, 10 mmol) and N-aminothiourea (0.91 g, 10 mmol) in phosphoryl trichloride (10 mL) was heated for 1 hour at 70 ° C and then cooled to room temperature. Water (100 mL) was added. The reaction mixture was heated to 70 °C and stirred for 5 hours. The pH value of the resulting solution was adjusted to 8 with saturated aqueous sodium hydroxide (30 ml). The solids were collected by filtration to provide the title compound (19 g, 87%) as a white solid. LC-MS (Q Method): m/z = 218.1 [M+H]+, 0.817 min. Step 2: Preparation of 2-bromo-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole

[001251] To a mixture of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-amine (1.1 g, 5.0 mmol) in acetonitrile (20 mL) was added cupric bromide (2. 2 g, 10 mmol). The resulting mixture was stirred at room temperature for 15 minutes before adding tert-butyl nitrite (1.5 mL, 10 mmol) dropwise to the mixture over a period of 15 minutes at room temperature. The reaction mixture was heated to 60°C and stirred for 16 hours before adding water (50 mL). The solids were removed by filtration and the filtrate was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound ( 1.0 g, 70%) as a yellow solid. LC-MS (Method K): m/z = 281.0 [M+H]+, 1.107 min. Step 3: Preparation of ethyl 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-carboxylate

[001252] Bis(triphenylphosphine)palladium(II) chloride (277 mg, 0.395 mmol) was added to a mixture of 2-bromo-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole (1.0 g, 3.57 mmol) and triethylamine (879 mg, 8.70 mmol) in methanol (20 mL). After stirring for 16 hours at 100°C in a carbon monoxide atmosphere (50 atm), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give the title compound (600 mg, 61%) as a yellow solid. LC-MS (Method E): m/z = 261.1 [M+H]+, 0.923min. Step 4: Preparation of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-carboxylic acid

[001253] Lithium hydroxide (5.4 mg, 2.0 mmol) was added to a solution of ethyl 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-carboxylate (100 mg, 0. 41 mmol) in tetrahydrofuran (9 mL) and water (3 mL). The resulting mixture was stirred for 2 hours at room temperature. After removing tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 3-4 with aqueous hydrochloric acid (1N, 20 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (80 mg, 76%) as a yellow oil. LC-MS (Method C): m/z = 247.0 [M+H]+, 1.288 min. Step 5: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1 -phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxamide

[001254] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: column: Xbridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: water (10 mmol/L NH4HCO3) and ACN (20% to 80% in 12 min); Detector, 220 & 254 nm UV to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.49-7.18 (m, 9H), 4.77-4.75 (m, 1H), 4.69- 4.62 (m, 1H), 4.41-4.35 (m, 1H), 3.27 (s, 3H), 1.82-1.76 (m, 2H), 1.66-1, 57 (m, 2H). LC-MS (Method V): m/z = 421.1 [M+H]+, 3.918 min. Example 59: 5-benzyl-N-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-3-yl]- 1H-pyrazole-3-carboxamide

[001255] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBD column, 5.19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (50.0% ACN to 70.0% for 7 min); Detector, UV at 254 and 220 nm to provide the title compound, 1H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H) , 7.45-7.36 (m, 2H), 7.35-7.18 (m, 7H), 6.34 (s, 1H), 4.46-4.36 (m, 1H), 3 .97 (s, 2H), 3.29 (s, 3H), 2.72-2.64 (m, 1H), 1.51 (t, J = 12.0 Hz, 1H), 1.10- 1.04 (m, 1H), 0.74-0.66 (m, 2H), 0.43-0.37 (m, 1H). LC-MS (Method D): m/z = 401.2 [M+H]+, 1.994 min. Examples 60A and 60B: 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepina-2-yl)-1H-pyrazol- 3-carboxamide (60A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a, 2,3,4 ,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazol-3-carboxamide (60B) Schematic legend: Rt - TaStep 1: Preparation of 5-benzyl-N-(4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin- 2-yl)-1H-pyrazol-3-carboxamide

[001256] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile phase A: water (0.05% TFA), mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to provide the title compound. LC-MS (Method I): m/z = 387.2 [M+H]+, 1.405 min. Step 2: Preparation of 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepina-2-yl)-1H-pyrazol-3- carboxamide (first eluting isomer) and 5-benzyl-N-((1aR,2R,8bS)- 4-methyl-3-oxo-1,1a, 2, 3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazol-3-carboxamide (second elution isomer)

[001257] 5-benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6.4.0.0A{2,4}]dodeca- 1(8),9,11-trien-5-yl}- 1H-pyrazole-3-carboxamide (30 mg, 0.077 mmol) was separated by chiral preparation HPLC with the following conditions: Column: CHIRALPAK IC, 2.0 cm x 25 cm (5 μm); Mobile phase A: hexanes, mobile phase B: EtOH; flow rate: 20 mL/min; Gradient: 50% B to 50% B over 30 min; 254/220nm; RT1: 10.478 min; RT2: 13.826 min to provide the title compounds:

[001258] Example 60A (first elution isomer): 1H NMR (300 MHz, Chloroform-d) δ 8.47 (d, J = 7.7 Hz, 1H), 7.41-7.08 (m, 9H ), 6.57 (s, 1H), 4.85 (d, J = 7.6 Hz, 1H), 4.04 (s, 2H), 3.32 (s, 3H), 2.18-1 .92 (m, 2H), 1.16-0.88 (m, 2H). LC-MS (Method J): m/z = 387.2 [M+H]+, 2.043 min.

[001259] Example 60B (second elution isomer): 1H NMR (300 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.39-7.05 (m, 9H), 6.53 (s , 1H), 4.85 (d, J = 7.6 Hz, 1H), 4.04 (s, 2H), 3.31 (s, 3H), 2.18-1.92 (m, 2H) , 1,161.07 (m, 1H), 1.02-0.89 (m, 1H). LC-MS (Method J): m/z = 387.2 [M+H]+, 1.409 min. Example 61: (S)-N-(5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1-phenylcyclopropyl)oxazol-4-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 1-phenylcyclopropanecarboxamide

[001260] To a stirred solution of 1-phenylcyclopropanecarboxylic acid (1.62 g, 10.0 mmol) in dichloromethane (10 mL) was added thionyl chloride (6 g, 50.0 mmol) dropwise at 0oC. The resulting solution was stirred for 5 hours at room temperature and the reaction mixture was concentrated in high vacuum. The residue was then added to ammonium hydroxide (28%, 50 mL) dropwise at 0oC. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.50 g, 93%) as a yellow solid. LC-MS (Method I): m/z = 162.1 [M+H]+, 0.725 min. Step 2: Preparation of Ethyl 2-(1-phenylcyclopropyl)oxazole-4-carboxylate

[001261] A mixture of ethyl e3-bromo-2-oxopropanoate (970 mg, 5.0 mmol) and 1-phenylcyclopropanecarboxamide (810 mg, 5.0 mmol) in ethanol (10 mL) was heated for 16 hours at 80°C under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (420 mg, 33%) as a white solid. LC-MS (Method C): m/z = 258.1 [M + H]+, 1.527 min. Step 3: Preparation of 2-(1-phenylcyclopropyl)oxazol-4-carboxylic acid

[001262] Lithium hydroxide (5.4 mg, 2.02 mmol) was added to a mixture of ethyl 2-(1-phenylcyclopropyl) oxazol-4-carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was stirred for 16 hours at room temperature. After removing the tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 5 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (67 mg, 76%) as a yellow oil. LC-MS (Method C): m/z =230.1 [M+H]+, 1.291 min. Step 4: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1 -phenylcyclopropyl)oxazole -4- carboxamide

[001263] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A:water (10mmol/ L NH4HCO3); Phase B: ACN (20% to 80% in 12 min); Detector, 220 & 254nm UV to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.49-7.19 (m, 9H), 4 .85-4.76 (m, 1H), 4.57-4.50 (m, 1H), 4.39-4.33 (m, 1H), 3.29 (s, 3H), 1.61 -1.58 (m, 2H), 1.42-1.38 (m, 2H). LC-MS (Method D): m/z = 404.2 [M+H]+, 2.148 min. Example 62: (S)-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl -5-(1-phenylcyclopropyl) isoxazol-3-carboxamide

[001264] The crude product obtained using Amide Bond Procedure C was purified by Prep-HPLC with the following conditions: Column: Column X Select CSH Prep C18 OBD, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 70% B over 7 min; UV 254 & 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.15 (dd, J = 4.4, 1, 2 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.41-7.29 (m, 5H), 7.17 (dd, J = 8.0 , 4.8 Hz, 1H), 6.41(s, 1H), 4.85-4.78 (m, 1H), 4.53-4.42 (m, 2H), 1.58-1, 43 (m, 4H). LC-MS (Method D): m/z = 391.1 [M+H]+, 1.981 min. Example 63: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5- (1-phenylcyclopropyl)thiazol-2-carboxamide Scheme legend: Rt – ta Step 1: Preparation of (1-phenylcyclopropyl)methanol

[001265] A solution of borane in tetrahydrofuran (1 M, 60 mL, 60 mmol) was slowly added to a solution of 1-phenylcyclopropanecarboxylic acid (6.5 g, 40 mmol) in tetrahydrofuran (40 mL) at 0oC. The reaction mixture was stirred for 2 hours at room temperature, quenched with water (50 ml) and extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (5.5 g, 93%) as a colorless oil. LC-MS (Method C): m/z =131.2 [M-H2O+H]+, 1.125 min. Step 2: Preparation of 1-phenylcyclopropanecarbaldehyde

[001266] Dess-Martin Periodinane (35.6 g, 84 mmol) was added to a solution of (1-phenylcyclopropyl)methanol (5.4 g, 42 mmol) in dichloromethane (40 mL) at 0°C. The resulting mixture was stirred at 0°C for 1.5 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound (4.4 g, 72% ) as a colorless oil. LC-MS (Method C): m/z = 147.2 [M+H]+, 1.215 min. Step 3: Preparation of (E)-(1-(2-methoxyvinyl)cyclopropyl)benzene

[001267] To a solution of methoxymethyl)triphenylphosphonium chloride (22.4 g, 65 mmol) in tetrahydrofuran (30 mL), a solution of potassium 2-methylpropan-2-olate in tetrahydrofuran ( 1 M, 65 mL, 65 mmol) at 0°C. The resulting mixture was stirred at 0°C for 0.5 hour, followed by the addition of 1-phenylcyclopropanecarbaldehyde (4.2 g, 29 mmol). The reaction mixture was stirred at room temperature for 1 hour, quenched by addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (20 g crude) as a yellow oil, which was used directly in the next step without further purification. . Step 4: Preparation of 2-bromo-2-(1-phenylcyclopropyl)acetaldehyde

[001268] To a solution of (E)-(1-(2-methoxyvinyl)cyclopropyl)benzene (3.8 g, 22 mmol) in tetrahydrofuran (20 mL) and water (2 mL), N was added -bromosuccinimide (4.3 g, 24 mmol) at -20°C. The solution was stirred at -20°C for 1 hour and concentrated to give the title compound (8 g crude) as a yellow oil, which was used directly in the next step without further purification. Step 5: Preparation of Ethyl 5-(1-phenylcyclopropyl)thiazol-2-carboxylate

[001269] To a solution of 2-bromo-2-(1-phenylcyclopropyl)acetaldehyde (2 g, 8 mmol) in ethanol (20 mL), ethyl 2-amino-2-thioxoacetate (1.1 g) was added , 8 mmol). The reaction mixture was stirred at 80°C for 4 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (310 mg, 14%) as a yellow oil. LC-MS (Method I): m/z = 274.0 [M+H]+, 1.034 min. Step 6: Preparation of 5-(1-phenylcyclopropyl)thiazol-2-carboxylic acid

[001270] Lithium hydroxide (52.8 mg, 2.2 mmol) was added to a solution of ethyl 5-(1-phenylcyclopropyl)thiazol-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and diluted with water (10 mL). The resulting mixture was adjusted to pH = 5 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (49 mg, 56%) as a yellow oil, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 246.1 [M+H]+, 1,200 min. Step 7: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-5- (1-phenylcyclopropyl)thiazol-2-carboxamide

[001271] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 x 250 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (45% to 65% over 7 min); Detector, 220 & 254 nm UV to generate the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 7.5 Hz, 1H), 8.36 (dd, J = 4.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.40-7.23 (m, 6H), 4.88-4.71 (m, 2H ), 4.52 (dd, J = 9.1, 6.7 Hz, 1H), 3.35 (s, 3H), 1.47 (s, 4H), LC-MS (Method T): m/ z = 421.3 [M+H]+, 1.729 min Example 64: (S)-1-benzyl-4-fluoro-N-(-5-methyl-4-oxo-2,3,4,5-tetra - hydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Step 1: Preparation of 1-benzyl-4-fluoro-1H-pyrazol-3-carboxylic acid

[001272] Sodium hydride (60%, 1 g, 25 mmol) was added to a solution of ethyl 4-fluoro-1H-pyrazol-3-carboxylate (1.2 g7.6 mmol) in N,N-dimethylformamide (20 mL) at 0°C. The resulting mixture was stirred for 0.5 hour at room temperature followed by the addition of benzyl bromide (1.36 g, 8.0 mmol). The resulting mixture was stirred for 2 hours at room temperature. Water (20 mL) was added dropwise. The resulting solution was then stirred at room temperature for 5 hours. The pH value of the solution was adjusted to 7 with aqueous hydrochloric acid (1N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by Prep-HPLC with the following conditions: Column: Prep Column. XBridge C18, 5.19mm x 250mm; Mobile Phase A: water (0.1% formic acid), mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; 254 nm to provide the title compound (370 mg, 22%) as a white solid. LC-MS (Method D): m/z = 221.1 [M+H]+, 1.206 min. Step 2: Preparation of (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)-1H-pyrazol-3-carboxamide

[001273] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; Detector, UV at 220 and 254 nm to provide the title compound. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 6.8 Hz, 1H), 7.43-7.40 (m, 3H),7.39-7.21 (m, 6H), 5.26 (s, 2H), 5.13-5.07 (m, 1H), 4.83-4.81 (m, 1H), 4.31-4.26 (m, 1H) , 3.47 (s, 3H), LC-MS (Method J): m/z = 395.2 [M+H]+, 1.474 min. Example 65: N-[(4S,9aR)-5-oxo-octahydropyrrolo[2,1- c][1,4]oxazepin-4-yl]-5-benzyl-4H-1,2,4- triazole-3-carboxamide

[001274] The title compound was prepared from N-Boc-D-prolinol using the procedure described in Example 27.

[001275] The crude product was purified by column chromatography on KP-NH modified silica gel (CH2Cl2-MeOH, 97:3 to 90:10) to yield the title compound. 1H NMR (400MHz, CDCl3) δ 8.31 (d, J=6.3 Hz, 1H), 7.37-7.23 (m, 5H), 4.90 (ddd, J=9.3, 6 .3, 2.8 Hz, 1H), 4.21 (s, 2H), 4.17 (dd, J=11.7, 2.6 Hz, 1H), 4.09 (q, J=8, 8 Hz, 1H), 3.98 (d, J=12.5 Hz, 1H), 3.93-3.82 (m, 1H), 3.52-3.39 (m, 2H), 3, 24 (dd, J=12.8, 9.3 Hz, 1H), 2.33-2.17 (m, 1H), 2.01-1.90 (m, 1H), 1.87-1, 70 (m, 1H), 1.66-1.51 (m, 1H), LC-MS (Method A): m/z = 356.4 [M+H]+, 0.71 min Example 66: ( S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl )-1,3,4-oxadiazol-2-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 1-phenylcyclopropanecarbohydrazide

[001276] Triethylamine (93.5 g, 925.5 mmol) was added to a stirred mixture of hydrazine dihydrochloride (32.1 g, 308.6 mmol) in N,N-dimethylformamide (300 mL). The resulting mixture was added to a mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28.2 g, 74.0 mmol) and N,N-diisopropylethylamine (23.9 g, 185.1 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (500 mL) and extracted with ethyl acetate (5 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (6 g, 2%) as a white solid. LC-MS (Method E): m/z = 177.0 [M+H]+, 1.139 min. Step 2: Preparation of ethyl 2-oxo-2-(2-(1-phenylcyclopropanecarbonyl)hydrazinyl)acetate

[001277] Ethyl 2-chloro-2-oxoacetate (1.56 g, 11.4 mmol) was added to a stirred solution of 1-phenylcyclopropane-carbohydrazide (2.00 g, 11.4 mmol) and triethylamine (3.44 g, 34.1 mmol) in dichloromethane (40 mL) at room temperature. The reaction mixture was stirred for 12 hours at room temperature, quenched by addition of water (40 mL) and extracted with dichloromethane (3x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (3 g, 96.7%) as a yellow oil. LC-MS (Method E): m/z = 277.0 [M+H]+, 0.676 min. Step 3: Preparation of ethyl 5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxylate

[001278] Tosyl chloride (0.80 g, 3.62 mmol) was added to a stirred solution of ethyl 2-oxo-2-(2-(1-phenylcyclopropanecarbonyl)hydrazinyl)acetate (1.0 g, 3.62 mmol) and triethylamine (1.1 g, 6.6 mmol) in dichloromethane (25 mL). The reaction mixture was stirred for 12 hours at room temperature, quenched by addition of water (20 mL) and extracted with dichloromethane (3x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (0.80 g, 85.6%) as a yellow oil. LC-MS (Method C): m/z = 259.0 [M+H]+, 1.457 min. Step 4: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3-yl)- 5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

[001279] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD, 5μm, 19 x 150 mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (40% ACN to 70% B over 7 min); detector, UV at 254 and 220 nm to produce the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.378.35 (m, 1H), 7.71-7.69 (m, 1H), 7.42-7.30 ( m, 6H), 4.82-4.80 (m, 1H), 4.75-4.73 (m, 1H), 4.54-4.50 (m, 1H), 3.33 (s, 3H), 1.70-1.69 (m, 2H), 1.54-1.50 (m, 2H), LC-MS (Method T): m/z = 406.3 [M+H]+ , 2.463 min Example 67A and 67B: 5-benzyl-N-((1aR,2S,8bS)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cycloprope [d]azepine- 2-yl)-4H-1,2,4- triazol-3-carboxamide(67A) and 5-benzyl-N-((1aS,2R,8bR)-4-methyl-3- oxo- 1,1a,2 3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide (67B) Step 1: Preparation of tert-butyl (trans-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate

[001280] A solution of tert-butyl (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate ( 100 mg, 0.33 mmol) in 1,8-diazabicyclo[5.4.0]undec-7-ene was stirred at 90°C overnight. The solution was purified by TLC (ethyl acetate/petroleum ether, 1/8) to give the title compound (60 mg, 60%) as a yellow solid. LC-MS (Method E): m/z = 325.0 [M+Na]+, 0.930 min. Step 2: Preparation of trans-2-amino-4-methyl-1,1a, 2,8b- tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one hydrochloride

[001281] To a solution of tert-butyl (trans4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate (60 mg, 0.20 mmol) in 1,4-dioxane (2 mL), a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL, 20 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature and concentrated in high vacuum to provide the title compound (40 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method S): m/z = 203.3 [M+H]+, 0.592 min. Step 3: Preparation of trans-5-benzyl-N-(4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl) -4H-1,2,4-triazol-3-carboxamide

[001282] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD, 5μm, 19 x 150mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to provide the title compound. LC-MS (Method J): m/z = 388.2 [M+H]+, 1.305 min. Step 7: Preparation of 5-benzyl-N-((1aR,2S,8bS)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepina-2-yl)-4H-1,2,4-triazol- 3-carboxamide (first eluting isomer) and 5-benzyl-N- ((1aS,2R,8bR)-4-methyl-3-oxo- 1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2yl)-4H-1,2,4-triazol-3-carboxamide (second elution isomer)

[001283] The enantiomers of trans-5-benzyl-N-(4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl )-4H-1,2,4-triazol-3-carboxamide (25 mg, 0.065 mmol) were separated by prechiral HPLC with the following conditions: Column: Chiralpak ID-2, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; flow rate: 17 mL/min; Gradient: 50% B to 50% B over 22 min; UV of 254 and 220 nm; RT 1: 11.72 min; RT 2: 18.02 min to generate the title compounds.

[001284] Example 67A (first elution isomer)): 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4,234.13 (m, 3H), 3.43 (s, 3H), 2.25-2.15 (m, 1H), 1.72-1.58 (m, 1H), 1.25 - 1.13 (m, 1H), 0.79-0.65 (m, 1H), LC-MS (Method D): m/z = 388.2 [M+H]+, 1.806 min

[001285] Example 67B (second elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.5 Hz, 1H), 7.42-7.19 (m, 9H ), 4,234.13 (m, 3H), 3.43 (s, 3H), 2.25-2.15 (m, 1H), 1.72-1.58 (m, 1H), 1,251.13 ( m, 1H), 0.79-0.65 (m, 1H), LC-MS (Method D): m/z = 388.2 [M+H]+, 1.812 min Example 68A: (R)-5 -benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2- d][1,4] oxazepin-4-yl)-4H-1,2,4-triazol-3-carboxamide

[001286] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV at 254 & 220 nm to produce the title compound. 1H NMR (300 MHz, DMSO-d6) δ 14.42 (s, 1H), 8.80 (br, s, 1H), 7.70-7.64 (m, 2H), 7.43-7, 25 (m, 8H), 7.07 (d, J = 1.2 Hz, 1H), 5.40-5.29 (m, 1H), 4.64-4.49 (m, 2H), 4 .14 (s, 2H), LC-MS (Method D): m/z = 387.1 [M+H]+, 1.322 min Example 68B: (S)-5-benzyl-N-(4,5- dihydrobenzo[b]imidazo[1,2- d][1,4]oxazepin-4-yl)-4H-1,2,4-triazol-3-carboxamide

[001287] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV at 254 & 220 nm to produce the title compound 1H NMR (300 MHz, DMSO-d6) δ 14.39 (s, 1H), 8.80 (s, 1H), 7.70-7.65 (m , 2H), 7.41-7.22 (m, 8H), 7.07 (d, J = 1.2 Hz, 1H), 5.40-5.31 (m, 1H), 4.64- 4.49 (m, 2H), 4.14 (s, 2H), LC-MS (Method D): m/z = 387.1 [M+H]+, 1.325 min Examples 69A and 69B: (S) -5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]-triazolo[4,3-a]azepin-4-yl)-4H-1,2 ,4-triazol-3-carboxamide (69A) and (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3- a]azepin-4-yl)-4H-1,2,4-triazol-3-carboxamide (69B) Step 1: Preparation of benzyl (5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)carbamate

[001288] Formylhydrazine (0.54 g, 9 mmol) was added to a stirring solution of (S)-benzyl(2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b] azepin-3-ylcarbamate (1.00 g, 3 mmol) in 1-butanol (15 mL) After stirring at 60°C for 1 hour and at 150°C for 15 hours, the reaction mixture was concentrated at high. vacuum, diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. on column (ethyl acetate/petroleum ether, r, 1/3) to obtain the title compound (0.64 g, 63%) as a white solid LC-MS (Method E): m/z = 335. .1 [M+H]+, 0.746 min. Step 2: Preparation of 5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3- a]azepine-4- the mine

[001289] Benzyl (5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)carbamate (0.63 g, 1. 9 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.2 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred at room temperature for 6 h in a hydrogen atmosphere. The solids were removed by filtration and the filtrate was concentrated in high vacuum to give the title compound (0.36 g, 95%) as a colorless oil. LC-MS (Method C): mz = 201.1 [M + H]+, 0.848 min. Step 3: Preparation of (S)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine and (R)-5, 6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine

[001290] The enantiomers of 5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine (0.36 g, 1.8 mmol ) were separated by pre-chiral HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 60% B to 60% B over 23 min; 220/254nm; RT 1: 12.04 min; RT 2: 20.81 min to provide the title compounds.

[001291] (S)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine (first elution isomer): 110 mg (62%) as a white solid. LC-MS (Method C): mz = 201.1 [M + H]+, 0.848 min.

[001292] (R)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-4-amine (second elution isomer): 110 mg (62%) as a white solid. LC-MS (Method C): mz = 201.1 [M + H]+, 0.848 min. Step 4: Preparation of (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl )-4H-1,2,4-triazole-3-carboxamide

[001293] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100Â, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 40% B over 7 min; UV at 254 and 220 nm to generate the title compound 1H NMR (300 MHz, DMSO-d6) δ 14.39 (s, 1H), 8.93 (m, 2H), 7,627.59 (m, 1H), 7.56-7.43 (m, 3H), 7.38-7.23 (m, 5H), 5.02-4.92 (m, 1H), 4.14 (s, 2H), 2, 84-2.77 (m, 1H), 2.60-2.55 (m, 1H), 2.48-2.40 (m, 2H), LC-MS (Method D): m/z = 386 .2 [M+H]+, 1.489 min Example 69B: (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4, 3- a]azepin-4-yl)-4H-1,2,4-triazol-3-carboxamide Scheme legend: Rt - ta

[001294] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 250 mm, 100Â, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to 40% B over 7 min; UV at 254 and 220 nm to produce the title compound 1H NMR (300 MHz, DMSO-d6) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m , 1H), 7.56-7.43 (m, 3H), 7.37-7.22 (m, 5H), 5.02-4.92 (m, 1H), 4.14 (s, 2H ), 2.84-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.48-2.41 (m, 2H), LC-MS (Method D): m /z = 386.2 [M+H]+, 1.486 minExample 70A: (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4 ]oxazepin-4-yl)isoxazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (S)-benzyl (4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)carbamate

[001295] A solution of potassium carbonate (4.8 g, 35 mmol) in water (9 mL) was added to a solution of (S)-3-amino-2,3-dihydrobenzo[b] hydrochloride [1,4]oxazepin-4(5H)-one (1.5 g, 7 mmol) in dichloromethane (70 mL) and then benzyl chloroformate (1.8 g, 10.5 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. The precipitate was collected by filtration, washed with water (20 mL) and dried in high vacuum to give the title compound (1.44 g, 66%) as a white solid. LC-MS (Method C): m/z = 313.1 [M+H]+, 1.365 min. Step 2: Preparation of Benzyl (S)-4-thioxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate

[001296] Lawesson's reagent (2.43 g, 6 mmol) was added to a solution of (S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Benzyl -3-ylcarbamate (1.9 g, 6 mmol) in tetrahydrofuran (50 mL) and the reaction mixture was stirred in a nitrogen atmosphere for 16 hours at room temperature. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.85 g crude) as a pale yellow solid. LC-MS (Method E): m/z = 351.0 [M+Na]+, 0.946 min. Step 3: Preparation of Benzyl (R)-4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][1,4]-oxazepin-3-ylcarbamate

[001297] 2,2-dimethoxyethamine (2.37 g, 22.6 mmol) was added to a solution of (S)-4-thioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]oxazepin-3-ylcarbamate benzyl (1.85 g, 5.65 mmol) and mercury dichloride (2.0 g, 7.35 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 55T for 2 hours and cooled to room temperature. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound (2.20 g, 98%) as a light yellow oil. LC-MS (Method C): m/z = 400.2 [M+H]+, 1.157 min. Step 4: Preparation of benzyl (4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate

[001298] Solution of benzyl (R)-4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][1,4]-oxazepin-3-ylcarbamate (2.2 g, 5. 5 mmol) in formic acid (15 mL, 96%) was stirred at 100 °C for 2 hours. The black sediment was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL), basified with aqueous sodium hydroxide (1 N, 30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give the title compound (0.45 g, 24%) as a white solid. LC-MS (Method E): m/z = 336.0 [M+H]+, 0.655 min. Step 5: Preparation of (4,5-dihydrobenzo[b]imidazo[1,2- d][1,4]oxazepin-4-yl)carbamate (first elution isomer) and (R)-benzyl(4 (S)-benzyl ,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (second elution isomer)

[001299] The enantiomers of benzyl (4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (450 mg, 1.35 mmol) were separated by SFC with the following conditions: Column: CHIRALPAK-IC-SFC, 5 cm x 25 cm (5 μm); Mobile Phase A: 50% CO2, mobile phase B: MeOH: 50%; Flow rate: 150 mL/min; 220nm; RT 1: 5.65 min; RT 2: 6.91 min to provide the title compounds:

[001300] Benzyl (S)-(4,5dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate: (250 mg, 56%) as a white solid . LC-MS (Method E): m/z = 336.0 [M+H]+, 0.655 min.

[001301] (R)-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)benzyl carbamate (second elution isomer): (200 mg , 45%) as a white solid. LC-MS (Method E): m/z = 336.0 [M+H]+, 0.655 min. Step 6: Preparation of (R)-4,5-dihydrobenzo[b]imidazo[1,2- d][1,4]oxazepin-4-amine

[001302] Benzyl (R)-(4,5-Dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (0.25 g, 0.75 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.5 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred for 6 hours at room temperature in a hydrogen atmosphere. The solids were removed by filtration and the filtrate was concentrated in high vacuum to give the title compound (0.14 g, 93%) as a white solid. LC-MS (Method C): mz = 202.1 [M + H]+, 0.758 min. Step 7: Preparation of (R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2- d][1,4]oxazepin-4-yl)isoxazol-3-carboxamide

[001303] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 65% B over 7 min; UV at 254 & 220 nm to generate the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, J = 8.7 Hz, 1H), 7.71-7.65 (m, 2H), 7.40-7.28 (m, 8H), 7.07 (d, J =1.2Hz, 1H), 6.59 (s, 1H), 5.43-5.34 (m, 1H), 4.61-4.46 (m , 2H), 4.24 (s, 2H), LC-MS (Method D): m/z = 387.1 [M+H]+, 1.579 min Example 70B: (S)-5-benzyl-N- (4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazol-3-carboxamide Step 1: Preparation of (S)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-amine

[001304] Benzyl (S)-(4,5-Dihydrobenzo [b] imidazo [1,2-d] [1,4] oxazepin-4-yl)carbamate (0.2 g, 0.6 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.2 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred at room temperature for 6 h in a hydrogen atmosphere. The solids were removed by filtration and the filtrate was concentrated in high vacuum to give the title compound (0.11 g, 92%) as a white solid. LC-MS (Method C): mz = 202.1 [M + H]+, 0.758 min. Step 2: Preparation of (S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2- d][1,4]oxazepin-4-yl)isoxazol-3-carboxamide

[001305] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 45% B to 57% B over 7 min; UV at 254 & 220 nm to generate the title compound, 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, J = 8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.42-7.28 (m, 8H), 7.07 (d, J = 1.5 Hz, 1H), 6.59 (s, 1H), 5.43-5.34 (m , 1H), 4.62-4.45 (m, 2H), 4.24 (s, 2H), LC-MS (Method V): m/z = 387.1 [M+H]+, 2.491 min . Example 71A: (S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]-triazolo[4,3-a]azepin-4-yl) isoxazol-3 –carboxamide

[001306] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 58% B over 7 min; UV at 254 & 220 nm to generate the title compound 1H NMR (300 MHz, DMSO-d6) δ 9.36 (d, J = 8.4 Hz, 1H), 8.93 (s, 1H), 7, 62-7.59 (m, 1H), 7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 (s, 1H), 5.01- 4.92 (m, 1H), 4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.39 (m, 3H), LC-MS (Method D ):m/z = 386.2 [M+H]+, 1.805 min.Example 71B: (R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1, 2,4]-triazolo[4,3-a]azepin-4-yl)isoxazol-3-carboxamide

[001307] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; UV at 254 & 220 nm to generate the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.36 (d, J = 8.1 Hz, 1H), 8.93 (s, 1H), 7.63-7.59 (m, 1H), 7 .55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 (s, 1H), 5.01-4.92 (m, 1H), 4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.38 (m, 3H), LC-MS (Method D): m/z = 386.2 [M+ H]+, 1.809 min.Example 72: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) -5-(1-phenylcyclopropyl)-1H-pyrazol-3-carboxamide Step 1: Preparation of N-methoxy-N-methyl-1-phenylcyclopropanecarboxamide

[001308] N,N-diisopropylethylamine (47.2 g, 219.6 mmol) was added to a mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O,N-dimethyl-hydrochloride hydroxylamine (6.5 g, 67.8 mmol), N-(3-dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (14.2 g, 73.9 mmol) and 1-hydroxybenzotriazole (10.0 g, 73 .9 mmol) in N,N-dimethylformamide (60 mL). The resulting mixture was stirred overnight at room temperature, diluted with water (300 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to provide the title compound (11.2 g, 89.6%) as a colorless oil. LC-MS (Method K): m/z =206.0 [M+H]+, 1.489 min. Step 2: Preparation of 1-(1-phenylcyclopropyl)ethanone

[001309] To a solution of methylmagnesium bromide (3 M, 14 mL, 42 mmol) in tetrahydrofuran was added a solution of N-methoxy-N-methyl-1-phenylcyclopropanecarboxamide (11.2 g, 24.4 mmol ) in tetrahydrofuran (50 mL) at 0°C. The resulting mixture was stirred overnight at room temperature, quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to give the title compound (7, 4 g, 85%) as a colorless oil. LC-MS (Method E): m/z = 161.0 [M+H]+, 0.889 min. Step 3: Preparation of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate

[001310] To a mixture of 1-(1-phenylcyclopropyl)ethanone (1.92 g, 12 mmol) and diethyl oxalate (2.1 g, 14.4 mmol) in toluene (8 mL), 2- potassium methylpropan-2-olate (1.7 g, 15.6 mmol) at 0°C. The resulting mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was diluted with water (20 mL). The resulting mixture was neutralized to pH = 6 with aqueous hydrochloric acid (1N) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (1.95 g, 61%) as a yellow solid. LC-MS (Method S): m/z = 261.2 [M+H]+, 1.076 min. Step 4: Preparation of Ethyl 5-(1-phenylcyclopropyl)-1H-pyrazol-3-carboxylate

[001311] To a solution of ethyl 2,4-dioxo-4-(1-phenyl-cyclopropyl)butanoate (800 mg, 3.0 mmol) in ethanol (8 mL), hydrazine hydrate (aqueous solution) was added 80%, 200 mg, 3.0 mmol). The reaction mixture was stirred at 80°C for 1.5 hours and concentrated in vacuo. The resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (550 mg, 70%) as a yellow solid. LC-MS (Method K): m/z =256.7 [M+H]+, 1,640 min. Step 5: Preparation of 5-(1-phenylcyclopropyl)-1H-pyrazol-3-carboxylic acid

[001312] A solution of ethyl 5-(1-phenylcyclopropyl)-1H-pyrazol-3-carboxylate (470 mg, 1.8 mmol) in methanol (4.5 mL) and water (1.5 mL) was sodium hydroxide (432 mg, 10.8 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was diluted with water (20 mL) and adjusted to pH = 5 using aqueous hydrochloric acid (1 N) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the title compound (280 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method K): m/z =228.7 [M+H]+, 1.434 min. Step 6: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1 -phenylcyclopropyl)-1H-pyrazol-3-carboxamide

[001313] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD, 5μm, 19 x 150mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (40% ACN to 65% B over 7 min); detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (300 MHz, DMSO-d6) 13.16 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.55-7.46 (m, 1H), 7. 38-7.17 (m, 8H), 6.34 (s, 1H), 4,934.75 (m, 1H), 4.60-4.28 (m, 2H), 3.31 (s, 3H) , 1.39-1.16 (m, 4H), LC-MS (Method O): m/z = 403.05 [M+H]+, 1.511 min. Example 73: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-1- (1-phenylcyclopropyl)-1H-pyrazol-3-carboxamide

[001314] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD, 100Â, 19 x 250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; 254 & 220 nm UV to generate the title compound 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.38-8.35 (m, 1H), 8.24 (d , J = 7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.36-7.20 (m, 6H), 6.54-6.35 (m, 1H), 4.90-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.53-4.46 (m, 1H), 3.35 (s, 3H), 1, 34-1.30 (m, 4H), LC-MS (Method D): m/z = 404.2 [M+H]+, 1.872 min. Example 74: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl )-1-(pyridine-2-ylmethyl)-1H-pyrazol-3-carboxamide

[001315] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 57% B over 7 min; UV at 254 & 220 nm to generate the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 4.8 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 7.87-7.77 (m, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 4.88-4.80 (m, 1H), 4.71-4.64 (m, 1H), 4.52-4.47 (m, 1H), 3.35 (s, 3H), LC- MS (Method V): m/z = 397.1 [M+H]+, 2.159 min. Example 75A and 75B: 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo -1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide(75A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b] azepin-2-yl)- 4H-1,2,4-triazol-3-carboxamide (75B) Schematic legend: Rt - taStep 1: Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b- hexahydrocyclopropa[d]pyrido[2, 3-b]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide

[001316] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: X bridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: MeCN (20% to 80% in 12 min); Detector, UV 220 & 254 nm to obtain the title compound (55 mg, 44.3%) as a white solid. LC-MS (Method C): m/z = 389.2 [M + H]+, 1.111 min. Step 2: Preparation of 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2, 3- b]azepin-2-yl)-4H-1,2,4- triazol-3-carboxamide (first elution isomer) and 5-benzyl-N- ((1aS,2S,8bR)-4-methyl- 3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide (second elution isomer)

[001317] The enantiomers of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3- b]azepine -2-yl)-4H-1,2,4-triazol-3-carboxamide (55 mg, 0.14 mmol) were separated by prep HPLC. chiral with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; flow rate: 19 mL/min; Gradient: 35% B to 35% B over 18.5 min; UV 220 and 254 nm; RT 1: 13.00 min; RT 2: 15.67 min to provide the title compounds:

[001318] Example 75B (first elution isomer): 1H NMR (400 MHz, DMSO-d6) 14.37 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.40 -8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.35-7.25 (m, 6H), 4.46 (d, J = 7.2 Hz, 1H ), 4.16 (s, 2H), 3.30 (s, 3H), 2.33-2.26 (m, 1H), 2.05-1.99 (m, 1H), 1.21- 1.14 (m, 1H), 1.11- 1.04 (m, 1H). LC-MS (Method D): m/z = 389.2 [M+H]+, 1.651 min.

