RU2797922C2 - Bicyclic ketones and methods of their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound having the general formula (I)

where R¹, ring A and ring B are as described in the claims, which is used to inhibit the activity of RIP1 kinase, to a pharmaceutical composition containing this compound, to the use of this compound and to a method of treatment using this compound.

EFFECT: development of a new RIP1 kinase inhibitor useful for the treatment of diseases and disorders associated with inflammation, cell death and other causes.

28 cl, 2 tbl, 163 ex

Description

FIELD OF THE INVENTION

The present invention relates to organic compounds useful in the therapy and/or prevention of a mammal, and in particular to RIP1 kinase inhibitors useful in the treatment of diseases and disorders associated with inflammation, cell death and other causes.

PRIOR ART

Receptor-interacting protein-1 kinase ("RIP1") is a serine/threonine protein kinase. RIP1 is a cell signaling pathway regulator that is involved, among other things, in mediating programmed cell death pathways such as necroptosis. The most studied form of necroptotic cell death is initiated by TNFα (tumor necrosis factor), however, necroptosis can also be induced by other members of the TNFα family of "death ligands" (Fas and TRAIL/Apo2L (TNF-dependent apoptosis-inducing ligand/apolipoprotein 2 ligand) ), interferons, signal transduction via Toll-like receptors (TLRs), and viral infection via the DNA sensor DAI (DNA-dependent activator of interferon-regulating factors) [1-3]. Binding of TNFα to TNF receptor 1 (TNFR1) causes trimerization of TNFR1 and formation of an intracellular complex, complex-1. TRADD (TNF receptor death domain interacting protein) binds to the TNFR1 intracellular death domain and recruits RIP1 protein kinase (receptor interacting protein 1) through the death domain present in both proteins [4]. After initial recruitment to the TNFR1-associated signaling complex, RIP1 translocates to the secondary cytoplasmic complex, complex-II [5-7]. Complex-II is formed with the participation of the death-domain-containing protein FADD (Fas-associated death domain protein), RIP1, caspase-8 and cFLIP (cellular inhibitory protein of interleukin-1-beta-converting enzyme like Fas-associated death domain protein) . If caspase-8 is not fully activated or its activity is blocked, then protein kinase RIP3 is recruited into this complex with the formation of a necrosome, which will lead to the initiation of necroptotic cell death [8-10]. Once the necrosome is formed, RIP1 and RIP3 are involved in a series of auto- and cross-phosphorylation events that are required for necroptotic cell death. Necroptosis can be completely blocked either due to the presence of a kinase-inactivating mutation in either of these two kinases, or chemically using RIP1 kinase inhibitors (necrotatins) or RIP3 kinase inhibitors [11-13]. Phosphorylation of RIP3 promotes binding and phosphorylation of pseudokinase MLKL (pseudokinase of mixed origin), a key component of necroptotic cell death [14, 15].

Necroptosis is of decisive pathophysiological significance in myocardial infarction, stroke, atherosclerosis, ischemic/reperfusion injury, inflammatory bowel disease, retinal degenerative changes, and a number of other general clinical disorders [16]. In view of this, selective inhibitors of RIP1 kinase activity are desirable as a possible treatment for diseases mediated by this pathway and associated with inflammation and/or necroptotic cell death.

RIP1 kinase inhibitors have been described previously. Necrostatin 1 (Nec-1) was the first inhibitor of RIP1 kinase activity reported in the literature [17]. This first discovery was followed by the development of modified versions of Nec-1 with different abilities to block RIP1 kinase activity [11, 18]. Recently, other RIP1 kinase inhibitors have been described that are structurally different from compounds of the necrostatin class [19, 20, 21].

The above are references, each of which is hereby incorporated by reference in its entirety:

1) Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. and Vandenabeele, P. (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. nature reviews. Molecular cell biology. 15, 135-147.

2) Newton, K. (2015) RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends in cell biology. 25, 347-353.

3) de Almagro, M.C. and Vucic, D. (2015) Necroptosis: Pathway diversity and characteristics. Semin. cell dev. Biol., 39, 56-62.

4) Chen, Z.J. (2012) Ubiquitination in signaling to and activation of IKK. Immunological reviews. 246, 95-106.

5) O'Donnell, M.A., Legarda-Addison, D., Skountzos, P., Yeh, W.C. and Ting, A.T. (2007) Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol., 17, 418-424.

6) Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D.P., Langlais, C, Hupe, M., Cain, K., MacFarlane, M., Hacker, G. and Leverkus, M. ( 2011) clAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. molecular cell. 43, 449-463.

7) Bertrand, M.J., Milutinovic, S., Dickson, K.M., Ho, W.C., Boudreault, A., Durkin, J., Gillard, J.W., Jaquith, J.B., Morris, S.J. and Barker, P.A. (2008) clAP1 and clAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. cell. 30, 689-700.

8) Wang, L., Du, F. and Wang, X. (2008) TNF-alpha induces two distinct caspase-8 activation pathways. cell. 133, 693-703.

9) He, S., Wang, L, Miao, L, Wang, T., Du, F., Zhao, L. and Wang, X. (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF- alpha. cell. 137, 1100-1111.

10) Cho, Y.S., Challa, S., Moquin, D., Genga, R., Ray, T.D., Guildford, M. and Chan, F.K. (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. cell. 137, 1112-1123.

11) Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I.L, Korkina, O., Teng, X., Abbott, D., Cuny, G.D., Yuan, C, Wagner, G. , Hedrick, S.M., Gerber, S.A., Lugovskoy, A. and Yuan, J. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol., 4, 313-321.

12) Newton, K., Dugger, D.L, Wickliffe, K.E., Kapoor, N., de Almagro, M.C, Vucic, D., Komuves, L, Ferrando, R.E., French, D.M., Webster, J., Roose-Girma , M., Warming, S. and Dixit, V. M. (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 343, 1357-1360.

13) Kaiser, W.J., Sridharan, H., Huang, C, Mandal, P., Upton, J.W., Gough, P.J., Sehon, C.A., Marquis, R.W., Bertin, J. and Mocarski, E.S. (2013) Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. The Journal of Biological Chemistry. 288, 31268-31279.

14) Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J. and Liu, Z.G. (2012) Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proceedings of the National Academy of Sciences of the United States of America. 109, 5322-5327.

15) Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X and Wang, X. (2012) Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase. cell. 148, 213-227.

16) Linkermann, A. and Green, D.R. (2014) Necroptosis. The New England journal of medicine. 370, 455-465.

17) Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A. and Yuan, J. (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol., 1, 112-119.

18) Takahashi, N., Duprez, L, Grootjans, S., Cauwels, A., Nerinckx, W., DuHadaway, J. B., Goossens, V., Roelandt, R., Van Hauwermeiren, F., Libert , C., Declercq, W., Callewaert, N., Prendergast, G.C., Degterev, A., Yuan, J. and Vandenabeele, P. (2012) Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis., 3, e437.

19) Harris, P.A., Bandyopadhyay, D., Berger, S.B., Campobasso, N., Capriotti, C.A., Cox, J.A., Dare, L., Finger, J.N., Hoffman, S.J., Kahler, K.M., Lehr, R., Lich, J.D., Nagilla, R., Nolte, R.T., Ouellette, M.T., Pao, C.S., Schaeffer, M.C., Smallwood, A., Sun, H.H., Swift, B.A., Totoritis, R.D. , Ward, P., Marquis, R.W., Bertin, J. and Gough, P.J. (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243.

20) Najjar, M., Suebsuwong, C., Ray, S.S., Thapa, R.J., Maki, J.L., Nogusa, S., Shah, S., Saleh, D., Gough, P.J., Bertin, J., Yuan, J., Balachandran, S., Cuny, G.D. and Degterev, A. (2015) Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1. Cell Rep.

21) International Patent Application Publication No. WO 2014/125444.

22) Publication of International Patent Application No. WO 2017/004500.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I:

or their pharmaceutically acceptable salts, where

R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl groups -N(R ^N ) ₂ , phenyl, benzyl, 4-8 membered heterocyclyl and 5-6 membered heteroaryl; wherein R ¹ is bonded to the adjacent carbonyl via a carbon atom, and wherein R ¹ is optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C 1 -C ₆ haloalkoxy, C _{1 -C 6} alkyl-N (R ^N ) ₂ groups, hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C (O) C ₁ -C ₆ alkyl, phenyl, benzyl, CH ₂ -(C ₃ -C ₆ cycloalkyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl);

each ^RN is independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl; or two ^RN together with the adjacent N atom may form a 4-6 membered ring;

ring A is a 5-membered heteroaryl having as heteroatoms only either (1) two or three nitrogen atoms, or (2) one nitrogen atom and one oxygen atom, or (3) one nitrogen atom and one sulfur atom; wherein ring A is bonded to the adjacent carbonyl via a carbon atom; And

ring B is a 4-8 membered cycloalkyl or a 4-8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; wherein ring B is substituted according to (a), (b) or both (a) and (b):

(a) 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkyl-N(R ^N ) ₂ groups, and cyano; while two C ₁ -C ₆ alkyl substituents together can form a bridged or spirocyclic ring; and wherein, if the nitrogen atom in ring B is substituted, then the substituent is not a halogen, cyano or C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thioalkyl having an oxygen or sulfur atom directly bonded to a nitrogen atom;

(b) 1 substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ - C ₆ thioalkyl, C ₁ -C ₆ alkyl-N (R ^N ) ₂ groups, phenyl, benzyl, CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ -(4-6 membered heterocyclyl), CH ₂ CH ₂ -(4-6 membered heterocyclyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, in the case of the presence of a phenyl ring or a 5-6-membered heteroaryl ring, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, cyano and cyclopropyl.

Also according to this invention, pharmaceutical compositions are provided comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

Also according to this invention, oral compositions are provided based on a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

The invention also provides methods for treating diseases and disorders associated with inflammation, cell death, and other causes associated with RIP1 kinase, as further described below.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

Also according to this invention, a compound of formula I or a pharmaceutically acceptable salt thereof is provided for the treatment of a disease or disorder selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, parkinsonism-plus syndromes, taupathies, Alzheimer's disease, frontal - temporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy , peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

Also according to this invention, a compound of formula I or a pharmaceutically acceptable salt thereof or a composition based on it (her) according to any of the embodiments proposed in this application is provided for the treatment of a disease or disorder selected from the group consisting of Parkinson's disease, dementia with Lewy bodies , multiple system atrophy, parkinsonism-plus syndromes, taupathies, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

The invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, parkinsonism-plus syndromes, taupathies , Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

Also according to this invention, a compound of formula I or a pharmaceutically acceptable salt thereof is provided for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis and osteoarthritis.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

All chemical formulas and general chemical structures that are given in this description should be interpreted in terms of providing proper valency and chemically stable bonds between atoms, as understood by a person of ordinary skill in the art. Where appropriate, substituents may be bonded to more than one adjacent atom (eg, alkyl includes methylene where two bonds are present).

In the chemical formulas given in this description, the term "halogen" or "halogen atom" refers to a fluorine, chlorine and bromine atom (ie F, Cl, Br).

Alkyl, unless specifically stated otherwise, refers to a possibly substituted straight or branched C ₁ -C ₁₂ alkyl group. In some embodiments, alkyl refers to a C ₁ -C ₆ alkyl group. Representative alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. The substituted alkyl groups described herein are substituted with one or more substituents selected from the group consisting of halo, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C ₃ -C ₆ cycloalkyl, phenyl, OH, CO ₂ H, groups CO ₂ (C ₁ -C ₄ alkyl), NH ₂ , NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , NH (C \u003d O)C ₁ -C ₄ alkyl, ( C \u003d O) NH (C ₁ -C ₄ alkyl), (C \u003d O) N (C ₁ -C ₄ alkyl) ₂ , S (C ₁ -C ₄ alkyl), SO (C ₁ -C ₄ alkyl), SO ₂ (C ₁ -C ₄ alkyl), SO ₂ NH (C ₁ -C ₄ alkyl), SO ₂ N (C ₁ -C ₄ alkyl) ₂ and NHSO ₂ (C ₁ -C ₄ alkyl). In some embodiments, the substituted alkyl group has 1 or 2 substituents. In some embodiments, the alkyl group is unsubstituted.

Cycloalkyl, unless specifically stated otherwise, refers to a possibly substituted C ₃ -C ₁₂ cycloalkyl group and includes fused, spirocyclic and bridged bicyclic groups, where the substituents are selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy , C ₃ -C ₆ cycloalkyl, phenyl, OH, CO ₂ H, CO ₂ groups (C ₁ -C ₄ alkyl), NH ₂ , NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , NH(C=O)C ₁ -C ₄ alkyl, (C=O)NH(C ₁ -C ₄ alkyl), (C=O)N(C ₁ -C ₄ alkyl) ₂ , S(C ₁ -C ₄ alkyl), SO (C ₁ -C ₄ alkyl), SO ₂ (C ₁ -C ₄ alkyl), SO ₂ NH (C ₁ -C ₄ alkyl), SO ₂ N (C ₁ -C ₄ alkyl) ₂ and NHSO ₂ (C ₁ -C ₄ alkyl). In some embodiments, cycloalkyl refers to a C ₃ -C ₆ cycloalkyl group. In some embodiments, the C ₃ -C ₆ cycloalkyl group is optionally substituted with 1 to 3 halogen atoms. In some embodiments, the C ₃ -C ₆ cycloalkyl group is optionally substituted with 1 to 3 fluorine atoms. Typical C ₃ -C ₆ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Representative C ₃ -C ₁₂ cycloalkyl groups further include bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[4.1.0]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantanyl, decalinyl and spiro[5.4]desanyl. Where appropriate, cycloalkyl groups may be fused with other groups so that more than one chemical bond exists between the cycloalkyl group and another ring system (eg, the C ring of Formula I). In some embodiments, the cycloalkyl group is unsubstituted.

Haloalkyl, unless specifically stated otherwise, refers to a straight or branched C ₁ -C ₁₂ alkyl group where one or more hydrogen atoms have been replaced by a halogen. In some embodiments, haloalkyl refers to a C ₁ -C ₆ haloalkyl group. In some embodiments, 1-3 hydrogen atoms in the haloalkyl group are replaced by halogen atoms. In some embodiments, each hydrogen atom in the haloalkyl group is replaced by a halogen atom (eg, in trifluoromethyl). In some embodiments, haloalkyl is as defined herein, in which case the halogen atom is a fluorine atom in each case. Representative haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and pentafluoroethyl.

Alkoxy, unless specifically stated otherwise, refers to a straight or branched C ₁ -C ₁₂ alkyl group where one or more oxygen atoms are present, in each case between two carbon atoms. In some embodiments, alkoxy refers to the group C ₁ -C ₆ alkoxy. In some embodiments, the C ₁ -C ₆ alkoxy groups described herein have one oxygen atom. Representative alkoxy groups include methoxy, ethoxy, CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ OCH ₂ CH ₃ , CH ₂ CH ₂ OCH ₂ CH ₃ , CH ₂ OCH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CH ₂ OCH ₃ , CH ₂ OCH (CH ₃ ) ₂ , CH ₂ OS (CH ₃ ) ₃ , CH (CH ₃ ) OCH ₃ , CH ₂ CH (CH ₃ ) OCH ₃ , CH (CH ₃ ) OCH ₂ CH ₃ , CH ₂ OCH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ and CH ₂ OCH ₂ OCH ₂ OCH ₃ .

Cycloalkoxy, unless specifically stated otherwise, refers to a C ₄ -C ₁₀ - or C ₄ -C ₆ alkoxy group as defined above, which group is cyclic and contains one oxygen atom. Representative cycloalkoxy groups include oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

Haloalkoxy, unless specifically stated otherwise, refers to a C ₁ -C ₆ haloalkyl group as defined above, where one or two oxygen atoms are present, in each case between two carbon atoms. In some embodiments, the C ₁ -C ₆ haloalkoxy groups described herein have one oxygen atom. Representative haloalkoxy groups include OCF ₃ , OCHF ₂ and CH ₂ OCF ₃ .

Thioalkyl, unless specifically indicated otherwise, refers to the group C ₁ -C ₁₂ - or C ₁ -C ₆ alkoxy, as defined above, where the oxygen atom is replaced by a sulfur atom. In some embodiments, thioalkyl groups may include sulfur atoms substituted with one or two oxygen atoms (ie, in alkyl sulfones and alkyl sulfoxides). Typical thioalkyl groups are those exemplified above in the definition for alkoxy, where in each case each oxygen atom is replaced by a sulfur atom.

Thiocycloalkyl, unless specifically stated otherwise, refers to a C ₄ -C ₁₀ - or C ₄ -C ₆ -thioalkyl group as defined above, which group is cyclic and contains one sulfur atom. In some embodiments, the sulfur atom in the thiocycloalkyl group is replaced by one or two oxygen atoms (ie, in a cyclic sulfone or sulfoxide). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiolanyl, and 1,1-dioxothianyl.

Heterocyclyl, unless specifically stated otherwise, refers to a single saturated or partially unsaturated 4- to 8-membered ring having at least one ring atom other than carbon, which atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multi-fused ring systems that have at least one such saturated or partially unsaturated ring, wherein these multi-fused ring systems have 7 to 12 atoms and are further described below. Thus, this term includes single saturated or partially unsaturated rings (for example, 3-, 4-, 5-, 6-, 7- or 8-membered rings) containing from about 1 to 7 carbon atoms in the ring and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The ring may be C-branched (ie, substituted with a C ₁ -C ₄ alkyl group). The ring may be substituted with one or more (eg 1, 2 or 3) oxo groups, and sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The rings in such a system of multiple fused rings can be connected to each other through bonds resulting in fused, spiro and bridged structures if allowed by valency requirements. It should be understood that the individual rings in a system of multiple fused rings may be connected in any order relative to each other. It should also be understood that the point of attachment in a multi-fused ring system (as defined above for a heterocycle) may be at any position in such a multi-fused ring system. It should also be understood that the site of attachment for a heterocycle or a heterocyclic system of multiple fused rings may be any suitable atom of the heterocyclyl group, including a carbon atom and a nitrogen atom. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, hromanil, 1 ,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropan-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa- 6-azaspiro[3.3]heptanil, imidazolidin-2-one, N-methylpiperidine, imidazolidine, pyrazolidin, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine- S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s )-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

In some embodiments, heterocyclyl is C ₄ -C ₁₀ heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. In some embodiments, the heterocyclyl group is neither bicyclic nor spirocyclic. In some embodiments, the heterocyclyl is a C ₅ -C ₆ heterocyclyl having 1 to 3 heteroatoms, with at least 2 atoms being a nitrogen atom if 3 heteroatoms are present.

Aryl, unless specifically stated otherwise, refers to a single carbon-only aromatic ring or a carbon-only system of multiple fused rings, wherein at least one of the rings is aromatic and the aryl group has 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9-20 carbon atoms, in which at least one ring is aromatic, while the other rings may be aromatic or non-aromatic (i.e. carbocycles). Such multiple fused ring systems are optionally substituted with one or more (eg, 1, 2, or 3) oxo groups on any carbocyclic portion of such multiple fused ring system. Rings in a system of multiple fused rings may be connected to each other through bonds resulting in fused, spiro and bridged structures if allowed by valence requirements. It should be understood that the point of attachment in the multi-fused ring system as defined above may be at any position in such ring system, including the aromatic or carbocyclic portion of the ring. Representative aryl groups include phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

Heteroaryl, unless specifically stated otherwise, refers to a 5-6 membered aromatic ring having at least one ring atom other than carbon, which atom is selected from the group consisting of oxygen, nitrogen and sulfur atoms; the term "heteroaryl" also includes multiple fused ring systems having 8-16 atoms that contain at least one such aromatic ring, with multiple fused ring systems being further described below. Thus, the term "heteroaryl" includes single aromatic rings of about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. The sulfur and nitrogen atoms can also be in oxidized form, provided the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. The term "heteroaryl" also includes multiple fused ring systems (e.g. ring systems containing 2 or 3 rings) wherein the heteroaryl group as defined above is fused to one or more rings selected from heteroaryls (to form, for example , naphthyridinyl such as 1,8-naphthyridinyl), heterocycles (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles ( to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example, indazolyl) to form a system of several fused rings. Thus, heteroaryl (a single aromatic ring or a system of several fused rings) has 1-15 carbon atoms and approximately 1-6 heteroatoms within the heteroaryl ring. Such multiple fused ring systems may optionally be substituted with one or more (eg 1, 2, 3 or 4) oxo groups on the carbocyclyl or heterocyclyl portion of the fused ring. The rings in such a system of multiple fused rings can be connected to each other through bonds resulting in fused, spiro and bridged structures if allowed by valency requirements. It should be understood that the individual rings in a system of multiple fused rings may be connected in any order relative to each other. It should also be understood that the point of attachment in a multi-fused ring system (as defined above for heteroaryl) may be at any position in such a multi-fused ring system, including the heteroaryl, heterocyclyl, aryl, or carbocyclyl portion of the multi-fused ring system. It should also be understood that the site of attachment for a heteroaryl or heteroaryl multi-fused ring system may be any suitable atom of a heteroaryl or heteroaryl multi-fused ring system, including a carbon atom and a heteroatom (eg, a nitrogen atom). Representative heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalil , quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, tianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro- 1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

As used herein, the term "chiral" refers to molecules that have the property of being mismatched when superimposed on their mirror image partner, while the term "achiral" refers to molecules that are congruent when superimposed on their mirror image partner.

Used in this description, the term "stereoisomers" refers to compounds that have identical chemical composition, but differ in the arrangement of atoms or groups in space.

которая пересекает связь в химической структуре, указывает место присоединения связи, к которой отмеченная волнистой линией связь присоединяется в этой химической структуре к остальной части молекулы.As used in this description, wavy line

that crosses a bond in a chemical structure indicates the bond attachment point to which the bond marked with a wavy line is attached in that chemical structure to the rest of the molecule.

Used in this description, the term "C-linked" means that the group that describes this term is attached to the costal part of the molecule through a carbon atom in the ring.

Used in this description, the term "N-linked" means that the group that describes this term is attached to the costal part of the molecule through the nitrogen atom in the ring.

The term "diastereomer" refers to a stereoisomer with two or more centers of chirality, and such molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high resolution analytical techniques such as electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of a compound that are not mirror images of each other.

In this specification, the stereochemical definitions and rules provided in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel E. and WilenS., "Stereochemistry of Organic Compounds", John Wiley and Sons, Inc., New York, 1994. Compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule relative to its chiral center(s). The prefixes d and l, or (+) and (- ), while (-) or l means that the connection is left-handed. A connection with a (+) or d prefix is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be defined as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A mixture with a ratio of enantiomers of 50:50 is called a racemic mixture or racemate, which can be formed if no stereoselection or stereospecificity in the chemical reaction or process is observed. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species without optical activity.

If a bond in a compound formula is depicted in this description without conforming to stereochemical rules (for example, a simple line in the plane of the drawing), then the atom to which this bond is attached includes all stereochemically possible options. When a bond in a compound formula is depicted in this specification according to certain stereochemical rules (e.g., heavy line, thick wedge, dashed line, hatched wedge), it should be understood that the compound contains more of the atom in the depicted absolute stereochemical configuration, unless otherwise noted. otherwise. In one embodiment, the compound may be at least 51% stereoisomer in the depicted absolute configuration. In another embodiment, the compound may be at least 80% in the depicted absolute configuration. In another embodiment, the compound may be at least 90% in the depicted absolute configuration. In another embodiment, the compound may be at least 95% in the depicted absolute configuration. In another embodiment, the compound may be at least 97% in the depicted absolute configuration. In another embodiment, the compound may be at least 98% in the depicted absolute configuration. In another embodiment, the compound may be at least 99% in the depicted absolute configuration.

Used in this description, the term "tautomer" or "tautomeric form" refers to structural isomers with different energies, the interconversion of which proceeds through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) are characterized by interconversions by proton migration, such as in the keto-enol and imine-enamine isomerisms. Valence tautomers involve interconversions through reorganization of some of the bonding electrons.

As used herein, the term "solvate" refers to an associate or complex of one or more solvent molecules and a molecule of a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is a water molecule. In some embodiments, a hydrate of ketones is provided as the hydrate of a compound of this invention.

As used herein, the term "protecting group" refers to a substituent usually used to block or protect a particular functional group of a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects an amino functional group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, the term "hydroxy protecting group" refers to a substituent on a hydroxy group that blocks or protects a hydroxy functional group. Suitable protecting groups include acetyl and silyl. The term "carboxy-protecting group" refers to a substituent on a carboxy group that blocks or protects a carboxy functional group. Commonly used carboxy protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulphenyl)ethyl, 2-(diphenylphosphino)- ethyl, nitroethyl and the like. For a general description of protecting groups and their uses, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis, ^4th edition, Wiley-Interscience, New York, 2006.

As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, bovines, pigs, and sheep.

As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. Where compounds of the present invention contain relatively acidic functional groups, base addition salts can be prepared by contacting such compounds in neutral form with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, ferric manganese, ferrous manganese, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, natural amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines , theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Where compounds of the present invention contain relatively basic functional groups, acid addition salts may be prepared by contacting such compounds in neutral form with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic to form carbonate and hydrogen carbonate, phosphoric to form phosphate, hydrogen phosphate and dihydrogen phosphate, sulfuric to form sulfate and hydrogen sulfate, hydroiodic or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic and the like . Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge S. M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66:1-19). Some specific compounds of the present invention contain both basic and acidic functional groups, allowing these compounds to be converted into either base or acid addition salts.

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

In addition to salt forms, the present invention provides compounds in the form of prodrugs. Used in this description, the term "prodrug" refers to those compounds that easily undergo chemical changes under physiological conditions to obtain compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods under ex vivo conditions. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir along with a suitable enzyme or chemical.

Prodrugs of the invention include compounds in which an amino acid residue or polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently attached via an amide or ester bond to a free amino, hydroxy, or carboxyl group in a compound of the present invention. . Amino acid residues include, but are not limited to, the 20 natural amino acid residues, usually denoted by three letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2- carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, para-benzoylphenylalanine , phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

In addition, additional types of prodrugs are included. For example, compounds of the invention may be modified at the free carboxyl group to form an amide or alkyl ester. As another example, compounds of this invention containing free hydroxyl groups can be modified to form prodrugs by converting the hydroxyl group into a group such as, but not limited to, a phosphate ester group, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, such that see Fleisher D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Advanced Drug Delivery Reviews, 19:115. prodrugs, sulfonate esters and sulfate esters obtained by modification of hydroxy groups. Also included are derivatives at hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group may be an alkyl ester group optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups. , or where the acyl group is an amino acid ester group as described above. Prodrugs of this type are described in J. Med. Chem. (1996), 39:10. More specific examples include replacing the hydrogen atom of the alcohol group with a group such as (C _1-6 )alkanoyloxymethyl, 1-((C _1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C _1-6 )alkanoyloxy) ethyl, (C _1-6 )alkoxycarbonyloxymethyl, N-(C _1-6 )alkoxycarbonylaminomethyl, succinoyl, (C _1-6 )alkanoyl, alpha-amino(C _1-4 )alkanoyl, arylacyl, and alpha-aminoacyl or alpha-aminoacyl -alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the groups of natural L-amino acids, groups -P(O)(OH) ₂ , -P(O)(O(C _1-6 )alkyl) ₂ or glycosyl ( the radical resulting from the removal of the hydroxyl group in the hemiacetal form of the carbohydrate).

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

In addition, the present invention provides metabolites of the compounds of the invention. Used in this description, the term "metabolite" refers to a product formed during the metabolism of a particular compound or its salt in the body. Such products can be obtained from the administered compound, for example, by its oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like.

Metabolic products are typically identified by obtaining a radiolabeled (e.g., ¹⁴ C or ³ H) isotope compound of the invention, administering it parenterally at a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as a rat, mouse, guinea pig, monkey, or human, with sufficient time (usually from about 30 seconds to 30 hours) to carry out metabolism and excrete metabolic products from urine, blood or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies capable of binding to epitopes retained in the metabolite). The structures of the metabolites are determined in the traditional way, for example, in the analysis using mass spectrometry (MS), liquid chromatography in combination with MS (LC/MS) or nuclear magnetic resonance (NMR). Typically, metabolite assays are performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolic products, provided that they are not otherwise detected in vivo, are useful in diagnostic assays to determine the therapeutic dose of the compounds of the invention.

Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent in terms of the uses contemplated by the present invention and are intended to be included within the scope of the present invention.

Some compounds of the present invention contain asymmetric carbon atoms (optical centers) or double bonds; all racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (eg, individual enantiomers) are intended to be included within the scope of the present invention.

The term "composition" as used herein is intended to cover a product containing specific ingredients in specific amounts, as well as any product that results from combining, directly or indirectly, those specific ingredients in specific amounts. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not adversely affect the recipient to whom it is administered.

The terms "treat" and "treatment" refer to both therapeutic treatment and/or prophylactic treatment, and preventive measures in which an undesirable physiological change or disorder is to be prevented or attenuated (alleviated) in the subject, such as, for example, the development or the spread of cancer. For the purposes of this invention, useful or desirable clinical results include, but are not limited to, relief of symptoms, reduction in the extent of a disease or disorder, a stabilized (i.e., no worsening) state of the disease or disorder, delaying or slowing the progression of a disease, amelioration of symptoms, or temporary alleviation of the disease state or disorder; and remission (whether partial or complete), whether detectable or not. "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. Those in need of such treatment include those who already have the disease or disorder, as well as those who are predisposed to the disease or disorder, or those in whom the disease or disorder is to be prevented.

The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound of the present invention that (1) treats or prevents a particular disease, condition or disorder, (2) relieves, reduces symptoms or eliminates one or more symptoms of a particular disease, condition or disorder, or (3) prevents or delays the onset of one or more of the symptoms of a particular disease, condition, or disorder described herein. In the case of cancer therapy, efficacy can be measured, for example, by evaluating the time to disease progression (TTP) or by determining the response rate (RR).

The term "bioavailability" refers to the systemic availability (ie, blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that refers to the measurement of both the time (rate) and the total amount (level) of a drug reaching the systemic circulation, depending on the dosage form administered.

RIP1 KINASE INHIBITORS

The present invention provides novel compounds having the general formula I:

or their pharmaceutically acceptable salts, where

R ¹ is selected from the group consisting of C _1-6 alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl- N(R ^N ) ₂ , phenyl, benzyl, 4-8 membered heterocyclyl and 5-6 membered heteroaryl; wherein R ¹ is bonded to the adjacent carbonyl via a carbon atom, and wherein R ¹ is optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C 1 -C ₆ haloalkoxy, groups _{C 1 -C 6} alkyl-N (R ^N ) ₂ , hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C (O) C ₁ -C ₆ alkyl, phenyl, benzyl, CH ₂ -(C ₃ -C ₆ cycloalkyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl);

each ^RN is independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl; or two ^RN together with the adjacent N atom may form a 4-6 membered ring;

ring A is a 5-membered heteroaryl having as heteroatoms only either (1) two or three nitrogen atoms, or (2) one nitrogen atom and one oxygen atom, or (3) one nitrogen atom and one sulfur atom; wherein ring A is bonded to the adjacent carbonyl via a carbon atom; And

ring B is a 4-8 membered cycloalkyl or a 4-8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; wherein ring B is substituted according to (a), (b) or both (a) and (b):

(a) 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkyl-N(R ^N ) ₂ groups and cyano; while two C ₁ -C ₆ alkyl substituents together can form a bridged or spirocyclic ring; and wherein, if the nitrogen atom in ring B is substituted, then the substituent is not a halogen, cyano or C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thioalkyl having an oxygen or sulfur atom directly bonded to a nitrogen atom;

(b) 1 substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ - C ₆ thioalkyl, C ₁ -C ₆ alkyl-N (R ^N ) ₂ groups, phenyl, benzyl, CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ -(4-6 membered heterocyclyl), CH ₂ CH ₂ -(4-6 membered heterocyclyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, in the case of the presence of a phenyl ring or a 5-6-membered heteroaryl ring, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ aloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and cyano.

In another embodiment of this invention, compounds of formula I are provided:

or their pharmaceutically acceptable salts, where

R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl groups -N(R ^N ) ₂ , phenyl, benzyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein R ¹ is bonded to the adjacent carbonyl via a carbon atom, and wherein R ¹ is optionally substituted with one or two substituents selected from the group consisting of F, Cl, methyl, ethyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy ;

each ^RN is independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl; or two ^RN together with the adjacent N atom may form a 4-6 membered ring;

ring A is a 5-membered heteroaryl having as heteroatoms only either (1) two or three nitrogen atoms, or (2) one nitrogen atom and one oxygen atom, or (3) one nitrogen atom and one sulfur atom; wherein ring A is bonded to the adjacent carbonyl via a carbon atom; And

ring B is a 4-8 membered cycloalkyl or a 4-8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; wherein ring B is substituted according to (a), (b) or both (a) and (b):

(a) 1-2 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy , C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkyl-N(R ^N ) ₂ groups and cyano; while two C ₁ -C ₆ alkyl substituents together can form a bridged or spirocyclic ring; and wherein, if the nitrogen atom in ring B is substituted, then the substituent is not a halogen, cyano or C ₁ -C alkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thioalkyl having an oxygen or sulfur atom directly bonded to the atom nitrogen;

(b) 1 substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ - C ₆ thioalkyl, C ₁ -C ₆ alkyl-N (R ^N ) ₂ groups, phenyl, benzyl, CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ -(4-6 membered heterocyclyl), CH ₂ CH ₂ -(4-6 membered heterocyclyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, if a phenyl ring is present, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, cyano and cyclopropyl.

In some embodiments, R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ haloalkyl, phenyl, benzyl, oxetanyl, oxabicyclo[3.1.0]hexan-6-yl, thienyl and pyrazolyl; wherein R ¹ is optionally substituted with: (1) one substituent selected from the group consisting of F, Cl, methyl, hydroxyl, hydroxymethyl, cyano and trifluoromethyl, or (2) two substituents F. In some of the above embodiments, R ¹ is C ₁ -C ₆ alkyl. In some embodiments, R ¹ is C ₁ -C ₄ alkyl. In some embodiments, R ¹ is C ₃ -C ₅ cycloalkyl. In some embodiments, R ¹ is C ₃ -C ₄ cycloalkyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is CF ₃ CH ₂ . In some embodiments, R ¹ is 2-propyl. In some embodiments, R ¹ is tert-butyl. In some embodiments, R ¹ is (2-hydroxy)-2-propyl. In some embodiments, R ¹ is (2-cyano)-2-propyl. In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments, R ¹ is C ₁ -C ₄ haloalkyl. In some embodiments, R ¹ is cyclopropyl. In some embodiments, R ¹ is mono- or di-fluorocyclopropyl. In some embodiments, R ¹ is 1-fluorocyclopropyl. In some embodiments, R ¹ is 2-fluorocyclopropyl. In some embodiments, R ¹ is 2,2-difluorocyclopropyl. In some embodiments, R ¹ is 1-(trifluoromethyl)cyclopropyl. In some embodiments, R ¹ is 1-methylcyclopropyl. In some embodiments, R ¹ is 1-(hydroxymethyl)cyclopropyl. In some embodiments, R ¹ is cyclobutyl. In some embodiments, R ¹ is cyclopentyl. In some embodiments, R ¹ is phenyl. In some embodiments, R ¹ is benzyl. In some embodiments, R ¹ is oxetan-3-yl. In some embodiments, R ¹ is 3-methyloxetan-3-yl. In some embodiments, R ¹ is oxabicyclo[3.1.0]hexan-6-yl. In some embodiments, R ¹ is 2-pyridyl. In some embodiments, R ¹ is 1-methylpyrazol-4-yl. In some embodiments, R ¹ is 2-thienyl.

In some embodiments, each ^RN is independently selected from the group 5 consisting of H and C ₁ -C ₆ alkyl. In some embodiments, each ^RN is C ₁ -C ₄ alkyl. In some embodiments, each ^RN is methyl.

In some embodiments of formula (I), R ¹ is as defined above, and Ring A and Ring B are jointly selected from the group consisting of:

Where

R ² is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thioalkyl, phenyl, benzyl, CH ₂ groups - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ - (4-6-membered heterocyclyl), CH ₂ CH ₂ - (4-6 membered heterocyclyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, if a phenyl ring is present, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and cyano; And

R ^3a and R ^3b are selected as follows:

(1) one of R ^3a and R ^3b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy;

(2) each of R ^3a and R ^3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, with the proviso that R ^3a and R ^3b cannot both be OH or CN; or

(3) R ^3a and R ^3b together form cyclopropyl.

In some embodiments of formula (I), R ¹ is as defined above, and Ring A and Ring B are jointly selected from the group consisting of:

Where

R ^3a and R ^3b are selected as follows:

(1) one of R ^3a and R ^3b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy;

(2) each of R ^3a and R ^3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, with the proviso that R ^3a and R ^3b cannot both be OH or CN; or

(3) R ^3a and R ^3b together form cyclopropyl;

each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, and C _{1 -C} haloalkoxy; And

m is 1, 2, or 3.

In some embodiments of formula (I), R ¹ is as defined above, and Ring A and Ring B together are:

Where

each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy; And

m is 1, 2, or 3.

In some embodiments of formula (I), R ¹ is as defined above, and Ring A and Ring B are jointly selected from the group consisting of:

Where

R ² is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thioalkyl, phenyl, benzyl, CH ₂ groups - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ - (4-6-membered heterocyclyl), CH ₂ CH ₂ - (4-6 membered heterocyclyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, if a phenyl ring is present, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and cyano;

R ^4a and R ^4b are selected as follows:

(1) one of R ^4a and R ^4b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy; or

(2) each of R ^4a and R ^4b is selected from the group consisting of D, F, Cl and methyl; And

each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkoxy.

In some embodiments of formula (I), R ¹ is as defined above, and Ring A and Ring B are jointly selected from the group consisting of:

Where

R ^4a and R ^4b are selected as follows:

(1) one of R ^4a and R ^4b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy; or

(2) each of R ^4a and R ^4b is selected from the group consisting of D, F, Cl and methyl;

each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy; And

m is 1, 2, or 3.

In some of the above embodiments, R ² is phenyl. In some embodiments, R ² is mono- or difluorophenyl. In some embodiments, R ² is mono- or dichlorophenyl. In some of the above embodiments, R ² is pyridinyl. In some of the above embodiments, R ² is chloro-substituted pyridinyl. In some of the above embodiments, R ² is a fluoro-substituted pyridinyl. In some of the above embodiments, R ² is pyrazolyl. In some of the above embodiments, R ² is 1-methyl-1H-pyrazol-4-yl. In some of the above embodiments, R ² is 4-chloro-1-methyl-1H-pyrazol-3-yl.

In some of the above embodiments, R ^3a and R ^3b are each H. In some of the above embodiments, R ^3a is H and R ^3b is F. In some of the above embodiments, R ^3a is H and R ^3b is Cl . In some of the above embodiments, R ^3a and R ^3b are each F. In some of the above embodiments, R ^3a and R ^3b are each Cl. In some of the above embodiments, R ^3a and R ^3b are each methyl. In some of the above embodiments, R ^3a is methyl and R ^3b is F. In some of the above embodiments, R ^3a is methyl and R ^3b is Cl. In some of the above embodiments, R ^3a is methyl and R ^3b is OH. In some of the above embodiments, R ^3a is methyl and R ^3b is CN. In some of the above embodiments, R ^3a and R ^3b are each D. In some of the above embodiments, R ^3a is H and R ^3b is D. In some of the above embodiments, R ^3a is D and R ^3b is F In some of the above embodiments, R ^3a is D and R ^3b is Cl. In some of the above embodiments, R ^3a is D and R ^3b is methyl.

In some of the above embodiments, R ^4a and R ^4b are each H. In some of the above embodiments, one of R ^4a is H and R ^4b is F. In some of the above embodiments, one of R ^4a is H and R ^4b is methyl. In some of the above embodiments, one of R ^4a is H and R ^4b is Cl. In some of the above embodiments, R ^4a and R ^4b are each F. In some of the above embodiments, R ^4a and R ^4b are each D. In some of the above embodiments, R 4a is H and R 4b is D. In some of the above embodiments, R ^4a is H and R ^4b is D. of the above embodiments, R ^4a is D and R ^4b is F. In some of the above embodiments, R ^4a is D and R ^4b is Cl.

In some of the above embodiments, R ⁵ is selected from the group consisting of H, F, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , CF ₃ , OCF ₃ , CF ₂ H and OCF ₂ H.

In some of the above embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In another embodiment, the present invention provides a compound selected from the compounds of Table 1 below, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound of Table 1 having a K _i of less than 100 nM in a RIP1 kinase (RIP1K) biochemical or cell-based assay, including that described herein. In another embodiment, the compound of Table 1 has a K _i of less than 50 nM in a RIP1K chemistry or cell-based assay, including the one described herein. In yet another embodiment, the compound of Table 1 has a K _i of less than 25 nM in a RIP1K chemistry or cell-based assay, including the one described herein. In yet another embodiment, the compound of Table 1 has a K _i of less than 10 nM in a RIP1K chemistry or cell-based assay, including the one described herein.

In another embodiment, the present invention provides a compound selected from the compounds of Table 2 below, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound of Table 2 having a K _i of less than 100 nM in a RIP1K chemistry or cell-based assay, including the one described herein. In another embodiment, the compound of Table 2 has a K _i of less than 50 nM in a RIP1K chemistry or cell-based assay, including the one described herein. In yet another embodiment, the compound of Table 2 has a K _i of less than 25 nM in a RIP1K chemistry or cell-based assay, including the one described herein. In yet another embodiment, the compound of Table 2 has a K _i of less than 10 nM in a RIP1K chemistry or cell-based assay, including the one described herein.

In some embodiments of the present invention, an individual stereoisomer of a compound of Table 1 or Table 2 is provided, characterized with reference to separation and isolation using chiral chromatography (eg, as described in the examples by chiral supercritical fluid chromatography (SFC)).

In some embodiments of this invention, pharmaceutical compositions are provided comprising a compound of formula I as described in any of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

The invention also provides oral compositions based on a compound of formula I as described in any of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

In some embodiments of the present invention, the uses of a compound of formula I as described in any of the above embodiments, or a pharmaceutically acceptable salt thereof, are provided for the treatment of neurodegenerative diseases and disorders. In some embodiments, the diseases and disorders to be treated are synnucleopathies such as Parkinson's disease, Lewy body dementia, multiple system atrophy, parkinsonism-plus syndromes. In some embodiments, the diseases and disorders to be treated are taupathies such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the diseases and disorders to be treated are demyelinating diseases such as multiple sclerosis.

In some embodiments, the diseases and disorders to be treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Additional exemplary neurodegenerative diseases to be treated herein include, but are not limited to, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

In some embodiments, the disease or disorder to be treated is Alzheimer's disease. In some embodiments, the disease or disorder being treated is Parkinson's disease. In some embodiments, the disease or disorder being treated is Huntington's disease. In some embodiments, the disease or disorder being treated is multiple sclerosis. In some embodiments, the disease or disorder being treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder being treated is spinal muscular atrophy (SMA).

In some embodiments of the present invention, the uses of a compound of formula I as described in any of the above embodiments, or a pharmaceutically acceptable salt thereof, are provided for the treatment of inflammatory diseases and disorders. In some embodiments, the disease or disorder being treated is selected from the group consisting of inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic-onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver injury/disease (as a result of non-alcoholic steato hepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune diseases of the liver and biliary tract, primary sclerosing cholangitis (PSC), acetaminophen intoxication, due to hepatotoxicity), kidney damage/damage (from nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs eg, cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemic/reperfusion injury to whole organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), infarction myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, granulomatosis Wegener's disease, pulmonary sarcoidosis, Behçet's disease, interleukin-1-converting enzyme (ICE, also known as caspase-1) associated febrile syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis , NEMO gene deficiency syndrome (deficiency syndrome of the NF-kappa-B essential modulator gene (also known as IKK-gamma or IKKG)), HOIL-1 deficiency (deficiency of ubiquitin ligase 1 that recognizes heme-oxidized IRP2 (protein 2 that regulates metabolism iron) (also known as RBCK1)), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and whole organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (particularly Gaucher disease, including GM2-gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber's disease, fucosidosis, galactosialidosis, GM1-gangliosidosis, mucolipidosis, free-storage disease sialic acids in children, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff's disease, Schindler's disease, storage disease sialic acids, Tay-Sachs and Wolman diseases).

In some embodiments, the disease or disorder being treated is inflammatory bowel disease. In some embodiments, the disease or disorder being treated is Crohn's disease. In some embodiments, the disease or disorder being treated is ulcerative colitis. In some embodiments, the disease or disorder being treated is glaucoma. In some embodiments, the disease or disorder being treated is psoriasis. In some embodiments, the disease or disorder being treated is rheumatoid arthritis. In some embodiments, the disease or disorder being treated is spondyloarthritis. In some embodiments, the disease or disorder being treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder being treated is osteoarthritis.

In some embodiments, the present invention provides methods for treating or preventing a disease or disorder with a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and/or necroptosis. In some embodiments, the specified disease or disorder is selected from the specific diseases and disorders mentioned in this description.

In some embodiments of the invention, methods are provided for inhibiting RIP1 kinase activity by contacting a cell with a compound of formula I, or a pharmaceutically acceptable salt thereof.

PHARMACEUTICAL COMPOSITIONS AND INTRODUCTION

The present invention provides pharmaceutical compositions or medicaments comprising compounds of the invention (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof) and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds. according to the invention for the preparation of such compositions and medicines. In one example, compounds of formula I can be formulated by mixing at ambient temperature at an appropriate pH and the desired degree of purity with physiologically acceptable carriers, i. carriers that are non-toxic to recipients, in dosages and concentrations used in the form of a galenic preparation for administration. The pH of the composition depends primarily on the particular application and concentration of the compound, but preferably ranges from about 3 to about 8 throughout. I are sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized composition, or as an aqueous solution.

The compositions are prepared, dosed and administered in a manner consistent with good medical practice. Factors considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, route of administration, schedule of administration, and other factors known to physicians. In some embodiments, the "effective amount" of the compound to be administered will be such considerations and is the minimum amount necessary to inhibit RIP1 kinase activity in order to have a therapeutic effect on the treated mammal. Also, such an effective amount may be below an amount that is toxic to normal cells or the mammalian body as a whole.

In one example, a pharmaceutically effective amount of a compound of the invention administered intravenously or parenterally will be in the dosage range of about 0.1 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, or alternatively about 0.3 to 15 mg/kg/day.

In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 1 to about 1000 mg (e.g., 1 mg; 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; 40 mg; 50 mg; 100 mg; 200 mg; 250 mg; 400 mg; 500 mg; 600 mg; 700 mg; 800 mg; 900 mg; or 1000 mg) of the compound of the invention. In some embodiments, the daily dose is taken as a single daily dose, or in divided doses between two and six times per day, or in a sustained release form. In the case of a 70 kg adult human, the total daily dose will typically be from about 7 mg to about 1400 mg. This mode of administration can be adjusted to obtain the optimal therapeutic response. The compounds can be administered on a schedule of 1 to 4 times per day, preferably once or twice per day.

In some embodiments, a low dose of a compound of the invention is administered in order to provide a therapeutic benefit while minimizing or preventing adverse effects.

The compounds of the invention can be administered by any suitable route, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal administration, and, if necessary, for local treatment, introduction to the affected area. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In specific embodiments, the compound of formula I is administered orally. In other specific embodiments, the compound of formula I is administered intravenously.

The compounds of the present invention can be administered in any form convenient for administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and so on. Such compositions may contain components conventionally used in pharmaceutical formulations, such as diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents.

A typical composition is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Compositions may also include one or more of the following: buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweeteners, flavoring agents, flavoring agents, diluents and other excipients known to provide the best presentation of a medicinal product (i.e., a compound of the present invention or a pharmaceutical composition based on it) or to facilitate the production of a pharmaceutical product (i.e. . medicinal product).

Suitable carriers, diluents and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The choice of the particular carrier, diluent or excipient used will depend on the vehicle and purpose for which the compound of the present invention will be used. In general, solvents are selected from solvents recognized by those skilled in the art as harmless (GRAS) for administration to a mammal. In general, harmless solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (eg PEG400, PEG300), etc. and their mixtures. The compositions may also include one or more of the following: buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavors, flavors and other known excipients to provide the best presentation of a drug (ie, a compound of the present invention or a pharmaceutical composition based on it) or assist in the production of a pharmaceutical product (ie, a drug).

Acceptable diluents, carriers, excipients and stabilizers are non-toxic to recipients at the dosages and concentrations used and include buffers such as those based on phosphate, citrate and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as ammonium octadecyldimethylbenzyl chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as ethylenediaminetetraacetic acid (EDTA); sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (eg Zn-protein complexes) and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). In addition, the active pharmaceutical ingredient of the invention (for example, a compound of formula I or an embodiment thereof) can be enclosed in microcapsules prepared, for example, using coacervation methods or by interfacial polymerization, for example, microcapsules of hydroxymethyl cellulose or gelatin and microcapsules of poly- (methyl methacrylate), respectively, in colloidal drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such methods are described in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) ^21st Edition, Lippincott Williams and Wilkins, Philidelphia, PA.

A compound of the invention (eg, a compound of formula I or an embodiment thereof) can be formulated into sustained release formulations. Suitable examples of sustained release formulations include semi-permeable matrices of hydrophobic polymers in solid form containing the compound of Formula I or any embodiment thereof, these matrices being in the form of molded articles such as films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (US Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers, 22: 547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res., 15: 167, 1981), degradable copolymers of lactic acid and glycolic acid, such as LUPRON DEPOT™ (injectable microspheres consisting of a copolymer of lactic acid and glycolic acid and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid (EP 133988A). Sustained release formulations also include liposome-embedded compounds that can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA, 77: 4030, 1980; US Pat. Nos. 4,485,045 and 4,544,545; and EP 102324A). Typically, liposomes are small (about 200-800 angstroms) vesicles of the unilamellar type, the lipid composition of which is characterized by the presence of more than about 30 mol% cholesterol, this selectable proportion being adjusted to achieve optimal therapy.

In one example, based on the compounds of formula I or their embodiments, compositions can be prepared by mixing at ambient temperature at an appropriate pH and the desired degree of purity with physiologically acceptable carriers, i. carriers that are non-toxic to recipients, in dosages and concentrations used in the form of a galenic preparation for administration. The pH value of the composition depends primarily on the particular application and the concentration of the compound, but preferably varies throughout the range from about 3 to about 8. In one example, a composition is prepared based on the compound of formula I (or its embodiment) in acetate buffer, at pH 5. In another embodiment, the compounds of formula I, or embodiments thereof, are sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized composition, or as an aqueous solution.

As an example of a suitable oral dosage form of this invention, a tablet containing from about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, , 150 mg, 250 mg, 300 mg and 500 mg) of a compound of the invention in admixture with appropriate amounts of lactose anhydrous, croscarmellose sodium, polyvinylpyrrole idone (PVP) K30 and magnesium stearate. The ground ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.

Compositions based on a compound of the invention (eg, a compound of formula I or an embodiment thereof) may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be prepared according to methods known in the art using such suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared from a lyophilized powder. Among the acceptable diluents and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be used as the solvent or suspending medium. For this purpose, any low viscosity fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the same way to prepare injectables.

The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will vary depending on the recipient being treated and the particular route of administration. For example, a sustained release composition intended for oral administration to humans may contain about 1-1000 mg of the active agent in admixture with an appropriate and appropriate amount of carrier material, which may vary from about 5% to about 95% by weight of the total composition (wt: weight). The pharmaceutical composition may be formulated in such a way as to allow a measurable amount to be administered without hindrance. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 micrograms of the active ingredient per milliliter of solution so that a suitable volume can be infused at a rate of about 30 ml/hour.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners.

The compositions may be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid vehicle, such as water, for injection immediately prior to use. Extemporaneous solutions and suspensions for injection are prepared from sterile powders, granules and tablets of the type described earlier.

Thus, one of the embodiments includes a pharmaceutical composition containing a compound of formula I or its pharmaceutically acceptable salt. A further embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

If the binding target is located in the brain, then some embodiments of the invention are contemplated for passage of a compound of Formula I (or an embodiment thereof) across the blood-brain barrier. In these embodiments, the compounds of this invention demonstrate sufficient penetration into the brain as possible therapeutic agents for neurological diseases. In some embodiments, the extent of brain penetration is determined by assessing the brain/plasma ratio of the free compound (B _u /P _u ) as measured in in vivo pharmacokinetic studies in rodents or by other methods known to those skilled in the art (see , for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325: 349-56, 2008).

Some neurological diseases are associated with an increase in the permeability of the blood-brain barrier, so that the compound of formula I (or an embodiment thereof) can easily enter the brain. For the case where the blood-brain barrier is maintained intact, there are several approaches known in the art for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-mediated methods. Physical means of transporting a compound of Formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, penetration entirely bypassing the blood-brain barrier, or penetration by creating holes in the blood-brain barrier.

Workarounds include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy, 9: 398-406, 2002), delivery by interstitial infusion/convection delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA, 91: 2076-2080, 1994) and implantation of a delivery device in the brain (see, e.g., Gill et al., Nature Med., 9: 589 -595, 2003; and Gliadel Wafers™, Guildford).