[001319] Example 75A (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 7.2 Hz, 1H), 8.40-8.38 (m, 1H ), 8.02-7.98 (m, 1H), 7.38-7.23 (m, 6H), 4.46 (d, J = 7.2 Hz, 1H), 4.14 (s, 2H), 3.30 (s, 3H), 2.32-2.26 (m, 1H), 2.06-1.99 (m, 1H), 1.20-1.15 (m, 1H) , 1,101.04 (m, 1H), LC-MS (Method D): m/z = 389.2 [M+H]+, 1.656 min. Example 76: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-1H-pyrazol-3-carboxamide Scheme legend: Rt - ta

[001320] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 32% B to 54% B over 7 min; UV at 254 & 220 nm to generate the title compound 1H NMR (300 MHz, DMSO-d6) δ 8.37 (dd, J = 4.5, 1.5 Hz, 1H), 8.26 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 4.5 Hz, 1H), 7.71 (dd, J = 8.1, 1.8 Hz, 1H), 7.43-7 .27 (m, 6H), 5.36 (s, 2H), 4.90-4.80 (m, 1H), 4.73-4.65 (m, 1H), 4.55-4.48 (m, 1H), 3.36 (s, 3H), LC-MS (Method D): m/z = 396.1 [M+H]+, 1.893 min. Example 77: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl -5-( 1-phenylcyclopropyl)isoxazole-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 5-(1-phenylcyclopropyl)isoxazole-3-carboxylate

[001321] To a mixture of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate (970 mg, 3.7 mmol) in ethanol (10 mL), hydroxylamine hydrochloride (255 mg, 3.7 mmol) was added. 7 mmol). The reaction mixture was heated to reflux and stirred for 4 hours. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (260 mg, 27%) as a yellow solid. LC-MS (Method K): m/z = 258.1 [M]+, 1.603 min. Step 2: Preparation of 5-(1-phenylcyclopropyl)isoxazole-3-carboxylic acid

[001322] To a solution of ethyl 5-(1-phenylcyclopropyl)isoxazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (3 mL) and water (1 mL) was added sodium hydroxide (93 mg , 2.33 mmol). The resulting mixture was stirred at room temperature overnight, concentrated to dryness and diluted with water (10 mL). The reaction mixture was adjusted to pH = 5 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (80 mg crude) as a yellow solid. LC-MS (Method E): m/z = 229.9 [M+H]+, 0.840 min. Step 3: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl-5 -(1-phenylcyclopropyl)isoxazole-3-carboxamide

[001323] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 75% B over 7 min; UV at 254 & 220 nm to generate the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J = 8.1 Hz, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 7.70 (dd, J = 7.8, 1.5 Hz, 1H), 7.43-7.29 (m, 6H), 6.38 (s, 1H), 4.90-4.80 (m, 1H ), 4.70-4.62 (m, 1H), 4.55-4.48 (m, 1H), 3.35 (s, 3H), 1.58-1.51 (m, 2H), 1.50-1.42 (m, 2H), LC-MS (Method D): m/z = 405.1 [M+H]+, 2.134 min. Example 78: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1-phenylcyclopropyl )-1H-imidazole- 3-carboxamide Schematic legend :Rt – ta Step 1: Preparation of 2-bromo-1-(1-phenylcyclopropyl)ethanone

[001324] To a solution of 1-(1-phenylcyclopropyl)ethanone (4.0 g, 25.0 mmol) and triethylamine (5.0 g, 50 mmol) in dichloromethane (100 mL), trimethylsilyl trifluoromethanesulfonate was added (5.55 g, 25.0 mmol) at 0oC. After stirring for 0.5 hour, 1-bromopyrrolidine-2,5-dione (4.9 g, 27.5 mmol) was added in portions at 0°C. The reaction mixture was stirred for a further 2 hours, quenched with 100 ml of water and extracted with dichloromethane (3 x 80 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to provide the title compound (3.4 g, 57%) as a yellow oil. LC-MS (Method E): m/z =238.8 [M+H]+, 0.971 min. Step 2: Preparation of Ethyl 5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxylate

[001325] A solution of 2-bromo-1-(1-phenylcyclopropyl)ethanone (3.4 g, 14.2 mmol), ethyl 2-amino-2-iminoacetate (1.65 g, 14.2 mmol) and triethylamine (4.3 g, 42.6 mmol) in ethanol (50 mL) was heated at reflux for 5 hours. After concentration under reduced pressure, the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (520 mg, 14%) as a yellow solid. LC-MS (Method C): m/z = 257.0 [M+H]+, 1,000 min. Step 3: Preparation of 5-(1-phenylcyclopropyl)-1H-imidazol-2-carboxylic acid

[001326] To a solution of ethyl 5-(1-phenylcyclopropyl)-1H-imidazol-2-carboxylate (300 mg, 1.2 mmol) in methanol (9 mL) and water (3 mL), hydroxide was added sodium (288 mg, 7.2 mmol). The mixture was then stirred at room temperature overnight. The solution was adjusted to pH = 5 and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (130 mg crude) as a yellow solid. LC-MS (Method C): m/z = 229.1 [M+H]+, 0.906 min. Step 4: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1 -phenylcyclopropyl)-1H-imidazole-2-carboxamide

[001327] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD, 5μm, 19 x 150mm; mobile phase, water (10 mmol/L NH4HCO3), ACN (40% ACN to 70% B over 7 min); detector, UV at 254 and 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.11-12.79 (m, 1H), 8.32-8.17 (m, 1H), 7.51 (dd, J = 7.6, 1 .9Hz, 1H), 7.37-7.16 (m, 8H), 6.85-6.44 (m, 1H), 4.88-4.74 (m, 1H), 4.66- 4.50 (m, 1H), 4.45-4.35 (m, 1H), 3.32 (s, 3H), 1.38-1.27 (m, 2H), 1.25-1, 12 (m, 2H), LC-MS (Method Q): m/z = 403.3 [M+H]+, 1.533 min. Example 79: (S)-7-(2-fluorophenyl)-N-( 5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]thiazol-2-carboxamide Step 1: Preparation of (S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo [d]thiazol-2-carboxamide

[001328] Using the procedure described in Example 54 provided the title compound (370 mg) as a yellow solid that was used in the next step, without purification. LC-MS (Method S): m/z = 432.2 [M+H]+, 1.102 min. Step 2: Preparation of 7-(2-fluorophenyl)-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)benzo[d]thiazol-2-carboxamide

[001329] [1,1'-bis(diphenylphosphine)ferrocene] dichloropalladium (II) (29 mg, 0.04 mmol) was added to a mixture of (S)-7-bromo-N-(5-methyl-4 -oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxaz-epin-3-yl)benzo[d]thiazol-2-carboxamide (170 mg, 0.39 mmol), acid 2- fluorophenylboronic acid (85 mg, 0.59 mmol) and potassium carbonate (109 mg, 0.79 mmol) in dioxane (2 mL) and water (0.5 mL) in a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD, 5μm, 19 x 150mm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 38% B over 7 min; 254 and 220 nm; RT: 6.33 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.31-9.29 (d, J = 7.5 Hz, 1H), 8.29-8.26 (d, J = 8.1 Hz, 1H) , 7.79-7.77 (m, 1H), 7.68-7.60 (m, 2H), 7.60-7.51 (m, 2H), 7.43-7.26 (m, 5H), 4.89-4.72 (m, 2H), 4.50-4.44 (m, 1H), 3.33 (s, 3H), LC-MS (Method T): m/z = 448.3 [M+H]+, 1.884 min. Example 80A and 80B: 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2, 3-b]azepin-2-yl)-1H- pyrazol-3-carboxamide (80A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2 ,3 4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazol-3-carboxamide (80B) Schematic legend :Rt – ta Step 1: Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a, 2,3,4,8b- hexahydrocyclopropa [d] pyrido [2 ,3-b] azepin-2-yl)-1H-pyrazol-3-carboxamide

[001330] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD, 100Â, 19 x 250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; UV at 254 & 220 nm to generate the title compound LC-MS (Method D): m/z = 388.2 [M+H]+, 1.757 min. Step 2: Preparation of 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo cyclopropa[d]pyrido[2 ,3-b]azepine-2-yl)-1H- pyrazol-3-carboxamide (first eluting isomer) and 5-benzyl-N- ((1aR,2R,8bS)-4-methyl-3-oxo-1 ,1a,2,3,4,8b-hexa-hydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazol-3-carboxamide (second elution isomer)

[001331] 5-Benzyl-N-(cis-4-methyl-3-oxo-1,1a, 2,3,4,8b- hexahydrocyclopropa[d]pyrido[2,3-b]azepine racemate -2-yl)-1H-pyrazol-3-carboxamide (60 mg, 0.16 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL IC, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 60% B to 60% B over 16.5 min; UV of 254 and 220 nm; TA 1: 8.27 minutes; RT 2: 13.00 min to provide the title compounds:

[001332] Example 80A (first elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J = 7.8, 1.8 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.05 (s, 2H), 3.40 (s, 3H), 2.31-2.23 (m, 1H), 2.12-2.03 (m, 1H), 1.32-1.26 (m, 1H) , 1,221.13 (m, 1H), LC-MS (Method D): m/z = 388.2 [M+H]+, 1.757 min.

[001333] Example 80B (second elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.38 (dd, J = 4.5, 1.8 Hz, 1H), 7.94 (dd, J = 7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 2.31-2.23 (m, 1H), 2.12-2.04 (m, 1H), 1.33-1.26 (m, 1H) , 1,221.13 (m, 1H), LC-MS (Method D): m/z = 388.2 [M+H]+, 1.757 min. Example 81A and 81B: 5-benzyl-N-((1aS, 2S,8bR)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3- b]azepin-2-yl)isoxazole-3-carboxamide (81A) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo- 1,1a,2,3 4,8b-hexahydrocyclopropa[d]pyrido[2,3- b]azepin-2-yl)isoxazol-3-carboxamide (81B) Schematic legend: Rt–ta Step 1: Preparation of 5-benzyl-N-hexahydrocyclopropa[d]pyrido carboxamide

[001334] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV at 254 & 220 nm to generate the title compound LC-MS (Method D): m/z = 389.1 [M+H]+, 2.036 min. Step 2: Preparation of 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2, 3-b]azepin-2-yl)isoxazol-3-carboxamide (first eluting isomer) and 5-benzyl-N-((1aS,2S,8bR)- 4-methyl-3-oxo-1,1a,2 ,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide (second elution isomer)

[001335] 5-Benzyl-N-(cis-4-methyl-3-oxo-1,1a, 2,3,4,8b- hexahydrocyclopropa[d]pyrido[2,3-b]azepine racemate -2-yl)isoxazol-3-carboxamide (60 mg, 0.15 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 μm; Mobile phase A: hexanes, mobile phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% B over 17 min; UV of 254 and 220 nm; RT 1: 12.098 min; RT 2: 14.358 min to provide the title compounds:

[001336] Example 81B (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 7.5 Hz, 1H), 8.40 (dd, J = 4.5 , 1.8 Hz, 1H), 7.98 (dd, J = 7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H) , 4.45 (d, J = 7.2 Hz, 1H), 4.24 (s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2, 02-1.94 (m, 1H), 1.25-1.06 (m, 2H), LC-MS (Method D): m/z = 389.1 [M+H]+, 2.036 min.

[001337] Example 81A (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 7.2 Hz, 1H), 8.40 (dd, J = 4.5 , 1.8 Hz, 1H), 7.98 (dd, J = 7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H) , 4.45 (d, J = 7.2 Hz, 1H), 4.24 (s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2, 02-1.94 (m, 1H), 1.22-1.06 (m, 2H), LC-MS (Method D): m/z = 389.1 [M+H]+.2.027 min.Example 82A and 82B: 1-benzyl-4-fluoro-N-((1aS,2S,8bR)-4-methyl-3-oxo- 1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido [2,3- b]azepin-2-yl)-1H- pyrazol-3-carboxamide (82A) and 1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4- methyl-3- oxo-1,1a,2,3 4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazol-3-carboxamide (82B) Step 1: Preparation of 1-benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3- b]azepin-2-yl)-1H-pyrazol-3-carboxamide

[001338] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 100Â, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; UV of 254 and 220 nm; to yield the title compound (58 mg, 50%) as a white solid. LC-MS (Method V): m/z = 406.1 [M+H]+, 2.852 min. Step 2: Preparation of 1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-methyl-3-oxo- 1,1a, 2,3,4,8b-hexahydrocyclopropa[d] pyrido[2,3- b]azepin-2-yl)-1H- pyrazol-3-carboxamide (first elution isomer) and 1-benzyl-4-fluoro- N-((1aS,2S,8bR)-4- methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazol-3-carboxamide (second isomer of elution)

[001339] 1-Benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3] racemate -b]azepin-2-yl)-1H-pyrazol-3-carboxamide (58 mg, 0.15 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 μm ; Mobile phase A: hexanes, mobile phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% B over 23 min; UV 254 and 220 nm; RT 1: 10.936 min; RT 2: 16.976 min to provide the title compounds:

[001340] Example 82B (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 8.39 (dd, J = 4.8, 1.8 Hz, 1H), 8.17-8.12 (m, 2H), 8.00 (dd, J = 7.8, 1.8 Hz, 1H), 7.44-7.28 (m, 6H), 5.36 (s, 2H), 4, 46 (d, J = 6.9 Hz, 1H), 3.30 (s, 3H), 2.33-2.24 (m, 1H), 2.06-1.98 (m, 1H), 1 .26-1.14 (m, 1H), 1.12-1.03 (m, 1H), LC-MS (Method V): m/z = 406.1 [M+H]+, 2.852 min.

[001341] Example 82A (second elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J = 7.5, 1.8 Hz, 1H), 7.77 (d, J = 4.5 Hz, 1H), 7.44-7.27 (m, 6H), 5.35 (s, 2H) , 4.66 (s, 1H), 3.41 (s, 3H), 2.32-2.23 (m, 1H), 2.15-2.03 (m, 1H), 1.33-1 .26 (m, 1H), 1.22-1.14 (m, 1H), LC-MS (Method D): m/z = 406.1 [M+H]+, 1.932 min. Example 83A: 5-Benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 2,4-difluoro-6-vinylbenzenamine

[001342] To a solution of 2-bromo-4,6-difluoroaniline (10.0 g, 48.0 mmol) in N,N-dimethylformamide (50 mL), tributyl(ethenyl)stannan (18.0 g, 56.7 mmol) and tetrakis(triphenylphosphine)palladium. (2.2 g, 1.90 mmol) in a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80°C. After cooling to room temperature, the reaction mixture was quenched by adding water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to provide the title compound (6.0 g, 80%) as a yellow oil. LC-MS (Method C): m/z = 156.0 [M + H]+, 1.216 min.Step 2: Preparation of N-(2,4-difluoro-6-vinylphenyl)but-3-enamide

[001343] Thionyl chloride (9.3 g, 46.46 mmol) was added to a solution of but-3-enoic acid (4.0 g, 46.46 mmol) in dichloromethane (20 mL) dropwise . After stirring for 1 hour at room temperature, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 2-ethenyl-4,6-difluoroaniline (6.0 g, 38.67 mmol ) in dichloromethane (20 mL). The reaction mixture was stirred for 3 hours at room temperature, quenched by addition of water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to provide the title compound (5.7 g, 66%) as a yellow oil. LC-MS (Method C): m/z = 224.0 [M + H]+, 1.145 min. Step 3: Preparation of (Z)-7,9-difluoro-1H-benzo[b]azepine-2(3H)-one

[001344] [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene)ruthenium tricyclohexylphosphine (3.4 g, 4.0 mmol) was added to a solution of N-(5-ethenyl-2,4-difluorophenyl)but-3-enamide (4.4 g, 19.9 mmol) in toluene (150 mL). The resulting solution was stirred for 16 hours at 80°C and then concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (2.8 g, 69%) as a yellow oil. LC-MS (Method S): m/z = 196.0 [M+H]+, 0.754 min. Step 4: Preparation of 5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one

[001345] To a solution of potassium hydroxide (40 g, 714 mmol) in water (60 mL), a solution of 1-methyl-1-nitrosourea (20.6 g, 199.8 mmol) in ether was added (150 mL) dropwise at 0oC in a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to provide a diazomethane solution (150 ml). To a solution of 7,9-difluoro-2,3-dihydro-1H-1-benza-zepin-2-one (2.0 g, 10.25 mmol) in tetrahydrofuran (60 mL) was added the diazomethane solution (150 mL) dropwise, followed by adding a mixture of palladium diacetate (224.5 mg, 1.00 mmol) in tetrahydrofuran (10 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo to obtain the title compound (1.2 g crude) as a yellow oil. LC-MS (Method C): m/z = 210.0 [M+H]+, 1.117 min. Step 5: Preparation of trans-5,7-difluoro-2-iodo-1,1a, 2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one

[001346] A mixture of 5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one (1.2 g, 6.0 mmol) in dichloromethane (60 mL) was added N,N,N',N'-tetramethylethylenediamine (2.1 g, 18.0 mmol) followed by the addition of iodotrimethylsilane (3.6 g, 18.0 mmol) at 0° W. After stirring for 2 hours at 0°C, iodine (2.3 mg, 9.0 mmol) was added. The reaction mixture was stirred for 1 hour at 0°C, treated with aqueous sodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (1.32 g crude) as a yellow oil. LC-MS (Method C): m/z = 336.0 [M+H]+, 1.213 min. Step 6: Preparation of cis-2-azido-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one

[001347] Sodium azide (250 mg, 3.84 mmol) was added to a solution of trans-5,7-difluoro-2-iodo-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d] azepine-3(4H)-one (860 mg, 2.56 mmol) in N,N-dimethylformamide (40 mL). The resulting mixture was stirred for 16 hours at room temperature, quenched by addition of water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (520 mg crude) as a yellow oil. LC-MS (Method C): m/z = 251.0 [M + H]+, 1.176 min. Step 7: Preparation of cis-2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one

[001348] Triphenylphosphine (629 mg, 2.40 mmol) was added to a solution of cis-2-azido-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine -3(4H)-one (400 mg, 1.60 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred for 16 hours at room temperature, diluted with water (50 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to provide the title compound (310 mg, 86%) as a yellow oil. LC-MS (Method C): m/z = 225.0 [M+H]+, 0.776 min. Step 8: Preparation of (1aR,2R,8bS)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one ( first eluting isomer) and (1aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one (second elution isomer).

[001349] Cis-2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one racemate (310 mg, 1, 38 mmol) was separated by prep HPLC. chiral with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B over 28 min; 254/220nm; RT1: 10.247 min; RT2: 20.789 min to give the title compounds:

[001350] (1aR,2R,8bS)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one (first isomer elution): (150 mg, 48%) as a white solid. LC-MS (Method C): m/z = 225.0 [M+H]+, 0.776 min.

[001351] (1aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one (second isomer elution): (140 mg, 45%) as a white solid. LC-MS (Method C): m/z = 225.0 [M+H]+, 0.776 min. Step 9: 5-Benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a, 2,3,4,8b- hexahydrobenzo[b]cyclopropa[d] azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide

[001352] N,N-Diisopropylethylamine (50 mg, 0.39 mmol) was added to a mixture of (1aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,2,8b- tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one (30 mg, 0.13 mmol), 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (32 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole (22 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column, Prep Column. XBridge C18 OBD, 5.19mm x 250mm; mobile phase, water (10 mmoL/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, 254 nm UV to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.30 (br, s, 1H), 9.96 (br, s, 1H), 8.43 (d, J = 6.8 Hz, 1H), 7 .36-7.19 (m, 7H), 4.61 (d, J = 6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26 (m, 1H) , 2.07-2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H), LC-MS (Method Q): m/ z = 410.3 [M+H]+, 1.144 min. Example 83B: 5-Benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide Scheme legend: Rt - ta

[001353] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 μm, 19 x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, 254 nm UV to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.95 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 7.35-7 .19 (m, 7H), 4.61 (d, J = 6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26 (m, 1H), 2.07- 2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H), LC-MS (Q Method): m/z = 410.30 [M+H]+, 1.143 min. Example 84: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-phenylbenzo[d] thiazol-2-carboxamide

[001354] [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (34 mg, 0.05 mmol) was added to a mixture of (S)-7-bromo-N-(5-methyl-4 -oxo-2, 3,4,5-tetra-hydrobenzo[b][1,4]oxaz-epin-3-yl)benzo[d]thiazol-2-carboxamide (200 mg, 0.47 mmol), acid phenylboronic acid (85 mg, 0.70 mmol) and potassium carbonate (128 mg, 0.93 mmol) in dioxane (2 mL) and water (0.5 mL) in a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 38% B over 7 min; 254 and 220 nm; RT: 6.33 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.30 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.79-7.60 (m, 4H), 7.60-7.49 (m, 4H), 7.347.26 (m, 3H), 4.96-4.68 (m, 2H), 4.50-4.45 (m , 1H), 3.33 (s, 3H), LC-MS (Method T): m/z = 430.3 [M+H]+, 1.906 min. Example 85: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3 -yl)-1,3,4-thiadiazol-2-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate

[001355] To a stirred solution of 2-phenylacetohydrazide (2 g, 13.3 mmol) and triethylamine (4.04 g, 39.9 mmol) in dichloromethane (30 mL) was added 2-chloro-2- ethyl oxoacetate (1.8 g, 13.4 mmol) dropwise at 0oC. The resulting solution was stirred for 12 hours at room temperature, diluted with water (20 ml) and extracted with dichloromethane (5 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (1.2 g, 36%) as a white solid. LC-MS (Method I): m/z = 251.0[M+H]+, 0.944 min. Step 2: Preparation of ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate

[001356] To a mixture of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate (0.65 g, 2.6 mmol) in tetrahydrofuran (8 mL), reagent was added of Lawesson (1.89 g, 4.7 mmol). The resulting mixture was stirred for 3 hours at 70°C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL). The phases were separated and the organic layer was washed with aqueous sodium bicarbonate (10%, 3 x 20 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (500 mg, 78%) as a yellow oil. LC-MS (Method I): m/z = 249.0 [M+H]+, 0.991 min. Step 3: Preparation of 5-Benzyl-1,3,4-thiadiazole-2-carboxylic acid

[001357] To a mixture of ethyl 5-benzyl-1,3,4-thiadiazol-2-carboxylate (500 mg, 2.01 mmol) in tetrahydrofuran (6 mL) and water (2 mL), added if lithium hydroxide (97 mg, 4.04 mmol). The resulting solution was stirred for 12 hours at room temperature and concentrated in vacuo. The residue was diluted with water (10 mL) and the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (250 mg crude) as a white solid. LC-MS (Method I): m/z = 221.0 [M+H]+, 0.574 min. Step 4: Preparation of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepine -3-yl)-1,3,4-thiadiazol-2-carboxamide

[001358] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 38% B to 70% B over 7 min; UV at 254 & 220 nm to generate the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.46 (d, J = 6.6 Hz, 1H), 8.37 (dd, J = 4.8, 1.8 Hz, 1H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.38-7.26 (m, 6H), 4.91-4.75 (m, 2H), 4.58-4.52 (m, 3H), 3.36 (s, 3H), LC-MS (Method D): m/z = 396.1 [M+H]+, 1.912 min. Example 86: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3-yl ) thiazol-2-carboxamide

[001359] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 38% B to 70% B over 7 min; UV at 254 & 220 nm to generate the title compound 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J = 7.2 Hz, 1H), 8.37 (dd, J = 4.8 , 1.5 Hz, 1H), 7.88 (s, 1H), 7.71 (dd, J = 8.1, 1.5 Hz, 1H), 7.37-7.23 (m, 6H) , 4.89-4.72 (m, 2H), 4.56-4.50 (m, 1H), 4.28 (s, 2H), 3.36 (s, 3H), LC-MS (Method D): m/z = 395.1 [M+H]+, 2.096 min.Example 87: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1-(1-phenylcyclopropyl)-1H-1,2,3-triazol-4-carboxamide Schematic legend: Rt – ta Step 1: Preparation of tert-butyl 1-phenylcyclopropylcarbamate

[001360] To a stirring mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol) and diphenyl phosphorazidate (17.0 g, 61.7 mmol) in toluene (100 mL), triethylamine was added (18.6 g, 185 mmol). The reaction mixture was stirred for 5 hours at 100°C, cooled to room temperature and then 2-methylpropan-2-ol (33.7 mg, 0.216 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated in high vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether 1/5) to provide the title compound (4.00 g, 28%) as a yellow solid. LC-MS (Method C): m/z = 234.2 [M+H]+, 1.345 min. Step 2: Preparation of 1-phenylcyclopropanamine hydrochloride

[001361] Tert-butyl 1-phenylcyclopropylcarbamate (4.0 g, 17.2 mmol) was added to a solution of hydrogen chloride in dioxane (4 N, 50 mL, 200 mmol). The reaction mixture was stirred for 3 hours at room temperature and concentrated in high vacuum to provide the title compound (2.00 g, 88%) as a white solid. LC-MS (Method C): m/z = 134.2 [M + H]+, 0.775 min. Step 3: Preparation of (1-azidocyclopropyl)benzene

[001362] To a stirred solution of 1-phenylcyclopropanamine hydrochloride (320 mg, 1.89 mmol) in ether (10 mL), a solution of methylmagnesium bromide in ether (3 M, 1.89 mL, 5 .67 mmol) at -60°C in an argon atmosphere. After stirring for 30 minutes at -60°C, 4-methylbenzenesulfonyl azide (745 mg, 3.78 mmol) was added. The reaction mixture was stirred for 1 hour at -60°C, quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (500 mg crude) as a yellow solid. Step 4: Preparation of ethyl 1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylate

[001363] Cupric acetate (468 mg, 3.14 mmol) was added to a solution of (1-azidocyclopropyl)benzene in ethyl propiolate (5 mL). The reaction mixture was stirred at room temperature overnight and concentrated in high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (100 mg, 12%) as a yellow oil. LC-MS (Method C): m/z = 258.1 [M+H]+, 1,250 min. Step 5: Preparation of 1-(1-phenylcyclopropyl)-1H-1,2,3-triazol-4-carboxylic acid

[001364] Lithium hydroxide (18.7 mg, 0.78 mmol) was added to a solution of ethyl 1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.39 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The resulting solution was stirred overnight at room temperature, concentrated in vacuo and diluted with water (5 mL). The pH of the solution was adjusted to 5 with aqueous hydrochloric acid (1N, 5 mL). The resulting solution was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (30 mg crude) as a white solid. LC-MS (Method D): m/z = 230.2 [M+H]+, 0.532 min. Step 6: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1 -phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxamide

[001365] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: OBD Shield XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 220nm; RT: 6 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 7.53-7.49 (m, 1H), 7 .39-7.20 (m, 5H), 7.07-7.04 (m, 2H), 4.89-4.81 (m, 1H), 4.65-4.55 (m, 1H) , 4.43-4.30 (m, 1H), 3.32 (s, 3H), 1.79-1.78 (m, 2H), 1.73-1.64 (m, 2H), LC -MS (Method D): m/z = 404.1 [M+H]+, 1.992 min. Example 88: (S)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1-phenylcyclopropyl)-1H- imidazole-5-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (Z)-N'-hydroxy-1-phenylcyclopropanecarboximidamide

[001366] Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a mixture of 1-phenylcyclopropanecarbonitrile (1.5 g, 10.5 mmol) and sodium carbonate (2.2 g, 20.7 mmol) in ethanol (20 mL) and water (10 mL). The resulting mixture was stirred at 80°C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to provide the title compound (1.2 g, 68%) as a white solid. LC-MS (Method E): m/z = 176.8 [M + H]+, 0.371 min. Step 2: Preparation of Ethyl 2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxylate

[001367] A solution of (Z)-N'-hydroxy-1-phenylcyclopropanecarboximidamide (1.2 g, 6.8 mmol) and ethyl propiolate (1.0 g, 10.2 mmol) in ethanol (50 mL) it was stirred at 80°C overnight and concentrated in vacuo. The residue was dissolved in oxydibenzene (20 ml) and the mixture was stirred at 200°C for 2 hours. The resulting mixture was concentrated and purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (0.7 g, 40%) as a yellow solid. LC-MS (Method C): m/z = 257.0 [M + H]+, 1,200 min. Step 3: Preparation of 2-(1-phenylcyclopropyl)-1H-imidazol-5-carboxylic acid

[001368] Lithium hydroxide (288 mg, 7.2 mmol) was added to a solution of 2-(1-phenylcyclopropyl)-1H-imidazol-5-carboxylate (300 mg, 1.2 mmol) in tetrahydrofuran ( 9 mL) and water (3 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (20 mL), adjusted to pH 5 with aqueous hydrochloric acid (1 N, 10 mL), and extracted with ethyl acetate (3 x 20 mL ). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (130 crude) as a yellow solid. LC-MS (Method C): m/z = 229.1 [M + H]+, 0.906 min. Step 4: Preparation of (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1 -phenylcyclopropyl)-1H-imidazole-5-carboxamide

[001369] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B over 7 min; 254 & 220 nm UV to generate the title compound 1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7, 52-7.49 (m, 2H), 7.37-7.19 (m, 8H), 4.89-4.79 (m, 1H), 4.54-4.38 (m, 2H), 3.33 (s, 3H), 1.48-1.40 (m, 2H), 1.28-1.20 (m, 2H), LC-MS (Method O): m/z = 403.1 [M+H]+, 1.389 min. Example 89A: 5-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b- hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1,3,4-oxadiazol-2-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate

[001370] Ethyl 2-chloro-2-oxoacetate (603 mg, 4.4 mmol) was added to a stirred solution of 2-phenylacetohydrazide (660 mg, 4.4 mmol) and triethylamine (1.33 g , 13.2 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 5 hours, quenched by adding water (20 mL) and extracted with dichloromethane (3x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (550 mg, 50%) as a yellow oil. LC-MS (Method S): m/z = 251.0 [M+H]+, 0.679 min.Step 2: Preparation of ethyl 5-benzyl-1,3,4-oxadiazole-2-carboxylate

[001371] Tosyl chloride (840 mg, 4.4 mmol) was added to a stirred solution of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate (666 mg, 6.6 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at room temperature overnight, quenched by addition of water (20 mL) and extracted with dichloromethane (3x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (500 mg, 98%) as a yellow oil. LC-MS (Method C): m/z = 233.0 [M + H]+, 1,200 min. Step 3: Preparation of 5-Benzyl-1,3,4-oxadiazole-2-carboxylic acid

[001372] Lithium hydroxide (103 mg, 4.3 mmol) was added to a stirred solution of ethyl 5-benzyl-1,3,4-oxadiazol-2-carboxylate (500 mg, 2.15 mmol) in tetrahydrofuran (5 mL) and water (2 mL). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo and diluted with water (20 mL). The pH value of the mixture was adjusted to pH = 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (250 mg crude) as a yellow semi-solid. LC-MS (Method I): m/z = 205.0 [M+H]+, 0.058 min.Step 4: Preparation of 5-benzyl-N-((1aR,2R,8bS)-5,7-difluoro -3-oxo- 1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1,3,4-oxadiazol-2-carboxamide

[001373] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 μm, 19 x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, 254 nm UV to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 7.38-7.29 (m, 5H), 7.12-7.08 (m, 1H), 6.98-6.93 (m, 1H), 4 .82 (d, J = 0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (m, 1H), LC-MS (Method V): m/z = 411.05 [M+H]+, 2.915 min.Example 89B: 5-benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[ d]azepin-2-yl)-1,3,4-oxadiazol-2-carboxamide

[001374] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 μm, 19 x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, 254 nm UV to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 7.39-7.28 (m, 5H), 7.11-7.08 (m, 1H), 6.98-6.93 (m, 1H), 4 .81 (d, J = 0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (m, 1H), LC-MS (Q Method): m/z = 411.30 [M+H]+, 0.965 min.Example 90A: 1-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[ d]azepin-2-yl)-1H-1,2,3-triazol-4-carboxamide

[001375] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column, Prep C18 OBD Xbridge Column, 5 μm, 19 x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, 254 nm UV to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (br, s, 1H), 8.77 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 7.43 -7.33 (m, 5H), 7.32-7.26 (m, 1H), 7.24-7.19 (m, 1H), 5.67 (s, 2H), 4.63 (d , J = 6.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.06-2.00 (m, 1H), 1.44-1.40 (m, 1H), 1.14-1.08 (m, 1H), LC-MS (Method D): m/z = 410.10 [M+H]+, 1.876 mi.Example 90B: 1-benzyl-N-((1aS ,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-1,2 ,3-triazole-4-carboxamide

[001376] The crude product obtained using Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column, 5 μm, 19 x 250 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (30.0% ACN to 60.0% for 7 min); Detector, 254 nm UV to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.77 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 7.46-7 .33 (m, 5H), 7.30-7.26 (m, 1H), 7.24-7.19 (m, 1H), 5.67 (s, 2H), 4.63 (d, J = 6.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.05-2.00 (m, 1H), 1.45-1.40 (m, 1H), 1, 14-1.08 (m, 1H), LC-MS (Method J): m/z = 410.15 [M+H]+, 1.269 min.Example 91: (S)-N-(4-oxo- 2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1-(1-phenylcyclopropyl)-1H-pyrazol-3-carboxamide

[001377] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. Phenyl OBD XBridge, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 60% B over 7 min; UV 254 & 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.53 (s, 1H), 8.24-8.14 (m, 2H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.34-7.15 (m, 6H), 6.38 (s, 1H), 4.84-4.77 (m, 1H), 4.52 -4.41 (m, 2H), 1.35-1.30 (m, 4H), LC-MS (Method D): m/z = 390.1 [M+H]+, 1.537 min.Example 92 : 1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3 -yl)-4-fluoro-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyridin-3-yloxy)-butanoic acid

[001378] Sodium hydride (60%, 9.2 g, 230 mmol) was added to a solution of (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid (25 g, 115 mmol) in N,N-dimethylformamide (500 mL) and the reaction mixture was stirred at 0°C for 1 hour. After addition of 3-fluoro-2-nitropyridine (16.4 g, 115 mmol), the reaction mixture was stirred at room temperature for a further 2 hours and then quenched by addition of hydrochloric acid (3N, 20 ml). The pH value of the reaction solution was adjusted to 3-4 with hydrogen chloride (3 N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile/water, 1/2) to provide the title compound (3.8 g, 10%) as a pale yellow oil. LC-MS (Method C): m/z = 286.1 [M+H-56]+, 1.167 min. Step 2: Preparation of (2S,3R)-3-(2-aminopyridin-3-yloxy)-2-(tert-butoxycarbonylamino)-butanoic acid

[001379] (2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyridin-3-yloxy)butanoic acid; (3.77 g, 11 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium carbon (10%, 1.0 g) in a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred for 6 hours at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (3.12 g, 91%) as a colorless oil. LC-MS (Method C): m/z = 312.1 [M + H]+, 0.887 min. Step 3: Preparation of tert-butyl (2R,3S)2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-ylcarbamate

[001380] N,N-diisopropylethylamine (1.43 g, 11 mmol) was added to a stirring solution of (2S,3R)-3-(2-aminopyridin-3-yloxy)-2-(tert-butoxycarbonylamino acid )butanoic acid (3.0 g, 10 mmol) and N,N,N',N'- (7-azabenzotriazol-1-yl)uronium tetramethyl-O-hexafluorophosphate (4.18 g, 11 mmol) in N, N-dimethylformamide (50 mL). The reaction mixture was stirred for 5 hours at room temperature, quenched by addition of water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to provide the title compound (2.2 g, 78%) as a white solid. LC-MS (Method C): m/z = 294.1 [M+H]+, 1.136 min. Step 4: Preparation of (2R,3S)-2,5-dimethyl-4-oxo-2,3, tert-butyl 4,5-tetrahydropyrid [3,2-b][1,4]oxazepin-3-ylcarbamate

[001381] Iodomethane (388 mg, 2.73 mmol) was added dropwise to a stirring solution of (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[ tert-butyl 3,2-b][1,4]oxazepin-3-ylcarbamate (800 mg, 2.73 mmol) and cesium carbonate (890 mg, 2.73 mmol) in N,N-dimethylformamide (15 mL). The action mixture was stirred for 1 hour at 0°C and for 3 hours at room temperature, diluted with water (20 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (670 mg, 80%) as a white solid. LC-MS (Method C): m/z = 308.2 [M+H]+, 1,250 min. Step 5: Preparation of (2R,3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2-b] [1,4] oxazepin-4(5H)-one hydrochloride

[001382] (2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate tert- butyl (670 mg, 2.18 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 mL, 40 mmol). The reaction mixture was stirred for 5 hours at room temperature and concentrated under reduced pressure to provide the title compound (460 mg crude) as a white solid. LC-MS (Method E): m/z = 207.90 [M+H]+, 0.432 min. Step 6: Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepine-3-yl)-4-fluoro-1H-pyrazol-3-carboxamide

[001383] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Prep column. XBridge C18 OBD, 19 x 250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV at 254 & 220 nm to generate the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 4.4, 1.6 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 6.4 Hz, 1H), 7.42-7.31 (m, 4H), 7.31- 7.27 (m, 2H), 5.37 (s, 2H), 5.00-4.93 (m, 1H), 4.92-4.88 (m, 1H), 3.40 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H), LC-MS (Method F): m/z = 409.9 [M+H]+, 1.336 min.Example 93: 1-Benzyl -N-((2S,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)- 4-fluoro-1H-pyrazole-3-carboxamide

[001384] The title compound was prepared from (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid using the procedure described in Example 92.

[001385] The crude product obtained was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV at 254 & 220 nm to produce the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 4.8, 1.2 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.42- 7.27 (m, 6H), 5.36 ( s, 2H), 5.10-5.01 (m, 1H), 4.45-4.40 (m, 1H), 3.34 (s, 3H), 1.26 (d, J = 6, 0 Hz, 3H), LC-MS (Method D): m/z = 410.1 [M+H]+, 1.923 min. Example 94: 5-benzyl-N-((2R,3S)-2.5 -dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4H-1,2,4-triazol-3-carboxamide Scheme legend: Rt - ta

[001386] N,N-diisopropylethylamine (95 mg, 0.73 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (50 mg, 0.24 mmol) , (2R,3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride (50 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (60 mg, 0.32 mmol) and 1-hydroxybenzotriazole (43 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product obtained using Amide Bond Procedure C was purified by Prep-HPLC with the following conditions: Column: OBD Shield XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 5% B over 4 min; UV 254 & 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.46 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.98 (d, J = 6, 0 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.23 (m, 6H), 5.014.94 (m, 1H), 4, 93-4.89 (m, 1H), 4.14 (s, 2H), 3.40 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H), LC-MS (Method D): m/z = 393.1 [M+H]+, 1.725 min. Example 95: 5-benzyl-N-((2S,3S)-2,5-dimethyl-4-oxo-2,3, 4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4H-1,2,4-triazol-3-carboxamide Example 96: 5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3 -yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (2R,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4 hydrochloride (5H)-one

[001387] tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate ( 100 mg, 0.34 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 mL). The reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to provide the title compound (100 mg crude) as a white solid. LC-MS (Method E): m/z = 194.0 [M+H]+, 0.432 min. Step 2: Preparation of 5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-4H-1,2,4-triazol-3-carboxamide

[001388] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 10 μm, 19 mm * 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 35% B over 7 min; UV 254 & 220 nm; RT: 7 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 14.41 (s, 1H), 10.84 (s, 1H), 8.19-8.08 (m, 2H), 7.62 (dd, J = 8.1, 1.2Hz, 1H), 7.37-7.20 (m, 6H), 4,984.86 (m, 2H), 4.15 (s, 2H), 1.30 (d, J = 6.0 Hz, 3H), LC-MS (Method D): m/z = 379.1 [M+H]+, 1.546 min. Example 97: 5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3 -yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (2S,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4 hydrochloride (5H)-one

[001389] tert-butyl (2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate ( 50 mg, 0.17 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 mL, 20 mmol). The reaction mixture was stirred for 2 hours at room temperature and concentrated in vacuo to give the title compound (35 mg crude) as a white solid. LC-MS (Method E): m/z = 194.0 [M+H]+, 0.432 min. Step 2: Preparation of 5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-4H-1,2,4-triazol-3-carboxamide

[001390] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. C18 OBD X Select CSH, 5μm, 19mm x 150mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 60% B over 7 min; UV 254 & 220 nm. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 10.56 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.23-8 .20 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.39-7.17 (m, 6H), 5.11-4.90 (m, 1H), 4.44 (m, 1H), 4.16 (s, 2H), 1.32 (d, J = 6.0 Hz, 3H), LC-MS (Method F): m/z = 378.95 [ M+H]+, 0.932 min. Example 98A and 98B: (R)-5-benzyl-N-(8'-oxo-6',7',8',9'-tetrahydrospiro [cyclopropane-1,5'-pyrido[2,3- b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (98A) and (S)-5-benzyl-N-(8'-oxo-6',7', 8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (98B) Step 1: Preparation of 7'-amino-6',7'-dihydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-8'(9'H)-one hydrochloride

[001391] A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL, 40 mmol) was added to a solution of (8'-oxo-6',7',8',9'- tert-butyl tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'-yl) carbamate (100 mg, 0.34 mmol) in 1,4-dioxane (4 mL ). The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to give the title compound (80 mg crude) as a white solid. LC-MS (Method C): m/z = 204.1 [M + H]+, 0.677 min. Step 2: Preparation of 5-benzyl-N-(8'-oxo-6', 7', 8', 9'-tetrahydro-spiro-[cyclopropane-1,5'-pyrido[2,3-b ]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide

[001392] The crude product obtained using Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep column. XBridge C18 OBD, 5μm, 19 x 150mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; 254/220 nm to provide the title compound (50 mg, 56%) as a white solid. LC-MS (Method V): m/z = 389.2 [M+H]+, 0.982 min. Step 2: Preparation of (R)-5-benzyl-N-(8'-oxo-6',7',8',9'-tetrahydro-spiro-[cyclopropane-1,5'-pyrido[ 2 ,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-(8'-oxo- 6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'-yl)- 4H-1,2,4-triazole- 3-carboxamide (second elution isomer)

[001393] 5-Benzyl-N-(8'-oxo-6',7',8',9'-tetrahydrospiro-[cyclopropane-1,5'-pyrido[2,3-b] racemate azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (50 mg, 0.128 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak ID-2, 2 x 25cm, 5μm; Mobile Phase A: hexane/DCM (4.5:1), Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2: 18.02 min to provide the title compounds:

[001394] Example 98A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.28 (s, 1H), 10.37 (s, 1H), 8.27 (dd, J = 4 .8, 1.8 Hz, 1H), 7.69 (dd, J = 7.6, 1.8 Hz, 1H), 7.34-7.08 (m, 6H), 4.42-4, 33 (m, 1H), 3.30 (s, 3H), 2.82-2.68 (m, 1H), 1.72 (s, 1H), 1.23-1.05 (m, 1H) , 0.880.78 (m, 1H), 0.70-0.65 (m, 1H), 0.40-0.25 (m, 1H), LC-MS (Method D): m/z = 389, 2 [M+H]+, 1.499 min.