Methods for creating holes in this barrier include, but are not limited to, the use of ultrasonic treatment (see, for example, US Patent Application Publication No. 2002/0038086), osmotic pressure (for example, by injecting hypertonic mannitol solution (Neuwelt, E.A. , Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, N.Y., 1989)) and permeabilization under the action of, for example, bradykinin or permeabilizer A-7 (see, for example, US patents No. 5112596, 5268164, 5506206 and 5686416).

Lipid-based methods of transporting a compound of Formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating a compound of Formula I or I-I (or an embodiment thereof) in liposomes coupled to antibody binding fragments that bind to receptors on the endothelium. vessels of the blood-brain barrier (see, for example, US Patent Application Publication No. 20020025313), and applying a compound of formula I (or embodiments thereof) to low density lipoprotein particles (see, for example, US Patent Application Publication No. 2004/0204354) or for arolipoprotein E (see, for example, US Patent Application Publication No. 2004/0131692).

Receptor- and channel-mediated methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, the use of glucocorticoid receptor blockers to increase the permeability of the blood-brain barrier (see, for example, U.S. Patent Application Publication No. 2002/0065259, 2003/0162695 and 2005/0124533); activation of potassium channels (see, for example, US Patent Application Publication No. 2005/0089473); inhibition of ATP-binding cassette (ABC) drug transporters (see, for example, US Patent Application Publication No. 2003/0073713); applying a compound of formula I or I-I (or an embodiment thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, for example, US Patent Application Publication No. 2003/0129186) and cationization of antibodies (see, for example, US patent No. 5004697 ).

With regard to intracerebral administration, in some embodiments, the compounds may be administered continuously by infusion into fluid-containing cavities of the central nervous system (CNS), although bolus injection may also be acceptable. Inhibitors can be administered into the ventricles of the brain or otherwise administered into the fluid of the CNS cavities or cerebrospinal fluid. Administration may be by use of an implanted catheter and a continuous delivery device such as a pump, or administration may be by implantation, eg intracerebral implantation, in a sustained release vehicle. More specifically, the inhibitors can be injected through permanently implanted cannulas or continuously infused using osmotic minipumps. Subcutaneous injection pumps are commercially available, which deliver proteins through small supply tubes to the ventricles of the brain. New modern pumps can refill through the skin and set the delivery rate without surgery. Examples of suitable administration protocols and delivery systems involving a pumping device used for subcutaneous administration or continuous intracerebroventricular infusion through a fully implanted drug delivery system are those used to administer dopamine, dopamine receptor agonists and cholinergic agonists to Alzheimer's patients and animals, which are models of Parkinson's disease, as described in Harbaugh, J. Neural. Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord., 2:143, 1987.

INDICATIONS AND TREATMENT METHODS

The compounds of the invention inhibit the activity of the RIP1 kinase. Accordingly, the compounds of the invention are useful in the treatment of diseases and disorders mediated by this pathway and associated with inflammation and/or necroptotic cell death.

In some embodiments, the disease or disorder being treated is a neurodegenerative disease or disorder. In some embodiments, the diseases and disorders to be treated are synnucleopathies such as Parkinson's disease, Lewy body dementia, multiple system atrophy, parkinsonism-plus syndromes. In some embodiments, the diseases and disorders to be treated are taupathies such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the diseases and disorders to be treated are demyelinating diseases such as multiple sclerosis.

In some embodiments, the diseases and disorders to be treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Additional typical neurodegenerative diseases treated herein include, but are not limited to, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

In some embodiments, the disease or disorder to be treated is Alzheimer's disease. In some embodiments, the disease or disorder being treated is Parkinson's disease. In some embodiments, the disease or disorder being treated is Huntington's disease. In some embodiments, the disease or disorder being treated is multiple sclerosis. In some embodiments, the disease or disorder being treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder being treated is spinal muscular atrophy (SMA).

In some embodiments, the disease or disorder being treated is an inflammatory disease or disorder. In some embodiments, the disease or disorder being treated is selected from the group consisting of inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic-onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver injury/disease (as a result of non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune diseases of the liver and biliary tract, primary sclerosing cholangitis (PSC), acetaminophen intoxication, due to hepatotoxicity), kidney damage/injury (from nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, e.g., cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemic/reperfusion injury to whole organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction ( MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis , Behçet's disease, interleukin-1-converting enzyme-associated (ICE, also known as caspase-1) febrile syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, gene deficiency syndrome NEMO (NF-kappa-B essential modulator gene deficiency syndrome (also known as IKK-gamma or IKKG)), HOIL-1 deficiency (deficiency of ubiquitin ligase 1 that recognizes heme-oxidized IRP2 (also known as RBCK1)), deficiency syndrome linear ubiquitin chain assembly complex (LUBAC), hematological and whole organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (particularly Gaucher disease and including GM2 gangliosidosis, alpha- mannosidosis, aspartylglucosamineuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1-gangliosidosis, mucolipidosis, free sialic acid storage disease in children, juvenile form of hexosaminidase A deficiency, diseases Krabbe, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase insufficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff's disease, Schindler's disease, sialic acid storage disease, Tay-Sachs disease and Wolman disease).

In some embodiments, the disease or disorder being treated is inflammatory bowel disease. In some embodiments, the disease or disorder being treated is Crohn's disease. In some embodiments, the disease or disorder being treated is ulcerative colitis. In some embodiments, the disease or disorder being treated is glaucoma. In some embodiments, the disease or disorder being treated is psoriasis. In some embodiments, the disease or disorder being treated is rheumatoid arthritis. In some embodiments, the disease or disorder being treated is spondyloarthritis. In some embodiments, the disease or disorder being treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder being treated is osteoarthritis.

In some embodiments, a method of treatment according to this invention is provided for the treatment of one or more symptoms of a disease or disorder from the above list.

Also according to this invention proposed the use of the compounds according to the invention in therapy. In some embodiments, this invention provides the use of a compound of the invention for the treatment or prevention of the aforementioned diseases and disorders. The present invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment or prevention of the aforementioned diseases and disorders.

Also according to the present invention, there is provided a method of treating a disease or disorder as defined above in a mammal in need of such treatment, the method comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the mammal is a human.

Also according to the present invention, there is provided a method for treating a symptom of a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of inflammatory bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemic/reperfusion injury to the kidneys, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, degenerative changes in the retina, chronic kidney disease, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), the method comprising administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Also according to the present invention, there is provided a method of treating a disease or disorder in a human patient in need of such treatment, said disease or disorder being selected from the diseases or disorders set forth above, the method comprising orally administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable thereof. salt, as an orally acceptable pharmaceutical composition.

COMBINATION THERAPY

The compounds of the invention may be combined with one or more other compounds of the invention, or with one or more other therapeutic agents, in any combination thereof, in the treatment of the diseases and disorders described herein. For example, a compound of the invention may be administered concurrently, sequentially, or separately in combination with other therapeutic agents known to be useful in the treatment of a disease or disorder selected from those listed above.

As used herein, the term "combination" refers to any mixture or any combination of one or more compounds of the invention and one or more other compounds of the invention, or one or more additional therapeutic agents. Unless the context dictates otherwise, the term "combination" may refer to the simultaneous or sequential delivery of a compound of the invention along with one or more therapeutic agents. Unless the context dictates otherwise, "combination" may include dosage forms based on a compound of the invention with another therapeutic agent. Unless the context dictates otherwise, "combination" may refer to routes of administration of a compound of the invention with another therapeutic agent. Unless the context dictates otherwise, "combination" may include compositions based on a compound of the invention together with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, all of the above, as set forth in this description.

In some embodiments, the compound of this invention may be combined with another therapeutically active agent mentioned in WO 2016/027253, the contents of which are hereby incorporated by reference in its entirety. In such embodiments, the compound that inhibits the RIP1 kinase in the combinations mentioned in WO 2016/027253 is replaced with a compound of formula I of the present invention.

In some embodiments, a compound of this invention may be combined with a DLK (leucine double zip kinase) inhibitor for the treatment of neurodegenerative diseases and disorders such as those listed elsewhere herein, and including, but not limited to, the following: Parkinson's disease, Lewy body dementia, multiple system atrophy, parkinsonism-plus syndromes, Alzheimer's disease, frontotemporal dementia, demyelinating diseases such as multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia and stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathies, progressive supranuclear palsy and corticobasal degeneration. DLK inhibitors are described, for example, in WO 2013/174780, WO 2014/177524, WO 2014/177060, WO 2014/111496, WO 2015/091889 and WO 2016/142310.

EXAMPLES

The present invention will be better understood with reference to the following examples. They should not, however, be construed as limiting the scope of the present invention.

These examples serve as a guide for a person skilled in the art for the preparation and use of the compounds, compositions and methods of the invention. Although specific embodiments of the present invention have been described, it will be apparent to a person skilled in the art that various changes and modifications can be made without deviating from the spirit and scope of the present invention.

The chemical reactions described in the examples can easily be adapted to produce a number of other compounds of the invention, and alternative methods for preparing compounds of the invention are considered to be within the scope of this invention. For example, the synthesis of non-illustrated compounds of the invention can be successfully carried out using modifications obvious to those skilled in the art, for example, by introducing an appropriate protection on the interfering group through the use of other suitable reagents known in the art, for example, by introducing appropriate protection to the interfering group through the use of other suitable reagents known in the art, but different from those described, and/or by performing the usual modifications of the reaction conditions.

In the examples below, unless otherwise noted, all temperatures are in degrees Celsius. Commercially available reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI, or Maybridge and used without further purification unless otherwise noted. The reactions below were usually carried out under positive pressure of nitrogen or argon or using a drying tube (unless otherwise noted) in anhydrous solvents, and the reaction flasks were usually equipped with rubber seals for the introduction of substrates and reagents using a syringe. The glassware was dried in an oven and/or dried using heat. ¹ H NMR spectra were obtained from solutions in deuterated solvents CDCl ₃ , d ₆ -DMSO, CH ₃ OD or d ₆ -acetone (given in ^ppm ) using either tetramethylsilane (TMS) or residual non-deuterated solvent peaks as a reference standard . If peak multiplicity is reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt ( doublet of triplets). Spin-spin coupling constants, if specified, are given in hertz (Hz).

All abbreviations used to describe reagents, reaction conditions, or equipment are intended to be as defined in the following list of abbreviations. The chemical names of the individual compounds of the invention are usually derived using the ChemDraw naming program, with the ability to define structure names.

Abbreviations

ACN - acetonitrile,

Boc - tert-butoxycarbonyl,

DAST - diethylaminosulfur trifluoride,

DCE - 1,2-dichloroethane,

DCM - dichloromethane,

DMF - N,N-dimethylformamide,

DMSO - dimethyl sulfoxide,

DPPH - 2,2-diphenyl-1-picrylhydrazyl,

HPLC - high pressure liquid chromatography,

LCMS - liquid chromatography/mass spectrometry,

PCC - pyridinium chlorochromate,

RP - reversed phase,

RT or R _T - retention time,

SEM - 2-(trimethylsilyl)ethoxymethyl,

SFC - supercritical liquid chromatography,

TFA - trifluoroacetic acid,

THF - tetrahydrofuran.

Synthesis schemes

In addition to the specific synthesis methods set forth in the examples below, other compounds of the present invention can be obtained, for example, according to the synthesis schemes below.

After performing stages 1-5 of the method 9 below, gem-difluoro-containing groups are obtained according to scheme 1.

Scheme 1

Scheme 2 is used to prepare additional compounds of formula I with diversity in ring B, using a variety of nucleophiles, including, but not limited to, halide and cyanide sources.

Scheme 2

Scheme 3 is used to prepare compounds of formula I substituted on the gem-dimethyl-containing ring B.

Scheme 3

The following intermediates used in the examples below were prepared according to the procedures described in WO 2017/004500 (the entire content of which is incorporated herein by reference):

Unless stated in a specific method, any N-methoxy-N-methyl-alkyl-, -aryl-, -heteroaryl-containing or heterocyclic carboxamide used was prepared analogously to the preparation of cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide described below in method 5.

Method 1: Compound Examples 1 and 2

[(1S,2S)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone and [(1R,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl]methanone

To a cooled (-70°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (150 mg; 0.53 mmol) and cis-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (157 mg; 1.06 mmol) in tetrahydrofuran (12 ml) n-butyllithium was added dropwise under nitrogen atmosphere (2.5 M solution in hexanes; 0.64 ml; 1.60 mmol). Upon completion of the addition, the mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (reverse phase HPLC) (acetonitrile 20-45%/0.225% HCl in water). The racemic product was further resolved with chiral SFC to give, as tentatively indicated:

[(1S,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 1, retention time = 3.635 min) (4.0 mg; 2.5%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.39 (m, 3H), 7.30-7.28 (m, 2H), 6.20-6.18 (m, 0.5H), 6.06-6.04 (m, 0.5H ), 5.65-5.64 (m, 1H), 5.04-5.02 (m, 0.5H), 4.90-4.87 (m, 0.5H), 3.80-3.74 (m, 1H), 3.25-3.21 (m, 1H) , 2.88-2.81 (m, 1H), 2.03-1.96 (m, 1H), 1.34-1.28 (m, 1H). LCMS: R _T = 1.662 min, m/z = 290.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.662 min, ESI+: detected [M+H] = 290.1;

[(1R,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 2, retention time=3.995 min) (15.9 mg; 10%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.38 (m, 3H), 7.30-7.28 (m, 2H), 6.21-6.18 (m, 0.5H), 6.06-6.05 (m, 0.5H ), 5.66-5.65 (m, 1H), 5.05-5.04 (m, 0.5H), 4.90-4.87 (m, 0.5H), 3.82-3.74 (m, 1H), 3.23-3.20 (m, 1H) , 2.88-2.82 (m, 1H), 2.02-1.96 (m, 1H), 1.34-1.30 (m, 1H). LCMS: R _T = 1.654 min, m/z = 290.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.654 min, ESI+: [M+H] = 290.1 detected.

SFC Conditions: Column: Chiralcel OD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: isopropanol (with 0.05% DEA (diethylamine)); gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min; column temperature 35°C.

Method 2: Compound Examples 3 and 4

[(1S,2S)-2-Fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl] methanone and [(1R,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl]methanone

To a cooled (-70°C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (150 mg; 0.53 mmol) and cis-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (156.5 mg; 1.06 mmol) in tetrahydrofuran (10 ml) -butyl lithium (2.5 M solution in hexanes; 0.64 ml; 1.60 mmol). Upon completion of the addition, the mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (30 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to give [cis-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro -5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (35 mg; 22.5%) as a pink solid. The racemic product was resolved with chiral SFC to give, as tentatively indicated:

[(1S,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 1, retention time = 4.787 min) (5.9 mg; 17%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.39 (m, 3H), 7.28-7.27 (m, 2H), 6.13-6.11 (m, 1H), 5.99-5.97 (m, 1H), 5.53-5.49 (m, 1H), 3.69-3.61 (m, 1H), 3.27-3.24 (m, 1H), 3.03-2.96 (m, 1H), 2.23-2.15 (m, 1H), 1.29-1.24 (m, 1H) . LC-MS: R _T = 0.846 min, m/z = 289.9 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.846 min, ESI+: detected [M+H] = 289.9;

[(1R,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 2, retention time = 5.711 min) (11.7 mg; 33%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.37 (m, 3H), 7.28-7.27 (m, 2H), 6.13-6.11 (m, 1H), 5.99-5.97 (m, 1H), 5.53-5.50 (m, 1H), 3.69-3.63 (m, 1H), 3.27-3.23 (m, 1H), 3.03-2.96 (m, 1H), 2.23-2.16 (m, 1H), 1.29-1.24 (m, 1H) . LC-MS: R _T = 0.849 min, m/z = 289.9 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.849 min, ESI+: [M+H] = 289.9 detected.

SFC Conditions: Column: Chiralcel OD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: isopropanol (with 0.05% DEA); gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min; column temperature: 35°C.

Purification conditions by chiral SFC and analysis conditions

In the methods presented in the following table, solvent A is carbon dioxide and solvent B is 0.1% NH ₄ (aq.) in CH ₃ OH.

Method SP 5

2-Hydroxy-2-methyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]propan-1-one

For conventionally designated as 2-hydroxy-2-methyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]propan-1-one (10.94 mg; 43% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50-7.33 (m, 2H), 7.29- 7.14 (m, 2Н), 6.40-6.05 (m, 1Н), 5.81-5.63 (m, 1Н), 5.23 (s, 1Н), 2.98-2.56 (m, 1Н), 1.51 (s, 3Н), 1.48 ( s, 3H). LC-MS: R _T = 4.029 min, m/z = 290.1 (M+H) ⁺ .

Method SP 6

2-Hydroxy-2-methyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]propan-1-one

For conventionally designated as 2-hydroxy-2-methyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]propan-1-one (11.1 mg; 43% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.31 (m, 3H), 7.30- 7.12 (m, 2H), 6.37-6.01 (m, 1H), 5.82-5.53 (m, 1H), 5.23 (s, 1H), 2.85-2.59 (m, 1H), 1.52-1.47 (m, 6H). LC-MS: R _T = 4.029 min, m/z = 290.1 (M+H) ⁺ .

Method SP 37

2,2-Dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl] propane-1-one

For conventionally designated as 2,2-dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]propan-1-one (2.84 mg; 48% yield): LC-MS: R _T = 5.26 min, m/z = 288.1 (M+H) ⁺ .

Method SP 38

2,2-Dimethyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl] propane-1-one

For conventionally designated as 2,2-dimethyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]propan-1-one (4.2 mg; 77% yield): LC-MS: R _T = 5.26 min, m/z = 288.1 (M+H) ⁺ .

Method SP 39

(1-Methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

For conventionally designated as (1-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone (19.23 mg; 77% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.18 (d, J=0, 7 Hz, 1H), 7.48-7.34 (m, 3H), 7.30-7.22 (m, 2H), 6.43-6.09 (m, 1H), 5.88-5.62 (m, 1H), 3.93 (s, 3H), 3.87 -3.58 (m, 1H). LC-MS: R _T = 3.99 min, m/z = 312.1 (M+H) ⁺ .

Method SP 40

(1-Methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

For conventionally designated as (1-methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone (20.4 mg; 82% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.18 (s, 1H), 7.48 -7.33 (m, 3H), 7.32-7.06 (m, 2H), 6.43-6.08 (m, 1H), 5.92-5.62 (m, 1H), 3.93 (s, 3H), 2.96-2.57 (m, 1H) . LC-MS: R _T = 3.99 min, m/z = 312.1 (M+H) ⁺ .

Method 3

2-Phenyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt]ethanone

To a solution of ethyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 100 mg; 0.363 mmol) in tetrahydrofuran (2 ml) was added benzylmagnesium chloride (2 M solution in tetrahydrofuran; 0.20 ml; 0.400 mmol) at -78° C. under nitrogen atmosphere. Upon completion of the addition, the reaction mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (1 ml). The mixture was extracted with isopropyl acetate (3×10 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to give 2-phenyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone as a white solid (80 mg; 69% yield). LCMS: R _T = 5.24 min, m/z = 322.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min): retention time 5.24 min, ESI+: [M+H] = 322.1 detected.

Method 4

[(1S,2R)-2-Fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone and [(1R,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl]methanone

To a cooled (-70°C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (150 mg; 0.53 mmol) and trans-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (156 mg; 1.06 mmol) in tetrahydrofuran (10 ml) n-butyllithium (2 .5 M solution in hexanes, 0.64 ml, 1.60 mmol). Upon completion of the addition, the mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (30 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to give [trans-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro -5-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (35 mg; 23%) as a pink solid. This racemic product was further resolved with chiral SFC to give, as tentatively indicated:

[(1S,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 1, retention time = 2.836 min) (14.3 mg; 40%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.39 (m, 3H), 7.28-7.27 (m, 2H), 6.13-5.97 (m, 1H), 5.54-5.51 (m, 1H), 5.02-4.84 (m, 1Н), 3.69-3.53 (m, 2Н), 3.03-2.97 (m, 1Н), 1.70-1.63 (m, 2Н). LC-MS: R _T = 0.866 min, m/z = 289.9 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.866 min, ESI+: detected [M+H] = 289.9;

[(1R,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 2, retention time = 3.725 min) (11.3 mg; 32%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.39 (m, 3H), 7.28-7.27 (m, 2H), 6.12-5.97 (m, 1H), 5.54-5.50 (m, 1H), 5.03-4.87 (m, 1Н), 3.69-3.51 (m, 2Н), 3.04-2.97 (m, 1Н), 1.70-1.62 (m, 2Н). LC-MS: R _T = 0.865 min, m/z = 289.9 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.865 min, ESI+: detected [M+H] = 289.9.

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: methanol (with 0.05% DEA); gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min.

Method 5

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac- (1S,2S)-2-fluorocyclopropyl]methanone

Stage 1: cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide

Mixture of cis-2-fluorocyclopropanecarboxylic acid (500 mg; 4.80 mmol), N,O-dimethylhydroxylamine hydrochloride (610 mg; 6.25 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (2375 mg; 6.25 mmol) and N,N-diisopropylethylamine (1552 mg; 12.0 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25°C for 12 hours the Mixture was poured into water (10 ml) and was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide (420 mg; 59%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.87-4.67 (m, 1H), 3.78 (s, 3H), 3.26 (s, 3H), 2.35-2.33 (m, 1H), 1.94-1.86 (m, 1H ), 1.11-1.05 (m, 1H).

Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- [rac-(1S,2S)-2-fluorocyclopropyl]methanone

To a chilled (-78°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg ; 0.18 mmol) and cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide (52 mg; 0.35 mmol) in tetrahydrofuran (5 ml) were added dropwise under nitrogen atmosphere n-butyllithium (2.5 M solution in hexanes, 0.21 ml, 0.53 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2S)-2-fluorocyclopropyl]methanone (2.0 mg; 4%) as light yellow oil . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.37 (m, 3H), 7.29-7.27 (m, 2H), 6.19-6.18 (m, 0.5H), 6.04-6.03 (m, 0.5H ), 5.67-5.61 (m, 1Н), 5.08-4.89 (m, 1Н), 3.81-3.70 (m, 1Н), 3.26-3.16 (m, 1Н), 2.91-2.75 (m, 1Н), 2.07-1.90 (m, 1H), 1.36-1.29 (m, 1H). LCMS: R _T = 1.038 min, m/z = 290.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.038 min, ESI+: detected [M+H] = 290.1.

Method 6

(2,2-Difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl) methanone

Stage 1: 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

Mixture of 2,2-difluorocyclopropanecarboxylic acid (300 mg; 2.46 mmol), N,O-dimethylhydroxylamine hydrochloride (312 mg; 3.19 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1214 mg; 3.19 mmol) and N,N-diisopropylethylamine (794 mg; 6.14 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25°C for 12 hours the Mixture was poured into water (10 ml) and was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (200 mg; 49%) as a colorless oil . LCMS: R _T = 0.427 min, m/z = 166.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.427 min, ESI+: [M+H] = 166.1 detected.

Step 2: (2,2-difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl) methanone

To a chilled (-70°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg ; 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (59 mg; 0.35 mmol) in tetrahydrofuran (3 ml) was added n-butyllithium (2.5 M solution in hexanes; 0.25 ml; 0.62 mmol) under nitrogen atmosphere. After the addition was completed, the mixture was stirred at -70° C. for 1 h and then quenched by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to give (2,2-difluorocyclopropyl)-(rac-(5S,7S)-7 -fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (10.6 mg; 19%) as a colorless oil . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.39 (m, 3H), 7.30-7.29 (m, 2H), 6.21-6.05 (m, 1H), 5.69-5.64 (m, 1H), 3.84- 3.74 (m, 2H), 2.90-2.82 (m, 1H), 2.32-2.27 (m, 1H), 1.97-1.90 (m, 1H). LCMS: R _T = 0.875 min, m/z = 307.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.875 min, ESI+: [M+H] = 307.9 detected.

Method 7

Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone was obtained from ethyl [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate and phenylmagnesium according to method 3. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to give the final product (17 mg; 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20-8.12 (m, 2H), 7.74-7.65 (m, 1H), 7.61-7.52 (m, 2H), 7.48-7.33 (m, 3H), 7.32 -7.24 (m, 2H), 6.28 (ddd, J=56.4; 7.2; 1.9 Hz, 1H), 5.78 (ddd, J=8.5; 6.5; 3.1 Hz, 1H ), 3.78 (dddd, J=25.8; 15.4; 8.5; 7.1 Hz, 1H), 2.74 (dddd, J=26.7; 15.2; 3.2; 2.0 Hz , 1H). LC-MS: R _T = 5.04 min, m/z = 308.1 (M+H) ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min): retention time 5.04 min, ESI+: [M+H] = 308.1 detected.

Method 8

Stage 1: (E)-benzaldehyde oxime

To a solution of benzaldehyde (45.0 g; 424.1 mmol) in ethanol (100 ml) were added sodium carbonate (112.3 g; 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g; 508.9 mmol). The reaction mixture was stirred at 25°C for 3 h and filtered. The filtrate was concentrated under reduced pressure and the residue was diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with brine (60 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude (E)-benzaldehyde oxime as a colorless oil (51.0 g; 99%) which was used in the next step without additional cleaning.

Stage 2: methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate

To a solution of (E)-benzaldehyde oxime (20.0 g; 165.1 mmol) in 1,4-dioxane (500 ml) was added methyl acrylate (14.2 g; 165.1 mmol), sodium iodide ; 165.1 mmol), 2,6-lutidine (17.6 g; 165.1 mmol) and hypochlorous acid tert-butyl ester (17.9 g; 165.1 mmol). The reaction mixture was stirred at 25°C for 24 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g; 74%). LCMS: R _T = 0.871 min, m/z = 206.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min): retention time 0.871 min, ESI+: [M+H] = 206.2 detected.

Stage 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one

A mixture of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (25.0 g; 121.8 mmol) and palladium (10% on charcoal; 2.5 g) in ethanol (800 mL) was hydrogenated ( 50 psi (344.7 kPa)) at 25° C. for 2 hours, then filtered and the filtrate concentrated under reduced pressure to give crude 3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid substance (18.0 g; 83%), which was used in the next step without further purification. LCMS: R _T = 0.270 min, m/z = 177.8 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.270 min, ESI+: [M+H] = 177.8 detected.

Stage 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one and trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenylpyrrolidin-2 -He

To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g; 84.6 mmol) in dichloromethane (300 ml) was added tert-butyldimethylchlorosilane (19.1 g; 126.9 mmol) and imidazole ( 11.5 g, 169.3 mmol). The reaction mixture was stirred at 25°C for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give:

cis-3-[t-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (12.4 g; 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.25 (m, 5H), 4.88-4.53 (m, 1H), 4.54-4.46 (m, 1H), 2.89-2.79 (m, 1H), 1.80-1.71 (m, 1Н), 0.93-0.90 (m, 9Н), 0.19-0.12 (m, 6Н); And

trans-3-[t-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g; 38%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.34 (m, 2H), 7.29-7.24 (m, 3H), 4.87-4.80 (m, 1H), 4.44-4.41 (m, 1H), 2.45-2.37 (m, 1Н), 2.27-2.22 (m, 1Н), 0.93-0.90 (m, 9Н), 0.16-0.13 (m, 6Н).

Stage 5: cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

Hydride sodium (60%; 2.6 g; 64.1 mmol) at 0°C. After the addition was complete, the mixture was stirred at 0° C. for 20 minutes and then O-(diphenylphosphoryl)hydroxylamine (14.9 g; 64.1 mmol) was added. The reaction mixture was stirred at 25°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure to give the crude cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a yellow oil (9.5 g, 73%), which was used in the next step without further purification. LCMS: R _T = 0.877 min, m/z = 307.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.877 min, ESI+: detected [M+H] = 307.0.

Stage 6: ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate

Ethyl- 2-ethoxy-2-imino-acetate (6.7 g; 46.5 mmol). The reaction mixture was stirred at 60° C. for 6 hours and then concentrated under reduced pressure to give crude ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidine -1-yl]amino]-2-imino-acetate as a yellow oil (10.6 g; 84%), which was used in the next step without further purification. LCMS: R _T = 2.106 min, m/z = 406.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3.0 min): retention time 2.106 min, ESI+: [M+H] = 406.2 detected.

Stage 7: ethyl cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -carboxylate

To a solution of ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate (10.6 g ; 26.1 mmol) in toluene (200 ml) was added p-toluenesulfonic acid (4.5 g; 26.1 mmol). The reaction mixture was heated at 120°C for 24 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 80% ethyl acetate in petroleum ether) to give ethyl cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate as a white solid (6.5 g; 64%), which was used as such in the next step.

Step 8: Ethyl cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-iminoacetate mixture (3.1 g; 7.6 mmol) and tert-butylammonium fluoride (1.0 M solution in THF; 7.6 ml; 7.6 mmol) in tetrahydrofuran (60 ml) were heated at 60°C for 18 h and then concentrated under reduced pressure . The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give ethyl cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate as a white solid (1.4 g; 69%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.32 (m, 5H), 5.73 (d, J=3.5 Hz, 1H), 5.50(m, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.73-3.65 (m, 1H), 2.76 (td, J=4.5Hz, 13.9Hz, 1H), 1.35 (t, J=7.1Hz, 3H).

Stage 1: trans-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of cis-ethyl-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg; 0.37 mmol ) in dichloromethane (8 ml) was added diethylaminosulfur trifluoride (176.9 mg; 1.10 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h and then extinguished by adding water (20 ml). The mixture was extracted with dichloromethane (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (TLC) (50% ethyl acetate in petroleum ether, retention factor (R _f )=0.5) to give trans-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg; 30%) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.37 (m, 3H), 7.14-7.12 (m, 2H), 6.14 (d, J=5.2 Hz, 0.5H), 6.00 (d, J =5.2 Hz, 0.5H), 5.74-5.71 (m, 1H), 4.51-4.45 (m, 2H), 3.42-3.35 (m, 1H), 3.07-2.96 (m, 1H), 1.42 (t , J=7.2 Hz, 3H).

Stage 2: trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

To a solution of trans-ethyl 7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg; 0.11 mol ) in tetrahydrofuran (4 ml) and water (1 ml) was added lithium hydroxide monohydrate (14 mg; 0.33 mmol). The reaction mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure. The pH of the residue was adjusted to 5 by adding hydrochloric acid (2N). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole-2-carboxylic acid as a white solid (13 mg; 48%), which was used in the next step without further purification.

1-[rac-(5R,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-he

To a cooled (-78°C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide (15 mg; 0.05 mmol) in tetrahydrofuran (10 ml) was added ethylmagnesium bromide (3 M solution in THF; 0.03 ml; 0.10 mmol) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and extinguished by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 34-64%/0.05% hydrochloric acid in water) to give 1-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (7.4 mg; 50%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.38 (m, 3H), 7.30-7.26 (m, 2H), 6.27-6.26 (m, 0.5H), 6.14-6.12 (m, 0.5H ), 5.87-5.84 (m, 1H), 3.44-3.41 (m, 1H), 3.12-3.02 (m, 3H), 1.16 (t, J=7.2 Hz, 3H). LCMS: R _T = 0.840 min, m/z = 260.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.840 min, ESI+: [M+H] = 260.1 detected.

Method 9

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1- (trifluoromethyl)cyclopropyl]methanone

Step 1: 3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

To a solution of 3,5-dibromo-1H-1,2,4-triazole (150.0 g; 661.2 mmol) in tetrahydrofuran (1500 ml) was slowly added p-toluenesulfonic acid (17.1 g; 99.2 mmol ), then 3,4-dihydro-2H-pyran (166.9 g; 1983.6 mmol) at 0°C. After the addition was completed, the reaction mixture was heated at 70° C. for 3 hours and concentrated under reduced pressure. The residue was poured into water (500 ml) and the pH was adjusted to 9 by adding saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×400 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was washed with methanol (2×50 ml), dried under reduced pressure to give the crude 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (155 g; 75%) as white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.49-5.46 (m, 1H), 4.12-3.99 (m, 1H), 3.72-3.61 (m, 1H), 2.38-2.26 (m, 1H), 2.18-2.07 (m, 1H), 1.98-1.90 (m, 1H), 1.78-1.60 (m, 3H).

Stage 2: 1-phenylbut-3-en-1-ol

To a chilled (0°C) solution of benzaldehyde (130 g; 1.23 mol) in tetrahydrofuran (1000 ml) was added allylmagnesium chloride (2 M solution in THF; 858 ml; 1.72 mol) over 30 minutes. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was then quenched by adding saturated aqueous ammonium chloride (1000 ml) and extracted with ethyl acetate (3×500 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give 1-phenylbut-3-en-1-ol (140 g; 77%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.34 (m, 4H), 7.29-7.26 (m, 1H), 5.83-5.75 (m, 1H), 5.21-5.08 (m, 2H), 4.76-4.69 (m, 1H), 2.55-2.45 (m, 2H), 2.12 (d, J=2.8 Hz, 1H).

Stage 3: tert-butyldimethyl ((1-phenylbut-3-en-1-yl)oxy)silane

To a stirred solution of 1-phenyl-3-buten-1-ol (29.0 g, 195.7 mmol) in dichloromethane (400 ml) was added imidazole (27.0 g, 391.6 mmol) and tert-butyldimethylchlorosilane (39 .0 g; 254.4 mmol). Upon completion of the addition, the reaction mixture was stirred at 25°C for 16 h and then extinguished by adding water (200 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to give t-butyl-dimethyl-(1-phenylbut-3-enoxy)silane (43.0 g; 84%) as a colorless oil , which was used in this form in the next step.

Stage 4: 3-((tert-butyldimethylsilyl)oxy)-3-phenylpropanal

Osmium tetroxide (968 mg, 3 .8 mmol). After stirring for 30 min at 15° C., sodium periodate (163 g; 762.0 mmol) was added in small portions over 2 h. The resulting mixture was stirred for another 2 h at 30° C. and then quenched by adding cold saturated aqueous solution sodium thiosulfate (500 ml). The mixture was stirred for 30 min and then extracted with ethyl acetate (3×400 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-3-phenyl-propanal (33.0 g; 65% ) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.94 (t, J=2.4 Hz, 1H), 7.48 (d, J=4.2 Hz, 4H), 7.44-7.39 (m, 1H), 5.37- 5.34 (m, 1H), 2.99-2.97 (m, 1H), 2.80-2.75 (m, 1H), 1.01 (s, 9H), 0.19 (s, 3H), 0.00 (s, 3H).

Step 5: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-phenylpropan-1-ol

To a cooled (-78°C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (39.0 g; 125.4 mmol) in tetrahydrofuran (400 ml) was added dropwise n-butyl lithium (2.5 M solution in hexanes; 55.0 ml; 137.5 mmol) under N ₂ atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-phenyl-propanal (33.0 g; 124.2 mmol) in tetrahydrofuran (50 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1.5 h and then extinguished by adding saturated aqueous ammonium chloride solution (500 ml). The resulting mixture was extracted with ethyl acetate (3×300 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1.2 ,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-phenylpropan-1-ol (50.0 g; 80%) as a light yellow oil.

Stage 6: trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

To a stirred solution of 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-phenylpropan-1-ol (50.0 g; 100.7 mmol) in dichloromethane (150 ml) trifluoroacetic acid (150 ml) was added slowly. The resulting mixture was heated at 50° C. for 2 hours and then concentrated under reduced pressure. The pH of the residue was adjusted to 9 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 32% ethyl acetate in petroleum ether) to give trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazol-7-ol (5.5 g; 20%) as a yellow solid (also received a second crop (8.5 g; 30%) as a 4:3 mixture of trans-cis- products). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.32 (m, 3H), 7.15 (d, J=7.6 Hz, 2H), 5.65 (t, J=6.6 Hz, 1H), 5.50 ( br s, 1H), 5.45 (d, J=6.4 Hz, 1H), 3.19-3.11 (m, 1H), 3.01-2.92 (m, 1H). LCMS: R _T = 0.682 min, m/z = 279.8 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.682 min, ESI+: detected [M+H] = 279.8.

Step 7: (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (5R,7R )-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a stirred solution of trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (3.0 g; 10.71 mmol) in dichloromethane (60 ml) diethylaminosulfur trifluoride (7.8 g; 48.19 mmol) was added slowly at 0°C. The reaction mixture was stirred at 0°C for 2.5 h and then slowly added to a stirred aqueous saturated sodium bicarbonate solution (100 ml) at 0°C. The mixture was extracted with dichloromethane (3×100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give racemic cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole (1.5 g; 49%) as light yellow solid and racemic trans-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazole (650 mg; 21%) as a white solid.

cis-2-Bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31-7.24 (m, 3H), 7.17-7.07 (m, 2H), 5.97-5.77 (m, 1H), 5.37-5.27 (m, 1H), 3.52-3.37 (m, 1H), 2.84-2.70 (m , 1H). LCMS: R _T = 0.632 min, m/z = 281.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.632 min, ESI+: detected [M+H] = 281.9.

trans-2-Bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58-7.29 (m, 3H), 7.24-7.05 (m, 2H), 6.14-5.93 (m, 1H), 5.70-5.65 (m, 1H), 3.41-3.25 (m, 1H), 3.04-2.87 (m , 1H).

The racemic cis product was further resolved with chiral SFC to give, as conventionally indicated:

(5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 1, retention time = 2.963 min) (350 mg; 44%) as a white solid and

(5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 3.174 min) (350 mg; 44%) as a white solid.

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min.

Stage 8: N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide

A mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (400mg; 2.60mmol), N,O-dimethylhydroxylamine hydrochloride (329mg; 3.37mmol), 1-[bis(dimethylamino)methylene]-1H-1,2, 3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1283 mg; 3.37 mmol) and N,N-diisopropylethylamine (838 mg; 6.49 mmol) in N,N-dimethylformamide (15 ml) stirred at 25° C. for 12 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (330 mg; 64%) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.74 (s, 3H), 3.29 (s, 3H), 1.37-1.17 (m, 4H).

Step 9: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- [1-(trifluoromethyl)cyclopropyl]methanone

To a chilled (-70°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg ; 0.18 mmol) and N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (70 mg; 0.35 mmol) in tetrahydrofuran (4 ml) was added n-butyl lithium (2.5 M solution in hexanes; 0 .1 ml; 0.25 mmol) under a nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (5 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 45-75%/0.05% ammonium hydroxide in water) to give, as conventionally indicated, (rac-(5S,7S)-7-fluoro- 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(trifluoromethyl)cyclopropyl]methanone (14.1 mg; 23 %) as a red solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.35 (m, 3H), 7.24-7.22 (m, 2H), 6.15-5.99 (m, 1H), 5.61-5.60 (m, 1H), 3.77 -3.68 (m, 1H), 2.84-2.77 (m, 1H), 2.27-2.17 (m, 2H), 1.60-1.55 (m, 2H). LC-MS: R _T = 0.933 min, m/z = 339.9 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min): retention time 0.933 min, ESI+: detected [M+H] = 339.9.

Method 10

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3- methyloxetan-3-yl) methanone

Stage 1: N-methoxy-N,3-dimethyl-oxetane-3-carboxamide

Mixture of 3-methyloxetane-3-carboxylic acid (300 mg; 2.58 mmol), N,O-dimethylhydroxylamine hydrochloride (328 mg; 3.36 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2 ,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1277 mg; 3.36 mmol) and N,N-diisopropylethylamine (835 mg; 6.46 mmol) in N,N-dimethylformamide (15 ml ) was stirred at 25° C. for 12 hours. The mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (120 mg; 29.2%) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.97 (d, J=6.4 Hz, 2H), 4.30 (d, J=6.4 Hz, 2H), 3.67 (s, 3H), 3.19 (s, 3Н), 1.67 (s, 3Н).

Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- (3-methyloxetan-3-yl) methanone

To a chilled (-70°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (40 mg ; 0.14 mmol) and N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (45 mg; 0.28 mmol) in tetrahydrofuran (3 ml) was added n-butyllithium (2.5 M solution in hexanes; 0.17 ml; 0.43 mmol) under nitrogen atmosphere. After the addition was completed, the mixture was stirred at -70° C. for 1 h and then quenched by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3-methyloxetan-3-yl)methanone (11.5 mg; 27%) as yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.37 (m, 3H), 7.26-7.23 (m, 2H), 6.17-6.01 (m, 1H), 5.65-5.63 (m, 1H), 5.08- 5.03 (m, 2H), 4.52-4.48 (m, 2H), 3.78-3.70 (m, 1H), 2.86-2.76 (m, 1H), 1.75 (s, 3H). LCMS: R _T = 0.816 min, m/z = 302.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.816 min, ESI+: [M+H] = 302.0 detected.

Method 11

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac- (1S,2R)-2-fluorocyclopropyl]methanone

Stage 1: trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

Mixture of trans-2-fluorocyclopropane-1-carboxylic acid (100 mg; 0.96 mmol), N,O-dimethylhydroxylamine hydrochloride (122 mg; 1.25 mmol), 1-[bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (475 mg; 1.25 mmol) and N,N-diisopropylethylamine (310 mg; 2.40 mmol) in N,N-dimethylformamide ( 5 ml) was stirred at 25° C. for 12 hours. The mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (70 mg; 50%) as a colorless oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.89-4.71 (m, 1H), 3.79 (s, 3H), 3.21 (s, 3H), 2.62-2.60 (m, 1H), 1.48-1.35 (m, 2H ). LCMS: R _T = 0.292 min, m/z = 148.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.292 min, ESI+: [M+H] = 148.1 detected.

Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- [rac-(1S,2R)-2-fluorocyclopropyl]methanone

To a chilled (-70°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (40 mg ; 0.14 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (42 mg; 0.28 mmol) in tetrahydrofuran (3 ml) was added n-butyl lithium (2.5 M solution in hexanes; 0.07 ml; 0.18 mmol) under nitrogen atmosphere. After the addition was completed, the mixture was stirred at -70° C. for 1 h and then quenched by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2R)-2-fluorocyclopropyl]methanone (3.3 mg; 7 .6%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.37 (m, 3H), 7.28-7.27 (m, 2H), 6.13-5.97 (m, 1H), 5.54-5.52 (m, 1H), 5.03-4.85 (m, 1H), 3.71-3.51 (m, 2H), 3.04-2.94 (m, 1H), 1.70-1.62 (m, 2H). LCMS: R _T = 0.862 min, m/z = 289.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.862 min, ESI+: detected [M+H] = 289.9.

Method 12

1-(7-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-а]imidazol-2-yl)propan-1-one

Step 1: 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

To a solution of imidazole (40.0 g; 587.5 mmol), acetic acid (1.8 ml) and 1,4-dioxane (600 ml) was added acrolein (58.8 ml; 881.3 mmol). The resulting mixture was stirred at 110°C for 24 h and cooled to 0°C. The resulting solid was collected by filtration, washed with petroleum ether (200 mL) to give crude 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (50.0 g; 69%) as a white solid substances. Used in this form in the next step.

Stage 2: 3-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (10.0 g; 80.6 mmol) in dichloromethane (300 ml) was added N-chlorosuccinimide (10.8 g; 80.6 mmol). The mixture was stirred at 50° C. for 2 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 3-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (8 .0 g, 63%) as a white solid, which was used as such in the next step.

Stage 3: 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

N -iodosuccinimide (8.3 g; 37.1 mmol). The mixture was heated at 60°C for 3 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-7 -ol (5.3 g; 53%) as a light yellow solid, which was used as such in the next step.

Step 4: 3-chloro-2-iodo-5H-pyrrolo[1,2-a]imidazol-7(6H)-one

The dioxide manganese (8.1 g; 93.2 mmol). The mixture was heated at 40° C. for 5 hours and filtered. The filtrate was concentrated to dryness under reduced pressure to give crude 3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-one (3.2 g; 61%) as a brown solid which used as such in the next step.

Step 5: N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methylbenzenesulfonamide

A mixture of 4-methylbenzenesulfonhydrazide (2.1 g, 11.3 mmol) and 3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-one (3.2 g, 11.3 mmol) in ethanol (70 ml) was heated at 90°C for 7 h and cooled to 15°C. The resulting solid was collected by filtration and dried under reduced pressure to give crude N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]- 4-methyl-benzenesulfonamide (2.8 g; 54%) as a pale green solid, which was used as such in the next step.

Stage 6: 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methyl-benzenesulfonamide mixture (1.8 g; 3 .88 mmol), phenylboronic acid (710 mg; 5.82 mmol), potassium carbonate (1.6 g; 11.65 mmol) in 1,4-dioxane (40 ml) was heated at 110°C for 18 h in N ₂ atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2- a]imidazole (200 mg; 15%) as a light brown solid. LCMS: r _t = 0.879 min, m/z = 334.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.879 min, ESI+: detected [M+H] = 334.9.

Stage 7: methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate

A mixture of 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200 mg; 0.58 mmol), dichloromethane complex of 1,1'-bis( diphenylphosphino)ferrocene-palladium(II) (24 mg; 0.03 mmol) and triethylamine (0.4 ml; 2.9 mmol) in N,N-dimethylformamide (24 ml)/methanol (8 ml) were heated at 90 °C for 18 hours in CO atmosphere (50 psi (344.7 kPa)). The mixture was filtered through a short pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole -2-carboxylate (140 mg; 87%) as a light brown solid. LCMS: r _t = 0.676 min, m/z = 277.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.676 min, ESI+: detected [M+H] = 277.0.

Stage 8: methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate

A mixture of methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (120 mg; 0.43 mmol) and palladium (10% on carbon ; 103 mg; 0.10 mmol; 50% moisture in methanol (50 ml) was hydrogenated (40 psi (275.8 kPa)) at 50° C. for 24 h and then filtered. The filtrate was concentrated under reduced pressure to give crude methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (100 mg; 95%) as a brown oil which was used in like this in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.60 (m, 1H), 7.40-7.25 (m, 4H), 4.70-4.55 (m, 1H), 4.40-4.15 (m, 2H), 3.89 (s , 3Н), 3.30-3.20 (m, 1H), 2.75-2.70 (m, 1H), 1.70-1.60 (m, 1H). LCMS: r _t = 0.513 min, m/z = 243.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.513 min, ESI+: detected [M+H] = 243.1.

Stage 9: 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid

Mixture of methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (100 mg; 0.41 mmol) and lithium hydroxide monohydrate (118 mg; 2.89 mmol) in tetrahydrofuran (2 ml), water (1 ml) and methanol (2 ml) was heated at 25°C for 18 hours. Sodium hydroxide (100 mg) was added and the mixture was heated at 40°C for another 2 hours. concentrated under reduced pressure. The residue was dissolved in water (5 ml) and the pH was adjusted to 3 by adding 2 M HCl solution. The resulting mixture was lyophilized to dryness to give crude 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (94 mg; 99%) as a white solid, which was used in this view in the next stage.

Step 10: N-methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide

A mixture of 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (60 mg; 0.26 mmol), N,O-dimethylhydroxylamine hydrochloride (77 mg; 0.79 mmol), triethylamine (0.11 ml; 0.79 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (105 mg; 0.28 mmol) in N,N-dimethylformamide (4 ml) was stirred at 15° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.5) to give N-methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a ]imidazole-2-carboxamide (70 mg; 98%) as a white solid. LCMS: r _t = 0.506 min, m/z = 272.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.506 min, ESI+: detected [M+H] = 272.1.

Step 11: 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one

To a chilled (-70°C) solution of N-methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (50 mg; 0.18 mmol ) in tetrahydrofuran (2 ml) was added ethyl magnesium bromide (3.0 M solution in THF; 0.61 ml; 1.83 mmol) under N ₂ atmosphere. Upon completion of the addition, the mixture was stirred at -70°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride solution (3 ml). The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2 -a]imidazol-2-yl)propan-1-one (4.6 mg; 9%) as a light brown solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.86 (s, 1H), 7.35-7.31 (m, 2H), 7.30-7.21 (m, 3H), 4.42-4.38 (m, 1H), 4.25-4.23 ( m, 1H), 4.20-4.11 (m, 1H), 3.12-3.10 (m, 1H), 2.89-2.83 (m, 2H), 2.58-2.50 (m, 1H), 1.14-1.10 (m, 3H). LCMS: r _t = 0.634 min, m/z = 241.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.634 min, ESI+: detected [M+H] = 241.1.

Method 13

Cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (50 mg; 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg; 0.24 mmol), 1-hydroxybenzotriazole (5 mg; 0.04 mmol), N,O-dimethylhydroxylamine hydrochloride (12 mg; 0.20 mmol) in N,N-dimethylformamide (5 ml) was stirred at 20° C. for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.7) to give trans -7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (30 mg; 51 %) as a white solid.

Stage 2: cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]Methanone

To a cooled (-78°C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide (15 mg; 0.05 mmol) in tetrahydrofuran (10 ml) was added cyclopropyl magnesium bromide (0.5 M solution in THF; 0.2 ml; 0.10 mmol) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and extinguished by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 35-65%/0.05% hydrochloric acid in water) to give cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (7.6 mg; 50%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.40 (m, 3H), 7.30-7.26 (m, 2H), 6.29-6.26 (m, 0.5H), 6.14-6.12 (m, 0.5H ), 5.92-5.87 (m, 1H), 3.44-3.41 (m, 1H), 3.01-3.02 (m, 2H), 1.19-1.16 (m, 2H), 1.12-1.09 (m, 2H). LCMS: r _t = 0.849 min, m/z = 272.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.849 min, ESI+: [M+H] = 272.0 detected.

Method 14

1-(6-Phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one

Stage 1: ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate

To a solution of prop-2-yn-1-ol (30.0 g; 535.14 mmol) in toluene (300 ml) was added ethyl 2-diazoacetate (67.2 g; 588.66 mmol). The reaction mixture was stirred at 110°C for 5 h and cooled to room temperature. The crude product was collected by filtration and washed with 10% ethyl acetate in petroleum ether (50 ml) to give a mixture of ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (15.8 g; 17%) and ethyl 3- (hydroxymethyl)-1H-pyrazole-5-carboxylate (inseparable, 1:3; 63.1 g; 69%) as a light yellow solid, which was used as a mixture in the next step.

Ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (basic isomer): ¹ H NMR (DMSO-d ₆ ) 12.60 (1H, s, broadened); 6.70 (1H, s); 4.70 (1H, s); 4.35 (2H, q, J=7.0 Hz); 4.45 (1H, s, broadened); 1.25 (3H, t, J=7.0 Hz).

Ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (minor isomer): ¹ H NMR (DMSO-d ₆ ) 12.60 (1H, s, broadened); 7.65 (1H, s); 4.75 (1H, s); 4.35 (2H, q, J=7.0 Hz); 4.13(1H, s, broadened); 1.25 (3H, t, J=7.0 Hz).

Stage 2: ethyl 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazole-5-carboxylate

A mixture of ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (3:1; 4.0 g; 23.5 mmol), (2 -(chloromethoxy)ethyl)trimethylsilane (11.2 ml; 70.5 mmol) and cesium carbonate (45.9 g; 141.0 mmol) in acetone (100 ml) was stirred at 25°C for 3 h and then filtered . The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to give ethyl 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (inseparable, 3.7 g; 52%) which were used as a mixture in the next step. LC-MS: r _t = 0.855 min, m/z = 322.9 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.855 min, ESI+: [M+Na]=322.9 detected.

Stage 3: ethyl-3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

To a solution of ethyl 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-pyrazole-5-carboxylate (2.0 g; 6.66 mmol) in dichloromethane (100 ml) was added manganese dioxide (7.0 g; 80.52 mmol). The mixture was stirred at 25° C. for 15 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give ethyl 5-formyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (700 mg; 35%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 7.38 (s, 1H), 5.94 (s, 2H), 4.40 (q, J=8.0 Hz, 2H), 3.69-3.60 ( m, 2H), 1.40 (t, J=8.0 Hz, 3H), 0.98-0.89 (m, 2H), 0.02-0.07 (m, 9H).

Step 4: (E)-ethyl-3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylate

To a solution of ethyl 5-formyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (700 mg; 2.35 mmol) in dichloromethane (100 ml) was added trimethyl ((1-phenylvinyl)oxy)silane (499 mg; 2.59 mmol) and titanium tetrachloride (875 mg; 4.61 mmol). The mixture was stirred at 40°C for 48 h and then extinguished by adding water (50 ml). The resulting mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give (E)-ethyl-3-(3-oxo-3-phenylprop-1 -en-1-yl)-1H-pyrazol-5-carboxylate (310 mg; 49%) as a yellow solid. LC-MS: r _t = 0.853 min, m/z = 270.9 (M+H) ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.853 min, ESI+: [M+H] = 270.9 detected.

Stage 5: ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate

A mixture of (E)-ethyl-3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylate (310 mg; 1.15 mmol) and palladium (10% on carbon; 122 mg) in methanol (20 ml) was hydrogenated (15 psi (103.4 kPa)) at 25°C for 15 h and then filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate (314 mg; 99%) as a light yellow oil. This crude oil was used directly in the next step without further purification.