[001395] Example 98B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 10.38 (d, J = 2.8 Hz, 1H), 8.37-8.22 (m, 2H ), 7,717.67 (m, 1H), 7.44-7.08 (m, 6H), 4.43-4.34 (m, 1H), 4.06 (s, 2H), 2,782.71 ( m, 1H), 1.73 (t, J = 12.3 Hz, 1H), 1.23-1.05 (m, 2H), 0.86-0.79 (m, 1H), 0.71 -0.64 (m, 1H), 0.27 (s, 1H), LC-MS (Method D): m/z = 389.2 [M+H]+, 1.503 min. Example 99: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-5- (1-phenylcyclopropyl)-1H-imidazol-2-carboxamide Scheme legend: Rt - ta

[001396] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A:water (10mmol/ L NH4HCO3); Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; Detector, 220 & 254nm UV; RT: 6.32 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.50-8.32 (m, 2H), 7.727.70 (m, 1H), 7.39-7.15 ( m, 6H), 6.78-6.65 (m, 1H), 4.92-4.63 (m, 2H), 4.52-4.48 (m, 1H), 3.36 (s, 3H), 1.35-1.30 (m, 2H), 1.28-1.11 (m, 2H), LC-MS (Method O): m/z = 404.0 [M+H]+ , 1,412 min. Example 100A and 100B: 4-(2-fluorophenoxy)-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d] pyrido[2,3-b]azepin-2- yl)picolinamide (100A) and 4-(2-fluorophenoxy)-N-((1aR,2R,8bS)-4-methyl- 3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide (100B) Step 1: Preparation of 4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydro-cyclopropa[d]pyrido [2, 3-b]azepin-2-yl)picolinamide

[001397] The crude product obtained using the Amide Bonding Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 1/3) to obtain the racemic title compound. LC-MS (Method J): m/z = 419.1 [M+H]+, 1,330 min. Step 2: Preparation of 4-(2-fluorophenoxy)-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d] pyrido[2,3-b]azepin-2-yl) picolinamide (first eluting isomer) and 4-(2-fluorophenoxy)-N- ((1aR,2R,8bS)-4-methyl-3-oxo-1 ,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide (second elution isomer)

[001398] 4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydro-cyclopropa[d]pyrido[2] racemate ,3-b]azepine-2-yl)picolinamide (25 mg, 0.096 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 19 min; 220/254nm; RT1: 13.609 min; RT2: 15,738 min to generate the title compounds:

[001399] Example 100A (first elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.59 (d, J = 5.6 Hz, 1H), 8.39 (dd, J = 4.7 , 1.8 Hz, 1H), 7.95 (dd, J = 7.7, 1.8 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.42 -7 .27 (m, 5H), 7.15 (dd, J = 5.6, 2.6 Hz, 1H), 4.66 (s, 1H), 3.42 (s, 3H), 2,322.26 ( m, 1H), 2.17-2.06 (m, 1H), 1.36-1.32 (m, 1H), 1.23-1.14 (m, 1H), LC-MS (Method J ): m/z = 419.2 [M+H]+, 1.467 min.

[001400] Example 100B (second elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.58 (d, J = 5.6 Hz, 1H), 8.38 (dd, J = 4.7 , 1.8 Hz, 1H), 7.95 (dd, J = 7.7, 1.8 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.41-7 .28 (m, 5H), 7.14 (dd, J = 5.6, 2.6 Hz, 1H), 4.65 (s, 1H), 3.42 (s, 3H), 2,352.25 ( m, 1H), 2.15-2.03 (m, 1H), 1.37-1.25 (m, 1H), 1.24-1.16 (m, 1H), LC-MS (Method T ): m/z = 419.3 [M+H]+, 2.774 min. Example 101A and 101B: (R) -5-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8- hexahydropyrazole [4,3-b] azepin- 6- yl) -4H-1,2,4-triazol-3-carboxamide (101A) and (S) -5-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6 , 7,8-hexahydropyrazole [4,3-b] azepin-6-yl) - 4H-1,2,4-triazol-3-carboxamide (101B) Schematic legend: Rt – ta Step 1: Preparation of ethyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)butanoate

[001401] To a stirring solution of 5-bromo-1-methyl-4-nitro-1H-pyrazole (2.0 g, 9.76 mmol), (4-ethoxy-4-oxobutyl)zinc(II) bromide ) (0.5 M in tetrahydrofuran) (29.2 mL, 14.6 mmol) and dicyclohexyl (2', 6'- dimethoxybiphenyl-2-yl) phosphine (402.3 mg, 0.98 mmol )in tetrahydrofuran (100 mL) a solution of palladium diacetate (109.8 mg, 0.49 mmol) in tetrahydrofuran was added dropwise with stirring under a nitrogen atmosphere. The resulting mixture was heated overnight at 40°C. The reaction mixture was concentrated under high vacuum and the residue was purified by column chromatography (methanol/dichloromethane, 1/99) to provide the title compound (445 mg, 18.9%) as a yellow oil. LC-MS (Method C): m/z = 242.1 [M + H]+, 1.156 min. Step 2: Preparation of 4-(4-amino-1-methyl-1H-pyrazol-5-yl) butanoate ethyl

[001402] Ethyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl) butanoate (405 mg, 1.68 mmol) was hydrogenated in the presence of palladium on carbon (10%, 41 mg) under an atmosphere of hydrogen (2-3 atm) in methanol (20 mL). The reaction mixture was stirred for 2 hours at room temperature. Then, the solids were removed by filtration and the solvents were evaporated under vacuum to provide the title compound (320 mg crude) as a yellow solid. LC-MS (Method C): m/z = 212.2 [M + H]+, 0.768 min. Step 3: Preparation of 4-(4-amino-1-methyl-1H-pyrazol-5-yl) butanoic acid

[001403] A solution of ethyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl) butanoate (320 mg, 1.51 mmol) and lithium hydroxide (108.9 mg, 4.53 mmol) in tetrahydrofuran/water = 3/1 (4 mL), was stirred for 3 hours at room temperature. The pH value of the solution was adjusted to 6-7 with hydrochloric acid (1 N). The resulting solution was concentrated in vacuo to provide the title compound (220 mg crude) as a yellow solid. LC-MS (Method C): m/z = 184.1 [M + H]+, 0.318 min. Step 4: Preparation of 1-methyl-7,8-dihydropyrazol[4,3-b]azepin- 5 (1H, 4H,6H)-one

[001404] N,N-diisopropylethylamine (465.2 mg, 3.6 mmol) was added to a stirred solution of 4-(4-amino-1-methyl-1H-pyrazol-5-yl) butanoic acid. (220 mg, 1.2 mmol) and N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (548.2 mg, 1.44 mmol) in N, N-dimethylformamide (5 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (160 mg, 80.8%) as a yellow solid. LC-MS (Method C): m/z = 166.2 [M + H]+, 0.751 min. Step 5: Preparation of 1,4-dimethyl-7,8-dihydropyrazole[4,3-b]azepin-5(1H, 4H, 6H)-one

[001405] Iodomethane (150.5 mg, 1.06 mmol) was added dropwise to a stirred solution of 1-methyl-7,8-dihydropyrazole [4,3-b] azepin-5 (1H, 4H , 6H)-one (160 mg, 0.96 mmol) and sodium hydride (60%) (42.4 mg, 1.06 mmol) in N,N-dimethylformamide (5 mL) with stirring. The reaction mixture was stirred for 2 hours at room temperature, quenched with water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 3/1) to provide the title compound (140 mg, 81.5%) as a yellow solid. LC-MS (Method C): m/z = 180.2 [M + H]+, 0.816 min. Step 6: Preparation of 6-iodo-1,4-dimethyl-7,8-dihydropyrazole[4,3-b]azepin-5(1H, 4H, 6H)-one

[001406] N1, N1, N2, N2-tetramethylethane-1,2-diamine (271.4 mg, 2.34 mmol) was added to a stirred solution of 1,4-dimethyl-7,8-dihydropyrazole [ 4,3-b] azepin-5 (1H, 4H, 6H)-one (140 mg, 0.78 mmol) in dichloromethane (5 mL) at 0°C followed by addition of iodotrimethylsilane (468 mg, 2.34 mmol ). The reaction mixture was stirred for 1 hour at 0°C. After adding iodine (137.2 mg, 0.54 mmol), the reaction mixture was stirred for an additional 1 hour at 0°C and quenched with aqueous sodium thiosulfate (5%, 15 mL). The reaction mixture was stirred for a further 15 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (214 mg crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 306.0 [M + H]+, 0.953 min. Step 7: Preparation of 6-amino-1,4-dimethyl-7,8-dihydropyrazole[4,3-b]azepin-5(1H, 4H, 6H)-one

[001407] To a solution of 6-iodo-1,4-dimethyl-7,8-dihydropyrazol[4,3-b]azepin-5(1H,4H,6H)-one (214 mg, 0.70 mmol) in N,N-dimethylformamide (4 mL) sodium azide (136.9 mg, 2.1 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL) and water (2 mL) and tripenylphosphine (551.8 mg, 2.1 mmol) was added in one portion. The reaction mixture was stirred at 50°C overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (100 mg, 73.6%) as a yellow solid. LC-MS (Method C): m/z = 195.1 [M + H]+, 0.386 min. Step 8: Preparation of 5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl) -4H-1,2,4-triazole-3-carboxamide

[001408] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: column: X bridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A:water (10mmol/ L NH4HCO3); Phase B: ACN (20% to 80% in 12 min); Detector, UV 220 and 254nm to provide the title compound. LC-MS (Method C): m/z = 380.2 [M + H]+, 1.290 min. Step 9: Preparation of (R)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin- 6-yl)-4H-1,2,4-triazol-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N- (1,4-dimethyl-5-oxo- 1,4, 5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (second elution isomer)

[001409] 5-Benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazole [4,3-b] azepin-6-yl racemate )-4H-1 2,4-triazol-3-carboxamide (50 mg, 0.13 mmol) were separated by prechiral HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 μm; Mobile Phase A: Hex, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 60% B to 60% B over 21 min; 220/254nm; RT1: 12.12 min; RT2: 18.44 min.

[001410] Example 101A (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 7.51 (s, 1H), 7.34-7.22 (m, 5H), 4.60 (dd , J = 2.0, 10.0 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 ( m, 1H), 2.99-2.91 (m, 1H), 2.48-2.41 (m, 1H), 2.25-2.14 (m, 1H), LC-MS (Method V ): m/z = 380.1 [M+H]+, 2.240 min.

[001411] Example 101B (second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 7.51 (s, 1H), 7.35-7.22 (m, 5H), 4.60 (dd , J = 2.4, 10.4 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 ( m, 1H), 2.99-2.91 (m, 1H), 2.49-2.41 (m, 1H), 2.25-2.14 (m, 1H), LC-MS (Method D ): m/z = 380.2 [M+H]+, 1.471 min. Example 102A and 102B: 5-((R)-2,3-dihydro-1H-inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetra- hydropyrido[3, 2-b] [1,4] oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-((S)-2,3-dihydro-1H -inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H -1,2,4-triazol-3-carboxamide Step 1: Preparation of 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido[3, 2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001412] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5.19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 36% B over 7 min; 254nm; RT: 7 min to provide the title compound. LC-MS (Method D): m/z = 391.1 [M + H]+, 1.593 min. Step 2: Preparation of 5-((R)-2,3-dihydro-1H-inden-1-yl) -N-((S)-4-oxo- 2,3,4,5-tetra- hydropyrid [3, 2-b] [1,4] oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide and 5-((S)-2,3-dihydro-1H -inden-1-yl) -N-((S)-4-oxo-2,3,4,5- tetrahydropyrido [3,2-b] [1,4] oxazepin-3-yl)-4H -1,2,4-triazol-3-carboxamide

[001413] 5-(2,3-dihydro-1H-inden-1-yl)-N-((S)-4-oxo-2,3,4,5-tetrahydropyrido racemate [3 ,2-b] [1, 4] oxazepin-3-yl)-4H-1, 2,4-triazol-3-carboxamide (10 mg) was separated by prechiral HPLC with the following conditions: Column: CHIRALPAK IA , 2.12 x 15 cm, 5 μm; Mobile Phase A: Hex: DCM 4.5:1, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 17.5 min; 220/254nm; RT 1: 10.95 min; RT2: 15.02 min to give the title compounds.

[001414] Example 102A (First elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7 .33-7.31 (m, 1H), 7.31-7.10 (m, 3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H) , 4.69-4.61 (m, 2H), 4.47-4.42 (m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H), 2.44-2.39 (m, 1H), LC-MS (Method T): m/z = 391.3 [M+H]+ , 1,133 min.

[001415] Example 102B (Second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7 .33-7.31 (m, 1H), 7.31-7.10 (m, 3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H) , 4.69-4.61 (m, 2H), 4.47-4.42 (m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H), 2.44-2.39 (m, 1H), LC-MS (Method T): m/z = 391.3 [M+H]+ , 1,135 min. Example 103A and 103B: (R)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo[b]azepine-5,1'-cyclopropane ]-3-yl)-4H- 1,2,4-triazol-3-carboxamide and (S)-5-benzyl-N- (7,9-difluoro-2-oxo- 1,2,3,4- tetrahydrospiro [benzo[b]azepine-5,1'-cyclopropan]-3-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt - ta Step 1: Preparation of dimethyl 2-(3,5-difluoro-2-nitrophenyl)malonate

[001416] Dimethyl malonate (15 g, 114 mmol) was added dropwise to a stirred mixture of 1,3,5-trifluoro-2-nitrobenzene (10 g, 56 mmol) and potassium carbonate (23 g , 168 mmol) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred overnight at 70oC and quenched by adding water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give the title compound (15 g, 92%) as yellow oil. LC-MS (Method C): m/z = 290.0 [M + H]+, 1.235 min. Step 2: Preparation of methyl 2-(3,5-difluoro-2-nitrophenyl) acetate

[001417] A solution of lithium chloride (6.3 g, 150 mmol) in water (20 mL) was added to a solution of dimethyl 2-(3,5-difluoro-2-nitrophenyl) malonate (15 g, 52 mmol) in dimethylsulfoxide (50 mL). The reaction mixture was stirred overnight at 100°C and quenched by addition of water (250 mL). The resulting solution was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (11 mg crude) as a yellow oil, which was used directly in the next step without further purification. 3: Preparation of methyl 1-(3,5-difluoro-2-nitrophenyl) cyclopropanecarboxylate

[001418] 1,2-Dibromoethane (13 g, 70 mmol) was added dropwise to a stirring solution of 2-(3,5-difluoro-2-nitrophenyl) methyl acetate (11 g, 48 mmol) and carbonate potassium (20 g, 145 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred overnight at 70oC and quenched by adding water (250 mL). The resulting solution was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give the title compound (1.1 g, 9%) as yellow oil. LC-MS (Method C): m/z = 258.1 [M + H]+, 1.291 min. Step 4: Preparation of (1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)methanol

[001419] A solution of diisobutylaluminum hydride in toluene (1 M, 9.4 mL, 9.4 mmol) was added dropwise to a stirred solution of 1-(3,5-difluoro-2-nitrophenyl) methyl cyclopropanecarboxylate (1.1 g, 4.3 mmol) in toluene (30 mL) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at -78°C for 2 hours, quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to provide the title compound (0.92 g, 94%) as a yellow oil. LC-MS (Method C): m/z = 230.1 [M + H]+, 1.192 min. Step 5: Preparation of 1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde

[001420] Dess-Martin Periodinane (3.4 g, 8 mmol) was added to a stirring solution of (1-(3,5-difluoro-2-nitrophenyl) cyclopropyl) methanol (0.92 g, 4 mmol ) in dichloromethane (30 mL). The reaction mixture was stirred at 0oC for 2 hours, quenched by adding water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to give the title compound (0.85 mg, 92%) as yellow oil. Step 6: Preparation of (E) ethyl 3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl) acrylate

[001421] Ethyl acetate (triphenylphosphoranylidene) (1.5 g, 4.3 mmol) was added to a stirring solution of 1-(3,5-difluoro-2-nitrophenyl) cyclopropanecarbaldehyde (800 mg, 3.5 mmol ) in tetrahydrofuran (50 mL). The reaction mixture was stirred overnight at 50oC, quenched by adding water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to give the title compound (0.64 g, 61%) as a yellow oil. LC-MS (Method C): m/z = 298.0 [M + H]+, 1.382 min. Step 7: Preparation of ethyl 3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoate

[001422] (E)-ethyl 3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)acrylate (640 mg, 2.2 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium in carbon (10%, 65 mg) under a hydrogen atmosphere (2-3 atm). After stirring overnight at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to provide the title compound (400 mg crude) as a yellow oil. LC-MS (Method C): m/z = 270.1 [M + H]+, 1.361 min. Step 8: Preparation of 3-(1-(2-amino-3,5-difluorophenyl)-cyclopropyl) propanoic acid

[001423] Lithium hydroxide (180 mg, 7.5 mmol) was added to a solution of ethyl 3-(1-(2-amino-3,5-difluorophenyl) cyclopropyl) propanoate (400 mg, 1.5 mmol ) in tetrahydrofuran (30 mL) and water (10 mL). The reaction mixture was stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (320 mg crude) as a yellow oil. LC-MS (Method C): m/z = 242.1 [M + H]+, 1.143 min. Step 9: Preparation of 7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1'-cyclopropane]-2(1H)-one

[001424] N,N-diisopropylethylamine (515 mg, 4.0 mmol) was added to a mixture of 3-(1-(2-amino-3,5-difluorophenyl) cyclopropyl) propanoic acid (320 mg, 1 .3 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (608 mg, 1.6 mmol) in N,N-dimethylformamide (10 mL) . The reaction mixture was stirred at room temperature for 2 hours and quenched by adding water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to provide the title compound (270 mg, 91%) as a yellow oil. LC-MS (Method C): m/z = 224.1 [M + H]+, 1.303 min. Step 10: Preparation of 7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepine-5,1'-cyclopropane]-2(1H)-one

[001425] N, N, N', N'-tetramethylethylenediamine (418 mg, 3.6 mmol) was added to a solution of 7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine- 5,1'-cyclopropane]-2(1H)-one (270 mg, 1.2 mmol) in dichloromethane (40 mL) at 0°C followed by addition of iodotrimethylsilane (720 mg, 3.6 mmol) dropwise during 20 min. The mixture was stirred for 1 hour at 0°C and then iodine (457 mg, 1.8 mmol) was added to the mixture. After stirring for an additional 1 hour at 0°C, the reaction mixture was quenched by adding aqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (410 mg crude) as yellow oil. LC-MS (Method C): m/z = 350.1 [M + H]+1.262 min. Step 11: Preparation of 3-azido-7,9-difluoro-3,4-dihydrospiro [benzo[b]azepine-5,1'-cyclopropane]-2(1H)-one

[001426] Sodium azide (117 mg, 1.8 mmol) was added to a solution of 7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepine-5,1'- cyclopropane]-2(1H)-1 (410 mg, 1.2 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred overnight at room temperature and quenched by addition of water (40 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (260 mg crude) as a yellow oil. LC-MS (Method E): m/z = 265.1 [M + H]+, 0.875 min. Step 12: Preparation of 3-amyo-7,9-difluoro-3,4-dihydrospiro [benzo[b]azepine-5,1'-cyclopropane]-2(1H)-one

[001427] Triphenylphosphine (393 mg, 1.5 mmol) was added to a solution of 3-azido-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1'-cyclopropane] -2(1H)-one (260 mg, 1.0 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred overnight at room temperature, diluted with water (20 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 5/1) to provide the title compound (210 mg, 90%) as a yellow oil. LC-MS (Method C): m/z = 239.1 [M + H]+, 0.814 min. Step 13: Preparation of 5-Benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropan]-3- il)4H-1,2,4-triazol-3-carboxamide

[001428] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV at 254 and 220 nm to give the title compound (30 mg, 26%) as a white solid. LC-MS (Method O): m/z = 423.9 [M + H]+, 1.204 min. Step 14: Preparation of (R)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo[b]azepine-5,1'-cyclopropane ]-3-yl)-4H-1,2,4-triazol-3-carboxamide (example 103A) and (S)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2, 3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropan]-3-yl)-4H-1,2,4-triazol-3-carboxamide (example 103B)

[001429] 5-Benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1'-cyclopropan]-3 racemate -yl)-4H-1,2,4-triazol-3-carboxamide was separated by prechiral HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 μm; Mobile phase A: hexanes, mobile phase B: EtOH; Flow rate: 16 mL/min; Gradient: 55% B to 55% B over 27 min; UV 220 and 254 nm; Ta1: 13.94 min; Ta2: 21.44 min to provide the two title compounds.

[001430] Example 103A (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 7.33-7.26 (m, 5H), 7.10-6.99 (m, 2H), 4 .72-4.62 (m, 1H), 4.17 (s, 2H), 3.08-2.99 (m, 1H), 1.63-1.57 (m, 1H), 1.25 -1.18 (m, 1H), 1.07-1.01 (m, 1H), 0.85-0.77 (m, 1H), 0.59-0.52 (m, 1H), LC -MS (Method O): m/z = 423.9 [M+H]+, 1.204 min.

[001431] Example 103B (second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.23 (m, 5H), 7.07-6.98 (m, 2H), 4 .73-4.64 (m, 1H), 4.23 (s, 2H), 3.07-2.96 (m, 1H), 1.68-1.53 (m, 1H), 1.25 -1.18 (m, 1H), 1.06-0.99 (m, 1H), 0.84-0.77 (m, 1H), 0.59-0.52 (m, 1H), LC -MS (Method V): m/z = 424.2 [M+H]+, 2.031 min. Example 104A and 104B: (R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole [4,3-b] azepin-6- yl) 4H-1,2,4-triazol-3-carboxamide and (S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole [4,3-b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt - taStep 1: Preparation of ethyl 4-(1-methyl-4-nitro-1H-pyrazol-3-yl) butanoate

[001432] A solution of (4-ethoxy-4-oxobutyl) zinc (II) bromide in tetrahydrofuran (0.5 M, 41.5 mL, 20.7 mmol) was added to a stirred mixture of 3- iodo-1-methyl-4-nitro-1H-pyrazole (4.32 g, 17.1 mmol) and dicyclohexyl (2', 6'-dimethoxybiphenyl-2-yl) phosphine (864 mg, 2.1 mmol ) in tetrahydrofuran (50 mL) under a nitrogen atmosphere, followed by adding a mixture of palladium diacetate (432 mg, 1.9 mmol) in tetrahydrofuran dropwise. The resulting mixture was stirred overnight at room temperature and concentrated under high vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/99) to give the title compound (1.7 g, 41.3%) as a yellow oil. LC-MS (Method E): m/z = 242.1 [M + H]+, 0.852 min. Step 2: Preparation of 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoic acid

[001433] Lithium hydroxide (339 mg, 14.1 mmol) was added to a mixture of ethyl 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoate (1.7g, 7. 05 mmol) in tetrahydrofuran (30 mL) and water (10 mL). The reaction mixture was stirred for 2 hours at room temperature. After removing tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 6-7 with aqueous hydrochloric acid (1N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under high vacuum to provide the title compound (1.2g crude) as a yellow solid. LC-MS (Method E): m/z = 213.9 [M + H]+, 0.617 min. Step 3: Preparation of 4-(4-amino-1-methyl-1H-pyrazol-3-yl) butanoic acid

[001434] A solution of 4-(1-methyl-4-nitro-1H-pyrazol-3-yl) butanoic acid (1.2 g, 5.61 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium in carbon (10%, 120mg) under a hydrogen atmosphere (2-3 atm). After stirring for 5 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under high vacuum to provide the title compound (1g crude) as a yellow solid. LC-MS (Method C): m/z = 184.1 [M + H]+, 0.304 min. Step 4: Preparation of 2-methyl-7,8-dihydropyrazol[4,3-b]azepin-5(2H, 4H, 6H)-one

[001435] N,N-diisopropylethylamine (2.2 g, 17.05 mmol) was added to a stirred mixture of 4-(4-amino-1-methyl-1H-pyrazol-3-yl) butanoic acid ( 1.0 g, 5.46 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.5g, 6.58 mmol) in N, N-dimethylformamide (20 mL). The reaction mixture was stirred for 3 hours at room temperature and diluted with water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (560 mg, 62.1%) as a yellow solid. LC-MS (Method C): m/z = 166.2 [M + H]+, 0.331min. Step 5: Preparation of 6-iodo-2-methyl-7,8-dihydropyrazol[4,3-b]azepin-5(2H, 4H, 6H)-one

[001436] N1,N1,N2,N2-tetramethylethane-1,2-diamine (1.01 g, 8.73 mmol) was added to a stirred mixture of 2-methyl-7,8-dihydropyrazol[4, 3- b]azepin-5(2H, 4H, 6H)-one (0.48 g, 2.91 mmol) in dichloromethane (30 mL) at 0°C followed by addition of iodotrimethylsilane (1.16 g, 5. 82 mmol) dropwise over 20 min. The reaction mixture was stirred for 1 hour at 0°C. Iodine (1.11 g, 4.37 mmol) was added to the mixture. The reaction mixture was stirred for a further 1 hour at 0°C and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting solution was stirred for 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (550 crude) as a yellow solid. LC-MS (Method I): m/z = 291.9 [M + H]+, 0.522 min. Step 6: Preparation of 6-azido-2-methyl-7,8-dihydropyrazol[4,3- b]azepin-5(2H, 4H, 6H)-one

[001437] Sodium azide (246 mg, 3.78 mmol) was added to a solution of 6-iodo-2-methyl-7,8-dihydropyrazole [4,3-b] azepin-5 (2H, 4H, 6H )-one (550 mg, 1.89 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred overnight at 40oC, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (480 mg crude) as a brown solid, which was used directly in the next step without further purification. LC-MS (Method I): m/z = 207.0[M + H]+, 0.481 min. Step 7: Preparation of 6-amino-2-methyl-7,8-dihydropyrazol[4,3- b]azepin-5(2H, 4H, 6H)-one

[001438] Triphenylphosphine (1.5 g, 7.28 mmol) was added to a solution of 6-azido-2-methyl-7,8-dihydropyrazol[4,3-b]azepin-5(2H, 4H , 6H)-one (0.48 g, 2.18 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred for 16 hours at room temperature, diluted with water (50 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to provide the title compound (300 mg, 70.9%) as a yellow oil. LC-MS (R Method): m/z = 181.3 [M + H]+, 0.655 min. Step 8: Preparation of 5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole[4,3-b]azepin-6-yl)-4H -1,2,4-triazol-3-carboxamide

[001439] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 47% B over 7 min; UV 254 and 220 nm; RT: 6.22 min to provide the title compound (50 mg, 26.8%) as a white solid. LC-MS (Method Y): m/z = 366.0 [M + H]+.0.779 min. Step 9: Preparation of (R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6- yl)4H-1,2,4-triazol-3-carboxamide (example 104A) and (S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8 -hexahydropyrazol[4,3- b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (example 104B)

[001440] 5-Benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl)- racemate 4H-1,2,4-triazol-3-carboxamide (50 mg, 0.13 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: i-PrOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 21 min; UV 254 and 220 nm; Ta1: 9.68 min; Ta2: 14.84 min to give the title compounds:

[001441] Example 104A (First elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 14.37 (br. s, 1H), 9.86 (s, 1H), 8.39 (br. s , 1H), 7.40 (s, 1H), 7.34-7.22 (m, 5H), 4.40-4.35 (m, 1H), 4.11 (s, 2H), 3, 74 (s, 3H), 2.90-2.81 (m, 2H), 2.26-2.20 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (Method X): m/z = 366.2 [M+H]+, 2.165 min.

[001442] Example 104B (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 14.37 (br. s, 1H), 9.86 (s, 1H), 8.39 (br. s, 1H), 7.40 (s, 1H), 7.34-7.22 (m, 5H), 4.40-4.35 (m, 1H), 4.11 (s, 2H), 3.74 (s, 3H), 2.89-2.84 (m, 2H), 2.25-2.21 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (Method T): m/z = 366.3 [M+H]+, 0.858 min. Example 105A and 105B: (S)-5-benzyl-N-(2,4-dimethyl-5-oxo -2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl)4H-1,2,4-triazol-3-carboxamide and (R)-5-benzyl -N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole [4, 3-b] azepin-6-yl)-4H-1,2,4 -triazol-3-carboxamide Step 1: Preparation of 6-azido-2,4-dimethyl-7,8-dihydropyrazol[4,3-b]azepin-5(2H, 4H, 6H)-one

[001443] Iodomethane (664 mg, 4.68 mmol) was added dropwise to a stirred mixture of 6-azido-2-methyl-7,8-dihydropyrazole [4,3-b] azepin-5 (2H , 4H, 6H)-one (480 mg, 2.33 mmol) and cesium carbonate (1.5 g, 4.66 mmol) in N, N-dimethylformamide (10 mL). The reaction mixture was stirred for 2 hours at room temperature and quenched by adding water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (480 crude) as a yellow solid. LC-MS (Method I): m/z = 221.0[M + H]+, 0.565 min. Step 2: Preparation of 6-amino-2,4-dimethyl-7,8-dihydropyrazole[4,3-b]azepin-5(2H, 4H, 6H)-one

[001444] Triphenylphosphine (2.44 g, 9.31 mmol) was added to a solution of 6-azido-2,4-dimethyl-7,8-dihydropyrazole [4,3-b] azepin-5 (2H , 4H, 6H)-one (480 mg, 2.18 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred for 16 hours at room temperature, diluted with water (50 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to give the title compound (300 mg, 71%) as a yellow oil. LC-MS (Method I): m/z = 195.0 [M + H]+, 0.168 min. Step 3: Preparation of 5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole[4,3-b]azepin-6-yl) -4H-1,2,4-triazole-3-carboxamide

[001445] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 Prep OBD Column, 100 Â, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 30% B over 10 min; UV 254 and 220 nm; RT: 7 min to provide the title compound (50 mg, 26.8%) as a white solid. LC-MS (Q Method): m/z = 380.4 [M + H]+.0.786 min. Step 4: Preparation of (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin- 6-yl)4H-1,2,4-triazol-3-carboxamide (example 105A) and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6 ,7,8-hexahydropyrazole[4,3-b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (example 105B)

[001446] 5-Benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole [4,3-b] azepin-6-yl racemate )-4H-1, 2,4-triazol-3-carboxamide (50 mg, 0.13 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 μm; Mobile Phase A: hexane: DCM = 4.5: 1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 21 min; UV 220 and 254 nm; Ta1: 8.88 min; Ta2: 16.76 min to give the title compounds:

[001447] Example 105A (First elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 14.35 (br. s, 1H), 8.32 (br. s, 1H), 7.83 (s , 1H), 7.34- 7.22 (m, 5H), 4.53-4.45 (m, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 3, 19 (s, 3H), 2.85-2.66 (m, 2H), 2.35-2.31 (m, 1H), 2.30-2.26 (m, 1H). LC-MS (Method T): m/z = 380.2 [M+H]+, 0.958 min.

[001448] Example 105B (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 14.29 (br. s, 1H), 8.30 (br. s, 1H), 7.83 (s, 1H), 7,347.22 (m, 5H), 4.52-4.46 (m, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 3.19 (s, 3H ), 2.85-2.68 (m, 2H), 2.35-2.31 (m, 1H), 2.30-2.27 (m, 1H). LC-MS (Method T): m/z = 380.2 [M+H]+, 0.953 min. Example 106: (S) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2- b][1,4]oxazepin-3-yl)- 5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide

[001449] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column:XSelect CSH Prep Column C18 OBD, 5 μm, 19 * 150 mm; Mobile Phase A: water (0.1% formic acid); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; Detector, UV 254 and 220 nm; RT: 5.47 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.37 (dd, J = 4.8, 1, 5Hz, 1H), 7.71 (dd, J = 8.0, 1.5Hz, 1H), 7.407.22 (m, 6H), 4.92-4.66 (m, 2H), 4, 56-4.55 (m, 1H), 3.36 (s, 3H), 1,521.27 (m, 4H). LC-MS (Method O): m/z = 405.0 [M+H]+, 1.126 min. Example 107A and 107B: (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepin-7 -yl) 4H-1,2,4-triazol-3-carboxamide and (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H- pyrido[2, 3-b]azepin-7-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt–ta Step 1: Preparation of (E)-6,7-dihydroquinolin-8(5H)-one oxime

[001450] Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a solution of 6,7-dihydroquinolin-8(5H)-one (1.5 g, 10.2 mmol) and hydroxide of sodium (1.2 g, 30.0 mmol) in ethanol (20 mL) and water (10 mL). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/20) to provide the title compound (1.4 g, 86.4%) as a white solid. LC-MS (Method E): mz = 163.1 [M + H]+, 0.362 min. Step 2: Preparation of (E)-6,7-dihydroquinolin-8(5H)-one O-methylsulfonyl oxime

[001451] Triethylamine (3.5 g, 30.6 mmol) and methanesulfonyl chloride (0.74 g, 6.4 mmol) were added to a solution of (E)-6,7-dihydroquinolin-8 (5H)-one oxime (1.4 g, 8.64 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (1.7 g, 82%) as a yellow solid. LC-MS (Method C): m/z = 241.0 [M + H]+, 0.810 min. Step 3: Preparation of 6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[001452] Potassium acetate (5 g, 51 mmol) was added to a solution of (E)-6,7-dihydroquinolin-8 (5H) -one O-methylsulfonyloxime (1.7 g, 7 mmol) in ethanol (40 mL) and water (20 mL). The reaction mixture was stirred overnight at 110 oC and 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, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/5) to provide the title compound (1.0 g, 87%) as a yellow solid. LC-MS (Method C): m/z = 162.8 [M + H]+, 0.612 min. Step 4: Preparation of 9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[001453] Iodomethane (1.0 g, 0.70 mmol) was added dropwise to a stirred mixture of 6,7-dihydro-5H-pyrido [2,3-b]azepin-8 (9H) - one (1.0 g, 0.60 mmol) and cesium carbonate (3.0 g, 0.92 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature overnight, quenched by addition of water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/30) to provide the title compound (0.97 g, 89.8%) as a yellow solid. LC-MS (Method C): m/z = 177.1 [M + H]+, 1.192 min. Step 5: Preparation of 7-iodo-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[001454] N1, N1, N2, N2-tetramethylethane-1,2-diamine (1.9 g, 16.4 mmol) was added to a stirred mixture of 9-methyl-6,7-dihydro-5H- pyrido[2,3-b]azepin-8(9H)-one (0.97 g, 5.5 mmol) in dichloromethane (100 mL) at 0°C followed by addition of iodotrimethylsilane (3.3 g, 16. 5 mmol) for 20 minutes. The reaction mixture was stirred for 1 hour at 0°C. After adding iodine (4.2 g, 16.5 mmol), the reaction mixture was stirred for a further 4 hours at room temperature before quenching by adding aqueous sodium thiosulfate (5%, 30 mL). The resulting solution was stirred for 15 minutes and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/30) to provide the title compound (1.5 g, 89.8%) as a white solid. LC-MS (Method C): m/z = 303.0 [M + H]+, 1,350 min. Step 6: Preparation of 7-azido-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[001455] Sodium azide (650 mg, 10.0 mmol) was added to a solution of 7-iodo-9-methyl-6,7-dihydro-5H-pyrido [2,3-b] azepin-8 (9H)-one (1.5 g, 4.9 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 5 hours at room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (900 mg, 84%) as a white solid. LC-MS (Method C): mz = 218.2 [M + H]+, 0.586 min. Step 7: Preparation of 7-amino-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

[001456] Triphenylphosphine (1.6 g, 6.1 mmol) was added to a solution of 7-azido-9-methyl-6,7-dihydro-5H-pyrido [2,3-b] azepin-8 (9H )-one (0.9 g, 4.1 mmol) in tetrahydrofuran (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (0.65 mg, 82%) as a white solid. LC-MS (Method C): m/z = 192.1 [M + H]+, 0.386 min. Step 8: Preparation of 5-Benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H -1 2,4-triazol-3-carboxamide

[001457] N,N-diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (104.6 mg , 0.52 mmol), 7-amino-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (100 mg, 0.52 mmol) , N-(3-dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) in N,N-dimethylformamide ( 4 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: OBD XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 35% B over 11 min; UV 254 and 220 nm; RT: 10 min to provide the title compound (50 mg, 25%) as a white solid. LC-MS (Method D): mz = 377.2 [M + H]+, 1.51 min. Step 9: Preparation of (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7- il) 4H-1,2,4-triazol-3-carboxamide (example 107A) and (S)-5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro -5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazol-3-carboxamide (example 107B)

[001458] 5-Benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido 2,3-b]azepin-7-yl)-4H racemate -1,2,4-triazol-3-carboxamide (50 mg, 0.14 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak ID-2, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: MeOH: EtOH = 1: 1; Flow rate: 17 mL/min; Gradient: 60% B to 60% B over 23 min; UV 220 and 254 nm; Ta1: 8.53 min; Ta2: 18.27 min to give the title compounds:

[001459] Example 107A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.35 (br, s, 1H), 8.52-8.42 (m, 2H), 7.82 -7.79 (m, 1H), 7.34-7.21 (m, 6H), 4.35-4.26 (m, 1H), 4.10 (s, 2H), 3.34 (s , 3H), 2.75-2.62 (m, 2H), 2.41-2.16 (m, 2H), LC-MS (Method D): m/z = 377.2 [M+H] +, 1,551 min.

[001460] Example 107B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.35 (br, s, 1H), 8.45-8.41 (m, 2H), 7.83 -7.79 (m, 1H), 7.35-7.15 (m, 6H), 4.35-4.23 (m, 1H), 4.10 (s, 2H), 3.34 (s , 3H), 2.75-2.61 (m, 2H), 2.50-2.20 (m, 2H), LC-MS (Method D): m/z = 377.2 [M+H] +, 1,546 min. Example 108: (S)-2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3-yl )-1H-imidazole-5-carboxamide Step 1: Preparation of (Z)-N'-hydroxy-2-phenylacetimidamide

[001461] Sodium bicarbonate (1.44 g, 17.1 mmol) was added to a mixture of 2-phenylacetonitrile (1.0 g, 8.54 mmol) and hydroxylamine hydrochloride (1.19 g, 17.1 mmol) in ethanol (15 mL) and water (5.0 mL). The reaction mixture was stirred at 80°C overnight, diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 5/95) to provide the title compound (1.15 mg, 90%) as a white solid. MS (Method I): m/z = 151.1 [M + H]+, 0.194 min. Step 2: Preparation of ethyl 2-benzyl-1H-imidazole-5-carboxylate

[001462] A reaction mixture of (Z) N'-hydroxy-2-phenylacetimidamide (1.0 g, 6.67 mmol) and ethyl propiolate (1.96 g, 20 mmol) in ethanol (20 mL) was stirred at 80°C overnight. Diphenyl ether (50 mL) was added to the mixture and stirred at 130°C for 2 hours. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/99) to provide the title compound (650 mg, 43%) as a gray solid. LC-MS (Method L): mz = 231.1 [M + H]+, 1.197 min. Step 3: Preparation of (S)-2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3 -yl)-1H-imidazol-5-carboxamide

[001463] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 and 220 nm; RT: 6 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.01 (d, J = 8, 0 Hz, 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.38-7.17 ( m, 6H), 4.90-4.76 (m, 1H), 4.64 (dd, J = 11.5, 9.8 Hz, 1H), 4.54-4.45 (m, 1H) , 4.02 (s, 2H), 3.36 (s, 3H), LC-MS (Method O): m/z = 378.0 [M+H]+, 1.047 min. Example 109A and 109B: (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin- 6-yl)-4-fluoro-1H-pyrazol-3-carboxamide and (R)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8- hexahydropyrazol[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazol-3-carboxamide Step 1: Preparation of 1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl) -4-fluoro-1H-pyrazole-3-carboxamide

[001464] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 50% B over 7 min; UV 254 and 220 nm; RT: 6 min to give the title compound (80 mg, 55.6%) as a white solid. LC-MS (Q Method): m/z = 397.4 [M + H]+.1.115 min. Step 2: Preparation of (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin- 6-yl)-4-fluoro-1H-pyrazol-3-carboxamide (example 109A) and (R)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6, 7,8-hexahydropyrazol[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazol-3-carboxamide (example 109B).

[001465] 1-Benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazole [4,3-b] azepin-6-yl racemate )-4-fluoro-1H-pyrazole-3-carboxamide(80 mg, 0.20 mmol) was separated by pre-chiral HPLC with the following conditions: Column: Lux 5u Cellulose-3, AXIA Packed, 2.12 x 25 cm, 5μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 40% B to 40% B over 15 min; UV 254 and 220 nm; Ta1: 9.89 min; Ta2: 12.58 min to give the title compounds:

[001466] Example 109A (first elution isomer): 1HNMR (400 MHz, DMSO-d6) δ 8.13 (d, J=4.4 Hz, 1H), 7.92 (d, J=7.2 Hz , 1H), 7.83 (s, 1H), 7.40-7.31 (m, 3H), 7.31-7.28 (m, 2H), 5.33 (s, 2H), 4, 50-4.44 (m, 1H), 3.78 (s, 3H), 3.18 (s, 3H), 2.84-2.77 (m, 1H), 2.75-2.67 ( m, 1H), 2.33-2.24 (m, 1H), 2.16-2.04 (m, 1H), LC-MS (Method T): m/z = 397.2 [M+H ]+, 1,155 min.