Stage 6: ethyl 3-(3-chloro-3-phenylpropyl)-1H-pyrazole-5-carboxylate

To a solution of ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate (314 mg; 1.14 mmol) in acetonitrile (5 ml) was added thionyl chloride (681 mg; 5.72 mmol). The mixture was heated at 65° C. for 15 h and then concentrated under reduced pressure to give crude ethyl 3-(3-chloro-3-phenyl-propyl)-1H-pyrazole-5-carboxylate (335 mg; 100%) in yellow oil. This crude oil was used directly in the next step without further purification. LC-MS: r _t = 0.861 min, m/z = 314.9 (M+H) ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.861 min, ESI+: [M+H] = 314.9 detected.

Stage 7: ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate

A mixture of ethyl 3-(3-chloro-3-phenyl-propyl)-1H-pyrazole-5-carboxylate (335 mg; 1.14 mmol) and cesium carbonate (3.0 g; 9.21 mmol) in acetonitrile ( 20 ml) was stirred at 15°C for 15 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25% ethyl acetate in petroleum ether) to give ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylate (120 mg; 41%) as a light yellow oil. LC-MS: r _t = 0.824 min, m/z = 279.0 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.824 min, ESI+: [M+H] = 279.0 detected.

Stage 8: 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

Mixture of ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (60 mg; 0.23 mmol) and lithium hydroxide monohydrate (50 mg; 1.2 mmol) in tetrahydrofuran (5 ml), methanol (5 ml) and water (2 ml) was stirred at 25°C for 3 h and then concentrated under reduced pressure. The pH of the residue was adjusted to 5 by adding hydrochloric acid (2N). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole -2-carboxylic acid (30 mg; 56%) as a yellow solid, which was used as such in the next step.

Step 9: N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

A mixture of 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (30 mg; 0.13 mmol), N,O-dimethylhydroxylamine hydrochloride (17 mg; 0.17 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (65 mg; 0.17 mmol), N,N-diisopropylethylamine (42 mg; 0.33 mmol) in tetrahydrofuran (5 ml) was stirred at 25°C for 2 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxamide (25 mg; 70%) as a white solid. LC-MS: r _t = 0.952 min, m/z = 272.1 (M+H) ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min): retention time 0.952 min, ESI+: [M+H] = 272.1 detected.

Step 10: 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one

To a chilled (-78°C) solution of N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (24 mg; 0.09 mmol ) in tetrahydrofuran (5 ml) was added dropwise ethyl magnesium chloride (3.0 M solution in THF; 0.07 ml; 0.21 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazol-2-yl)propan-1-one (13.0 mg; 61%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.39-7.30 (m, 3H), 7.11-7.09 (m, 2H), 6.60 (s, 1H), 5.54-5.50 (m, 1H), 3.11-3.01 ( m, 3H), 2.95-2.89 (m, 2H), 2.52-2.48 (m, 1H), 1.11 (t, J=7.2 Hz, 3H). LC-MS: r _t = 1.858 min, m/z = 241.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min): retention time 1.858 min, ESI+: found [M+H] = 214.2.

Method 15

1-[(4S)-4-(2-Fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one and 1- [(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one

To a chilled (-78°C) solution of 4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (200 mg; 0.63 mmol) in tetrahydrofuran (13 ml) was added dropwise ethylmagnesium chloride (2 M solution in THF; 0.63 ml; 1.26 mmol) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 1-[4-(2-fluorophenyl)-6,7-dihydro-4H -pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (120 mg; 70%) as a white solid. This racemic product was further resolved with chiral SFC to give, as tentatively indicated:

1-[(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 1 , retention time = 2.979 min) (45.0 mg; 37%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.34 (m, 2H), 7.16-7.14 (m, 2H), 6.22 (s, 1H), 6.07 (s, 1H), 4.42-4.18 (m, 4H), 2.96-2.92 (m, 2H), 1.10 (t, J=7.2 Hz, 3H). LC-MS: r _t = 1.761 min, m/z = 275.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min): retention time 1.761 min, ESI+: detected [M+H] = 275.2;

1-[(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 2 , retention time = 3.234 min) (52 mg; 43%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.34 (m, 2H), 7.16-7.14 (m, 2H), 6.22 (s, 1H), 6.08 (s, 1H), 4.41-4.15 (m, 4H), 3.00-2.92 (m, 2H), 1.10 (t, J=7.2 Hz, 3H). lc-msr _t = 1.755 min, m/z = 275.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min): retention time 1.752 min, ESI+: detected [M+H] = 275.2.

SFC conditions: column: Chiralpak AD-3, 150 x 4.6 mm (id), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 2.5 ml/min; column temperature: 40°C.

Method 16

3-(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2 ,2-dimethyl-3-oxo-propanenitrile

Step 1: cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-oxopropanenitrile

To a cooled (-78°C) solution of acetonitrile (298 mg; 7.27 mmol) in tetrahydrofuran (15 ml) was added potassium tert-butoxide (611.4 mg; 5.45 mmol). After stirring for 30 minutes, ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate was added dropwise (500 mg; 1.82 mmol) in tetrahydrofuran (5 ml). Upon completion of the addition, the mixture was stirred at -78° C. for 2 h and then quenched by slowly adding cold saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure to give crude cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl)-3-oxo-propanenitrile (150 mg; 31%) as a white solid, which was used as such in the next step.

Step 2: 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl )-2,2-dimethyl-3-oxo-propanenitrile

To a cooled (0°C) solution of cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) -3-oxo-propanenitrile (140 mg; 0.52 mmol) in N,N-dimethylformamide (6 ml) was added cesium carbonate (422 mg; 1.30 mmol). After stirring for 30 min, iodomethane (2800 mg; 19.7 mmol) was added and the reaction mixture was stirred at 0° C. for 4 h. The mixture was then quenched by adding cold saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3 × 15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-3-oxo-propanenitrile (28.0 mg; 17%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.38 (m, 3H), 7.27-7.25 (m, 2H), 6.15-6.13 (m, 0.5H), 6.01-5.99 (m, 0.5H) , 5.57-5.56 (m, 1H), 3.74-3.63 (m, 1H), 3.06-2.95 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H). LC-MS: r _t = 1.734 min, m/z = 299.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min): retention time 1.734 min, ESI+: detected [M+H] = 299.2.

Method 17

1-[(4S)-4-Phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one and 1-[(4R)-4-phenyl- 5,6-dihydro-4Н-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one

Stage 1: N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

A mixture of 4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (93 mg; 0.41 mmol), N,O-dimethylhydroxylamine hydrochloride (80 mg; 0.81 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (163 mg; 0.43 mmol) and triethylamine (124 mg; 1.22 mmol) in N,N-dimethylformamide (4 ml) was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (10% methanol in dichloromethane, R _f = 0.7 ) to give N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (100 mg; 91%) as a colorless oil. LCMS: r _t = 0.593 min, m/z = 272.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.593 min, ESI+: [M+H] = 272.1 detected.

Stage 2: 1-[(4S)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one and 1-[(4R)-4 -phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one

To a chilled (-78°C) solution of N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (100 mg; 0.37 mmol ) in tetrahydrofuran (5 ml) was added dropwise ethyl magnesium chloride (2.7 M solution in THF; 0.54 ml; 1.47 mmol) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (2×15 ml). The combined organic layers were concentrated under reduced pressure to give crude 1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one (80 mg; 90% ) as a light brown solid, which was further resolved with chiral SFC to give, as tentatively indicated:

(R)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one (peak 1, retention time = 2.581 min) (25 .4 mg, 32%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.32-7.21 (m, 5H), 6.43 (s, 1H), 4.50-4.37 (m, 1H), 4.36-4.33 (m, 1H), 4.24-4.22 ( m, 1H), 3.13-3.10 (m, 1H), 2.99-2.95 (m, 2H), 2.57-2.53 (m, 1H), 1.15 (t, J=7.2 Hz, 3H). LCMS: r _t = 0.843 min, m/z = 240.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.843 min, ESI+: detected [M+H] = 240.9;

(S)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one (peak 2, retention time = 2.968 min) (22 .7 mg, 28%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.35-7.22 (m, 5H), 6.43 (s, 1H), 4.51-4.38 (m, 1H), 4.37-4.33 (m, 1H), 4.25-4.22 ( m, 1H), 3.14-3.12 (m, 1H), 3.02-2.96 (m, 2H), 2.58-2.54 (m, 1H), 1.16 (t, J=7.2 Hz, 3H). LCMS: r _t = 0.838 min, m/z = 241.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.838 min, ESI+: detected [M+H] = 241.0.

SFC conditions: column: Chiralpak AD (250 mm x 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in iPrOH; first at 15%, at the end at 15%; flow rate 60 ml/min; column temperature 40°C.

Method 18

1-(rac-(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2 -hydroxy-2-methyl-propan-1-one

To a solution of 1-[cis-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] -2-methyl-propan-1-one (50 mg; 0.18 mmol) in dimethyl sulfoxide (4 ml) was added 1-bromo-2,5-pyrrolidinedione (33 mg; 0.18 mmol). The mixture was heated at 100°C for 15 h in air. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) followed by preparative TLC (ethyl acetate, R _f = 0.6) to give 1-(rac-( 5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxy-2-methyl -propan-1-one (48.6 mg; 91%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.37 (m, 3H), 7.27-7.25 (m, 2H), 6.20-6.03 (m, 1H), 5.66-5.57 (m, 1H), 3.79- 3.71 (m, 1H), 2.87-2.77 (m, 1H), 1.60 (s, 3H), 1.56 (s, 3H). LC-MS: r _t = 0.771 min, m/z = 290.1 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.771 min, ESI+: detected [M+H] = 290.1.

Method 19

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1- methylcyclopropyl) methanone

Step 1: cis-1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methylprop- 2-en-1-he

A mixture of cis-1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)propan-1-one (120 mg; 0.46 mmol), dibromomethane (1931 mg; 11.11 mmol) and diethylamine (1625 mg; 22.22 mmol) in acetonitrile (10 ml) were heated at 100° C. for 30 min with microwave irradiation. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to give cis-1-(7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-prop-2-en-1-one (52 mg; 41%) as a white solid. LC-MS: r _t = 1.020 min, m/z = 272.1 [M+H] ⁺ . LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.020 min, ESI+: [M+H] = 272.1 detected.

Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- (1-methylcyclopropyl) methanone

To a mixture of diethylzinc (123 mg; 1.00 mmol) and nickel chloride (8 mg; 0.07 mmol) in dichloromethane (5 ml) was added diiodomethane (355 mg; 1.33 mmol) at 0°C. After stirring for 30 minutes, 1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2- methyl-prop-2-en-1-one (90 mg; 0.33 mmol) and the reaction mixture was stirred at 0°C for 2 hours. The mixture was quenched by adding cold saturated aqueous ammonium chloride (10 ml) and extracted with ethyl acetate (3 × 15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 25-55%/0.05% HCl in acetonitrile) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone (3.0 mg; 3%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.41-7.37 (m, 3H), 7.24-7.23 (m, 2H), 6.15-6.13 (m, 0.5H), 6.01-5.99 (m, 0.5H ), 5.60-5.59 (m, 1H), 3.76-3.68 (m, 1H), 2.84-2.74 (m, 1H), 1.82-1.76 (m, 2H), 1.41 (s, 3H), 0.97-0.92 (m , 2H). LC-MS: r _t = 1.068 min, m/z = 286.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.068 min, ESI+: [M+H] = 286.1 detected.

Method 20

1-[(4S)-4-Phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one and 1-[(4R) -4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one

Step 1: N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide

A mixture of 4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid (156 mg; 0.64 mmol), N,O-dimethylhydroxylamine hydrochloride (125 mg; 1.28 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (291.42 mg; 0.77 mmol ) and triethylamine (258 mg; 2.55 mmol) in N,N-dimethylformamide (5 ml) was stirred at 15°C for 2 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (10% methanol in dichloromethane, R _f = 0.7) to give N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5.1-c] [1,4]oxazine-2-carboxamide (80 mg; 43.6%) as a colorless oil.

Step 2: 1-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one and 1-[ (4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one

To a chilled (-78°C) solution of N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide (60 mg ; 0.21 mmol) in tetrahydrofuran (6 ml) was added dropwise under nitrogen atmosphere ethylmagnesium chloride (2.7 M solution in THF; 0.39 ml; 1.04 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure to give the crude racemic product, which was further resolved with chiral SFC to give, as conventionally indicated:

1-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 1, retention time = 3.254 min) (11.5 mg; 21%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.39-7.37 (m, 5H), 6.21 (s, 1H), 5.82 (s, 1H), 4.42-4.36 (m, 2H), 4.30-4.28 (m, 1H), 4.21-4.18 (m, 1H), 3.00-2.95 (m, 2H), 1.13 (t, J=7.2 Hz, 3H). LCMS: r _t = 1.026 min, m/z = 257.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.026 min, ESI+: detected [M+H] = 257.1;

1-[(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 2, retention time = 4.381 min) (13.6 mg; 25%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.39-7.37 (m, 5H), 6.21 (s, 1H), 5.82 (s, 1H), 4.42-4.36 (m, 2H), 4.31-4.25 (m, 1H), 4.21-4.19 (m, 1H), 3.00-2.92 (m, 2H), 1.13 (t, J=7.2 Hz, 3H). LCMS: r _t = 1.023 min, m/z = 257.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.023 min, ESI+: [M+H] = 257.1 detected.

SFC conditions: column: OD (250 mm × 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first B: 30%, end B: 30%; flow rate 60 ml/min; column temperature 40°C.

Method 21

3,3,3-Trifluoro-1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4] triazol-2-yl)propan-1-one

Step 1: 1-cis-7-fluoro-5-phenyl-2-(1-((trimethylsilyl)oxy)vinyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazole

To a solution of 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)ethanone (200 mg; 0 .82 mmol) in 1,4-dioxane (6 ml) were added triethylamine (165 mg; 1.63 mmol) and trimethylsilyl trifluoromethanesulfonate (254 mg; 1.14 mmol) at 0°C. The mixture was stirred at 0°C for 2 h and quenched by adding cold saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure to give crude 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl)vinyloxytrimethylsilane (245 mg; 95%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17-7.10 (m, 3H), 6.98-6.96 (m, 2H), 5.79-5.78 (m, 0.5H), 5.65-5.64 (m, 0.5H) , 5.21-5.17 (m, 2H), 4.40 (s, 1H), 4.49 (s, 1H), 3.37-3.27 (m, 1H), 2.66-2.56 (m, 1H), 0.03 (s, 9H).

Step 2: 3,3,3-trifluoro-1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2 ,4]triazol-2-yl)propan-1-one

A mixture of 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (418 mg; 1.32 mmol), 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazol-2-yl)vinyloxy-trimethylsilane (210 mg; 0.66 mmol) and copper thiocyanate (16 mg; 0.13 mmol) in N,N-dimethylformamide ( 4 ml) was stirred at 15°C for 15 h and then concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 25-55%/0.05% HCl in acetonitrile) to give 3,3,3-trifluoro-1-(rac-(5R,7R)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)propan-1-one (31 mg; 15%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.37 (m, 3H), 7.28-7.26 (m, 2H), 6.19-6.17 (m, 0.5H), 6.05-6.03 (m, 0.5H ), 5.65-5.63 (m, 1H), 4.09-4.01 (m, 2H), 3.78-3.29 (m, 1H), 2.89-2.77 (m, 1H). LC-MS: r _t = 1.072 min, m/z = 314.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 2.0 min): retention time 1.072 min, ESI+: detected [M+H] = 314.1.

Method 22

1-[(5S)-5-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

To a chilled (-78°C) solution of ethyl (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (200 mg ; 0.78 mmol) in tetrahydrofuran (20 ml) was added dropwise under nitrogen atmosphere ethylmagnesium chloride (3.0 M solution in THF; 0.58 ml; 1.74 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 1-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl]propan-1-one (60 mg; 32%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.32 (m, 3H), 7.12-7.10 (m, 2H), 5.49 (dd, J=5.6, 8.4 Hz, 1H), 3.31-3.21 (m, 1H), 3.17-3.01 (m, 4H), 2.72-2.64 (m, 1H), 1.21 (t, J=7.2 Hz, 3H). LCMS: r _t = 1.523 min, m/z = 242.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.523 min, ESI+: detected [M+H] = 242.2.

Method 23

1-[(5S)-5-(2-Fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

To a chilled (-70°C) solution of ethyl 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (496 mg ; 1.8 mmol) in tetrahydrofuran (10 ml) was added dropwise under nitrogen atmosphere ethylmagnesium chloride (2.7 M solution in THF; 1.33 ml; 3.6 mmol). After the addition was completed, the mixture was stirred at -70° C. for 1 h and then quenched by adding saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude racemic product, which was further purified with chiral SFC and RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give, as conventionally indicated:

1-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one ( peak 2, retention time = 3.038 min) (17 mg; 8%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.35 (m, 1H), 7.20-7.12 (m, 3H), 5.80-5.75 (m, 1H), 3.30-3.28 (m, 1H), 3.15- 3.05 (m, 2H), 3.01-2.97 (m, 2H), 2.72-2.66 (m, 1H), 1.12 (t, J=7.2 Hz, 3H). LCMS: r _t = 0.977 min, m/z = 260.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.977 min, ESI+: [M+H] = 260.1 detected.

SFC conditions: column: OJ (250 mm × 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first B: 20%, end B: 20%; flow rate 60 ml/min; column temperature 40°C.

Method 24

1-[rac-(5R,6S)-6-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-he

Stage 1: (E)-methyl 4-phenylbut-3-enoate

To a solution of (E)-4-phenylbut-3-enoic acid (15.0 g; 92.48 mmol) in methanol (60 ml) was added sulfuric acid (2.3 g; 23.12 mmol). The mixture was heated at 90°C for 18 h and cooled. The mixture was diluted with water (20 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (30 ml), aqueous saturated sodium bicarbonate (30 ml), brine (30 ml), dried and concentrated under reduced pressure to give crude methyl-(E)-4-phenylbut-3-enoate (14 .8 g, 91%) as a clear oil, which was used as such in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.21 (m, 5Н), 6.54-6.45 (m, 1H), 6.35-6.25 (m, 1H), 3.72 (s, 3H), 3.30-3.25 (m , 2H).

Stage 2: methyl-2-(3-phenyloxiran-2-yl)acetate

To a mixture of methyl-(E)-4-phenylbut-3-enoate (14.8 g; 84.0 mmol) and sodium bicarbonate (34.4 g; 409.0 mmol) in acetone (300 ml) dropwise at 0 °C was added a solution of the triple salt of potassium monopersulfate (67.1 g; 109.2 mmol) in water (80 ml). At the end of the addition, the resulting mixture was allowed to warm to 25° C., stirred for 4 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give methyl 2-(3-phenyloxiran-2-yl)acetate (15.0 g; 93%) as a colorless oil. LC-MS: r _t = 0.799 min, m/z = 233.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.799 min, ESI+: [M+H] = 233.9 detected.

Stage 3: methyl-(rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate

To a solution of methyl 2-(3-phenyloxiran-2-yl)acetate (15.0 g; 78.0 mmol) in acetonitrile (400 ml) were added lithium bromide (6.8 g; 78.0 mmol) and magnesium perchlorate (1.7 g; 78.0 mmol) at 0°C. The mixture was stirred at 20°C for 12 h and diluted with dichloromethane (100 ml). The resulting mixture was washed with hydrochloric acid (1 N; 100 ml). The separated aqueous layer was washed with dichloromethane (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude methyl-(rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate (20.0 g, 94%) as a colorless oil. The crude compound was used in the next step without further purification. LC-MS: r _t = 0.610 min, m/z = 256.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.610 min, ESI+: [M+H] = 256.9 detected.

Stage 4: methyl-(rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate

A mixture of methyl-(rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate (20.0 g; 73.2 mmol) and sodium azide (14.3 g; 219.7 mmol) in N, N-dimethylformamide (500 ml) was stirred at 20° C. for 16 h. The mixture was diluted with water (500 ml) and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude methyl-(rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate (17.0 g; 99%) as a yellow oil. LC-MS: r _t = 0.978 min, m/z = 208.3 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min): retention time 0.978 min, ESI+: [M+H] = 208.3 detected.

Stage 5: methyl-(rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate

Mixture of methyl-(rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate (17.0 g; 72.3 mmol) and palladium (10% on charcoal; 7.7 g) in ethyl acetate (800 ml) hydrogenated (15 psi (103.4 kPa)) at 25°C for 24 h and then filtered. The filtrate was concentrated under reduced pressure to give crude methyl (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate (15.0 g, 99%) as a colorless oil. The crude oil was used in the next step without further purification. LC-MS: r _t = 0.315 min, m/z = 210.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min): retention time 0.315 min, ESI+: [M+H] = 210.2 detected.

Stage 6: cis-4-hydroxy-5-phenylpyrrolidin-2-one

A solution of methyl-(rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate (15.0 g; 71.7 mmol) in methanol (200 ml) was heated at 50°C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to give cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g; 76%) as a white solid . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.26 (m, 5H), 6.39 (br s, 1H), 4.89-4.87 (m, 1H), 4.66-4.48 (m, 1H), 2.80-2.62 ( m, 1Н), 2.53-2.30 (m, 1Н). LC-MS: r _t = 0.678 min, m/z = 178.2 [M+H] ⁺ .

LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.678 min, ESI+: detected [M+H] = 178.2.

Step 7: cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

To a solution of cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g; 54.2 mmol) in dichloromethane (300 ml) was added imidazole (11.1 g; 162.5 mmol) and tert-butyldimethylsilyl chloride ( 16.3 g, 108.4 mmol). The resulting mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (10.0 g; 63%) as a white solid. LC-MS: r _t = 1.257 min, m/z = 292.3 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.257 min, ESI+: detected [M+H] = 292.3.

Stage 8: cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

Sodium hydride (60%- ny; 2.1 g; 51.5 mmol) at 0°C. After stirring at 0° C. for 30 minutes, (aminooxy)diphenylphosphine oxide (12.0 g; 51.47 mmol) was added in portions. The resulting mixture was stirred at room temperature for 12 hours and filtered. The filtrate was concentrated under reduced pressure to give crude cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (9.0 g, 86%) as a brown solid. This crude material was used in the next step without further purification. LC-MS: r _t = 1.225 min, m/z = 307.4 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.225 min, ESI+: [M+H] = 307.4 detected.

Step 9: Ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate

A mixture of cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (9.0 g; 29.4 mmol) and ethyl 2-ethoxy-2-imino-acetate (21 .3 g; 146.8 mmol) in toluene (500 ml) was heated at 90°C for 18 h and concentrated under reduced pressure. The residue was diluted with water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were concentrated under reduced pressure to give crude ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate (10, 0 g; 84%) as brown oil. LC-MS: r _t = 1.128 min, m/z = 406.4 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.128 min, ESI+: [M+H] = 406.4 detected.

Step 10: Ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate (10.0 g; 24.7 mmol) and 4-methylbenzenesulfonic acid hydrate (4.7 g; 24.7 mmol) in toluene (300 ml) was heated at 120° C. for 16 h and then concentrated under reduced pressure. The residue was diluted with water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (5.5 g; 58%) as a brown oil. LC-MS: r _t = 1.345 min, m/z = 388.4 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.345 min, ESI+: [M+H] = 388.4 detected.

Step 11: Ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of tetrabutylammonium fluoride (18.5 g; 70.9 mmol) in tetrahydrofuran (200 ml) was added ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazole-2-carboxylate (5.5 g; 14.2 mmol). The resulting mixture was stirred at 25°C for 16 h and diluted with ethyl acetate (300 ml). The mixture was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (1.8 g; 46%) as a yellow solid. LC-MS: r _t = 1.036 min, m/z = 274.3 [M+H] ⁺ . LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.036 min, ESI+: [M+H] = 274.3 detected.

Step 12: Ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.0 g; 3. 66 mmol) in dichloromethane (50 ml) diethylaminosulfur trifluoride (10.0 g; 62.0 mmol) was added dropwise at 25°C. The resulting mixture was stirred at 25° C. for 1 h and then quenched by slowly adding saturated aqueous sodium bicarbonate (10 ml). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to give ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (400 mg; 40%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.24 (m, 3H), 6.92-6.89 (m, 2H), 5.70-5.55 (m, 1H), 5.62-5.48 (m, 1H), 4.49-4.34 (m, 2H), 3.52-3.35 (m, 1H), 3.35-3.15 (m, 1H), 1.40-1.36 (m, 3H). LC-MS: r _t = 0.958 min, m/z = 276.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time: 0.958 min, ESI+: detected [M+H] = 276.2.

Step 13: 1-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]propane-1-he

To a cooled (-78°C) solution of ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 30 mg; 0.11 mmol) in tetrahydrofuran (5 ml) was added dropwise under nitrogen atmosphere ethylmagnesium chloride (3.0 M solution in THF; 0.25 ml; 0.75 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give, by convention, 1-[rac-(5R,6S)-6-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (13.6 mg; 45%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.31 (m, 3H), 6.90-6.87 (m, 2H), 5.63-5.61 (m, 0.5H), 5.59-5.57 (m, 1H), 5.46 -5.44 (m, 0.5H), 3.42-3.28 (m, 1H), 3.26-3.21 (m, 1H), 3.03-3.01 (m, 2H), 1.16 (t, J=7.2Hz, 3H) . LCMS: r _t = 0.977 min, m/z = 260.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.977 min, ESI+: [M+H] = 260.1 detected.

Method 25

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2- pyridyl) methanone

To a solution of 2-bromopyridine (435 mg; 2.76 mmol) in tetrahydrofuran (20 ml) was added n-butyllithium (2.5 M solution in hexanes; 1.10 ml; 2.76 mmol) at -78°C. After the addition was complete, the mixture was allowed to warm to 30° C. and stirred for 2 hours. The mixture was cooled to -78° C. and cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (200 mg; 0.69 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at -78°C for 6 h and extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl)methanone (32.0 mg; 15%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69-8.65 (m, 1H), 8.00-7.90 (m, 2H), 7.62-7.59 (m, 1H), 7.42-7.30 (m, 3H), 7.25 -7.20 (m, 2H), 6.30-6.22 (m, 0.5H), 6.18-6.14 (m, 0.5H), 5.75-5.55 (m, 1H), 3.77-3.67 (m, 1H), 2.74- 2.45(m, 1H). LCMS: r _t = 1.510 min, m/z = 309.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.510 min, ESI+: [M+H] = 309.1 detected.

Method 26

Cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl- [(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone

To a cooled (-78°C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 100 mg; 0.36 mmol) in tetrahydrofuran (4 ml) was added dropwise under nitrogen atmosphere cyclopropylmagnesium bromide (0.5 M solution in THF; 1.45 ml; 0.73 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give cis racemic cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (15 mg; 10%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.35 (m, 3H), 7.27-7.25 (m, 2H), 6.18-6.15 (m, 0.5H), 6.05-6.00 (m, 0.5H ), 5.65-5.60 (m, 1H), 3.77-3.65 (m, 1H), 3.05-2.95 (m, 1H), 2.90-2.70 (m, 1H), 1.17-1.13 (m, 2H), 1.10-1.05 (m, 2H). LCMS: r _t = 1.031 min, m/z = 272.3 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.031 min, ESI+: [M+H] = 272.3 detected.

Stage 2: cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Racemic cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (100 mg; 0.37 mmol) was resolved with chiral SFC to give, as tentatively indicated:

cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1 , retention time = 3.575 min) (25.5 mg; 24%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.38 (m, 3H), 7.29-7.27 (m, 2H), 6.19 (d, J=5.6 Hz, 0.5H), 6.05 (d, J=5.2 Hz, 0.5H), 5.66-5.62 (m, 1H), 3.79-3.71 (m, 1H), 3.05-3.02 (m, 1H), 3.01-2.81 (m, 1H), 1.29- 1.09 (m, 4H). LCMS: r _t = 0.816 min, m/z = 271.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.816 min, ESI+: detected [M+H] = 271.9;

cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2 , retention time = 3.849 min) (18.5 mg; 17%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.27 (m, 5H), 6.20-6.17 (m, 0.5H), 6.06-6.03 (m, 0.5H), 5.66-5.64 (m, 1H ), 3.79-3.71 (m, 1H), 3.05-3.02 (m, 1H), 3.01-2.81 (m, 1H), 1.19-1.09 (m, 4H). LCMS: r _t = 0.817 min, m/z = 271.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.817 min, ESI+: [M+H] = 271.9 detected.

SFC conditions: column: Chiralpak AD (250 mm x 30 mm, 10 µm); medium: 0.1% NH ₃ H ₂ O in iPrOH; first at 25%, at the end at 25%; flow rate 60 ml/min; column temperature 40°C.

Method 27

Cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Stage 1: cyclopentyl-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol

Cyclopentylmagnesium bromide (1 M solution in THF; 0.73 ml; 0.73 mmol) was added dropwise to a stirred and cooled (-78°C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg; 0.36 mmol) in tetrahydrofuran (10 ml) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at 25°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude cis-cyclopentyl-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl)methanol (100 mg; 91%) as a white solid. LCMS: r _t = 0.611 min, m/z = 302.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.611 min, ESI+: detected [M+H] = 302.1.

Stage 2: cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone

To a solution of cis-cyclopentyl-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol (100 mg; 0 .33 mmol) in dichloromethane (15 ml) was added manganese dioxide (288 mg; 3.32 mmol). The reaction mixture was stirred at 35° C. for 2 hours and then filtered through a short pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to give cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl)methanone (18.2 mg; 18%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.40 (m, 3H), 7.28-7.26 (m, 2H), 6.19-6.17 (m, 0.5H), 6.05-6.03 (m, 0.5H ), 5.64-5.63 (m, 1H), 3.89-3.68 (m, 2H), 2.88-2.75 (m, 1H), 2.02-1.60 (m, 8H). LCMS: r _t = 2.070 min, m/z = 300.2 [M+H] ⁺ . LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min): retention time 2.070 min, ESI+: [M+H] = 300.2 detected.

Method 28

(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2- thienyl) methanone

To a cooled (-78°C) solution of 2-iodothiophene (289 mg; 1.38 mmol) in tetrahydrofuran (10 ml) was added dropwise n-butyllithium (2.5 M solution in hexanes; 0.55 ml; 1.38 mmol) in N ₂ atmosphere. The mixture was stirred at -78°C for 1 h, then cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazole-2-carboxamide (100 mg; 0.34 mmol) in tetrahydrofuran (2 ml). The mixture was stirred at -78°C for another 2 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 40-70%/0.05% hydrochloric acid in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazol-2-yl)-(2-thienyl)methanone (15.6 mg; 14%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.50-8.49 (m, 1H), 7.96-7.94 (m, 1H), 7.49-7.35 (m, 3H), 7.35-7.27 (m, 2H), 7.26- 7.20 (m, 1H), 6.24-6.22 (m, 0.5H), 6.10-6.08 (m, 0.5H), 5.74-5.68 (m, 1H), 3.86-3.72 (m, 1H), 2.91-2.79 (m, 1H). LCMS: r _t = 0.891 min, m/z = 314.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.891 min, ESI+: [M+H] = 314.1 detected.

Method 29

Cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a chilled (0°C) mixture of magnesium (234 mg; 9.65 mmol), iodine (12 mg; 0.05 mmol), 1,2-dibromoethane (0.1 ml; 0.10 mmol) in tetrahydrofuran (15 ml) was added dropwise bromocyclobutane (0.5 ml; 5.85 mmol) under N ₂ atmosphere. The mixture was stirred at 35°C for about 1 hour. The above freshly prepared solution of cyclobutyl magnesium bromide (1.0 ml; 0.39 mmol) was added dropwise to the stirred and cooled (-78°C) solution of cis-7-fluoro-N -methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (28 mg; 0.10 mmol) in tetrahydrofuran (2 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (2×5 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 42-62%/0.05% hydrochloric acid in water) to give cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (2 mg; 7%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.30 (m, 3H), 7.25-7.21 (m, 2H), 6.15-6.10 (m, 0.5H), 6.01-5.95 (m, 0.5H ), 5.60-5.55 (m, 1H), 4.15-4.07 (m, 1H), 3.74-3.65 (m, 1H), 2.80-2.70 (m, 1H), 2.35-2.20 (m, 3H), 2.20 -2.15 (m, 1H), 2.12-2.00 (m, 1H), 1.90-1.85 (m, 1H). LCMS: r _t = 0.883 min, m/z = 286.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.883 min, ESI+: detected [M+H] = 286.0.

Method 30

1-(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2 ,2-dimethyl-propan-1-one

To a cooled (-78°C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 30 mg; 0.11 mmol) in tetrahydrofuran (3 ml) was added dropwise under nitrogen atmosphere tert-butyllithium (1.3 M solution in pentane, 0.17 ml; 0.22 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 45-75%/0.05% hydrochloric acid in water) to give 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-propan-1-one (12.7 mg; 40%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42-7.36 (m, 3H), 7.36-7.23 (m, 2H), 6.16-6.13 (m, 0.5H), 6.02-5.99 (m, 0.5H ), 5.65-5.61 (m, 1H), 3.77-3.68 (m, 1H), 2.85-2.73 (m, 1H), 1.35 (s, 9H). LCMS: r _t = 0.907 min, m/z = 288.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.907 min, ESI+: [M+H] = 288.0 detected.

Method 31

1-(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2 -methyl-propan-1-one

To a cooled (-78°C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 200 mg; 0.73 mmol) in tetrahydrofuran (10 ml) isopropylmagnesium chloride (2.0 ml in THF; 1.1 ml; 2.20 mmol) was added dropwise under nitrogen. Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give racemic 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-propan-1-one (6.9 mg; 3.4%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.46-7.36 (m, 3H), 7.28-7.26 (m, 2H), 6.18-6.16 (m, 0.5H), 6.05-6.02 (m, 0.5H ), 5.65-5.61 (m, 1H), 3.78-3.72 (m, 1H), 3.64-3.61 (m, 1H), 2.87-2.76 (m, 1H), 1.19 (d, J=7.2 Hz, 3H ), 1.17 (d, J=6.8 Hz, 3H). LCMS: r _t = 1.971 min, m/z = 274.2 [M+H] ⁺ . LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min): retention time 1.971 min, ESI+: [M+H] = 274.2 detected.

Method 32

1-[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1- he and 1-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-he

Step 1: 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]propane-1-he

To a cooled (-70°C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide (30 mg; 0.10 mmol) in tetrahydrofuran (3 ml) was added dropwise under nitrogen atmosphere ethylmagnesium bromide (3.0 M solution in THF; 0.1 ml; 0.30 mmol). Upon completion of the addition, the mixture was stirred at 30°C for about 3 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (6.3 mg; 23%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.38-7.35 (m, 3H), 7.25-7.23 (m, 2H), 6.15-6.13 (m, 0.5H), 6.01-5.99 (m, 0.5H ), 5.59-5.53 (m, 1H), 3.77-3.67 (m, 1H), 3.05-2.99 (m, 2H), 2.84-2.73 (m, 1H), 1.13 (t, J=7.2 Hz, 3H). LCMS: r _t = 1.038 min, m/z = 260.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.038 min, ESI+: [M+H] = 260.2 detected.

Step 2: 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane -1-one and 1-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]propane-1-he

Racemic 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane -1-one (220 mg) was resolved with chiral SFC to give, as tentatively indicated:

1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1- he (peak 1, retention time = 2.265 min) (78 mg; 35%; enantiomeric excess (ee) 88%) as a light yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.32 (m, 3H), 7.27-7.23 (m, 2H), 6.17-6.14 (m, 0.5H), 6.02-6.00 (m, 0.5H ), 5.65-5.58 (m, 1H), 3.84-3.64 (m, 1H), 3.06-3.00 (m, 2H), 2.88-2.69 (m, 1H), 1.13 (t, J=7.2 Hz, 3H ). LCMS: r _t = 0.822 min, m/z = 260.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.822 min, ESI+: detected [M+H] = 260.0;

1-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1- he (peak 2, retention time = 2.382 min) (80 mg; 35%; 91% ee) as a light yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.32 (m, 3H), 7.27-7.23 (m, 2H), 6.17-6.14 (m, 0.5H), 6.02-6.00 (m, 0.5H ), 5.65-5.58 (m, 1H), 3.84-3.64 (m, 1H), 3.06-3.00 (m, 2H), 2.88-2.69 (m, 1H), 1.13 (t, J=7.2 Hz, 3H ). LCMS: r _t = 0.817 min, m/z = 260.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.817 min, ESI+: [M+H] = 260.0 detected.

SFC conditions: column: AS (250 mm × 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first at 20%, at the end at 20%; flow rate (60 ml/min); column temperature 40°C.

Method 33

(1-Methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

To a cooled (-70°C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide (137 mg; 0.47 mmol) and 1-methyl-4-iodo-1H-pyrazole (393 mg; 1.89 mmol) in tetrahydrofuran (10 ml) were added dropwise tert-butyl lithium (1, 3 M solution in hexane; 1.45 ml; 1.89 mmol) under nitrogen atmosphere. The mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 27-57%/0.05% hydrochloric acid in water) to give cis racemic (1-methylpyrazol-4-yl)-[rac-(5R, 7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (53.4 mg; 36%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 8.24 (s, 1H), 7.46-7.34 (m, 3H), 7.32-7.25 (m, 2H), 6.22-6.19 (m, 0.5H), 6.08-6.05 (m, 0.5H), 5.72-5.65 (m, 1H), 3.93 (s, 3H), 3.85-3.70 (m, 1 H), 2.90-2.75 (m, 1 H ). LCMS: r _t = 0.791 min, m/z = 311.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.791 min, ESI+: [M+H] = 311.9 detected.

Method 34

1-[rac-(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone

Stage 1: (E)-benzaldehyde oxime

To a solution of benzaldehyde (45.0 g; 424.1 mmol) in ethanol (100 ml) were added sodium carbonate (112.3 g; 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g; 508.9 mmol). The reaction mixture was stirred at 25°C for 3 h and filtered. The filtrate was concentrated under reduced pressure and the residue was diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with brine (60 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude (E)-benzaldehyde oxime as a colorless oil (51.0 g; 99%) which was used in the next step without additional cleaning.

Stage 2: methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate

To a solution of (E)-benzaldehyde oxime (20.0 g; 165.1 mmol) in 1,4-dioxane (500 ml) was added methyl acrylate (14.2 g; 165.1 mmol), sodium iodide ; 165.1 mmol), 2,6-lutidine (17.6 g; 165.1 mmol) and hypochlorous acid tert-butyl ester (17.9 g; 165.1 mmol). The reaction mixture was stirred at 25°C for 24 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g; 74%). LCMS: r _t = 0.871 min, m/z = 206.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.871 min, ESI+: [M+H] = 206.2 detected.

Stage 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one

A mixture of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (25.0 g; 121.8 mmol) and palladium (10% on charcoal; 2.5 g) in ethanol (800 mL) was hydrogenated ( 50 psi (344.7 kPa)) at 25° C. for 2 h, then filtered and the filtrate concentrated under reduced pressure to give crude 3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid substance (18.0 g; 83%), which was used in the next step without further purification. LCMS: R _T = 0.270 min, m/z = 177.8 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.270 min, ESI+: [M+H] = 177.8 detected.

Stage 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one and trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenylpyrrolidin-2 -He

To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g; 84.6 mmol) in dichloromethane (300 ml) was added tert-butyldimethylchlorosilane (19.1 g; 126.9 mmol) and imidazole ( 11.5 g, 169.3 mmol). The reaction mixture was stirred at 25°C for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give, as conventionally indicated: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine- 2-one (12.4 g; 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.25 (m, 5H), 4.88-4.53 (m, 1H), 4.54-4.46 (m, 1H), 2.89-2.79 (m, 1H), 1.80-1.71 (m, 1H), 0.93-0.90 (m, 9H), 0.19-0.12 (m, 6H) and trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one in the form colorless oil (9.3 g; 38%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.34 (m, 2H), 7.29-7.24 (m, 3H), 4.87-4.80 (m, 1H), 4.44-4.41 (m, 1H), 2.45-2.37 (m, 1H), 2.27-2.22 (m, 1H), 0.93-0.90 (m, 9H), 0.16-0.13 (m, 6H).

Stage 5: trans-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

Sodium hydride was added to a solution of trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g; 24.0 mmol) in N,N-dimethylformamide (200 ml) (1.44 g; 36.0 mmol) at 0°C and the mixture was stirred at 0°C for 20 min. Then o-(diphenylphosphoryl)hydroxylamine (8.40 g; 36.03 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give trans-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g; 95.1%) in as a yellow oil which was used in the next step without further purification. LCMS: R _T = 0.775 min, m/z = 307.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.775 min, ESI+: [M+H] = 307.0 detected.

Stage 6: trans-ethyl-2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetate

Ethyl- 2-ethoxy-2-imino-acetate (6.63 g; 45.7 mmol). The reaction mixture was stirred at 60° C. for 16 h and then concentrated under reduced pressure to give crude trans-ethyl 2-(3-((t-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl) amino)-2-iminoacetate (8.50 g; 92%) as a yellow oil which was used in the next step without further purification. LCMS: R _T = 2.154 min, m/z = 406.3 [M+H] ⁺ . LCMS (0 to 60% acetonitrile in water + 0.03% trifluoroacetic acid for 3 min): retention time 2.143 min, ESI+: [M+H] = 406.3 detected.

Step 7: trans-ethyl 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 2-[[trans-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate (8.5 g ; 21.0 mmol) in toluene (100 ml) was added p-toluenesulfonic acid (4.4 g; 25.2 mmol). The reaction mixture was stirred at 120° C. for 16 h and then concentrated under reduced pressure to give crude trans-ethyl 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole-2-carboxylate (7.5 g; 92.3%) as a yellow oil which was used in the next step without further purification. LCMS: R _T = 1.022 min, m/z = 374.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.022 min, ESI+: [M+H] = 374.2 detected.

Stage 8: trans-ethyl-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- carboxylate (7.0 g; 18.06 mmol) in tetrahydrofuran (120 ml) tetrabutylammonium fluoride (1N solution in THF; 18.06 ml; 18.06 mmol) was added. The reaction mixture was stirred at 40° C. for 3 hours and then concentrated under reduced pressure to give crude trans-ethyl-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazole-2-carboxylate (3.5 g; 57%) as a yellow oil, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.39-7.35 (m, 3H), 7.14-7.12 (m, 2H), 5.73-5.70 (m, 1H), 5.54-5.51 (m, 1H), 4.47- 4.40 (m, 2H), 3.24-3.21 (m, 1H), 3.05-3.00 (m, 1H), 1.41-1.36 (m, 3H).

Step 9: cis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of trans-ethyl 7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg; 0.37 mmol ) in dichloromethane (8 ml) was added diethylaminosulfur trifluoride (176.9 mg; 1.10 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h and then extinguished by adding water (20 ml). The resulting mixture was extracted with dichloromethane (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.5) to give cis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazole-2-carboxylate (54 mg; 54%) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.31 (m, 3H), 7.25-7.17 (m, 2H), 6.09 (dd, J=1.4 Hz, 7.2 Hz, 1H), 5.95 ( dd, J=1.4 Hz; 7.2 Hz, 1H), 5.52-5.47 (m, 1H), 4.53-4.37 (m, 2H), 3.74-3.54 (m, 1H), 3.05-2.82 (m, 1H), 1.48-1.33 (m, 3H).

Step 10: cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

To a solution of cis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (54 mg; 0.20 mol ) in tetrahydrofuran (4 ml) and water (1 ml) was added lithium hydroxide monohydrate (25 mg; 0.59 mmol). The reaction mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure. The pH of the residue was adjusted to 5 by adding hydrochloric acid (2N). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole-2-carboxylic acid (45 mg; 93%) as a white solid, which was used in the next step without further purification.

1-[rac-(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone

Step 11: cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (350 mg; 1.42 mmol), 1-hydroxybenzotriazole (201 mg; 1.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (407 mg; 2.12 mmol), N,O-dimethylhydroxylamine hydrochloride (180 mg; 1.84 mmol) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.7) to give cis -7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (225 mg; 54 .7%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.35 (m, 3H), 7.26-7.22 (m, 2H), 6.09-6.07 (m, 0.5H), 5.96-5.93 (m, 0.5H) , 5.49-5.46 (m, 1H), 3.78 (s, 3H), 3.66-3.59 (m, 1H), 3.55-3.35 (brs, 3H), 2.99-2.88 (m, 1H). LCMS: R _T = 0.564 min, m/z = 291.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.564 min, ESI+: detected [M+H] = 291.1.

Step 12: 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]ethanone

To a cooled (-70°C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide (30 mg; 0.10 mmol) in tetrahydrofuran (3 ml) was added dropwise under nitrogen atmosphere methylmagnesium bromide (3.0 M solution in THF; 0.1 ml; 0.30 mmol). Upon completion of the addition, the mixture was stirred at 30°C for about 3 h and then extinguished by adding saturated aqueous ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone (4 mg; 15%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.41-7.35 (m, 3H), 7.26-7.24 (m, 2H), 6.16-6.14 (m, 0.5H), 6.01-6.00 (m, 0.5H ), 5.62-5.58 (m, 1H), 3.77-3.68 (m, 1H), 2.85-2.74 (m, 1H), 2.55 (s, 3H). LCMS: R _T = 0.954 min, m/z = 246.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.954 min, ESI+: [M+H] = 246.2 detected.

Method 35

[(1S,2R)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone and [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl]methanone

To a cooled (-70°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (150 mg; 0.53 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (157 mg; 1.06 mmol) in tetrahydrofuran (10 ml) n-butyllithium was added dropwise under nitrogen atmosphere (2.5 M solution in hexanes; 0.64 ml; 1.60 mmol). Upon completion of the addition, the mixture was stirred at -70°C for 1 h, then extinguished by adding saturated aqueous ammonium chloride solution (30 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 37-67%/0.05% ammonium hydroxide in water) to give [trans-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (25 mg; 16%) as a dark red solid. This substance was further separated by chiral SFC, giving, as conventionally indicated:

[(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 1, retention time = 3.130 min) (11.2 mg; 44%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.51-7.33 (m, 3H), 7.30-7.28 (m, 2H), 6.21-6.03 (m, 1H), 5.68-5.64 (m, 1H), 5.02- 4.94 (m, 1H), 4.84-4.80 (m, 1H), 3.84-3.70 (m, 1H), 3.47-3.44 (m, 1H), 2.90-2.78 (m, 1H), 1.73-1.62 (m, 1H ), 1.60-1.52 (m, 1H). LCMS: R _T = 1.765 min, m/z = 290.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 2 min): retention time 1.765 min, ESI+: detected [M+H] = 290.1;

[(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone (peak 2, retention time = 3.464 min) (10.2 mg; 40%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.51-7.33 (m, 3H), 7.32-7.20 (m, 2H), 6.21-6.04 (m, 1H), 5.70-5.62 (m, 1H), 5.00- 4.82 (m, 1H), 3.83-3.70 (m, 1H), 3.47-3.42 (m, 1H), 2.90-2.77 (m, 1H), 1.74-1.63 (m, 1H), 1.60-1.52 (m, 1 H). LCMS: R _T = 1.756 min, m/z = 290.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 2 min): retention time 1.756 min, ESI+: detected [M+H] = 290.1.

SFC Conditions: Column: Chiralcel OD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min.

Method 36

(1-Fluorocyclopropyl)(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Stage 1: 1-fluoro-N-methoxy-N-methylcyclopropanecarboxamide

A mixture of 1-fluorocyclopropanecarboxylic acid (150 mg; 1.44 mmol), N,N-diisopropylethylamine (465 mg; 3.60 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium-3-oxide hexafluorophosphate (712 mg; 1.87 mmol) and N,O-dimethylhydroxylamine hydrochloride (183 mg; 1.87 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (15 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (2×20 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give 1-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (140 mg; 66%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.75 (s, 3H), 3.26 (s, 3H), 1.31-1.21 (m, 4H).

Step 2: (1-fluorocyclopropyl)(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl) methanone

To a chilled (-78°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg ; 0.18 mmol) and 1-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (52 mg; 0.35 mmol) in tetrahydrofuran (5 ml) was added dropwise under nitrogen atmosphere n-butyllithium (2.5 M solution in hexanes, 0.21 ml, 0.53 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (2×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.05% HCl in water) to give the crude product (20 mg). This crude product was further purified by preparative TLC (30% ethyl acetate in petroleum ether, R _f = 0.3) to give (1-fluorocyclopropyl)(rac-(5S,7S)-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (10.2 mg; 19%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.37 (m, 3H), 7.23-7.21 (m, 2H), 6.09-6.07 (m, 0.5H), 5.96-5.93 (m, 0.5H) , 5.51-5.50 (m, 1H), 3.67-3.58 (m, 1H), 3.00-2.90 (m, 1H), 1.92-1.88 (m, 2H), 1.62-1.58 (m, 2H). LCMS: R _T = 1.726 min, m/z = 290.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time: 1.726 min, ESI+: detected [M+H] = 290.1.

Method 37

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyloxetan-3 -yl) methanone

To a cooled (-78°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (80 mg; 0.28 mmol) and N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (90 mg; 0.57 mmol) in tetrahydrofuran (2 ml) n-butyllithium was added dropwise under nitrogen atmosphere (2.5 M solution in hexanes; 0.34 ml; 0.85 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (2×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give [(5S,7S)-7-fluoro-5-phenyl-6,7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(3-methyloxetan-3-yl)methanone (16.3 mg; 19%) as a pink solid substances. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.37 (m, 3H), 7.25-7.23 (m, 2H), 6.17-6.15 (m, 0.5H), 6.03-6.01 (m, 0.5H ), 5.65-5.62 (m, 1H), 5.09-5.02 (m, 2H), 4.52-4.26 (m, 2H), 3.78-3.70 (m, 1H), 2.86-2.76 (m, 1H), 1.74 (s , 3H). LCMS: R _T = 0.675 min, m/z = 302.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.675 min, ESI+: detected [M+H] = 302.1.

Method 38

((5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyloxetan-3 -yl) methanone

Stage 1: N-methoxy-N,3-dimethyloxetane-3-carboxamide

Mixture of N,O-dimethylhydroxylamine hydrochloride (252 mg; 2.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (396 mg; 2.07 mmol), 3-methyloxetane-3-carboxylic acid (200 mg ; 1.72 mmol), 1-hydroxybenzotriazole (140 mg; 1.03 mmol) and N,N-diisopropylethylamine (556 mg; 4.31 mmol) in dichloromethane (10 ml) were stirred at 25°C for 12 h. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml), dried and concentrated under reduced pressure to give crude N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (270 mg; 98%) in the form of a colorless oil. This crude oil was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.96-4.93 (m, 2H), 4.29-4.27 (m, 2H), 3.66 (s, 3H), 3.18 (s, 3H), 1.66 (s, 3H).

Step 2: ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3- methyloxetan-3-yl) methanone

To a cooled (-78°C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (100 mg; 0.35 mmol) and N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (113 mg; 0.71 mmol) in tetrahydrofuran (2 ml) n-butyllithium was added dropwise under nitrogen atmosphere (2.5 M solution in hexanes; 0.43 ml; 1.06 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (2×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give [(5R,7R)-7-fluoro-5-phenyl-6,7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(3-methyloxetan-3-yl)methanone (13.6 mg; 13%) as a pink solid substances. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.37 (m, 3H), 7.25-7.23 (m, 2H), 6.17-6.15 (m, 0.5H), 6.03-6.01 (m, 0.5H ), 5.65-5.62 (m, 1H), 5.09-5.02 (m, 2H), 4.52-4.26 (m, 2H), 3.78-3.70 (m, 1H), 2.86-2.76 (m, 1H), 1.74 (s , 3H). LCMS: R _T = 0.678 min, m/z = 302.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.678 min, ESI+: detected [M+H] = 302.1.

Method 39

3-Oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone

Stage 1: N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide

A mixture of 3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (trans-; 300 mg; 2.34 mmol), N,O-dimethylhydroxylamine hydrochloride (297 mg; 3.04 mmol), 1-[bis(dimethylamino )methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1157 mg; 3.04 mmol) and N,N-diisopropylethylamine (756 mg; 5.85 mmol) in N,N-dimethylformamide (15 ml) was stirred at 25°C for 12 hours the Reaction mixture was diluted with water (30 ml) and was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide (180 mg; 45 %) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.95-3.93 (m, 2H), 3.80-3.78 (m, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 2.17-2.09 (m, 3H ).

Stage 2: 3-oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazol-2-yl]methanone

To a chilled (-70°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg ; 0.18 mmol) and N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide (61 mg; 0.35 mmol) in tetrahydrofuran (2 ml) was added dropwise under nitrogen atmosphere to n -butyllithium (2.5 M solution in hexanes; 0.21 ml; 0.53 mmol). Upon completion of the addition, the mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give 3-oxabicyclo[3.1.0]hexan-6-yl-[rac-( 5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (2.2 mg; 3 .9%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.39 (m, 3H), 7.27-7.26 (m, 2H), 6.12-5.96 (m, 1H), 5.53-5.49 (m, 1H), 4.02-3.99 (m, 2H), 3.82-3.80 (m, 2H), 3.70-3.61 (m, 1H), 3.07-3.05 (m, 1H), 3.02-2.95 (m, 1H), 2.45-2.43 (m, 2H) . LCMS: R _T = 0.821 min, m/z = 313.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.821 min, ESI+: [M+H] = 313.9 detected.