[001467] Example 109B (second elution isomer): 1HNMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 4.4 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m, 3H), 7.31-7.26 (m, 2H), 5.33 (s, 2H), 4.51 -4.42 (m, 1H), 3.78 (s, 3H), 3.18 (s, 3H), 2.87-2.63 (m, 2H), 2.35-2.21 (m , 1H), 2.18-2.03 (m, 1H), LC-MS (Method T): m/z = 397.2 [M+H]+, 1.154 min. Example 110A and 110B: 5-benzyl-N-((1aR, 2R, 8bS)-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b] azepina-2-yl)-4H-1,2,4-triazol-3-carboxamide and 5-benzyl-N-((1aS,2S,8bR)-3-oxo- 1,1a,2,3,4, 8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H- 1,2,4-triazol-3-carboxamide Schematic legend: Rt - taStep 1: Preparation of 5-benzyl-N-(cis-3-oxo-1,1a, 2,3,4,8b-hexa-hydrocyclopropa[d]pyrido[2,3-b] azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide

[001468] The crude product obtained using the Amide Bond Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 1/3) to provide the title compound (20 mg, 26.7% ) as a yellow solid. LC-MS (Method I): mz = 375.2 [M + H]+, 1.007 min. Step 2: Preparation of 5-benzyl-N-((1aR,2R,8bS)-3-oxo-1,1a, 2,3,4,8b- hexahydrocycloprop-pa[d]pyrido[2,3- b]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide (example 110A) and 5-benzyl-N-((1aS,2S,8bR)-3-oxo- 1, 1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide (example 110B)

[001469] 5-Benzyl-N-(cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b] azepin-2-yl racemate )-4H-1,2,4-triazol-3-carboxamide (20 mg, 0.053 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 20 min; UV 254 and 220 nm; Ta1: 12.8 min; Ta2: 16.08 min to give the title compounds:

[001470] Example 110A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.24 (dd, J = 4.8, 1.6 Hz, 1H), 7.91 (dd, J = 7.6, 1.6 Hz, 1H), 7.38-7.16 (m, 6H), 4.84 (s, 1H), 4.17 (s, 2H), 2.25-2, 21 (m, 1H), 2.15-2.09 (m, 1H), 1.62-1.57 (m, 1H), 1.16-1.12 (m, 1H), LC-MS ( Method J): m/z = 375.2 [M+H]+, 1.007 min.

[001471] Example 110B (second elution isomer): 1H NMR (300 MHz, CD3OD-d4) δ 8.23 (dd, J = 4.8, 1.8 Hz, 1H), 7.90 (dd, J = 7.5, 1.8 Hz, 1H), 7.39-7.13 (m, 6H), 4.84 (s, 1H), 4.18 (s, 2H), 2.19-2, 09 (m, 2H), 1.64-1.55 (m, 1H), 1.17-1.10 (m, 1H), LC-MS (Method F): m/z = 374.9 [M +H]+, 0.919 min. Example 111A and 111B: (R)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b] azepina-7-yl)-1H-pyrazol-3-carboxamide and (S)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro- 5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide Step 1 Preparation of 1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl )-1H-pyrazole-3-carboxamide

[001472] N,N-diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixture of 1-benzyl-4-fluoro-1H-pyrazol-3-carboxylic acid (104.6 mg, 0 .52 mmol), 7-amino-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (100 mg, 0.52 mmol), N hydrochloride -(3-dimethylaminopropyl))-N'-ethylcarbodiimide (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) in N,N-dimethylformamide (3 mL) . The reaction mixture was stirred overnight at room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC under the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow Rate: 20 mL/min; Gradient: 35% B to 55% B over 7 min; UV 254 and 220 nm; RT: 5.6 min to provide the title compound (32 mg, 25.4%) as a white solid. LC-MS (Method D): mz = 394.2 [M + H]+, 1.571 min. Step 2: Preparation of (R)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b] azepina-7-yl)-1H-pyrazol-3-carboxamide (example 111A) and (S)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9- tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide (example 111B)

[001473] 1-Benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7 racemate -yl)-1H-pyrazole-3-carboxamide (32 mg, 0.081 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 15 min; UV 254 and 220 nm; Ta1: 11.47 min; Ta2: 13.24 min to give the title compounds:

[001474] Example 111A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7 .80-7.77 (m, 1H), 7.39-7.24 (m, 6H), 5.31 (s, 2H), 4.32-4.23 (m, 1H), 3.33 (s, 3H), 2.78-2.60 (m, 2H), 2.38-2.25 (m, 2H), LC-MS (Method D): m/z = 394.2 [M+ H]+, 1.571 min.

[001475] Example 111B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7 .80-7.77 (m, 1H), 7.39-7.24 (m, 6H), 5.31 (s, 2H), 4.32-4.23 (m, 1H), 3.32 (s, 3H), 2.72-2.66 (m, 2H), 2.39-2.26 (m, 2H), LC-MS (Method D): m/z = 394.2 [M+ H]+, 1.570 min. Example 112: 5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b ][1,4]oxazepine-3-yl)isoxazole-3-carboxamide

[001476] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 7 min; UV 254 and 220 nm; RT: 7 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 8.27 (d, J = 7.0 Hz, 1H), 7.73 (dd, J = 7.9, 1.5 Hz, 1H), 7,397.23 (m, 6H), 6.61 (s, 1H), 4.99-4.87 (m, 2H), 4, 22 (s, 2H), 3.39 (s, 3H), 1.36 (d, J = 6.2 Hz, 3H), LC-MS (Method X): m/z = 393.2 [M+ H]+, 3.187 min.Example 113: (S)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,4-b][1,4] oxazepin-3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide

[001477] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 40% B over 7 min; 254 and 220 nm; RT: 6 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1H), 8.91-8.36 (m, 3H), 7.53 (d, J = 5.3 Hz, 1H), 7 .33 (m, 5H), 4.94-4.82 (m, 1H), 4.82-4.70 (m, 1H), 4.51 (dd, J = 9.6, 7.2 Hz , 1H), 3.32 (s, 3H), 1.59-1.20 (m, 4H), LC-MS (Method O): m/z = 405.0 [M+H]+, 1.127 min .Example 114A and 114B: (S)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazole [4,3-b] azepin -6-yl)-4-fluoro-1H-pyrazol-3-carboxamide and (R)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8 -hexa-hydropyrazol[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazol-3-carboxamide Schematic legend: Rt - taStep 1: Preparation of 1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b] azepin-6-yl)-4-fluoro-1H-pyrazol-3-carboxamide

[001478] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV of 254 and 220 nm; RT: 6 min to give the title compound (50 mg, 48.6%) as a white solid. LC-MS (Method C): mz = 397.2 [M + H]+, 1.512 min. Step 2: Preparation of (S)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin- 6-yl)-4-fluoro-1H-pyrazol-3-carboxamide (example 114A) and (R)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6, 7,8-hexahydropyrazol[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazol-3-carboxamide (example 114B).

[001479] 1-Benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl racemate )-4-fluoro-1H-pyrazole-3-carboxamide (50 mg, 0.13 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART cellulose, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 18 min; UV 254 and 220 nm; Ta1: 12.54 min; Ta2: 15.41 min to give the title compounds:

[001480] Example 114A (first elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.50 (s, 1H), 7.41-7.27 (m, 5H), 5.34 (s, 2H), 4.43-4.37 (m, 1H), 3 .74 (s, 3H), 3.24 (s, 3H), 3.06-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-2.23 (m, 1H), 2.10-1.99 (m, 1H), LC-MS (Method D): m/z = 397.1 [M+H]+, 1,500 min.

[001481] Example 114B (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.41-7.26 (m, 5H), 5.34 (s, 2H), 4.43-4.37 (m, 1H), 3 .74 (s, 3H), 3.24 (s, 3H), 3.06-2.96 (m, 1H), 2.91-2.83 (m, 1H), 2.30-2.22 (m, 1H), 2.10-1.99 (m, 1H), LC-MS (Method D): m/z = 397.1 [M+H]+, 1.514 min. Example 115: (S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Step 1: Preparation of 4-fluoro-1-(4-fluorobenzyl)-1H-pyrazol-3-carboxylic acid

[001482] Sodium hydride (60%, 152 mg, 3.8 mmol) was added to a solution of methyl 4-fluoro-1H-pyrazol-3-carboxylate (200 mg, 1.27 mmol) in N,N- dimethylformamide (10 mL) at 0oC. The resulting mixture was stirred at room temperature for 0.5 hour followed by addition of 1-(bromomethyl)-4-fluorobenzene (264 mg, 1.40 mmol). The reaction mixture was stirred at room temperature for another 1.5 hours and quenched by the addition of water (20 mL). The resulting solution was then stirred at room temperature for 5 hours. The pH value of the solution was adjusted to 7 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 9 min; UV 254 and 220 nm; RT: 7 min to provide title compound (100 mg, 33.2%). LC-MS (Methods): m/z = 239.2[M + H]+1.093 min. Step 2: Preparation of (S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001483] The crude product obtained using Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150mm 5μm; Mobile Phase A: water (10mmol/ L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV254 and 220nm; RT: 6.32 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.35 (m, 1H), 8.27 (d, J = 8 Hz, 1H), 8.14 (d, J = 4.4 Hz , 1H), 7.71-7.69 (m, 1H), 7.36-7.32 (m, 3H), 7.257.20 (m, 2H), 5.33 (s, 2H), 4, 87-4.81 (m, 1H), 4.70-4.65 (m, 1H), 4,524.48 (m, 1H), 3.35 (s, 3H), LC-MS (Method X): m/z = 414.2 [M+H]+, 2.606 min. Example 116: (S)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-(2-fluorophenoxy)pyridazine-3- carboxamide Schematic legend: Rt - taStep 1: Preparation of 3-chloro-5-(2-fluorophenoxy) pyridazine

[001484] 2-Fluorophenol (2 g, 17.8 mmol) was added dropwise to a stirring mixture of 3,5-dichloropyridazine (3.17 g, 21.4 mmol) and cesium carbonate (8.7 g, 26.9 mmol) in acetonitrile (40 mL). The reaction mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether) to provide the title compound (2.8g, 70%) as a white solid. LC-MS (Method X): m/z = 225.1 [M + H]+, 0.919 min. Step 2: Preparation of ethyl 5-(2-fluorophenoxy)pyridazine-3-carboxylate

[001485] 1,1'-Bis(diphenylphosphine)ferrocene-palladium (II) dichloride dichloromethane (0.95 g, 1.16 mmol) was added to a mixture of 3-chloro-5-(2-fluorophenoxy) pyridazine (2.6 g, 11.6 mmol) and sodium acetate (1.9 g, 23.2 mmol) in ethanol (125 mL) and N,N-dimethylformamide (25 mL). The reaction mixture was stirred overnight at 90°C under a carbon monoxide atmosphere (1 MPa). After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (2.4 g, 79%) as a colorless oil. LC-MS (Method X): m/z = 263.1 [M + H]+, 0.905 min. Step 3: Preparation of 5-(2-fluorophenoxy)pyridazine-3-carboxylic acid

[001486] Lithium hydroxide (48 mg, 2 mmol) was added to a stirred solution of ethyl 5-(2-fluorophenoxy) pyridazine-3-carboxylate (131 mg, 0.5 mmol) in tetrahydrofuran (8 mL ) and water (2 mL). The reaction mixture was stirred for 1 hour at room temperature. After removing the tetrahydrofuran under reduced pressure, the residue was diluted with water (20 mL). The pH of the resulting solution was adjusted to 4 with aqueous hydrochloric acid (2N, 5 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (100 mg crude) as a white solid. LC-MS (R Method): m/z = 235.2 [M + H]+, 0.507 min. Step 4: Preparation of (S)-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2- a]azepin-4-yl)-5-(2-fluorophenoxy)pyridazine- 3-carboxamide

[001487] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 45% B to 50% B over 5 min; UV 254 and 220 nm to produce the title compound. 1H NMR (400 MHz, Methanol-d4) δ 9.25 (d, J = 2.8 Hz, 1H), 7.51-7.32 (m, 10H), 7.08 (d, J = 1, 2Hz, 1H), 5.11-5.06 (m, 1H), 2.88-2.81 (m, 1H), 2.80-2.71 (m, 1H), 2.66-2 .57 (m, 1H), 2.51-2.42 (m, 1H), LC-MS (Method D): m/z = 416.1 [M+H]+, 1.337 min. Example 117: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl )-4-(2-fluorophenoxy)picolinamide

[001488] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: OBD Shield XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 85% B over 7 min; UV 254 and 220 nm; RT: 6.35 min to provide the title compound. 1HNMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 6.8 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.54-7.39 (m, 3H), 7.38-7 .33 (m, 3H), 7.27-7.29 (m, 1H), 5.02-4.95 (m, 1H), 4.94-4.89 (m, 1H), 3.41 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H), LC-MS (Q Method): m/z = 423.0 [M+H]+, 2.885 min. Example 118A and 118B: (R)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6- il)4H-1,2,4-triazol-3-carboxamide and (S)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazole [4,3- b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepine -6-yl)-4H-1,2,4-triazol-3-carboxamide

[001489] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column 19 x 150 mm 5 μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 35% B over 10 min; UV 254 and 220 nm; RT: 9 min to provide the title compound (50 mg, 38.1%) as a white solid. LC-MS (Method C): m/z = 366.2 [M + H]+, 1.174 min. Step 2: (R)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3- b]azepin-6-yl) 4H-1,2,4-triazol-3-carboxamide (example 118A) and (S)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexa -hydropyrazol[4,3-b]azepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (example 118B)

[001490] 5-Benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazol[4,3-b]azepin-6-yl)- racemate 4H-1,2,4-triazol-3-carboxamide (50 mg, 0.14 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: i-PrOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 12 min; 254/220nm; Ta1: 8.84 min; Ta2: 10.81 min to give the title compounds:

[001491] Example 118A (first elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7, 41-7.29 (m, 5H), 7.17 (s, 1H), 4.41-4.37 (m, 1H), 4.18 (s, 2H), 3.76 (s, 3H) , 3.05-3.00 (m, 2H), 2.34-2.30 (m, 1H), 2.10-2.05 (m, 1H), LC-MS (Method D): m/ z = 366.1 [M+H]+, 1.180 min.

[001492] Example 118B (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7, 35-7.10 (m, 5H), 7.10 (s, 1H), 4.35-4.30 (m, 1H), 4.12 (s, 2H), 3.69 (s, 3H) , 3.00-2.92 (m, 2H), 2.27-2.23 (m, 1H), 2.04-1.98 (m, 1H), LC-MS (Method D): m/ z = 366.1 [M+H]+, 1.177 min. Example 119A and 119B: 5-benzyl-N-((7R, 7aR, 8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[ 2,3-b]azepin-7-yl)- 4H-1,2,4-triazol-3-carboxamide and 5-benzyl-N-((7S, 7aS, 8aR)-5-methyl- 6-oxo- 5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazol-3-carboxamide Scheme legend: Grubbs catalyst; 2nd generation; Rt–ta Step 1: Preparation of 3-vinylpyrazine-2-amine

[001493] To a solution of 3-bromopyrazine-2-amine (10 g, 57 mmol) in N, N-dimethylformamide (50 mL) was added tributyl (ethenyl) stannan (20 g, 63 mmol) and tetrakis (triphenylphosphine ) palladium (2.7 g, 2.3 mmol) under a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80°C, quenched by addition of water (200 ml) and extracted with dichloromethane (3 x 200 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 3/97) to provide the title compound (6.0 g, 86%) as a yellow solid. LC-MS (Method C): m/z = 122.1 [M + H]+, 0.658 min. Step 2: Preparation of N-(3-vinylpyrazin-2-yl)but-3-enamide

[001494] Thionyl chloride (9.3 g, 46.5 mmol) was added to a solution of but-3-enoic acid (4.0 g, 46.5 mmol) in dichloromethane (20 mL) dropwise . After stirring for 1 hour at room temperature, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 3-vinylpyrazine-2-amine (4.7 g, 38.7 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 2 hours at room temperature, quenched by addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/1) to provide the title compound (5.7 g, 78%) as a yellow oil. LC-MS (Method C): m/z = 190.1 [M + H]+, 0.881 min. Step 3: Preparation of (Z)-5H-pyrazino[2,3-b]azepine-6(7H)-one

[001495] [1,3-bis (2,4,6-trimethylphenyl) imidazolidin-2-ylidene] dichloro (phenylmethylidene) ruthenium tricyclohexylphosphine (340 mg, 0.4 mmol) was added to a solution of N- (3-vinylpyrazin-2-yl)but-3-enamide (380 mg, 2 mmol) in toluene (50 mL). The resulting solution was stirred for 16 hours at 80°C and then concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 5/1) to provide the title compound (210 mg, 65%) as a yellow oil. LC-MS (Method C): m/z = 162.1 [M + H]+, 0.762 min. Step 4: Preparation of (Z)-5-methyl-5H-pyrazino[2,3-b]azepine-6(7H)-one

[001496] Iodomethane (180 mg, 1.3 mmol) was added dropwise to a stirring solution of (Z)-5H-pyrazino [2,3-b]azepin-6(7H)-one (210 mg, 1.3 mmol) and cesium carbonate (1.3 g, 3.9 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred for 4 hours at room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 4/1) to provide the title compound (200 mg, 88%) as a yellow solid. LC-MS (Method E): m/z = 176.1 [M + H]+, 0.776 min. Step 5: Preparation of 5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

[001497] To a solution of potassium hydroxide (4 g, 71.4 mmol) in water (6 mL) was added a solution of 1-methyl-1-nitrosourea (2.1 g, 20 mmol) in ether (30 mL) dropwise at 0oC under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to provide a diazomethane solution (30 ml). To a solution of (Z)-5-methyl-5H-pyrazino[2,3-b]azepine-6(7H)-one (200 mg, 1.1 mmol) in tetrahydrofuran (10 mL) was added diazomethane solution (30 mL) dropwise, followed by the addition of a mixture of palladium diacetate (25 mg, 0.11 mmol) in tetrahydrofuran (5 mL) dropwise at 0oC. The resulting mixture was stirred at room temperature overnight. The solids were removed by filtration and the filtrates were concentrated in vacuo to provide the title compound (110 mg crude) as a yellow oil. LC-MS (Method E): m/z = 190.1 [M + H]+, 0.825 min. Step 6: Preparation of trans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

[001498] A mixture of 5-methyl-7,7a, 8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepin-6(5H)-one (110 mg, 0.6 mmol) in dichloromethane (20 mL) N,N,N',N'-tetramethylethylene-diamine (210 mg, 1.8 mmol) was added, followed by the addition of iodotrimethylsilane (360 mg, 1.8 mmol) at 0oC. After stirring for 2 hours at 0°C, iodine (230 mg, 0.9 mmol) was added. The reaction mixture was stirred for 1 hour at 0°C, quenched with aqueous sodium thiosulfate (5%, 40 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (132 mg crude) as a yellow oil. LC-MS (Method E): m/z = 316.1 [M + H]+, 0.840 min. Step 7: Preparation of cis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

[001499] Sodium azide (39 mg, 0.6 mmol) was added to a mixture of trans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3 - b]azepine-6(5H)-one (132 mg, 0.4 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred for 16 hours at room temperature, quenched by the addition of water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (60 mg crude) as a yellow oil. LC-MS (Method C): m/z = 231.1 [M + H]+, 1.036 min. Step 8: Preparation of cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

[001500] Triphenylphosphine (102 mg, 0.39 mmol) was added to a mixture of cis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b ]azepin-6(5H)-one (60 mg, 0.26 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred for 16 hours at room temperature, diluted with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/19) to give the title compound (40 mg, 75%) as a yellow oil. LC-MS (Method E): m/z = 205.1 [M + H]+, 0.406 min. Step 9: Preparation of 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7 -yl)-4H-1,2,4-triazol-3-carboxamide

[001501] N,N-diisopropylethylamine (93 mg, 0.72 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (51 mg, 0.24 mmol), cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one(40 mg, 0.20 mmol), N-(3-dimethylamino-propyl))-N'-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in N,N-dimethylformamide ( 4 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 and 220 nm to provide the title compound (20 mg, 26%) as a white solid. LC-MS (Method D): m/z = 390.2 [M + H]+.1.386 min. Step 10: Preparation of 5-benzyl-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[ 2,3-b]azepin-7-yl)-4H- 1,2,4-triazol-3-carboxamide (example 119A) and 5-benzyl-N- ((7S,7aS,8aR)-5-methyl- 6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]-pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazol-3- carboxamide (example 119B)

[001502] 5-Benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin- racemate 7-yl)-4H-1,2,4-triazol-3-carboxamide (20 mg, 0.05 mmol) was separated by Prep-Chiral HPLC with the following conditions: Column: Chiralpak IA, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 55% B to 55% B over 27 min; 220/254nm; Ta1: 13.94 min; Ta2: 21.44 min to provide the title compounds:

[001503] Example 119A (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.44-8.40 (m, 2H), 7.36-7.21 (m, 5H), 4 .81 (s, 1H), 4.18 (s, 2H), 3.42 (s, 3H), 2.66-2.58 (m, 1H), 2.29-2.18 (m, 1H ), 1.57- 1.48 (m, 1H), 1.36-1.25 (m, 1H), LC-MS (Method D): m/z = 390.1 [M+H]+, 1,389 min.

[001504] Example 119B (second elution isomer): 1HNMR (400 MHz, Methanol-d4) δ 8.46-8.38 (m, 2H), 7.39-7.21 (m, 5H), 4, 81 (s, 1H), 4.18 (s, 2H), 3.42 (s, 3H), 2.66-2.58 (m, 1H), 2.30-2.22 (m, 1H) , 1,571.50 (m, 1H), 1.35-1.26 (m, 1H), LC-MS (Method D): m/z = 390.2 [M+H]+, 1.384 min. Example 120A and 120B: 5-benzyl-N-((1aS, 2S, 8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2, 3-b]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo- 1,1a, 2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide Step 1: Preparation of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b- hexahydrocyclopropa[d]pyrido[2,3-b]azepin- 2-yl)-1,3,4-thiadiazol-2-carboxamide

[001505] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV of 254 and 220 nm; RT: 6.32 to give the title compound (20 mg, 32.9%) as a white solid. LC-MS (Method I): m/z = 406.2 [M + H]+, 1.001 min.Step 2: Preparation of 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3 -oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide (example 120A ) and 5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3- b]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide (example 120B)

[001506] The racemate of 5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa-[d]-pyrido[2,3-b ]azepin-2-yl)-1,3,4-thiadiazol-2-carboxamide (20 mg, 0.049 mmol) was separated by Prechiral separation with the following conditions: Column: Lux Cellulose-4, 0.46 x 5 cm, 3μm; Mobile phase A: hexane; Mobile phase B: EtOH; Flow rate: 1.0 mL/min; Gradient: 50% B to 50% B over 8 min; UV 254 and 220 nm; Ta1: 4.09 min; Ta2: 6.43 min to give the title compounds:

[001507] Example 120A (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.38 (dd, J = 4.8, 2.0 Hz, 1H), 7.94 (dd, J = 7.6, 2.0 Hz, 1H), 7.41-7.26 (m, 6H), 4.64 (s, 1H), 4.53 (s, 2H), 3.41 (s, 3H), 2,332.25 (m, 1H), 2.15-2.06 (m, 1H), 1.34-1.28 (m, 1H), 1.21-1.12 (m, 1H) . LC-MS (Method D): m/z = 406.1 [M+H]+, 1.703 min.

[001508] Example 120B (second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.36 (dd, J = 4.8, 2.0 Hz, 1H), 7.91 (dd, J = 7.6, 2.0 Hz, 1H), 7.38-7.24 (m, 6H), 4.62 (s, 1H), 4.50 (s, 2H), 3.38 (s, 3H), 2.29- 2.24 (m, 1H), 2.12-2.06 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.14 ( m, 1H). LC-MS (Method V): m/z = 406.1 [M+H]+, 2.915 min. Example 121A and 121B: (R)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepin-7-yl)picolinamide and (S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b]azepin-7-yl) picolinamide Schematic legend: Rt – ta Step 1: Preparation of methyl 4-(2,4-difluorophenoxy)picolinate

[001509] To a sealed tube were added ethyl m4-chloropicolinate (1 g, 5.85 mmol), 2,4-difluorophenol (1.14 g, 8.77 mmol), cesium carbonate (5.7 g, 17.5 mmol), copper powder (0.38 g, 5.94 mmol) and N,N-dimethylformamide (10 mL). The resulting mixture was heated to 100°C by microwave irradiation and stirring for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (0.5 g crude) as a white solid. LC-MS (Method I): m/z = 265.9 [M + H]+, 0.926 min. Step 2: Preparation of 4-(2,4-difluorophenoxy)picolinic acid

[001510] Lithium hydroxide (260 mg, 10.8 mmol) was added to a stirred mixture of methyl 4-phenoxypicolinate (500 mg, 1.89 mmol) in tetrahydrofuran (10 mL) and water (5 mL) . The resulting solution was stirred overnight at room temperature. After removing the tetrahydrofuran under reduced pressure, the pH of the aqueous solution was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to provide the title compound (200 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method X): m/z = 252.2[M + H]+, 0.639 min. Step 3: Preparation of 4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin- 7-yl)picolinamide

[001511] The crude product obtained using Amide C Coupling Procedure was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19 x 150mm5μm; Mobile Phase A: water (10mmol/ L NH4HCO3), Phase Mobile B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 70% B over 7 min; 254 and 220 nm; RT: 5.590 minutes to provide the title compound (80 mg, 40.1%) as a white solid. LC-MS (Method R): m/z = 425.3[M + H]+, 1.442 min. Step 4: Preparation of (R)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepin-7-yl)picolinamide (example 121A) and (S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro - 5H-pyrido[2,3-b]azepin-7-yl)picolinamide (example 121B)

[001512] 4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepin racemate -7-yl) picolinamide (80mg, 0.19 mmol) was separated by Prep-Chiral HPLC with the following conditions: Column: Chiralpak ID-2, 2 x 25cm, 5μm; Mobile Phase A: hexane, Mobile Phase B: EtOH ; Flow rate: 15 mL/min; Gradient: 55% B to 55% B over 23 min; UV220e254nm; Ta1:14.83 min; Ta2:18.87 min to give the title compounds:

[001513] Example 121A (first elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.448.43 (m, 1H), 7.84-7.81 (m, 1H), 7.65-7.48 (m, 2H), 7.36-7.22 (m, 4H), 4.36-4.29 (m, 1H), 3.36 (s, 3H), 2.81-2.70 (m, 2H), 2.50-2.44 (m, 1H) , 2.35-2.21 (m, 1H), LC-MS (Method T): m/z = 425.25 [M+H]+, 1.432 min.

[001514] Example 121B (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 7.6 Hz, 1H), 8.60 (d, J = 5.6 Hz , 1H), 8.44-8.43 (m, 1H), 7.84-7.81 (m, 1H), 7.61-7.50 (m, 2H), 7.34-7.24 (m, 4H), 4.34-4.31 (m, 1H), 3.36 (s, 3H), 2.77-2.73 (m, 2H), 2.51-2.50 (m , 1H), 2.31-2.21 (m, 1H), LC-MS (Method X): m/z = 425.25 [M+H]+, 1.437 min. Example 122: 3-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)isoxazol-5-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (E)-2-phenylacetaldehyde oxime

[001515] Sodium hydroxide (1.2 g, 30.0 mmol) was added to a mixture of 2-phenylacetaldehyde (1.2 g, 10.0 mmol) and hydroxylamine hydrochloride (1.4 g, 20.3 mmol) in ethanol (40 mL) and water (20 mL). The resulting mixture was stirred at room temperature for 5 hours, diluted with water (50 ml) and extracted with dichloromethane (3 x 80 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to provide the title compound (400 mg, 29.6%) as a white solid. LC-MS (Method E): m/z = 136.0 [M + H]+, 0.371 min. Step 2: Preparation of ethyl 3-benzylisoxazole-5-carboxylate

[001516] Ethyl propiolate (2.7 g, 27.5 mmol) was added to a mixture of (E)-2-phenylacetaldehyde oxime (400 mg, 2.9 mmol) and chromium oxide (2.5 g, 29.7 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 80oC for 5 hours. Solids were removed by filtration and the filtrate was evaporated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to provide the title compound (200 mg, 40%) as a yellow solid. LC-MS (Method C): m/z = 232.0 [M + H]+, 1,200 min. Step 3: Preparation of 3-benzyl-N-((2R, 3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepine-3-yl)isoxazole-5-carboxamide

[001517] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep, 100 A, 19 mm x 250 mm 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 55% B over 7 min; UV254 and 220 nm; RT: 7 min to provide the title compound. 1HNMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 7.6 Hz, 1H), 8.34-8.33 (m, 1H), 7.71-7.69 (m, 1H ), 7.36-7.24 (m, 6H), 7.18 (s, 1H), 5.03-4.99 (m, 1H), 4.84-4.78 (m, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H), LC-MS (Method D): m/z = 393.1 [ M+H]+, 1.787 min.Example 123: (S)-5-benzyl-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3-yl)thiazol-2-carboxamide

[001518] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep, 100 A, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 40% B over 7 min; 254 and 220 nm; RT: 7 min to give the title compound, 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.92 (d, J = 7.9 Hz, 1H), 8.15 (dd, J = 4.7, 1.5 Hz, 1H), 7.88 (s, 1H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.41- 7.12 (m, 6H), 4.88-4.74 (m, 1H), 4.62-4.41 (m, 2H), 4.28 (s, 2H), LC-MS (Method O ): m/z = 381.0 [M+H]+, 1.290 min.Example 124: 5-benzyl-N-((2R, 3S)-2,5-dimethyl-4-oxo-2,3,4 ,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)thiazol-2-carboxamide

[001519] The crude product obtained using the Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 19 x 150 mm, 5 μm; Mobile Phase A: water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV at 254 and 220 nm to provide the title compound (18.8 mg, 9%) as a semisolid. 1H NMR (400 MHz, Methanol-d4) δ 8,368.30 (m, 1H), 7.76-7.65 (m, 2H), 7.37-7.22 (m, 6H), 5.04- 4.96 (m, 2H), 4.26 (s, 2H), 3.50 (s, 3H), 1.42 (d, J= 6.0 Hz, 3H). LC-MS (Method D): m/z = 409.2 [M + H]+, 1.638 min. Example 125A and 125B: (R)-5-benzyl-N-(9'-methyl-8'-oxo -6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2, 3-b]zepin]-7'-yl)-4H-1,2,4-triazole -3-carboxamide (125A) and (S)-5-benzyl-N-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5 '-pyrido[2,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (125B) Step 1: Preparation of Dimethyl 2-(2-nitropyridin-3-yl)malonate

[001520] Dimethyl malonate (14 g, 105.6 mmol) was added dropwise to a stirred mixture of 3-fluoro-2-nitropyridine (10 g, 70.4 mmol) and potassium carbonate (19 .5 g, 140.8 mmol) in N,N-dimethylformamide (25 mL) at room temperature. The reaction mixture was stirred overnight at 70°C, quenched by addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (18 g, 89.8%) as a yellow oil. LC-MS (R Method): m/z = 255.1 [M + H]+, 0.762 min. Step 2: Preparation of Methyl 2-(2-nitropyridin-3-yl)acetate

[001521] A solution of lithium chloride (8 g, 189 mmol) in water (10 mL) was added to a mixture of dimethyl 2-(2-nitropyridin-3-yl)malonate (16 g, 63 mmol) in dimethylsulfoxide (50 mL). The reaction mixture was stirred at 100°C overnight quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (12 g crude) as a brown oil. LC-MS (R Method): m/z = 197.1 [M + H]+, 0.673 min. Step 3: Preparation of methyl 1-(2-nitropyridin-3-yl)cyclopropanecarboxylate

[001522] 1,2-Dibromoethane (17 g, 91.8 mmol) was added dropwise to a stirred mixture of 3-fluoro-2-nitropyridine (12 g, 61.2 mmol) and potassium carbonate (25.3 g, 183.6 mmol) in N,N-dimethylformamide (25 mL) at room temperature. The reaction mixture was stirred overnight at 70°C, quenched by addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to give the title compound (5 g, 36.8%) as a red oil. LC-MS (R Method): m/z = 223.1 [M + H]+, 0.802 min. Step 4: Preparation of (1-(2-nitropyridin-3-yl)cyclopropyl)methanol

[001523] A solution of diisobutylaluminum hydride in toluene (1 M, 45 mL, 45 mmol) was added dropwise to a stirred solution of 1 (2-nitropyridin-3-yl) methyl cyclopropanecarboxylate (5 g, 22.5 mmol) in toluene (50 mL) at -78°C. The reaction mixture was stirred at -78°C for 2 hours, quenched by addition of water (2 ml) and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (3 g, 68.6%) as a yellow solid. LC-MS (Method C): m/z = 195.1 [M + H]+, 0.975 min. Step 5: Preparation of 1-(2-nitropyridin-3-yl)cyclopropanecarbaldehyde

[001524] Dess-Martin Periodinane (13 g, 30.9 mmol) was added to a stirring solution of (1-(2-nitropyridin-3-yl) cyclopropyl) methanol (3 g, 15.5 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 0oC for 2 hours, quenched by adding water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (2.5 g, 84.2%) as a yellow oil. LC-MS (Method C): m/z = 193.0 [M + H]+, 1.002 min. Step 6: Preparation of 2-(tert-butoxycarbonylamino)-3-(1-(2-nitropyridin-3-yl)cyclopropyl) (Z)-methyl acrylate

[001525] 1,8-Diazabicyclo [5.4.0] undec-7-ene (4 g, 26 mmol) was added to a stirring solution of 2-{[(tert-butoxy)carbonyl]amino}-2-( dimethoxyphosphoryl) methyl acetate (7.7 g, 26 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 70oC for 1 hour followed by the addition of a solution of 1-(2-nitropyridin-3-yl) cyclopropanecarbaldehyde (2.5 g, 13 mmol) in tetrahydrofuran (50 mL). Then the reaction mixture was stirred overnight at 70oC, quenched by adding water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (3 g, 63.5%) as a yellow solid. LC-MS (Method E): m/z = 364.0 [M + H]+, 0.860 min. Step 7: Preparation of Methyl 3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonyl-amino)propanoate

[001526] (Z)-methyl-2-(tert-butoxycarbonylamino)-3-(1-(2-nitropyridin-3-yl) cyclopropyl) acrylate (3 g, 8.26 mmol) in methanol (50 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.3 g) under a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred at room temperature under a hydrogen atmosphere. The solids were removed by filtration and the filtrate was concentrated under high vacuum to provide the title compound (2.5 g crude) as a white solid. LC-MS (Method C): m/z = 336.1 [M + H]+, 0.926 min. Step 8: Preparation of 3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoic acid

[001527] Lithium hydroxide (358 mg, 14.9 mmol) was added to a solution of methyl 3-(1-(2-aminopyridin-3-yl) cyclopropyl)-2-(tert-butoxycarbonylamino) propanoate (2 .5 g, 7.46 mmol) in tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was diluted with water (20 mL) and adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (1 g crude) as a white solid. LC-MS (R Method): m/z = 322.1 [M + H]+, 0.580 min. Step 9: Preparation of (8'-oxo-6',7',8',9'-tetrahydro-spiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'- il) tert-butyl carbamate

[001528] N,N-diisopropylethylamine (1.2 g, 9.34 mmol) was added to a mixture of 3-(1-(2-aminopyridin-3-yl) cyclopropyl)-2-(tert - propanoic butoxycarbonylamino) (1 g, 3.11 mmol) 2-(7-aza-1H-benzotriazol-1-yl)-1, 1, 3,3-tetramethyluronium hexafluorophosphate (1.59 g, 3.73 mmol ) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred for 2 hours at room temperature, quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (500 mg, 53%) as a yellow solid. LC-MS (R Method): m/z = 304.0 [M + H]+, 0.842 min. Step 10: Preparation of (9'-methyl-8'-oxo-6',7',8',9'-tetrahydro-spiro[cyclopropane-1,5'-pyrido[2,3-b]azepine tert-butyl]-7'-yl)carbamate

[001529] Iodomethane (52 mg, 0.36 mmol) was added dropwise to a stirred solution of (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1.5 '-pyrido[2,3-b]azepin]-7'-yl) tert-butyl carbamate (110 mg, 0.36 mmol) and cesium carbonate (119 mg, 0.36 mmol) in N, N- dimethylformamide (5 mL) at 0oC. The reaction mixture was stirred 2 hours at room temperature, quenched by addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (110 mg, 95.6%) as a white solid. LC-MS (Method C): m/z = 218.1 [M + H-100]+, 1.613 min. Step 11: Preparation of 7'-amino-9'-methyl-6',7'-dihydrospiro[cyclopropane-1,5'-pyrido[2,3-b]azepin]-8'(9' hydrochloride H)-one

[001530] A solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL, 40 mmol) was added to a solution of (9'-methyl-8'-oxo-6', 7', 8 ',9'-tetrahydrospiro [cyclopropane-1,5'-pyrido[2,3-b]azepin]-7'-yl) tert-butyl carbamate (110 mg, 0.34 mmol) in 1,4 -dioxane (4 mL). The reaction mixture was stirred for 2 hours at room temperature and concentrated under high vacuum to provide the title compound (80 mg crude) as a white solid. LC-MS (Method C): m/z = 218.1 [M + H]+, 0.777 min. Step 12: Preparation of 5-benzyl-N-(9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydro-spiro-[cyclopropane-1,5'-pyrido [ 2,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide

[001531] N,N-diisopropylethylamine (107 mg, 0.828 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (62 mg, 0.304 mmol), hydrochloride of 7'-amino-9'-methyl-6', 7'-dihydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepin] -8' (9'H) -one(60 mg, 0.276 mmol), N-(3-dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (69 mg, 0.359 mmol) and 1-hydroxybenzotriazole (49 mg, 0.359 mmol) in N,N-dimethylformamide (4 mL ). The reaction mixture was stirred overnight at room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3) Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 and 220 nm to provide the title compound. LC-MS (Method D): m/z = 403.1 [M + H]+.1.460 min. Step 13: Preparation of (R)-5-benzyl-N-(9'-methyl-8'-oxo-6',7',8',9'-tetrahydro-spiro-[cyclopropane-1,5 '-pyrido[2,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (first eluting isomer) and (S)-5-benzyl-N-( 9'- methyl-8'-oxo-6',7',8',9'-tetrahydrospiro[cyclopropane-1,5'-pyrido[2,3- b]azepin]-7'-yl)- 4H-1,2,4-triazol-3-carboxamide (second elution isomer)

[001532] 5-Benzyl-N- (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro-[cyclopropane-1,5'-pyrido) racemate [2 ,3-b]azepin]-7'-yl)-4H-1,2,4-triazol-3-carboxamide (60 mg, 0.149 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak ID -2.2 x 25 cm, 5 μm; Mobile Phase A: hexane/DCM (4.5/1), Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 and 220 nm; RT 1: 11.72 min; RT 2: 18.02 min to provide the title compounds:

[001533] Example 125A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.27 (s, 1H), 8.41 (dd, J = 4.8, 1.8 Hz, 2H ), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.34-7.18 (m, 6H), 4.42-4.33 (m, 1H), 4, 09 (s, 2H), 3.31 (s, 3H), 2.73-2.63 (m, 1H), 1.73-1.62 (m, 1H), 1.09-1.05 ( m, 1H), 0.70 (d, J = 5.4 Hz, 2H), 0.36 (d, J = 10.0 Hz, 1H), LC-MS (Method D): m/z = 403 .1 [M+H]+, 1.661 min.