Method 40

Oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt] methanone

Stage 1: N-methoxy-N-methyl-oxetane-3-carboxamide

Mixture of oxetane-3-carboxylic acid (300 mg; 2.94 mmol), 1,1'-carbonyldiimidazole (524 mg; 3.23 mmol) and N,O-dimethylhydroxylamine hydrochloride (286 mg; 2.94 mmol) in dichloromethane (8 ml) was stirred at 25°C for 12 hours the Reaction mixture was diluted with water (20 ml) and was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate in petroleum ether, R _f = 0.3) to give N-methoxy-N-methyl-oxetane-3-carboxamide (60 mg; 14%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.92-4.89 (m, 2H), 4.80-4.76 (m, 2H), 4.19-4.13 (m, 1H), 3.63 (s, 3H), 3.21 (s, 3H ).

Step 2: oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone

To a chilled (-70°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (38 mg ; 0.13 mmol) and N-methoxy-N-methyl-oxetane-3-carboxamide (39 mg; 0.27 mmol) in tetrahydrofuran (2 ml) were added dropwise under nitrogen atmosphere n-butyllithium (2.5 M solution in hexanes, 0.16 ml, 0.40 mmol). Upon completion of the addition, the mixture was stirred at -70°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give oxetan-3-yl-[rac-(5S,7S)-7-fluoro -5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (6.3 mg; 15.5%) as a white solid substances. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.40 (m, 3H), 7.27-7.23 (m, 2H), 6.11-5.95 (m, 1H), 5.50-5.49 (m, 1H), 4.97-4.90 (m, 4H), 4.72-4.68 (m, 1H), 3.68-3.59 (m, 1H), 3.03-2.92 (m, 1H). LCMS: R _T = 0.782 min, m/z = 287.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.782 min, ESI+: [M+H] = 287.9 detected.

Method 41

[1-(Hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone

Stage 1: 1-(((tert-butyldimethylsilyl)oxy)methyl)-cyclopropanecarboxylic acid

To a solution of 1-(hydroxymethyl)cyclopropanecarboxylic acid (200 mg; 1.72 mmol) in dichloromethane (5 ml) was added tert-butyldimethylchlorosilane (532 mg; 3.53 mmol) and imidazole (240 mg; 3.53 mmol). The mixture was stirred at 25°C for 5 h and then extinguished by adding water (10 ml). The mixture was extracted with dichloromethane (2×10 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (6 ml)/water (6 ml) and sodium hydroxide (138 mg; 3.44 mmol) was added. The resulting mixture was stirred at 25°C for 10 h and then the pH was adjusted to 4 by adding citric acid. The solution was extracted with ethyl acetate (2×20 ml). The combined organic layers were dried and concentrated under reduced pressure to give crude 1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropanecarboxylic acid (400 mg; 100%) as a colorless oil.

Stage 2: 1-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methyl-cyclopropanecarboxamide

Mixture of 1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropanecarboxylic acid (400 mg; 1.74 mmol), N,O-dimethylhydroxylamine hydrochloride (423 mg; 4.34 mmol), 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (499 mg; 2.6 mmol), 1-hydroxybenzotriazole (235 mg; 1.74 mmol) and N,N-diisopropylethylamine (1.23 ml; 6.95 mmol) in dichloromethane (10 ml) stirred at 25° C. for 18 hours. The resulting mixture was partitioned between water (30 ml) and dichloromethane (30 ml). The separated organic layer was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 1-[[t-butyl(dimethyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropanecarboxamide (200 mg; 42%) as a colorless oil. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.848 min, ESI+: detected [M+H] = 274.1.

Stage 3: (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazol-2-yl]methanone

To a chilled (-78°C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg ; 0.21 mmol) and 1-[[tert-butyl(dimethyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropanecarboxamide (116 mg; 0.43 mmol) in tetrahydrofuran (2 ml) was added n-butyllithium (2.5 M solution in hexanes; 0.26 ml; 0.64 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give [1-[[t-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[ cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (34 mg; 38%) as light - brown butter.

Step 4: [1-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]methanone

A mixture of [1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone (34 mg; 0.08 mmol) and 2,2,2-trifluoroacetic acid (0.50 ml) in dichloromethane (3 ml) was stirred at 20° C for 2 h and then concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give [1-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (4.1 mg; 16%) as light brown oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.37 (m, 3H), 7.27-7.25 (m, 2H), 6.17-6.15 (m, 0.5H), 6.03-6.01 (m, 0.5H ), 5.63-5.61 (m, 1H), 3.96-3.85 (m, 2H), 3.77-3.71 (m, 1H), 2.86-2.75 (m, 1H), 1.71-1.67 (m, 2H), 1.10-1.07 (m, 2H). LCMS: R _T = 0.648 min, m/z = 302.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.648 min, ESI+: [M+H] = 302.1 detected.

Method 42

((1S)-2,2-Difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl)methanone and ((1R)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl)methanone

Stage 1: 2,2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide

A mixture of 2,2-difluorocyclopropanecarboxylic acid (1.00 g; 8.19 mmol), N,N-diisopropylethylamine (2646 mg; 20.5 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2, 3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (4.05 g; 10.6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.04 g; 10.7 mmol) in N,N- dimethylformamide (10 ml) was stirred at 25°C for 12 hours, the Reaction mixture was diluted with saturated aqueous ammonium chloride (20 ml) and was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (2×20 ml), brine (30 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide (700 mg; 52%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.77 (s, 3H), 3.26 (s, 3H), 2.96-2.91 (m, 1H), 2.16-2.12 (m, 1H), 1.69-1.65 (m, 1H ).

Step 2: ((1S)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl)methanone and ((1R)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)methanone

To a cooled (-78°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (300 mg; 1.06 mmol) and 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (351 mg; 2.13 mmol) in tetrahydrofuran (15 ml) n-butyl lithium was added dropwise under nitrogen atmosphere (2.5 M solution in hexanes; 1.28 ml; 3.19 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.225% HCl in water) to give (2,2-difluorocyclopropyl)-[(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (120 mg; 37%) as a white solid. This substance was further separated by chiral SFC, giving, as conventionally indicated:

((1S)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl)methanone (peak 1, retention time = 2.069 min) (35.0 mg; 29%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42-7.38 (m, 3H), 7.31-7.29 (m, 2H), 6.21-6.19 (m, 0.5H), 6.07-6.05 (m, 0.5H ), 5.68-5.66 (m, 1H), 3.85-3.76 (m, 2H), 2.86-2.83 (m, 1H), 2.32-2.28 (m, 1H), 1.96-1.93 (m, 1H). LCMS: R _T = 1.834 min, m/z = 308.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time: 1.834 min, ESI+: detected [M+H] = 308.1;

((1R)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl)methanone (peak 2, retention time = 3.055 min) (35.0 mg; 29%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.41 (m, 3H), 7.30-7.28 (m, 2H), 6.21-6.19 (m, 0.5H), 6.07-6.05 (m, 0.5H ), 5.66-5.65 (m, 1H), 3.87-3.74 (m, 2H), 2.89-2.79 (m, 1H), 2.33-2.28 (m, 1H), 1.98-1.97 (m, 1H). LCMS: R _T = 1.822 min, m/z = 308.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time: 1.822 min, ESI+: detected [M+H] = 308.1.

SFC conditions: Chiralcel OD-3 column, 150×4.6 mm (id. dia.), 3 µm; mobile phase: A: CO ₂ , B: isopropanol (with 0.05% DEA); gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 43

(1-Fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

To a chilled (-78°C) solution of 1-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (313 mg; 2.13 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (300 mg; 1.06 mmol) in tetrahydrofuran (30 ml) was added dropwise under nitrogen atmosphere to n-butyllithium (2 .5 M solution in hexanes, 1.28 ml, 3.19 mmol). Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.05% HCl in water) and then preparative TLC (30% ethyl acetate in petroleum ether, R _f = 0.3) , giving (1-fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone (80 mg; 25%) as a light yellow oil. 1Н NMR (400 MHz, CDCl ₃ ) δ 7.40-7.37 (m, 3H), 7.23-7.21 (m, 2H), 6.09-6.07 (m, 0.5H), 5.96-5.94 (m, 0.5H), 5.51-5.49 (m, 1H), 3.67-3.58 (m, 1H), 3.00-2.90 (m, 1H), 1.92-1.88 (m, 2H), 1.62-1.60 (m, 2H). LCMS: R _T = 1.736 min; m/z = 290.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time: 1.736 min, ESI+: detected [M+H] = 290.1.

Method 44

Cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone

Step 1: 1-(2-fluorophenyl)but-3-en-1-ol

To a solution of 2-fluorobenzaldehyde (15.0 g; 120.86 mmol) in tetrahydrofuran (250 ml) was added allylmagnesium bromide (1.0 M in tetrahydrofuran; 150.0 ml; 150.0 mmol) at 0°C under nitrogen atmosphere . At the end of the addition, the mixture was allowed to warm to 25° C. and stirred for 2 h, then quenched by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give 1-(2-fluorophenyl)but-3-en-1-ol (6.0 g; 24%) in yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.27 (m, 1H), 7.29-7.12 (m, 2H), 7.05-7.00 (m, 1H), 5.89-5.80 (m, 1H), 5.20-5.13 (m, 2H), 5.15-5.07 (m, 1H), 2.66-2.55 (m, 1H), 2.57-5.48 (m, 1H).

Step 2: tert-butyl((1-(2-fluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a solution of 1-(2-fluorophenyl)but-3-en-1-ol (6.0 g; 36.1 mmol) in dichloromethane (50 ml) was added imidazole (4.9 g; -butyldimethylchlorosilane (7.1 g; 146.9 mmol). The reaction mixture was stirred at 25°C for 16 h and extinguished by adding water (100 ml). The mixture was extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to give t-butyl-[1-(2-fluorophenyl)but-3-enoxy]-dimethyl-silane (8.5 g; 84 %) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60-7.36 (m, 1H), 7.34-7.18 (m, 2H), 7.13-7.02 (m, 1H), 5.97-5.85 (m, 1H), 5.21-5.07 (m, 3H), 2.60-2.48 (m, 2H), 0.99 (s, 9H), 0.15 (s, 3H), 0.00 (s, 3H).

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2-fluorophenyl)propanal

Osmium tetroxide was added to a solution of tert-butyl-[1-(2-fluorophenyl)but-3-enoxy]-dimethylsilane (8.50 g; 30.3 mmol) in water (100 ml) and tetrahydrofuran (100 ml) (0.15 g; 0.6 mmol). After stirring for 30 minutes at 25° C., sodium periodate (25.90 g; 121.2 mmol) was added in small portions over 2 hours. The resulting mixture was stirred for 2 h at 25° C. and quenched by adding cold saturated aqueous sodium thiosulfate (100 ml). The mixture was stirred for 30 min and then extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g ; 64%) as a black oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.84-9.77 (m, 1H), 7.53-7.51 (m, 1H), 7.31-7.24 (m, 1H), 7.21-7.13 (m, 1H), 7.09-6.98 (m, 1H), 5.58-5.55 (m, 1H), 2.85-2.80 (m, 1H), 2.74-2.64 (m, 1H), 0.92-0.85 (m, 9H), 0.09 (s, 3H), - 0.09 (s, 3H).

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(2-fluorophenyl)propan-1-ol

n- butyl lithium (2.5 M solution in hexanes; 8.6 ml; 21.4 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g; 19.5 mmol) in tetrahydrofuran (25 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1.5 h and then extinguished by adding saturated aqueous ammonium chloride (50 ml). The resulting mixture was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propan-1-ol (8.0 g; 80%) as a yellow oil. Used in this form in the next step.

Step 5: 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

Mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propane -1-ol (8.0 g; 15.55 mmol) and trifluoroacetic acid (30.0 ml) in dichloromethane (3.0 ml) were stirred at 50°C for 5 h and concentrated under reduced pressure. The pH of the residue was adjusted to 9 by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-7-ol (2.0 g; 43%) as a light yellow solid. LCMS: R _T = 0.505 min, m/z = 298.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.505 min, ESI+: detected [M+H] = 298.1.

Step 6: (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a solution of 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (750 mg; 2.52 mmol ) in toluene (20 ml) was added diethylaminosulfur trifluoride (1.62 g; 10.06 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then slowly added to ice water (20 ml) at 0°C. The mixture was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to give rac-(5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (250 mg; 33%) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.27 (q, J=6.6 Hz, 1H), 7.20-7.10 (m, 2H), 7.01-6.97 (m, 1H), 6.10-5.89 (m , 1Н), 5.84-5.75 (m, 1Н), 3.70-3.53 (m, 1Н), 2.96-2.75 (m, 1Н). LCMS: R _T = 1.112 min, m/z = 300.0 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.112 min, ESI+: [M+H] = 300.0 detected.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated:

(5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 3.408 min) (100 mg; 40%) as a white solid. (The (5R,7R) isomer was also collected (peak 1, retention time = 3.139 min) (100 mg; 40%)).

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Stage 7: cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone

To a solution of (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg; 0.33 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (86 mg; 0.67 mmol) in tetrahydrofuran (10 ml) was added n-butyl lithium (2.5 M solution in hexanes; 0.27 ml; 0.67 mmol) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 2 h and extinguished by adding saturated aqueous ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to give, by convention, cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (7.2 mg; 7%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.41 (m, 1H), 7.25-7.18 (m, 2H), 7.16-7.13 (m, 1H), 6.22-6.06 (m, 1H), 5.92- 5.88 (m, 1H), 3.85-3.78 (m, 1H), 3.08-3.02 (m, 1H), 2.93-2.78 (m, 1H), 1.22-1.17 (m, 2H), 1.15-1.09 (m, 2H ). LCMS: R _T = 1.043 min, m/z = 290.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min): retention time 1.043 min, ESI+: detected [M+H] = 290.2.

Method 45

(S)-Cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

To a solution of ethyl (5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg; 0. 36 mmol) in tetrahydrofuran (3 ml) was added dropwise under nitrogen atmosphere cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 0.72 ml; 0.36 mmol) at -78°C. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The resulting mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 40-50%/0.05% ammonium hydroxide in water) to give cyclopropyl-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl]methanone (50 mg; 51%) as a white solid (80% ee). The product was further purified with chiral SFC to give, as conventionally indicated, (S)-cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl) methanone (17.5 mg; 34%) as a brown oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.35 (m, 1H), 7.23-7.16 (m, 3H), 5.81-5.77 (m, 1H), 3.37-3.29 (m, 1H), 3.21- 3.03 (m, 2H), 2.99-2.93 (m, 1H), 2.77-2.65 (m, 1H), 1.16-1.09 (m, 2H), 1.09-1.00 (m, 2H). LC-MS: R _T = 0.699 min, m/z = 272.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.699 min, ESI+: detected [M+H] = 272.1.

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B in 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 2.5 ml/min; column temperature: 40°C.

Method 46

(3,3-Difluorocyclobutyl)((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone

To a solution of 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (76 mg; 0.43 mmol) and (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg; 0.21 mmol) in tetrahydrofuran (13 ml) was added dropwise n-butyllithium (2.5 M solution in hexanes; 0 .26 ml; 0.64 mmol) at -78°C. Upon completion of the addition, the mixture was stirred at -78°C for 2 h and extinguished by adding saturated aqueous ammonium chloride (25 ml). The mixture was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 20-45%/0.225% hydrochloric acid in water) to give (3,3-difluorocyclobutyl)-[(5R,7R)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (11.0 mg; 16%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.38 (m, 3H), 7.29-7.27 (m, 2H), 6.19-6.17 (m, 0.5H), 6.05-6.03 (m, 0.5H ), 5.64-5.63 (m, 1H), 3.94-3.93 (m, 1H), 3.79-3.75 (m, 1H), 2.90-2.82 (m, 5H). LCMS: R _T = 1.904 min, m/z = 322.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.904 min, ESI+: [M+H] = 322.1 detected.

Method 47

[(5S)-7,7-Difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2- fluorocyclopropyl] methanone and [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S )-2-fluorocyclopropyl] methanone

Step 1: 2-bromo-5-phenyl-5H-pyrrolo[1,2-b][1,2,4]triazol-7(6H)-one

To a solution of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (2.0 g; 7.14 mmol) in dichloromethane (100 ml) was added pyridinium chlorochromate (1.7 g; 7.85 mmol). The mixture was stirred at 20°C for 18 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 2-bromo-5-phenyl-5,6-dihydropyrrolo[1,2-b] [1,2,4]triazol-7-one (1.8 g; 88%) as a white solid. Used in this form in the next step.

Stage 2: (S)-2-bromo-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a chilled solution of 2-bromo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-one (1.7 g; 6.11 mmol) in dichloromethane (80 ml) diethylaminosulfur trifluoride (7.88 ml; 61.13 mmol) was added at 0°C. After stirring at 25°C for 2 h, the mixture was poured into ice water (10 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give racemic 2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b ][1,2,4]triazole (1.5 g; 82%) as a pink solid. LC-MS: R _T = 0.774 min, m/z = 303.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.774 min, ESI+: [M+H] = 303.1 detected.

The racemic product (950 mg; 3.17 mmol) was further resolved with chiral SFC to give, as conventionally indicated:

(5R)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (peak 1, retention time = 2.308 min) (410 mg, 43%) as a light brown solid;

(5S)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.614 min) (440 mg, 46%) as a light brown solid.

SFC conditions: column: OJ (250 mm × 50 mm, 10 µm); mobile phase: A: CO ₂ , B: 0.1% NH ₃ H ₂ O in EtOH; gradient: 20% to 20% B; flow rate: 180 ml/min; column temperature: 40°C.

Step 3: [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R) -2-fluorocyclopropyl]methanone and [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[( 1R,2S)-2-fluorocyclopropyl]methanone

To a mixture of (5S)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (200 mg; 0.67 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (196 mg; 1.33 mmol) in tetrahydrofuran (10 ml) was added dropwise under nitrogen atmosphere n-butyllithium (2.5 M solution in hexanes; 0. 8 ml; 2.0 mmol) at -78°C. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated to dryness under reduced pressure to give a crude product which was purified by RP-HPLC (acetonitrile 45-75%/0.05% ammonium hydroxide in water) to give [(5S)-7,7-difluoro-5- phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[trans-2-fluorocyclopropyl]methanone (50 mg; 24%) as a brown oil. This racemic product was resolved with chiral SFC to give, as tentatively indicated:

[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2- fluorocyclopropyl] methanone (peak 1, retention time = 2.365 min) (15.1 mg; 30%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.44 (m, 3H), 7.33-7.30 (m, 2H), 5.99-5.92 (m, 1H), 5.02-5.00 (m, 0.5H), 4.86-4.82 (m, 0.5H), 3.89-3.86 (m, 1H), 3.51-3.47 (m, 1H), 3.34-3.33 (m, 0.5H), 3.32-3.22 (m, 0.5H) , 1.78-1.70 (m, 1H), 1.63-1.57 (m, 1H). LC-MS: R _T = 0.822 min, m/z = 308.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.822 min, ESI+: [M+H] = 308.0 detected.

[(5S)-7,7-Difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S)-2- fluorocyclopropyl] methanone (peak 2, retention time = 3.163 min) (13.6 mg; 27%) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.43 (m, 3H), 7.31-7.29 (m, 2H), 5.98-5.94 (m, 1H), 5.05-4.99 (m, 0.5H), 4.86-4.83 (m, 0.5H), 3.91-3.86 (m, 1H), 3.47-3.45 (m, 1H), 3.34-3.26 (m, 1H), 1.74-1.68 (m, 1H), 1.62-1.56 (m, 1H). LC-MS: R _T = 0.818 min, m/z = 308.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.818 min, ESI+: [M+H] = 308.1 detected.

SFC conditions: column: column: AD (250 mm × 30 mm, 5 µm); mobile phase: A: CO ₂ , B: 0.1% NH ₃ H ₂ O in EtOH; gradient: 20% to 20% B; flow rate: 50 ml/min; column temperature: 40°C.

Method 48

Cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R) -7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of 7,7-difluoro-N-methoxy-N-methyl-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg; 0. 32 mmol) in tetrahydrofuran (10 ml) was added cyclopropylmagnesium bromide (0.5 M solution in tetrahydrofuran; 2.6 ml; 1.3 mmol) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 2 h and extinguished by adding saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give cyclopropyl-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][ 1,2,4]triazol-2-yl)methanone (60 mg; 64%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.31 (m, 3H), 7.16-7.11 (m, 2H), 5.66-5.60 (m, 1H), 3.73-3.61 (m, 1H), 3.23-3.11 (m, 1H), 3.00-2.96 (m, 1H), 1.31-1.19 (m, 2H), 1.11-0.96 (m, 2H).

This racemate was further resolved with chiral SFC to give, as tentatively indicated:

cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 2.971 min) (22.4 mg; 37%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.41 (m, 3H), 7.23-7.21 (m, 2H), 5.73-5.68 (m, 1H), 3.75-3.70 (m, 1H), 3.31-3.19 (m, 1H), 3.09-3.04 (m, 1H), 1.37-1.32 (m, 2H), 1.14-1.09 (m, 2H). LCMS: R _T = 1.238 min, m/z = 290.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.238 min, ESI+: detected [M+H] = 290.2;

cyclopropyl-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.677 min) (24.7 mg; 41%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.41 (m, 3H), 7.23-7.20 (m, 2H), 5.72-5.68 (m, 1H), 3.81-3.66 (m, 1H), 3.28-3.21 (m, 1H), 3.09-3.05 (m, 1H), 1.37-1.27 (m, 2H), 1.17-1.05 (m, 2H). LCMS: R _T = 1.239 min, m/z = 290.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.239 min, ESI+: detected [M+H] = 290.2.

SFC conditions: column: Chiralcel OJ (250 mm x 30 mm, 5 µm); mobile phase: A: CO ₂ , B: ethanol (0.1% NH ₃ H ₂ O); gradient: 25% to 25% B over 5 min; 2.5 ml/min; column temperature: 35°C.

Method 49

(2,2-Difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone

Stage 1: 1,1-difluoro-N-methoxy-N-methylspiro[2.3]hexane-5-carboxamide

A mixture of 1-hydroxybenzotriazole (83 mg; 0.62 mmol), N,O-dimethylhydroxylamine hydrochloride (180 mg; 1.85 mmol), 2,2-difluorospiro[2.3]hexane-5-carboxylic acid (200 mg; 1, 23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg; 1.48 mmol) and N,N-diisopropylethylamine (478 mg; 3.70 mmol) in dichloromethane (10 ml) was stirred at 25° C for 12 h and diluted with water (30 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (130 mg ; 51%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.67 (s, 3Н), 3.65-3.51 (m, 1H), 3.21 (s, 3Н), 2.78-2.68 (m, 1H), 2.57-2.47 (m, 1H ), 2.48-2.37 (m, 1H), 2.28-2.17 (m, 1H), 1.32-1.13 (m, 2H).

Step 2: (2,2-difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazol-2-yl]methanone

To a cooled (-78°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (50 mg; 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (73 mg; 0.35 mmol) in tetrahydrofuran (10 ml) was added n-butyl lithium (2.5 M solution in n-hexane; 0.28 ml; 0.71 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 2 h and extinguished by adding saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 47-77%/0.2% formic acid in water) to give (2,2-difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro -5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (10.8 mg; 17%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.38 (m, 3H), 7.28-7.26 (m, 2H), 6.18-6.02 (m, 1H), 5.64-5.62 (m, 1H), 4.24- 4.08 (m, 1H), 3.87-3.64 (m, 1H), 2.91-2.74 (m, 1H), 2.68-2.28 (m, 4H), 1.32-1.23 (m, 2H). LCMS: R _T = 1.281 and 1.298 min, m/z = 348.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention times 1.281 and 1.298 min, ESI+: [M+H] = 348.1 detected.

Method 50

1-[(5S)-5-(2-Chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

Stage 1: ethyl 4-(2-chlorophenyl)-4-oxobutanoate

To a solution of 2-chloroacetophenone (100.0 g; 646.87 mmol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (156.4 ml; 1293.70 mmol) in tetrahydrofuran (500 ml) was added [bis(trimethylsilyl)amino]lithium (1.0 M solution in tetrahydrofuran; 711.6 ml; 711.56 mmol) at -60°C. The mixture was stirred at -60°C for 100 min and ethyl bromoacetate (143.5 ml; 1293.7 mmol) was added rapidly. The resulting mixture was allowed to warm to 25° C. and stirred for 15 hours. The reaction was quenched by adding water (400 ml) and the reaction mixture was extracted with ethyl acetate (3×1000 ml). The combined organic layers were washed with water (2×500 ml), brine (1500 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give ethyl 4-(2-chlorophenyl)-4-oxo-butanoate (50.0 g; 32%) as colorless oil. Used in this form in the next step.

Stage 2: tert-butyl-(2-(2-chlorophenyl)-5-oxopyrrolidin-1-yl)carbamate

To a solution of ethyl 4-(2-chlorophenyl)-4-oxo-butanoate (10.0 g; 41.55 mmol) in acetic acid (33 ml) and tetrahydrofuran (100 ml) was added tert-butyl hydrazine carboxylate (11, 0 g; 83.10 mmol). The mixture was stirred at 85° C. for 12 h and sodium cyanoborohydride (7.8 g; 124.65 mmol) was added. The resulting mixture was stirred at 85°C for another 12 h and concentrated under reduced pressure. The residue was diluted with water (100 ml) and extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with saturated sodium carbonate solution (80 ml), hydrochloric acid (2 M solution; 80 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 20 to 50% ethyl acetate in petroleum ether) to give t-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (5.0 g; 39%) as a light yellow oil. LCMS: R _T = 0.840 min, m/z = 255.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.840 min, ESI+: detected [M-55] = 255.0.

Stage 3: 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one

A solution of tert-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (5.0 g; 16.09 mmol) in hydrochloric acid (4.0 M solution in 1, 4-dioxane; 40.2 ml; 160.89 mmol) was stirred at 25° C. for 12 hours and filtered. The filter cake was washed with ethyl acetate (20 ml) and dissolved in water (20 ml). The pH of the solution was adjusted to 9 by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one (3.3 g, 97%) as a white solid. LCMS: R _T = 0.615 min, m/z = 211.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.615 min, ESI+: [M+H] = 211.0 detected.

Stage 4: 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one

A mixture of 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one (3.3 g; 15.67 mmol) and ethyl 2-ethoxy-2-iminoacetate (4.6 g; 31.33 mmol ) in ethanol (50 ml) was stirred at 70° C. for 18 h and concentrated under reduced pressure to give crude ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]amino] -2-imino-acetate (4.8 g; 99%) as a brown oil. LCMS: R _T = 0.675 min, m/z = 310.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.675 min, ESI+: [M+H] = 310.0 detected.

Stage 5: (S)-ethyl-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]amino]-2-iminoacetate (4.8 g; 15.5 mmol) and phosphorus oxychloride (21, 4 g; 139.5 mmol) was stirred at 100°C for 3 h and cooled to 25°C. The mixture was carefully poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 40% ethyl acetate in petroleum ether) to give ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazole-2-carboxylate (3.0 g; 66%) as brown oil. LCMS: R _T = 0.741 min, m/z = 292.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.741 min, ESI+: [M+H] = 292.1 detected.

The above racemic product (1.0 g; 3.43 mmol) was further resolved using SFC to give, as conventionally indicated:

(S)-ethyl-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (peak 2, retention time = 4.111 min) (400 mg; 40%) and (R)-ethyl-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -carboxylate (peak 1, retention time = 3.762 min) (400 mg; 40%), both as yellow solids.

SFC conditions: column: AD-3 (250 mm × 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first at 30%, at the end at 30%; flow rate 60 ml/min; column temperature 40°C.

Step 6: (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Ethyl (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate mixture (400 mg; 1.37 mmol) and lithium hydroxide monohydrate (287 mg; 6.86 mmol) in ethanol (2 ml), water (2 ml) and tetrahydrofuran (2 ml) were stirred at 25°C for 12 h and concentrated under reduced pressure. The residue was diluted with ice water (2 ml) and the pH was adjusted to 3 by adding hydrochloric acid (2 M solution). The solid was collected by filtration and washed with acetonitrile to give crude (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (350 mg; 97%) as a white solid. LCMS: R _T = 0.642 min, m/z = 264.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.642 min, ESI+: [M+H] = 264.0 detected.

Step 7: (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- carboxamide

A mixture of 1-hydroxybenzotriazole (215 mg; 1.59 mmol), N,O-dimethylhydroxylamine hydrochloride (194 mg; 1.99 mmol), (S)-5-(2-chlorophenyl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (350 mg; 1.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (305 mg; 1.59 mmol) and N,N-diisopropylethylamine (515 mg; 3.98 mmol) in dichloromethane (8 ml) was stirred at 25°C for 12 h. 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 (2×25 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 10% to 35% ethyl acetate in petroleum ether) to give (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (300 mg; 74%) as a colorless oil. LCMS: R _T = 0.700 min, m/z = 307.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.700 min, ESI+: [M+H] = 307.0 detected.

Step 8: 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1 -He

To a cooled (0°C) solution of (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazole-2-carboxamide (20 mg; 0.07 mmol) in tetrahydrofuran (5 ml) was added ethylmagnesium bromide (1.0 M solution in hexane; 0.42 ml; 0.42 mmol). The mixture was stirred at 0-5°C for 1 h and quenched by adding saturated aqueous ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 32-62%/0.2% formic acid in water) to give 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl]propan-1-one (5.7 mg; 31%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.52-7.50 (m, 1H), 7.38-7.33 (m, 2H), 6.96-6.94 (m, 1H), 5.99-5.96 (m, 1H), 3.40- 3.33 (m, 1H), 3.14-3.11 (m, 2H), 3.07-3.03 (m, 2H), 2.68-2.65 (m, 1H), 1.18 (d, J=7.2 Hz, 3H). LCMS: R _T = 1.185 min, m/z = 276.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.185 min, ESI+: [M+H] = 276.1 detected.

Method 51

[1-(Hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone

Step 1: 1-(ethoxycarbonyl)cyclopropanecarboxylic acid

To a mixture of diethyl 1,1-cyclopropanedicarboxylate (10.0 g; 53.7 mmol) in ethanol (70 ml) and water (35 ml) was added sodium hydroxide (2.1 g; 53.7 mmol). The reaction mixture was stirred at 25°C for 16 h and diluted with ethyl acetate (60 ml). The organic layer was discarded. The pH of the aqueous phase was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution). The mixture was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude 1-ethoxycarbonylcyclopropanecarboxylic acid (6.6 g; 78%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.86 (br s, 1H), 4.31-4.17 (m, 2H), 1.87-1.81 (m, 2H), 1.77-1.69 (m, 2H), 1.32-1.24 ( m, 3H).

Stage 2: ethyl 1-(hydroxymethyl)cyclopropanecarboxylate

To a mixture of 1-ethoxycarbonylcyclopropanecarboxylic acid (6.6 g; 41.7 mmol) and triethylamine (6.98 ml; 50.1 mmol) in tetrahydrofuran (60 ml) was added dropwise isobutyl chloroformate (8.12 ml; 62.6 mmol ) at 0°C. After the addition was completed, the reaction mixture was stirred at 0° C. for 1 h and filtered. The filtrate was then added to a mixture of sodium borohydride (1.6 g; 41.7 mmol) in tetrahydrofuran (40 ml) and water (10 ml). The resulting mixture was stirred at 0° C. for 1 h and quenched by adding 10% acetic acid solution (20 ml). The mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (3.8 g; 63%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.17-4.08 (m, 2H), 3.62 (s, 2H), 1.29-1.21 (m, 5H), 0.87-0.84 (m, 2H).

Stage 3: ethyl 1-(((tert-butyldiphenylsilyl)oxy)-methyl)cyclopropanecarboxylate

To a stirred solution of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (1.0 g; 6.94 mmol) in N,N-dimethylformamide (20 ml) was added imidazole (1.4 g; 20.81 mmol) and tert-butyldiphenylchlorosilane (3.8 g; 13.87 mmol) at 0°C. The mixture was stirred at 25°C for 18 h and poured into water (30 ml). The solution was extracted with dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give ethyl 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylate (2.3g, 87%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.70-7.61 (m, 4H), 7.46-7.35 (m, 6H), 4.15-4.06 (m, 2H), 3.85 (s, 2H), 1.23 (t, J=7.0 Hz, 3H), 1.17-1.11 (m, 2H), 1.04 (s, 9H), 0.93-0.87 (m, 2H).

Stage 4: 1-(((tert-butyldiphenylsilyl)oxy)-methyl)cyclopropanecarboxylic acid

A mixture of ethyl 1-[[tert-butyl(diphenyl)silyl]oxymethyl]-cyclopropanecarboxylate (1.0 g; 2.61 mmol) and lithium hydroxide monohydrate (438 mg; 10.46 mmol) in tetrahydrofuran (16 ml), methanol (16 ml) and water (8 ml) was stirred at 25°C for 18 h. The organic solvent was removed under reduced pressure. The aqueous residue was washed with ethyl acetate (15 ml) and the pH was brought to 3 by adding aqueous hydrochloric acid (4 M solution) at 0°C. The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg; 100%) as a slightly sticky white solid. This crude material was used in the next step without further purification.

Stage 5: 1-(((tert-butyldiphenylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropanecarboxamide

A mixture of 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg; 2.68 mmol), N,O-dimethylhydroxylamine hydrochloride (523 mg; 5.36 mmol), N,N-diisopropylethylamine (1 .43 ml; 8.04 mmol), 1-hydroxybenzotriazole (217 mg; 1.61 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (771 mg; 4.02 mmol) in dichloromethane (20 ml) stirred at 25° C. for 18 hours. The resulting mixture was poured into water (20 ml) and extracted with dichloromethane (3×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (15% ethyl acetate in petroleum ether, R _f = 0.4) to give 1-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropanecarboxamide (700 mg ; 66%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.63 (m, 4H), 7.42-7.25 (m, 6H), 3.79 (s, 2H), 3.62 (s, 3H), 3.23 (s, 3H), 1.04-0.99 (m, 9H), 0.75-0.71 (m, 2H).

Stage 6: (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl)methanone

To a mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg; 0. N -butyllithium (2.5 M solution in hexanes; 0.43 ml; 1.06 mmol) at -78°C. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give [1-[[t-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7- fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (60 mg; 31%) as light brown oil.

Step 7: [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

To a solution of [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl]methanone (60 mg; 0.11 mmol) in tetrahydrofuran (3 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 0.17 ml; 0.17 mmol). The mixture was stirred at 25°C for 3 h and poured into water (10 ml). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to give, by convention, [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5 -phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (7.8 mg; 18%) as light brown oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.38 (m, 3H), 7.30-7.26 (m, 2H), 6.19-6.16 (m, 0.5H), 6.05-6.02 (m, 0.5H ), 5.65-5.61 (m, 1H), 3.97-3.85 (m, 2H), 3.84-3.68 (m, 1H), 2.87-2.80 (m, 1H), 1.72-1.67 (m, 2H), 1.11-1.08 (m, 2H). LC-M3: R _T = 0.695 min, m/z = 302.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.695 min, ESI+: [M+H] = 302.1 detected.

Method 52

(3,3-Difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone

Stage 1: 3,3-difluoro-N-methoxy-N-methylcyclobutanecarboxamide

A mixture of 1-hydroxybenzotriazole (297 mg; 2.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (845 mg; 4.41 mmol), 3,3-difluorocyclobutanecarboxylic acid (500 mg; 3.67 mmol ), N,O-dimethylhydroxylamine hydrochloride (537 mg; 5.51 mmol) and N,N-diisopropylethylamine (1187 mg; 9.18 mmol) in dichloromethane (8 ml) was stirred at 25°C for 5 h and diluted with water (20 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (2×20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (430 mg; 65%) as a colorless oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.67 (s, 3H), 3.33-3.22 (m, 1H), 3.20 (s, 3H), 2.93-2.78 (m, 2H), 2.76-2.64 (m, 2H ).

Step 2: (3,3-difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl) methanone

To a solution of 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (76 mg; 0.43 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg; 0.21 mmol) in tetrahydrofuran (13 ml) was added dropwise n-butyllithium (2.5 M solution in hexanes; 0 .26 ml; 0.64 mmol) at -78°C. Upon completion of the addition, the mixture was stirred at -78°C for 2 h and extinguished by adding saturated aqueous ammonium chloride (25 ml). The mixture was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 20-45%/0.225% hydrochloric acid in water) to give (3,3-difluorocyclobutyl)-[(5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (12.4 mg; 18%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.39 (m, 3H), 7.30-7.28 (m, 2H), 6.20-6.17 (m, 0.5H), 6.06-6.03 (m, 0.5H ), 5.66-5.64 (m, 1Н), 3.97-3.80 (m, 1Н), 3.78-3.74 (m, 1Н), 2.91-2.83 (m, 5Н). LCMS: R _T = 1.241 min, m/z = 322.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.241 min, ESI+: [M+H] = 322.2 detected.

Method 53

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-(pyridine- 2-yl)cyclopropyl)methanone

Stage 1: N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide

A mixture of 1-hydroxybenzotriazole (149 mg; 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (423 mg; 2.21 mmol), 2-(pyridin-2-yl)cyclopropanecarboxylic acid (300 mg ; 1.84 mmol), N,O-dimethylhydroxylamine hydrochloride (269 mg; 2.76 mmol) and N,N-diisopropylethylamine (594 mg; 4.60 mmol) in dichloromethane (10 ml) was stirred at 25°C for 16 h and diluted with water (20 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide (300 mg; 79%) in the form of a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47-8.43 (m, 1H), 7.57-7.51 (m, 1H), 7.27-7.22 (m, 1H), 7.10-7.02 (m, 1H), 3.68 (s , 3Н), 3.21 (s, 3Н), 2.76 (s, 1Н), 2.61-2.52 (m, 1Н), 1.63-1.55 (m, 2Н).

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2- (pyridin-2-yl)cyclopropyl)methanone

To a cooled (-78°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole (150 mg; 0.53 mmol) and N-methoxy-N-methyl-2-(2-pyridyl)cyclopropanecarboxamide (219 mg; 1.06 mmol) in 2-methyltetrahydrofuran (3 ml) was added n-butyllithium (2 .5 M solution in n-hexane; 0.64 ml; 1.6 mmol) under nitrogen atmosphere. The mixture was stirred at -78° C. for about 30 minutes and quenched by adding saturated ammonium chloride solution (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 32-62%/0.05% ammonium hydroxide in water) to give, as conventionally indicated, [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(2-pyridyl)cyclopropyl]methanone (11.0 mg; 6%) as a pale pink solid substances. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39-8.37 (m, 1H), 7.69-7.65 (m, 1H), 7.42-7.31 (m, 4H), 7.27-7.17 (m, 3H), 6.18- 6.02 (m, 1H), 5.65-5.61 (m, 1H), 3.83-3.67 (m, 1H), 3.56-3.51 (m, 1H), 2.88-2.73 (m, 2H), 1.86-1.79 (m, 2H ). LCMS: R _T = 0.745 min, m/z = 348.9 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 0.745 min, ESI+: [M+H] = 348.9 detected.

Method 54

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(1S ,2S)-2-methylcyclopropyl]methanone

To a solution of trans-N-methoxy-N,2-dimethyl-cyclopropanecarboxamide (137 mg; 0.96 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazole (180 mg; 0.64 mmol) in tetrahydrofuran (5 ml) isopropylmagnesium bromide (3.0 M solution in tetrahydrofuran; 0 .85 ml; 2.55 mmol) at 0°C. Upon completion of the addition, the mixture was stirred at 0° C. for 1 h and quenched by adding saturated aqueous ammonium chloride (20 ml). The resulting solution was extracted with ethyl acetate (2×15 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether, R _f = 0.2) to give, as conventionally indicated, [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(1S,2S)-2-methylcyclopropyl]methanone (trans-mixture containing methylcyclopropyl derivative) (80 mg; 44%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42-7.37 (m, 3H), 7.28-7.26 (m, 2H), 6.20-6.16 (m, 0.5H), 6.05-6.02 (m, 0.5H ), 5.65-5.63 (m, 1Н), 3.78-3.68 (m, 1Н), 2.83-2.75 (m, 2Н), 1.59-1.52 (m, 1Н), 1.45-1.37 (m, 1Н), 1.19-1.14 (m, 3Н), 1.01-0.91 (m, 1Н). LC-MS: R _T = 0.793 min, m/z = 286.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.793 min, ESI+: [M+H] = 286.1 detected.

Method 55

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexane -5-yl-methanone

Stage 1: N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide

A mixture of spiro[2.3]hexane-5-carboxylic acid (150 mg; 1.19 mmol), N,N-diisopropylethylamine (0.5 ml; 2.97 mmol), 1-hydroxybenzotriazole (96.4 mg; 0.71 mmol) and N,O-dimethylhydroxylamine hydrochloride (174 mg; 1.78 mmol) in dichloromethane (10 ml) was stirred at 25°C for 16 h and diluted with water (30 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (170 mg; 84%) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.66 (s, 3H), 3.20 (s, 3H), 2.60-2.54 (m, 2H), 2.17-2.12 (m, 2H), 0.50-0.40 (m, 4H ).

Stage 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[ 2.3]hexan-5-yl-methanone

To a solution of N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (43 mg; 0.25 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg; 0.18 mmol) in tetrahydrofuran (2 ml) isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran) was added dropwise; 0.21 ml; 0.42 mmol) at 0°C. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (5 ml). The solution was then extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (water (with 0.05% ammonium hydroxide, v/v)/acetonitrile, 45-70%) to give, by convention, [(5S,7S)-7-fluoro-5 -phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexan-5-yl-methanone (42 mg; 75% ) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.37 (m, 3H), 7.27-7.23 (m, 2H), 6.10-5.94 (m, 1H), 5.50-5.47 (m, 1H), 4.32-4.26 (m, 1Н), 3.67-3.60 (m, 1H), 3.01-2.70 (m, 1Н), 2.65-2.57 (m, 2Н), 2.31-2.26 (m, 2Н), 0.51-0.47 (m, 2Н) , 0.43-0.40 (m, 2H). LC-MS: R _T = 0.904 min, m/z = 312.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.904 min, ESI+: [M+H] = 312.0 detected.

Method 56

Cyclopropyl-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a cooled (-78°C) solution of (5S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazole-2-carboxamide (100 mg; 0.33 mmol) in tetrahydrofuran (10 ml) was added cyclopropylmagnesium bromide (0.5 M solution in tetrahydrofuran; 4.24 ml; 2.12 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 38-68%/0.2% formic acid in water) to give, by convention, cyclopropyl-[(5S)-5-(2-chlorophenyl)-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (23.5 mg; 25%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.51 (d, J=1.6 Hz, 1H), 7.49-7.33 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.00 -5.96 (m, 1H), 3.45-3.36 (m, 1H), 3.15-3.10 (m, 2H), 3.05-2.98 (m, 1H), 2.70-2.60 (m, 1H), 1.20-1.15 (m, 2Н), 1.11-1.07 (m, 2Н). LCMS: R _T = 1.187 min, m/z = 288.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.187 min, ESI+: detected [M+H] = 288.1.

Method 57

Cyclopropyl-[rac-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone and cyclopropyl-[(4S,6S )-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone

Stage 1: rac-(4S,6S)-4-fluoro-N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

Rac-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid mixture (800 mg; 3.25 mmol), N ,O-dimethylhydroxylamine hydrochloride (412 mg; 4.22 mmol), N,N-diisopropylethylamine (1.34 ml; 8.12 mmol) and 2-(3H-[1.2.3]triazolo[4.5- b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.6 g; 4.22 mmol) in N,N-dimethylformamide (20 ml) was stirred at 25°C for 3 hours The mixture was diluted with water (30 ml) and was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give rac-(4S,6S)-4-fluoro-N-methoxy-N-methyl-6-phenyl-5, 6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (800 mg; 85%) as a white solid. LCMS: R _T = 0.707 min, m/z = 290.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.707 min, ESI+: detected [M+H] = 290.1.

Stage 2: cyclopropyl-[rac-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone

To a cooled (0°C) solution of rac-(4S,6S)-4-fluoro-N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole- 2-carboxamide (40 mg; 2.77 mmol) was added cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 1.5 ml; 0.75 mmol) under nitrogen atmosphere. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give, by convention, cyclopropyl-[rac-(4S,6S)-4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone (28.6 mg; 75%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.36 (m, 3H), 7.27-6.90 (m, 2H), 6.93 (s, 1H), 6.09-5.92 (m, 1H), 5.53-5.49 (m , 1Н), 3.58-3.47 (m, 1Н), 2.97-2.79 (m, 2Н), 1.22-1.19 (m, 2Н), 0.99-0.96 (m, 2Н). LCMS: R _T = 0.870 min, m/z = 270.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.870 min, ESI+: [M+H] = 270.9 detected.

Stage 3: cyclopropyl-[(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone (G03280299)

Cyclopropyl-[rac-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone (600 mg; 2.22 mmol , enlarged from another batch) was further resolved with chiral SFC to give, as conventionally indicated, cyclopropyl-[(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-yl]methanone (peak 1, retention time = 3.306 min) (250 mg; 41.7%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.37 (m, 3H), 7.23-7.21 (m, 2H), 6.93 (d, J=2.8 Hz, 1H), 6.09-6.07 (m, 0 .5H), 5.95-5.93 (m, 0.5H), 5.51-5.49 (m, 1H), 3.54-3.45 (m, 1H), 2.96-2.92 (m, 1H), 2.85-2.82 (m, 1H) , 1.23–1.20 (m, 2Н), 0.99–0.96 (m, 2Н). LCMS: R _T = 0.883 min, m/z = 271.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.883 min, ESI+: [M+H] = 271.0 detected.

SFC conditions: column: OD-H (250 mm × 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first at 30%, at the end at 30%; flow rate 60 ml/min; column temperature 40°C.

Method 58

[1-(Fluoromethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone

Stage 1: 1-(fluoromethyl)-N-methoxy-N-methyl-cyclopropanecarboxamide

A mixture of 1-(fluoromethyl)cyclopropanecarboxylic acid (543 mg; 4.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1057 mg; 5.52 mmol), 1-hydroxybenzotriazole (372 mg; 2.76 mmol), N,O-dimethylhydroxylamine hydrochloride (897 mg; 9.19 mmol) and N,N-diisopropylethylamine (594 mg; 4.60 mmol) in dichloromethane (15 ml) was stirred at 30°C for 18 h and quenched by adding water (10 ml). The separated organic layer was washed with brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give 1-(fluoromethyl)-N-methoxy-N-methyl-cyclopropanecarboxamide (135 mg; 18%) as a brown oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.63-4.47 (m, 2H), 3.74 (s, 3H), 3.26 (s, 3H), 1.30-1.23 (m, 2H), 0.95-0.85 (m, 2H ).

Step 2: [1-(fluoromethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

To a solution of 1-(fluoromethyl)-N-methoxy-N-methyl-cyclopropanecarboxamide (80 mg; 0.50 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazole (70 mg; 0.25 mmol) in tetrahydrofuran (5 ml) was added dropwise n-butyl lithium (2.5 M solution in hexanes; 0 .3 ml; 0.75 mmol) at -78°C. Upon completion of the addition, the mixture was stirred at -78°C for 1 h and then extinguished by adding saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give, by convention, [1-(fluoromethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (15.6 mg; 20%) as a brown oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.33 (m, 3H), 7.26-7.23 (m, 2H), 6.17-6.12 (m, 0.5H), 6.01-5.98 (m, 0.5H ), 5.62-5.60 (m, 1Н), 4.83-4.76 (m, 1Н), 4.73-4.63 (m, 1Н), 3.76-3.65 (m, 1Н), 2.85-2.77 (m, 1Н), 1.86-1.79 (m, 2H), 1.23-1.16 (m, 2H). LC-MS: R _T = 1.188 min, m/z = 304.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.188 min, ESI+: [M+H] = 304.2 detected.

Method 59

(3,3-Difluorobicyclo[3.1.0]hexan-6-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone

Step 1: tert-butyl(cyclopent-3-en-1-yloxy)dimethylsilane

To a solution of 3-cyclopenten-1-ol (10.0 g; 118.88 mmol) in tetrahydrofuran (130 ml) were added imidazole (16.0 g; 237.76 mmol) and tert-butyldimethylchlorosilane (23.0 g; 154 .54 mmol). Upon completion of the addition, the reaction mixture was stirred at 30°C for 16 h and extinguished by adding water (100 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 3% ethyl acetate in petroleum ether) to give t-butyl-cyclopent-3-en-1-yloxy-dimethyl-silane (22.0 g; 93%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.61 (s, 2H), 4.49-4.44 (m, 1H), 2.54-2.48 (m, 2H), 2.24-2.19 (m, 2H), 0.82 (s, 9H ), 0.02 (s, 6H).

Stage 2: ethyl 3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylate

Ethyl diazoacetate (13.8 g, 120.98 mmol) was added to a solution of tert-butyl-cyclopent-3-en-1-yloxy-dimethylsilane (20.0 g, 100.82 mmol) in dichloromethane (160 ml). The reaction mixture was stirred for 12 h at 25°C and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 5% ethyl acetate in petroleum ether) to give ethyl 3-[tert-butyl(dimethyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylate (15 .0 g, 52%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.49-4.44 (m, 2H), 2.53-2.48 (m, 2H), 2.24-2.19 (m, 2H), 1.65-1.24 (m, 2H), 1.25-1.22 (m, 2Н), 0.83 (s, 9Н), 0.00 (s, 6Н).

Stage 3: ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate

Tetrabutylammonium fluoride (20.7 g; 79.09 mmol). The reaction mixture was stirred at 50°C for 12 h and diluted with water (200 ml). The mixture was extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate (8.8 g; 98%) as a yellow oil .

Stage 4: ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate

To a solution of Dess-Martin periodinan (32.9 g; 77.55 mmol) in dichloromethane (200 ml) was added ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate (8.8 g; 51.70 mmol) . The reaction mixture was stirred at 25°C for 12 h and diluted with water (200 ml). The resulting mixture was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate (8.0 g; 92%) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.15-4.12 (m, 2H), 2.68-2.62 (m, 2H), 2.30-2.25 (m, 2H), 2.17-2.15 (m, 2H), 1.27-1.24 (m, 4H).

Stage 5: ethyl 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylate

To a solution of ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate (2.0 g, 11.89 mmol) in dichloromethane (20 ml) was added diethylaminosulfur trifluoride (19.2 g, 118.91 mmol). The reaction mixture was stirred at 25°C for 12 h and extinguished by adding water (100 ml) at 0°C. The mixture was extracted with dichloromethane (3×40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give ethyl 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylate (1.7 g; 75%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.12-4.07 (m, 2H), 2.48-2.38 (m, 2H), 2.29-2.20 (m, 2H), 1.93-1.92 (m, 2H), 1.63-1.62 (m, 1H), 1.25-1.22 (m, 3H).

Step 6: 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid

To a solution of ethyl 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylate (500 mg; 2.63 mmol) in tetrahydrofuran (24 ml) was added a solution of lithium hydroxide monohydrate (330 mg; 7.89 mmol) in water (7 ml). The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The pH of the aqueous residue was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution) at 0°C. The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude 3,3-difluoro-bicyclo[3.1.0]hexane-6-carboxylic acid (250 mg; 59%) as a colorless oil.

Stage 7: 3,3-difluoro-N-methoxy-N-methylbicyclo[3.1.0]hexane-6-carboxamide

A mixture of 1-hydroxybenzotriazole (250 mg; 1.85 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (426 mg; 2.22 mmol), 3,3-difluorobicyclo[3.1.0]hexane-6- carboxylic acid (300 mg; 1.85 mmol), N,O-dimethylhydroxylamine hydrochloride (271 mg; 2.78 mmol) and N,N-diisopropylethylamine (598 mg; 4.63 mmol) in dichloromethane (40 ml) was stirred at 25°C for 16 h and diluted with water (20 ml). The mixture was extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give 3,3-difluoro-N-methoxy-N-methyl-bicyclo[3.1.0]hexane-6-carboxamide ( 102 mg; 27%) as a colorless oil. LCMS: R _T = 0.522 min, m/z = 206.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.522 min, ESI+: detected [M+H] = 206.1.

Step 8: (3,3-difluoro-6-bicyclo[3.1.0]hexanyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone

To a solution of 3,3-difluoro-N-methoxy-N-methyl-bicyclo[3.1.0]hexane-6-carboxamide (102 mg; 0.50 mmol) and (5S,7S)-2-bromo-7-fluoro -5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (70 mg; 0.25 mmol) in tetrahydrofuran (10 ml) was added dropwise isopropyl magnesium chloride ( 2.0 M solution in tetrahydrofuran; 0.37 ml; 0.74 mmol) at -78°C under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at -78°C for 2 h and extinguished by adding saturated aqueous ammonium chloride (25 ml). The mixture was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 20-45%/0.225% hydrochloric acid in water) to give (3,3-difluoro-6-bicyclo[3.1.0]hexanyl)-[(5S,7S )-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (11 mg; 13%) as white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.40 (m, 3H), 7.29-7.27 (m, 2H), 6.19-6.16 (m, 0.5H), 6.05-6.02 (m, 0.5H ), 5.65-5.64 (m, 1Н), 3.79-3.73 (m, 1Н), 3.03-3.02 (m, 1Н), 2.90-2.80 (m, 1Н), 2.54-2.30 (m, 2Н), 2.30- 2.25 (m, 2H), 2.20-2.18 (m, 2H). LCMS: R _T = 1.255 min, m/z = 348.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.255 min, ESI+: [M+H] = 348.2 detected.