[001534] Example 125B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.27 (s, 1H), 8.41 (dd, J = 4.8, 1.8 Hz, 2H ), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.35-7.18 (m, 6H), 4.40-4.33 (m, 1H), 4, 09 (s, 2H), 3.30 (s, 3H), 2.69 (t, J = 10.6 Hz, 1H), 1.68 (t, J = 12.3 Hz, 1H), 1, 07 (d, J = 10.0 Hz, 1H), 0.70 (d, J = 5.5 Hz, 2H), 0.36 (d, J = 9.9 Hz, 1H), LC-MS ( Method D): m/z = 403.1 [M+H]+, 1.673 min. Example 126: (S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)thiazol-2-carboxamide Schematic legend: Rt–ta Step 1: Preparation of methyl 4-fluoro-5-methylthiazol-2-carboxylate

[001535] 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) (7.0 g, 19.8 mmol) was added to a mixture of 4-fluoro-5-methylthiazole Methyl -2-carboxylate (1.6 g, 10.2 mmol) in acetonitrile (50 mL) under a nitrogen atmosphere. The reaction mixture was heated to reflux and stirred overnight, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (600 mg, 33.7%) as a white solid. LC-MS (Method C): m/z = 176.1 [M + H]+, 1,240 min. Step 2: Preparation of Methyl 5-(bromomethyl)-4-fluorothiazole-2-carboxylate

[001536] Benzoyl peroxide (10 mg, 0.04 mmol) was added to a mixture of N-bromosuccinimide (650 mg, 3.6 mmol) and methyl 4-fluoro-5-methylthiazol-2-carboxylate (600 mg, 3.4 mmol) in carbon tetrachloride (20 mL). The reaction mixture was stirred overnight at 75oC. Solids were removed by filtration. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 ml) and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to provide the title compound (600 mg, 68.9%) as a yellow solid. LC-MS (Method F): m/z = 254 [M + H]+, 1.490 min. Step 3: Preparation of methyl 5-benzyl-4-fluorothiazol-2-carboxylate

[001537] Tetrakis (triphenylphosphine) palladium (147 mg, 0.13 mmol) was added to a mixture of methyl 5-(bromomethyl)-4-fluorothiazol-2-carboxylate (582 mg, 2.3 mmol), phenylboronic acid (402 mg, 3.3 mmol) and sodium carbonate (1 g, 9.4 mmol) in toluene (20 mL) and ethanol (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 80°C overnight, quenched by addition of water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to provide the title compound (400 mg, 66.6%) as a yellow solid. LC-MS (Method C): m/z = 252.2 [M + H]+, 1.971 min. Step 4: (S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)thiazol-2-carboxamide

[001538] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep, 19 mm x 150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: 40% ACN to 70% B over 7 min; UV254 and 220 nm to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 7.6 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.39-7.21 (m, 6H), 4.88-4.71 (m, 2H), 4.51 (t, J = 5.6 Hz, 1H), 4.17 (s, 2H), 3.34 (s, 3H), LC-MS (Method V): m/z = 413.00 [M+H]+, 2.480 min. Example 127: 1-(4-Cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-4-fluoro-1H-pyrazol-3-carboxamide Scheme legend: Rt – ta Step 1: Preparation of 1-(4-cyanobenzyl)-4-fluoro-1H-pyrazol-3-carboxylic acid

[001539] Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirred mixture of ethyl 4-fluoro-1H-pyrazol-3-carboxylate (474 mg, 3 mmol) in N, N-dimethylformamide (20 mL). The resulting mixture was stirred for 2 hours at room temperature, followed by the addition of 4-(bromomethyl)benzonitrile (585 mg, 3 mmol). The resulting mixture was stirred for 2 hours at room temperature. After addition of water (20 mL), the reaction mixture was stirred overnight at room temperature, the pH was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: Column: XBridge C18 OBD Prep, 100 A, 5 μm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; UV 254 and 220 nm; RT: 7 min to provide the title compound (250 mg, 34%) as a white solid. LC-MS (Method C): m/z = 246.1 [M + H]+, 0.969 min. Step 2: Preparation of 1-(4-cyanobenzyl)-N-((2R, 3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazol-3-carboxamide

[001540] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 A, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 48% B over 12 min; UV 254 and 220 nm; RT: 7 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.88 -7.85 (m, 2H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 6.4 Hz, 1H), 7.44- 7.41 (m, 2H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 5.50 (s, 2H), 4.99-4.88 (m, 2H) , 3.39 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H), LC-MS (Method X): m/z = 435.2 [M+H]+, 1.355 min . Example 128: 1-(3-Cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-4-fluoro-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 1-(3-cyanobenzyl)-4-fluoro-1H-pyrazol-3-carboxylic acid

[001541] Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirred mixture of ethyl 4-fluoro-1H-pyrazol-3-carboxylate (474 mg, 3 mmol) in N,N-dimethylformamide (20 mL) at 0°C. The resulting mixture was stirred for 2 hours at room temperature, followed by the addition of 4-(bromomethyl)benzonitrile (585 mg, 3 mmol). The reaction mixture was stirred for another 2 hours at room temperature. After adding water (20 mL), the resulting mixture was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm, 5 μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 50% B over 7 min; UV 254 and 220 nm; RT: 6 min to provide the title compound (230 mg, 31%) as a white solid. LC-MS (Method C): m/z = 246.1 [M + H]+, 1.236 min. Step 2: Preparation of 1-(3-cyanobenzyl)-N-((2R, 3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazol-3-carboxamide

[001542] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 A, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 48% B over 12 min; UV 254 and 220 nm; RT: 7 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (d, J = 4.4 Hz, 1H), 7.86 -7.79 (m, 2H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.62-7.60 (m, 3H), 7.36 (dd, J = 8.0, 4.4 Hz, 1H), 5.45 (s, 2H), 4.99-4.88 (m, 2H), 3.40 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H), LC-MS (Method D): m/z = 435.1 [M+H]+, 1.659 min. Example 129A and 129B: (S)-5-Benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-4H-1,2 ,4-triazol-3-carboxamide and (R)-5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5- a][1,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of methyl 4-(3-methyl-5-nitro-1H-pyrazol-1-yl)butanoate

[001543] Sodium hydride (60%, 2.5 g, 63 mmol) was added to a mixture of 3-methyl-5-nitro-1H-pyrazole (8 g, 63 mmol) in tetrahydrofuran (80 mL) at 0°C. The resulting mixture was stirred for 0.5 hour at 0°C followed by the addition of methyl 4-bromobutanoate (11.2 g, 63 mmol). The reaction mixture was stirred for 1 hour at 0°C, quenched by addition of water (40 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to give the title compound (2.2 g, 15%) as a colorless oil. LC-MS (Method C): m/z = 228.1 [M + H]+.1.180 min. Step 2: Preparation of Methyl 4-(5-amino-3-methyl-1H-pyrazol-1-yl)butanoate

[001544] A mixture of methyl 4-(3-methyl-5-nitro-1H-pyrazol-1-yl) butanoate (2.2 g, 9.7 mmol) in methanol (50 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.2 g) under a hydrogen atmosphere (2-3 atm). After stirring for 2 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to give the title compound (1.8 g94%) as a yellow solid. LC-MS (Method C): m/z = 198.1 [M + H]+, 0.733 min. Step 3: Preparation of 2-methyl-7,8-dihydro-4H-pyrazol[1,5- a][1,3]diazepin-5(6H)-one

[001545] The crude product obtained using the procedure described in Example 54 was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (1.0 g, 66%) as a yellow solid. LC-MS (Method C): m/z = 166.1 [M + H]+, 0.755 min. Step 4: Preparation of 2,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5- a][1,3]diazepin-5(6H)-one

[001546] Iodomethane (0.74 g, 5.4 mmol) was added dropwise to a stirred mixture of 2-methyl-7,8-dihydro-4H-pyrazole [1,5-a] [1, 3] diazepin-5(6H)-one (0.90 g, 5.4 mmol) and cesium carbonate (5.28 g, 16.2 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred for 3 hours at room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to provide the title compound (0.72 g, 74%) as a yellow solid. LC-MS (Method C): m/z = 180.1 [M + H]+, 0.865 min. Step 5: Preparation of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a][1,3]diazepin-5(6H)-one

[001547] N1, N1, N2, N2-tetramethylethane-1,2-diamine (1.2 g, 12.0 mmol) was added to a stirred mixture of 2,4-dimethyl-7,8-dihydro- 4H-pyrazole[1,5-a][1,3]diazepin-5(6H)-one (720 mg, 4.0 mmol) in dichloromethane (10 mL) at 0°C followed by addition of iodotrimethylsilane (2, 4 g, 12.0 mmol) dropwise over 20 min. The reaction mixture was stirred for 1 hour at 0°C. After addition of iodine (2.0 g, 8.0 mol), the reaction mixture was stirred for an additional 1 hour at 0°C. The mixture was then quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL), stirred for a further 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to provide the title compound (500 mg41%) as a yellow solid. LC-MS (Method C): m/z = 306.0 [M + H]+, 1.033 min. Step 6: Preparation of 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a][1,3]diazepin-5(6H)-one

[001548] Sodium azide (137 mg, 2.10 mmol) was added to a mixture of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazole [1,5-a] [1 ,3] diazepin-5(6H)-one (500 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred for 2 hours at room temperature, quenched by the addition of water (40 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound (280 mg crude) as a yellow oil. LC-MS (Method S): m/z = 221.3 [M + H]+, 0.763 min. Step 7: Preparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a]1,3]iazepin-5(6H)-one

[001549] Triphenylphosphine (734 mg, 2.80 mmol) was added to a stirred mixture of 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazole [1,5-a] [1 ,3] diazepin-5 (6H)-one in tetrahydrofuran (10 mL) and water (2 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (200 mg, 62%) as a yellow oil. LC-MS (Method I): m/z = 195.0 [M + H]+, 0.263 min. Step 8: Preparation of 5-benzyl-N-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin- 6-yl)-4H-1,2,4-triazol-3-carboxamide

[001550] N,N-diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (73 mg, 0.36 mmol), 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (70 mg, 0. 36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 45% B over 7 min; UV 254 and 220 nm; RT: 6 min to provide the title compound (50 mg, 36%) as a white solid. LC-MS (Method Y): m/z = 380.2 [M + H]+, 0.750 min. Step 9: Preparation of (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1 ,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (129A) and (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (129B)

[001551] 5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3] racemate diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide was separated by Prep-chiral-HPLC, with the following conditions: column: Chiralpak IC, 2 x 25 cm, 5 μm; A: Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B about 22 min; UV 254 and 220 nm; RT 1: 10.04 min; RT 2: 18.12 min to provide the title compounds:

[001552] Example 129A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.31 (s, 1H), 8.55 (s, 1H), 7.40-7.18 (m , 5H), 6.13 (s, 1H), 4.41-4.20 (m, 2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2, 65-2.26 (m, 2H), 2.18 (s, 3H), LC-MS (Method D): m/z = 380.2 [M+H]+, 1.298 min.

[001553] Example 129B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.30 (s, 1H), 8.46 (s, 1H), 7.38-7.20 (m , 5H), 6.13 (s, 1H), 4.41-4.20 (m, 2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2, 61-2.37 (m, 2H), 2.17 (s, 3H), LC-MS (Method D): m/z = 380.2 [M+H]+, 1,300 min. Example 130: (S)-1-(3-Cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 3-fluoro-5-(hydroxymethyl)benzonitrile

[001554] Sodium borohydride (1.0 g, 6.71 mmol) was added to a stirred mixture of 3-fluoro-5-formylbenzonitrile (306 mg, 8.05 mmol) in ethanol (10 mL) and tetra -hydrofuran (10 mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 1 hour, the reaction mixture was concentrated in vacuo, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (980 mg crude) as a yellow solid. LC-MS (Method T): m/z = 152.3 [M + H]+, 0.671 min. Step 2: Preparation of 3-(bromomethyl)-5-fluorobenzonitrile

[001555] Tribromophosphine (2.9 g, 10.7 mmol) was added to a stirred mixture of 3-fluoro-5-(hydroxymethyl) benzonitrile (0.8 g, 5.30 mmol) in dichloromethane (10 mL) . After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to provide the title compound (0.8 g crude) as a yellow solid, which was used directly in the next step without further purification. Step 3: Preparation of (S)-1-(3-cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3, 2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001556] Potassium carbonate (55 mg, 0.40 mmol) was added to a stirred mixture of (S)-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetra - hydropyrid [3,2-b] [1,4] oxazepin-3-yl)-1H-pyrazol-3-carboxamide (40 mg, 0.13 mmol) and 3-(bromomethyl)-5-fluorobenzonitrile (34 mg , 0.16 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3Mobile Phase B: ACN; Flow Rate: 30 mL/min; Gradient: 35% B to 65% B over 5 min; UV 254 and 220 nm; RT: 3.75 min to provide the title compound. 1HNMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.28 (d, J = 8 .0 Hz, 1H), 8.18 (d, J = 4.4 Hz, 1H), 7.90-7.86 (m, 1H), 7.71 (dd, J = 7.6, 1, 2Hz, 1H), 7.66 (s, 1H), 7,567.52 (m, 1H), 7.36-7.32 (m, 1H), 5.44 (s, 2H), 4.89- 4.81 (m, 1H), 4,704.64 (m, 1H), 4.54-4.49 (m, 1H), 3.36 (s, 3H), LC-MS (Method X): m/ z = 439.2 [M+H]+, 1.291 min Example 131A and 131B: (S)-5-Benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetra. -hydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide and (R)-5-Benzyl-N-( 3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-4H-1,2, 4-triazole-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of methyl 4-(4-methyl-5-nitro-1H-pyrazol-1-yl)butanoate

[001557] Diisopropyl azodicarboxylate (3.4 g, 16.9 mmol) was slowly added to a stirred mixture of methyl 4-hydroxybutanoate (2 g, 16.9 mmol), 4-methyl-5-nitro -1H-pyrazole (1 g, 7.8 mmol) and triphenylphosphine (4.44 g, 16.9 mmol) in tetrahydrofuran (40 mL) at 0°C under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to provide the title compound (1.0 g, 56%) as a colorless oil. LC-MS (Method C): m/z = 228.1 [M + H]+.1.130 min. Step 2: Preparation of Methyl 4-(5-amino-4-methyl-1H-pyrazol-1-yl)butanoate

[001558] A solution of methyl 4-(4-methyl-5-nitro-1H-pyrazol-1-yl) butanoate (1.0 g, 4.4 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium on carbon (10%, 0.1 g) under a hydrogen atmosphere (2-3 atm). After stirring for 2 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to give the title compound (0.85 mg, 97%) as a yellow solid. LC-MS (Method I): m/z = 197.9 [M + H]+, 1.013 min. Step 3: Preparation of 3-methyl-7,8-dihydro-4H-pyrazol[1,5- a][1,3]diazepin-5(6H)-one

[001559] The crude product obtained using the procedure described in Example 54 was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (600 mg, 84%) as a yellow solid. LC-MS (Method C): m/z = 166.1 [M + H]+, 0.782 min. Step 4: Preparation of 3,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a][1,3]diazepin-5(6H)-one

[001560] Iodomethane (511 mg, 3.6 mmol) was added to a stirred mixture of 3-methyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepin- 5(6H)-one (600 mg, 3.6 mmol) and cesium carbonate (3.52 g, 10.8 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred for 3 hours at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to provide the title compound (480 mg, 78%) as a yellow solid. LC-MS (Method C): m/z = 180.1 [M + H]+, 0.876 min. Step 5: Preparation of 6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a][1,3]diazepin-5(6H)-one

[001561] N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.82 mg, 8.02 mmol) was added to a stirred mixture of 3,4-dimethyl-7,8-dihydro -4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.48 mg, 2.67 mmol) in dichloromethane (10 mL) at 0°C followed by addition of iodotrimethylsilane (1.6 g, 8.01 mmol). After stirring for 1 hour at 0°C, iodine (1.36 g, 5.35 mmol) was added. The reaction mixture was stirred for another 1 hour at 0°C and quenched by addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting mixture was stirred for a further 15 minutes and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to provide the title compound (0.427 g, 52%) as a yellow solid. LC-MS (Method I): m/z = 305.9 [M + H]+, 0.756 min. Step 6: Preparation of 6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a][1,3]diazepin-5(6H)-one

[001562] Sodium azide (137 mg, 2.1 mmol) was added to a stirred mixture of 6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][ 1,3]diazepin-5(6H)-one (427 mg, 1.39 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2 hours at room temperature, quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (400 mg crude) as a yellow oil. LC-MS (Method C): m/z = 220.7 [M + H]+, 1.383 min. Step 7: Preparation of 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazol[1,5-a][1,3]diazepin-5(6H)-one

[001563] Triphenylphosphine (734 mg, 2.80 mmol) was added to a stirred mixture of 6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazole [1,5-a] [1 ,3] diazepin-5(6H)-one (400 mg, 1.80 mmol) in tetrahydrofuran (10 mL) and water (2 mL). After stirring overnight at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to provide the title compound (232 mg, 86%) as a yellow oil. LC-MS (Method C): m/z = 194.7 [M + H]+, 0.378 min. Step 8: Preparation of 5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepine -6-yl)-4H-1,2,4-triazol-3-carboxamide

[001564] N,N-diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of 5-benzyl-4H-1,2,4-triazol-3-carboxylic acid (73 mg, 0.36 mmol), 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (70 mg, 0. 36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL). After stirring overnight at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: Column: XBridge C18 OBD Prep, 100 Å, 10 μm, 19 mm x 250 mm; Mobile Phase A: Water (0.05% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 22% B to 43% B over 7 min; UV 254 and 220 nm; RT: 7 min to provide the title compound (50 mg, 36%) as a white solid. LC-MS (Method T): m/z = 380.3 [M + H]+, 1.041 min. Step 9: Preparation of (S)-5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1 ,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (131A) and (R)-5-benzyl-N-(3,4-dimethyl-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (131B)

[001565] 5-Benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3] racemate diazepin-6-yl)-4H-1,2,4-triazol-3-carboxamide (50 mg, 0.13 mmol) was separated by Prep-chiral-HPLC, with the following conditions: column: Chiralpak IF, 2 x 25cm, 5μm; A: Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow Rate: 17 mL/min; Gradient: B 40% B to 40% B about 24 min; UV 254 and 220 nm; RT 1: 7.35 min; RT 2: 8.28 min to provide the title compounds:

[001566] Example 131A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.31 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7, 40-7.18 (m, 6H), 4.36-4.09 (m, 5H), 3.22 (s, 3H), 2.61-2.23 (m, 2H), 2.02 ( s, 3H), LC-MS (Method D): m/z = 380.2 [M+H]+, 1.312 min.

[001567] Example 131B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 14.31 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 7, 38-7.20 (m, 6H), 4.30-4.14 (m, 5H), 3.22 (s, 3H), 2.60-2.27 (m, 2H), 2.02 ( s, 3H), LC-MS (Method D): m/z = 380.2 [M+H]+, 1.312 min. Example 132: 1-Benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepine-3-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 4-chloro-1H-pyrazol-3-carboxylate

[001568] 1-Chloropyrrolidine-2,5-dione (5.75 g, 42.9 mmol) was added to a stirred mixture of ethyl 1H-pyrazol-3-carboxylate (5.00 g, 35.7 mmol ) in N,N-dimethylformamide (40 mL). The reaction mixture was stirred overnight at room temperature and diluted with water (100 mL). The solids were removed by filtration and the filtrates were concentrated in vacuo to give the title compound (6.0 g crude) as a yellow oil. LC-MS (Methods): m/z = 175.2 [M + H]+, 0.695 min. Step 2: Preparation of ethyl 1-benzyl-4-chloro-1H-pyrazol-3-carboxylate

[001569] Potassium carbonate (7.1 g, 51.4 mmol) was added to a stirred mixture of ethyl (4-chloro-1H-pyrazol-3-carboxylate (3.0 g, 17.1 mmol) and (bromomethyl)benzene (3.6 g, 21.1 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (30 mL) and extracted with acetate. of ethyl (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (2.0 g, 44%) as a colorless oil LC-MS (Methods): m/z = 265.2 [M + H]+, 1.040 min. : Preparation of 1-benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepine-3-yl)-1H-pyrazol-3-carboxamide

[001570] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep, 100 A, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 65% B over 7 min; UV254 and 220 nm; RT: 7 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (s, 1H), 7.76-7.71 (m, 2H), 7.42-7.29 (m, 6H), 5.42 (s, 2H), 4.99-4.88 (m, 2H), 3.40 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H). LC-MS (Method T): m/z = 426.2 [M+H]+, 1.518 min. Example 133: (S)-4-Fluoro-1-(2-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Scheme legend: Rt - ta

[001571] Potassium carbonate (34 mg, 0.25 mmol) was added to a mixture of (S)-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetra -hydropyrido [3,2-b] [1,4] oxazepin-3-yl)-1H-pyrazol-3-carboxamide (25 mg, 0.08 mmol) and 1-(bromomethyl)-2-fluorobenzene (19 mg , 0.10 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 5μm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 30 mL/min; Gradient: 35% B to 65% B over 5 min; UV 254 and 220 nm; RT: 3.75 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 4.4 Hz, 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.35- 7.21 (m, 4H), 5.43 (s, 2H), 4.88-4.80 (m, 1H), 4.70-4.64 (m, 1H), 4.53-4, 48 (m, 1H), 3.35 (s, 3H), LC-MS (Method T): m/z = 414.2 [M+H]+, 1.346 min.Example 134: 5-Benzyl-N- ((2R, 3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1,3 ,4-oxadiazole-2-carboxamide

[001572] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: OBD Shield XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 60% B over 15 min; UV 254 and 220 nm; RT: 14.5 min to provide the title compound (13.3 mg, 17%) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 8.33-8.31 (m, 1H), 7.71-7.67 (m, 1H), 7.37-7.28 (m, 6H), 5.07-4.97 (m, 2H), 4.34 (s, 2H), 3.50 (s, 3H), 1.44 (d, J = 6.0 Hz, 3H), LC-MS (Method J): m/z = 394.15 [M+H]+, 2.483 min. Example 135: (S)-4-Fluoro-1-(3-fluorobenzyl)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Step 1: Preparation of 4-fluoro-1H-pyrazol-3-carboxylic acid

[001573] Sodium hydroxide (253 mg, 6.33 mmol) was added to a mixture of ethyl 4-fluoro-1H-pyrazol-3-carboxylate (500 mg, 3.16 mmol) in methanol (10 mL) and water (4 mL). The resulting solution was heated to 40°C and stirred overnight. After removing methanol under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1N, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (400 mg, 97.2%) as a white solid. LC-MS (Method T): m/z = 131.4 [M + H]+, 0.567 min. Step 2: Preparation of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3 -yl)-1H-pyrazol-3-carboxamide

[001574] N,N-diisopropylethylamine (993 mg, 7.70 mmol) was added to a mixture of (S)-3-amino-5-methyl-2,3-dihydropyrido [3,2- b] [1,4] oxazepin-4(5H)-one hydrochloride (354 mg, 1.54 mmol), 4-fluoro-1H-pyrazol-3-carboxylic acid (200 mg, 1.54 mmol), hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (355 mg, 1.85 mmol) and 1-hydroxybenzotriazole (250 mg, 1.85 mmol) in N,N-dimethylformamide (10 mL). After stirring overnight at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-TLC (ethyl acetate) to provide the title compound (200 mg, 42.6%) as a white solid. LC-MS (Method T): m/z = 306.3 [M + H]+, 0.696 min. Step 3: Preparation of (S)-4-fluoro-1-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001575] Potassium carbonate (68 mg, 0.49 mmol) was added to a mixture of (S)-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetra- hydropyrid [3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (50 mg, 0.16 mmol) and 1-(bromomethyl)-3-fluorobenzene (38 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: OBD XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3)Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 78% B over 7 min; UV 254 and 220 nm; RT: 6.5 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.49-7.38 (m, 1H), 7.38-7.28 (m, 1H) , 7.22-6.98 (m, 3H), 5.38 (s, 2H), 4.92-4.78 (m, 1H), 4.78-4.61 (m, 1H), 4 .61-4.41 (m, 1H), 3.36 (s, 3H), LC-MS (Method T): m/z = 414.2 [M+H]+, 1.347 min.Example 136: 1 -Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl )-1H-1,2,4-triazole-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of methyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate

[001576] Sodium hydride (60%, 192 mg, 8 mmol) was added to a stirred mixture of methyl 1H-1,2,4-triazol-3-carboxylate (508 mg, 4 mmol) in N,N- dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of (bromomethyl)benzene (680 mg, 4 mmol) under a nitrogen atmosphere. After stirring for an additional 2 hours, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to provide the title compound (400 mg, 46%) as a white solid. LC-MS (Method E): m/z = 217.9 [M + H]+, 0.661 min. Step 2: Preparation of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid

[001577] Lithium hydroxide (48 mg, 2 mmol) was added to a stirred mixture of methyl 1-benzyl-1H-1,2,4-triazol-3-carboxylate (108 mg, 0.5 mmol) in tetra -hydrofuran (3 mL) and water (1 mL). After stirring at 0°C for 2 hours, the pH of the reaction mixture was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound (80 mg, 79%) as a white solid. LC-MS (Method E): m/z = 203.9 [M + H]+, 0.560 min. Step 3: Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

[001578] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 100Â, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; UV 254 and 220 nm; RT: 6.3 min to give the title compound (31.5 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 8.01 (d, J = 6, 4 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.41-7.31 (m, 6H), 5.50 (s, 2H), 5, 00-4.88 (m, 2H), 3.40 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H), LC-MS (Method D): m/z = 393, 15 [M+H]+, 1.553 min. Example 137: (S)-4-Fluoro-1-((5-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3 ,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 3-(bromomethyl)-5-fluoropyridine

[001579] Tribromophosphine (853 mg, 3.15 mmol) was added to a solution of (5-fluoropyridin-3-yl) methanol (200 mg, 1.57 mmol) in dichloromethane (2 mL). The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under vacuum to give the title compound (150 mg crude). LC-MS (Methods): m/z = 190.1 [M + H]+, 0.787 min. Step 2: Preparation of (S)-4-fluoro-1-((5-fluoropyridin-5-yl)methyl)-3-fluoro- N-(5-methyl-4-oxo-2,3,4,5 -tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001580] Potassium carbonate (181 mg, 1.31 mmol) was added to a mixture of (S)-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetra- hydropyrid [3,2-b] [1,4] oxazepin-3-yl)-1H-pyrazol-3-carboxamide (80 mg, 0.26 mmol) and 3-(bromomethyl)-5-fluorobenzonitrile (107 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (2 ml) and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: Prep XBridge C18 OBD Prep Column, 100Â, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 35% B over 7 min; UV 254 and 220 nm; RT: 7 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.8 Hz, 1H), 8.46 (s, 1H), 8.37 (dd, J = 4.8, 1, 6 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.72-7.67 (m, 2H) , 7.36-7.32 (m, 1H), 5.46 (s, 2H), 4.88-4.81 (m, 1H), 4.70-4.64 (m, 1H), 4 .54-4.49 (m, 1H), 3.36 (s, 3H), LC-MS (Method T): m/z = 415.2 [M+H]+, 1.057 min. Example 138: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl )-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide Scheme legend: Rt - ta

[001581] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep, 100 Å, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV254 and 220 nm; RT: 7 min to give the title compound 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.36 (dd, J = 4.5, 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.44-7.29 (m, 6H), 4.96-4.90 (m, 2H), 3.40 ( s, 3H), 1.72-1.68 (m, 2H), 1.56-1.52 (m, 2H), 1.39-1.36 (m, 3H), LC-MS (Method D ): m/z = 420.15 [M+H]+, 1.777 min.Example 139: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetra -hydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(2-fluorophenoxy)pyridazine-3-carboxamide Scheme legend: Rt - ta

[001582] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 mm, 19 mm x 150 mm; Mobile Phase A: Water (10 mmol /L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV254 and 220 nm; RT: 6.5 min to give the title compound 1H NMR (300 MHz, DMSO-d6) δ 9.48 (d, J = 3.0 Hz, 1H), 8.89 (d, J = 6.3 Hz, 1H), 8.36 (dd, J = 4.8, 1.8 Hz, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.58-7 .34 (m, 5H), 7.27 (dd, J = 3.0, 0.9 Hz, 1H), 5.05-4.93 (m, 2H), 3.42 (s, 3H), 1.35 (d, J = 5.7 Hz, 3H), LC-MS (Method D): m/z = 424.1 [M+H]+, 1.747 min.Example 140: 1-Benzyl-N- ((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1H-imidazole -4-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 1-benzyl-1H-imidazole-4-carboxylate

[001583] Sodium hydride (60%, 0.51 g, 21.3 mmol) was added to a stirred solution of ethyl 1H-imidazol-4-carboxylate (2.0 g, 14.3 mmol) in N , N-dimethylformamide (15 mL). The resulting mixture was stirred for 30 minutes at 0°C followed by the addition of (bromomethyl)benzene (2.93 g, 17.13 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was quenched by adding water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (1.0 g, 30%) as a yellow oil. LC-MS (Method C): m/z = 231.1 [M + H]+, 0.985 min. Step 2: Preparation of 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepine-3-yl)-1H-imidazol-4-carboxamide

[001584] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: Water (10 mmol /L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 55% B over 7 min; UV254 and 220 nm to give the title compound 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 4.4, 1.2 Hz, 1H), 7.89 (d, J = 1 .2Hz, 1H), 7.78-7.71 (m, 3H), 7.37-7.27 (m, 6H), 5.21 (s, 2H), 4.924.84 (m, 2H) , 3.37 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H), LC-MS (Method F): m/z = 392.0 [M+H]+, 1.029 min . Example 141A and 141B: (S)-5-Benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)- 4H-1,2,4-triazol-3-carboxamide and (R)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2- b][1, 4]oxazepine 7-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt - ta Step 1: Preparation of 2-chloro-1-(1-trityl-1H-imidazol-2-yl)ethanone

[001585] A solution of n-butyllithium in hexane (2.5 M, 13.2 mL, 33.0 mmol) was added to a stirred mixture of 1-trityl-1H-imidazole (9.3 g, 30 .0 mmol) in tetrahydrofuran (190 mL) dropwise at -78°C under a nitrogen atmosphere. After the addition was complete, the reaction mixture was warmed to -10°C slowly and stirred for 1 hour. Then, the mixture was cooled to -78°C again and a solution of tert-butyl 2-chloroacetate (5.4 g, 36.0 mol) in tetrahydrofuran (10 mL) was added in one portion. The resulting mixture was warmed to room temperature with stirring for 2-3 hours, quenched with ice water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (900 mg, 7.8%) as a yellow solid. Step 2: Preparation of 2-(2-bromopyridin-3-yloxy)-1-(1-trityl-1H-imidazol-2-yl)ethanone

[001586] 2-Chloro-1-(1-trityl-1H-imidazol-2-yl)ethanone (772.0 mg, 2.0 mmol) was added to a stirred mixture of 2-bromopyridin-3-ol (346 .0 mg, 2.0 mmol) and potassium carbonate (414.0 mg, 3.0 mmol) in acetonitrile (10 mL) under a nitrogen atmosphere. The resulting mixture was heated to reflux and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (700 mg, 66.9%) as a yellow solid. LC-MS (Method C): m/z = 524.1 [M+H]+, 1,490 min. Step 3: Preparation of 2-(2-bromopyridin-3-yloxy)-1-(1H-imidazol-2-yl)ethanone

[001587] A mixture of 2-(2-bromopyridin-3-yloxy)-1-(1-trityl-1H-imidazol-2-yl)ethanone (700 mg, 1.34 mmol) in methanol/acetic acid (5 mL/1 mL) was heated to reflux and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (300 mg, 79.7%) as a yellow solid. LC-MS (R Method): m/z = 282.2 [M + H]+, 0.628 min. Step 4: Preparation of imidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one

[001588] Copper iodide (19 mg, 0.1 mmol) was added to a mixture of 2-(2-bromopyridin-3-yloxy)-1-(1H-imidazol-2-yl) ethanone (281 mg, 1 .0 mmol), L-proline (23.1 mg, 0.2 mmol) and potassium carbonate (345 mg, 2.50 mmol) in toluene (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with dichloromethane/methanol (10/1) (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/40) to provide the title compound (70 mg, 34.8%) as a yellow solid. LC-MS (R Method): m/z = 202.3 [M + H]+, 0.540 min. Step 5: Preparation of 6,7-dihydroimidazo[1,2-d]pyrido[3,2- b][1,4]oxazepin-7-amine

[001589] Sodium cyanoborohydride (11.0 mg, 0.17 mmol) was added to a stirred mixture of imidazo [1,2-d] pyrido [3,2-b] [1,4] oxazepin- 7(6H)-one (50.0 mg, 0.29 mmol) and ammonium acetate (383.0 mg, 4.98 mmol) in methanol (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (methanol/dichloromethane, 1/15) to provide the title compound (30 mg, 59.4%) as a yellow solid. LC-MS (Method C): m/z = 203.1 [M + H]+, 0.778 min. Step 7: Preparation of 5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2- b][1,4]oxazepin-7-yl)-4H-1, 2,4-triazol-3-carboxamide

[001590] The crude product obtained using the Amide Bond Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to provide the title compound (16 mg, 27.6% ) as a white solid. LC-MS (Method C): m/z = 388.1 [M + H]+, 0.921 min. Step 7: Preparation of (S)-5-benzyl-N-(6,7-dihydroimidazo[1,2- d]pyrido[3,2-b][1,4]oxazepin-7-yl)- 4H-1,2,4-triazol-3-carboxamide (141A) and (R)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido-3,2-b] [1,4]oxazepine-7-yl)-4H-1,2,4-triazol-3-carboxamide (141B).

[001591] 5-Benzyl-N-(6,7-dihydroimidazo[1,2-d] pyrido [3,2-b][1,4]oxazepin-7-yl)-4H-1 racemate ,2,4-triazol-3-carboxamide (16 mg, 0.041 mmol) was separated by prechiral HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 30 min; UV254 and 220 nm; TA 1: 16,881; TA 2:24,391 to give the title compounds:

[001592] Example 141A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.43 (s, 1H), 8.31 (dd, J = 4.4, 1.2 Hz, 1H ), 7.70 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (dd, J = 8.0, 4.4 Hz, 1H), 7.33-7.22 ( m, 6H), 5.86 (s, 1H), 4.59-4.48 (m, 2H), 4.15 (s, 2H), LC-MS (Method D): m/z = 388, 1 [M+H]+, 1.139 min.

[001593] Example 141B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.37 (s, 1H), 8.29 (dd, J = 4.4, 1.6 Hz, 1H ), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.38 (dd, J = 8.0, 4.4 Hz, 1H), 7.32-7.20 ( m, 6H), 5.83 (s, 1H), 4.57-4.47 (m, 2H), 4.10 (s, 2H), LC-MS (Method D): m/z = 388, 1 [M+H]+, 1.139 min. Example 142: (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl )isoxazole-3-carboxamide

[001594] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV 254 and 220 nm; RT: 5.6 min to give the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.94 (d, J = 7.8 Hz, 1H), 8.33 (dd, J = 4, 8, 1.5 Hz, 1H), 7.66 (dd, J = 7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H ), 4.86-4.77 (m, 1H), 4.67-4.59 (m, 1H), 4.51-4.44 (m, 1H), 4.19 (s, 2H), 3.31 (s, 3H), LC-MS (Method D): m/z =379.1 [M+H]+, 1.719 min. Example 143: N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl )-4-fluoro-1-(4-fluorobenzyl)-1H-pyrazol-3-carboxamide

[001595] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over 7 min; UV254 and 220 nm; RT: 5 min to provide the title compound (26.2 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.35-7.29 (m, 3H), 7.22- 7.14 (m, 2H), 5.31 (s, 2H), 4.94-4.83 (m, 2H), 3.36 (s, 3H), 1.27 (d, J = 6, 3 Hz, 3H), LC-MS (Method D): m/z =428.1 [M+H]+, 1.771 min. Example 144: (S)-1-(3-cyanobenzyl)-4-fluoro- N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001596] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV 254 and 220 nm; RT: 5.5 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 4.2 Hz, 1H), 7.81-7.74 (m, 2H), 7.68-7.64 (m, 1H), 7.61-7.55 (m, 2H ), 7.32-7.27 (m, 1H), 5.39 (s, 2H), 4.85-4.76 (m, 1H), 4.67-4.59 (m, 1H), 4.50-4.44 (m, 1H), 3.32 (s, 3H), LC-MS (Method D): m/z =421.1 [M+H]+, 1.550 min. Example 145A and 145B: (S)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1 -phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide and (R)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3 -b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide Step 1: Preparation of N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1- phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide

[001597] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC: Column: XBridge Shield RP18 OBD, 19 x 150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: ACN (35.0% ACN to 41.0% for 7 min); Detector, UV220 and 254 nm; RT: 5.88 min to provide the title compound (45 mg, 25.4%) as a white solid. LC-MS (Method E): m/z = 404.00 [M + H]+, 0.833 min.Step 2: Preparation of (S)-N-(9-methyl-8-oxo-6,7,8 ,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide (first eluting isomer) and (R) -N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl )- 1,3,4-oxadiazol-2-carboxamide (second elution isomer).

[001598] N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepin-7-yl)-5-(1) racemate -phenylcyclopropyl)-1 3,4-oxadiazol-2-carboxamide (45 mg, 0.11 mmol) was separated by Prep-chiral HPLC with the following conditions: Column: Chiralpak IA, 5 μm, 2.12 x 15 cm; Mobile phase A: hexane, mobile phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 13.5 min; UV 220 and 254 nm; TA 1: 8.78; TA 2:11.03 to give the title compounds:

[001599] Example 145A (first elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.41 (dd, J = 4.9, 1.8 Hz, 1H), 7.78 (dd, J = 7.5, 1.8 Hz, 1H), 7.45-7.42 (m, 2H), 7.38-7.25 (m, 4H), 4.48-4.44 (m, 1H ), 3.45 (s, 3H), 2.91-2.76 (m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1,771.74 (m, 2H), 1.55-1.53 (m, 2H), LC-MS (Method X): m/z = 404.10 [M+H]+, 1,180 min.

[001600] Example 145B (second elution isomer): 1H NMR (400 MHz, Methanol-d4) δ 8.41 (dd, J = 4.9, 1.8 Hz, 1H), 7.79 (dd, J = 7.6, 1.8 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.25 (m, 4H), 4.49-4.44 (m, 1H ), 3.45 (s, 3H), 2.90-2.77 (m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1,771.74 (m, 2H), 1.55-1.53 (m, 2H), LC-MS (Method X): m/z = 404.00 [M+H]+, 1.179 min. Example 146: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3 -yl)-1,3,4-oxadiazol-2-carboxamide

[001601] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 mm, 19 mm x 150 mm; Mobile Phase A: Water (10 mmol /L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min; UV254 and 220 nm; RT: 5 min to give the title compound 1H NMR (300 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.33 (dd, J = 4.8, 1.5 Hz, 1H), 7.69-7.65 (m, 1H), 7.38-7.24 (m, 6H), 4.84-4.65 (m, 2H), 4.53-4.47 (m, 1H ), 4.34 (s, 2H), 3.31 (s, 3H). LC-MS (Method D): m/z = 380.1 [M+H]+, 1.531 min. Example 147: 5-benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepine-3-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (2R, 3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4] tert-butyl oxazepin-3-yl-carbamate

[001602] Bromine (1.63 g, 10.2 mmol) was added to a stirred mixture of (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[ tert-butyl 3,2-b][1,4]oxazepin-3-ylcarbamate (1.0 g, 3.4 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for 4 hours and quenched by addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (900 mg, 71%) as a white solid. LC-MS (Method C): m/z = 372.0 [M + H]+, 1.283 min. Step 2: Preparation of (2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4-tert- butyl] oxazepin-3-ylcarbamate

[001603] Iodomethane (306 mg, 2.2 mmol) was added to a stirred mixture of (2R,3S)-8-Bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido tert-butyl [3,2-b][1,4]oxazepin-3-ylcarbamate (800 mg, 2.2 mmol) and cesium carbonate (703 mg, 2.2 mmol) in N,N-dimethylformamide ( 20 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/6) to provide the title compound (650 mg, 79%) as a white solid. LC-MS (Method C): m/z = 330.0 [M + H-56]+, 1.408 min. Step 3: Preparation of (2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] tert-butyl oxazepin-3-ylcarbamate

[001604] A solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.52 mL, 1.04 mmol) was added to a stirred mixture of (2R,3S)-8-bromo-2,5- tert-butyl dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-ylcarbamate (200 mg, 0.52 mmol) in tetra- hydrofuran (5 mL) at 0°C. The reaction mixture was stirred for 1 hour at 0°C followed by the addition of methanesulfonyl chloride (60 mg, 0.52 mmol). The reaction mixture was stirred for another 2 hours at room temperature, diluted with water (15 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to provide the title compound (55 mg, 28%) as a white solid. LC-MS (Method C): m/z = 330.1 [M + H-56]+, 1.208 min. Step 4: Preparation of (2R,3S)-3-amino-2,5-dimethyl-8-(methylsulfonyl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-hydrochloride 4(5H)-one

[001605] To a stirred mixture of (2R, 3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1 ,4] tert-butyl oxazepin-3-ylcarbamate (55 mg, 0.15 mmol) in 1,4-dioxane (5 mL) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8 mmol). The reaction mixture was stirred for 2 hours at room temperature and concentrated in high vacuum to provide the title compound (46 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 286.1 [M + H]+, 0.783 min. Step 5: Preparation of 5-benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepine-3-yl)- 4H-1,2,4-triazol-3-carboxamide

[001606] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD column, 100 Å, 5 μm, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV 254 and 220 nm; RT: 7 min to give the title compound: 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.01 (br s, 1H), 7.36-7.21 (m, 5H), 5.15-5.04 (m, 2H), 4 .16 (s, 2H), 3.45 (s, 3H), 3.39 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H), LC-MS (Method D): m/z =471.1 [M+H]+, 1.519 min.Example 148A and 148B: (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetra - hydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide and (R)-5-benzyl-N-(9-methyl-8-oxo -6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide Step 1: Preparation of 5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1 ,3,4-oxadiazol-2-carboxamide

[001607] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 mm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 52% B over 4 min; UV 254 and 220 nm; RT: 4 min to provide the title compound (20 mg, 14.2%) as a white solid. LC-MS (Method D): m/z = 378.1 [M + H]+, 1.492 min. Step 2: Preparation of (S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7- il)-1,3,4-oxadiazol-2-carboxamide (first elution isomer) and (R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetra- hydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide (second elution isomer)

[001608] 5-Benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepin-7-yl)- racemate 1,3,4-oxadiazol-2-carboxamide (20 mg) was separated by Prep-chiral HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile phase A: hexane; Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 12 min; UV 254 and 220 nm; TA 1: 7.106; RT 2: 9.363 min to give the title compounds:

[001609] Example 148A (first elution isomer): 1H NMR (300 MHz, CD3OD -d4) δ 8.44 (dd, J = 5.1, 1.8 Hz, 1H), 7.81 (dd, J = 7.5, 1.5 Hz, 1H), 7.38-7.26 (m, 6H), 4.54-4.46 (m, 1H), 4.34 (s, 2H), 3, 48 (s, 3H), 2.90-2.78 (m, 2H), 2.65-2.51 (m, 1H), 2.41-2.97 (m, 1H), LC-MS ( Method D): m/z = 378.1 [M+H]+, 1.492 min.

[001610] Example 148B (second elution isomer): 1H NMR (300 MHz, CD3OD -d4) δ 8.41 (dd, J = 4.8, 1.8 Hz, 1H), 7.78 (dd, J = 7.2, 1.5 Hz, 1H), 7.39-7.21 (m, 6H), 4.52-4.41 (m, 1H), 4.31 (s, 2H), 3, 45 (s, 3H), 2.91-2.75 (m, 2H), 2.64-2.45 (m, 1H), 2.41-2.25 (m, 1H), LC-MS ( Method D): m/z = 378.1 [M+H]+, 1.496 min. Example 149: (S)-5-(2-fluorophenoxy)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3 -yl)pyridazine-3-carboxamide

[001611] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 A, 5 mm, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol /L NH4HCO3); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over 7 min; UV254 and 220 nm; RT: 6.5 min to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.45-9.42 (m, 2H), 8.34-8.31 (m, 1H), 7.69-7.65 (m, 1H), 7.53-7.38 (m, 3H), 7.37-7.27 (m, 2H), 7.22 (d, J = 3.6 Hz, 1H), 4.91-4.74 ( m, 2H), 4.56-4.50 (m, 1H), 3.32 (s, 3H), LC-MS (Method V): m/z = 410.1 [M+H]+, 2.765 min. Example 150: 5-benzyl-N-((2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepine-3-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of (2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] tert-butyl [1,4]oxazepin-3-yl-carbamate

[001612] Tetrakis (triphenylphosphanyl) palladium (60 mg, 0.052 mmol) was added to a suspension of zinc cyanide (80 mg, 0.68 mmol) and (2R, 3S)-8-bromo-2,5-dimethyl tert-Butyl -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3-ylcarbamate (200 mg, 0.52 mmol) in N, N - dimethylformamide (2 mL) under a nitrogen atmosphere. The reaction mixture was heated to 140°C by microwave and stirred for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (110 mg, 64%) as a white solid. LC-MS (Method C): m/z = 277.1 [M + H-56]+, 1,300 min. Step 2: Preparation of (2R,3S)-3-amino-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] hydrochloride oxazepine-8-carbonitrile

[001613] To a solution of (2R, 3S) -8-cyano-2,5-dimethyl-4-oxo- 2,3,4,5-tetrahydropyrido [3,2-b] [1,4] tert-butyl oxazepin-3-ylcarbamate (68 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8 mmol). The resulting mixture was stirred for 2 hours at room temperature and concentrated in high vacuum to provide the title compound (55 mg crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 233.1 [M + H]+, 0.825 min. Step 3: Preparation of 5-Benzyl-N-((2R, 3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001614] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 65% B over 7 min; UV 254 and 220 nm; RT: 6 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H ), 8.00 (br s, 1H), 7.36-7.23 (m, 5H), 5.08-5.01 (m, 2H), 4.15 (s, 2H), 3.42 (s, 3H), 1.33 (d, J = 6.0 Hz, 3H), LC-MS (Method F): m/z = 418.0 [M+H]+, 1.187 min.Example 151: (S)-5-benzyl-4-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3- il)thiazol-2-carboxamide

[001615] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/LNH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; 254nm; RT: 6.32 min to give the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 7.43-7.26 (m, 6H), 4.98 (dd, J = 11.5, 7.4 Hz, 1H), 4.70 -4.55 (m, 2H), 4.42 (s, 2H), 3.48 (s, 3H), LC-MS (Method Q): m/z = 420.3 [M+H]+, 1.503 min. Example 152A and 152B: (R)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide and (S)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6 ,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1 Preparation of 1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[ 2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide

[001616] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100Â, 5 μm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 20 mL/min; Gradient: 20% B to 50% B over 7 min; UV 254 and 220 nm; RT: 7 min to provide the title compound (65 mg, 60%) as a white solid. LC-MS (Method D): m/z = 419.1 [M + H]+, 1.508 min. Step 2: Preparation of (R)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2, 3-b]azepin-7-yl)-1H-pyrazol-3- carboxamide (first elution isomer) and (S)-1-(3-cyanobenzyl)-4- fluorine-N-(9-methyl-8- oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)- 1H-pyrazol-3-carboxamide (second elution isomer)

[001617] 1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido racemate [2,3-b ] azepin-7-yl)-1H-pyrazol-3-carboxamide (65 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2, 5 μm, 2 x 25 cm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 60% B to 60% B over 20 min; UV 254 and 220 nm; RT 1: 12.92 min; RT 2: 16.60 min to provide the title compounds:

[001618] Example 152A (first elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.85-7.78 (m, 3H), 7.64-7.58 (m, 2H) , 7.30-7.26 (m, 1H), 5.42 (s, 2H), 4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2 .65 (m, 2H), 2.43-2.25 (m, 2H), LC-MS (Method F): m/z = 419.0 [M+H]+, 1.070 min.

[001619] Example 152B (second elution isomer): 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.85-7.78 (m, 3H), 7.64-7.58 (m, 2H) , 7.30-7.26 (m, 1H), 5.42 (s, 2H), 4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2 .64 (m, 2H), 2.43-2.24 (m, 2H), LC-MS (Method F): m/z = 419.1 [M+H]+, 1.071 min. Example 153: (S)-1-(2-cyanobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001620] 2-(Bromomethyl)benzonitrile (39 mg, 0.20 mmol) was added to a stirred mixture of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4, 5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (50 mg, 0.16 mmol) and potassium carbonate (68 mg, 0. 49 mmol) in N,N-dimethylformamide (4 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (5 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dry in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD 5 μm column, 19 x 150 mm; Mobile Phase A: water (10 mmol/L NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; 254 nm; RT: 6. 32 min to provide the title compound, 1H NMR (400 MHz, CD3OD-d4) δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.88 (d, J = 4, 5 Hz, 1H), 7.83 (dd, J = 7.7, 1.3 Hz, 1H), 7.73-7.66 (m, 2H), 7.56 (td, J = 7.6 , 1.1 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 5.59 (s , 2H), 5.01 (dd, J = 11.5, 7.2 Hz, 1H), 4.68 (dd, J = 9.8, 7.2 Hz, 1H), 4.50 (dd, J = 11.5, 9.9 Hz, 1H), 3.49 (s, 3H), LC-MS (Method Q): m/z = 421.3 [M+H]+, 1.201 min Example 154A. and 154B: (R)-1-benzyl-N-(6,7-dihydroimidazo[1,2- d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4- fluoro-1H-pyrazol-3-carboxamide and (S)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b]1,4]oxazepine-7 -yl)-4-fluoro-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7- il)-4-fluoro-1H-pyrazol-3-carboxamide

[001621] The crude product obtained using the Amide Bond Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to provide the title compound (16 mg, 33.0% ) as a white solid. LC-MS (Method S): m/z = 405.2 [M + H]+, 0.954 min. Step 2: Preparation of (S)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)- 4-fluoro-1H-pyrazol-3-carboxamide (first eluting isomer) and (R)-1-benzyl-N-(6,7-dihydroimidazo[1,2- d]pyrido[3,2-b ][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazol-3-carboxamide (second elution isomer)

[001622] 1-Benzyl-N-(6,7-dihydroimidazo [1,2-d] pyrido [3,2-b] [1,4] oxazepin-7-yl)-4-fluoro racemate -1H-pyrazole-3-carboxamide (16 mg, 0.039 mmol) was separated by Prep-chiral HPLC with the following conditions: Column: CHIRALPAK IC, 5 μm, 2 x 25 cm; Mobile Phase A: hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 26 min; UV 254 and 220 nm; RT 1: 3.96 min; RT 2: 6.18 min to provide the title compounds:

[001623] Example 154A (first elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.25-8.22 (m, 2H), 7.70 (d, J = 4.5 Hz, 1H ), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 7.34-7.22 (m, 6H), 7.07 (d, J = 1.5 Hz, 1H) , 5,735.69 (m, 1H), 5.25 (s, 2H), 4.47-4.44 (m, 2H), LC-MS (Method T): m/z = 405.2 [M+ H]+, 1.063 min.

[001624] Example 154B (second elution isomer): 1H NMR (300 MHz, Methanol-d4) δ 8.25-8.22 (m, 2H), 7.70 (d, J = 4.5 Hz, 1H ), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 7.34-7.22 (m, 6H), 7.07 (d, J = 1.5 Hz, 1H) , 5,735.69 (m, 1H), 5.25 (s, 2H), 4.47-4.44 (m, 2H), LC-MS (Method T): m/z = 405.2 [M+ H]+, 1.069 min. Example 155: 1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of 1-benzyl-1H-pyrazol-3-carboxylic acid

[001625] Sodium hydride (96 mg, 4 mmol) to a stirred mixture of ethyl 1H-pyrazol-3-carboxylate (280 mg, 2 mmol) in N, N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 2 hours followed by the addition of (bromomethyl)benzene (340 mg, 2 mmol). After stirring for another 2 hours, the reaction mixture was diluted with water (5 mL). Lithium hydroxide (96 mg, 4 mmol) was added and the resulting mixture was stirred overnight at room temperature, the pH was adjusted to 6 with hydrochloric acid (2 N, 20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 55% B over 7 min; UV 254 and 220 nm; RT: 4.9 min to provide the title compound (220 mg, 54.4%) as a white solid. LC-MS (Method E): m/z = 202.9 [M + H]+, 0.855 min. Step 2: Preparation of 1-benzyl-N-((2R, 3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001626] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: OBD Shield XBridge Shield RP18 column, 5 μm, 19 x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; UV 254 and 220 nm; RT: 3.3 min to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.42-7.25 (m, 6H), 6.70 ( d, J = 2.0 Hz, 1H), 5.46 (s, 2H), 4,994.89 (m, 2H), 3.40 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H), LC-MS (Method V): m/z = 392.1 [M+H]+, 2.961 min. Example 156A and 156B: 4-fluoro-1-(4-fluorobenzyl)-N-( (1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3- b]azepin-2-yl)-1H -pyrazole-3-carboxamide and 4-fluoro-1-(4-fluorobenzyl)- N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b- hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazol-3-carboxamide

[001627] The crude product obtained using Amide Coupling Procedure C was purified using Prep-TLC (methanol/dichloromethane, 1/20) to provide the title compound as a white solid.

[001628] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 19 mL/min; Gradient: 35% B to 35% B over 18.5 min; UV 220 and 254 nm; Ta1: 13.00; Ta2: 15.67 to give the title compounds:

[001629] Example 156A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.35 (dd, J = 4.8, 2.0 Hz, 1H), 7.92 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.38-7.35 (m, 2H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 7.14-7.07 (m, 2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H ), 2.28-2.22 (m, 1H), 2.10-2.05 (m, 1H), 1.27-1.20 (m, 1H), 1.18-1.12 (m , 1H), LC-MS (Method D): m/z = 424.1 [M+H]+, 1.658 min.

[001630] Example 156B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.35 (dd, J = 4.8, 2.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.76 (d, J = 4.4 Hz, 1H), 7.49 - 7.35 (m, 2H), 7.26 (dd, J = 7.6, 4.8 Hz, 1H), 7.12-7.08 (m, 2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H ), 2.28-2.22 (m, 1H), 2.10-2.04 (m, 1H), 1.26-1.19 (m, 1H), 1.18-1.27 (m , 1H), LC-MS (Method D): m/z = 424.1 [M+H]+, 1.664 min. Example 157A and 157B: 5-benzyl-N-((1aR,2R,8bS)-4 -methyl-3-oxo- 1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4- oxadiazol-2- carboxamide and 5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b ]azepin-2-yl)-1,3,4-oxadiazol-2-carboxamide

[001631] The crude product obtained using the procedure described in Example 54 was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound as a white solid.

[001632] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AS-H, 2.0 cm I.D x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 16 min; UV 220 and 254 nm; Ta1: 8.212; Ta2: 10.554 to give the title compounds:

[001633] Example 157A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 9.48 (d, J = 6.6 Hz, 1H), 8.39 (dd, J = 4.8 , 1.8 Hz, 1H), 7.99 (dd, J = 7.5, 1.8 Hz, 1H), 7.37-7.27 (m, 6H), 4.42 (d, J = 6.3 Hz, 1H), 4.38 (s, 2H), 3.34 (s, 3H), 2.31-2.26 (m, 1H), 2.07-1.96 (m, 1H ), 1,231.08 (m, 2H), LC-MS (Method X): m/z = 390.1 [M+H]+, 2.745 min.

[001634] Example 157B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 9.47 (d, J = 6.0 Hz, 1H), 8.39 (dd, J = 6.6 , 1.8 Hz, 1H), 7.97 (dd, J = 7.5, 1.8 Hz, 1H), 7.37-7.21 (m, 6H), 4.43 (d, J = 6.3 Hz, 1H), 4.39 (s, 2H), 3.33 (s, 3H), 2.32-2.26 (m, 1H), 2.03-1.99 (m, 1H ), 1,231.08 (m, 2H), LC-MS (Method D): m/z = 390.1 [M+H]+, 1.533 min. Example 158: (S)-1-benzyl-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-1H-pyrazol-3-carboxamide Step 1: Preparation of ethyl 5-cyano-1H-pyrazol-3-carboxylate

[001635] Sodium nitrite (10.56 g, 153 mmol) was added to a mixture of ethyl propiolate (5.00 g, 51.1 mmol) and 2-aminoacetonitrile hydrochloride (9.44 g, 102 mmol) in chloroform (150 mL) and water (5 mL). The reaction mixture was stirred for 12 hours at room temperature, then heated to 60°C and stirred for a further 6 hours. After cooling to room temperature, the resulting mixture was filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/9) to provide the title compound (2.90 g, 35%) as a yellow solid. LC-MS (Method C): m/z = 166.1 [M + H]+, 1.032 min. Step 2: Preparation of 5-cyano-1H-pyrazol-3-carboxylic acid

[001636] A solution of sodium hydroxide in water (2 M, 30 mL, 60 mmol) was added to a mixture of ethyl 5-cyano-1H-pyrazol-3-carboxylate (1.5 g, 9.09 mmol) in ethanol (25 mL). The reaction mixture was stirred for 4 hours at room temperature. After removal of ethanol under reduced pressure, the pH value of the solution was adjusted to 3-4 with aqueous hydrochloric acid (1 M, 100 ml, 100 mmol). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (400 mg crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.89 (s, 1H), 7.43 (s, 1H), 3.15 (s, 1H). Step 3: Preparation of (S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3 -yl)-1H-pyrazol-3-carboxamide

[001637] The crude product obtained using the Amide Bond Procedure C was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to provide the title compound (180 mg, 53%) as a yellow solid. LC-MS (Method S): m/z = 313.2 [M + H]+, 0.749 min. Step 4: Preparation of ((S)-1-benzyl-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1, 4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001638] Cesium carbonate (80 mg, 0.25 mmol) was added to a mixture of (S)-5-cyano-N- (5-methyl-4-oxo-2,3,4,5-tetra -hydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (60 mg, 0.19 mmol) and (bromomethyl)benzene (39 mg, 0.23 mmol ) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred for 0.5 hour at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 5μm, 19 x 150 mm; Mobile Phase A: Water (0.1% formic acid); Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 and 220 nm; RT: 7 min to give the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 7.9 Hz, 1H), 8.35 (dd, J = 4.7, 1.6 Hz, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (s, 1H), 7.44-7.29 (m, 4H), 7.28-7.22 (m, 2H), 5.65 (s, 2H), 4.90-4.84 (m, 1H), 4.73-4.67 (m, 1H), 4, 54-4.50 (m, 1H), 3.35 (s, 3H), LC-MS (Method T): m/z = 403.2 [M+H]+, 1.412 min. Example 159: (S)-5-cyano-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Scheme legend: Rt - ta

[001639] The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: Water (10 mmol /L NH4HCO3 ); Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B over 12 min; UV254 and 220 nm; RT: 6.5 min to give the title compound 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 7.9 Hz, 1H), 8.36 (dd, J = 4.8 , 1.6 Hz, 1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.59 (s, 1H), 7.36-7.29 (m, 3H) , 7.27-7.20 (m, 2H), 5.64 (s, 2H), 4.90-4.84 (m, 1H), 4.72-4.67 (m, 1H), 4 .54-4.50 (m, 1H), 3.36 (s, 3H), LC-MS (Method T): m/z = 421.1 [M+H]+, 1.433 min. Example 160A and 160 B: (S)-5-benzyl-N-(5'-methyl-4'-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[3, 2-b][1,4]oxazepin]-3'-yl)-1,3,4-oxadiazol-2-carboxamide and (R)-5-benzyl-N-(5'-methyl-4'-oxo -4', 5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepin]-3'-yl)-1,3, 4-oxadiazol-2-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 2-cyclopropylideneacetate

[001640] Ethyl 2-(triphenylphosphoranylidene) acetate (52 g, 149.42 mmol) was added to a mixture of (1-ethoxycyclopropoxy) trimethylsilane (20 g, 114.94 mmol) and benzoic acid (1.83 g , 14.95 mmol) in toluene (150 mL). The reaction mixture was stirred at 80°C overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/petroleum ether, 1/1) to provide the title compound (2.1 g, 14%) as a colorless oil. LC-MS (Method S): m/z = 127.2 [M + H]+, 0.886 min. Step 2: Preparation of Ethyl 2-(1-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate

[001641] 2-Nitropyridin-3-ol (3.36 g, 24.00 mmol) was added to a mixture of ethyl 2-cyclopropylideneacetate (1.00 g, 7.93 mmol) and 4Å molecular sieves (2 .80 g) in dimethylacetamide (40 mL). The reaction mixture was stirred at 130°C overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with diethyl ether (150 mL) and washed with aqueous sodium hydroxide (0.2 M, 3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/petroleum ether, 2/1) to provide the title compound (450 mg, 21%) as a yellow oil. LC-MS (Method S): m/z = 267.2 [M + H]+, 0.935 min. Step 3: Preparation of Ethyl 2-(1-((2-aminopyridin-3-yl)oxy)cyclopropyl)acetate

[001642] A mixture of ethyl 2-(1-((2-nitropyridin-3-yl)oxy)cyclopropyl) acetate (800 mg, 3.00 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium in carbon (10%, 80 mg) under a hydrogen atmosphere (2-3 atm). The reaction mixture was stirred for 2 hours at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under high vacuum to provide the title compound (650 mg, 92%) as a yellow oil. LC-MS (Method S): m/z = 237.1 [M + H]+, 0.587 min. Step 4: Preparation of 3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4] oxazepine]-4'(5'H)-one

[001643] A solution of trimethylaluminum in toluene (2 M, 5.3 mL, 10.55 mmol) was added dropwise to a stirring mixture of 2-(1-((2-aminopyridin-3-yl)oxy ) cyclopropyl) ethyl acetate (500 mg, 2.11 mmol) in toluene (50 mL). The resulting mixture was stirred overnight at room temperature, quenched by addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/3) to provide the title compound (290 mg, 72%) as a yellow oil. LC-MS (Method S): m/z = 191.1 [M + H]+, 0.704 min. Step 5: Preparation of 5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H)-one

[001644] Iodomethane (178 mg, 1.26 mmol) was added dropwise to a stirring mixture of 3'H-spiro [cyclopropane-1,2'-pyrido [3,2b] [1,4] oxazepine] -4'(5'H)-one (200 mg, 1.05 mmol) and cesium carbonate (341 mg, 1.05 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2 hours at 0°C, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/17) to provide the title compound (150 mg, 69%) as a white solid. LC-MS (Method S): m/z = 205.1 [M+H]+, 0.767 min. Step 6: Preparation of 3'-iodo-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H ) -ona

[001645] N,N,N',N'-tetramethylethylenediamine (0.49 g, 4.25 mmol) was added to a mixture of 5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido [3,2-b][1,4]oxazepine]-4'(5'H)-one (0.18 g, 0.85 mmol) in dichloromethane (40 mL) at 0°C followed by addition of iodotrimethylsilane (1.70 g, 8.50 mmol) dropwise over 20 minutes. The mixture was stirred for 1 hour at 0°C and then a solution of iodine (0.32 g, 1.25 mmol) in dichloromethane (100 mL) was added to the mixture. The reaction mixture was stirred for a further 1 hour at 0°C, quenched by addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (280 mg crude) as a yellow oil. LC-MS (Method C): m/z = 330.8 [M + H]+, 0.946 min. Step 7: Preparation of 3'-azido-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H ) -one

[001646] Sodium azide (109 mg, 1.68 mmol) was added to a mixture of 3'-iodo-5'-methyl-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b ] [1,4] oxazepine]-4'(5'H)-one (280 mg, 0.84 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was stirred for 2 hours at room temperature, quenched by the addition of water (40 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-TLC (ethyl acetate/petroleum ether, 1/2) to provide the title compound (70 mg, 33%) as a yellow solid. LC-MS (Method C): m/z = 246.0 [M + H]+, 0.925 min. Step 8: Preparation of 3'-amino-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazepine]-4'(5'H ) -ona

[001647] A mixture of 3'-Azido-5'-methyl-3'H-spiro[cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine]-4'(5' H)-one (70 mg, 0.28 mmol) in methanol (10 mL) was hydrogenated in the presence of palladium on carbon (10%, 10 mg) under a hydrogen atmosphere (2-3 atm). After stirring for 30 minutes at room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to provide the title compound (50 mg, 78%) as a white solid. LC-MS (Method S): m/z = 220.2 [M + H]+, 0.690 min. Step 9: Preparation of 5-benzyl-N-(5'-methyl-4'-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[3,2 -b ][1,4]oxazepine]-3'-yl)-1,3,4-oxadiazol-2-carboxamide

[001648] The crude product obtained using the procedure described in Example 54 was purified by Prep-TLC (ethyl acetate/petroleum ether, 1/1) to yield the title compound (42 mg, 45%) as a white solid. LC-MS (Method S): m/z = 406.0 [M + H]+, 1.024 min. Step 10: Preparation of (S)-5-benzyl-N-(5'-methyl-4'-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido [3, 2-b] [1,4] oxazepin]-3'-yl)-1,3,4-oxadiazol-2-carboxamide and (R)-5-benzyl-N- (5'-methyl-4 '-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4] oxazepin]-3'-yl)- 1 ,3,4-oxadiazole-2-carboxamide

[001649] 5-Benzyl-N- (5'-methyl-4'-oxo-4 ', 5'-dihydro-3'H- spiro racemate [cyclopropane-1,2'-pyrido [3, 2-b][1,4] oxazepine]-3'-yl)-1,3,4-oxadiazol-2-carboxamide (42 mg, 0.10 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 14 min; UV 254 and 220 nm; TA 1: 12,359; TA 2:20.087 to give the title compounds:

[001650] Example 160A (first elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J = 8.7 Hz, 1H), 8.39 (dd, J = 4.8 , 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.39-7.27 (m, 6H), 5.20 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.40 (s, 3H), 1.36-1.28 (m, 1H), 1.16-1.02 (m, 1H ), 1,000.94 (m, 1H), 0.58-0.50 (m, 1H). LC-MS (Method V): m/z = 406.1 [M+H]+, 2.745 min.

[001651] Example 160B (second elution isomer): 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J = 8.4 Hz, 1H), 8.39 (dd, J = 4.8 , 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.39-7.27 (m, 6H), 5.20 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.40 (s, 3H), 1.36-1.31 (m, 1H), 1.16-1.03 (m, 1H ), 1,000.94 (m, 1H), 0.58-0.50 (m, 1H). LC-MS (Method D): m/z = 406.1 [M+H]+, 1.652 min. Example 161: (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo -2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of methyl 2-(3-cyanophenyl) acetate

[001652] Sulfuric acid (98%, 2.0 mL) was added to a mixture of 2-(3-cyanophenyl)acetic acid (3.5 g, 22.0 mmol) in methanol (80 mL). The resulting mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was diluted with water (40 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (3.30 g, 87%) as a colorless oil. LC-MS (Method S): m/z = 176.2 [M + H]+, 0.504 min. Step 2: Preparation of 2-(3-cyanophenyl) acetohydrazide

[001653] Hydrazine hydrate (80%, 3.3 mL, 85.0 (mmol) was added to a mixture of methyl 2-(3-cyanophenyl) acetate in methanol (50 mL). The reaction mixture was stirred at 65°C overnight and then concentrated under reduced pressure. The residue was diluted with water (40 ml) and extracted with ethyl acetate (3 x 100 ml). filtrate. The filtrate was concentrated in vacuo to provide the crude title compound (2.4 g, 80%) as a white solid (Method S): m/z = 176.2 [M+H]. +, 0.506 min. Step 3: Preparation of ethyl 2-(2-(2-(3-cyanophenyl)acetyl)hydrazinyl)-2- iminoacetate

[001654] Ethyl 2-ethoxy-2-iminoacetate (1.82 g, 12.6 mmol) was added to a stirred mixture of 2-(3-cyanophenyl) acetohydrazide (2.0 g, 11.5 mmol ) in ethanol (20 mL) and diethyl ether (60 mL). The reaction mixture was stirred at room temperature overnight. The white solid was collected by filtration and rinsed with diethyl ether to provide the title compound (2.88 g, 92%) as a white solid. LC-MS (Method C): m/z = 275.1 [M + H]+, 0.913 min. Step 4: Preparation of 5-(3-cyanobenzyl)-4H-1,2,4-triazol-3-carboxylate

[001655] 4Â molecular sieves (50 mg) were added to a mixture of ethyl 2-(2-(2-(3-cyanophenyl)-acetyl)-hydrazinyl)-2-iminoacetate (1.0 g, 3.65 mmol) in xylene (10 mL). The reaction mixture was stirred at 160°C overnight in a sealed tube and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to obtain the title compound (500 mg, 54%) as a white solid. LC-MS (Method S): m/z = 257.2 [M + H]+, 0.767 min. Step 5: Preparation of 5-(3-cyanobenzyl)-4H-1,2,4-triazol-3-carboxylic acid

[001656] A solution of lithium hydroxide (94 mg, 4.0 mmol) in water (5 mL) was added to a solution of 5-(3-cyanobenzyl)-4H-1,2,4-triazol-3- ethyl carboxylate (500 mg, 2.0 mmol) in tetrahydrofuran (15 mL). The mixture was then stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (430 mg crude) as a white solid. LC-MS (Method C): m/z = 229.1 [M + H]+, 0.816 min. Step 6: Preparation of (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001657] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 and 220 nm; RT: 7 min to obtain the title compound: 1H NMR (400 MHz, DMSO-d6) δ 14.53 (br s, 1H), 8.68 (s, 1H), 8.37 (dd, J = 4 .4, 1.2Hz, 1H), 7.79-7.69 (m, 3H), 7.64-7.61 (m, 1H), 7.58-7.53 (m, 1H), 7.36-7.32 (m, 1H), 4.90-4.82 (m, 1H), 4.75-4.69 (m, 1H), 4.55-4.49 (m, 1H ), 4.22 (s, 2H), 3.36 (s, 3H). LC-MS (Method T): m/z = 404.2 [M+H]+, 1.095 min. Example 162: (S)-5-(3-cyano-5-fluorobenzyl)-N-(5-methyl -4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide Schematic legend: Rt – ta Step 1: Preparation of methyl 2-(3-bromo-5-fluorophenyl) acetate

[001658] Thionyl chloride (4.26 g, 35.8 mmol) was added to a stirred mixture of methyl 2-(3-bromo-5-fluorophenyl) acetic acid (2.6 g, 11.93 mmol) in methanol (30 mL) dropwise, followed by the addition of N,N-dimethylformamide (two drops). The reaction mixture was stirred for 2 hours at room temperature and concentrated in high vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/8) to obtain the title compound (2.79 g, 92.2%) as a yellow solid. LC-MS (Method S): m/z = 247.1 [M + H]+, 1.079 min. Step 2: Preparation of methyl 2-(3-cyano-5-fluorophenyl) acetate

[001659] Tetrakis(triphenylphosphanyl)palladium (1.2 g, 1.05 mmol) was added to a mixture of methyl 2-(3-bromo-5-fluorophenyl) acetate (2.6 g, 10.5 mmol ) and dicyanoazinc (1.64 g, 14.17 mmol) in N,N-dimethylformamide (30 mL) under nitrogen atmosphere. The reaction mixture was heated to 140°C by microwave and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/10) to obtain the title compound (1.12 g, 54%) as a yellow solid. LC-MS (Method C): m/z = 194 [M+H]+, 0.914 min. Step 3: Preparation of 2-(3-cyano-5-fluorophenyl) acetohydrazide

[001660] Hydrazine hydrate (1.45 g, 29 mmol) was added to a mixture of methyl 2-(3-cyano-5-fluorophenyl) acetate (1.12 g, 5.80 mmol) in methanol (20 mL). The resulting mixture was heated to reflux, stirred for 3 hours and concentrated under high vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 3/1) to obtain the title compound (0.92 g, 82.2%) as a white solid. LC-MS (Method S): m/z = 194 [M + H]+, 0.30 min. Step 4: Preparation of 2-(2-(2-(3-cyano-5-fluorophenyl) acetyl) hydrazinyl )- ethyl 2-iminoacetate

[001661] Ethyl 2-ethoxy-2-iminoacetate (692 mg, 4.77 mmol) was added to a stirred mixture of 2-(3-cyano-5-fluorophenyl) acetohydrazide (910 mg, 4.77 mmol) in ethanol (5 mL) and diethyl ether (15 mL). The reaction mixture was stirred for 4 hours at room temperature. The solid was collected by filtration and dried under high vacuum to obtain the title compound (160 mg, 80.8%) as a white solid. LC-MS (Method C): m/z = 293 [M + H]+, 0.727 min. Step 5: Preparation of 5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole 3- ethyl carboxylate

[001662] A mixture of ethyl 2-(2-(2-(3-cyano-5-fluorophenyl)acetyl) hydrazinyl)-2-iminoacetate (1 g, 3.42 mmol) and 4Å molecular sieves in xylenes ( 20 mL) was stirred for 4 hours at 160°C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/1) to obtain the title compound (0.75 g, 79.5%) as a white solid. LC-MS (Method C): m/z = 275.0 [M + H]+, 0.811 min. Step 6: Preparation of 5-(3-Cyano-5-fluorobenzyl)-4H-1,2,4 Acid - 3-carboxylic triazole

[001663] Lithium hydroxide (79.2 mg, 3.3 mmol) was added to a stirred mixture of 5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate ethyl (140 mg, 0.78 mmol) in tetrahydrofuran (10 mL) and water (3 mL). The reaction mixture was then stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1 M, 20 mL, 20 mmol) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (250 mg crude) as a yellow solid. LC-MS (Method C): m/z = 247.0 [M+H]+, 0.633 min.Step 7: Preparation of (S)-5-(3-cyano-5-fluorobenzyl)-N-(5 -methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide

[001664] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: X bridge Prep C18, 19 x 150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH4HCO3); Phase B: MeCN (20% to 80% in 12 min); Detector, UV at 220 and 254 nm to obtain the title compound: 1H NMR (300 MHz, DMSO-d6) δ 14.37 (s, 1H), 8.56 (s, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 7.77-7.67 (m, 3H), 7.59-7.55 (m, 1H), 7.33 (dd, J = 8, 1, 4.8 Hz, 1H), 4.91-4.71 (m, 2H), 4.45-4.48 (m, 1H), 4.26 (s, 2H), 3.36 (s , 3H). LC-MS (Method D): m/z = 422.1 [M+H]+, 1.367 min. Example 163: (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl )-4H-1,2,4-triazole-3-carboxamide

[001665] The crude product obtained using the Amide Coupling Procedure C was purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column 19 x 150 mm 5 μm 10 nm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B in 7 min; UV 254 and 220 nm; RT: 6.34 min.: 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.78-7.73 (m, 2H), 7.64-7.61 (m , 1H), 7.57-7.49 (m, 2H), 7.36-7.22 (m, 3H), 4.87-4.79 (m, 1H), 4.62-4.56 (m, 1H), 4.44-4.38 (m, 1H), 4.20 (s, 2H), 3.32 (s, 3H). LCMS (Method D): m/z = 403.1 [M+H]+, 1.367 min. Example 164: (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazol-2-carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 5-(bromomethyl) thiazole-2carboxylate

[001666] Benzoyl peroxide (6 mg, 0.02 mmol) was added to a mixture of ethyl 5-methylthiazol-2-carboxylate (420 mg, 2.45 mmol) and N-bromosuccinimide (459 mg, 2.58 mmol) in carbon tetrachloride (6 mL). The resulting mixture was stirred overnight at 75°C under a nitrogen atmosphere, quenched by addition of water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/2) to obtain the title compound (300 mg, 48.8%) as a yellow solid. LC-MS (Method S): m/z = 252.3 [M + H]+, 0.928 min. Step 2: Preparation of 5-(3-cyanobenzyl)thiazol2-carboxylic acid

[001667] Tetrakis (triphenylphosphine) palladium (28 mg, 0.02 mmol) was added to a mixture of ethyl 5-(bromomethyl) thiazol-2carboxylate (300 mg, 1.20 mmol), acid (3-cyanophenyl) boronic acid (194 mg, 1.32 mmol) and potassium carbonate (190 mg, 1.37 mmol) in toluene/ethanol (5 mL/5 mL) under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 90°C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was diluted with water (30 mL), the pH value of the resulting solution was adjusted to 3 with aqueous hydrochloric acid (1 M, 50 mL, 50 mmol) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to obtain the title compound (100 mg, 34.1%) as a yellow oil. LC-MS (Method C): m/z = 245.2 [M + H]+, 1.208 min. Step 3: Preparation of (S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4] oxazepin-3 -yl) thiazole 2-carboxamide

[001668] The crude product obtained using the Amide Binding Procedure B was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over 7 min; UV 254 and 220 nm; RT: 6.5 min to obtain the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 8.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.84-7.80 (m, 1H), 7.78-7.71 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.44 ( m, 2H), 7.40-7.20 (m, 3H), 4.88-4.75 (m, 1H), 4.73-4.60 (m, 1H), 4,484.37 (m, 1H), 4.34 (s, 2H), 3.30 (s, 3H). LC-MS (Method V): m/z = 419.2 [M+H]+, 3.361 min. Example 165: (S)-1-benzyl-5-fluoro-N-(5-methyl-4-oxo -2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt - ta Step 1: Preparation of 5-fluoro-1H-pyrazol-3-carboxylic acid

[001669] A solution of sodium hydroxide (2 M, 0.63 mL, 1.26 mmol) was added to a stirred mixture of ethyl 5-fluoro-1H-pyrazol-3-carboxylate (100 mg, 0. 63 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature overnight. After removing methanol under reduced pressure, the resulting solution was adjusted to pH = 5 with aqueous hydrochloric acid (1N, 2 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound (80 mg, 97%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), δ 13.49 (s, 1H), δ 6.47 (dd, J = 6.3, 2.2 Hz, 1H) . Step 2: Preparation of (S)-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3 -yl)-1H-pyrazol-3-carboxamide

[001670] The crude product obtained using Amide Coupling Procedure C was purified by column chromatography (methanol/dichloromethane, 1/10) to obtain the title compound (100 mg, 56.8%) as a white solid . LC-MS (Method E): m/z = 306.1 [M + H]+, 0.898 min. Step 3: Preparation of (S)-1-benzyl-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4 ]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001671] The crude product obtained using the procedure described in Example 158, Step 4, was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5 μm, 19 x 150 mm; Mobile phase: Phase A: Water (0.05% TFA), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B in 7 min; Detector, UV 254 and 220 nm to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.30 (dd, J = 4.7, 1.6 Hz, 1H), 7.63 (dd , J = 8.0, 1.6 Hz, 1H), 7.40-7.20 (m, 6H), 6.27 (d, J = 5.6 Hz, 1H), 5.30 (s, 2H), 4.96 (dd, J = 11.6, 7.2 Hz, 1H), 4.62 (dd, J = 9.8, 7.2 Hz, 1H), 4.46 (dd, J = 11.6, 9.8 Hz, 1H), 3.44 (s, 3H). LC-MS (Method D): m/z = 396.1 [M+H]+, 1.659 min. Example 166: (S)-5-fluoro-1-(4-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001672] The crude product obtained using the procedure described in Example 158, Step 4, was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 5μm, 19 x 150 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% B to 55% B over 7 min; Detector, UV 254 and 220 nm to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.30 (dd, J = 4.8, 1.6 Hz, 1H), 7.63 (dd , J = 8.0, 1.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.14-7.01 (m, 2H), 6.27 (d, J = 5 .6 Hz, 1H), 5.29 (s, 2H), 4.96 (dd, J = 11.5, 7.2 Hz, 1H), 4.62 (dd, J = 9.8, 7, 2 Hz, 1H), 4.46 (dd, J = 11.5, 9.8 Hz, 1H), 3.44 (s, 3H). LC-MS (Method D): m/z = 414.1 [M+H]+, 1.667 min. Example 167: (S)-5-cyano-1-(3-cyanobenzyl) -N- (5-methyl -4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide Scheme legend: Rt - ta

[001673] The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile Phase A: Water (10 mmol /L NH4HCO3); Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; UV254 and 220 nm; RT: 6.32 min to obtain the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 7.9 Hz, 1H), 8.36 (dd, J = 4, 7, 1.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.80-7.75 (m, 1H), 7.69 (dd, J = 8.0, 1, 6 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.58 (m, 1H), 7.35-7.28 (m, 1H), 5.73 (s , 2H), 4.90-4.81 (m, 1H), 4.72-4.63 (m, 1H), 4.54-4.47 (m, 1H), 3.35 (s, 3H ). LC-MS (Method T): m/z = 428.1 [M+H]+, 1,320 min. Example 168: (S)-1-((5-cyanopyridin-3-yl)methyl)-4-fluoro -N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001674] 5-(Bromomethyl)nicotinonitrile (35 mg, 0.18 mmol) was added to a stirred mixture of (S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4, 5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (45 mg, 0.15 mmol) and potassium carbonate (62 mg, 0.15 mmol) 45 mmol) in N,N-dimethylformamide (4 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product obtained using the procedure described in Example 158, Step 4 was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3)Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B over 7 min; UV 254 and 220 nm; RT: 6.5 min to obtain the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.91 (d, J = 1.9 Hz, 1H), 8.82 (d, J = 2, 1 Hz, 1H), 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (t, J = 2.0 Hz, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 5, 48 (s, 2H), 5.02 (dd, J = 11.5, 7.2 Hz, 1H), 4.69 (dd, J = 9.9, 7.2 Hz, 1H), 4.51 (dd, J = 11.5, 9.9 Hz, 1H), 3.50 (s, 3H). LC-MS (Method D): m/z = 422.0 [M+H]+, 1.328 min. Example 169: (S)-5-benzyl-N- (5-trideuteriomethyl-4-oxo-2,3 ,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazol-3-carboxamide Step 1: Preparation of (S)-tert-butyl carbamate (5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3- i)

[001675] Trideuterized iodomethane (233.5 mg, 1.61 mmol) was added to a stirred mixture of 4-oxo-2,3,4,5-tetrahydro-pyrido [3,2-b] [1, 4] (S)-tert-butyl oxazepin-3-ylcarbamate (450 mg, 1.61 mmol) and cesium carbonate (629.2 mg, 1.93 mmol) in N,N-dimethylformamide (10 mL) a 0°C. The reaction mixture was stirred at 0°C for 2 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound (360 mg, 75.5%) as a white solid. LC-MS (Method E): m/z = 297.2 [M + H]+, 0.903 min. Step 2: Preparation of (S)-3-amino-5-trideuteriomethyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazepin-4(5H)-one

[001676] (S)-tert-butyl (5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3-yl) carbamate ( 200 mg, 0.68 mmol) was added to a solution of hydrochloride in 1,4-dioxane (4 M, 5 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to obtain the title compound (140 mg of crude oil) as a white solid. LC-MS (Method E): m/z = 197.1 [M + H]+, 0.761 min. Step 3: Preparation of (S)-5-benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepine -3-yl)-4H-1,2,4-triazol-3-carboxamide

[001677] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4CO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; UV 254 and 220 nm to obtain the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.22 (m, 6H), 5.02 (dd, J = 11.6, 7.2 Hz, 1H), 4.67 ( dd, J = 9.9, 7.2 Hz, 1H), 4.51 (dd, J = 11.5, 9.9 Hz, 1H), 4.16 (s, 2H). LC-MS (Method D): m/z = 382.1 [M+H]+, 1.371 min. Example 170A and 170B: 1-(3-cyanobenzyl)-N-((1aS, 2S, 8bR)-5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[ b]cyclopropa[d]azepin-2-yl)-4-fluoro-1H-pyrazol-3-carboxamide and 1-(3-cyanobenzyl)-N-((1aR, 2R, 8bS)- 5,7-difluoro- 3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-1H-pyrazol-3-carboxamide

[001678] The crude product obtained using Amide Bonding Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the title compound as a white solid.