Method 60

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(trifluoromethyl )cyclopropyl]methanone

Step 1: (E)-4,4,4-trifluoro-N-methoxy-N-methylbut-2-enamide

A mixture of N,O-dimethylhydroxylamine hydrochloride (4.42 g; 45.30 mmol), N,N-diisopropylethylamine (10.2 ml; 56.94 mmol), 4,4,4-trifluorobut-2-enoic acid (5 .00 g; 35.70 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.21 g; 42.84 mmol) in dichloromethane (50 ml) were stirred at 0° C. for 5 h. washed with brine (2×50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give (E)-4,4,4-trifluoro-N-methoxy-N-methyl-but-2-enamide ( 2.50 g; 38%) as a colorless oil. LC-MS: R _T = 0.522 min, m/z = 184.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.522 min, ESI+: [M+H] = 184.1 detected.

Step 2: N-methoxy-N-methyl-2-(trifluoromethyl)-cyclopropanecarboxamide

To a solution of trimethylsulfoxonium iodide (6.01 g; 27.30 mmol) in dimethyl sulfoxide (50 ml) was added sodium hydride (60%; 1.09 g; 27.30 mmol). The mixture was stirred for 1 h and a solution of (E)-4,4,4-trifluoro-N-methoxy-N-methyl-but-2-enamide (2.50 g; 13.65 mmol) in dimethyl sulfoxide (20 ml) was added ). The resulting mixture was stirred at 25°C for 16 h and diluted with saturated aqueous ammonium chloride (100 ml). The solution was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (150 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (35-65% acetonitrile/0.05% ammonium hydroxide in water) to give N-methoxy-N-methyl-2-(trifluoromethyl)cyclopropanecarboxamide (700 mg; 26%) as a yellow oil. LC-MS: R _T = 0.722 min, m/z = 197.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.722 min, ESI+: [M+H] = 197.9 detected.

Stage 3: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2 -(trifluoromethyl)cyclopropyl]methanone

To a solution of N-methoxy-N-methyl-2-(trifluoromethyl)cyclopropanecarboxamide (98 mg; 0.50 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg; 0.35 mmol) in tetrahydrofuran (2 ml) was added isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 1.06 ml; 2.13 mmol) at 0°C under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at 25° C. for 16 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (3×10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0-40% ethyl acetate in petroleum ether) to give [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl]-[2-(trifluoromethyl)cyclopropyl]methanone (30 mg, 24%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.39 (m, 3H), 7.32-7.29 (m, 2H), 6.22-6.05 (m, 1H), 5.70-5.65 (m, 1H), 3.84- 3.71 (m, 1H), 3.41-3.37 (m, 1H), 2.90-2.79 (m, 1H), 2.45-2.40 (m, 1H), 1.53-1.46 (m, 2H). LC-MS: R _T = 0.904 min, m/z = 339.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.904 min, ESI+: detected [M+H] = 339.9.

Method 61

(6,6-Difluoro-3-bicyclo[3.1.0]hexanyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl]methanone

Stage 1: 6,6-difluoro-N-methoxy-N-methylbicyclo[3.1.0]hexane-3-carboxamide

A mixture of 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (150 mg; 0.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (355 mg; 1.85 mmol), N ,N-diisopropylethylamine (359 mg; 2.78 mmol), N,O-dimethylhydroxylamine hydrochloride (180 mg; 1.85 mmol) and 1-hydroxybenzotriazole (125 mg; 0.93 mmol) in dichloromethane (10 ml) was stirred at 25°C for 18 hours The mixture was diluted with water (15 ml) and was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0-30% ethyl acetate in petroleum ether) to give 6,6-difluoro-N-methoxy-N-methyl-bicyclo[3.1.0]hexane-3-carboxamide (100 mg; 53%) as a colorless oil. LCMS: R _T = 0.540 and 0.572 min, m/z = 206.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention times 0.540 and 0.572 min, ESI+: [M+H] = 206.0 detected.

Step 2: (6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone

To a solution of 6,6-difluoro-N-methoxy-N-methyl-bicyclo[3.1.0]hexane-3-carboxamide (33 mg; 0.16 mmol) and (5S,7S)-2-bromo-7-fluoro -5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (30 mg; 0.11 mmol) in tetrahydrofuran (6 ml) was added isopropyl magnesium chloride (2, 0 M solution in tetrahydrofuran; 0.16 ml; 0.32 mmol) under nitrogen at -78°C. The mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride solution (15 ml). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 40%-70%/0.05% ammonium hydroxide in water) to give, as conventionally indicated, (6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-[( 5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (3.9 mg; 11 %) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.39 (m, 3H), 7.26-7.23 (m, 2H), 6.12-5.94 (m, 1H), 5.52-5.48 (m, 1H), 4.19-4.15 (m, 0.5H), 3.88-3.85 (m, 0.5H), 3.68-3.59 (m, 1H), 3.02-2.91 (m, 1H), 2.39-2.30 (m, 4H), 2.08-2.04 ( m, 2H). LCMS: R _T = 0.896 min, m/z = 347.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.896 min, ESI+: [M+H] = 347.9 detected.

Method 63

Cyclopropyl-[(5S,7S)-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: cis-2-bromo-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a solution of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.20 g; 4.28 mmol) in tetrahydrofuran (50 ml) was added sodium hydride (60%; 342 mg; 8.57 mmol). The mixture was stirred for 20 minutes and methane (3.00 g; 21.14 mmol) was added dropwise. At the end of the addition, the mixture was stirred for 2 h and poured into ice water (70 ml). The resulting mixture was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (2×70 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 8 to 12% ethyl acetate in petroleum ether) to give cis-2-bromo-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazole (330 mg; 26%) as a white solid. LCMS: R _T = 0.748 min, m/z = 294.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.748 min, ESI+: [M+H] = 294.0 detected.

Stage 2: cyclopropyl-[(5S,7S)-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of cis-2-bromo-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (220 mg; 0.75 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (193 mg; 1.50 mmol) in tetrahydrofuran (6 ml) was added isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 2.24 ml; 4.49 mmol) under nitrogen atmosphere at 0°C. The mixture was stirred at 25° C. for 2 h and quenched by adding saturated aqueous ammonium chloride (25 ml). The solution was extracted with ethyl acetate (3×15 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 40% ethyl acetate in petroleum ether) to give cyclopropyl(cis-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)methanone (180 mg; 85%) as a brown oil.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl]methanone (peak 1, retention time = 4.247 min) (29.8 mg; 16%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.31 (m, 5H), 5.56-5.52 (m, 1H), 4.94-4.92 (m, 1H), 3.67-3.59 (m, 4H), 3.02- 3.01 (m, 1H), 2.62-2.57 (m, 1H), 1.17-1.15 (m, 2H), 1.10-1.07 (m, 2H). LCMS: R _T = 0.709 min, m/z = 284.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.709 min, ESI+: detected [M+H] = 284.1.

SFC Conditions: Column: Lux Cellulose-2, 150 x 4.6 mm (ID), 3 µm; mobile phase: 40% ethanol (with 0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature: 40°C.

Method 64

Cyclopropyl-[(5S,7S)-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone

Step 1: 1-(4-fluorophenyl)but-3-en-1-ol

To a solution of 4-fluorobenzaldehyde (50.0 g; 402.87 mmol) in tetrahydrofuran (500 ml) was added allylmagnesium chloride (1.82 M solution in tetrahydrofuran; 288.0 ml; 523.73 mmol) at 0° C. under atmospheric nitrogen. The reaction mixture was allowed to warm to 25° C. and stirred for 2 h, then quenched by adding saturated aqueous ammonium chloride (200 ml). The resulting mixture was extracted with ethyl acetate (3×300 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(4-fluorophenyl)but-3-en-1-ol (66.8 g, 99%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.28 (m, 2H), 7.04-7.00 (m, 2H), 5.80-5.73 (m, 1H), 5.17-5.12 (m, 2H), 4.70-4.67 (m, 1H), 2.48-2.46 (m, 2H), 2.44-2.31 (m, 1H).

Step 2: tert-butyl((1-(4-fluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a solution of 1-(4-fluorophenyl)but-3-en-1-ol (66.8 g; 401.95 mmol) in dichloromethane (500 ml) was added imidazole (54.7 g; -butylchlorodimethylsilane (72.7 g; 482.34 mmol). The reaction mixture was stirred at 25°C for 16 h and diluted with water (500 ml). The resulting mixture was extracted with dichloromethane (2×300 ml). The combined organic layers were washed with brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude t-butyl-[1-(4-fluorophenyl)but-3-enoxy]-dimethyl-silane (111.0 g; 98%) as a light oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.37 (m, 2H), 7.14-7.10 (m, 2H), 5.92-5.85 (m, 1H), 5.15-5.11 (m, 2H), 4.81-4.79 (m, 1Н), 2.58-2.45 (m, 2Н), 1.01 (s, 9Н), 0.15 (s, 3Н), 0.00 (s, 3Н).

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(4-fluorophenyl)propanal

Osmium tetroxide was added to a solution of tert-butyl-[1-(4-fluorophenyl)but-3-enoxy]-dimethylsilane (110.0 g; 392.23 mmol) in water (500 ml) and tetrahydrofuran (500 ml) (0.5 g; 1.97 mmol). After stirring for 30 min at 25°C, sodium periodate (335.6 g; 1568.90 mmol) was added in small portions over 2 h and the resulting mixture was stirred for another 2 h at 25°C. The mixture was quenched by adding cold saturated aqueous sodium thiosulfate (500 ml). The mixture was stirred for 30 min and then extracted with ethyl acetate (3×500 ml). The combined organic layers were washed with water (500 ml), brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 2% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(4-fluorophenyl)propanal (70.0 g ; 63%) as a yellow oil. ¹ H NMR (400 Hz, CDCl ₃ ) δ 9.95-9.90 (m, 1H), 7.48-7.44 (m, 2H), 7.19-7.15 (m, 2H), 5.37-5.34 (m, 1H), 3.02-2.95 (m, 1Н), 2.79–2.77 (m, 1Н), 1.01 (s, 9Н), 0.19 (s, 3Н), 0.00 (s, 3Н).

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(4-fluorophenyl)propan-1-ol

To a chilled (-78°C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (70.1 g; 225.32 mmol) in tetrahydrofuran (500 ml) dropwise in n-butyllithium (2.5 M solution in hexanes; 98.2 ml; 245.37 mmol) was added under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min and a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(4-fluorophenyl)propanal (63.0 g; 223.06 mmol) in tetrahydrofuran was added dropwise (50 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1.5 h and extinguished by adding saturated aqueous ammonium chloride solution (500 ml). The resulting mixture was extracted with ethyl acetate (2×500 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-fluorophenyl)propan-1-ol (95.0 g; 83%) as a yellow oil.

Step 5: 2-bromo-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

Mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-fluorophenyl)propane -1-ol (40.0 g; 77.75 mmol) and 2,2,2-trifluoroacetic acid (150 ml; 1554.9 mmol) were stirred at 55°C for 8 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 ml) and the pH was adjusted to 9 by adding saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (150 ml), brine (150 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 20 to 33% ethyl acetate in petroleum ether) to give 2-bromo-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-7-ol (23.5 g; 100%) as a yellow solid. LCMS: R _T = 0.679 min, m/z = 300.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.679 min, ESI+: [M+H] = 300.0 detected.

Step 6: cis-2-bromo-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a cooled (0°C) solution of 2-bromo-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (6 0 g; 20.13 mmol) in dichloromethane (50 ml) was added diethylaminosulfur trifluoride (10.7 ml; 80.51 mmol) in dichloromethane (8 ml). After stirring for 30 minutes, the mixture was poured into ice water (100 ml). The resulting mixture was extracted with dichloromethane (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give cis-bromo-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazole (2.1 g; 35%) as a light yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.26-7.23 (m, 2H), 7.12-7.08 (m, 2H), 6.07-5.91 (m, 1H), 5.45-5.42 (m, 1H), 3.64-3.52 (m, 1H), 2.92-2.85 (m, 1H).

Stage 7: cyclopropyl-[(5S,7S)-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone

To a solution of N-methoxy-N-methyl-cyclopropanecarboxamide (378 mg; 2.94 mmol) and cis-2-bromo-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole (400 mg; 1.34 mmol) in tetrahydrofuran (15 ml) was added isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 2.66 ml; 5.34 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 0° C. for 8 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether, R _f = 0.25) to give cyclopropyl-[cis-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazol-2-yl]methanone (180 mg; 47%) as a pale yellow solid. LCMS: R _T = 0.733 min, m/z = 290.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.733 min, ESI+: [M+H] = 290.1 detected.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 3.981 min) (71 mg; 39%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.36-7.32 (m, 2H), 7.19-7.14 (m, 2H), 6.20-6.04 (m, 1H), 5.65-5.65 (m, 1H), 3.83- 3.69 (m, 1H), 3.10-2.97 (m, 1H), 2.89-2.77 (m, 1H), 1.20-1.09 (m, 4H). LCMS: R _T = 0.833 min, m/z = 289.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.833 min, ESI+: detected [M+H] = 289.9.

The (5R,7R) isomer (peak 1, retention time = 3.439 min) (65 mg; 36%) was also collected as a white solid.

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B in 5.5 minutes and hold at 40% for 3 minutes, then at 5% B for 1.5 minutes; flow rate: 2.5 ml/min, column temperature: 40°C.

Method 65

2-(rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl)cyclopropanecarbonitrile

Step 1: 2-bromo-1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl)ethanone

To a mixture of 1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ethanone (250 mg; 1.02 mmol) in acetic acid (3 ml) pyridinium perbromide bromide (370 mg; 1.16 mmol) was added. The mixture was stirred at 25°C for 3 h and diluted with ethyl acetate (40 ml). The solution was washed with water (2×20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give 2-bromo-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone (185 mg; 56%) as a yellow oil. LCMS: R _T = 0.771 min, m/z = 326.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.771 min, ESI+: [M+H] = 326.0 detected.

Step 2: 2-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl )cyclopropanecarbonitrile

To a mixture of 2-bromo-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]ethanone (120 mg; 0.37 mmol) in tetrahydrofuran (2 ml) and dimethyl sulfoxide (0.5 ml) was added 1,4-diazabicyclo[2.2.2.]octane (53 mg; 0.48 mmol) . After stirring for 30 minutes at 20° C., sodium carbonate (76 mg; 0.72 mmol) and acrylonitrile (6.2 ml; 94.23 mmol) were added to the mixture. The resulting mixture was stirred at 90°C for 20 h and diluted with ethyl acetate (40 ml). The solution was washed with water (2×20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (water (with 0.05% ammonium hydroxide, v/v)/acetonitrile, 30-60%) to give 2-[rac-(5S,7S)-7 -fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropane-carbonitrile (3 mg; 3%) as a white solid substances. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.42 (m, 3H), 7.31-7.27 (m, 2H), 6.15-5.99 (m, 1H), 5.56-5.53 (m, 1H), 3.72-3.67 (m, 2Н), 3.07-3.03 (m, 1Н), 2.21-2.08 (m, 1Н), 1.75-1.70 (m, 1Н), 1.68-1.57 (m, 1Н). LCMS: R _T = 0.818 min, m/z = 296.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.771 min, ESI+: detected [M+H] = 296.9.

Method 66

Cyclopropyl-[(5S,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: (cis)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (trans)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a mixture of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1000 mg; 3.57 mmol) and triethylamine ( 1083 mg; 10.71 mmol) in dichloromethane (50 ml) was added tert-butyldimethylsilyl trifluoromethanesulfonate (1415 mg; 5.35 mmol). The mixture was stirred for 14 h at 25°C and diluted with water (50 ml). The resulting solution was extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give:

(trans)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (870 mg ; 62%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.36 (m, 5H), 5.31-5.28 (m, 1H), 5.26-5.23 (m, 1H), 3.47-3.40 (m, 1H), 2.58-2.52 (m, 1H), 0.99 (s, 9H), 0.23 (s, 3H), 0.20 (s, 3H);

(cis)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (430 mg ; 31%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.35 (m, 3H), 7.11-7.10 (m, 2H), 5.61-5.58 (m, 1H), 5.33-5.30 (m, 1H), 3.00-2.96 (m, 1Н), 2.90-2.83 (m, 1Н), 0.93 (s, 9Н), 0.23 (s, 3Н), 0.19 (s, 3Н).

Step 2: [cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]-cyclopropyl-methanone

To a solution of N-methoxy-n-methyl-cyclopropanecarboxamide (242 mg; 1.88 mmol) and (cis)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole (370 mg; 0.94 mmol) in tetrahydrofuran (2 ml) was added isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 1.41 ml; 2.81 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (50 ml). The resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 40% ethyl acetate in petroleum ether) to give [cis-7-[t-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methanone (220 mg; 61%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.34 (m, 5H), 5.39-5.36 (m, 1H), 5.29-5.28 (m, 1H), 3.54-3.48 (m, 1H), 3.08-3.05 (m, 1H). 2.65-2.61 (m, 1H), 1.30-1.28 (m, 2H), 1.07-1.02 (m, 2H), 0.91 (s, 9H), 0.24 (s, 3H), 0.22 (s, 3H).

Stage 3: cyclopropyl-[(5S,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of [cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]-cyclopropyl-methanone (200 mg; 0.52 mmol) in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 2.09 ml; 2.09 mmol) at 25°C. The mixture was stirred at 25°C for 14 h and diluted with dichloromethane (30 ml). The resulting mixture was washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 90% ethyl acetate in petroleum ether) to give cyclopropyl-[cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazol-2-yl]methanone (95 mg; 67%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.36 (m, 5H), 5.46-5.40 (m, 2H), 4.79-4.78 (d, 1H), 3.64-3.58 (m, 1H), 3.00-2.98 (m, 1Н), 2.81-2.76 (m, 1Н), 1.31-1.27 (m, 2Н), 1.07-1.03 (m, 2Н).

This cis mixture was further separated with chiral SFC to give, as conventionally indicated:

cyclopropyl-[(5S,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1 , retention time = 3.345 min) (22.2 mg; 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.36 (m, 5H), 5.44-5.41 (m, 2H), 4.81 (s, 1H), 3.65-3.60 (m, 1H), 2.99-2.96 (m , 1Н), 2.82-2.76 (m, 1Н), 1.30-1.29 (m, 2Н), 1.06-1.03 (m, 2Н). LCMS: R _T = 2.061 min, m/z = 270.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 7.0 min): retention time 2.061 min, ESI+: detected [M+H] = 270.2;

cyclopropyl-[(5R,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2 , retention time = 3.975 min) (32.2 mg; 35%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.34 (m, 5H), 5.44-5.39 (m, 2H), 3.65-3.57 (m, 1H), 3.07-3.00 (m, 1H), 2.79-2.74 (m, 1H), 1.31-1.28 (m, 2H), 1.07-1.04 (m, 2H). LCMS: R _T = 0.896 min, m/z = 270.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.896 min, ESI+: [M+H] = 270.2 detected.

SFC conditions: column: OD (250 mm×30 mm, 5 µm) mobile phase: A: CO ₂ , B: 0.1% NH ₃ H ₂ O in EtOH, gradient: 40% B; flow rate: 60 ml/min; column temperature: 40°C.

Method 67

Cyclopropyl-[(5S,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: [trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]-cyclopropyl-methanone

To a solution of N-methoxy-N-methyl-cyclopropanecarboxamide (47 mg; 0.36 mmol) and [trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (100 mg; 0.25 mmol) in tetrahydrofuran (10 ml) was added isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 0.3 ml; 0.60 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (50 ml). The resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether, R _f = 0.5) to give [trans-7-[t-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methanone (50 mg; 51%) as a colorless oil. LCMS: R _T = 1.008 min, m/z = 384.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.008 min, ESI+: [M+H] = 384.2 detected.

Stage 2: cyclopropyl-[(5S,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of [trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]-cyclopropyl-methanone (50 mg; 0.13 mmol) in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 0.52 ml; 0.52 mmol). The mixture was stirred at 25°C for 14 h and diluted with dichloromethane (20 ml). The solution was washed with water (10 ml), brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (2.5% methanol in dichloromethane, R _f = 0.5) to give cyclopropyl-[(trans)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl]methanone (20 mg; 57%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.38 (m, 3H), 7.19-7.17 (m, 2H), 5.76-5.73 (m, 1H), 5.54-5.52 (m, 1H), 3.29-3.25 (m, 1Н), 3.03-3.00 (m, 2Н), 1.31-1.28 (m, 2Н), 1.06-1.03 (m, 2Н).

This trans mixture (70 mg from another batch) was further separated with chiral SFC to give, as tentatively indicated:

cyclopropyl-[(5S,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1 , retention time = 3.515 min) (10.5 mg; 15%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.38 (m, 3H), 7.20-7.18 (m, 2H), 5.76-5.73 (m, 1H), 5.70-5.62 (m, 1H), 5.52-5.49 (m, 1Н), 3.29-3.25 (m, 1Н), 3.01-2.96 (m, 2Н), 1.32-1.26 (m, 2Н), 1.06-1.04 (m, 2Н). LCMS: R _T = 0.906 min, m/z = 270.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.906 min, ESI+: detected [M+H] = 270.2;

cyclopropyl-[(5R,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2 , retention time = 3.729 min) (17.0 mg; 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.38 (m, 3H), 7.20-7.18 (m, 2H), 5.76-5.73 (m, 1H), 5.65 (brs, 1H), 5.51-5.50 (m , 1Н), 3.28-3.25 (m, 1Н), 3.01-2.96 (m, 2Н), 1.32-1.26 (m, 2Н), 1.06-1.04 (m, 2Н). LCMS: R _T = 0.905 min, m/z = 270.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.905 min, ESI+: [M+H] = 270.2 detected.

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: IPA (isopropyl alcohol) (with 0.05% DEA); gradient: 5% to 40% B in 5.5 minutes and hold at 40% for 3 minutes, then at 5% B for 1.5 minutes; flow rate: 25 ml/min; column temperature: 40°C.

Method 68

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S )-2-methylcyclopropyl]methanone and [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]-[(1R,2R)-2-methylcyclopropyl] methanone

Racemic [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-( 1S,2S)-2-methylcyclopropyl]methanone (trans-mixture LHS (left hand rotation)) (80 mg) was further separated with chiral SFC to give, as conventionally indicated:

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S )-2-methylcyclopropyl]methanone (peak 1, retention time = 3.714 min) (28 mg; 35%; ee: 96.1%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.38 (m, 3H), 7.29-7.26 (m, 2H), 6.19-6.17 (m, 0.5H), 6.05-6.03 (m, 0.5H ), 5.67-5.62 (m, 1Н), 3.81-3.71 (m, 1Н), 2.89-2.75 (m, 2Н), 1.62-1.54 (m, 1Н), 1.45-1.39 (m, 1Н), 1.18 (d , J=6.4 Hz, 3H), 0.99-0.96 (m, 1H). LC-MS: R _T = 0.756 min, m/z = 286.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.756 min, ESI+: detected [M+H] = 286.1;

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2R )-2-methylcyclopropyl]methanone (peak 2, retention time = 3.901 min) (48 mg; 60%; ee: 86%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.40 (m, 3H), 7.29-7.27 (m, 2H), 6.20-6.16 (m, 0.5H), 6.06-6.02 (m, 0.5H ), 5.67-5.61 (m, 1Н), 3.79-3.73 (m, 1Н), 2.89-2.74 (m, 2Н), 1.64-1.60 (m, 1Н), 1.44-1.39 (m, 1Н), 1.17 ( d, J=6.0 Hz, 3H), 1.00-0.95 (m, 1H). LC-MS: R _T = 0.757 min, m/z = 286.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.757 min, ESI+: [M+H] = 286.1 detected.

SFC conditions: column: AD (250 mm × 30 mm, 5 µm); mobile phase: A: CO ₂ , B: 0.1% NH ₃ H ₂ O in EtOH; gradient: 25% to 25% B; flow rate: 50 ml/min; column temperature: 40°C.

Method 69

[(1R,2S)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone and [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (trans-mixture) (245 mg; 1.65 mmol) and (5S,7S)-2-bromo-7-fluoro-5-(2 -fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (250 mg; 0.85 mmol) in tetrahydrofuran (10 ml) was added isopropyl magnesium chloride (2.1 ml; 4.15 mmol; 2 M in tetrahydrofuran solution) at 0° C. under nitrogen. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding water (10 ml) and was extracted with ethyl acetate (3×20 ml). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (33% ethyl acetate in petroleum ether, R _f = 0.6) to give [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2 -fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (trans-mix) (105 mg; 41%) as a white solid substances. LCMS: R _T = 0.739 min, m/z = 308.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.739 min, ESI+: [M+H] = 308.1 detected.

The above trans mixture was further separated with chiral SFC to give, conventionally, [(1R,2S)-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.773 min) (48.1 mg; 45%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.42 (m, 1H), 7.25-7.13 (m, 3H), 6.22-6.06 (m, 1H), 5.93-5.89 (m, 1H), 5.01- 4.87 (m, 0.5H), 4.85-4.82 (m, 0.5H), 3.88-3.75 (m, 1H), 3.51-3.42 (m, 1H), 2.93-2.81 (m, 1H), 1.75-1.64 (m, 1H), 1.62-1.54 (m, 1H). LC-MS: R _T = 0.852 min, m/z = 308.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.852 min, ESI+: [M+H] = 308.0 detected.

SFC Conditions: Column: Chiralcel OD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min; column temperature: 35°C.

A larger batch of the trans mixture (215 mg; 0.70 mmol) was separated with chiral SFC to give [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl) -6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.445 min) (19.5 mg; 9%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.38 (m, 1H), 7.18-7.15 (m, 2H), 6.98-6.97 (m, 1H), 6.13-6.11 (m, 0.5H), 5.99 -5.98 (m, 0.5H), 5.87-5.85 (m, 1H), 5.05-5.04 (m, 0.5H), 4.89-4.88 (m, 0.5H), 3.73-3.67 (m, 1H), 3.58-3.54 (m, 1H), 3.01-2.95 (m, 1H), 1.72-1.65 (m, 2H). LC-MS: R _T = 1.763 min, m/z = 308.1 (M+H) ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.763 min, ESI+: detected [M+H] = 308.1. Note: The (1R,2S)-isomer corresponded to peak 2 (retention time = 2.728 min) under SFC conditions on an AD column.

SFC conditions: column: Daicel Chiralpak AD-H (250 mm x 30 mm, 5 µm); mobile phase: A: CO ₂ , B: ethanol (0.1% NH ₃ H ₂ O in methanol); gradient: 15% to 15% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 70

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S )-2-methylcyclopropyl]methanone and [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]-[(1R,2R)-2-methylcyclopropyl] methanone

Racemic [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-( 15,25)-2-Methylcyclopropyl]methanone (trans-mix LHS) (80 mg) was further separated with chiral SFC to give, as conventionally indicated:

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S )-2-methylcyclopropyl]methanone (peak 1, retention time = 3.714 min) (28 mg; 35%; ee: 96.1%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.38 (m, 3H), 7.29-7.26 (m, 2H), 6.19-6.17 (m, 0.5H), 6.05-6.03 (m, 0.5H ), 5.67-5.62 (m, 1Н), 3.81-3.71 (m, 1Н), 2.89-2.75 (m, 2Н), 1.62-1.54 (m, 1Н), 1.45-1.39 (m, 1Н), 1.18 ( d, J=6.4 Hz, 3H), 0.99-0.96 (m, 1H). LC-MS: R _T = 0.756 min, m/z = 286.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.756 min, ESI+: detected [M+H] = 286.1;

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2R )-2-methylcyclopropyl]methanone (peak 2, retention time = 3.901 min) (48 mg; 60%; ee: 86%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.40 (m, 3H), 7.29-7.27 (m, 2H), 6.20-6.16 (m, 0.5H), 6.06-6.02 (m, 0.5H ), 5.67-5.61 (m, 1Н), 3.79-3.73 (m, 1Н), 2.89-2.74 (m, 2Н), 1.64-1.60 (m, 1Н), 1.44-1.39 (m, 1Н), 1.17 ( d, J=6.0 Hz, 3H), 1.00-0.95 (m, 1H). LC-MS: R _T = 0.757 min, m/z = 286.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.757 min, ESI+: [M+H] = 286.1 detected.

SFC conditions: column: AD (250 mm × 30 mm, 5 µm); mobile phase: A: CO ₂ , B: 0.1% NH ₃ H ₂ O in EtOH; gradient: 25% to 25% B; flow rate: 50 ml/min; column temperature: 40°C.

Method 71

Cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: ethyl-3-ethyl-4,5-dihydroisoxazole-5-carboxylate

To a solution of ethyl acrylate (89.6 ml; 841.85 mmol), di-tert-butyl dicarbonate (58.0 ml; 252.55 mmol) and 4-dimethylaminopyridine (2.1 g; 16.84 mmol) in acetonitrile (50 ml) was added a solution of 1-nitropropane (15.1 ml; 168.37 mmol) at 25°C. The mixture was stirred at 25° C. for 5 h and quenched by adding saturated ammonium chloride solution (80 ml). The mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give ethyl 3-ethyl-4,5-dihydroisoxazole-5-carboxylate (25.5 g; 88%) in the form of a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.94-4.86 (m, 1H), 4.24-4.13 (m, 2H), 3.21-3.14 (m, 2H), 2.40-2.29 (m, 2H), 1.30-1.24 (m, 3H), 1.16-1.11 (m, 3H).

Stage 2: 5-ethyl-3-hydroxy-pyrrolidin-2-one

A mixture of ethyl 3-ethyl-4,5-dihydroisoxazole-5-carboxylate (15.0 g; 87.62 mmol) and palladium (10% on charcoal; 6.7 g) in ethanol (300 ml) was stirred in hydrogen atmosphere (50 psi (344.7 kPa)) at 40°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude 5-ethyl-3-hydroxy-pyrrolidin-2-one (11.0 g; 97%) as a colorless oil.

Stage 3: 3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidin-2-one

To a solution of 5-ethyl-3-hydroxy-pyrrolidin-2-one (11.0 g; 85.17 mmol) in dichloromethane (200 ml) was added imidazole (11.6 g; 170.33 mmol) and tert-butyldimethylchlorosilane ( 19.2 g, 127.75 mmol). The reaction mixture was stirred at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidin-2-one (10.0 g; 48%) as a colorless oil.

Stage 4: 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidin-2-one

Sodium hydride (60 %; 2.5 g; 61.62 mmol). After stirring at 0°C for 20 min, 0-(diphenylphosphoryl)hydroxylamine (14.4 g; 61.62 mmol) was added to the mixture and stirred at 25°C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidin-2-one (10.0 g; 94%) as a yellow oil. LCMS: R _T = 1.130 min, m/z = 259.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.130 min, ESI+: [M+H] = 259.2 detected.

Stage 5: ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate

A mixture of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidin-2-one (10.0 g; 38.7 mmol) and ethyl 2-ethoxy-2-imino-acetate (14.0 g; 96.74 mmol) in ethanol (250 ml) was stirred at 90°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate ( 13.0 g; 94%) as a yellow oil. LCMS: R _T = 1.148 min, m/z = 358.3 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.148 min, ESI+: [M+H] = 358.3 detected.

Stage 6: ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Ethyl 2-[[3-[t-butyl(dimethyl)silyl]oxy-5-ethyl-2-oxo-pyrrolidin-1-yl]amino]-2-iminoacetate mixture (13.0 g; 36. 36 mmol) and p-toluenesulfonic acid (7.5 g; 43.63 mmol) in toluene (250 ml) was stirred at 120° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxylate (12.0 g; 97%) as a yellow oil. LCMS: R _T = 0.823 min, m/z = 340.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.823 min, ESI+: [M+H] = 340.2 detected.

Stage 7: ethyl-trans-5-ethyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 12.0 g; 35.35 mmol) in tetrahydrofuran (200 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 35.35 ml; 35.35 mmol). The reaction mixture was stirred at 40°C for 16 h and concentrated under reduced pressure. The residue was diluted with water (70 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 100% ethyl acetate in petroleum ether) to give ethyl trans-5-ethyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (2.3 g; 29%) as a pale red oil (together with the cis isomer (2.8 g; 35%)). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.32-5.27 (m, 1H), 4.49-4.43 (m, 3H), 3.24-3.17 (m, 1H), 2.41-2.36 (m, 1H), 2.21-2.12 (m, 1H), 1.94-1.84 (m, 1H), 1.36 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H).

Step 8: Ethyl cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl trans-5-ethyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.3 g; 10, 21 mmol) in dichloromethane (50 ml) diethylaminosulfur trifluoride (6.6 g; 40.85 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 h and extinguished by adding saturated sodium bicarbonate solution (20 ml). The mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give ethyl-fluoro-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazole-2-carboxylate (800 mg; 34%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.00-5.78 (m, 1H), 4.53-4.37 (m, 3H), 3.35-3.16 (m, 1H), 2.69-2.54 (m, 1H), 2.13-2.05 (m, 1H), 1.98-1.91 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.02 (t, J=7.6 Hz, 3H).

Step 9: cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

To a mixture of ethyl cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (200 mg; 0.88 mmol ) in tetrahydrofuran (3 ml), water (2 ml) and methanol (1 ml) was added lithium hydroxide monohydrate (148 mg; 3.52 mmol). The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was diluted with ice water (20 ml) and the pH was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were concentrated under reduced pressure to give crude cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ( 150 mg; 86%) as a yellow oil.

Step 10: cis-5-ethyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide, cis mixture

A mixture of cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (100 mg; 0.50 mmol), 1-hydroxybenzotriazole (34 mg; 0.25 mmol), N,N-diisopropylethylamine (0.21 ml; 1.26 mmol), N,O-dimethylhydroxylamine hydrochloride (74 mg; 0.75 mmol) and 1-(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg; 0.60 mmol) in dichloromethane (5 ml) was stirred at 25°C for 16 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 60% ethyl acetate in petroleum ether) to give cis-5-ethyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (120 mg; 99%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.99-5.79 (m, 1H), 4.40-4.39 (m, 1H), 3.84 (s, 3H), 3.43 (s, 3H), 3.36-3.16 (m, 1H ), 2.67-2.54 (m, 1H), 2.14-2.03 (m, 1H), 1.97-1.90 (m, 1H), 1.07-1.03 (m, 3H) LCMS: R _T = 0.481 min, m/z = 243 ,1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.481 min, ESI+: [M+H] = 243.1 detected.

Step 11: cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of cis-5-ethyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg; 0.41 mmol) cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 2.0 ml; 1.0 mmol) was added under nitrogen at 0°C. Upon completion of the addition, the mixture was stirred at 0° C. for 1 h and quenched by adding saturated aqueous ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give cyclopropyl-[cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone (80 mg; 87%) as a yellow oil. This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl]methanone (peak 1, retention time = 3.928 min) (22.5 mg; 28%) as an orange solid (also collected (5S,7R) isomer as peak 2 (retention time = 4.391 min, 18.8 mg; 22%)). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.09-5.89 (m, 1H), 4.55-4.45 (m, 1H), 3.43-3.36 (m, 1H), 3.15-3.06 (m, 1H), 2.67- 2.53 (m, 1H), 2.09-1.93 (m, 2H), 1.23-1.18 (m, 2H), 1.17-1.11 (m, 2H), 1.05 (t, J=7.2 Hz, 3H). LCMS: R _T = 0.770 min, m/z = 224.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.770 min, ESI+: [M+H] = 224.0 detected.

SFC Conditions: Column: Chiralcel IC, 100 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: methanol (with 0.05% DEA); gradient: 5% to 40% B in 3.5 minutes and holding at 40% for 2.5 minutes, then at 5% B for 1.5 minutes; flow rate: 3 ml/min; column temperature: 40°C.

Method 72

Cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: ethyl 3-propyl-4,5-dihydroisoxazole-5-carboxylate

To a solution of ethyl acrylate (10.32 ml; 96.97 mmol), di-tert-butyl dicarbonate (6.68 ml; 29.09 mmol) and 4-dimethylaminopyridine (0.24 g; 1.94 mmol) in acetonitrile (20 ml) was added a solution of 1-nitrobutane (2.01 ml; 19.39 mmol) at 25°C. Upon completion of the addition, the mixture was stirred at 25° C. for 5 h and quenched by adding saturated ammonium chloride solution (80 ml). The mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (silica gel, 100-200 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give ethyl 3-propyl-4,5-dihydroisoxazole-5-carboxylate (3.2 g; 89% ) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.98-4.93 (m, 1H), 4.27-4.20 (m, 2H), 3.21-3.18 (m, 2H), 2.37-2.33 (m, 2H), 1.64-1.58 (m, 2Н), 1.33-1.28 (m, 3Н), 0.98-0.94 (m, 3Н).

Stage 2: hydroxy-5-propyl-pyrrolidin-2-one

A mixture of ethyl 3-propyl-4,5-dihydroisoxazole-5-carboxylate (8.0 g; 43.19 mmol) and palladium (10% on charcoal; 3.3 g) in ethanol (200 ml) was stirred in hydrogen atmosphere (50 psi (344.7 kPa)) at 40°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-propyl-pyrrolidin-2-one (6.1 g, 99%) as a light yellow oil. LCMS: R _T = 0.263 min, m/z = 144.3 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.263 min, ESI+: found [M+H] = 144.3.

Stage 3: 3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidin-2-one

To a solution of 3-hydroxy-5-propyl-pyrrolidin-2-one (6.1 g; 42.60 mmol) in dichloromethane (200 ml) was added imidazole (5.8 g; 85.21 mmol) and tert-butyldimethylchlorosilane ( 9.6 g, 63.91 mmol). The reaction mixture was stirred at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidine-2 -one (7.5 g; 68%) as a yellow oil. LCMS: R _T = 1.474 min, m/z = 258.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.474 min, ESI+: [M+H] = 258.2 detected.

Stage 4: 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidin-2-one

Sodium hydride (60 %, 1.6 g, 40.79 mmol, 60%). After stirring at 0° C. for 20 min, O-(diphenylphosphoryl)hydroxylamine (9.5 g; 40.79 mmol) was added to the mixture and stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidin-2-one (6.8 g, 92%) as a yellow oil. This crude oil was used in the next step without further purification. LCMS: R _T = 0.766 min, m/z = 273.3 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.766 min, ESI+: [M+H] = 273.3 detected.

Stage 5: ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-propyl-pyrrolidin-1-yl]amino]-2-imino-acetate

Mixture of 1-amino-3-[t-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidin-2-one (6.6 g; 24.22 mmol) and ethyl 2-ethoxy-2-imino-acetate (8.8 g; 60.56 mmol) in ethanol (100 ml) was stirred at 90°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-propyl-pyrrolidin-1-yl]amino]-2-imino-acetate ( 9.0 g; 100%) as a yellow oil. LCMS: R _T = 1.192 min, m/z = 372.3 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.192 min, ESI+: [M+H] = 372.3 detected.

Stage 6: ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-propyl-pyrrolidin-1-yl]amino]-2-imino acetate mixture (9.0 g; 24. 22 mmol) and p-toluenesulfonic acid (6.3 g; 36.33 mmol) in toluene (150 ml) was stirred at 120° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxylate (8.3 g; 97%) as a yellow oil. LCMS: R _T = 0.803 min, m/z = 240.2 [M-TBS (tert-butyldimethylsilyl)] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.803 min, ESI+: detected [M-TBS] = 240.2.

Stage 7: ethyl trans-7-hydroxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 8.30 g; 23.48 mmol) in tetrahydrofuran (150 ml) was added tetrabutylammonium fluoride in tetrahydrofuran (11.74 ml; 11.74 mmol). The reaction mixture was stirred at 40°C for 15 h and concentrated under reduced pressure. The residue was diluted with water (70 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100-200 mesh; 0 to 60% ethyl acetate in petroleum ether) to give ethyl trans-7-hydroxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole-2-carboxylate (1.0 g; 18%) as yellow oil (together with the same amount of cis product): ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.33-5.31 (m, 1H), 4.64-4.63 (m, 1H), 4.46-4.40 (m, 2H), 2.87-2.85 (m, 1H), 2.70-2.66 (m, 1H), 2.66-2.06 (m , 1H), 1.63–1.33 (m, 6H), 0.96–0.92 (m, 3H).

Step 8: Ethyl cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl trans-7-hydroxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (800 mg; 3.34 mmol ) in dichloromethane (30 ml) was added diethylaminosulfur trifluoride (2.2 g; 13.37 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h and extinguished by adding saturated sodium bicarbonate solution (20 ml). The mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 60% ethyl acetate in petroleum ether) to give ethyl cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (270 mg; 34%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.99-5.78 (m, 1H), 4.53-4.40 (m, 3H), 3.34-3.15 (m, 1H), 2.70-2.54 (m, 1H), 2.14-2.02 (m, 1H), 1.91-1.78 (m, 1H), 1.63-1.50 (m, 1H), 1.46-1.41 (m, 4H), 0.98 (t, J=7.2 Hz, 3H).

Step 9: cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Ethyl cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate mixture (260 mg; 1.08 mmol) and lithium hydroxide monohydrate (135 mg; 3.23 mmol) in tetrahydrofuran (2 ml), water (1 ml) and methyl alcohol (0.5 ml) were stirred at 25°C for 4 h and then concentrated under reduced pressure. The residue was diluted with ice water (20 ml) and the pH was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were concentrated under reduced pressure to give crude cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ( 225 mg; 98%) as a yellow solid.

Stage 10: cyclopropyl-[cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture of cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (200 mg; 0.94 mmol), 1-hydroxybenzotriazole (63 mg; 0.47 mmol), N,O-dimethylhydroxylamine hydrochloride (137 mg; 1.41 mmol), N,N-diisopropylethylamine (0.39 ml; 2.35 mmol) and 1-(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg; 1.13 mmol) was stirred at 25° C. for 3 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 60% ethyl acetate in petroleum ether) to give cis-7-fluoro-N-methoxy-N-methyl-5-propyl-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (180 mg; 75%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.00-5.76 (m, 1H), 4.51-4.37 (m, 1H), 3.84 (s, 3H), 3.43 (s, 2H), 3.33-3.17 (m, 1H ), 2.70-2.53 (m, 1H), 2.11-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.66-1.53 (m, 1H), 1.51-1.38 (m, 1H), 0.98 (t , J=7.2 Hz, 3H).

Stage 11: cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of cis-7-fluoro-N-methoxy-N-methyl-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (170 mg; 0.66 mmol) cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 3.21 ml; 1.61 mmol) was added under nitrogen at 0°C. Upon completion of the addition, the mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give cyclopropyl-[cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone (100 mg; 64%) as a colorless oil. This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl]methanone (peak 1, retention time = 3.997 min) (40.0 mg; 40%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 6.07-5.91 (m, 1H), 4.59-4.53 (m, 1H), 3.42-3.33 (m, 1H), 3.11-3.07 (m, 1H), 2.67- 2.52 (m, 1H), 2.02-1.98 (m, 1H), 1.91-1.80 (m, 1H), 1.69-1.57 (m, 1H), 1.52-1.38 (m, 1H), 1.23-1.11 (m, 4H ), 1.01 (t, J=7.2 Hz, 3H). LCMS: R _T = 0.972 min, m/z = 238.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 0.972 min, ESI+: [M+H] = 238.2 detected.

SFC Conditions: Column: Chiralcel IC, 100 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: methanol (with 0.05% DEA); gradient: 5% to 40% B over 3.5 min and hold at 40% for 2.5 min, then at 5% B for 1.5 min; flow rate: 3 ml/min; column temperature: 40°C.

Note: The (5S,7R) isomer was also collected as a colorless oil (peak 2, retention time = 4.420 min) (42.0 mg; 42%).

Method 73

Cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt] methanone

Step 1: 1-(2,6-difluorophenyl)but-3-en-1-ol

To a solution of 2,6-difluorobenzaldehyde (90.0 g; 633.36 mmol) in tetrahydrofuran (2000 ml) was added allyl magnesium bromide (1.0 M solution in tetrahydrofuran; 760.0 ml; 760.0 mmol) dropwise at 0 °C in a nitrogen atmosphere. The mixture was allowed to warm to 25°C and stirred for 2 h, then quenched by adding saturated aqueous ammonium chloride (2000 ml). The resulting mixture was extracted with ethyl acetate (2×2000 ml). The combined organic layers were washed with brine (1000 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,6-difluorophenyl)but-3-en-1-ol (116 g; 99%) as a colorless oils.

Stage 2: tert-butyl ((1-(2,6-difluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a solution of 1-(2,6-difluorophenyl)but-3-en-1-ol (116.0 g; 629.82 mmol) in dichloromethane (2000 ml) was added imidazole (85.8 g; 1259.60 mmol) and t-butyldimethylchlorosilane (113.9 g; 755.78 mmol). The reaction mixture was stirred at 25°C for 4 h and filtered. The filtrate was washed with water (2×2000 ml), saturated aqueous sodium bicarbonate (2×2000 ml), brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude tert-butyl-[1-(2, 6-difluorophenyl)but-3-enoxy]-dimethylsilane (180.0 g; 96%) as a light yellow oil.

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,6-difluorophenyl)propanal

To a solution of tert-butyl-[1-(2,6-difluorophenyl)but-3-enoxy]-dimethylsilane (180.0 g; 603.14 mmol) in water (1000 ml) and tetrahydrofuran (1000 ml) was added osmium tetroxide (0.88 g; 3.45 mmol). After stirring for 30 min at 15°C, sodium periodate (516.0 g; 2412.6 mmol) was added in small portions over 2 h. The resulting mixture was stirred for another 2 h at 25°C and quenched by adding cold saturated aqueous solution of sodium thiosulfate (300 ml). The mixture was stirred for 30 min and was extracted with ethyl acetate (3×2000 ml). The combined organic layers were washed with water (2000 ml), brine (2000 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl ) propanal (180.0 g; 99%) as a yellow oil.

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(2,6-difluorophenyl)propan-1-ol

N -butyllithium (2.5 M solution in hexanes; 268.8 ml; 672.09 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl)propanal (177.0 g; 589.17 mmol) was added dropwise ) in tetrahydrofuran (100 ml). Upon completion of the addition, the mixture was stirred at -78° C. for 1.5 h and quenched by adding saturated aqueous ammonium chloride solution (500 ml). The resulting mixture was extracted with ethyl acetate (3×2000 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl)propan-1-ol (160 g; 49%) as a yellow oil.

Step 5: 2-bromo-5-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

1-(5-Bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl) mixture )propan-1-ol (80.0 g; 150.24 mmol), trifluoroacetic acid (400 ml; 6009.5 mmol) and trifluoromethanesulfonic acid (40 ml; 600.95 mmol) were stirred at 50°C for 12 h and concentrated under reduced pressure. The pH of the residue was adjusted to 9 by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×700 ml). The combined organic layers were washed with water (2×300 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether (80 ml) to give crude 2-bromo-5-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-7-ol (40 g; 84%) as a white solid. LCMS: R _T = 0.694 and 0.711 min, m/z = 317.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention times 0.694 and 0.711 min, ESI+: found [M+H] = 317.9.

Step 6: (5S,7S)-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole

To a cooled (0°C) solution of 2-bromo-5-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.5 g; 4.75 mmol) in dichloromethane (30 ml) was added diethylaminosulfur trifluoride (2.5 ml; 18.98 mmol). The mixture was stirred at 0°C for 1 h and extinguished by adding saturated aqueous sodium bicarbonate (100 ml) at 0°C. The mixture was extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give cis-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole (0.25 g; 16%) as a light yellow solid. LCMS: R _T = 0.808 min, m/z = 319.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.808 min, ESI+: [M+H] = 319.9 detected.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated, (5S,7S)-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole (peak 2, retention time = 3.293 min) (115 mg; 46%) as a light yellow solid.

SFC conditions: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B in 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 2.5 ml/min; column temperature: 40°C.

Stage 7: cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone

To a solution of (5S,7S)-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (115 mg; 0.36 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (93 mg; 0.72 mmol) in tetrahydrofuran (6 ml) was added isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 0.36 ml ; 0.72 mmol) at 0°C under nitrogen. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 37-67%/0.05% ammonium hydroxide in water) to give cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (32.6 mg; 29%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.54-7.48 (m, 1H), 7.10-7.06 (m, 2H), 6.24-6.21 (m, 0.5H), 6.10-6.07 (m, 0.5H ), 5.98-5.94 (m, 1H), 3.89-3.81 (m, 1H), 3.03-2.91 (m, 2H), 1.18-1.16 (m, 2H), 1.11-1.08 (m, 2H). LCMS: R _T = 0.740 min, m/z = 308.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.740 min, ESI+: [M+H] = 308.1 detected.

Method 74

1-[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarbonitrile

Stage 1: 1-cyano-N-methoxy-N-methyl-cyclopropanecarboxamide

Mixture of 1-cyanocyclopropanecarboxylic acid (500 mg; 4.5 mmol), 1-hydroxybenzotriazole (365 mg; 2.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g; 5.4 mmol ), N,O-dimethylhydroxylamine hydrochloride (878 mg; 9.0 mmol) and N,N-diisopropylethylamine (0.8 ml; 4.5 mmol) in dichloromethane (40 ml) was stirred at 25°C for 16 h and extinguished by adding water (100 ml). The resulting mixture was extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 50% to 60% ethyl acetate in petroleum ether) to give 1-cyano-N-methoxy-N-methyl-cyclopropanecarboxamide (410 mg; 59%) as a yellow oil.

Stage 2: 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarbonitrile

To a chilled (0°C) mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (200 mg; 0.71 mmol) and 1-cyano-N-methoxy-N-methyl-cyclopropanecarboxamide (164 mg; 1.06 mmol) in tetrahydrofuran (2 ml) isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 1.06 ml, 2.13 mmol). Upon completion of the addition, the mixture was stirred at 25°C for 3 h and then extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to give, as conventionally indicated, 1-[(5S,7S)-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarbonitrile (20 mg; 9.2%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.40 (m, 3H), 7.78-7.27 (m, 2H), 6.15-5.99 (m, 1H), 5.57-5.55 (m, 1H), 3.69-3.61 (m, 1H), 3.06-2.96 (m, 1H), 2.10-2.03 (m, 2H), 1.84-1.81 (m, 2H). LCMS: R _T = 0.813 min, m/z = 296.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.813 min, ESI+: detected [M+H] = 296.9.

Method 75

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.2]pentane -2-yl-methanone

Stage 1: N-methoxy-N-methylspiro[2.2]pentane-1-carboxamide

A mixture of spiro[2.2]pentane-2-carboxylic acid (0.5 g; 4.46 mmol), N,O-dimethylhydroxylamine hydrochloride (0.65 g; 6.69 mmol), 1-[bis(dimethylamino)methylene ]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1.70 g; 4.46 mmol) and N,N-diisopropylethylamine (1.44 g; 11.15 mmol) in N,N-dimethylformamide (10 ml) was stirred at 25° C. for 5 hours. The reaction mixture was poured into water (30 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (20 ml) and concentrated under reduced pressure to give crude N-methoxy-N-methyl-spiro[2.2]pentane-2-carboxamide (690 mg; 100%) as a colorless oil. The crude oil was used in the next step without further purification.

LC-MS: R _T = 0.638 min, m/z = 156.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.638 min, ESI+: [M+H] = 156.1 detected.

Stage 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[ 2.2]pentan-2-yl-methanone

To a mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg; 0. 35 mmol) and N-methoxy-N-methyl-spiro[2.2]pentane-2-carboxamide (110 mg; 0.71 mmol) in tetrahydrofuran (2 ml) was added isopropyl magnesium bromide (3.0 M in 2-methyltetrahydrofuran; 0 .71 ml; 2.13 mmol) under nitrogen at 0°C. Upon completion of the addition, the mixture was stirred at 0° C. for 2 h and quenched by adding saturated aqueous ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (40-70% acetonitrile/0.05% ammonium hydroxide in water) to give, as conventionally indicated, [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.2]pentan-2-yl-methanone (18.6 mg; 18%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.33 (m, 3H), 7.29-7.23 (m, 2H), 6.09-5.93 (m, 1H), 5.52-5.44 (m, 1H), 3.68-3.60 (m, 1H), 3.40-3.36 (m, 1H), 3.01-2.89 (m, 1H), 1.88-1.82 (m, 1H), 1.63-1.61 (m, 1H), 1.05-0.97 (m, 2H) , 0.95–0.89 (m, 1H), 0.88–0.83 (m, 1H). LC-MS: R _T = 0.786 min, m/z = 298.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.786 min, ESI+: [M+H] = 298.1 detected.

Method 76

[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexane -2-yl-methanone

Stage 1: N-methoxy-N-methylspiro[2.3]hexane-1-carboxamide

A mixture of spiro[2.3]hexane-2-carboxylic acid (300 mg; 2.38 mmol), N,O-dimethylhydroxylamine hydrochloride (464 mg; 4.76 mmol), N,N-diisopropylethylamine (922 mg; 7.13 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (949 mg; 2.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at 20°C for 2 hours the Mixture was poured into water (60 ml) and was extracted with dichloromethane (2×30 ml). The combined organic layers were washed with water (2×20 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude N-methoxy-N-methyl-spiro[2.3]hexane-2-carboxamide (400 mg; 99%) as a light yellow oil which was used in the next step without further purification. LC-MS: R _T = 0.725 min, m/z = 170.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.725 min, ESI+: [M+H] = 170.2 detected.

Stage 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[ 2.3]hexan-2-yl-methanone

To a solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg; 0. 35 mmol) and N-methoxy-N-methyl-spiro[2.3]hexane-2-carboxamide (120 mg; 0.71 mmol) in tetrahydrofuran (2 ml) was added dropwise isopropyl magnesium bromide (3.0 M solution in 2- methyltetrahydrofuran; 0.71 ml; 2.13 mmol) under nitrogen at 0°C. Upon completion of the addition, the mixture was stirred at 0°C for 2 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (2×5 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 45-75%/0.05% ammonium hydroxide in water) to give, as conventionally indicated, [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexan-2-yl-methanone (21.6 mg; 19%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.38 (m, 3H), 7.29-7.26 (m, 2H), 6.11-5.95 (m, 1H), 5.51-5.48 (m, 1H), 3.69-3.60 (m, 1H), 3.10-3.03 (m, 1H), 3.02-2.90 (m, 1H), 2.38-2.13 (m, 4H), 2.08-1.99 (m, 1H), 1.98-1.89 (m, 1H) , 1.56-1.52 (m, 1H), 1.29-1.24 (m, 1H). LC-MS: R _T = 0.821 min, m/z = 312.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.821 min, ESI+: [M+H] = 312.1 detected.

Method 77

[1-(2-Pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone

Stage 1: N-methoxy-N-methyl-1-(2-pyridyl)cyclopropanecarboxamide

A mixture of 1-(2-pyridyl)cyclopropanecarboxylic acid (200 mg; 1.23 mmol), N,N-diisopropylethylamine (475 mg; 3.68 mmol), 1-hydroxybenzotriazole (198 mg; 1.47 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (282 mg; 1.47 mmol) and N,O-dimethylhydroxylamine hydrochloride (179 mg; 1.84 mmol) in dichloromethane (10 ml) was stirred at 30°C for 18 h and diluted with water (30 ml). The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (2×10 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-1-(2-pyridyl)cyclopropanecarboxamide (200 mg; 79%) as white solid. LC-MS: R _T = 0.733 min, m/z = 207 (M+H) ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.733 min, ESI+: detected [M+H] = 207.

Step 2: [1-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]methanone

To a solution of N-methoxy-N-methyl-1-(2-pyridyl)cyclopropanecarboxamide (55 mg; 0.27 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg; 0.18 mmol) in tetrahydrofuran (3 ml) was added dropwise at 0° C. isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 0.4 ml; 0.80 mmol). The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (5 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (water (with 0.05% ammonium hydroxide, v/v)/acetonitrile, 35-65%) to give, by convention, [1-(2-pyridyl)cyclopropyl]-[ (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (15.4 mg; 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42-8.40 (m, 1H), 7.50-7.47 (m, 1H), 7.34-7.32 (m, 3H), 7.26-7.10 (m, 1H), 7.06-7.02 (m, 3H), 6.00-5.83 (m, 1H), 5.40-5.35 (m, 1H), 3.60-3.49 (m, 1H), 2.92-2.81 (m, 1H), 2.02-1.90 (m, 1H) , 1.83-1.78 (m, 2H), 1.60-1.50 (m, 1H). LCMS: R _T = 1.678 min, m/z = 349.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.678 min, ESI+: detected [M+H] = 349.2.

Method 78

(1-Cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone

Stage 1: 1-cyclopropyl-N-methoxy-N-methyl-cyclopropanecarboxamide

Mixture of 1-cyclopropylcyclopropanecarboxylic acid (500 mg; 3.96 mmol), 1-hydroxybenzotriazole (321 mg; 2.38 mmol), N,O-dimethylhydroxylamine hydrochloride (773 mg; 7.93 mmol), 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (912 mg; 4.76 mmol) and N,N-diisopropylethylamine (512 mg; 3.96 mmol) in dichloromethane (10 ml) was stirred at 25°C for 18 h and quenched by adding water (10 ml). The separated organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 50 to 60% ethyl acetate in petroleum ether) to give 1-cyclopropyl-N-methoxy-N-methyl-cyclopropanecarboxamide (370 mg; 55%) as a yellow oil.

Stage 2: (1-cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone

To a solution of 1-cyclopropyl-N-methoxy-N-methyl-cyclopropanecarboxamide (340 mg; 2.01 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazole (288 mg; 1.02 mmol) in tetrahydrofuran (20 ml) isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran) was added dropwise at 0° C.; 3.57 ml; 7.15 mmol). The reaction mixture was stirred at 0°C for 1 h and extinguished by adding saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether, R _f = 0.6) to give (1-cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (100 mg; 31%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.36 (m, 3H), 7.24-7.22 (m, 2H), 6.09-5.91 (m, 1H), 5.52-5.45 (m, 1H), 3.69-3.54 (m, 1H), 2.99-2.86 (m, 1H), 1.88-1.83 (m, 1H), 1.54-1.50 (m, 2H), 0.78-0.76 (m, 2H), 0.43-0.39 (m, 2H) , 0.07–0.03 (m, 2H). LC-MS: R _T = 0.816 min, m/z = 312.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min): retention time 1.935 min, ESI+: [M+H] = 312.2 detected.

Method 79

Cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone

Stage 1: 1-(2-chlorophenyl)but-3-en-1-ol

To a solution of 2-chlorobenzaldehyde (90.0 g; 640.25 mmol) in tetrahydrofuran (1000 ml) was added allylmagnesium chloride (2.0 M solution in tetrahydrofuran; 448.1 ml; 896.35 mmol) at -78°C in nitrogen atmosphere. The resulting mixture was allowed to warm to 25°C and stirred for 1 h, then quenched by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (2×500 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2-chlorophenyl)but-3-en-1-ol (116.0 g, 99%) as a yellow oil.

Stage 2: tert-butyl-[1-(2-chlorophenyl)but-3-enoxy]-dimethyl-silane

To a solution of 1-(2-chlorophenyl)but-3-en-1-ol (116.0 g; 634.55 mmol) in dichloromethane (1.5 L) was added imidazole (86.4 g; 1269.1 mmol) and tert-butyldimethylchlorosilane (124.3 g; 824.9 mmol). The reaction mixture was stirred at 25°C for 16 h and extinguished by adding water (1 l). The mixture was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine (1 L), dried over sodium sulfate and concentrated under reduced pressure to give crude t-butyl-[1-(2-chlorophenyl)but-3-enoxy]-dimethyl-silane (188.0 g; 99%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.59-7.54 (m, 1H), 7.31-7.23 (m, 2H), 7.20-7.14 (m, 1H), 5.92-5.79 (m, 1H), 5.17-5.12 ( m, 1H), 5.07-5.00 (m, 2H), 2.49-2.42 (m, 1H), 2.40-2.32 (m, 1H), 0.89 (s, 9H), 0.05 (s, 3H), from -0.10 to -0.13 (m, 3H).

Step 3: 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propanal

To a solution of tert-butyl-[1-(2-chlorophenyl)but-3-enoxy]-dimethylsilane (188.0 g; 633.19 mmol) in water (1.0 L) and tetrahydrofuran (1.0 L ) was added osmium tetroxide (0.04% solution in water; 41.55 ml; 6.65 mmol). After stirring for 30 minutes at 15° C., sodium periodate (541.7 g; 2532.8 mmol) was added in small portions over 2 hours. The resulting mixture was stirred for another 2 hours at 30° C. and quenched by adding cold saturated aqueous sodium thiosulfate (500 ml). The mixture was stirred for 30 min and was extracted with ethyl acetate (3×500 ml). The combined organic layers were washed with water (500 ml), brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 5% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propanal (189.0 g ; 99%) as colored oil. ¹ H NMR (400 MHz, CDCl ₃ ) 9.84-9.81 (m, 1H), 7.63-7.59 (m, 1H), 7.35-7.28 (m, 2H), 7.25-7.19 (m, 1H), 5.66-5.62 ( m, 1H), 2.76-2.69 (m, 2H), 0.89 (s, 9H), 0.09 (s, 3H), -0.10 (s, 3H).

Step 4: 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl) )propan-1-ol

N -butyl lithium (2.5 M solution in hexanes; 278.2 ml; 695.6 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propanal (189.0 g; 632.4 mmol) in tetrahydrofuran (400 ml). Upon completion of the addition, the mixture was stirred at -78°C for 2 h and then extinguished by adding saturated aqueous ammonium chloride (200 ml). The resulting mixture was extracted with ethyl acetate (2×800 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propan-1-ol (202.0 g; 60%) as a yellow oil. LC-MS: R _T = 2.657 min, m/z = 446.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3 min): retention time 2.657 min, ESI+: detected [M+H] = 446.1.

Step 5: 2-bromo-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6 -trifluorophenyl)propan-1-ol (50.0 g; 94.17 mmol) and trifluoroacetic acid (280.7 ml; 3766.8 mmol) were stirred at 55° C. for 16 h and concentrated under reduced pressure. The pH of the residue was adjusted to 9 by adding saturated aqueous sodium bicarbonate, and was extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give 2-bromo-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-7-ol (9.2 g; 31%) as a white solid. ¹ H NMR (400 MHz, CD ₃ Cl) δ 7.48-7.41 (m, 1H), 7.34-7.27 (m, 2H), 7.10-6.79 (m, 1H), 6.08-5.83 (m, 1H), 5.70- 5.53 (m, 1H), 5.41 (br s, 1H), 3.74-3.57 (m, 0.5H), 3.35-3.21 (m, 0.5H), 2.99-2.84 (m, 1H), 2.67-2.52 ( m, 0.5H). LC-MS: R _T = 0.614 min, m/z = 314.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.614 min, ESI+: [M+H]=314.0 detected.

Stage 6: 2-bromo-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a cooled (0°C) solution of 2-bromo-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (5 .2 g; 16.53 mmol) in dichloromethane (80 ml) was added diethylaminosulfur trifluoride (8.8 ml; 66.12 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at 0°C for 1 h and extinguished by adding saturated aqueous sodium bicarbonate (300 ml) at 0°C. The mixture was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give 2-bromo-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazole (3.9 g; 75%) as thick yellow oil.

Stage 7: cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone

To a mixture of N-methoxy-N-methyl-cyclopropanecarboxamide (402 mg; 3.11 mmol), 2-bromo-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole (500 mg; 1.58 mmol) in tetrahydrofuran (30 ml) isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 5.5 ml; 11 .06 mmol). The mixture was stirred at 0°C for 1 h and extinguished by adding water (30 ml). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether, R _f = 0.5) to give [5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]-cyclopropyl-methanone (250 mg; 52%) as a white solid. LC-MS: R _T = 0.685 min, m/z = 306.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.685 min, ESI+: [M+H] = 306.1 detected.

The above cis/trans mixture was further separated with chiral SFC to give, as conventionally indicated:

cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone (peak 2, retention time = 2.509 min) (50.6 mg; 12%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.43 (m, 1H), 7.34-7.28 (m, 1H), 7.26-7.24 (m, 1H), 6.76-6.72 (m, 1H), 6.10-6.06 (m, 0.5H), 6.01-5.95 (m, 1H), 5.95-5.93 (m, 0.5H), 3.78-3.62 (m, 1H), 3.12-3.04 (m, 1H), 2.93-2.80 ( m, 1H), 1.37-1.32 (m, 2H), 1.14-1.09 (m, 2H). LC-MS: R _T = 1.049 min, m/z = 306.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.049 min, ESI+: detected [M+H] = 306.1;

cyclopropyl-[(5R,7R)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone (peak 4, retention time = 3.571 min) (65.6 mg; 15%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.43 (m, 1H), 7.34-7.26 (m, 1.5H), 7.25-7.22 (m, 0.5H), 6.76-6.72 (m, 1H) , 6.10-6.06 (m, 0.5H), 6.01-5.96 (m, 1H), 5.95-5.93 (m, 0.5H), 3.78-3.62 (m, 1H), 3.12-3.04 (m, 1H), 2.93-2.80 (m, 1H), 1.37-1.32 (m, 2H), 1.14-1.08 (m, 2H). LC-MS: R _T = 0.776 min, m/z = 306.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.776 min, ESI+: [M+H] = 306.1 detected.

Note: Peak 1 and peak 3 represent the trans isomers.

SFC Method: Column: Chiralcel OJ-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 80

Cyclopropyl-[(5S,7S)-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt] methanone

Step 1: 1-(2,5-difluorophenyl)but-3-en-1-ol

To a solution of 2,5-difluorobenzaldehyde (10.0 g; 70.4 mmol) in tetrahydrofuran (20 ml) was added allylmagnesium bromide (2.0 M solution in tetrahydrofuran; 49.3 ml; 98.5 mmol) at 0°C in a nitrogen atmosphere. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was quenched by adding saturated aqueous ammonium chloride (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,5-difluorophenyl)but-3-en-1-ol (11.0 g; 85%) as a yellow oil.

Step 2: tert-butyl((1-(2,5-difluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a solution of 1-(2,5-difluorophenyl)but-3-en-1-ol (11.0 g; 59.7 mmol) in dichloromethane (200 ml) was added imidazole (8.1 g; 119.5 mmol) and tert-butyldimethylchlorosilane (11.7 g; 77.6 mmol). Upon completion of the addition, the reaction mixture was stirred at 25°C for 16 h and extinguished by adding water (100 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude t-butyl-[1-(2,5-difluorophenyl)but-3-enoxy]-dimethyl-silane (17.0 g; 95%) as a light oil.

Stage 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,5-difluorophenyl)propanal

To a solution of tert-butyl-[1-(2,5-difluorophenyl)but-3-enoxy]-dimethylsilane (17.0 g; 57.0 mmol) in tetrahydrofuran/water (100 ml; 1:1) osmium tetroxide (80.0 mg; 0.33 mmol) was added. After stirring for 30 minutes at 15°C, sodium periodate (48.7 g, 227.9 mmol) was added in small portions over 2 hours and the resulting mixture was stirred for another 2 hours at 30°C. The mixture was quenched by adding cold saturated aqueous sodium thiosulfate (100 ml). The mixture was stirred for 30 min and then extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,5-difluorophenyl)propanal (10, 8 g; 63%) as a light yellow oil.

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(2,5-difluorophenyl)propan-1-ol

N -butyllithium (2.5 M solution in hexanes; 16.1 ml; 40.3 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propanal (10.8 g; 36.0 mmol) was added dropwise ) in tetrahydrofuran (100 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1.5 h and extinguished by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,5-difluorophenyl)propan-1-ol (10.0 g; 52%) as a yellow oil.

Step 5: 2-bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

To a solution of 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,5-difluorophenyl)propan-1- ol (3.96 g; 8.83 mmol) in trifluoroacetic acid (25 ml; 88.3 mmol) trifluoromethanesulfonic acid (2.5 ml; 8.83 mmol) was added. The resulting mixture was heated at 60° C. for 2 hours and concentrated under reduced pressure. The pH of the residue was adjusted to 9 by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 100-200 mesh; 50 to 60% ethyl acetate in petroleum ether) to give the crude product, which was washed with methyl t-butyl ether (20 ml) to give 2-bromo-5-(2.5 -difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.1 g; 39%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11-7.03 (m, 1H), 6.98-6.75 (m, 1H), 5.84-5.68 (m, 1H), 5.47-5.30 (m, 2H), 3.64-3.18 (m, 1H), 3.02–2.63 (m, 1H). LCMS: R _T = 0.727 min, m/z = 318.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.727 min, ESI+: [M+H] = 318.0 detected.

Step 6: (5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole

To a solution of 2-bromo-5-(2,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (5.0 g; 15.8 mmol) in toluene (50 ml) diethylaminosulfur trifluoride (10.2 g; 63.3 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 16 h and then slowly added to a saturated aqueous sodium bicarbonate solution (100 ml) at 0°C. The mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 15% ethyl acetate in petroleum ether) to give rac-(5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (1.3 g; 26%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15-7.05 (m, 2H), 6.72-6.68 (m, 1H), 6.07-5.91 (m, 1H), 5.78-5.74 (m, 1H), 3.68-3.55 (m, 1H), 2.90-2.79 (m, 1H). LCMS: R _T = 0.821 min, m/z = 317.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.821 min, ESI+: detected [M+H] = 317.9.

This cis mixture (500 mg; 1.7 mmol) was further separated with chiral SFC to give, as conventionally indicated, (5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.600 min) (220 mg; 44%) as a brown solid (together with (5R, 7R)-isomer (peak 1, retention time = 2.295 min) (220 mg; 44%)).

SFC Conditions: Column: Chiralpak IC-3, 150 x 4.6 mm (ID), 3 µm. Mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA). Gradient: 5% to 40% B over 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 2.5 ml/min; column temperature: 40°C.

Stage 7: cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl]methanone

To a mixture of (5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg; 0.31 mmol), N-methoxy-N-methyl-cyclopropanecarboxamide (81 mg; 0.63 mmol) in tetrahydrofuran (3 ml) was added dropwise isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran; 0. 31 ml; 0.63 mmol) at 0°C. The mixture was stirred at 0° C. for 0.5 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC to give cyclopropyl-[(5S,7S)-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]methanone (22.1 mg; 23%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.28-7.17 (m, 2H), 6.93-6.88 (m, 1H), 6.22-6.06 (m, 1H), 5.90-5.86 (m, 1H), 3.88- 3.74 (m, 1H), 3.09-3.02 (m, 1H), 2.93-2.82 (m, 1H), 1.21-1.18 (m, 2H), 1.15-1.11 (m, 2H). LCMS: R _T = 1.007 min, m/z = 308.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.007 min, ESI+: [M+H] = 308.1 detected.

Method 81

Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone

Step 1: 1-(2,3,6-trifluorophenyl)but-3-en-1-ol

To a solution of 2,3,6-trifluorobenzaldehyde (25.0 g; 156.2 mmol) in tetrahydrofuran (350 ml) was added allylmagnesium bromide (2.5 M solution in hexane; 93.7 ml; 187.4 mmol) at 0 °C in a nitrogen atmosphere. The resulting mixture was allowed to warm to 25°C and stirred for 1 h, then quenched by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,3,6-trifluorophenyl)but-3-en-1-ol (30 g; 95%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.01-7.17 (m, 1H), 6.79-6.92 (m, 1H), 5.72-5.91 (m, 1H), 5.07-5.26 (m, 3H), 2.74-2.88 (m, 1H), 2.65-2.69 (m, 1H), 2.44 (s, 1H).

Step 2: tert-butyldimethyl((1-(2,3,6-trifluorophenyl)but-3-en-1-yl)oxy)silane

To a solution of 1-(2,3,6-trifluorophenyl)but-3-en-1-ol (30.0 g; 148.4 mmol) in dichloromethane (250 ml) mmol) and tert-butyldimethylchlorosilane (29.1 g; 192.9 mmol). The reaction mixture was stirred at 25°C for 16 h and then extinguished by adding water (100 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude t-butyl-dimethyl-[1-(2,3,6-trifluorophenyl)but-3-enoxy]silane (46, 0 g; 98%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 (s, 1H), 7.07-6.95 (m, 1H), 6.97-6.77 (m, 1H), 5.58-5.82 (m, 1H), 4.97-5.11 (m , 3Н), 2.84-2.64 (m, 1Н), 2.62-2.44 (m, 1Н), 0.83-0.86 (m, 9H), 0.03-0.07 (m, 3Н), -0.17-0.13 (m, 3H).

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,3,6-trifluorophenyl)propanal

To a solution of tert-butyl-dimethyl-[1-(2,3,6-trifluorophenyl)but-3-enoxy]silane (5.0 g; 15.8 mmol) in water (30 ml) and tetrahydrofuran (30 ml) osmium tetroxide (0.5 g; 1.97 mmol) was added. After stirring for 30 min at 15° C., sodium periodate (13.5 g; 63.2 mmol) was added in small portions over 2 h. The resulting mixture was stirred for another 2 h at 30° C. and then quenched by adding cold saturated aqueous sodium thiosulfate solution (300 ml). The mixture was stirred for 30 min and then extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product, 3-[tert-butyl(dimethyl)silyl]oxy-3-(2.3, 6-trifluorophenyl)propanal (5 g; 99%) as a yellow oil.

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(2,3,6-trifluorophenyl)propan-1-ol

n- butyl lithium (2.5 M solution in hexanes; 38.0 ml; 95.0 mmol) under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6-trifluorophenyl)propanal (27.0 g; 84. 8 mmol) in tetrahydrofuran (100 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1.5 h and extinguished by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2 ,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(2,3,6-trifluorophenyl)propan-1-ol (23 g; 49%) as a yellow oil.

Step 5: 2-bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6 -trifluorophenyl)propan-1-ol (22.9 g; 41.6 mmol) and trifluoromethanesulfonic acid (12.2 ml; 138.4 mmol) in dichloromethane (200 ml) were heated at 55°C for 4 days and concentrated under reduced pressure. The residue was diluted with water (100 ml) and the pH was adjusted to 9 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×200 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give 2-bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazol-7-ol (9.2 g; 66%) as a yellow solid. LCMS: R _T = 0.873 and 0.897 min, m/z = 334.0/336.0 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention times 0.873 and 0.897 min, ESI+: found [M+H] = 334.0/336.0.

Step 6: rac-(5S,7S)-2-bromo-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazole

To a cooled (0°С) solution of 2-bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazole-7 -ol (9.2 g; 27.5 mmol) in toluene (100 ml) diethylaminosulfur trifluoride (14.6 ml; 110.2 mmol) in toluene (4 ml) was added. The reaction mixture was stirred at 0°C for 1 h and then slowly added to a saturated aqueous sodium bicarbonate solution (100 ml) at 0°C. The mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give rac-(5S,7S)-2-bromo-7-fluoro-5-(2,3,6-trifluorophenyl )-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (1.8 g; 19%) as a light yellow solid.

Stage 7: cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl]methanone

To a cooled (0°C) solution of N-methoxy-N-methyl-cyclopropanecarboxamide (188 mg; 1.47 mmol) and rac-(5S,7S)-2-bromo-7-fluoro-5-(2.3, 6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg; 0.72 mmol) in tetrahydrofuran (10 ml) was added isopropyl magnesium chloride (2, 0 M solution in tetrahydrofuran, 0.73 ml, 1.46 mmol). The mixture was stirred at 0°C for 1 h and extinguished by adding water (30 ml). The resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 5% ethyl acetate in petroleum ether) to give cyclopropyl-[rac-(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl) -6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (95 mg; 40%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25-7.16 (m, 1H), 6.92-6.89 (m, 1H), 6.23-5.96 (m, 1H), 5.91-5.77 (m, 1H), 3.87-3.72 (m, 1H), 3.14-2.97 (m, 2H), 1.37-1.27 (m, 2H), 1.14-1.03 (m, 2H). LCMS: R _T = 0.655 min, m/z = 326.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.655 min, ESI+: [M+H] = 326.1 detected.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.856 min) (40 mg; 42%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.20 (m, 1H), 6.93-6.90 (m, 1H), 6.19-6.03 (m, 1H), 5.86-5.83 (m, 1H), 3.84-3.74 (m, 1H), 3.10-3.04 (m, 2H), 1.34-1.31 (m, 2H), 1.13-1.08 (m, 2H). LCMS: R _T = 0.864 min, m/z = 325.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.864 min, ESI+: [M+H] = 325.9 detected.

SFC Conditions: Column: Chiralcel OJ-3, 150 x 4.6 mm (ID), 3 µm. Mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA). Gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 82

Cyclopropyl-[(5S,7S)-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: cis-2-bromo-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole

To a chilled (0°C) solution of trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (400 mg; 1.42 mmol) in toluene (10 ml) was added diethylaminosulfur trifluoride (917 mg; 5.69 mmol). The mixture was stirred at 0°C for 1 h and extinguished by adding saturated sodium bicarbonate solution (30 ml) at 0°C. The mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 12% ethyl acetate in petroleum ether) to give cis-2-bromo-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1, 2-b][1,2,4]triazole (0.22 g; 55%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.38 (m, 3H), 7.27-7.24 (m, 2H), 5.47-5.42 (m, 1H), 3.63-3.51 (m, 1H), 2.94-2.84 (m, 1H).

Stage 2: cyclopropyl-[(5S,7S)-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of cis-2-bromo-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (210 mg; 0.74 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (192 mg; 1.48 mmol) in tetrahydrofuran (6 ml) isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 0.74 ml; 1.48 mmol) was added at 0°C in a nitrogen atmosphere. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 44-74%/0.05% ammonium hydroxide in water) to give cyclopropyl-[cis-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2 -b][1,2,4]triazol-2-yl]methanone (55 mg; 27%) as a white solid. LCMS: R _T = 0.646 min, m/z = 273.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.646 min, ESI+: detected [M+H] = 273.2.

The above cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][ 1,2,4]triazol-2-yl]methanone (peak 2, retention time = 4.354 min) (16.6 mg; 29%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.38 (m, 3H), 7.29-7.27 (m, 2H), 5.67-5.63 (m, 1H), 3.80-3.70 (m, 1H), 3.05- 3.02 (m, 1H), 2.88-2.80 (m, 1H), 1.19-1.16 (m, 2H), 1.12-1.09 (m, 2H). LCMS: R _T = 0.738 min, m/z = 273.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time: 0.738 min, ESI+: detected [M+H] = 273.1.

SFC Conditions: Column: Daicel Chiralpak AD-H, 250 mm × 30 mm (ID), 5 µm; mobile phase: A: CO ₂ , B: ethanol (0.1% NH ₃ H ₂ O in IPA). Gradient: 30% to 30% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 83

[(1R,2S)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone and [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (trans-mixtures) (245 mg; 1.65 mmol) and (5S,7S)-2-bromo-7-fluoro-5-(2 -fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (250 mg; 0.85 mmol) in tetrahydrofuran (10 ml) was added isopropyl magnesium chloride (2.1 ml; 4.15 mmol; 2 M solution in tetrahydrofuran) at 0° C. under nitrogen. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding water (10 ml) and was extracted with ethyl acetate (3×20 ml). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (33% ethyl acetate in petroleum ether, R _f = 0.6) to give [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2 -fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (trans-mix) (105 mg; 41%) as a white solid substances. LCMS: R _T = 0.739 min, m/z = 308.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.739 min, ESI+: [M+H] = 308.1 detected.

The above trans mixture was further separated with chiral SFC to give, conventionally, [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.773 min) (48.1 mg; 45%) as a white solid substances. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.42 (m, 1H), 7.25-7.13 (m, 3H), 6.22-6.06 (m, 1H), 5.93-5.89 (m, 1H), 5.01- 4.87 (m, 0.5H), 4.85-4.82 (m, 0.5H), 3.88-3.75 (m, 1H), 3.51-3.42 (m, 1H), 2.93-2.81 (m, 1H), 1.75-1.64 (m, 1H), 1.62-1.54 (m, 1H). LC-MS: R _T = 0.852 min, m/z = 308.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.852 min, ESI+: [M+H] = 308.0 detected.

The (1S,2R)-isomer was not isolated.

SFC Conditions: Column: Chiralcel OD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

A larger batch of the trans mixture (215 mg; 0.70 mmol) was separated by chiral SFC to give, as conventionally indicated, [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5- (2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.445 min) (19.5 mg, 9%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.38 (m, 1H), 7.18-7.15 (m, 2H), 6.98-6.97 (m, 1H), 6.13-6.11 (m, 0.5H), 5.99 -5.98 (m, 0.5H), 5.87-5.85 (m, 1H), 5.05-5.04 (m, 0.5H), 4.89-4.88 (m, 0.5H), 3.73-3.67 (m, 1H), 3.58-3.54 (m, 1H), 3.01-2.95 (m, 1 H), 1.72-1.65 (m, 2H). LC-MS: R _T = 1.763 min, m/z = 308.1 (M+H) ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.763 min, ESI+: detected [M+H] = 308.1. Note: The (1R,2S)-isomer corresponded to peak 2 (retention time = 2.728 min) under SFC conditions on an AD column.

SFC conditions: column: Daicel Chiralpak AD-H, 250 mm × 30 mm, 5 µm; mobile phase: A: CO ₂ , B: ethanol (0.1% NH ₃ H ₂ O in methanol). Gradient: 15% to 15% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 84

rac-(1R,2R)-2-[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carbonyl]cyclopropanecarbonitrile

Stage 1: trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid

To a solution of diethyl-trans-cyclopropane-1,2-dicarboxylate (2000 mg; 10.74 mmol) in ethanol (26 ml) was added a solution of sodium hydroxide (429 mg; 10.74 mmol) in water (3 ml). The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The pH of the aqueous residue was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution) at 0°C. The mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give trans-2-ethoxycarbonylcyclopropanecarboxylic acid (820 mg; 48%) as a white solid. LCMS: R _T = 0.430 min, m/z = 159.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.430 min, ESI+: detected [M+H] = 159.1.

Stage 2: ethyl-trans-2-(methoxy(methyl)carbamoyl)-cyclopropanecarboxylate

A mixture of 1-hydroxybenzotriazole (684 mg; 5.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1164 mg; 6.07 mmol), trans-2-ethoxycarbonylcyclopropanecarboxylic acid (800 mg; 5.06 mmol ), N,O-dimethylhydroxylamine hydrochloride (740 mg; 7.59 mmol) and N,N-diisopropylethylamine (1634 mg; 12.65 mmol) in dichloromethane (20 ml) was stirred at 25°C for 16 h and diluted with water (20 ml). The reaction mixture was extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give ethyl trans-2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate (600 mg; 59%) as light yellow oils. LCMS: R _T = 0.525 min, m/z = 202.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.525 min, ESI+: [M+H] = 202.2 detected.

Stage 3: ethyl trans-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -carbonyl)cyclopropanecarboxylate

To a solution of ethyl trans-2-[methoxy(methyl)carbamoyl]cyclopropane-carboxylate (571 mg; 2.84 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (400 mg; 1.42 mmol) in tetrahydrofuran (13 ml) isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran; 2 .84 ml; 5.67 mmol) at 0° C. under nitrogen. Upon completion of the addition, the mixture was stirred at 0°C for 2 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 40% ethyl acetate in petroleum ether) to give ethyl trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]-cyclopropanecarboxylate (350 mg; 72%) as a light yellow oil. LCMS: R _T = 0.693 min, m/z = 344.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.693 min, ESI+: [M+H] = 344.1 detected.

Step 4: trans-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl )cyclopropanecarboxylic acid

To a solution of ethyl trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- carbonyl]cyclopropanecarboxylate (100 mg; 0.29 mmol) in tetrahydrofuran (10 ml) was added a solution of lithium hydroxide (42 mg; 1.75 mmol) in water (2 ml). The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The pH of the aqueous residue was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution) at 0°C. The mixture was then extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarboxylic acid (90 mg; 98%) as a white solid. LCMS: R _T = 0.590 min, m/z = 316.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.590 min, ESI+: [M+H] = 316.2 detected.

Step 5: trans-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl )cyclopropanecarboxamide

A mixture of 1-hydroxybenzotriazole (34 mg; 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49 mg; 0.25 mmol), ammonium chloride (27 mg; 0.51 mmol), N, N-diisopropylethylamine (98 mg; 0.76 mmol) and trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazole-2-carbonyl]cyclopropanecarboxylic acid (80 mg; 0.25 mmol) in N,N-dimethylformamide (3 ml) was stirred at 25° C. for 18 h and diluted with water (10 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in methanol) to give trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarboxamide (75 mg; 94%) as a white solid. LCMS: R _T = 0.555 min, m/z = 315.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.555 min, ESI+: [M+H] = 315.1 detected.

Step 6: rac-(1R,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazole-2-carbonyl]cyclopropanecarbonitrile

To a solution of trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl] cyclopropanecarboxamide (65 mg; 0.21 mmol) in 1,4-dioxane (3 ml) were added triethylamine (62 mg; 0.62 mmol) and trifluoroacetic anhydride (87 mg; 0.41 mmol). The reaction mixture was stirred at 25°C for 2 h and diluted with water (15 ml). The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 15-45%/0.05% ammonium hydroxide in water) to give rac-(1R,2R)-2-[(5S,7S)-7-fluoro- 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarbonitrile (24.0 mg; 38%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.39 (m, 3H), 7.32-7.30 (m, 2H), 6.22-6.20 (m, 0.5H), 6.08-6.06 (m, 0.5H ), 5.70-5.67 (m, 1H), 3.81-3.75 (m, 1H), 3.62-3.31 (m, 1H), 2.90-2.75 (m, 1H), 2.28-2.24 (m, 1H), 1.68-1.63 (m, 2H). LCMS: R _T = 0.957 min, m/z = 297.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 2 min): retention time 0.957 min, ESI+: detected [M+H] = 297.2.

Method 85

Cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt] methanone

Step 1: 1-(2,3-difluorophenyl)but-3-en-1-ol

To a cooled (0°C) solution of 2,3-difluorobenzaldehyde (10.0 g; 70.4 mmol) in tetrahydrofuran (100 ml) was added allylmagnesium chloride (2.0 M solution in tetrahydrofuran; 46.0 ml; 92.0 mmol) for 30 min. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h and then quenched by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,3-difluorophenyl)but-3-en-1-ol (12.9 g, 99%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27-7.24 (m, 1H), 7.11-7.06 (m, 2H), 5.87-5.77 (m, 1H), 5.20-5.08 (m, 3H), 2.62-2.47 (m, 2H).

Stage 2: tert-butyl ((1-(3,4-difluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a stirred solution of 1-(2,3-difluorophenyl)but-3-en-1-ol (12.9 g, 70.6 mmol) in dichloromethane (20 ml) was added imidazole (9.6 g, 141.2 mmol ) and tert-butyldimethylchlorosilane (12.8 g; 84.7 mmol). Upon completion of the addition, the reaction mixture was stirred at 25°C for 16 h and extinguished by adding water (100 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude t-butyl-[1-(2,3-difluorophenyl)but-3-enoxy]-dimethylsilane (21.0 g; 99%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25-7.22 (m, 1H), 7.08-7.03 (m, 2H), 5.82-5.75 (m, 1H), 5.10-4.99 (m, 3H), 2.49-2.42 (m, 2H), 0.89 (s, 9H), 0.67 (s, 3H), -0.08 (s, 3H).

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(3,4-difluorophenyl)propanal

Tetraoxide osmium (0.1 g; 0.39 mmol). After stirring for 30 min at 15°C, sodium periodate (60.2 g; 281.5 mmol) was added in small portions to the mixture over 2 h. The resulting mixture was stirred for another 2 h at 30°C and then quenched by adding cold saturated aqueous sodium thiosulfate (300 ml). The mixture was stirred for 30 min and then extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 3% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propanal (15, 0 g; 71%) as a yellow oil.

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(3,4-difluorophenyl)propan-1-ol

To a chilled (-78°C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (15.7 g; 50.4 mmol) in tetrahydrofuran (150 ml) dropwise in n-butyllithium (2.5 M solution in hexanes; 22.0 ml; 54.9 mmol) was added under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min, then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propanal (15.0 g; 49.9 mmol) was added dropwise ) in tetrahydrofuran (20 ml). Upon completion of the addition, the mixture was stirred at -78°C for 1.5 h and then extinguished by adding saturated aqueous ammonium chloride solution (100 ml). The resulting mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 12% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[t-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propan-1-ol (12.0 g; 45%) as a yellow oil.

Step 5: 2-bromo-5-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

1-(5-Bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,4-difluorophenyl) solution )propan-1-ol (56.0 g; 105.2 mmol) in trifluoroacetic acid (150 ml) was heated at 55° C. for 16 h and concentrated under reduced pressure. The pH of the residue was adjusted to 9 by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude 2-bromo-5-(2,3-difluorophenyl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-7-ol (22.0 g; 66%) as a white solid.

Step 6: (5S,7S)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole and (5R,7R)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a stirred solution of 2-bromo-5-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (30.0 g ; 94.9 mmol) in toluene (200 ml) diethylaminosulfur trifluoride (45.9 g; 284.7 mmol) was added slowly at 0°C. The reaction mixture was stirred at 0°C for 16 h and then slowly added to a stirred saturated aqueous sodium bicarbonate solution (200 ml) at 0°C. The mixture was extracted with dichloromethane (3×150 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 15% ethyl acetate in petroleum ether) to give cis-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole. This cis product was further resolved with chiral SFC to give, as conventionally indicated:

(5S,7S)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 1, retention time = 2.828 min) (1.1 g; 3.7%) as white solid and (5R,7R)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.935 min) (1.1 g; 3.7%) as a white solid.

SFC Conditions: Column: Chiral Cel OJ-H, 150 x 4.6 mm (ID), 5 µm. Mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B in 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 2.5 ml/min; column temperature: 40°C.

Stage 7: cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone

To a solution of (5S,7S)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg; 0.47 mmol), N-methoxy-N-methyl-cyclopropanecarboxamide (122 mg; 0.94 mmol) in tetrahydrofuran (3 ml) was added dropwise isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran; 0. 47 ml; 0.94 mmol) at 0°C. Upon completion of the addition, the mixture was stirred at 0° C. for 0.5 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 40-70%/0.225% formic acid in water) to give cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (49.1 mg; 34%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.16 (m, 1H), 7.14-7.08 (m, 1H), 6.75-6.72 (m, 1H), 6.13-6.10 (m, 0.5H), 5.99 -5.96 (m, 0.5H), 5.88-5.84 (m, 1H), 3.74-3.67 (m, 1H), 3.09-3.04 (m, 1H), 2.99-2.92 (m, 1H), 1.36-1.31 ( m, 2H), 1.14-1.09 (m, 2H). LC-MS: R _T = 0.666 min, m/z = 308.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.666 min, ESI+: detected [M+H] = 308.1.

Method 86

Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone

Step 1: 1-(2,3,5-trifluorophenyl)but-3-en-1-ol

To a solution of 2,3,5-trifluorobenzaldehyde (20.0 g; 124.93 mmol) in dichloromethane (120 ml) and water (120 ml) was added tetrabutylammonium iodide (4.6 g; 12.49 mmol) and potassium allyl trifluoroborate ( 40.7 g; 137.42 mmol) at 25°C. The mixture was stirred for 2 h at 25°C and was extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure to give crude 1-(2,3,5-trifluorophenyl)but-3-en-1-ol (29.0 g; 100%) as a yellow oil .

Step 2: tert-butyldimethyl((1-(2,3,5-trifluorophenyl)but-3-en-1-yl)oxy)silane

To a mixture of 1-(2,3,5-trifluorophenyl)but-3-en-1-ol (20.5 g; 101.4 mmol) and imidazole (13.8 g; 202.7 mmol) in dichloromethane (120 ml) tert-butyldimethylchlorosilane (19.9 g; 131.9 mmol) was added. The mixture was stirred at 35°C for 16 h and diluted with dichloromethane (50 ml). The mixture was washed with water (2×50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give t-butyldimethyl((1-(2,3,5-trifluorophenyl)but-3-en-1-yl) oxy)silane (28.0 g; 87%) as a colorless oil.

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,3,5-trifluorophenyl)propanal

A mixture of tert-butyl-dimethyl-[1-(2,3,5-trifluorophenyl)but-3-enoxy]silane (5.0 g; 15.8 mmol) and osmium tetroxide (5.0 g; 19.7 mmol ) in tetrahydrofuran (20 ml) and water (20 ml) was stirred at 20°C for 0.5 h and then sodium periodate (13.5 g; 63.2 mmol) was added in 3 portions over 0.5 h After the addition was complete, the reaction mixture was stirred at 20° C. for 3 hours and quenched by adding saturated aqueous sodium thiosulfate (30 ml). The solid was removed by filtration. The filtrate was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 5% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)propanal ( 1.6 g; 32%) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78 (t, J=2.2 Hz, 1H), 7.04-7.01 (m, 1H), 6.87-6.83 (m, 1H), 5.56-5.53 (m, 1H ), 2.85-2.79 (m, 1Н), 2.71-2.66 (m, 1Н), 0.89 (s, 1Н), 0.11 (s, 1Н), -0.05 (s, 1Н).

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(2,3,5-trifluorophenyl)propan-1-ol

To a mixture of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (1.6 g; 5.2 mmol) in tetrahydrofuran (20 ml) M solution in hexane; 2.1 ml; 5.2 mmol) under nitrogen at -78°C. After the addition was completed, the mixture was stirred at -78°C for 0.5 h, and a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)propanal (1.5 g; 4.71 mmol) in tetrahydrofuran (10 ml). The resulting mixture was stirred at -78°C for 4 h and extinguished by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 15% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)propan-1-ol (1.78 g; 69%) as a yellow gum. LCMS: R _T = 1.056 min, m/z = 466.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.056 min, ESI+: [M+H] = 466.0 detected.

Step 5: 2-bromo-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A solution of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2.3.5 -trifluorophenyl)propan-1-ol (1.8 g; 3.2 mmol) in trifluoroacetic acid (250 ml; 32.3 mmol) was stirred at 50° C. for 1 h and then trifluoromethanesulfonic acid (1 ml; 3 .2 mmol). The resulting mixture was stirred at 50° C. for 3 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml) and the pH was adjusted to 8 by adding aqueous sodium hydroxide solution (20%). The separated organic layer was washed with water (2×50 ml), brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 40 to 60% ethyl acetate in petroleum ether) to give the crude product. This crude product was washed with methyl tert-butyl ether (20 ml) to give 2-bromo-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-7-ol (0.55 g; 51%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.01-6.94 (m, 1H), 6.980-6.56 (m, 1H), 5.88-5.60 (m, 2H), 5.47-5.40 (m, 1H), 3.66-3.22 (m, 1H), 3.01-3.64 (m, 1H).

Step 6: (5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazole

To a mixture of 2-bromo-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (550 mg; 1.65 mmol) in toluene (10 ml) diethylaminosulfur trifluoride (1.06 g; 6.6 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 16 h and then extinguished by adding saturated aqueous sodium bicarbonate (50 ml). The resulting mixture was extracted with dichloromethane (3×30 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 15 to 20% ethyl acetate in petroleum ether) to give rac-(5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl )-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (197 mg; 36%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00-6.95 (m, 1H), 6.52-6.48 (m, 1H), 6.08-5.92 (m, 1H), 5.81-5.77 (m, 1H), 3.71-3.57 (m, 1H), 2.90-2.80 (m, 1H).

This racemate was further resolved with chiral SFC to give (5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazole (peak 2, retention time = 2.866 min) (80 mg; 41%) as a brown solid (together with the (5R,7R)-isomer (peak 1, time retention = 2.345 min) (80 mg; 41%)).

SFC Conditions: Column: Chiralpak IC-3, 150 x 4.6 mm (ID), 3 µm. Mobile phase: A: CO ₂ B: isopropanol (with 0.05% DEA). Gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Stage 7: cyclopropyl-((5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl) methanone

To a mixture of (5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazole (80 mg; 0.24 mmol), N-methoxy-N-methyl-cyclopropanecarboxamide (62 mg; 0.48 mmol) in tetrahydrofuran (3 ml) was added dropwise isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 0.24 ml; 0.48 mmol) at 0°C. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 40-70%/0.05% ammonium hydroxide in water) to give cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,5 -trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (11 mg; 14%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.29-7.26 (m, 1H), 6.78-6.75 (m, 1H), 6.23-6.06 (m, 1H), 5.96-5.93 (m, 1H), 3.88- 3.80 (m, 1H), 3.07-3.04 (m, 1H), 2.96-2.89 (m, 1H), 1.22-1.11 (m, 4H). LCMS: R _T = 1.029 min, m/z = 326.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.029 min, ESI+: [M+H] = 326.2 detected.

Method 87

Cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: (1E)-2-methylpropanal oxime

To a solution of isobutyraldehyde (200.0 g; 2773.5 mmol) in water (2.0 L) were added hydroxylamine hydrochloride (231.3 g; 3328.3 mmol) and sodium carbonate (587.9 g; 5547.1 mmol) . After the addition was completed, the reaction mixture was stirred at 20° C. for 4 hours and filtered. The filtrate was extracted with ethyl acetate (3×1 L). The combined organic layers were washed with brine (2×1 L), dried over sodium sulfate and concentrated under reduced pressure to give crude (1E)-2-methylpropanal oxime (220 g; 91%) as a colorless oil.

Stage 2: methyl 3-isopropyl-4,5-dihydroisoxazole-5-carboxylate

To a solution of n-chlorosuccinimide (268.2 g; 2008.7 mmol) in chloroform (1500 ml) were added pyridine (9.73 ml; 120.5 mmol) and (1E)-2-methylpropanal oxime (175.0 g; 2008.7 mmol) at 25°C. After stirring for 0.5 h at 25°C, a solution of methyl acrylate (227.2 ml; 2506.9 mmol) and triethylamine (292.4 ml; 2109.2 mmol) in chloroform (100 ml) was added dropwise over 30 min at 25°C. The reaction mixture was stirred at 25°C for 16 h and diluted with dichloromethane (1000 ml). The separated organic layer was washed with water (3×500 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give methyl 3-isopropyl-4,5-dihydroisoxazole-5-carboxylate (240 g; 70%) as a colorless oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.98-4.93 (m, 1H), 3.76 (s, 3H), 3.21-3.19 (m, 2H), 2.75-2.66 (m, 1H), 1.16 (d, J =6.8 Hz, 6H).

Stage 3: 3-hydroxy-5-isopropyl-pyrrolidin-2-one

A mixture of methyl 3-isopropyl-4,5-dihydroisoxazole-5-carboxylate (240.0 g; 1402 mmol) and palladium (10% on charcoal; 14.9 g) in ethanol (2 L) was hydrogenated (50 lb / sq. inch (344,7 kPa)) at 45°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-isopropyl-pyrrolidin-2-one (70 g; 35%) as a white solid.

Stage 4: 3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidin-2-one

To a chilled (0°C) mixture of 3-hydroxy-5-isopropyl-pyrrolidin-2-one (49.0 g; 342.2 mmol) and imidazole (69.9 g; 1026.7 mmol) in dichloromethane (1120 ml ) was added tert-butyldimethylchlorosilane (77.4 g; 513.3 mmol). Upon completion of the addition, the mixture was stirred at 25°C for 16 h and poured into water (1000 ml). The separated organic layer was washed with brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidin-2-one (35.0 g; 40%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.63 (s, 1H), 4.32-4.28 (m, 1H), 3.17-3.11 (m, 1H), 2.46-2.40 (m, 1H), 1.66-1.60 (m , 2Н), 0.92-0.89 (m, 14Н), 0.15 (d, J=10.4 Hz, 6Н).

Stage 5: 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidin-2-one

To a chilled (0°C) solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidin-2-one (5.0 g; 19.42 mmol) in N,N-dimethylformamide (200 ml ) was added sodium hydride (60%; 1.2 g; 29.13 mmol). Upon completion of the addition, the mixture was stirred at 0° C. for 30 minutes, then o-(diphenylphosphoryl)hydroxylamine (6.8 g; 29.13 mmol) was added. The resulting mixture was stirred at 20° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidin-2-one (5.3 g; 100%) as a yellow oil. LCMS : R _T = 1.178 min, m/z = 273.3 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.178 min, ESI+: [M+H] = 273.3 detected.

Stage 6: ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate

Ethyl-2- ethoxy-2-imino-acetate (8.44 g; 58.14 mmol). The reaction mixture was stirred at 90°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate (7 .10 g, 98%) as a yellow oil. LCMS: R _T = 0.948 min, m/z = 372.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.948 min, ESI+: [M+H] = 372.2 detected.

Stage 7: ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-2-oxo-pyrrolidin-1-yl]amino]-2-iminoacetate (7.1 g; 19 .11 mmol) in toluene (140 ml) p-toluenesulfonic acid monohydrate (4.4 g; 22.93 mmol) was added. The reaction mixture was stirred at 120°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-carboxylate (6.6 g; 98%) as a yellow oil. LCMS: R _T = 0.952 min, m/z = 354.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.952 min, ESI+: [M+H] = 354.2 detected.

Step 7: Ethyl cis-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 6.6 g; 18.67 mmol) in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 18.67 ml; 18.67 mmol) at 25°C. The reaction mixture was stirred at 40°C for 16 h and concentrated. The residue was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 70% ethyl acetate in petroleum ether) to give ethyl cis-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (2.8 g; 62.7%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.34-5.31 (m, 1H), 4.47-4.43 (m, 2H), 4.26-4.24 (m, 1H), 3.14-3.09 (m, 1H), 2.48-2.42 (m, 2H), 1.43-1.39 (m, 3H), 1.07 (d, J=7.2 Hz, 3H), 0.92 (d, J=7.2 Hz, 3H).

Step 8: Ethyl trans-5-isopropyl-7-(4-nitrobenzoyl)oxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a mixture of ethyl cis-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.0 g; 8. 36 mmol), 4-nitrobenzoic acid (2.1 g; 12.54 mmol) and triphenylphosphine (6.6 g; 25.08 mmol) in tetrahydrofuran (40 ml) were added diisopropyl azodicarboxylate (5.0 ml; 25.08 mmol ) at 0°C in a nitrogen atmosphere. The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 17% ethyl acetate in petroleum ether) to give ethyl trans-5-isopropyl-7-(4-nitrobenzoyl)oxy-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazole-2-carboxylate (2.5 g; 77%) as a yellow solid.

Step 9: Ethyl trans-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of potassium carbonate (1.23 g; 8.88 mmol) and ethyl trans-5-isopropyl-7-(4-nitrobenzoyl)oxy-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazole-2-carboxylate (2.3 g; 5.92 mmol) in ethanol (10 ml)/tetrahydrofuran (5 ml)/water (5 ml) was stirred at 25°C for 1 h and concentrated under reduced pressure. The residue was diluted with water (50 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl trans-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxylate (1.10 g; 78%) as a colorless oil.

Step 10: Ethyl cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a mixture of ethyl trans-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.0 g; 4. 18 mmol) in dichloromethane (20 ml) diethylaminosulfur trifluoride (2.23 ml; 16.72 mmol) was added at 0° C. under nitrogen atmosphere. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous sodium bicarbonate (200 ml). The solution was extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine (2×100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 7% ethyl acetate in petroleum ether) to give ethyl cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (550 mg; 55%) as a colorless oil.

Step 11: cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Mixture of ethyl cis-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (550 mg; 2.28 mmol) and hydroxide lithium hydrate (191 mg; 4.56 mmol) in methanol (10 ml)/tetrahydrofuran (5 ml)/water (5 ml) was stirred at 20°C for 1 h and concentrated under reduced pressure. The residue was diluted with water (20 ml) and washed with ethyl acetate (20 ml). The pH of the aqueous phase was adjusted to 6 by adding a solution of hydrochloric acid (1 M) and then extracted with ethyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carboxylic acid (420 mg; 86%) as a colorless oil.

Step 12: cis-7-fluoro-5-isopropyl-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (420 mg; 1.97 mmol), N,N-diisopropylethylamine (1.05 ml; 5.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (453 mg; 2.36 mmol), 1-hydroxybenzotriazole (160 mg; 1.18 mmol ) and N,O-dimethylhydroxylamine hydrochloride (384 mg; 3.94 mmol) in dichloromethane (10 ml) was stirred at 25° C. for 16 h and quenched by adding water (20 ml). The mixture was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with brine (2×50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 50 to 60%) to give cis-7-fluoro-5-isopropyl-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazole-2-carboxamide (200 mg; 40%) as a yellow oil. LCMS: R _T = 0.692 min, m/z = 257.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.692 min, ESI+: detected [M+H] = 257.1.

Stage 13: cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a cooled (0°C) solution of cis-7-fluoro-5-isopropyl-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-carboxamide (200 mg; 0.78 mmol) in tetrahydrofuran (5 ml) was added cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 1.0 ml; 0.50 mmol) under nitrogen atmosphere. The mixture was stirred at 25°C for 1 h and quenched by adding saturated aqueous ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (2×10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 40% ethyl acetate in petroleum ether) to give cyclopropyl-[cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazol-2-yl]methanone (100 mg; 52%) as a white solid. This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl]methanone (peak 2, retention time = 5.136 min) (24 mg; 23%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.99-5.83 (m, 1H), 4.39-4.34 (m, 1H), 3.22-3.18 (m, 1H), 3.12-3.08 (m, 1H), 2.72-2.62 (m, 1H), 2.42-2.38 (m, 1H), 1.34-1.33 (m, 2H), 1.13-1.10 (m, 2H), 1.08 (d, J=6.8 Hz, 3H), 0.94 (d , J=6.8 Hz, 3H). LCMS: R _T = 0.822 min, m/z = 238.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.822 min, ESI+: [M+H] = 238.0 detected.

SFC conditions: column: Lux 3u Cellulose-2, 150 x 4.6 mm; mobile phase: A: CO ₂ , B: methanol (with 0.05% DEA); gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then at 5% B for 2.5 minutes; flow rate: 2.5 ml/min; column temperature 35°C.