[001679] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: (R,R)WHELK-01 5/100 Kromasila, 2.11 cm x 25 cm (5 μm); Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 60% B to 60% B over 22 min; UV 254 and 220 nm; Ta1: 14.06; Ta2: 18.79 to obtain the title compounds:

[001680] Example 170A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 7.88 (d, J = 4.4, Hz, 1H), 7.75-7.72 (m, 2H), 7.667.63 (m, 1H), 7.61-7.56 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m, 1H) , 5.23 (s, 2H), 4.82 (s, 1H), 2.31-2.24 (m, 1H), 2.15-2.09 (m, 1H), 1,661.61 (m , 1H), 1.22-1.17 (m, 1H). LC-MS (Method D): m/z = 452.1 [M+H]+, 1.627 min.

[001681] Example 170B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 7.88 (d, J = 4.4 Hz, 1H), 7.74-7.72 (m, 2H ), 7.67-7.63 (m, 1H), 7.61-7.56 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m , 1H), 5.43 (s, 2H), 4.82 (s, 1H), 2.29-2.25 (m, 1H), 2.15-2.11 (m, 1H), 1, 66-1.60 (m, 1H), 1.22-1.15 (m, 1H). LC-MS (Method V): m/z = 452.1 [M+H]+, 2.781 min. Example 171: (S)-1-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-1H-1,2,4-triazol-3-carboxamide Step 1: Preparation of methyl 1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylate

[001682] Sodium hydride (60%, 0.38 g, 9.5 mmol) was added to a stirred mixture of methyl 1H-1,2,4-triazol-3-carboxylate (1.0 g, 7. 87 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred for 1 hour at room temperature, followed by the addition of 3-(bromomethyl)benzonitrile (1.69 g, 8.67 mmol). The resulting mixture was stirred for a further 1 hour at room temperature, diluted with water (30 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to obtain the title compound (600 mg, 31.5%) as a white solid. LC-MS (Method C): m/z = 243.1 [M + H]+, 0.925 min. Step 2: Preparation of 1-(3-cyanobenzyl)-1H-1,2,4-triazol-3-carboxylic acid

[001683] A solution of lithium hydroxide (360 mg, 15.0 mmol) in water (10 ml) was added to a stirred mixture of 1-(3-cyanobenzyl)-1H-1,2,4-triazol-3 -carboxylate (600mg, 2.48 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred at room temperature for 2 hours. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (250 mg, 17.7%) as a white solid. LC-MS (Method X): m/z =229.1 [M+H]+, 1.227 min. Step 3: Preparation of (S)-1-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

[001684] The crude product obtained using the Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7 min; 254nm; RT: 6 min to obtain the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.64 (s, 1H), 8.33 (dd, J = 4.8, 1.6 Hz, 1H) , 7.77-7.64 (m, 4H), 7.57 (t, J = 7.7 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 5.55 (s, 2H), 5.03 (dd, J = 11.7, 7.3 Hz, 1H), 4.69 (dd, J = 9.9, 7.1 Hz, 1H), 4 .52 (dd, J = 11.2, 9.6 Hz, 1H), 3.47 (s, 3H). LC-MS (Method D): m/z = 404.2 [M+H]+, 1.371 min. Example 172: 1-(3-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1 ,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide

[001685] The crude product obtained using the Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; 254nm; RT: 6.25 min to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.66 (s, 1H), 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.78-7.65 (m, 4H), 7.57 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H ), 5.56 (s, 2H), 5.07-5.01 (m, 2H), 3.49 (s, 3H), 1.38 (d, J = 5.9 Hz, 3H). LC-MS (Method D): m/z = 418.2 [M+H]+, 1.477 min. Example 173: (S)-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4] oxazepin-3-yl)-5- (1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

[001686] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4CO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; 254 nm UV detector to obtain the title compound: 1H NMR (300 MHz, DMSO-d6) δ 9.49 (d, J = 7.6 Hz, 1H), 8.36 (dd, J = 4.7, 1.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.50-7.28 (m, 6H), 4.87-4.62 (m , 2H), 4.50 (dd, J = 9.3, 7.1 Hz, 1H), 1.72-1.62 (m, 2H), 1.55-1.44 (m, 2H). LC-MS (Method D): m/z = 409.1 [M+H]+, 1.624 min. Example 174: 5-benzyl-N-((2R, 3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4 ]oxazepina-3-yl)-1,3,4-oxadiazole-2-carboxamide Step 1: Preparation of ((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3 tert-butyl -yl)carbamate

[001687] Trideuterized iodomethane (124 mg, 0.85 mmol) was added to a stirred mixture of (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2 -b][1,4]oxazepin-3-ylcarbamate tert-butyl (250 mg, 0.85 mmol) and cesium carbonate (278 mg, 0.85 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for 5 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to obtain the title compound (230 mg, 87.1%) as a white solid. LC-MS (Method C): m/z = 311.1 [M + H]+, 1.260 min. Step 2: Preparation of (2R,3S)-3-amino-2-imethyl-5-trideuterated methyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepin-4 hydrochloride ( 5H) -one.

[001688] ((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3-yl )tert-butyl carbamate (100 mg, 0.32 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 N, 6.0 mL, 24 mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo to obtain the title compound (80 mg, 99%) as a white solid. LC-MS (Method C): m/z = 211.1 [M + H]+, 0.757 min. Example 3: 5-benzyl-N-((2R, 3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4 ]oxazepina-3-yl)-1,3,4-oxadiazol-2-carboxamide

[001689] The crude product obtained using the procedure described in Example 54 was purified by Prep-HPLC with the following conditions: Column: XBridge OBD C18 19 mm x 250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over 7 min; UV 254 and 220 nm; RT: 6.85 min to obtain the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.28 (m, 6H), 4.98-4.90 (m, 2H), 4 .38 (s, 2H), 1.37 (d, J = 6.4 Hz, 3H). LC-MS (Method D): m/z = 397.2 [M+H]+, 1,680 min. Example 175: (S)-1-benzyl-4-fluoro-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine -3-yl)-1H-pyrazol-3-carboxamide

[001690] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over 7 min; UV 254 nm to obtain the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.32 (dd, J = 4.7, 1.6 Hz, 1H), 8.21 (d, J = 7 .8 Hz, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.42-7.19 (m, 6H), 5.31 (s, 2H), 4.85-4.76 (m, 1H), 4.64 (dd, J = 11.5, 9.7 Hz, 1H), 4, 47 (dd, J = 9.6, 7.4 Hz, 1H). LC-MS (Method J): m/z = 399.3 [M+H]+, 1.331 min. Example 176: 5-benzyl-N-((1aR,2S,8bS)-5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo[b]cyclopropa[d] azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide

[001691] The crude product obtained using the Amide Binding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD column, 5 μm, 30 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B over 7 min; 254nm; RT: 6.32 min to obtain the title compound: 1H NMR (400 MHz, DMSO-d6) δ 14.34 (br s, 1H), 9.72 (s, 1H), 8.62 (s, 1H ), 7,357.18 (m, 7H), 4.12 (s, 2H), 3.98 (dd, J = 10.5, 7.5 Hz, 1H), 2.26-2.17 (m, 1H), 1.87-1.77 (m, 1H), 1.13-1.04 (m, 1H), 0.60-0.57 (m, 1H). LC-MS (Q Method): m/z = 410.5 [M+H]+, 1.773 min. Example 177A and 177B: 5-benzyl-N-((7S, 7aS, 8aR)-5-methyl-6-oxo-5,6,7,7a, 8,8a-hexahydrocyclopropa [d] pyrazino [2, 3-b] azepin-7-yl)- 1,3,4-oxadiazol-2-carboxamide and 5-benzyl-N-((7R, 7aR, 8aS)-5-methyl- 6-oxo-5,6, 7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide

[001692] The crude product obtained using the procedure described in Example 54 was purified by means of Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the title compound as a white solid.

[001693] 5-Benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a, 8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepine racemate -7-yl)-1,3,4-oxadiazol-2-carboxamide (40 mg, 0.10 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB S-5 μm, 250 x 20 mm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 26 min; 220/254nm; Ta1: 19.32; TA 2: 23.55 to obtain the title compounds:

[001694] Example 177A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.42-8.37 (m, 2H), 7.37-7.25 (m, 5H), 4 .77 (s, 1H), 4.33 (s, 2H), 3.40 (s, 3H), 2.65-2.57 (m, 1H), 2.25-2.17 (m, 1H ), 1,551.48 (m, 1H), 1.35-1.30 (m, 1H). LCMS (Method D): m/z = 391.1 [M+H]+, 1.231 min.

[001695] Example 177B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.42-8.37 (m, 2H), 7.36-7.25 (m, 5H), 4 .77 (s, 1H), 4.33 (s, 2H), 3.39 (s, 3H), 2.64-2.56 (m, 1H), 2.24-2.16 (m, 1H ), 1,541.46 (m, 1H), 1.34-1.28 (m, 1H). LC-MS (Method D): m/z = 391.1 [M+H]+, 1.225 min. Example 178A and 178B: (S)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2, 3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide and (R)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7, 8,9-tetrahydro-5H-pyrazino [2,3-b]carboxamide Schematic legend: Rt – ta Step 1: Preparation of ethyl 4-(3-aminopyrazin-2-yl) butanoate

[001696] A solution of (4-ethoxy-4-oxobutyl) zinc (II) bromide in tetrahydrofuran (0.5 M, 26.0 mL, 13.0 mmol) was added to a mixture of 3- bromopyrazine-2-amine (1.0 g, 5.8 mmol) and tetrakis (triphenylphosphanyl) palladium (0.67 g, 0.58 mmol) in tetrahydrofuran (60 mL) under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to obtain the title compound (0.45 g, 37.0%) as a light yellow oil. LC-MS (Method S): m/z = 210.2 [M + H]+, 0.592 min. Step 2: Preparation of 8,9-dihydro-5H-pyrazino[2,3-b]azepine-6(7H)-one

[001697] A solution of trimethylaluminum in toluene (2 M, 6.0 mL, 12.0 mmol) was added to a stirred mixture of ethyl 4-(3-aminopyrazin-2-yl) butanoate (450 mg, 2. 2 mmol) in toluene (20 mL). After stirring overnight at room temperature, the reaction mixture was quenched by adding water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to obtain the title compound (0.32 g, 91.0%) as a light yellow oil. LC-MS (Method S): m/z = 164.2 [M + H]+, 0.473 min. Step 3: Preparation of 5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

[001698] Iodomethane (313 mg, 2.2 mmol) was added dropwise to a stirred mixture of 8,9-dihydro-5H-pyrazino [2,3-b] azepin-6 (7H) - one (320 mg, 2.0 mmol) and cesium carbonate (717 mg, 2.2 mmol) in N,N-dimethylformamide (15 mL). After stirring overnight at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to obtain the title compound (300 mg, 87.0%) as a light yellow solid. LC-MS (Method S): m/z = 178.1 [M + H]+, 0.570 min. Step 4: Preparation of 7-iodo-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

[001699] A mixture of 5-methyl-8,9-dihydro-5H-pyrazino [2,3-b] azepin-6 (7H) -one (300 mg, 1.70 mmol) and N, N , N',N'-tetramethylethylenediamine (1.97 g, 17.0 mmol) in dichloromethane (80 mL) at 0°C was added iodotrimethylsilane (2.38 g, 17.0 mmol) dropwise over 30 minutes. The resulting mixture was stirred for 2 hours at 0°C, followed by adding a solution of iodine (0.65 g, 2.6 mmol) in dichloromethane (100 mL) dropwise over 30 minutes. After stirring for 1 hour at room temperature, the reaction mixture was quenched by adding aqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (450 mg crude, 87.7%) as a yellow oil. LC-MS (Method S): m/z = 304.1 [M + H]+, 0.610 min. Step 5: Preparation of 7-azido-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

[001700] Sodium azide (290 mg, 4.47 mmol) was added to a stirred mixture of 7-iodo-5-methyl-8,9-dihydro-5H-pyrazino [2,3-b] azepin- 6(7H)-one (450 mg, 1.49 mmol) in N,N-dimethylformamide (50 mL). After stirring at room temperature for 3 hours, the reaction mixture was quenched by adding water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (260 mg crude) as a yellow oil. LC-MS (Method S): m/z = 219.1 [M + H]+, 0.600 min. Step 6: Preparation of 7-amino-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

[001701] 7-Azido-5-methyl-8,9-dihydro-5H-pyrazino [2,3-b] azepin-6 (7H) -one (260 mg, 1.2 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on carbon (10%, 26 mg) under a hydrogen atmosphere (2-3 atm). After stirring for 5 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and dried under high vacuum to obtain the title compound (200 mg, 88%) as a colorless oil. LC-MS (Method S): m/z = 193.1 [M + H]+, 0.356 min. Step 7: Preparation of 4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazine [2,3-b] azepina-7-yl)-1H-pyrazol-3-carboxamide

[001702] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3) Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B over 8 min; UV 254 and 220 nm; RT: 6.82 min to obtain the title compound (30 mg, 28%) as a white solid. LC-MS (Method O): m/z = 413.1 [M+H]+, 1.396 min. Step 8: Preparation of (S)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazine [2, 3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide and (R)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7, 8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazol-3-carboxamide

[001703] 4-Fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazine racemate [2,3-b ] azepin-7-yl)-1H-pyrazol-3-carboxamide (30.0 mg, 0.07 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in 30 min; UV 254 and 220 nm; Ta1: 17.00 min; Ta2: 24.16 min to obtain the title compounds:

[001704] Example 178A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.48 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.24 -7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m , 1H), 3.04-2.98 (m, 1H), 2.80-2.69 (m, 1H), 2.41-2.31 (m, 1H). LC-MS (Method T): m/z = 413.1 [M+H]+, 1.198 min.

[001705] Example 178B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.47 (d, J = 2.8 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.25 -7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.19-3.08 (m , 1H), 3.05-2.98 (m, 1H), 2.81-2.69 (m, 1H), 2.41-2.32 (m, 1H). LC-MS (Method X): m/z = 413.1 [M+H]+, 2.354 min. Example 179A and 179B: 4-fluoro-1-(2-fluorobenzyl)-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexa- hydrocyclopropa[d]pyrazino[2,3- b]azepin-7-yl)-1H-pyrazol-3-carboxamide and 4-fluoro-1-(2-fluorobenzyl)- N-((7R,7aR,8aS)- 5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide Scheme caption: Rt - ta

[001706] The crude product obtained using Amide Bonding Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the title compound as a white solid.

[001707] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in 38 min; UV 254 and 220 nm; Ta1: 22.995; Ta2: 30.882 to obtain the title compounds:

[001708] Example 179A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.30 (dd, J = 2.4, 6.4 Hz, 2H), 7.68 (d, J = 4.4 Hz, 1H), 7.34-7.27 (m, 1H), 7.25-7.20 (m, 1H), 7.13-7.04 (m, 2H), 5, 23 (s, 2H), 4.66 (s, 1H), 3.31 (s, 3H), 2.54-2.47 (m, 1H), 2.17-2.10 (m, 1H) , 1.43-1.37 (m, 1H), 1.22-1.15 (m, 1H). LC-MS (Method D): m/z = 425.0 [M+H]+, 1.679 min.

[001709] Example 179B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.42 (dd, J = 3.2, 6.8 Hz, 2H), 7.80 (d, J = 4.4 Hz, 1H), 7.45-7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.16 (m, 2H), 5, 44 (s, 2H), 4.78 (s, 1H), 3.42 (s, 3H), 2.65-2.58 (m, 1H), 2.28-2.22 (m, 1H) , 1.54-1.49 (m, 1H), 1.33-1.27 (m, 1H). LC-MS (Method D): m/z = 425.0 [M+H]+, 1.684 min. Example 180A and 180B: (S) -N- (5-methyl-6-oxo-6,7,8 ,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide and (R)-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3, 4-oxadiazol-2-carboxamide Scheme legend: Rt - ta

[001710] The crude product obtained using Amide Bonding Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 1/1) to obtain the title compound.

[001711] N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepin-7-yl)-5-(1) racemate -phenylcyclopropyl)-1 3,4-oxadiazol-2-carboxamide (30 mg, 0.08 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: 100% B to 100% B over 16 min; UV 254 and 220 nm; RT 1: 10.459 min; RT 2: 12.463 min to obtain the title compounds:

[001712] Example 180A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.49 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.48-7.46 (m, 2H), 7.41-7.31 (m, 3H), 4.57-4.51 (m, 1H), 3.49 (s, 3H), 3.18-3.09 (m, 1H), 3.05-2.99 (m, 1H), 2.74-2.63 (m, 1H), 2.50-2.41 ( m, 1H), 1.80-1.77 (m, 2H), 1.59-1.55 (m, 2H). LC-MS (Method D): m/z = 405.0 [M+H]+, 1.260 min.

[001713] Example 180B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.49 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.49-7.46 (m, 2H), 7.42-7.31 (m,3H), 4.57-4.50 (m, 1H), 3.50 (s, 3H), 3.18-3.09 (m, 1H), 3.06-2.99 (m, 1H), 2.74-2.63 (m, 1H), 2.50-2.40 ( m, 1H), 1.81-1.77 (m, 2H), 1.60-1.55 (m, 2H). LC-MS (Method D): m/z = 405.0 [M+H]+, 1.261 min. Example 181A and 181B: 5-(3-cyanobenzyl) -N-((1aR, 2R, 8bS)-5 ,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepin-2-yl)-4H-1,2,4-triazol-3- carboxamide and 5-(3-cyanobenzyl)-N-((1aS, 2S, 8bR)-5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cycloprope [d]azepin-2-yl)-4H-1,2,4-triazol-3-carboxamide Scheme legend: Rt - ta

[001714] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3) Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to 53% B over 8 min; 254 &220nm; RT: 7.43 min to obtain the title compound as a white solid.

[001715] The racemate was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 23 min; 254 and 220 nm; Ta1: 9.885; Ta2: 16.633 to obtain the title compounds:

[001716] Example 181A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 7.71 (s, 1H), 7.65-7.61 (m, 2H), 7.54-7 .48 (m, 1H), 7.18-7.05 (m, 1H), 6.99-6.90 (m, 1H), 4.81 (s, 1H), 4.24 (s, 2H ), 2,312.22 (m, 1H), 2.15-2.07 (m, 1H), 1.74-1.63 (m, 1H), 1.24-1.14 (m, 1H). LC-MS (Method J): m/z = 435.4 [M+H]+, 1,200 min.

[001717] Example 181B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 7.70 (s, 1H), 7.66-7.62 (m, 2H), 7.55-7 .49 (m, 1H), 7.19-7.07 (m, 1H), 6.98-6.91 (m, 1H), 4.81 (s, 1H), 4.24 (s, 2H ), 2,322.23 (m, 1H), 2.16-2.07 (m, 1H), 1.67-1.59 (m, 1H), 1.23-1.14 (m, 1H). LC-MS (Method V): m/z = 435.1 [M+H]+, 3.354 min. Example 182A and 182B: (R)-4-fluoro-N- (5-methyl-6-oxo-6 ,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)- 1H-pyrazol-3-carboxamide and (S)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1 -((2-methylpyridin-3-yl) Step 1: Preparation of ethyl 4-fluoro-1-((2-methylpyridin-3-yl) methyl)-1H-pyrazol- 3-carboxylate

[001718] 3-(Bromomethyl)-2-methylpyridine (283 mg, 1.52 mmol) was added to a stirred mixture of ethyl 4-fluoro-1H-pyrazol-3-carboxylate (200 mg, 1.27 mmol ) and cesium carbonate (1.24 g, 3.80 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched by adding water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 1/4) to obtain the title compound (300 mg, 90.9%) as a white solid. LC-MS (Method C): m/z = 264.1 [M + H]+, 1.291 min. Step 2: Preparation of 4-fluoro-1-((2-methylpyridin-3-yl) methyl)-1H-pyrazol-3-carboxylic acid

[001719] Lithium hydroxide (82 mg, 3.42 mmol) was added to a mixture of ethyl 4-fluoro-1-((2-methylpyridin-3-yl) methyl)-1H-pyrazol-3-carboxylate ( 300 mg, 1.14 mmol) in tetrahydrofuran (12 mL) and water (4 mL). The reaction mixture was stirred at room temperature overnight. After removing the tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (220 mg crude) as a white solid. LC-MS (Method C): m/z = 236.0 [M+H]+, 0.365 min. Step 3: Preparation of 4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1 -((2-methylpyridin-3-yl)methyl)-1H-pyrazol-3-carboxamide

[001720] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: XBridge Shield C18 OBD Column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3) Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 20% B to 33% B over 8 min; UV 254 and 220 nm; RT: 7.28 min to obtain the title compound. LC-MS (Method Y): m/z = 410.2 [M+H]+, 0.841 min. Step 4: Preparation of (R)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7- yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazol-3-carboxamide and (S)-4-fluoro-N-(5-methyl-6-oxo-6,7,8 ,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazol-3-carboxamide

[001721] 4-Fluoro-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepin-7-yl)- racemate 1-((2-methylpyridin-3-yl) methyl)-1H-pyrazol-3-carboxamide (40 mg, 0.10 mmol) was separated by prechiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB , 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 13 min; UV 254 and 220 nm; RT 1: 9.428 min; RT 2: 11.106 min to obtain the title compounds:

[001722] Example 182A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.49 (d, J = 2.8 Hz, 1H), 8.42-8.39 (m, 2H ), 7.80 (d, J = 4.4 Hz, 1H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 5.45 (s, 2H), 4,584.53 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H), 2,812.70 (m, 1H), 2.58 (s, 3H), 2.42-2.31 (m, 1H). LC-MS (Method D): m/z = 410.0 [M+H]+, 0.715 min.

[001723] Example 182B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.49 (d, J = 2.8 Hz, 1H), 8.42-8.39 (m, 2H ), 7.80 (d, J = 4.4 Hz, 1H), 7.52-7.48 (m, 1H), 7.34-7.29 (m, 1H), 5.45 (s, 2H), 4,584.53 (m, 1H), 3.50 (s, 3H), 3.18-3.07 (m, 1H), 3.05-2.98 (m, 1H), 2,812.70 (m, 1H), 2.58 (s, 3H), 2.42-2.30 (m, 1H). LC-MS (Method D): m/z = 410.0 [M+H]+, 0.720 min. Example 183A and 183B: 1-benzyl-4-fluoro-N-((1aR, 2R, 8bS)-4 -trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepin-2-yl)-1H-pyrazol-3-carboxamide and 1-Benzyl-4-fluoro-N-((1aS, 2S, 8bR)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b ] cyclopropa [d] azepin-2-yl)-1H-pyrazol-3-carboxamide Schematic legend: Rt–ta Step 1: Preparation of 7-bromo-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one

[001724] A solution of bromine (8 mL, 155 mmol) in acetic acid (100 mL) was added to a solution of 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one ( 10 g, 62 mmol). ) and sulfuric acid (5 mL) in acetic acid (100 mL) dropwise at 0oC. After stirring overnight at room temperature, the reaction mixture was poured into ice water (200 mL), neutralized with ammonium hydroxide (28%, 100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 99/1) to obtain the title compound (11.5 g, 77%) as a colorless oil. LC-MS (Method C): m/z = 240.0 [M+H]+, 1.152 min. Step 2: Preparation of 7-bromo-1-trideuteriomethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

[001725] Trideuterized iodomethane (5.9 g, 41 mmol) was added dropwise to a stirred mixture of 7-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (9 g, 38 mmol) and cesium carbonate (13.4 g, 41 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to obtain the title compound (7.2 g, 75%) as a yellow solid. LC-MS (Method C): m/z =257.1 [M + H]+, 1.234 min. Step 3: Preparation of 1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

[001726] Copper iodide (304 mg, 1.6 mmol) was added to a mixture of 7-bromo-1-trideuteriomethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)- one (4.1 g, 16 mmol). , L-proline (368 mg, 3.2 mmol), sodium hydroxide (64 mg, 1.6 mmol) and sodium methanesulfinate (8.16 g, 80 mmol) in dimethyl sulfoxide (20 mL) under nitrogen atmosphere. The reaction mixture was stirred overnight at 120°C. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol/dichloromethane, 1/20) to obtain the title compound (2.7 g, 66%) as a yellow solid. LC-MS (Method C): m/z =257.1 [M + H]+, 0.907 min. Step 4: Preparation of 3-iodo-1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

[001727] N1, N1, N2, N2-tetramethylethane-1,2-diamine (3.8 g, 33 mmol) was added to a stirred mixture of 1-trideuteriomethyl-7-(methylsulfonyl)-4,5-di- hydro-1H-benzo[b]azepin-2(3H)-one (2.7 g, 11 mmol) in dichloromethane (40 mL) at 0°C, followed by addition of iodotrimethylsilane (6.6 g, 33 mmol) drop by drop over 30 minutes. After stirring for 1 hour at 0°C, a solution of iodine (4.2 g, 16.5 mmol) in dichloromethane (100 mL) was added. The reaction mixture was stirred for 2 hours at 0°C, quenched by addition of aqueous sodium thiosulfate (5%, 60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to obtain the title compound (3.5 g, 88%) as a yellow solid. LC-MS (Method S): m/z = 382.9 [M + H]+, 0.826 min. Step 5: Preparation of methyl-7-(methylsulfonyl)-1H-benzo[b]azepin-2(3H)-one 1-trideuterate

[001728] 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.8 g, 25.2 mmol) was added to a stirred mixture of 3-iodo-1-trideuterated methyl-7- ( methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (3.2 g, 8.4 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at 80 °C, quenched by addition of water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to obtain the title compound (1.8 g, 85%) as a yellow solid. LC-MS (Method T): m/z = 255.2 [M+H]+, 0.698 min. Step 6: Preparation of 4-trideuteriomethyl-7-(methylsulfonyl)-1,1a, 2,8b- tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

[001729] 1-Methyl-1-nitrosourea (7.4 g, 70 mmol) was added to a solution of potassium hydroxide (14 g, 350 mmol) in water (21 mL) and ether (100 mL) at 0° W. The resulting mixture was stirred for 1 hour at 0°C and then the organic phase was separated to provide a solution of diazomethane in ether (100 mL). To diazomethane solution (100 ml) was added mixture of 1-trideuteriomethyl-7-(methylsulfonyl)-1H-benzo[b]azepin-2(3H)-one (1.8 g, 7 mmol) in tetrahydrofuran ( 30 mL) dropwise, followed by adding a mixture of palladium diacetate (158 mg, 0.7 mmol) in tetrahydrofuran (10 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The solids were removed by filtration and the filtrates were concentrated in vacuo to obtain the title compound (1.5 gm crude) as a yellow oil. LC-MS (Method E): m/z = 268.9 [M + H]+, 0.757 min. Step 7: Preparation of trans-2-iodo-4-trideuteriomethyl-7-(methylsulfonyl)- 1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

[001730] N1, N1, N2, N2-tetramethylethane-1,2-diamine (1.95 g, 16.8 mmol) was added to a stirring mixture of 4-trideuteriomethyl-7-(methylsulfonyl)-1,1a, 2,8b-tetrahydrobenzo [b]cyclopropa [d]azepin-3(4H)-one (1.5 g, 5.6 mmol) in dichloromethane (30 mL) at 0°C, followed by addition of iodotrimethylsilane ( 3.4 g, 16.8 mmol) dropwise over 30 minutes. After stirring for 1 hour at 0°C, a solution of iodine (2.1 g, 8.4 mmol) in dichloromethane (50 mL) was added. The reaction mixture was stirred for 2 hours at 0°C, quenched by addition of aqueous sodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. to obtain the title compound (1.6 g crude) as a yellow oil. LC-MS (Method S): m/z = 394.9 [M+H]+, 0.892 min. Step 8: Preparation of cis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)- 1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

[001731] Sodium azide (390 mg, 6 mmol) was added to a stirred mixture of trans-2-iodo-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a, 2,8b-tetrahydrobenzo [b] cycloprope [d]azepine-3(4H)-one (1.6 g, 4 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight at room temperature, quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound (800 mg crude) as a yellow oil. LC-MS (Method S): m/z = 309.9 [M+H]+, 0.855 min. Step 9: Preparation of cis-2-amino-4-trideuteriomethyl-7-(methylsulfonyl)- 1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

[001732] A solution of cis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepine-3(4H)-one (800 mg, 2.59 mmol) in methanol (30 mL) was hydrogenated in the presence of palladium on carbon (10%, 100 mg) under a hydrogen atmosphere (2-3 atm). After stirring for 2 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (dichloromethane) to obtain the title compound (500 mg, 68%) as a yellow solid. LC-MS (Method F): m/z = 283.9 [M + H]+, 0.715 min. Step 10: Preparation of 1-benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b] cyclopropa[d]azepin-2-yl)-1H-pyrazol-3-carboxamide

[001733] The crude product obtained using the Amide Bonding Procedure C was purified by Prep-HPLC with the following conditions: Column: Prep C18 Xbridge Column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 32% B to 55% B over 8 min; 254 and 220 nm; RT: 7.38 min to obtain the title compound. LC-MS (Method E): m/z = 486.1 [M + H]+, 1.037 min. Step 11: Preparation of 1-benzyl-4-fluoro-N-((1aR, 2R, 8bS)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a, 2,3,4,8b- hexahydrobenzo [b] cyclopropa [d] azepin-2-yl)-1H-pyrazol-3-carboxamide and 1-benzyl-4-fluoro-N-((1aS, 2S, 8bR)-4-trideuteriomethyl-7- (methylsulfonyl)-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepin-2-yl)-1H-pyrazol-3-carboxamide

[001734] 1-Benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo racemate [b ] cyclopropa[d]azepina-2-yl)-1H-pyrazol-3-carboxamide was separated by pre-chiral HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 22 min; 254 and 220 nm; Ta1: 10.61; Ta2: 16.166 to obtain the title compounds:

[001735] Example 183A (first elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.05 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.5 , 2.3 Hz, 1H), 7.75 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.42-7.31 (m , 5H), 5.33 (s, 2H), 4.66 (s, 1H), 3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2, 06 (m, 1H), 1.38-1.30 (m, 1H), 1.26-1.17 (m, 1H). LC-MS (Method V): m/z = 486.1 [M+H]+, 3.132 min.

[001736] Example 183B (second elution isomer): 1H NMR (400 MHz, CD3OD-d4) δ 8.05 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.5 , 2.3 Hz, 1H), 7.76 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.43-7.30 (m , 5H), 5.33 (s, 2H), 4.66 (s, 1H), 3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2, 07 (m, 1H), 1.37-1.31 (m, 1H), 1.28-1.17 (m, 1H). LC-MS (Method D): m/z = 486.1 [M+H]+, 1,390 min. Example 184: (S)-4-fluoro-1-((1-methyl-1H-pyrazol-4- yl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3-yl)-1H- pyrazol- 3-carboxamide

[001737] Cesium carbonate (453 mg, 1.39 mmol) was added to a stirred mixture of (S)-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5- tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide (100 mg, 0.33 mmol) and 4-(bromomethyl)-1-methyl hydrochloride -1H-pyrazole (208 mg, 0.82 mmol) in N,N-dimethylformamide (7 mL). After stirring for 3 hours at room temperature, the reaction mixture was quenched by adding water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column; Xbridge Prep C18, 5μm, 19 x 150mm; Mobile Phase A; Water (0.1 mmol/L NH4HCO3), Mobile phase B; MeCN; Flow rate: 20 mL/min; Gradient: 15% B to 36% B over 10 min; UV 254 and 220 nm to obtain the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 4.2 Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J = 8.1, 1.5 Hz , 1H), 7.49 (s, 1H), 7.34 (dd, J = 8.1, 4.8 Hz, 1H), 5.19 (s, 2H), 4.91-4.81 ( m, 1H), 4.69 (dd, J = 11.1, 9.6 Hz, 1H), 4.53 (dd, J = 9.6, 7.5 Hz, 1H), 3.82 (s , 3H), 3.37 (s, 3H). LC-MS (Method D): m/z = 400.0 [M+H]+, 1.357 min. Example 188: (S)-5-benzyl-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepin-7-yl) isoxazol-3-carboxamide Scheme caption: Rt - ta

[001738] The crude product was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method E): m/z = 378.2 [M+H]+, 0.998 min. 5-Benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl) isoxazol-3- racemate carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 min; UV 254 and 220 nm; Rt1: 11.1; Rt2: 15.01 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.48-8.35 (m, 2H), 7.35-7.23 ( m, 5H), 6.38 (s, 1H), 4.48 (dd, J = 8.0, 12.0 Hz, 1H), 4.16 (s, 2H), 3.47 (s, 3H ), 3.15-3.05 (m, 1H), 3.02-2.95 (m, 1H), 2.72-2.61 (m, 1H), 2,432.34 (m, 1H). LC-MS (Method D): m/z = 378.0 [M+H]+, 1.645 min. Example 190: (S)-5-benzyl-N- (5-methyl-6-oxo-6.7 ,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide

[001739] The residue was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method C): m/z = 378.1 [M+H]+, 1.141min. 5-Benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1,3 racemate ,4-oxadiazol-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 min; UV 254 and 220 nm; Ta1: 11.1; Ta2: 15.01 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.46 (d, J = 2.8 Hz, 1H), 8.37 (d , J = 2.4 Hz, 1H), 7.37-7.26 (m, 5H), 4.53 (dd, J = 12.0, 7.6 Hz, 1H), 4.32 (s, 2H), 3.48 (s, 3H), 3.18-3.06 (m, 1H), 3.03-2.97 (m, 1H), 2,732.62 (m, 1H), 2.49 -2.39 (m, 1H). LC-MS (Method J): m/z = 379.1 [M+H]+, 1.072 min. Example 192: 5-benzyl-N-((2R, 3S)-2,5-dimethyl-4-oxo -2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)oxazol-2-carboxamide

[001740] The crude product obtained was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18 column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 66% B over 8 min; UV 254 and 220 nm; RT: 6.98 min to obtain the title compound. 1H NMR (400 MHz, CD3OD -d4) δ 8.34 (dd, J = 4.8, 1.6 Hz, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H) , 7.38-7.22 (m, 6H), 7.04 (s, 1H), 5.07-4.96 (m, 2H), 4.13 (s, 2H), 3.50 (s , 3H), 1.42 (d, J = 5.9 Hz, 3H). LC-MS (Method D): m/z = 393.1 [M+H]+, 1.524 min. Example 193: 5-benzyl-N-((3S, 4R)-1,4-dimethyl-2-oxo -1,2,3,4-tetrahydropyrid [2,3-b] [1,4] oxazepine-3-yl)-1,3,4-oxadiazol-2-carboxamide Scheme legend: Rt - ta

[001741] The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.22-8.19 (m, 1H), 7.94-7.90 (m, 1H), 7.43-7.39 (m, 1H), 7.35-7.26 (m, 5H), 5.14-5 .07 (m, 2H), 4.31 (s, 2H), 3.44 (s, 3H), 1.45 (d, J = 6.0 Hz, 3H). LC-MS (Method T): m/z = 394.1 [M+H]+, 1.202 min.Example 194: 5-benzyl-N-((7S, 7aS, 8aR)-5-methyl-6-oxo -5,6,7,7a, 8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepin-7-yl) oxazol-2-carboxamide

[001742] The crude product was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the racemate. LC-MS (Method E): m/z = 390.2 [M + H]+, 1.018 min. 5-Benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a, 8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl racemate )-oxazol-2-carboxamide (50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30 B to 30 B in 15 min; UV 254 and 220 nm; Ta1: 7.635; Ta2: 9.685 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.45-8.40 (m, 2H), 7.39-7.23 (m, 5H), 7.04 (s, 1H), 4.77 (s, 1H), 4.14 (s, 2H), 3.42 (s, 3H), 2.67-2.59 (m, 1H ), 2.28-2.20 (m, 1H), 1.57-1.50 (m, 1H), 1.37-1.28 (m, 1H). LC-MS (Method D): m/z = 390.1 [M+H]+, 1.361 min. Example 195: 1-benzyl-N-((7S, 7aS, 8aR)-5-methyl-6-oxo -5,6,7,7a, 8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H-1,2,3-triazol-4-carboxamide

[001743] The crude product was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method E): m/z = 390.2 [M+H]+, 0.932min. 5-Benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a, 8,8a-hexahydro-cyclopropa [d] pyrazino [2,3-b] azepin-7 racemate -yl)- 1H-1,2,3-triazol-2-carboxamide (50 mg, 0.129 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 20 min; UV 254 and 220 nm; Ta1: 11.273; Ta2: 15.609 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.42-8.38 (m, 3H), 7.41-7.32 (m, 5H), 5.65 (s, 2H), 4.79 (s, 1H), 3.40 (s, 3H), 2.64-2.57 (m, 1H), 2.26-2.20 (m, 1H), 1.54-1.49 (m, 1H), 1.33-1.26 (m, 1H). LC-MS (Method J): m/z = 390.1 [M+H]+, 1.162 min. Example 197: 5-benzyl-N-((7S, 7aS, 8aR)-5-methyl-6-oxo -5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepin-7-yl) oxazol-3-carboxamide Scheme legend: Rt - ta

[001744] The crude product was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method E): m/z = 390.2 [M+H]+, 1.072min. 5-Benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl racemate )- isoxazole-2-carboxamide was separated by Prep-chiral-HPLC, with the following conditions: Column: CHIRALPAK IA, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane: DCM = 5:1, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 24 min; UV 254 and 220 nm; Ta1: 15.4; Ta2: 19.4 to obtain the compound title as the isomer first elution: 1H NMR (400 MHz, CD3OD-d4) δ 8.42-8.38 (m, 2H), 7.36-7.24 (m, 5H), 6.44 (s, 1H), 4.76 (s, 1H), 4.18 (s, 2H), 3.57 (s, 3H), 2.64-2.57 (m, 1H ), 2.24-2.17 (m, 1H), 1.53-1.48 (m, 1H), 1.32-1.26 (m, 1H). LC-MS (Method D): m/z = 390.0 [M+H]+, 1.747 min. Example 198: 5-benzyl-N-((7S, 7aS, 8aR)-5-methyl-6-oxo -5,6,7,7a, 8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-thiadiazole-2-carboxamide Scheme caption: Rt - ta

[001745] The crude product was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method E): m/z = 407.1 [M+H]+, 1.017 min.