Method 88

Cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: (E)-cyclopropanecarbaldehyde oxime

To a solution of cyclopropanecarboxaldehyde (50.0 g; 713.37 mmol) in ethanol (500 ml) were added sodium carbonate (166.3 g; 1569.4 mmol) and hydroxylamine hydrochloride (59.5 g; 856.04 mmol). The reaction mixture was stirred at 25°C for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water (1000 ml) and extracted with ethyl acetate (3×600 ml). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude (E)-cyclopropanecarbaldehyde oxime (40 g; 66%) as a colorless oil.

Stage 2: methyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate

Mixture of pyridine (2.85 ml; 35.25 mmol), N-chlorosuccinimide (78.5 g; 587.54 mmol) and (E)-cyclopropanecarbaldehyde oxime (50 g; 587.54 mmol) in chloroform (500 ml) stirred at 25°C for 2 h, then a solution of methyl acrylate (66.45 ml; 733.25 mmol) and triethylamine (85.35 ml; 615.75 mmol) in chloroform (100 ml) was added. The reaction mixture was stirred at 25°C for 12 h and extinguished by adding water (200 ml). The resulting mixture was extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give methyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate (75.0 g; 76%) as colorless oil.

Stage 3: 5-cyclopropyl-3-hydroxy-pyrrolidin-2-one

A mixture of methyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate (35.0 g; 206.88 mmol) and platinum oxide (6.1 g; 26.89 mmol) in ethylene glycol (300 ml) was stirred at 25 °C in a hydrogen atmosphere (30 psi (206.8 kPa)) for 48 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 100% ethyl acetate in petroleum ether) to give 5-cyclopropyl-3-hydroxy-pyrrolidin-2-one (15.5 g; 53%) as a colorless oil . LCMS: R _T = 0.297 min, m/z = 142.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 0.297 min, ESI+: [M+H] = 142.1 detected.

Stage 4: 3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidin-2-one

To a chilled (0°C) mixture of 5-cyclopropyl-3-hydroxy-pyrrolidin-2-one (13.0 g; 92.09 mmol) and imidazole (18.8 g; 276.26 mmol) in dichloromethane (150 ml ) was added tert-butyldimethylchlorosilane (20.8 g; 138.13 mmol). The mixture was stirred at 25°C for 16 h and then washed with water (2×50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give 3-[t-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidin-2-one (10.2 g; 43%) as a colorless oil.

Stage 5: 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidin-2-one

To a chilled (0°C) solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidin-2-one (10.2 g; 39.93 mmol) in N,N-dimethylformamide (150 ml ) sodium hydride (60% in mineral oil; 2.4 g; 59.9 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and then O-(diphenylphosphoryl)hydroxylamine (14.0 g; 59.9 mmol) was added. The resulting mixture was stirred at 10°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidin-2-one (10.5 g; 97%) as a yellow oil. LCMS : R _T = 0.810 min, m/z = 271.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.810 min, ESI+: [M+H] = 271.2 detected.

Stage 6: ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate

Mixture of 1-amino-3-[t-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidin-2-one (10.5 g; 38.83 mmol) and ethyl 2-ethoxy-2-imino-acetate (14.1 g; 97.06 mmol) in ethanol (150 mL) was stirred at 90° C. for 12 h and concentrated under reduced pressure to give crude ethyl 2-[[3-[t-butyl(dimethyl)silyl ]hydroxy-5-cyclopropyl-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate (10.0 g; 70%) as a yellow oil. LCMS: R _T = 0.804 min, m/z = 370.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.804 min, ESI+: [M+H] = 370.2 detected.

Stage 7: ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl-(2Z)-2-amino-2-[3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-2-oxo-pyrrolidin-1-yl]iminoacetate (10.0 g ; 27.06 mmol) in toluene (120 ml) was added p-toluenesulfonic acid (5.6 g; 32.47 mmol). The reaction mixture was stirred at 120°C for 16 h and concentrated under reduced pressure. The residue was diluted with water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were concentrated under reduced pressure to give crude ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazole-2-carboxylate (9.5 g; 99%) as a red oil. LCMS: R _T = 0.928 min, m/z = 352.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.928 min, ESI+: [M+H] = 352.2 detected.

Stage 8: ethyl 5-cyclopropyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ( 9.5 g; 27.03 mmol) in tetrahydrofuran (100 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 27.0 ml; 27.0 mmol). The reaction mixture was stirred at 40°C for 12 h and concentrated under reduced pressure. The residue was diluted with water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 100% ethyl acetate in petroleum ether) to give ethyl 5-cyclopropyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazole-2-carboxylate (2.2 g; 34%) as a yellow oil. LCMS: R _T = 0.521 min, m/z = 238.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.521 min, ESI+: [M+H] = 238.1 detected.

Step 9: Ethyl cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a cooled (0°C) solution of ethyl 5-cyclopropyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.0 g; 8.43 mmol) in dichloromethane (20 ml) was added diethylaminosulfur trifluoride (3.26 ml; 25.29 mmol). The reaction mixture was stirred for 12 h at 0° C. and quenched by adding water (5.0 ml). The resulting mixture was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give ethyl cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole-2-carboxylate (220 mg; 11%) as a yellow oil. LCMS: R _T = 0.701 min, m/z = 240.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.701 min, ESI+: [M+H] = 240.1 detected.

Step 10: cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of lithium hydroxide monohydrate (105 mg; 2.51 mmol) and ethyl cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-carboxylate (200 mg; 0.84 mmol) in ethanol (0.50 ml)/water (0.50 ml)/tetrahydrofuran (0.50 ml) was stirred at 25°C for 2 h and concentrated at reduced pressure. The pH of the aqueous residue was adjusted to 7 by adding aqueous hydrochloric acid (1M solution) and the residue was concentrated under reduced pressure to give crude cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole-2-carboxylic acid (175 mg; 99%) as a yellow oil. LCMS: R _T = 0.452 min, m/z = 212.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.452 min, ESI+: [M+H] = 212.1 detected.

Step 11: cis-5-cyclopropyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (175 mg; 0.83 mmol), 1-hydroxybenzotriazole (56 mg; 0.41 mmol), N,O-dimethylhydroxylamine hydrochloride (121 mg; 1.24 mmol), N,N-diisopropylethylamine (0.34 ml; 2.07 mmol) and 1-(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190.6 mg; 0.99 mmol) in dichloromethane (5 ml) was stirred at 25° C. for 16 h and quenched by adding water (10 ml). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 60% ethyl acetate in petroleum ether) to give cis-5-cyclopropyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (75 mg; 36%) as a colorless oil. LCMS: R _T = 0.604 min, m/z = 255.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.604 min, ESI+: detected [M+H] = 255.1.

Stage 12: cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a cooled (0°C) solution of cis-5-cyclopropyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-carboxamide (65 mg; 0.26 mmol) in tetrahydrofuran (5 ml) was added cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 1.24 ml; 0.62 mmol) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (3 ml). The resulting mixture was extracted with ethyl acetate (3×5 ml). The combined organic layers were washed with brine (5 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give cyclopropyl-[cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone (50 mg; 83%) as a yellow oil. LCMS: R _T = 0.676 min, m/z = 236.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.676 min, ESI+: [M+H] = 236.1 detected.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.841 min) (3.1 mg; 6%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 6.05-5.89 (m, 1H), 4.02-3.95 (m, 1H), 3.51-3.35 (m, 1H), 3.14-3.10 (m, 1H), 2.78- 2.70 (m, 1H), 1.26-1.12 (m, 5H), 0.79-0.67 (m, 3H), 0.58-0.52 (m, 1H). LCMS: R _T = 0.677 min, m/z = 236.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.677 min, ESI+: detected [M+H] = 236.1.

SFC conditions: column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 5 µm); mobile phase: A: CO ₂ , B: 0.1% NH ₃ H ₂ O in IPA; first at 40%, at the end at 40%; gradient elution mode: gradient: 40% to 40% B in 5 minutes and hold at 40% for 2.5 minutes; flow rate: 60 ml/min; column temperature: 35°C.

Method 89

Cyclopropyl-[(5S,7S)-7-deutero-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of cyclopropyl-[(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone ( 50 mg; 0.17 mmol) in methanol (2.0 ml) nickel (10 mg; 0.17 mmol) was added. The mixture was stirred at 20° C. under a hydrogen atmosphere (15 psi (103.4 kPa)) for 2 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with RP-HPLC (water (with 0.05% ammonium hydroxide, v/v)/acetonitrile: 33-63%) to give cyclopropyl-[(5S,7S)-7-deutero -5-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (14.8 mg; 33%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.36 (m, 3H), 7.14-7.11 (m, 2H), 5.52-5.48 (m, 1H), 3.28-3.21 (m, 1H), 3.06-3.00 (m, 2H), 2.70-2.65 (m, 1H), 1.30-1.27 (m, 2H), 1.06-1.03 (m, 2H). LCMS: R _T = 1.551 min, m/z = 255.1 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.551 min, ESI+: detected [M+H] = 255.1.

Method 90

Cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone, cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]methanone and cyclopropyl-[(5R,7R)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl]methanone

Stage 1: 1-nitrobutan-2-ol

To a mixture of nitromethane (52.6 g; 860.9 mmol), ammonium hexadecyltrimethyl chloride (27.6 g; 86.1 mmol), sodium hydroxide (34.4 g; 860.9 mmol) in water (2.5 L) propionaldehyde (50.0 g; 860.9 mmol) was added at 25°C. The mixture was stirred at 25°C for 4 h, then added sodium chloride (700 g) and was extracted with ethyl acetate (2×300 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-nitrobutan-2-ol (80.0 g; 78%) as a light brown oil. The crude oil was used directly in the next step without further purification.

Step 2: tert-butyldimethyl((1-nitrobutan-2-yl)oxy)silane

tert-Butyldimethylchlorosilane (53 .2 g; 352.6 mmol) under nitrogen at 25°C. Upon completion of the addition, the reaction mixture was stirred at 25°C for 15 hours Then the mixture was diluted with water (400 ml) and was extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give t-butyl-dimethyl-[1-(nitromethyl)propoxy]silane (28.0 g; 36%) as light brown oil.

Stage 3: methyl 3-(1-((tert-butyldimethylsilyl)oxy)propyl)-4,5-dihydroisoxazole-5-carboxylate

To a mixture of methyl acrylate (54.4 ml; 599.9 mmol), di-tert-butyl dicarbonate (39.3 g; 179.9 mmol) and 4-dimethylaminopyridine (1.5 g; 12.0 mmol) in acetonitrile (500 ml) was added a solution of tert-butyl-dimethyl-[1-(nitromethyl)propoxy]silane (28.0 g; 119.9 mmol) in acetonitrile (10 ml). The mixture was stirred at 25° C. for 5 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give methyl 3-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-4,5-dihydroisoxazole-5 -carboxylate (17.0 g; 47%) as a brown oil.

Step 4: 5-(1-((tert-butyldimethylsilyl)oxy)propyl)-3-hydroxypyrrolidin-2-one

A mixture of ethyl 3-[1-[t-butyl(dimethyl)silyl]oxypropyl]-4,5-dihydroisoxazole-5-carboxylate (17.0 g; 53.89 mmol) and palladium (10% on charcoal; 3.0 g) in ethanol (500 ml) was stirred at 40°C in an atmosphere of hydrogen (50 psi (344.7 kPa)) for 48 h and filtered. The filtrate was concentrated under reduced pressure to give crude 5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-3-hydroxy-pyrrolidin-2-one (12.0 g, 82%) as a white solid.

Stage 5: 3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)pyrrolidin-2-one

Tetrabutylammonium bromide (519 mg; 1.6 mmol), aqueous sodium hydroxide solution (30%, 60 ml) and benzyl bromide (8.3 g; 48.3 mmol). After the addition was complete, the mixture was stirred at 40° C. for 18 hours. The mixture was then poured into water (200 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 80% ethyl acetate in petroleum ether) to give 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]pyrrolidin-2-one ( 6.8 g; 58%) as a colorless oil.

Stage 6: 1-amino-3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)pyrrolidin-2-one

To a solution of 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-pyrrolidin-2-one (6.80 g; 18.7 mmol) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in mineral oil; 1.12 g; 28.1 mmol) at 0°C. After stirring at 25°C for 20 minutes, o-(diphenylphosphoryl)hydroxylamine (6.50 g; 28.1 mmol) was added to the mixture and stirred for another 18 hours at 25°C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 1-amino-3-benzyloxy-5-[1-[tert-butyl (dimethyl)silyl]oxypropyl]pyrrolidin-2-one (7.10 g; 100%) in as a light yellow solid. LC-MS: R _T = 0.876 min, m/z = 379.3 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.876 min, ESI+: detected [M+H] = 379.3.

Stage 7: ethyl 2-((3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)-oxy)propyl)-2-oxopyrrolidin-1-yl)amino)-2-iminoacetate

A mixture of 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-pyrrolidin-2-one (1.87 g; 4.94 mmol) and ethyl-2-ethoxy-2 -imino-acetate (1.79 g; 12.35 mmol) in ethanol (25 ml) was stirred at 90° C. for 33 h and concentrated under reduced pressure to give crude ethyl 2-((3-(benzyloxy)- 5-(1-((tert-Butyldimethylsilyl)oxy)propyl)-2-oxopyrrolidin-1-yl)amino)-2-iminoacetate (2.36 g; 99%) as a yellow oil. The crude product was used in the next step without further purification. LC-MS: R _T = 1.037 and 1.061 min, m/z = 478.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention times 1.037 and 1.061 min, ESI+: [M+H] = 478.2 detected.

Stage 8: ethyl-7-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)-propyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazole-2-carboxylate

To a solution of ethyl 2-[[3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]-hydroxypropyl]-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate (2 .2 g; 4.61 mmol) in toluene (50 ml) was added p-toluenesulfonic acid (monohydrate; 1.1 g; 5.53 mmol). The reaction mixture was stirred at 120°C for 16 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give ethyl 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.9 g; 43%) as a colorless oil. LC-MS: R _T = 0.935 min, m/z = 460.3 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.935 min, ESI+: [M+H] = 460.3 detected.

Step 9: Ethyl 7-(benzyloxy)-5-(1-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carboxylate (800 mg; 1.74 mmol) in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 5.22 ml; 5.22 mmol). The mixture was stirred at 25°C for 18 h and diluted with water (20 ml). The resulting mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl 7-benzyloxy-5-(1-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (70 mg; 93%) as a brown oil. This crude oil was used in the next step without further purification.

Step 10: Ethyl 7-(benzyloxy)-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a mixture of ethyl 7-benzyloxy-5-(1-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (600 mg; 1, 74 mmol) and sodium bicarbonate (584 mg; 6.95 mmol) in dichloromethane (20 ml) Dess-Martin periodinan (1473 mg; 3.47 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 40 min and then quenched by adding saturated aqueous sodium sulfite (20 ml). The separated organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.3) to give ethyl 7-benzyloxy-5-propanoyl-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazole-2-carboxylate (590 mg; 99%) as light brown oil. LC-MS: R _T = 0.834 min, m/z = 344.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.834 min, ESI+: [M+H] = 344.1 detected.

Step 11: Ethyl 7-hydroxy-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of ethyl 7-benzyloxy-5-propanoyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (450 mg; 1.31 mmol) in 2 ,2,2-trifluoroacetic acid (20 ml) was heated at 120° C. for 3 hours and concentrated under reduced pressure. The residue was redissolved in dichloromethane (30 ml), washed with saturated aqueous sodium bicarbonate (15 ml) and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate in petroleum ether, R _f = 0.3) to give ethyl 7-hydroxy-5-propanoyl-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazole-2-carboxylate (220 mg; 66%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.43-5.39 (m, 1H), 5.25-5.21 (m, 1H), 4.50-4.43 (m, 2H), 3.05-3.01 (m, 2H), 2.75-2.55 (m, 2H), 1.44-1.40 (m, 3H), 1.13-1.08 (m, 3H). LC-MS: R _T = 0.530 and 0.564 min, m/z = 254.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention times 0.530 and 0.564 min, ESI+: [M+H] = 254.1 detected.

Step 12: Ethyl cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Mixture of ethyl 7-hydroxy-5-propanoyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (220 mg; 0.87 mmol) and trifluoride diethylaminosulfur (140 mg; 0.87 mmol) was stirred at 10°C for 2 h and then extinguished by adding saturated aqueous sodium bicarbonate (15 ml). The resulting mixture was extracted with dichloromethane (2×10 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4 for the cis isomer and R _f = 0.6 for the trans isomer) to give ethyl trans-5-(1,1-difluoropropyl )-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (60 mg; 25%) and ethyl cis-5-(1 ,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (60 mg; 25%), both as brown oils.

Step 13: cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

To a solution of ethyl cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (55 mg; 0.20 mmol) in tetrahydrofuran (2 ml), ethanol (2 ml) and water (0.5 ml) was added lithium hydroxide monohydrate (83 mg; 1.98 mmol). The reaction mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure. The residue was diluted with ice water (20 ml) and the pH was adjusted to 3 by adding aqueous hydrochloric acid (4 M solution). The mixture was extracted with ethyl acetate (2×5 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazole-2-carboxylic acid (40 mg; 81%) as a light pink solid.

Step 14: cis-5-(1,1-difluoropropyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide

Cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid mixture (40 mg; 0.16 mmol), N,O-dimethylhydroxylamine hydrochloride (31 mg; 0.32 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium- Hexafluorophosphate 3-oxide (64 mg; 0.17 mmol) and N,N-diisopropylethylamine (0.08 ml; 0.48 mmol) in N,N-dimethylformamide (1 ml) was stirred at 20°C for 2 h and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.3) to give cis-5-(1,1-difluoropropyl)-7-fluoro-N-methoxy-N-methyl-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (27 mg; 58%) as a colorless oil. LC-MS: R _T = 0.714 min, m/z = 293.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.714 min, ESI+: detected [M+H] = 293.1

Stage 15: cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl]methanone

To a solution of cis-5-(1,1-difluoropropyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-carboxamide (27 mg; 0.09 mmol) in tetrahydrofuran (0.5 ml) was added cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 0.92 ml; 0.46 mmol) under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at 0°C for 1 h and extinguished by adding methanol (10 ml). The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.6) to give cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoropropyl) -7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (cis-mix) (9.9 mg; 35%) in form of a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 5.97-5.80 (m, 1H), 4.90-4.78 (m, 1H), 3.45-3.25 (m, 1H), 3.05-2.95 (m, 1H), 2.95- 2.75 (m, 1H), 2.28-2.00 (m, 2H), 1.20-1.11 (m, 2H), 1.07-0.98 (m, 5H). LC-MS: R _T = 0.766 min, m/z = 274.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.766 min, ESI+: [M+H] = 274.1 detected.

Step 16: cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone and cyclopropyl-[(5R,7R)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2 ,4]triazol-2-yl]methanone

Cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone (58 mg) was resolved with chiral SFC to give, as tentatively indicated:

cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]methanone (peak 2, retention time=5.085 min) (8.2 mg; 14%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.02-5.84 (m, 1H), 4.71-4.66 (m, 1H), 3.33-3.23 (m, 1H), 3.19-3.07 (m, 2H), 2.34- 2.26 (m, 1H), 2.18-2.01 (m, 1H), 1.35-1.25 (m, 2H), 1.18 (s, 1H), 1.17-1.15 (m, 2H), 1.14-1.11 (m, 2H). LC-MS: R _T = 0.818 min, m/z = 273.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.818 min, ESI+: detected [M+H] = 273.9;

cyclopropyl-[(5R,7R)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]methanone (peak 1, retention time = 3.815 min) (13.9 mg; 23%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.04-5.81 (m, 1H), 4.69-4.61 (m, 1H), 3.43-3.23 (m, 1H), 3.20-3.00 (m, 2H), 2.43-2.22 (m, 1H), 2.20-2.00 (m, 1H), 1.35-1.25 (m, 2H), 1.18 (s, 1H), 1.16-1.15 (m, 2H), 1.15-1.12 (m, 2H). LC-MS: R _T = 0.815 min, m/z = 273.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.815 min, ESI+: [M+H] = 273.9 detected.

Method 91

Cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: methyl 2-cyclopropyloxirane-2-carboxylate

To a mixture of sodium methoxide (40.5 g; 749.04 mmol) in methanol (250 ml) was added cyclopropanecarboxaldehyde (35.0 g; 499.36 mmol) at −10° C., then methyl chloroacetate ( 81.3 g; 749.04 mmol). Upon completion of the addition, the mixture was stirred at 25° C. for 16 h and quenched by adding acetic acid. The resulting mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude methyl 2-cyclopropyloxirane-2-carboxylate as a brown oil. The oil was distilled under reduced pressure to give methyl 2-cyclopropyloxirane-2-carboxylate (38 g; 53%) as a colorless oil.

Stage 2: (Z)-2-cyclopropylacetaldehyde oxime

To a solution of sodium hydroxide (19.9 g; 498.07 mmol) in water (70 ml) was added methyl 2-cyclopropyloxirane-2-carboxylate (59.0 g; 415.05 mmol) at 25°C for 2 h The reaction mixture was stirred at 25°C for 1 h and hydroxylamine sulfate (37.5 g; 228.28 mmol) was added over 30 min at 25°C. The mixture was stirred at 25°C for 2 h and diluted with water (300 ml). The solution was extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine (300 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 50% ethyl acetate in petroleum ether) to give (Z)-2-cyclopropylacetaldehyde oxime (23.5 g; 57%) as a white solid. LC-MS: R _T = 0.265 min, m/z = 100.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.265 min, ESI+: [M+H] = 100.1 detected.

Stage 3: methyl 3-(cyclopropylmethyl)-4,5-dihydroisoxazole-5-carboxylate

A solution of pyridine (0.85 ml; 10.59 mmol), N-chlorosuccinimide (28.3 g; 211.84 mmol) and (Z)-2-cyclopropylacetaldehyde oxime (21.0 g; 211.84 mmol) in chloroform (200 ml) was stirred at 25°C for 2 h and then a solution of methyl acrylate (23.96 ml; 264.38 mmol) and triethylamine (30.77 ml; 222.01 mmol) in chloroform (30 ml) was added. The mixture was stirred at 25°C for 16 h and diluted with water (300 ml). The mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0-50% ethyl acetate in petroleum ether) to give methyl 3-(cyclopropylmethyl)-4,5-dihydroisoxazole-5-carboxylate (21.0 g; 54%) in the form of a colorless oil. LC-MS: R _T = 0.565 min, m/z = 184.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.565 min, ESI+: [M+H] = 184.1 detected.

Step 4: 5-(cyclopropylmethyl)-3-hydroxypyrrolidin-2-one

A mixture of methyl 3-(cyclopropylmethyl)-4,5-dihydroisoxazole-5-carboxylate (18.0 g; 98.25 mmol) in methanol and palladium (10% on charcoal; 10.5 g) was stirred at 25° C in an atmosphere of hydrogen (15 psi (103.4 kPa)) for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh; 0-100% ethyl acetate in petroleum ether) to give 5-(cyclopropylmethyl)-3-hydroxy-pyrrolidin-2-one (6.2 g; 41%) as a colorless oil. LC-MS: R _T = 0.272 min, m/z = 165.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.272 min, ESI+: [M+H] = 165.2 detected.

Stage 5: 3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)pyrrolidin-2-one

tert- butyldimethylchlorosilane (11.1 g; 73.46 mmol). The mixture was stirred at 20°C for 16 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0-50% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidin-2-one (7.7 g; 78%) as a white solid. LC-MS: R _T = 0.872 min, m/z = 270.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.872 min, ESI+: [M+H] = 270.2 detected.

Stage 6: 1-amino-3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)pyrrolidin-2-one

Sodium hydride ( 60%, 1.6 g, 40.08 mmol) at 0°C. After stirring at 0° C. for 30 min, O-(diphenylphosphoryl)hydroxylamine (9.3 g; 40.08 mmol) was added and the mixture was stirred at 10° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidin-2-one (7.5 g, 99%) as a yellow oil. LC-MS: R _T = 0.772 min, m/z = 285.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.772 min, ESI+: [M+H] = 285.2 detected.

Step 7: (Z)-ethyl-2-amino-2-((3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)-2-oxopyrrolidin-1-yl)imino)acetate

A mixture of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidin-2-one (7.1 g; 24.96 mmol) and ethyl 2-ethoxy-2-imino- acetate (9.1 g; 62.4 mmol) in ethanol (150 ml) was stirred at 90° C. for 12 h and concentrated under reduced pressure to give crude (Z)-ethyl-2-amino-2-((3 -((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)-2-oxopyrrolidin-1-yl)imino)acetate (9.2 g; 96%) as a yellow oil. LC-MS: R _T = 0.783 min, m/z = 384.3 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.783 min, ESI+: [M+H] = 384.3 detected.

Stage 8: ethyl 5-(cyclopropylmethyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of (Z)-ethyl-2-amino-2-[3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)-2-oxo-pyrrolidin-1-yl]iminoacetate (9.2 g; 23.99 mmol) and p-toluenesulfonic acid (5.0 g; 28.78 mmol) in toluene (100 ml) was stirred at 120° C. for 16 h and diluted with water (200 ml). The mixture was extracted with ethyl acetate (3×200 ml). The combined organic layers were concentrated under reduced pressure to give crude ethyl 5-(cyclopropylmethyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (4.9 g; 82%) as red oil. LC-MS: R _T = 0.540 min, m/z = 252.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.540 min, ESI+: [M+H] = 252.2 detected.

Step 9: Ethyl cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 5-(cyclopropylmethyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.0 g; 11, 98 mmol) in dichloromethane (150 ml) was added diethylaminosulfur trifluoride (5.8 g; 35.94 mmol). The mixture was stirred at 0° C. for 16 h and quenched by adding saturated aqueous sodium bicarbonate (200 ml). The resulting mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give ethyl trans-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole-2-carboxylate (650 mg; 21%) and ethyl cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole-2-carboxylate (850 mg; 28%), both as yellow oil (TLC: 33% ethyl acetate in petroleum ether, R _f = 0.35 for the cis isomer and R _f = 0.85 for the trans isomer).

Step 10: cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Ethyl cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate mixture (750 mg; 2.96 mmol) and lithium hydroxide monohydrate (1.2 g; 29.61 mmol) in ethanol (3 ml) and water (1 ml) were stirred at 20°C for 16 h and concentrated under reduced pressure. The residue was diluted with ice water (2 ml) and the pH was adjusted to 3 by adding hydrochloric acid (2 M solution). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxylic acid (660 mg; 99%) as a clear oil. LC-MS: R _T = 0.491 min, m/z = 226.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.491 min, ESI+: detected [M+H] = 226.2.

Step 11: cis-5-(cyclopropylmethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- carboxamide

cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid mixture (660 mg; 3.11 mmol ), N,N-diisopropylethylamine (3.32 ml; 18.65 mmol), N,O-dimethylhydroxylamine hydrochloride (606 mg; 6.22 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2 ,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1536 mg; 4.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25°C for 3 h and diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude cis-5-(cyclopropylmethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (670 mg; 80%) as a brown solid. LC-MS: R _T = 0.706 min, m/z = 269.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.706 min, ESI+: detected [M+H] = 269.2.

Step 12: cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ]Methanone

To a solution of cis-5-(cyclopropylmethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (150 mg; 0.56 mmol) in tetrahydrofuran (1 ml) was added cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran; 3.35 ml; 1.68 mmol) at 0°C. The mixture was stirred at 0°C for 5 h and extinguished by adding water (5 ml). The resulting mixture was extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 30-60%/0.225% formic acid in water) and further purified with chiral SFC to give, by convention: cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 3.498 min) (13.6 mg; 9.5% ) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 6.02-6.00 (m, 0.5H), 5.88-5.86 (m, 0.5H), 4.60-4.55 (m, 1H), 3.37-3.23 (m, 1H ), 3.05-3.01 (m, 1Н), 2.75-2.60 (m, 1Н), 2.00-1.95 (m, 1Н), 1.68-1.65 (m, 1Н), 1.16-1.06 (m, 4Н), 0.90-0.77 (m, 1Н), 0.49–0.47 (m, 2Н), 0.10–0.02 (m, 2Н). LC-MS: R _T = 0.635 min, m/z = 250.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.635 min, ESI+: found [M+H] = 250.2.

The (5S,7R)-isomer (peak 1, retention time = 3.041 min) (13.5 mg; 9%) was also obtained as a colorless oil.

SFC Conditions: Column: Chiralpak AD-3, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B in 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 25 ml/min; column temperature: 40°C.

SFC Conditions: Column: Lux Cellulose-2, 150 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B in 5.5 min and hold at 40% for 3 min, then at 5% B for 1.5 min; flow rate: 2.5 ml/min; column temperature: 40°C.

Method 92

Cyclopropyl-[(5S)-7,7-dideutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: cyclopropyl-[(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R,7R)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Cyclopropyl-[rac-(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone ( 350 mg; from a batch of a different scale) were separated by chiral SFC, obtaining, as conventionally indicated:

cyclopropyl-[(5R,7R)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1 : retention time = 3.132 min, 100 mg; 10%) and cyclopropyl-[(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone (peak 2: retention time = 4.124 min, 100 mg; 10%), both as white solids.

SFC conditions: column: OJ-H (250 mm × 30 mm; 10 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first at 30%, at the end at 30%; flow rate (80 ml/min); column temperature 40°C.

Stage 2: cyclopropyl-[(5S)-7,7-dideutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A solution of cyclopropyl-[(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (40 mg; 0.14 mmol) and zinc (40 mg; 0.61 mmol) in formic acid-D ₂ (2.0 ml; 0.14 mmol) were stirred at 20°C for 48 hours. The mixture was diluted with ethyl acetate (20 ml), washed with water (2×10 ml) and concentrated under reduced pressure. The residue was purified with RP-HPLC (water (with 0.05% ammonium hydroxide, v/v)/acetonitrile, 36-66%) to give cyclopropyl-[(5S)-7,7-dideutero -5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (13.2 mg; 36%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.36 (m, 3H), 7.14-7.11 (m, 2H), 5.52-5.48 (m, 1H), 3.28-3.21 (m, 1H), 3.04-3.00 (m, 1Н), 2.70-2.65 (m, 1Н), 1.30-1.27 (m, 2Н), 1.06-1.03 (m, 2Н). LCMS: R _T = 1.549 min, m/z = 256.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia for 3 min): retention time 1.549 min, ESI+: detected [M+H] = 256.2.

Method 93

Cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl- [(5R,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture of thionyl chloride (441 mg; 3.71 mmol) and cyclopropyl-[trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone (400 mg; 1.49 mmol) was stirred at 0° C. for 0.5 h and quenched by adding water (100 ml). The mixture was extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give cyclopropyl-[cis-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazol-2-yl]methanone (220 mg; 52%) as a yellow solid. LC-MS: R _T = 0.692 min, m/z = 288.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.692 min, [M+H] = 288.1.

This cis mixture was further separated with chiral SFC to give, as conventionally indicated:

cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1 , retention time = 3.711 min) (72.9 mg; 33%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.39 (m, 2H), 7.33-7.28 (m, 3H), 5.56-5.51 (m, 1H), 5.40-5.35 (m, 1H), 3.95-3.88 (m, 1Н), 3.07-2.99 (m, 2Н), 1.34-1.31 (m, 2Н), 1.11-1.07 (m, 2Н). LCMS: R _T = 1.034 min, m/z = 288.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.034 min, ESI+: detected [M+H] = 288.2;

cyclopropyl-[(5R,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2 , retention time = 3.949 min) (84.6 mg; 38%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.39 (m, 2H), 7.33-7.28 (m, 3H), 5.56-5.51 (m, 1H), 5.40-5.35 (m, 1H), 3.96-3.86 (m, 1H), 3.10-2.99 (m, 2H), 1.35-1.28 (m, 2H), 1.10-1.06 (m, 2H). LCMS: R _T = 1.033 min, m/z = 288.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.033 min, ESI+: [M+H] = 288.2 detected.

SFC method: column: Chiralcel OJ-3, 150×4.6 mm (id. dia.), 3 µm; mobile phase: A: CO ₂ , B: ethanol (with 0.05% DEA); gradient: 5% to 40% B over 5 min and hold at 40% for 2.5 min, then at 5% B for 2.5 min; flow rate: 2.5 ml/min; column temperature: 35°C.

Method 94

Cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: [rac-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy -tert-butyl-dimethyl-silane

Rac-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol mixture (800 mg; 2 .86 mmol), imidazole (389 mg; 5.71 mmol) and tert-butyldimethylchlorosilane (646 mg; 4.28 mmol) in dichloromethane (20 ml) were stirred at 15°C for 1.5 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give [rac-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (900 mg; 80%) as a colorless oil.

Stage 2: cyclopropyl-[(rac-5S,7S)-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone

To a solution of N-methoxy-N-methyl-cyclopropanecarboxamide (589 mg; 4.56 mmol) and [rac-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1, Isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran; 3.42 ml; 6.85 mmol) at 0°C. The mixture was stirred at 0°C for 1 h and diluted with ethyl acetate (100 ml). The separated organic layer was washed with saturated aqueous ammonium chloride (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give cyclopropyl-[(rac-5S,7S)-7-[t-butyl(dimethyl)silyl]oxy-5- phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (450 mg; 51%) as a colorless oil. LCMS: R _T = 1.016 min, m/z = 384.3 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.016 min, ESI+: [M+H] = 384.3 detected.

Stage 3: cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

To a solution of cyclopropyl-[(rac-5S,7S)-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2 ,4]triazol-2-yl]methanone (450 mg, 1.17 mmol) in dichloromethane (10 mL) thionyl chloride (0.43 mL, 5.87 mmol) was added. The mixture was stirred at 25°C for 40 h and concentrated under reduced pressure. The residue was diluted with water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give cyclopropyl-[rac-(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (200 mg; 59%) as a colorless oil. LCMS: R _T = 0.803 min, m/z = 288.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.803 min, ESI+: detected [M+H] = 288.2.

This racemate was further resolved with chiral SFC to give cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2 ,4]triazol-2-yl]methanone (peak 2, retention time = 4.690 min) (60 mg; 40%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.38 (m, 3H), 7.34-7.32 (m, 2H), 5.85 (t, J=7.2 Hz, 1H), 5.69-5.67 (m, 1Н), 3.40-3.31 (m, 2Н), 3.03-3.00 (m, 1Н), 1.19-1.16 (m, 2Н), 1.11-1.08 (m, 2Н). LCMS: R _T = 1.028 min, m/z = 288.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.028 min, ESI+: [M+H] = 288.2 detected.

SFC Conditions: Column: Chiralcel OJ-H, 100 x 4.6 mm (ID), 3 µm; mobile phase: A: CO ₂ , B: methanol (with 0.05% DEA); gradient: 30% to 30% B; temperature: 40°C.

Method 95

Cyclopropyl-[rac-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone and cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl]methanone

Stage 1: ethyl-3-chloro-2-vinylpyridine

A mixture of 2-bromo-3-chloropyridine (62.5 g; 324.78 mmol), potassium vinyltrifluoroborate (47.9 g; 357.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II ) (13.2 g; 16.24 mmol) and sodium bicarbonate (68.2 g; 811.94 mmol) in 1,4-dioxane (600 ml) and water (150 ml) were stirred at 100°C for 24 h and concentrated under reduced pressure. The residue was diluted with petroleum ether (500 ml) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give 3-chloro-2-vinyl-pyridine (40.0 g; 88%) as a green oil. LCMS: R _T = 0.554 min, m/z = 140.1/142.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.554 min, ESI+: found [M+H] = 140.1 and 142.1.

Stage 2: 3-chloropicolinaldehyde

To a solution of 3-chloro-2-vinyl-pyridine (35.0 g; 250.75 mmol) in water (200 ml) and tetrahydrofuran (200 ml) was added osmium tetroxide (0.89 g; 3.51 mmol). The black solution was stirred for 30 min at 25° C. and sodium periodate (214.5 g; 1003 mmol) was added. The resulting mixture was stirred at 25°C for 2 h and quenched by adding saturated aqueous sodium sulfite (200 ml). The solution was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give 3-chloropyridine-2-carbaldehyde (18.5 g; 52%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45-10.18 (m, 1H), 8.73-8.70 (m, 1H), 7.86-7.84 (m, 1H), 7.48-7.44 (m, 1H).

Stage 3: 1-(3-chloropyridin-2-yl)but-3-en-1-ol

To a solution of 3-chloropyridine-2-carboxaldehyde (18.5 g; 130.7 mmol) in tetrahydrofuran (200 ml) was added allylmagnesium bromide (1.0 M solution in n-hexane; 162.2 ml) dropwise over 30 min. ; 162.2 mmol) at 0°C. After the addition was complete, the reaction mixture was allowed to warm to 20° C. and stirred for 2 hours. The mixture was quenched by adding saturated aqueous ammonium chloride (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give 1-(3-chloro-2-pyridyl)but-3-en-1-ol (10.0 g; 42%) as a colorless oil. LCMS: R _T = 0.524 min, m/z = 184.1/186.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.524 min, ESI+: found [M+H] = 184.1 and 186.1.

Step 4: 2-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-3-chloropyridine

To a solution of 1-(3-chloro-2-pyridyl)but-3-en-1-ol (10.0 g; 54.46 mmol) in dichloromethane (100 ml) mmol) and tert-butyldimethylchlorosilane (12.3 g; 81.69 mmol). The reaction mixture was stirred at 10°C for 16 h and diluted with water (50 ml). The separated organic layer was washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give t-butyl-[1-(3-chloro-2-pyridyl)but-3-enoxy]-dimethyl-silane (10 g; 62%) as a light oil.

Stage 5: 3-((tert-butyldimethylsilyl)oxy)-3-(3-chloropyridin-2-yl)propanal

To a solution of tert-butyl-[1-(3-chloro-2-pyridyl)but-3-enoxy]-dimethylsilane (10.0 g; 33.57 mmol) in water (100 ml) and tetrahydrofuran (100 ml ) was added osmium tetroxide (0.11 g; 0.44 mmol). After stirring for 30 min at 15°C, sodium periodate (28.7 g; 134.27 mmol) was added in small portions over 30 min and stirred at 25°C for another 2 h. The mixture was quenched by adding saturated an aqueous solution of sodium sulfite (1.50 l) and was extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine (300 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propanal ( 6.5 g; 65%) as a yellow oil. LCMS: R _T = 0.719 min, m/z = 300.1/302.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.719 min, ESI+: found [M+H] = 300.1 and 302.1.

Step 6: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-(3-chloropyridin-2-yl)propan-1-ol

To a chilled (-78°C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (8.1 g; 26.01 mmol) in tetrahydrofuran (50 ml) dropwise in n-butyllithium (2.5 M solution in n-hexane; 9.97 ml; 24.93 mmol) was added under nitrogen atmosphere. The mixture was stirred at -78°C for 30 min and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propanal (6.5 g; 21.68 mmol) was added ) in tetrahydrofuran (15 ml). The resulting mixture was stirred at -78°C for 1.5 h and quenched by adding saturated aqueous ammonium chloride (50 ml). The solution was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl )-3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propan-1-ol (10.0 g; 87%) as a yellow oil. LCMS: R _T = 0.941 min; m/z = 533.2 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.941 min, ESI+: [M+H] = 533.2 detected.

Step 7: [1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy) -3-(3-chloropyridin-2-yl)propyl]-2,2-dimethylpropanoate

To a mixture of 4-dimethylaminopyridine (321 mg; 2.63 mmol), 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl( dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propan-1-ol (14.0 g; 26.32 mmol) and triethylamine (7.01 ml; 52.64 mmol) in dichloromethane (100 ml) pivaloyl chloride (4.8 g; 39.48 mmol) was added. The mixture was stirred at 20°C for 2 h and extinguished by adding water (50 ml). The solution was extracted with dichloromethane (2×100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give [1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3- yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propyl]-2,2-dimethylpropanoate (12.5 g; 77%) as a colorless oil.

Stage 8: 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloropyridin-2-yl)-3-hydroxypropyl-2,2-dimethylpropanoate

A mixture of [1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]-hydroxy-3-(3-chloro -2-pyridyl)propyl]-2,2-dimethylpropanoate (12.0 g; 19.48 mmol) and p-toluenesulfonic acid (4.0 g; 23.37 mmol) in methanol (100 ml) was stirred at 50° C for 2 hours and then concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give [1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-( 3-chloro-2-pyridyl)-3-hydroxy-propyl]-2,2-dimethylpropanoate (6.8 g; 83%) as a white solid. LCMS: R _T = 0.760 and 0.768 min, m/z = 417.1/419.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.760 and 0.768 min, ESI+: found [M+H] = 417.1 and 419.0.

Step 9: rac-[(5S,7S)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-7-yl]-2,2-dimethylpropanoate

To a mixture of [1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro-2-pyridyl)-3-hydroxypropyl]-2,2-dimethylpropanoate ( 6.2 g, 14.84 mmol), triphenylphosphine (4.7 g, 17.81 mmol) in tetrahydrofuran (50 ml) was added a solution of diisopropyl azodicarboxylate (3.6 g, 17.81 mmol) in tetrahydrofuran (50 ml). The mixture was stirred at 25°C for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give rac-[(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]-2,2-dimethylpropanoate (2.3 g; 39%) as a colorless oil. LCMS: R _T = 0.753 and 0.781 min, m/z = 399.0/401.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.753 and 0.781 min, ESI+: found [M+H] = 399.0 and 401.0.

Step 10: rac-(5S,7S)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-7-ol

Rac-[(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole mixture -7-yl]-2,2-dimethylpropanoate (2.3 g; 5.75 mmol), lithium hydroxide monohydrate (2.4 g; 57.55 mmol) in tetrahydrofuran (10 ml) and water (10 ml) were stirred at 25°C for 12 h and then was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give rac-(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-7-ol (1.7 g; 94%) as a white solid. LCMS: R _T = 0.639 min, m/z = 315.0/317.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.639 min, ESI+: found [M+H] = 315.0 and 317.0.

Step 11: rac-(5S,7R)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-7-yl-4-nitrobenzoate

To a mixture of triphenylphosphine (1.25 g; 4.75 mmol), rac-(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-7-ol (1.2 g; 3.80 mmol) and 4-nitrobenzoic acid (790 mg; 4.75 mmol) in tetrahydrofuran (5 ml) dropwise at 0° C., diisopropyl azodicarboxylate (0.77 ml; 4.75 mmol) was added under nitrogen atmosphere. The solution was stirred at 0° C. for 12 h and filtered to give crude rac-[(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazol-7-yl]-4-nitrobenzoate (1.6 g; 91%) as a white solid.

Step 12: rac-(5S,7R)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-7-ol

A mixture of potassium carbonate (713 mg; 5.16 mmol) and rac-[(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-7-yl]-4-nitrobenzoate (1.6 g; 3.44 mmol) in methanol (5 ml) and water (5 ml) was stirred at 70°C in for 1 h and concentrated under reduced pressure. The residue was diluted with water (10 ml) and filtered. The solid was washed with acetonitrile (5 ml) to give the crude rac-(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-7-ol (800 mg; 74%) as a white solid. LCMS: R _T = 0.649 min, m/z = 315.0/317.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.649 min, ESI+: found [M+H] = 315.0 and 317.0.

Step 13: rac-(5S,7R)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazole

To a mixture of rac-(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -7-ol (350 mg; 1.11 mmol), imidazole (151 mg; 2.22 mmol) in dichloromethane (20 ml) was added tert-butyldimethylchlorosilane (251 mg; 1.66 mmol) at 0°C. The mixture was stirred at 0° C. for 1 hour and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give rac-(5S,7R)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-( 3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (450 mg; 94%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43-8.41 (m, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.25-7.21 (m, 1H), 6.22-6.19 (m, 1H ), 5.49-5.46 (m, 1Н), 3.12-3.08 (m, 1Н), 2.97-2.93 (m, 1Н), 0.95 (s, 9Н), 0.24-0.19 (m, 6Н).

Step 14: rac-((5S,7R)-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl)(cyclopropyl)methanone

To a solution of rac-(5S,7R)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole (450 mg; 1.05 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (270 mg; 2.09 mmol) in tetrahydrofuran (20 ml) was added isopropyl magnesium chloride (2 0 M solution in tetrahydrofuran; 2.62 ml; 5.23 mmol) at 0°C. Upon completion of the addition, the reaction mixture was stirred at 0°C for 1 h and extinguished by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give rac-((5S,7R)-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridine -2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl)methanone (125 mg; 28%) as a colorless oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41-8.40 (m, 1H), 7.75-7.73 (m, 1H), 7.24-7.22 (m, 1H), 6.28-6.25 (m, 1H), 5.53-5.50 (m, 1Н), 3.15-3.12 (m, 1Н), 3.10-3.06 (m, 1Н), 3.04-3.02 (m, 1Н), 1.06-1.04 (m, 2Н), 0.96 (s, 9Н), 0.91 -0.86 (m, 2H), 0.25 (d, J=6.8 Hz, 6H). LCMS: R _T = 0.857 min, m/z = 419.1 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.857 min, ESI+: [M+H] = 419.1 detected.

Step 15: rac-((5S,7R)-5-(3-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl)(cyclopropyl)methanone

A mixture of rac-((5S,7R)-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl)(cyclopropyl)methanone (120 mg; 0.29 mmol) and hydrochloric acid (4.0 M solution in methanol; 3.60 ml; 14.40 mmol) in methanol ( 10 ml) was stirred at 20°C for 1 h and then concentrated under reduced pressure. The residue was diluted with water (10 ml) and the pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (2×20 ml). The combined organic layers were concentrated under reduced pressure to give crude rac-((5S,7R)-5-(3-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b ][1,2,4]triazol-2-yl)(cyclopropyl)methanone (52 mg; 60%) as a yellow solid. LCMS: R _T = 0.567 min, m/z = 305.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.567 min, ESI+: [M+H] = 305.0 detected.

Stage 16: cyclopropyl-[rac-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2 ,4]triazol-2-yl]methanone and cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone

To a mixture of rac-((5S,7R)-5-(3-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl)(cyclopropyl)methanone (90 mg; 0.28 mmol) in dichloromethane (2 ml) was added diethylaminosulfur trifluoride (40 mg; 0.25 mmol) at 0°C. The mixture was stirred for 1 h and then quenched by adding water (5 ml). The resulting mixture was extracted with dichloromethane (3×5 ml). The combined organic layers were washed with brine (5 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 32-62/0.05% ammonium hydroxide in water) to give cyclopropyl-[rac-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (G03345456) (15.0 mg; 28.7%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (d, J=4.8 Hz, 1H), 7.97-7.95 (m, 1H), 7.42-7.38 (m, 1H), 6.24-6.03 (m, 2Н), 3.83-3.72 (m, 1Н), 3.04-2.89 (m, 2Н), 1.18-1.15 (m, 2Н), 1.11-1.08 (m, 2Н). LCMS: R _T = 0.780 min, m/z = 306.9 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.780 min, ESI+: [M+H] = 306.9 detected.

The cis mixture was further separated by SFC to give, as conventionally indicated, cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl]methanone (G03348054) (peak 1, retention time = 3.920 min) (5.2 mg; 34%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J=4.8 Hz, 1H), 7.79-7.76 (m, 1H), 7.29-7.27 (m, 1H), 6.14-6.12 (m, 1H ), 6.11-6.10 (m, 0.5H), 5.99-5.98 (m, 0.5H), 3.71-3.64 (m, 1H), 3.13-3.02 (m, 2H), 1.34-1.32 (m, 2H) , 1.11-1.08 (m, 2H). LCMS: R _T = 0.617 min, m/z = 307.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.617 min, ESI+: [M+H] = 307.0 detected.

SFC conditions: column: OJ-H (250 mm × 30 mm, 5 µm); medium: 0.1% NH ₃ H ₂ O in EtOH; first at 35%, at the end at 35%; flow rate (50 ml/min); column temperature 40°C.

Method 96

Cyclopropyl-[rac-(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol

To a solution of 2-bromo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-one (3.0 g; 10.79 mmol) in methanol (100 ml ) sodium borodeuteride (1.4 g; 32.36 mmol) was added. The mixture was stirred at 20° C. for 1 hour and concentrated under reduced pressure. The residue was diluted with water (50 ml), aqueous hydrochloric acid (1.0 M solution; 2 ml) and was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (40 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1 ,2,4]triazol-7-ol (3.0 g; 99%) as a yellow solid. LCMS: R _T = 0.681 min, m/z = 283.0 [M+H] ⁺ .

LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.681 min, ESI+: [M+H] = 283.0 detected.

Step 2: [trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]-4-nitrobenzoate

To a mixture of 4-nitrobenzoic acid (1.0 g; 6.24 mmol), triphenylphosphine (1.9 g; 7.21 mmol) and cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo [1,2-b][1,2,4]triazol-7-ol (1.4 g; 4.8 mmol) in tetrahydrofuran (20 ml) diisopropyl azodicarboxylate (1.5 g; 7 .21 mmol) at 0°C. This mixture was stirred for 1.5 hours and filtered. The solid was washed with tetrahydrofuran (10 ml) and methyl tert-butyl ether (10 ml) to give [trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1 ,2,4]triazol-7-yl]-4-nitrobenzoate (800 mg; 39%) as a white solid. LCMS: R _T = 0.904 min, m/z = 432.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.904 min, ESI+: [M+H] = 432.0 detected.

Stage 3: trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of potassium carbonate (514 mg; 3.72 mmol) and [trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7 -yl]-4-nitrobenzoate (800 mg; 1.86 mmol) in methanol (10 ml)/water (5 ml) was stirred at 25° C. for 16 h and diluted with water (20 ml). The mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (2×20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 35% ethyl acetate in petroleum ether) to give trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b] [1,2,4]triazol-7-ol (300 mg; 57%) as a dull yellow solid. LCMS: R _T = 0.689 min, m/z = 281.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.689 min, ESI+: detected [M+H] = 281.0.

Stage 4: [trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl -silane

To a solution of trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (300 mg; 1.07 mmol) and imidazole (145 mg; 2.13 mmol) in dichloromethane (20 ml) was added tert-butyldimethylchlorosilane (241 mg; 1.6 mmol). The mixture was stirred at 25°C for 18 h and diluted with water (30 ml). The solution was extracted with dichloromethane (2×30 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give [trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b ][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (350 mg; 83%) as a yellow oil. LCMS: R _T = 0.931 min, m/z = 397.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.931 min, ESI+: [M+H] = 397.1 detected.

Step 5: [trans-7-[tert-butyl(dimethyl)silyl]oxy-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2- yl]-cyclopropyl-methanone

To a solution of N-methoxy-N-methyl-cyclopropanecarboxamide (457 mg; 3.54 mmol) and [trans-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1 ,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (350 mg; 0.89 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran; 1.33 ml; 2.66 mmol) at 0° C. under nitrogen. The mixture was stirred at 0°C for 1 h and quenched by adding saturated aqueous ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether) to give [trans-7-[t-butyl(dimethyl)silyl]oxy-7-deutero-5-phenyl-5, 6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methanone (200 mg; 59%) as a yellow oil. LCMS: R _T = 0.935 min, m/z = 385.3 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.935 min, ESI+: [M+H] = 385.3 detected.

Stage 6: cyclopropyl-[rac-(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl ]Methanone

To a mixture of [trans-7-[tert-butyl(dimethyl)silyl]oxy-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl ]-cyclopropyl-methanone (200 mg; 0.52 mmol) in dichloromethane (3 ml) was added thionyl chloride (0.19 ml; 2.6 mmol) and 2 drops of dimethylformamide. The mixture was stirred at 25°C for 16 h and concentrated under reduced pressure. The residue was diluted with water (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified first by column chromatography (silica gel, 100-200 mesh; 0 to 30% ethyl acetate in petroleum ether), then by RP-HPLC (acetonitrile 54-84%/0.05% ammonium hydroxide in water) to give cyclopropyl-[rac -(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (35.0 mg ; 23%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.46-7.38 (m, 3H), 7.33-7.31 (m, 2H), 5.69-5.65 (m, 1H), 4.02-3.96 (m, 1H), 3.07- 2.99 (m, 1H), 2.91-2.86 (m, 1H), 1.21-1.16 (m, 2H), 1.13-1.09 (m, 2H). LCMS: R _T = 1.033 min, m/z = 289.1 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2 min): retention time 1.033 min, ESI+: detected [M+H] = 289.1.

Method 97

Cyclopropyl-[rac-(5S,7R)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Stage 1: [cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl -silane

To a solution of cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (1.5 g; 5.34 mmol ) and imidazole (726 mg; 10.67 mmol) in dichloromethane (50 ml) was added tert-butyldimethylchlorosilane (1.2 g; 8.00 mmol). The mixture was stirred at 15°C for 16 h and diluted with water (20 ml). The resulting mixture was extracted with dichloromethane (2×30 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give [cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b ][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (1.8 g; 85%) as a colorless oil. LCMS: R _T = 1.029 min, m/z = 395.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.029 min, ESI+: [M+H] = 395.1 detected.