[001746] 5-Benzyl-N- (cis-5-methyl-6-oxo-5,6,7,7a, 8,8a- hexahydrocyclopropa[d]pyrazino[2,3-b]- racemate azepin-7-yl)-1,3,4-thiadiazol-2-carboxamide and was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiralpak ID-2, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 26 min; UV 254 and 220 nm; Ta1: 19.418; Ta2: 22.874 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.41-8.37 (m, 2H), 7.38-7.26 (m, 5H), 4.77 (s, 1H), 4.51 (s, 2H), 3.48 (s, 3H), 2.65-2.58 (m, 1H), 2.28-2.22 (m, 1H), 1.56-1.50 (m, 1H), 1.34-1.27 (m, 1H). LC-MS (Method D): m/z = 407.1 [M+H]+, 1,680 min. Example 200: (S)-5-benzyl-N- (2,4-dimethyl-5-oxo-5 ,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-1,3,4-oxadiazol-2-carboxamide Scheme legend: Rt - ta

[001747] The crude product was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the racemate. LC-MS (Method D): m/z = 398.10 [M + H]+, 1.284 min. 5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazol[4,5-b]azepin-6-yl)-1 racemate ,3,4-oxadiazol-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 13 min; UV 220 and 254 nm; Ta1: 7.88; Ta2: 10.109, to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 7.41-7.24 (m, 5H), 4.65 (dd, J = 11 .5, 6.7 Hz, 1H), 4.33 (s, 2H), 3.36 (s, 3H), 3.06-2.84 (m, 2H), 2.72-2.54 ( m, 4H), 2.46-2.33 (m, 1H). LC-MS (Method D): m/z = 398.10 [M+H]+, 1.283min. Example 201: (S)-1-benzyl-N- (5-methyl-4-oxo-2,3 ,4,5-tetrahydro-pyrido[3,2-b][1,4] oxazepin-3-yl)-1H-1,2,3-triazol-4-carboxamide

[001748] The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 2/1) to obtain the title compound: 1H NMR (400 MHz, CD3OD -d4) δ 8.41-8, 33 (m, 2H), 7.68 (dd, J = 8.1, 1.6 Hz, 1H), 7.45-7.28 (m, 6H), 5.66 (s, 2H), 5 .04 (dd, J = 11.6, 7.2 Hz, 1H), 4.69 (dd, J = 9.9, 7.2 Hz, 1H), 4.54 (dd, J = 11.6 , 9.8 Hz, 1H), 3.49 (s, 3H). LC-MS (Method D): m/z = 379.1 [M+H]+, 1.239 min. Example 203: 1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo -2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepina-3-yl)-1H-1,2,3-triazol-4-carboxamide

[001749] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 μm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 66% B over 8 min; UV 254 and 220 nm; RT: 6.68 min to obtain the title compound. 1H NMR (300 MHz, CD3OD-d4) δ 8.27 (s, 1H), 8.23-8.20 (m, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.29-7.17 (m, 6H), 5.54 (s, 2H), 4.97-4.85 (m, 2H), 3.38 (s, 3H), 1.31 (d, J = 6.2 Hz, 3H). LC-MS (Q Method): m/z = 393.2 [M+H]+, 1.354 min. Example 204: 2-benzyl-N-((2R, 3S)-2,5-dimethyl-4-oxo -2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-3 -yl)-2H-1,2,3-triazol-4-carboxamide

[001750] The crude product obtained was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18 column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 72% B over 8 min; UV 254 and 220 nm; RT: 5.95 min to obtain the title compound. 1H NMR (300 MHz, CD3OD-d4) δ 8.32 (dd, J = 4.7, 1.5 Hz, 1H), 8.06 (s, 1H), 7.68 (dd, J = 8, 0, 1.6 Hz, 1H), 7.40-7.27 (m, 6H), 5.70 (s, 2H), 5.09-4.97 (m, 2H), 3.49 (s , 3H), 1.41 (d, J = 6.1 Hz, 3H). LC-MS (Method D): m/z = 393.10 [M+H]+, 1.479 min. Example 205: 1-benzyl-N-((3S, 4R)-1-trideuteriomethyl-4-methyl-2 -oxo- 1,2,3,4-tetrahydropyrido [2,3-b] [1,4] oxazepina-3-yl)-4-fluoro-1H-pyrazol-3-carboxamide Scheme legend: Rt - ta

[001751] The crude product was purified by Prep-HPLC with the following conditions: Column: Kinetex 5 μm EVO C18 OBD Column, 21.2 x 150 mm, 5 μm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Flow Rate: 25 mL/min; Gradient: 30% B to 60% B over 8 min; UV 254 and 220 nm; RT: 7.52 min to obtain the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.23 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.467.32 (m, 6H), 5.35 (s, 2H), 5, 18-5.07 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H). LC-MS (Method O): m/z = 413.2 [M+H]+, 1.472 min. Example 206: 1-benzyl-N-((1aS, 2S, 8bR)-7-cyano-4-trideuteriomethyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cycloprope [ d] azepin-2 - il)-4-fluoro-1H-pyrazol-3-carboxamide Scheme legend: MW - PM; Rt - ta

[001752] The crude product was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method C): m/z = 433.1 [M + H]+, 1.078 min. 1-Benzyl-N-(cis-7-cyano-4-trideuteriomethyl-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepin-2- racemate yl)-4-fluoro-1H-pyrazol-3-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 18 min; UV 254 and 220 nm; Ta1: 8.283; Ta2: 14.011 to obtain the title compound as the second elution isomer: 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d , J = 8.4 Hz, 1H), 7,417.28 (m, 5H), 5.35 (s, 2H), 4.46 (d, J = 6.8 Hz, 1H), 2.39-2 .32 (m, 1H), 2.03-1.96 (m, 1H), 1.19-1.14 (m, 1H), 1.12-1.08 (m, 1H). LC-MS (Method D): m/z = 433.2 [M+H]+, 1.321 min. Example 209: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3 ,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1-(oxazol-4-ylmethyl)-1H-pyrazol-3-carboxamide Scheme legend: Rt - ta

[001753] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18; 19 x 150mm; 5μm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 21% B to 25% B over 10 min; UV 254 and 220 nm to obtain the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J = 0.6 Hz, 1H), 8.36 (dd, J = 4.8 ,1.5 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 4 .5Hz,1H), 7.70 (dd, J = 7.8, 1.5Hz, 1H), 7.33 (dd, J = 8.1, 4.8Hz, 1H), 5.28 (s, 2H),4.89-4.78 (m, 1H), 4.67 (dd, J = 11.4, 9.9 Hz, 1H), 4.50 (dd, J = 9.6 , 7.5 Hz, 1H), 3.35 (s, 3H). LC-MS (Method T): m/z = 387.2 [M+H]+, 0.973 min. Example 213: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5- (pyridin-2-ylmethyl)thiazol-2-carboxamide Scheme legend: Rt - ta

[001754] The title compound was prepared according to the methods described in this document using the appropriate raw material. The crude product was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the title compound: 1H NMR (400 MHz, CD3OD-d4) δ 8.51-8.48 (m, 1H), 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (dd, J = 8.0 , 1.6 Hz, 1H), 7.44-7.38 (m, 1H), 7.34-7.27 (m, 2H), 4.97 (dd, J = 11.5, 7.2 Hz, 1H), 4.67 (dd, J = 9.9, 7.2 Hz, 1H), 4.52 (dd, J = 11.5, 9.9 Hz, 1H), 4.40 (s , 2H), 3.47 (s, 3H). LC-MS (Method D): m/z = 396.0 [M+H]+, 1.786 min. Example 214: (S)-4-fluoro-1-((5-fluoropyridin-2-yl)methyl) -N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001755] The crude product was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 45% B to 50% B over 8 min; UV 254 and 220 nm; RT: 7.33 to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.45 (d, J = 3.0 Hz, 1H), 7.84 (d, J = 4.5 Hz, 1H), 7.65-7.58 (m, 1H), 7.44-7.20 (m, 5H), 5.43 (s, 2H), 4.97 (dd, J = 11, 4, 7.5 Hz, 1H), 4.56 (dd, J = 9.9, 7.5 Hz, 1H), 4.37 (dd, J = 11.4, 9.9 Hz, 1H), 3.41 (s, 3H). LC-MS (Method D): m/z = 414.1 [M+H]+, 1.579 min. Example 215: (S)-5-benzyl-N- (5-methyl-4-oxo-2,3 ,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-1,2,4-oxadiazol-3-carboxamide

[001756] The residue was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 μm, 19 x 150 mm Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over 8 min; UV 254 and 220 nm; RT: 6.65 min to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.36-8.31 (m, 1H), 7.69-7.63 (m, 1H), 7.40-7.26 (m, 6H), 5.07-4.97 (m, 1H), 4.71-4.62 (m, 1H), 4.60-4.49 (s, 1H ), 4.38 (s, 2H), 3.47 (s, 3H). LC-MS (Method D): m/z = 380.1 [M+H]+, 1.322 min. Example 216: (S)-1-((5-chloropyridin-2-yl)methyl)-4-fluoro -N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001757] The residue was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 40% B to 55% B over 8 min; UV 254 and 220 nm; RT: 6.73 to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.51 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.4 , 3.6 Hz, 2H), 7.42-7.35 (m, 1H), 7.32-7.17 (m, 4H), 5.40 (s, 2H), 4.94 (dd, J = 11.4, 7.5 Hz, 1H), 4.54 (dd, J = 9.9, 7.5 Hz, 1H), 4.34 (dd, J = 11.7, 10.2 Hz , 1H), 3.37 (s, 3H). LC-MS (Method D): m/z = 430.1 [M+H]+, 1.673 min. Example 217: 5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo -2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-1,3,4-thiadiazol-2-carboxamide

[001758] The crude product was obtained using the Amide C Bonding Procedure and was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 55% B to 80% B over 6 min; UV 254 and 220 nm; RT: 4.60 to obtain the title compound: 1H NMR (300 MHz, CD3OD-d4) δ 8.34-8.25 (m, 1H), 7.70-7.66 (m, 1H), 7 .39-7.25 (m, 6H), 5.11-4.96 (m, 2H), 4.51 (s, 2H), 3.50 (s, 3H), 1.42 (d, J = 6.0 Hz, 3H). LC-MS (Method D): m/z = 410.0 [M+H]+, 1.725 min.Example 218: 5-benzyl-N-((1aS, 2S, 8bR)-7-cyano-4-methyl -3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazol-3- carboxamide Scheme legend: Rt - ta

[001759] The crude product was purified using Prep-TLC (ethyl acetate/hexane, 3/1) to obtain the racemate. LC-MS (Method D): m/z = 414.1 [M+H]+, 1.222 min. 5-Benzyl-N-(cis-7-cyano-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b] racemate azepina-2-yl)-4H-1,2,4-triazol-3-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20% B to 20% B over 16 min; UV 254 and 220 nm; Ta1: 7.89; Ta2: 8.598 to obtain the title compound as the second elution isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.71 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.37-7.25 (m, 5H), 4.73 (s, 1H), 4.20 (s, 2H), 3.44 (s, 3H), 2 .40-2.33 (m, 1H), 2.21-2.14 (m, 1H), 1.46-1.41 (m, 1H), 1.34-1.26 (m, 1H) . LC-MS (Method D): m/z = 414.1 [M+H]+, 1.221 min. Example 219: (S)-5-(3-cyanobenzyl)-N-(9-methyl-8-oxo -6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)thiazol-2-carboxamide Scheme legend: Rt - ta

[001760] The crude product obtained using the Amide Bonding Procedure C was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the racemate. LC-MS (Method S): m/z = 418.1 [M+H]+, 1.025 min. 5-(3-cyanobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl) racemate thiazol-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: (R,R)Whelk-O1, 21.1 x 250 mm, 5 μm; Mobile Phase A: Hexane: Dichloromethane = 4.5:1, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 70% B to 70% B over 23 min; UV 254 and 220 nm; Ta1: 12.88; TA 2: 18.81 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CD3OD-d4) δ 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 7.81 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.66-7.61 (m, 2H) , 7.55-7.51 (m, 1H), 7.31-7.27 (m, 1H), 4.52-4.46 (m, 1H), 4.35 (s, 2H), 3 .48 (s, 3H), 2.94-2.79 (m, 2H) 2.69-2.58 (m, 1H), 2.34-2.24 (m, 1H). LC-MS (Method D): m/z = 418.0 [M+H]+, 1.716 min. Example 220: (S)-4-fluoro-1-((6-methoxypyridin-2-yl)methyl) -N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide

[001761] The crude product was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 40% B to 50% B over 8 min; UV 254 and 220 nm; RT: 8.07 min to obtain the title compound. 1H NMR (300 MHz, CD3OD-d4) δ 7.85 (d, J = 4.5 Hz, 1H), 7.63 (dd, J = 8.1, 7.2 Hz, 1H), 7.43 -7.40 (m, 1H), 7.39-7.20 (m, 3H), 6.78 (d, J = 7.2, 1H), 6.71 (d, J = 8.4, 1H), 5.32 (s, 2H), 4.98 (dd, J = 11.4, 7.5 Hz, 1H), 4.58 (dd, J = 9.9, 7.5 Hz, 1H ), 4.37 (dd, J = 11.4, 9.9 Hz, 1H), 3.86 (s, 3H), 3.40 (s, 3H). LC-MS (Method D): m/z = 426.2 [M+H]+, 1.755 min. Example 221: 5-(difluoro(phenyl)methyl)-N-((2R,3S)-2.5 -dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazol-2-carboxamide

[001762] The crude product was purified by Prep-HPLC with the following conditions: Column: Gemini-NX/5u, C18 150 x 21.2 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 47% B to 60% B over 10 min; UV 254 and 220 nm; RT: 8.82 min to obtain the title compound. 1H NMR (300 MHz, CD3OD-d4) δ 8.33 (dd, J = 4.8, 1.8 Hz, 1H), 7.69-7.66 (m, 3H), 7.62-7, 53 (m, 3H), 7.32 (dd, J = 8.1, 4.8 Hz, 1H), 5.08-4.93 (m, 2H), 3.50 (s, 3H), 1 .44 (d, J = 6.3 Hz, 3H). LC-MS (Method O): m/z = 430.1 [M+H]+, 1.679 min. Example 222: 5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo -2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepina-3-yl)-1,2,4-oxadiazol-3-triazol-3-carboxamide Scheme legend: Rt - ta

[001763] The crude product obtained was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18 column, 5 μm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 40% B to 70% B over 8 min; UV 254 and 220 nm; RT: 5.87 min to obtain the title compound. 1H NMR (300 MHz, CD3OD-d4) δ 8.35-8.31 (m, 1H), 7.71-7.66 (m, 1H), 7.41-7.27 (m, 6H), 5.10-4.97 (m, 2H) 4.39 (s, 2H), 3.49 (s, 3H), 1.40 (d, J = 6.2 Hz, 3H). LC-MS (Method D): m/z = 394.1 [M+H]+, 2.709 min. Example 223: 5-(4-fluorobenzyl)-N-((7S,7aS,8aR)-5-methyl -6-oxo- 5,6,7,7a, 8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazol-2-carboxamide Scheme legend: Rt - ta

[001764] The crude product was purified using Prep-TLC (ethyl acetate/petroleum ether, 3/1) to obtain the racemate. LC-MS (Method D): m/z = 409.05 [M+H]+, 1.255min. 5-(4-fluorobenzyl)-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepine racemate -7-yl)-1,3,4-oxadiazol-2-carboxamide was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 16 min; UV 254 and 220 nm; Ta1: 10.514; Ta2: 13.482 to obtain the title compound as the first eluting isomer: 1H NMR (400 MHz, CDCl3-d) δ 8.49-8.32 (m, 3H), 7.39-7.28 (m, 2H), 7.14-6.94 (m, 2H), 4.85 (d, J = 7.0 Hz, 1H), 4.25 (s, 2H), 3.45 (s, 3H), 2.71-2.62 (m, 1H), 2.30-2.21 (m, 1H), 1.57-1.50 (m, 1H), 1.30-1.22 (m, 1H ). LC-MS (Method V): m/z = 409.05 [M+H]+, 2,450 min. Example 224: (S)-4-fluoro-N-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazol-3-carboxamide

[001765] The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5 μm, 19 x 150 mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 16% B to 43% B over 8 min; UV 254 and 220 nm; RT: 7.47 min to obtain the title compound. 1H NMR (300 MHz, CD3OD-d4) δ 8.81-8.77 (m, 2H), 7.91-7.87 (m, 1H), 7.48-7.41 (m, 2H), 7.38-7.21 (m, 3H), 5.58 (s, 2H), 5.03-4.95 (m, 1H), 4.62-4.56 (m, 1H), 4, 43-4.34 (m, 1H), 3.42 (s, 3H). LC-MS (Method D): m/z = 397.0 [M+H]+, 2.334 min. Example 225: (S)-5-benzyl-N-(1-methyl-2-oxo-2,3 ,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1,3,4-oxadiazol-2-carboxamide

[001766] 1H NMR (300 MHz, CD3OD -d4) δ 7.47-7.18 (m, 9H), 4.47 (dd, J = 11.7, 7.9 Hz, 1H), 4.31 (s, 2H), 3.40 (s, 3H), 2.93-2.82 (m, 1H), 2.73 (dd, J = 13.6, 6.8 Hz, 1H), 2, 52-2.43 (m, 1H), 2.33-2.21 (m, 1H). LC-MS (Method D): m/z = 377.0 [M+H]+, 1.732 min.

[001767] The other compounds in Table 1 were or can be prepared according to the Examples above and/or general procedures described in this document using appropriate raw materials.

Biological Tests

[001768] The compounds were tested for cellular kinase binding and activity according to the following protocols. The enzyme proGST-hRIPK1 (8-327) was generated by Proteros GmbH by the baculovirus expression system.

[001769] The cellular necroptosis assay (IC50 of cells in Tables 5-7) evaluates the ability of compounds to reverse necrosis induced by human TNFα. Ten concentrations of the test compounds were evaluated in duplicate on two different testing occasions. FADD-deficient Jurkat cells were purchased from ATCC (ATCC-CRL-2572) and cultured in suspension in RPMI medium supplemented with 10% heat-inactivating FBS and 1% Pen-Strep. The experimental cells were diluted to a density of 0.12x105 cells/mL (5,000 cells/well) with culture medium and added (40 μL) to the 384-well plate containing 0.2 μL/well of test compounds and reference compounds (CRCs) (200x). The cell plates were then incubated at 37°C-5% CO2. After 30 min, necroptotic cell death was induced with human TNFα (10 ng/mL) and cell viability was assessed 48 h later by measuring cellular ATP levels using the CellTiter-Glo® kit (Promega). Luminescence was read using the Victor V multi-label plate reader (Perkin Elmer). Data were expressed as % of maximum calculated viability, comparing values with non-TNFα-treated control cells representing 100% cell viability. CRCs were analyzed by Dotmatics and IC50 values were calculated by non-linear regression using the 4-parameter logistic equation.

[001770] Fluorescent Polarization Binding (FP Binding) Assay (Berger SB et al. (2015) Cell Death Discovery, 1: 15009; Maki J.L. et al. (2012) Anal Biochem, 427 (2): 164-174) was performed in a low-volume polystyrene 384-well black plate at room temperature (RT) in a final volume of 10.1 μl/well using 10 nM of GST-hRIPK1 (8-327) enzyme and 5 nM of labeled ligand with fluorescence (14-(2- {[3-({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-pyrimidinyl }amino)propyl]amino}-2-oxoethyl)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octa-hydrobenzo[2"3"]indolizino[ 8",7":5',6,]pyrano[3',2':3,4]pyrido[1,2-a]indole-5-io-2-sulfonate.

[001771] The Test Compounds of the invention were serially diluted in DMSO to final concentrations of 100 times the assay (1% final DMSO). Into each well of a 384-well plate, 0.1 μL of compound solution (or DMSO for controls) was dispensed followed by 5 μL of GST-hRIPK1 (8-327) at twice the final concentrations in assay buffer (HEPES 50 mM pH 7.5, 10 mM NaCl, 50 mM MgCl2, 0.02% CHAPS, 0.5 mM DTT and 0.01% Pluronic F127). For negative control, the addition of enzyme was replaced with assay buffer only.

[001772] After adding 5 μl of fluorescently labeled ligand at twice the final concentrations in assay buffer, the plate was incubated at room temperature for 30 min. At the end, binding was measured as FP value with the Envision plate reader (PerkinElmer) using a filter for an excitation À = 531 nm FP and an emission À = 595 nm FP (S and P-pol).

[001773] The enzyme GST-hRIPK1 (8-327) was generated by Proteros GmbH by the baculovirus expression system.

[001774] Test compounds were diluted in DMSO and 0.1 μL of solution was dispensed into each well of a 384-well white solid microplate. The assay buffer was 50 mM HEPES, pH 7.5, 50 mM NaCl, 30 mM MgCl2. The buffer was supplemented with 0.02% CHAPS, 0.01% Pluronic F127, 0.1 mg/mL BSA, and 1 mM DTT. MnCl2, 5 mM, was included in the assay buffer on the day of the experiment. The enzymatic reaction comprised 1.5 μL/mL GST-hRIPK1 (8-327) and 50 μM ATP for receptor-interacting protein kinase 1 and 15 μM ATP. 5 μL of enzyme and 5 μL of ATP were added to the plate at twice the final assay concentration and incubated at room temperature for 3 hours. After this reaction, 10 μL of ADP-Glo reagent (Promega) was added to each well and incubated for 40 min at room temperature. This stops the kinase reaction and uses up any remaining ATP. 20 μL of ADP-Glo detection reagent was then added to each well and incubated at room temperature for at least 15 minutes. The detection reagent converts ADP to ATP and introduces luciferase and luciferin to detect ATP. Luminescence is then measured with the Envision plate reader (PerkinElmer). Inhibition of the test compound was expressed as percentage inhibition of the assay's internal controls. For concentration response curves, normalized data is suitable and IC50 determined using XL-fit (IDBS) for Excel. The IC50 were averaged to determine a mean value for a minimum of two independent experiments.

[001775] The inhibition of the test compound was expressed as a percentage of inhibition of the assay's internal controls. For concentration response curves, normalized data is suitable and IC50 determined using XL-fit (IDBS) for Excel. The IC50 were averaged to determine a mean value for a minimum of two independent experiments.

[001776] the cellular activity of protein kinase 1 that interacts with the receptor and the binding of exemplary compounds was determined according to the general procedure above. The results are summarized in Table 5. In the table below, the activity is given as follows: +++ = 0.0001 μM <IC50 <1 μM; ++ = 1 μM <IC50 <10 μM; + = 10 μM <IC50; ++* = 3 μM <IC50.Table 5 Table 6 Table 7 Comparative Compounds

[001777] The comparative compounds in Table 7 were prepared as described in Examples 12, 146 and 77, respectively, of WO 2014/125444.

[001778] The in vivo efficacy of the compounds can be determined in mice using a TNF-induced systemic inflammatory response syndrome model as described by Duprez et al. al. (2011, Immunity 35 (6), 908-918) and Berger et. al. (2015, Cell Death Disc. 1, 15009). In this model, the TNF/zVAD system (tumor necrosis factor/Z-Val-Ala-DL-Asp-fluoromethylketone, a caspase inhibitor) treatment results in temperature loss and production of several inflammatory cytokines. The ability of a test compound to inhibit these inflammatory effects can be measured in this model by dosing mice with the test compound 15 minutes prior to administration of TNF/zVAD and measuring the inflammatory response. The dose required to inhibit the inflammatory response is a measure of the effectiveness of the compounds at that dose. Using this model, compound 42 was pre-administered orally at 5 mg/kg 15 minutes before intravenous administration of TNF/zVAD and temperature loss in mice was measured by an implanted temperature chip. Treatment of mice with 5 mg/kg of Compound 42 resulted in 96% inhibition of temperature loss when compared to TNF/zVAD vehicle-treated animals. In comparison, WO 2014/125444 discloses in Table 2 that Example 12, corresponding to Example A of Table 7 above, required a dose of 30 mg/kg to achieve 93% inhibition. Decreased dosage has several important potential advantages, including the need for less frequent administration to a patient, greater patient compliance, and improved safety profile, such as lower toxicities, while achieving similar efficacy.

[001779] Based on the known crystal structure of comparative Example C and protein that interacts with receptor kinase 1 (Harris et al. J. Med. Chem., 2016, 59 (5), pg. 2163-2178), the atom of the phenyl carbon adjacent to the azepinone moiety (i.e., X9 of the formulas disclosed herein) interacts with a lipophilic pocket of protein that interacts with receptor kinase 1

[001780] Certain compounds have been discovered to have significantly improved metabolic stability when X9 of the formulas disclosed herein is an N atom compared to a carbon atom. For example, Compound 42, compared to Comparative Example A, when tested according to the assay described below, was found to have a mean hepatocyte clearance of 0.8 ml/min/kg versus 6.8 ml/min /kg for Comparative Example A. As described in the metabolic stability section below, a CLhep of 6.8 ml/min/kg corresponds to a clearance of approximately 32% of hepatic blood flow, while for Compound 42, a value of CLhep of 0.8 mL/min/kg corresponds to a clearance of less than 4% of hepatic blood flow, demonstrating a significant improvement in the stability of compounds Those skilled in the art that compounds with lower human CLhep values should allow for lower human clinical doses, less frequent administration to a patient, greater patient compliance, and improved safety profile such as lower toxicity. MDCKII-MDR1 Permeability

[001781] The blood-brain barrier (BBB) separates circulating blood from the extracellular fluid of the central nervous system (CNS). Passive membrane permeability (Papp) and the efflux potential of the substrate P-gp (P-glycoprotein) were determined using the MDCKII-MDR1 cell line as a model of the effective in vitro permeability of a compound across the BBB. A bidirectional assay (Apical to Basolateral (A^B) and Basolateral to Apical (B^A)) in the absence and presence of GF120918 (a P-gp inhibitor) was conducted using preplated MDCKII-MDR1 cells (Corning HTS Transwell-96) obtained from SOLVO Biotechnology. The assay was performed at 3 μM for 90 min (minutes) in triplicate using a transport buffer HBSS + HEPES + 12.5 mM pH 7.4. After incubation of the donor and recipient samples, the wells were removed and measured by LC-MS/MS. Samples were extracted by protein precipitation with acetonitrile containing an appropriate internal standard (IS) having a known mass and molecular weight. The precipitate was centrifuged for 10 min at 3000 rpm (revolutions per minute). Supernatants were then collected, diluted if necessary, and injected into the LC-MS/MS system. Precursor/product ion pairs specific to the test article and IS were used to selectively measure the test articles. Papp values (apparent permeability expressed in nm/sec [nanometer/second]) were calculated according to the following equation:

[001782] Where dQ/dt is the permeability rate, C0 is the initial concentration in the donor solution (expressed as IS ratio), A and B are the surface areas of the filter (the surface area of the cell monolayer).

[001783] Monolayer efflux relationships (ER) were derived using the following equation:

[001784] Compounds with an MDCKII-MDR1 efflux ratio of less than or equal to 2.5 are likely to demonstrate the ability to cross the blood-brain barrier.

Metabolic Stability (Hepatocytes)

[001785] The metabolic stability of the compounds was evaluated in cryopreserved human hepatocytes (BioreclamationIVT, NY, USA) in duplicate. Test articles (or controls) were added to a 24-well incubation plate (Becton Dickinson Labware, USA) containing 0.5 x 106 hepatocytes/mL in suspension. The plate was maintained at 37°C and stirred with constant orbital shaking (orbital speed at 350 rpm). At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150 and 180 min) a Tecan Evo robot aspirated 50 μL of the incubation mixture and 100 μL of acetonitrile containing internal standard to quench the reaction. The quenched mixtures were dispensed into a 96-well plate along with 120 μL of aqueous solution to equilibrate the solvent content to 37%. Samples were centrifuged (3000 rpm for 10 minutes) and the plate sealed before injection into an LC-MS/MS system.

[001786] Appropriate precursor/product ions were monitored for the test article and the IS with the LC-MS/MS system. Intrinsic clearance (Clint; expressed μL/min/million cells) was determined from the first order elimination constant (k, min-1) of the test article decay and the incubation volume. scaled for intrinsic organ clearance (CLint) using human specific scaling factors (139 X 106 hepatocytes/g liver and 25.7 g liver/kg body weight). The intrinsic organ CL was then converted to hepatic clearance (CLhep) using the well-shaken model as shown below, where Qh is human hepatic blood flow.

[001787] Hepatic clearance is expressed in mL/min/kg. Hepatic clearance refers to the blood flow through the liver that is completely eliminated of the compound. A human CLhep of 20.9 mlL/min/kg corresponds to approximately complete compound clearance by the liver or 100% hepatic blood flow. Thus, a human CLhep of 6 mL/min/kg corresponds to a clearance of approximately 29% of hepatic blood flow. A human CLhep value of 2 mL/min/kg corresponds to a clearance of approximately 10% of hepatic blood flow. A human CLhep value of 1 mL/min/kg or less corresponds to a clearance of approximately 5% of hepatic blood flow or less. A human CLhep value of 0 mL/min/kg corresponds to undetectable compound clearance by the liver.

[001788] In certain embodiments, compounds are provided with a CLhep of less than 5, 4, 3, 2 or 1 mL/min/kg when tested in accordance with the above human liver stability assay. In certain embodiments, these compounds do not readily cross the blood-brain barrier. In certain embodiments, these compounds have an MDCKII-MDR1 efflux ratio greater than 2.5.

[001789] In certain embodiments, compounds are provided with a CLhep of less than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 mL/min/kg when tested according to the hepatic stability assay in humans above. In certain embodiments, these compounds are capable of crossing the blood-brain barrier. In certain embodiments, these compounds have an MDCKII-MDR1 efflux ratio of 2.5 or less.

[001790] Protein binding in plasma was determined using a fast equilibrium dialysis device (Thermo Scientific RED Device) or a 96-well dialysis device (HTDialysis LLC). Plasma was contaminated with test/control compounds to obtain a final concentration of 0.5 μM (plasma). If necessary, plasma samples were preincubated (2 hours at 37°C) with diisopropyl fluorophosphate (DFP) at a final concentration of 100 μM to prevent degradation of the compound due to amide hydrolysis. Appropriate volumes of spiked samples along with white phosphate buffer were added to either device and incubated at 37°C for a total of 5 hours with shaking at 500 rpm. After incubation, an equal aliquot of dialyzed matrix (plasma or buffer) is added to an equal volume of the opposite blank matrix, such that the volume of buffer to plasma is equal. Mixed matrix samples were extracted by protein precipitation using acetonitrile containing the appropriate IS. Samples were then centrifuged for 10 min at 2800 rpm. Supernatants were collected and diluted and then injected into an HPLC-MS/MS or UPLC-MS/MS system. Samples were analyzed by monitoring appropriate precursor/product ion transitions for test and control compounds. Peak area ratios were used to measure test item concentrations. The unbound fraction (Afu) was determined as the ratio of the peak area ratio in buffer divided by the peak area ratio in plasma. In Vivo Pharmacokinetic (PK) Studies

[001791] The PK properties of the test articles were determined in male Sprague-Dawley Crl:CD (SD) mice, male Beagle dogs and male cynomolgus monkeys. Studies were conducted to the highest standards of animal welfare, in accordance with national legislation and under approval by internal animal care and use committees.

[001792] The compounds were administered by IV bolus to the animals after an overnight fast. Compounds for IV administration were formulated as solutions using 1% DMSO (dimethylsulfoxide): 20% PEG400 (polyethylene glycol 400): 79% saline or 5-50% NMP in D5W (5% dextrose in water). The formulations were administered in dose volumes ranging from 0.52 mL/kg. The IV dose ranged from 0.5-1 mg/kg.

[001793] After dose administration, 8-9 serial blood samples were collected over 24 hours. Samples were mixed with anticoagulant and placed on wet ice before processing. Plasma was collected after centrifugation and extraction using protein precipitation with acetonitrile containing IS. The processed supernatant was analyzed using UPLC or LC-MS/MS using precursor/product ion pairs specific to the test article and IS. Plasma concentrations were determined using a calibration curve prepared using known analyte concentrations. Pharmacokinetic parameters using measured concentrations were calculated using Phoenix WinNonlin. Unbound plasma clearance was calculated as the ratio of total body clearance divided by the unbound fraction in plasma.

[001794] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs.

[001795] The inventions described illustratively in this document may conveniently be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed in this document. Thus, for example, the terms "comprising", "including", "containing", etc. should be read expansively and without limitation. Furthermore, the terms and expressions used in this document have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described, or parts thereof, but it is recognized that various modifications are possible within the scope of the claimed invention.

[001796] All publications, patent applications, patents and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, this descriptive report, including definitions, will serve as a basis for control.

[001797] It should be understood that although the description has been described in conjunction with the above embodiments, the previous description and examples are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications to the scope of the invention will be apparent to those skilled in the art to which the description pertains.

Claims (29)

1. Compound of Formula II: or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that q is 0 or 1; X6 and X7 are each N or CH; X8 is CH; X9 is N; R1 is H or C1-C6 alkyl optionally substituted with halo, hydroxy, deuterium or cyano; Y2 is -O- or -C(R6)2-; each R6 is independently H, or two R6, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; R3 and R4 are independently H or C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring, or R3 and R6, together with the carbon atoms to which they are attached which are linked, form a C3-C6 cycloalkyl ring; A is an optionally substituted heteroaryl ring; L is absent, -O- or -C(R8)2-; each R8 is independently H or halo, or two R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; R9 is optionally substituted phenyl, optionally substituted heteroaryl, or cycloalkyl, wherein said cycloalkyl refers to a cyclopentyl that is fused to a phenyl ring; and each R10 is independently cyan; provided that at least one of the following occurs: (1) at least one of R3 and R4 is C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring; (2) L is absent or -C(R8)2-, and each R8 is halo, or two R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; (3) Y2 is -C(R6)2-; and two R6, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; (4) Y2 is -O-; and A is replaced with halo or cyano; or A is thiazolyl; or (5) R1 is C2-C6 alkyl; wherein the term "heteroaryl" refers to furanyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl or thiophenyl; and the substituents to which “optionally substituted” refers are selected from halo, cyano or C1-C6 alkyl. 2. Compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that the compound is a compound of Formula (IIe) or (IIf): or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0 or 1; R1 is H or optionally deuterated C1-C6 alkyl; Y2 is -O- or -C(R6)2-, each R6 is independently H, or two R6, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; R3 and R4 are independently H or C1-C6 alkyl, or R3 and R4, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring, or R3 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring, or R3 and R6, together with the carbon atoms to which they are attached, which are linked, form a C3-C6 cycloalkyl ring; A is an optionally substituted heteroaryl ring; L is -C(R8)2- or is absent, or is -O-; each R8 is independently H or halo, or two R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; R9 is phenyl, optionally substituted heteroaryl, or cycloalkyl, wherein said cycloalkyl refers to cyclopentyl that is fused to a phenyl ring; and each R10 is independently cyan. 3. Compound according to claim 2, characterized by the fact that the compound is of Formula IIf-1 or IIe-1: tautomer, pharmaceutically acceptable stereoisomers thereof, wherein q is 0 or 1; R1 is H or C1-C6 alkyl; R4 is H; A is an optionally substituted heteroaryl ring; L is -C(R8)2- or is absent, or is -O-; each R8 is independently H or halo, or two R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; R9 is optionally substituted aryl, optionally substituted heteroaryl or cycloalkyl, wherein said cycloalkyl refers to cyclopentyl which is fused to a phenyl ring; and each R10 is independently cyano, wherein, unless otherwise specified, the term "aryl" independently refers to an aromatic carbocyclic group of 6 to 20 ring carbon atoms having a single ring or multiple rings, including fused systems. 4. Compound according to claim 2, characterized by the fact that the compound is a compound of Formula IIe: or a tautomer, stereoisomer or mixture of stereoisomers thereof. 5. Compound according to claim 4, characterized by the fact that the compound is of Formula IIe-2, Formula IIe-3, Formula IIe-4, Formula IIe-5 or Formula IIe-6: or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 6. Compound according to claim 5, characterized in that the compound is of Formula IIe-2 or IIe-4, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 7. Compound according to claim 2, characterized in that the compound is of Formula IIf, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 8. Compound according to claim 7, characterized in that the compound is of Formula IIf-2, Formula IIf-3, Formula IIf-4, Formula IIf-5 or Formula IIf-6: or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 9. Compound according to any one of claims 1 to 8, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that ring A is a furanyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, optionally substituted pyrazolyl, thiazolyl ring, thiadiazolyl, triazolyl, tetrazolyl, triazinyl or thiophenyl; or wherein A is phenyl; or where ring A is: wherein each ring is optionally substituted by one or more halo, cyano or C1-C6 alkyl. 10. Compound according to any one of claims 1 to 8, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl , triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, cyclobutyl, cyclopropyl or azetidinyl; and/or wherein A is pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl; and/or wherein A is oxadiazolyl. 11. Compound according to claim 10, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that A is triazolyl. 12. Compound according to any one of claims 1 to 8, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized by the fact that L is -C(R8)2-. 13. Compound, characterized by the fact that it is represented by Formula V: or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0 or 1; X6 is N or CR14; X9 is N; R1 is H or optionally substituted or optionally deuterated C1-C6 alkyl; Y2 is -O- or -C(R6)2-; each R6 is independently H, halo, or optionally substituted C1-C6 alkyl; R3 is H or C1-C6 alkyl, or R3 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring; L is -C(R8)2-; each R8 is independently H, or two R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring or heterocyclyl ring; R9 is optionally substituted phenyl or optionally substituted heteroaryl; each R10 is independently cyano, or -S(O)2-C1-C6 alkyl; and each R14 is independently hydrogen; wherein the term "heteroaryl" refers to furanyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl or thiophenyl; and the substituents to which “optionally substituted” refers are selected from halo or cyano. 14. Compound of Formula VI, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized by the fact that q is 0 or 1; X6 is N or CR14; R1 is H or optionally substituted or optionally deuterated C1-C6 alkyl; Y2 is -O- or -C(R6)2-; each R6 is H; R3 is H or C1-C6, or R3 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring; L is -C(R8)2-; each R8 is independently H or halo, or two R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl ring; R9 is optionally substituted phenyl; each R10 is independently halo or C1-C6 alkyl; and R14 is hydrogen; wherein the substituents to which “optionally substituted” refers are selected from halo. 15. Compound according to claim 13 or 14, characterized by the fact that X6 is CR14; or where X6 is N. 16. Compound according to any one of claims 1 to 8, 13 and 14, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized by the fact that R1 is C1-C6 alkyl; preferably wherein R1 is methyl. 17. Compound according to any one of claims 1-2, 4-8, 13 and 14, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized by the fact that Y2 is O; and/or wherein R3 is hydrogen or fluorine; and/or wherein R3 is H; and/or wherein R3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl, preferably wherein R3 and R6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring substituted; and/or wherein R4 is optionally substituted C1-C6 alkyl, preferably wherein R4 is methyl; and/or wherein R4 is H; and/or where L is -C(R8)2- and each R8 is independently H, or two R8, together with the carbon atom to which they are attached, form the C3-C6 cycloalkyl ring; or where L is -C(R8)2- and two R8, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl ring, preferably where L is -C(R8)2- and two R8 are taken together with the carbon atom to which they are attached to form cyclopropyl; and/or wherein L is CH2; and/or wherein R9 is optionally substituted phenyl; and/or wherein R9 is phenyl, dihydroindenyl, pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 3-cyano-4 -fluorophenyl, or 5-fluoropyridin-3-yl; and/or wherein R9 is phenyl optionally substituted by one or more halos, or cyano, preferably wherein R9 is phenyl substituted by one to two halos. 18. Compound, characterized by the fact that it is or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 19. Compound, characterized by the fact that it has the following structure: or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. 20. Compound, according to claim 19, characterized by the fact that it is: or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof. 21. Compound according to claim 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that the compound is: 22. Compound according to claim 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that the compound is: 23. Compound according to claim 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that the compound is: 24. Compound according to claim 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that the compound is: 25. Compound according to claim 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, characterized in that the compound is: 26. Pharmaceutical composition, characterized in that it comprises a compound, or a salt, tautomer, pharmaceutically acceptable stereoisomer or a mixture of stereoisomers thereof as defined in any one of claims 1 to 25 and an excipient. 27. Use of the compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer or stereoisomer mixture thereof, as defined in any one of claims 1 to 25, or a pharmaceutical composition as defined in claim 26, characterized in that it is for the manufacture of a drug for the treatment of a disease or disorder mediated by receptor-interacting protein kinase 1. 28. Use according to claim 27, characterized in that the disease or disorder is an inflammatory disease or disorder, a necrotic cellular disease, a neurodegenerative disease, a central nervous system (CNS) disease, an eye disease, a malignancy, an immune-mediated disease, an allergic disease, an autoimmune disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, rejection of transplant, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, stroke, myocardial or cardiac infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, fever syndrome associated with interleukin-1 converting enzyme, chronic obstructive pulmonary disease, periodic syndrome associated with tumor necrosis factor receptor, periodontitis, trauma, ischemia, stroke, heart attack cardiac, infection, lysosomal storage disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), HIV-associated dementia, retinal degenerative disease, glaucoma, related macular degeneration to age, psoriasis, psoriatic arthritis, brain injury, spinal cord injury, spinal muscular atrophy, dementia, Huntington's disease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, Friedreich's ataxia, dementia with Lewy bodies, or a disorder caused by prions. 29. Use according to claim 27, characterized by the fact that the disease or disorder is multiple sclerosis, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Alzheimer's disease, rheumatoid arthritis, or psoriasis.