Step 2: [cis-7-[tert-butyl(dimethyl)silyl]oxy-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2- yl]-cyclopropyl-methanone

To a solution of N-methoxy-N-methyl-cyclopropanecarboxamide (1.2 g; 9.10 mmol) and [cis-2-bromo-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b] Isopropyl magnesium chloride (2 .0 M solution in tetrahydrofuran, 6.83 ml, 13.66 mmol). The mixture was stirred at 0°C for 1.5 h and quenched by adding saturated aqueous ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 20% ethyl acetate in petroleum ether) to give [cis-7-[t-butyl(dimethyl)silyl]oxy-7-deutero-5-phenyl-5, 6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methanone (450 mg; 26%) as a colorless oil. LCMS: R _T = 1.030 min, m/z = 384.2 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.030 min, ESI+: [M+H] = 384.2 detected.

Stage 3: cyclopropyl-[rac-(5S,7R)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl ]Methanone

To a mixture of [cis-7-[tert-butyl(dimethyl)silyl]oxy-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl ]-cyclopropyl-methanone (450 mg; 1.17 mmol) in dichloromethane (4 ml) was added thionyl chloride (1.47 ml; 20.23 mmol). The mixture was stirred at 25° C. for 25 h and concentrated under reduced pressure. The residue was diluted with water (50 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (40 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified first by column chromatography on silica (solvent gradient: 0-30% ethyl acetate in petroleum ether), then by RP-HPLC (40-70% acetonitrile/0.05% ammonium hydroxide in water) to give, by convention, cyclopropyl -[rac-(5S,7R)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (110 mg, 32.2% yield as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74-7.69 (m, 3H), 7.63-7.61 (m, 2H), 6.14 (t, J=6.8 Hz, 1H), 3.73-3.62 (m, 2Н), 3.61-3.59 (m, 1Н), 1.48-1.45 (m, 2Н), 1.40-1.37 (m, 2Н). LCMS: R _T = 1.033 min, m/z = 289.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid for 2.0 min): retention time 1.033 min, ESI+: detected [M+H] = 289.2.

Method 98

Cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone

Stage 1: 1-nitropropan-2-ol

To a chilled (0°C) solution of acetaldehyde (45.9 ml; 819.13 mmol) and nitromethane (44.4 ml; 819.13 mmol) in sodium hydroxide (32.8 g; 819.13 mmol) in water ( 1000 ml) was added hexadecyltrimethyl ammonium chloride (26.2 g; 81.91 mmol). The reaction mixture was stirred at 15°C for 16 h and the pH was adjusted to 7 by adding acetic acid. The mixture was extracted with ethyl acetate (2×500 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude 1-nitropropan-2-ol (61.0 g, 71%) as a light brown oil.

Stage 2: tert-butyl-dimethyl-(1-methyl-2-nitro-ethoxy)silane

To a mixture of imidazole (83.0 g; 1219 mmol) and 1-nitropropan-2-ol (61.0 g; 580.45 mmol) in dichloromethane (1.00 L) was added tert-butyldimethylchlorosilane (104.9 g; 696 .55 mmol) at 0°C. The mixture was stirred at 20°C for 16 h and diluted with water (200 ml). The solution was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give t-butyl-dimethyl-(1-methyl-2-nitro-ethoxy)silane (115.0 g; 90% ) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.53-4.68 (m, 1H), 4.24-4.53 (m, 2H), 1.25-1.32 (m, 3H), 0.87-0.90 (m, 9H), 0.07-0.12 (m, 6H).

Stage 3: ethyl 3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dihydroisoxazole-5-carboxylate

To a mixture of ethyl acrylate (242.6 ml; 2279.5 mmol), di-tert-butyl dicarbonate (157.1 ml; 683.84 mmol) and 4-dimethylaminopyridine (5.6 g; 45.59 mmol) in acetonitrile (1 k) tert-butyl-dimethyl-(1-methyl-2-nitro-ethoxy)silane (100.0 g; 455.89 mmol) was added at 20°C. The mixture was stirred at 20°C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 10% ethyl acetate in petroleum ether) to give ethyl 3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dihydroisoxazole-5 -carboxylate (40.0 g; 29%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.89-5.07 (m, 1H), 4.66-4.84 (m, 1H), 4.16-4.33 (m, 2H), 3.21-3.41 (m, 2H), 1.32-1.37 (m, 3Н), 1.26-1.30 (m, 3Н), 0.86-0.87 (m, 9Н), 0.03-0.10 (m, 6Н).

Stage 4: 5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3-hydroxy-pyrrolidin-2-one

A mixture of ethyl 3-[1-[t-butyl(dimethyl)silyl]oxyethyl]-4,5-dihydroisoxazole-5-carboxylate (40.0 g; 132.69 mmol) and palladium (10% on charcoal; 7.06 g) in ethanol (1.0 L) was hydrogenated (50 psi (344.7 kPa)) at 40° C. for 48 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3-hydroxy-pyrrolidin-2-one (37.0 g, 92%) as a white solid.

Stage 5: 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-one

Tetrabutylammonium bromide (1 .94 g; 6.01 mmol), sodium hydroxide (30% solution in water; 80.2 g; 601.34 mmol) and benzyl bromide (30.9 g; 180.4 mmol). The mixture was stirred at 40°C for 18 h and cooled to 25°C. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 80% ethyl acetate in petroleum ether) to give 3-benzyloxy-5-[1-[t-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-one ( 22.0 g; 52%) as a colorless oil. LC-MS: R _T = 0.957 min, m/z = 350.2 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.957 min, ESI+: [M+H] = 350.2 detected.

Stage 6: 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-one

To a solution of 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-pyrrolidin-2-one (22.0 g; 62.94 mmol) in N,N-dimethylformamide (400 ml) was added sodium hydride (60% in mineral oil; 3.78 g; 94.41 mmol) at 0°C. After stirring at 20° C., o-(diphenylphosphoryl)hydroxylamine (19.1 g; 81.82 mmol) was added for 30 min. The mixture was stirred at 20° C. for 18 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-one (22.9 g, 99%) as a brown oil .

Stage 7: ethyl-2-((3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopyrrolidin-1-yl)amino)-2-iminoacetate

A mixture of 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-pyrrolidin-2-one (22.0 g; 60.4 mmol) and ethyl-2-ethoxy-2 -imino-acetate (20.3 ml; 150.9 mmol) in ethanol (220 ml) was stirred at 90° C. for 33 h and concentrated under reduced pressure to give crude ethyl 2-((3-(benzyloxy)- 5-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-2-oxopyrrolidin-1-yl)amino)-2-iminoacetate (27.9 g; 99%) as a yellow oil. LC-MS: R _T = 0.840 min, m/z = 365.3 [M+15] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.840 min, ESI+: found [M+15] = 365.3.

Step 8: Ethyl 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-carboxylate

To a solution of ethyl 2-[[3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate (27, 0 g; 58.2 mmol) in toluene (500 ml) p-toluenesulfonic acid monohydrate (13.3 g; 69.9 mmol) was added. The reaction mixture was stirred at 130°C for 16 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh; 0 to 50% ethyl acetate in petroleum ether) to give ethyl 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (11.2 g; 43%) as a yellow oil. LC-MS: R _T = 1.029 min, m/z = 446.3 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 1.029 min, ESI+: [M+H] = 446.3 detected.

Step 9: Ethyl 7-benzyloxy-5-(1-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carboxylate (5.1 g; 11.44 mmol) in tetrahydrofuran (100 ml) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 34.33 ml; 34.33 mmol). The mixture was stirred at 25°C for 18 h and diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with aqueous hydrochloric acid (1N, 15 ml) and brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl 7-benzyloxy-5-(1-hydroxyethyl)-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.8 g; 100%) as brown oil.

Step 10: Ethyl 5-acetyl-7-benzyloxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a cooled (0°C) solution of ethyl 7-benzyloxy-5-(1-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.8 g; 11.44 mmol) in dichloromethane (25 ml) was added sodium bicarbonate (3.8 g; 45.75 mmol) and Dess-Martin periodinan (9.7 g; 22.87 mmol). The mixture was stirred at 0° C. for 2 hours and filtered. The filtrate was diluted with water (20 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether; R _f = 0.5) to give ethyl 5-acetyl-7-benzyloxy-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazole-2-carboxylate (1.5 g; 40%) as light brown oil. LC-MS: R _T = 0.655 min, m/z = 330.2 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.655 min, ESI+: [M+H] = 330.2 detected.

Step 11: Ethyl 5-acetyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Ethyl 5-acetyl-7-benzyloxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate mixture (1.5 g; 4.6 mmol) in 2,2,2-trifluoroacetic acid (3 ml) was heated at 120°C for 3 h and concentrated under reduced pressure. The residue was purified by preparative TLC (solution of 5% methanol and 45% ethyl acetate in petroleum ether, R _f = 0.2) to give ethyl 5-acetyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxylate (350 mg; 32%) as light brown oil. LC-MS: R _T = 0.278 mn; m/z = 240.2 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.278 min, ESI+: [M+H] = 240.2 detected.

Step 12: Ethyl cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Mixture of ethyl 5-acetyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (350 mg; 1.46 mmol) and trifluoride diethylaminosulfur (5.0 ml; 1.46 mmol) in dichloromethane (10 ml) was stirred at 10° C. for 2 h and quenched by adding ice-cold saturated aqueous sodium bicarbonate (20 ml). The mixture was extracted with dichloromethane (3×10 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R _f = 0.4) to give ethyl cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazole-2-carboxylate (37 mg; 10%) as a colorless oil. LC-MS: R _T = 0.694 min, m/z = 264.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.694 min, ESI+: [M+H] = 264.1 detected.

Step 13: cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Ethyl cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate mixture (27 mg ; 0.10 mmol), lithium hydroxide monohydrate (22 mg; 0.51 mmol) in a mixture of methanol (0.7 ml) / water (0.7 ml) / tetrahydrofuran (0.7 ml) was stirred at 10 ° C in for 2 h and concentrated under reduced pressure. The residue was diluted with ice water (2 ml) and the pH was adjusted to 4 by adding aqueous hydrochloric acid (1 M solution). The mixture was concentrated to dryness under reduced pressure to give crude cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carboxylic acid together with lithium chloride salt (28 mg; 98%).

Step 14: cis-5-(1,1-difluoroethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide

A mixture of cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (28 mg; 0.12 mmol), N,O-dimethylhydroxylamine hydrochloride (23 mg; 0.24 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium- Hexafluorophosphate 3-oxide (48 mg; 0.13 mmol) and N,N-diisopropylethylamine (62 mg; 0.48 mmol) in N,N-dimethylformamide (2 ml) was stirred at 20°C for 3 h and concentrated at reduced pressure. The residue was purified by preparative TLC (70% ethyl acetate in petroleum ether, R _f = 0.3) to give cis-5-(1,1-difluoroethyl)-7-fluoro-N-methoxy-N-methyl-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (15 mg; 45%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.05-5.73 (m, 1H), 4.62 (br s, 1H), 3.86-3.82 (m, 3H), 3.54-3.21 (m, 5H), 3.14-2.99 ( m, 1H), 1.96-1.75 (m, 3H).

Stage 15: cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl]methanone

To a cooled (0°C) solution of cis-5-(1,1-difluoroethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazole-2-carboxamide (10 mg; 0.04 mmol) in tetrahydrofuran (1 ml) cyclopropylmagnesium bromide (0.5 M solution in tetrahydrofuran; 0.5 ml; 0.25 mmol). After stirring at 0°C for 1 h, the mixture was quenched by adding saturated aqueous ammonium chloride (0.5 ml) and concentrated under reduced pressure. The residue was redissolved in dichloromethane (50 ml), filtered to remove solids, the filtrate was concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 36-66%/0.05% ammonium hydroxide in water) to give cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (2.2 mg; 23%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.00-5.84 (m, 1H), 4.75-4.55 (m, 1H), 3.38-3.29 (m, 1H), 3.18-2.99 (m, 2H), 1.86 (t , J=19.2 Hz, 3H), 1.36-1.33 (m, 2H), 1.16-1.12 (m, 2H). LCMS: R _T = 0.828 min, m/z = 259.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid for 1.5 min): retention time 0.828 min, ESI+: detected [M+H] = 259.9.

Method 99

2-[(5S,7S)-2-(Cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile

A mixture of [(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]- cyclopropyl methanone (40 mg; 0.13 mmol), potassium hexacyanoferrate(II) trihydrate (28 mg; 0.07 mmol), potassium acetate (2 mg; 0.02 mmol), t-BuXPhos-Phos-biphenyl-2 -amine-palladium(II) mesylate (10 mg; 0.01 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (6 mg; 0.01 mmol) in water (5 ml ) and 1,4-dioxane (5 ml) was stirred at 100°C for 6 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified with RP-HPLC (acetonitrile 40-70%/0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ in water) to give 2-[(5S,7S)-2-(cyclopropanecarbonyl)-7 -fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile (6.1 mg; 16%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79-7.76 (m, 1H), 7.64-7.60 (m, 1H), 7.53-7.50 (m, 1H), 7.01 (d, J=8.0 Hz, 1H ), 6.15-6.12 (m, 0.5H), 6.00-5.98 (m, 1.5H), 3.90-3.74 (m, 1H), 3.10-3.06 (m, 1H), 2.99-2.85 (m, 1H), 1.39-1.33 (m, 2H), 1.17-1.09 (m, 2H). LC-MS: R _T = 0.915 min, m/z = 397.2 [M+H] ⁺ .

LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate for 3.0 min): retention time 0.915 min, ESI+: detected [M+H] = 397.2.

Method 100

(1-Ethylcyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Stage 1: 1-ethyl-N-methoxy-N-methylcyclopropane-1-carboxamide

Prepared from 1-ethylcyclopropanecarboxylic acid using method 5. The crude reaction mixture was purified by flash column chromatography (silica gel, 0-100% isopropyl acetate/heptane) to give 1-ethyl-N-methoxy-N-methylcyclopropane-1-carboxamide (435 mg ; yield 63%). ¹ H NMR (400 MHz, chloroform-d) δ 3.71 (s, 3H), 3.24 (s, 3H), 1.60 (q, J=7.4 Hz, 2H), 0.97 (d, J=2.0 Hz , 2Н), 0.96 (t, J=7.4 Hz, 3Н), 0.59-0.52 (m, 2Н). LCMS: R _T = 0.92 min, m/z = 157.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.92 min, ESI+: [M+H] = 157.9 detected.

Stage 2: (1-ethylcyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt) methanone

Prepared from 1-ethyl-N-methoxy-N-methylcyclopropane-1-carboxamide using method 2. The crude reaction mixture was purified by RP-HPLC (30-70% acetonitrile/0.1% formic acid in water; 10 min), giving (1-ethylcyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone (134 mg; 72% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46-7.34 (m, 3H), 7.25-7.19 (m, 2H), 6.20 (ddd, J=56.5; 7.1; 1.9 Hz, 1H), 5.69 (ddd, J=8.5; 6.6; 3.0 Hz, 1H), 3.72 (dddd, J=26.1; 15.4; 8.5; 7.1 Hz, 1H) , 2.68 (dddd, J=26.6; 15.3; 3.1; 1.9 Hz, 1H), 1.73 (qd, J=7.2; 1.7 Hz, 2H), 1.58 (dq, J =4.4; 1.7; 1.2 Hz, 2H), 0.93 (q, J=3.2; 2.6 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H). LCMS: R _T = 5.29 min, m/z = 300.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 5.29 min, ESI+: [M+H] = 300.1 detected.

Method 101

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran -4-yl) methanone

Stage 1: N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide

Prepared from tetrahydropyran-4-carboxylic acid using method 5. The crude reaction mixture was purified by flash column chromatography (silica gel, 0-100% isopropyl acetate/heptane) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide ( 721 mg; quantitative yield). ¹ H NMR (400 MHz, chloroform-d) δ 4.08-3.95 (m, 2H), 3.71 (s, 3H), 3.46 (td, J=11.8; 2.3 Hz, 2H), 3.18 (s, 3H), 2.91 (tt, J=11.4; 3.8 Hz, 1H), 1.94-1.78 (m, 2H), 1.73-1.59 (m, 2H). LCMS: R _T = 0.70 min, m/z = 173.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.70 min, ESI+: detected [M+H] = 173.9.

Step 2: ((5S,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro- 2Н-pyran-4-yl) methanone

Prepared from N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide using method 2. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% NH ₄ OH in water; 10 min) , giving ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H -pyran-4-yl)methanone (167 mg; 85% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.35 (m, 3H), 7.28-7.21 (m, 2H), 6.23 (ddd, J=56.4; 7.2; 1.9 Hz, 1H), 5.73 (ddd, J=8.9; 6.5; 3.0 Hz, 1H), 3.88 (ddt, J=11.0; 4.6; 2.4 Hz, 2H), 3.74 (dddd , J=26.1; 15.5; 8.6; 7.2 Hz, 1H), 3.60 (tt, J=11.5; 3.8 Hz, 1H), 3.42 (tdd, J=11.4 ; 3.6; 2.2 Hz, 2H), 2.70 (dddd, J=26.7; 15.2; 3.1; 1.9 Hz, 1H), 1.76 (tdt, J=10.8; 4 .5; 2.2 Hz, 2H), 1.58 (dtdd, J=13.3; 11.7; 8.8; 4.5 Hz, 2H). LCMS: R _T = 4.22 min, m/z = 316.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.22 min, ESI+: [M+H] = 316.1 detected.

Method 102

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran -3-yl) methanone

Stage 1: N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide

Prepared from tetrahydropyran-3-carboxylic acid using method 5. The crude reaction mixture was purified by flash column chromatography (silica gel, 0-100% isopropyl acetate/heptane) to give N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide ( 697 mg; quantitative yield). ¹ H NMR (400 MHz, chloroform-d) δ 4.03-3.96 (m, 1H), 3.96-3.89 (m, 1H), 3.71 (s, 3H), 3.49 (t, J=10.9 Hz, 1H) , 3.45-3.37 (m, 1H), 3.16 (s, 3H), 3.07-2.94 (m, 1H), 1.94 (dtd, J=11.1; 3.7; 1.9 Hz, 1H), 1.86- 1.61 (m, 3H). LCMS: R _T = 0.73 min, m/z = 173.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.73 min, ESI+: [M+H] = 173.9 detected.

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro- 2Н-pyran-3-yl) methanone

Prepared from N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide using method 2. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% NH ₄ OH in water; 10 min) , giving ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H -pyran-3-yl)methanone (169 mg; 86% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.34 (m, 3H), 7.25 (dt, J=7.8; 1.4 Hz, 2H), 6.23 (dddd, J=56.4; 7.2; 2.0; 0.9 Hz, 1H), 5.73 (ddd, J=8.8; 6.4; 3.0 Hz, 1H), 4.01 (tdd, J=10.5; 3, 9; 1.8 Hz, 1H), 3.84-3.65 (m, 2H), 3.57 (tdd, J=9.8; 3.8; 1.9 Hz, 1H), 3.45 (ddd, J=10.9 ; 9.5; 2.6 Hz, 1H), 3.41-3.33 (m, 1H), 2.79-2.62 (m, 1H), 2.05-1.89 (m, 1H), 1.78-1.47 (m, 3H). LCMS: R _T = 4.42 min, m/z = 316.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.42 min, ESI+: [M+H] = 316.1 detected.

Method 103

(5S,7S)-2-(D-Prolyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Stage 1: tert-butyl-(R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

Prepared from N-Boc-D-proline using Method 1 (1.23 g; quantitative yield). The product was used without purification. ¹ H NMR (400 MHz, chloroform-d) δ 4.65 (ddd, J=42.4; 8.5; 3.5 Hz, 1H), 3.74 (d, J=25.4 Hz, 3H), 3.57 ( dddd, J=15.0; 10.5; 7.8; 5.0 Hz, 1H), 3.44 (ddt, J=28.9; 10.3; 6.9 Hz, 1H), 3.19 (s, 3H), 2.27-2.08 (m, 1H), 2.08-1.74 (m, 3H), 1.43 (d, J=17.9 Hz, 9H). LCMS: R _T = 1.03 min, m/z = 158.9 [(M-Boc)+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 1.03 min, ESI+: found [(M-Boc)+H] = 158.9.

Step 2: tert-Butyl-(R)-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazole-2-carbonyl)pyrrolidine-1-carboxylate

Prepared from tert-butyl-(R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate using method 3. The product was used without purification. LCMS: R _T = 1.30 min, m/z = 300.9 [(M-Boc)+H] ⁺ .

LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 1.30 min, ESI+: found [(M-Boc)+H] = 300.9.

Step 3: (5S,7S)-2-(D-prolyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

tert-Butyl-(R)-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazole- 2-carbonyl)pyrrolidine-1-carboxylate was dissolved in dichloromethane (2 ml) and cooled to 0°C. Was added triperoxonane acid (2 ml) and the reaction mixture was stirred at 0°C. The reaction mixture was concentrated and purified using SFC (5-60% methanol in carbon dioxide; Pyridyl Amide column; 12 min) to give (5S,7S)-2-(D-prolyl)-7-fluoro-5-phenyl-6 ,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (3.7 mg, 3% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.29 (m, 3H), 7.23 (ddt, J=11.8; 6.1; 1.6 Hz, 2H), 6.35-5.99 (m, 1Н), 5.82-5.52 (m, 1Н), 4.37-3.89 (m, 1Н), 3.88-3.45 (m, 1Н), 3.12-2.51 (m, 3Н), 2.40-0.29 (m, 4Н). LCMS: R _T = 0.88 min, m/z = 300.9 [M+H] ⁺ .

LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.88 min, ESI+: [M+H] = 300.9 detected.

Method 104

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-methyltetrahydrofuran-2 -yl) methanone

Stage 1: N-methoxy-N,2-dimethyltetrahydrofuran-2-carboxamide

Prepared from 2-methyltetrahydrofuran-2-carboxylic acid using method 2 (76 mg; 38% yield). The product was used without purification. LCMS: R _T = 0.82 min, m/z = 174.0 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.82 min, ESI+: [M+H] = 174.0 detected.

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2- methyltetrahydrofuran-2-yl) methanone

Prepared from N-methoxy-N,2-dimethyltetrahydrofuran-2-carboxamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water; 10 min) to give ( (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-methyltetrahydrofuran-2- yl) methanone (24 mg; 17% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.35 (m, 3H), 7.28-7.19 (m, 2H), 6.23 (ddt, J=56.5; 7.2; 2.0 Hz, 1H), 5.72 (ddt, J=8.9; 6.3; 2.8 Hz, 1H), 3.93-3.82 (m, 1H), 3.82-3.65 (m, 2H), 2.71 (dddd, J=26 .6; 15.2; 3.1; 1.9 Hz, 1H), 2.52 (m, 1H), 1.99-1.85 (m, 2H), 1.85-1.72 (m, 1H), 1.53 (d, J= 3.6 Hz, 3H). LCMS: R _T = 4.66 min, m/z = 316.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.66 min, ESI+: detected [M+H] = 316.1.

Method 105

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3-yl ) methanone

Stage 1: N-methoxy-N-methyltetrahydrofuran-3-carboxamide

Prepared from tetrahydrofuran-3-carboxylic acid using method 3 (97 mg; 47% yield). The product was used without purification. LCMS: R _T = 0.80 min, m/z = 160.0 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.80 min, ESI+: detected [M+H] = 160.0.

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran- 3-yl) methanone

Prepared from N-methoxy-N-methyltetrahydrofuran-3-carboxamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water; 10 min) to give a diastereomeric mixture ( (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3-yl) methanone (49 mg; 37% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.35 (m, 3H), 7.30-7.21 (m, 2H), 6.24 (ddd, J=56.2; 7.1; 1.9 Hz, 1Н), 5.74 (ddd, J=9.2; 6.6; 3.1 Hz, 1Н), 4.14-4.05 (m, 1Н), 3.93 (dt, J=11.3; 8.4 Hz, 1Н ), 3.87-3.65 (m, 4H), 2.72 (dddd, J=26.7; 15.3; 3.1; 1.9 Hz, 1H), 2.19-2.00 (m, 2H). LCMS: R _T = 4.33 min, m/z = 302.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.33 min, ESI+: [M+H] = 302.2 detected.

Method 106

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((S)-tetrahydrofuran -3-yl) methanone

A diastereomeric mixture of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3 -yl)methanone was purified with chiral SFC (retention time = 1.241 min) to give ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)((S)-tetrahydrofuran-3-yl)methanone (15 mg; 11% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.35 (m, 3H), 7.30-7.21 (m, 2H), 6.24 (ddd, J=56.2; 7.1; 1.9 Hz, 1Н), 5.74 (ddd, J=9.2; 6.6; 3.1 Hz, 1Н), 4.14-4.05 (m, 1Н), 3.93 (dt, J=11.3; 8.4 Hz, 1Н ), 3.87-3.65 (m, 4H), 2.72 (dddd, J=26.7; 15.3; 3.1; 1.9 Hz, 1H), 2.19-2.00 (m, 2H). LCMS: R _T = 4.33 min, m/z = 302.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.33 min, ESI+: [M+H] = 302.2 detected.

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-tetrahydrofuran -3-yl) methanone

A diastereomeric mixture of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3 -yl)methanone was purified with chiral SFC (retention time = 1.627 min) to give ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)((R)-tetrahydrofuran-3-yl)methanone (23 mg; 17% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.35 (m, 3H), 7.30-7.21 (m, 2H), 6.24 (ddd, J=56.2; 7.1; 1.9 Hz, 1Н), 5.74 (ddd, J=9.2; 6.6; 3.1 Hz, 1Н), 4.14-4.05 (m, 1Н), 3.93 (dt, J=11.3; 8.4 Hz, 1Н ), 3.87-3.65 (m, 4H), 2.72 (dddd, J=26.7; 15.3; 3.1; 1.9 Hz, 1H), 2.19-2.00 (m, 2H). LCMS: R _T = 4.33 min, m/z = 302.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.33 min, ESI+: [M+H] = 302.2 detected.

SFC conditions: column: Chiralpak IA (150 mm x 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 10%, at the end at 10%; flow rate 70 ml/min; column temperature 40°C.

SFC conditions: column: Chiralpak IA (150 mm x 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 10%, at the end at 10%; flow rate 70 ml/min; column temperature 40°C.

Method 107

1-((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-methoxy -2,2-dimethylpropan-1-one

Stage 1: N,3-dimethoxy-N,2,2-trimethylpropanamide

Prepared from 3-methoxy-2,2-dimethylpropanoic acid using method 2 (184 mg; 46% yield). The product was used without purification. LCMS: R _T = 0.93 min, m/z = 176.0 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.93 min, ESI+: [M+H] = 176.0 detected.

Step 2: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- 3-methoxy-2,2-dimethylpropan-1-one

Prepared from N,3-dimethoxy-N,2,2-trimethylpropanamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give 1 -((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-methoxy- 2,2-dimethylpropan-1-one (16 mg; 18% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.34 (m, 3H), 7.25-7.18 (m, 2H), 6.23 (ddd, J=56.5; 7.1; 1.9 Hz, 1H), 5.74 (ddd, J=8.9; 6.5; 2.9 Hz, 1H), 3.84-3.71 (m, 2H), 3.79-3.66 (m, 1H), 3.07 (s, 3H), 2.71 (dddd, J=26.6; 15.2; 3.14; 1.9 Hz, 1H), 1.25 (d, J=6.0 Hz, 6H). LCMS: R _T = 5.44 min, m/z = 318.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 5.44 min, ESI+: detected [M+H] = 318.2.

Method 108

(S)-3,3,3-Trifluoro-1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2, 4]triazol-2-yl)-2-hydroxypropan-1-one

Stage 1: (S)-3,3,3-trifluoro-2-hydroxy-N-methoxy-N-methylpropanamide

Prepared from (S)-3,3,3-trifluoro-2-hydroxypropanoic acid using method 2 (52 mg; 13% yield). The product was used without purification. LCMS: R _T = 0.72 min, m/z = 187.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.72 min, ESI+: detected [M+H] = 187.9.

Step 2: (S)-3,3,3-trifluoro-1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)-2-hydroxypropan-1-one

Prepared from (S)-3,3,3-trifluoro-2-hydroxy-N-methoxy-N-methylpropanamide using method 3. The crude reaction mixture was purified with RP-HPLC (20-60% acetonitrile/0.1% formic acid). acid in water; 10 min) to give, as tentatively indicated, (S)-3,3,3-trifluoro-1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxypropan-1-one (7.5 mg; 9% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42 (dddd, J=9.2; 7.4; 6.3; 3.3 Hz, 3H), 7.26 (td, J=8.3; 7 .8; 1.6 Hz, 2H), 6.27 (dddd, J=56.3; 7.3; 3.5; 2.0 Hz, 1H), 5.77 (ddd, J=9.0; 6.3 ; 3.1 Hz, 1H), 5.62 (dd, J=10.2; 4.0 Hz, 1H), 3.77 (dddd, J=25.7; 15.5; 8.5; 7.2 Hz, 1H), 2.80-2.65 (m, 1H). LCMS: R _T = 4.82 min, m/z = 330.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 minutes): retention time 4.82 minutes, ESI+: detected [M+H] = 330.1.

Method 109

1-((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-( tetrahydro-2H-pyran-2-yl)ethan-1-one

Stage 1: N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-2-yl)acetamide

Prepared from 2-tetrahydropyran-2-ylacetic acid using method 2 (200 mg; 77% yield). The product was used without purification. LCMS: R _T = 0.84 min, m/z = 188.0 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.84 min, ESI+: detected [M+H] = 188.0.

Step 2: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- 2-(tetrahydro-2H-pyran-2-yl)ethan-1-one

Prepared from N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-2-yl)acetamide using method 3. The crude reaction mixture was purified with RP-HPLC (5-85% acetonitrile/0.1% formic acid in water; 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethan-1-one (2.5 mg; 3% yield). LCMS: R _T = 4.94 min, m/z = 330.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.94 min, ESI+: [M+H] = 330.2 detected.

Method 110

1-((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-( tetrahydro-2H-pyran-4-yl)ethan-1-one

Step 1: N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide

Prepared from 2-tetrahydropyran-4-ylacetic acid using method 2 (154 mg; 59% yield). The product was used without purification. LCMS: R _T = 0.78 min, m/z = 188.0 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.78 min, ESI+: [M+H] = 188.0 detected.

Step 2: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- 2-(tetrahydro-2H-pyran-4-yl)ethan-1-one

Prepared from N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide using method 3. The crude reaction mixture was purified with RP-HPLC (20-60% acetonitrile/0.1% formic acid in water; 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one (46 mg; 52% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46-7.34 (m, 3H), 7.28-7.22 (m, 2H), 6.22 (ddd, J=56.4; 7.2; 1.9 Hz, 1H), 5.71 (ddd, J=8.5; 6.5; 3.1 Hz, 1H), 3.84-3.63 (m, 3H), 3.28-3.21 (m, 1H), 2.94 (dd, J=6 .8; 2.1 Hz, 2H), 2.71 (dddd, J=26.7; 15.2; 3.2; 2.0 Hz, 1H), 2.10 (ttt, J=11.0; 7.1 ; 3.9 Hz, 1H), 1.55 (ddd, J=12.9; 4.2; 2.0 Hz, 2H), 1.23 (qd, J=12.4; 4.4 Hz, 2H), 0.87 -0.65 (m, 1 N). LCMS: R _T = 2.51 min, m/z = 330.2 [M+H] ⁺ .

LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 2.51 min, ESI+: [M+H] = 330.2 detected.

Method 111

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-3 -methyltetrahydrofuran-3-yl)methanone and ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl)((S)-3-methyltetrahydrofuran-3-yl)methanone

Stage 1: N-methoxy-N,3-dimethyltetrahydrofuran-3-carboxamide

Prepared from 3-methyltetrahydrofuran-3-carboxylic acid using method 2 (386 mg; 58% yield). The product was used without purification. LCMS: R _T = 0.89 min, m/z = 173.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.89 min, ESI+: [M+H] = 173.9 detected.

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-3 -methyltetrahydrofuran-3-yl)methanone

Prepared from N-methoxy-N,3-dimethyltetrahydrofuran-3-carboxamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water; 10 min) to give a diastereomeric a mixture of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) 3-yl)methanone (31 mg; 28% yield). ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyltetrahydrofuran) diastereomeric mixture -3-yl)methanone was purified with chiral SFC (retention time = 0.785 min) to give, as conventionally indicated, ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)((R)-3-methyltetrahydrofuran-3-yl)methanone (11 mg; 10%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46-7.35 (m, 3H), 7.28-7.21 (m, 2H), 6.24 (ddd, J=56.4; 7.1; 2.0 Hz, 1H), 5.73 (ddd, J=8.9; 6.4; 3.1 Hz, 1H), 4.18 (d, J=8.9 Hz, 1H), 3.84-3.66 (m, 3H), 3.64 ( d, J=8.9 Hz, 1H), 2.71 (dddd, J=26.6; 15.2; 3.1; 2.0 Hz, 1H), 2.56 (ddd, J=12.6; 8, 2; 6.8 Hz, 1H), 1.85 (ddd, J=13.0; 7.6; 5.6 Hz, 1H), 1.48 (s, 3H). LCMS: R _T = 4.68 min, m/z = 316.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.68 min, ESI+: [M+H] = 316.2 detected.

SFC conditions: column: Chiralpak IG (150 mm × 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 20%, at the end at 20%; flow rate (70 ml/min); column temperature 40°C.

((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((S)-3 -methyltetrahydrofuran-3-yl)methanone

((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyltetrahydrofuran) diastereomeric mixture -3-yl)methanone was purified with chiral SFC (retention time = 0.966 min) to give, as conventionally indicated, ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)((S)-3-methyltetrahydrofuran-3-yl)methanone (12 mg, 11% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.34 (m, 3H), 7.28-7.21 (m, 2H), 6.24 (ddd, J=56.3; 7.1; 1.9 Hz, 1H), 5.73 (ddd, J=8.9; 6.5; 3.1 Hz, 1H), 4.21 (d, J=8.9 Hz, 1H), 3.83-3.64 (m, 3H), 3.67 ( d, J=8.9 Hz, 1H), 2.71 (dddd, J=26.6; 15.2; 3.1; 2.0 Hz, 1H), 2.59-2.52 (m, 1H), 1.82 (ddd , J=12.6; 7.6; 5.7 Hz, 1H), 1.47 (s, 3H). LCMS: R _T = 4.68 min, m/z = 316.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.68 min, ESI+: [M+H] = 316.2 detected.

SFC conditions: column: Chiralpak IG (150 mm × 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 25%, at the end at 25%; flow rate (70 ml/min); column temperature 40°C.

Method 112

((1R,2R,4S)-7-Oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)methanone, ((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7 -fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone and ((1R,2S,4S)-7-oxabicyclo [2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl) methanone

Stage 1: N-methoxy-N-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Prepared from 7-oxabicyclo[2.2.1]heptane-2-carboxylic acid using method 2 (184 mg; 70% yield). The product was used without purification. LCMS: R _T = 0.76 min, m/z = 185.8 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.76 min, ESI+: [M+H] = 185.8 detected.

Step 2: ((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazol-2-yl)methanone

Prepared from N-methoxy-N-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water; 10 min) to give a diastereomeric mixture of (7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl)methanone (41 mg; 31% yield). The diastereomeric mixture of (7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone was purified with chiral SFC (retention time = 0.442 min) to give, as conventionally indicated, ((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2- yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone (3 mg ; yield 2%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.35 (m, 3H), 7.29-7.22 (m, 2H), 6.25 (ddd, J=56.4; 7.2; 2.0 Hz, 1H), 5.74 (ddd, J=9.1; 6.4; 3.1 Hz, 1H), 4.91 (t, J=4.9 Hz, 1H), 4.59 (t, J=5.2 Hz, 1H), 3.96-3.87 (m, 1H), 3.75 (dddd, J=25.8; 15.5; 8.5; 7.2 Hz, 1H), 2.72 (dddd, J=26.7; 15, 1; 3.1; 2.0 Hz, 1H), 2.00 (dd, J=11.9; 4.6 Hz, 1H), 1.75 (dddd, J=12.0; 10.9; 5.3; 2.8 Hz, 1H), 1.66-1.52 (m, 1H), 1.50-1.36 (m, 2H), 1.29-1.17 (m, 1H). LCMS: R _T = 4.61 min, m/z = 328.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.61 min, ESI+: [M+H] = 328.2 detected.

SFC conditions: column: Chiralpak ID (250 mm × 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 25%, at the end at 25%; flow rate (70 ml/min); column temperature 40°C.

((1S,2R,4R)-7-Oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)methanone

The diastereomeric mixture of (7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone was purified with chiral SFC (retention time = 0.523 min) to give, as conventionally indicated, ((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2- yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone (3 mg ; yield 2%). ¹ H NMR (400 MHz, chloroform-d) δ 7.43-7.34 (m, 3H), 7.25-7.19 (m, 2H), 6.03 (ddd, J=55.8; 7.1; 1.7 Hz, 1H ), 5.50 (ddd, J=8.8; 6.2; 2.8 Hz, 1H), 4.83 (d, J=4.7 Hz, 1H), 4.70 (t, J=4.8 Hz, 1H ), 3.77-3.51 (m, 2H), 2.95 (dddd, J=25.0; 15.4; 2.8; 1.7 Hz, 1H), 2.32 (dtd, J=12.2; 5.0 ; 2.1 Hz, 1H), 1.90-1.63 (m, 5H). LCMS: R _T = 4.54 min, m/z = 328.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.54 min, ESI+: [M+H] = 328.2 detected.

SFC conditions: column: Chiralpak ID (250 mm × 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 25%, at the end at 25%; flow rate (70 ml/min); column temperature 40°C.

((1R,2S,4S)-7-Oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)methanone

The diastereomeric mixture of (7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone was purified with chiral SFC (retention time = 1.220 min) to give, as conventionally indicated, ((1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2- yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (21 mg ; yield 16%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.35 (m, 3H), 7.31-7.24 (m, 2H), 6.23 (ddd, J=56.3; 7.2; 1.9 Hz, 1H), 5.74 (ddd, J=8.9; 6.5; 3.1 Hz, 1H), 4.94 (t, J=4.9 Hz, 1H), 4.59 (t, J=5.2 Hz, 1H), 3.93-3.83 (m, 1H), 3.75 (dddd, J=26.1; 15.5; 8.5; 7.2 Hz, 1H), 2.72 (dddd, J=26.6; 15, 2; 3.1; 1.9 Hz, 1H), 1.99 (dd, J=12.0; 4.6 Hz, 1H), 1.73 (dddd, J=11.9; 10.8; 5.3; 2.8 Hz, 1H), 1.59 (ddt, J=12.8; 8.5; 4.8 Hz, 1H), 1.51-1.37 (m, 2H), 1.28-1.17 (m, 1H). LCMS: R _T = 4.61 min, m/z = 328.2 [M+H] ⁺ .

LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.61 min, ESI+: [M+H] = 328.2 detected.

SFC conditions: column: Chiralpak ID (250 mm × 21.2 mm, 5 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 25%, at the end at 25%; flow rate (70 ml/min); column temperature 40°C.

Method 113

1-((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-( trifluoromethoxy)ethan-1-one

Stage 1: N-methoxy-N-methyl-2-(trifluoromethoxy)acetamide

Prepared from 2-(trifluoromethoxy)acetic acid using Method 2 (129 mg; 20% yield). The product was used without purification. LCMS: R _T = 0.88 min, m/z = 187.8 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.88 min, ESI+: detected [M+H] = 187.8.

Step 2: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- 2-(trifluoromethoxy)ethan-1-one

Prepared from N-methoxy-N-methyl-2-(trifluoromethoxy)acetamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-( trifluoromethoxy)ethan-1-one (2 mg, 2% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.36 (m, 3H), 7.30-7.24 (m, 2H), 6.26 (ddd, J=56.2; 7.2; 1.9 Hz, 1H), 5.75 (ddd, J=8.8; 6.5; 3.1 Hz, 1H), 5.50 (d, J=1.2 Hz, 2H), 3.84-3.63 (m, 1H), 2.74 ( dddd, J=26.8, 15.3, 3.2, 1.9 Hz, 1H). LCMS: R _T = 5.39 min, m/z = 330.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 5.39 min, ESI+: detected [M+H] = 330.1.

Method 114

((1R,5R)-3-Oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)methanone and ((1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5 -phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Step 1: N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-1-carboxamide

Prepared from 3-oxabicyclo[3.1.0]hexane-1-carboxylic acid using method 3 (150 mg; 56% yield). The product was used without purification. LCMS: R _T = 0.72 min, m/z = 171.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile in water + 0.1% formic acid for 1.6 min): retention time 0.72 min, ESI+: detected [M+H] = 171.9.

Stage 2: ((1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl)methanone

Prepared from N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-1-carboxamide using method 3. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water; 10 min) to give a diastereomeric mixture of (3-oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl)methanone (30 mg; 27% yield). The diastereomeric mixture of (3-oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone was purified with chiral SFC (retention time = 0.736 min) to give, as conventionally indicated, ((1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl) ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (28 mg; yield 25%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.33 (m, 3H), 7.24 (dt, J=7.8; 1.5 Hz, 2H), 6.22 (dddd, J=56.4; 7.2; 3.5; 1.9 Hz, 1H), 5.76-5.65 (m, 1H), 4.11-4.04 (m, 1H), 4.00 (dd, J=8.7; 1.7 Hz, 1H ), 3.81-3.64 (m, 3H), 2.83-2.61 (m, 2H), 1.84 (td, J=8.3; 3.9 Hz, 1H), 1.13 (dd, J=5.7; 4, 0 Hz, 1H). LCMS: R _T = 4.58 min, m/z = 314.1 [M+H] ⁺ .

LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 minutes): retention time 4.58 minutes, ESI+: [M+H] = 314.1 detected.

SFC conditions: column: Chiralcel OX (50 mm × 4.6 mm, 3 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 25%, at the end at 25%; flow rate (4 ml/min); column temperature 40°C.

((1S,5S)-3-Oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)methanone

The diastereomeric mixture of (3-oxabicyclo[3.1.0]hexan-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone was purified with chiral SFC (retention time = 0.914 min) to give, as conventionally indicated, ((1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl) ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone (0.5 mg ; yield 0.05%). LCMS: R _T = 4.58 min, m/z = 314.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile in water + 0.1% formic acid for 7 min): retention time 4.58 min, ESI+: [M+H] = 314.2 detected.

SFC conditions: column: Chiralcel OX (50 mm × 4.6 mm, 3 µm); Medium: 0.1% NH ₄ OH in MeOH; first at 25%, at the end at 25%; flow rate (4 ml/min); column temperature 40°C.

Method 115

Cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone and (S)-cyclopropyl(5-phenyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-а]pyridin-2-yl)methanone

Stage 1: 2-bromo-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Hydrogen was bubbled through a solution of 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (0.90 g; 4.28 mmol) and platinum(IV) oxide (97.2 mg ; 0.428 mmol) in acetic acid (43 ml). After 5 minutes, the needle was removed from the solution and the reaction mixture was allowed to stir under a hydrogen atmosphere for 48 hours (approximately 50% conversion). The reaction mixture was filtered through a pad of celite using methanol. The filtrate was concentrated under reduced pressure and the crude residue was taken to the next step without further purification.

Crude 5-phenyl-[ 1,2,4]triazolo[1,5-a]pyridine-2-amine (0.80 g; 3.81 mmol). The reaction mixture was then heated at 75° C. for 1 h. After cooling to room temperature (rt), 1 M HCl solution was added. The aqueous layer was extracted with isopropyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 50% isopropyl acetate in heptane) to give 2-bromo-5-phenyl-5,6,7,8-tetrahydro -[1,2,4]triazolo[1,5-a]pyridine (0.354 g; 1.27 mmol; 33% yield). LCMS: R _T = 1.15 min, m/z = 277.8 [M=H] ⁺ .

Stage 2: cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone

(S)-cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-а]pyridin-2-yl)methanone

Isopropyl magnesium chloride (2.0 M solution in THF; 0.27 ml; 0.540 mmol) was added dropwise to a solution of 2-bromo-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo [1,5-a]pyridine (50 mg; 0.180 mmol) and N-methoxy-N-methylcyclopropanecarboxamide (71 mg; 0.54 mmol) in THF (1.8 ml) at 0°C for 15 min. After 1 h, a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with isopropyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was purified by preparative TLC (100% isopropyl acetate) to give cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[ 1,5-a]pyridin-2-yl)methanone (20.9 mg; 0.078 mmol; 44% yield). The crude material was further purified by preparative SFC to give (S)-cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine- 2-yl) methanone.

Cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41-7.27 (m, 3H), 7.12-7.04 (m, 2H), 5.62 (t, J=5.9 Hz, 1H), 3.12-2.83 (m , 3Н), 2.46-2.35 (m, 1Н), 2.13-2.01 (m, 1Н), 1.93-1.81 (m, 2Н), 1.04-0.92 (m, 4Н). LCMS: R _T = 4.37 min, m/z = 268.1 [M+H] ⁺ .

(S)-Cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.23 (m, 3H), 7.12-7.04 (m, 2H), 5.62 (t, J=6.0 Hz, 1H), 3.12-2.85 (m , 3Н), 2.45-2.35 (m, 1Н), 2.13-2.00 (m, 1Н), 1.96-1.82 (m, 2Н), 1.05-0.93 (m, 4Н). LCMS: R _T = 4.39 min, m/z = 268.1 [M+H] ⁺ .

Preparative SFC Information: Column: Chiralcel OJ, 5 µm (250 x 21.2 mm); mobile phase: carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), elution program: isocratic, 15% B; flow rate: 70 ml/min; column temperature: 30°C; wavelength: 220 nm.

Method 116

Cyclopropyl ((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone , cyclopropyl-[rac-(5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl]methanone and cyclopropyl-[rac-(5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl]methanone

Step 1: 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(o-tolyl)propan-1,3-dione

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 26 ml; 26 mmol) was added to a solution of 1-(o-tolyl)ethanone (1.9 ml; 15 mmol) and methyl-3-bromo-1H- 1,2,4-triazole-5-carboxylate (2.0 g; 9.7 mmol) in THF (32 ml) at -78°C. The reaction mixture was then heated to rt and stirred for 1 h. The reaction mixture was diluted with water and isopropyl acetate. A 5% citric acid solution (100 ml) was added and the aqueous layer was extracted with isopropyl acetate (3×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 80% isopropyl acetate in heptane) to give 1-(3-bromo-1H-1,2,4-triazole -5-yl)-3-(o-tolyl)propan-1,3-dione (2.03 g; 6.59 mmol; 68% yield). LCMS: R _T = 1.28 min, m/z = 307.8 [M+H] ⁺ .

Step 2: (5S,7R)-2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (5S,7R)-2-bromo-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol and (5S, 7S)-2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Sodium borohydride (3.84 g; 97.4 mmol) was added to a solution of 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(o-tolyl)propan-1,3 -dione (2.00 g; 6.49 mmol) in ethanol (130 ml) at rt. After 1 h, a saturated aqueous ammonium chloride solution was added and the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in isopropyl acetate and water. The aqueous layer was extracted with isopropyl acetate (6×50 ml). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 0.96 min, m/z = 311.8 [M+H] ⁺ . To a solution of the crude residue in dichloromethane (65 ml) was added trifluoroacetic acid (65 ml) at rt. After 30 minutes the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in dichloromethane. Water and saturated aqueous sodium bicarbonate were added. The aqueous layer was extracted with dichloromethane (4×50 ml). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 1.08 min, m/z = 293.8 [M+H] ⁺ and LCMS: R _T = 0.98 min, m/z = 293.8 [M+H] ⁺ . To a solution of the crude residue in dichloromethane (65 ml) was added diethylaminosulfur trifluoride (3.60 ml; 26.0 mmol) at rt. After 30 minutes, a saturated aqueous sodium bicarbonate solution was carefully added. The aqueous layer was extracted with dichloromethane (4×50 ml). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by flash column chromatography (silica, 10% to 100% isopropyl acetate in heptane, then 10% methanol in dichloromethane) to give a 2:1 mixture (5S,7R )-2-bromo-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol and (5S,7R)-2 -bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.470 g) and (5S,7S)- 2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.350 g; 1.18 mmol; yield 18%).

(5S,7R)-2-Bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30-7.18 (m, 3H), 6.88 (d, J=7.6 Hz, 1H), 6.30 (ddd, J=56.2; 6.8; 1.6 Hz, 1H), 6.11 (td, J=6.8; 3.8 Hz, 1H), 3.44-3.27 (m, 1H), 2.92 (ddt, J=27.9; 15.2; 6.5 Hz , 1Н), 2.36 (s, 3Н). LCMS: R _T = 1.26 min, m/z = 295.8 [M+H] ⁺ .

(5S,7S)-2-Bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.38-7.09 (m, 3H), 6.78-6.69 (m, 1H), 6.20 (ddd, J=56.4; 7.2; 1.9 Hz, 1H), 5.95-5.80 (m, 1H), 3.69 (dddd, J=25.4; 15.4; 8.5; 7.2 Hz, 1H), 2.66-2.51 (m, 1H), 2.39 (s, 3H) . LCMS: R _T = 1.25 min, m/z = 295.7 [M+H] ⁺ .

Step 3: cyclopropyl((5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl) methanone and cyclopropyl ((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl) methanone

Isopropylmagnesium chloride (2.0 M solution in THF; 2.4 ml; 4.76 mmol) was added dropwise over 15 min to a solution of a 2:1 mixture of (5S,7R)-2-bromo-5-(o-tolyl )-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol and (5S,7R)-2-bromo-7-fluoro-5-(o- tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.470 g) and N-methoxy-N-methylcyclopropanecarboxamide (0.634 g; 4.76 mmol) in THF (15.9 ml) at 0°C. After 1 h, a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with isopropyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was purified by preparative HPLC/SFC to give cyclopropyl((5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (137 mg; 0.480 mmol) and cyclopropyl((5S,7R)-7-hydroxy-5-(o-tolyl )-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (33.8 mg; 0.119 mmol).

Cyclopropyl ((5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone : ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.33-7.14 (m, 3H), 6.89 (d, J=7.5 Hz, 1H), 6.35 (ddd, J=56.2; 6.8 ; 1.6 Hz, 1H), 6.19 (td, J=6.9; 3.2 Hz, 1H), 3.59-3.27 (m, 1H), 3.11-2.91 (m, 2H), 2.38 (s, 3H ), 1.14-1.01 (m, 4H). LCMS: R _T = 4.81 min, m/z = 286.1 [M+H] ⁺ .

Preparative SFC Information: Column: Torus Diol, 5 μm (150 x 30 mm), Mobile phase: Carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), Elution program: Isocratic, 5% B; flow rate: 150 ml/min; column temperature: 25°C; wavelength: 220 nm.

Cyclopropyl ((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone : ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30-7.13 (m, 3H), 7.01-6.94 (m, 1H), 6.25 (bs, 1H), 5.75 (dd, J=8.1; 5 .8 Hz, 1H), 5.23 (dd, J=7.9; 4.6 Hz, 1H), 3.63-3.52 (m, 1H), 3.03-2.92 (m, 1H), 2.38 (s, 3H), 2.31-2.14 (m, 1H), 1.09-0.96 (m, 4H). LCMS: R _T = 4.08 min, m/z = 284.1 [M+H] ⁺ .

Preparative HPLC information: Column: Gemini-NX C18, 5 µm (50x30 mm), Mobile phase: 0.1% ammonium hydroxide in water (A)/acetonitrile (B), elution program: gradient: 10% to 60% B; flow rate: 60 ml/min; column temperature: 25°C; wavelength: 254 nm.

Step 4: cyclopropyl((5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt) methanone

Isopropyl magnesium chloride (2.0 M solution in THF; 1.80 ml; 3.55 mmol) was added dropwise over 15 min to a solution of (5S,7S)-2-bromo-7-fluoro-5-(o-tolyl )-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.350 g; 1.18 mmol) and N-methoxy-N-methylcyclopropanecarboxamide (0.472 g; 3.55 mmol) in THF (11.8 ml) at 0°C. After 1 h, a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with isopropyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give, by convention, cyclopropyl((5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (0.179 g; 0.627 mmol; 53% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.35-7.14 (m, 3H), 6.76-6.66 (m, 1H), 6.26 (ddd, J=56.3; 7.2; 1.9 Hz, 1H), 5.94 (ddd, J=8.5; 6.6; 3.2 Hz, 1H), 3.94-3.48 (m, 1H), 3.01 (ddt, J=7.6; 6.1; 5, 2 Hz, 1H), 2.66 (dddd, J=26.8; 15.1; 3.2; 2.0 Hz, 1H), 2.42 (s, 3H), 1.18-0.99 (m, 4H). LCMS: R _T = 4.80 min, m/z = 286.1 [M+H] ⁺ .

Preparative SFC Information: Column: Torus Diol, 5 μm (150 x 30 mm), Mobile phase: Carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), Elution program: Isocratic, 5% B; flow rate: 150 ml/min; column temperature: 25°C; wavelength: 220 nm.

Method 117

Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2 -yl) methanone and cyclopropyl ((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl)methanone

Stage 1: methyl 3-(3-fluoropyridin-2-yl)-4,5-dihydroisoxazole-5-carboxylate

Triethylamine (9.8 ml; 70 mmol) was added to a solution of (2Z)-3-fluoro-N-hydroxy-pyridine-2-carboximidoyl chloride (12.0 g; 68.7 mmol) and methyl acrylate (6.3 ml; 70 mmol) in dichloromethane (460 ml) at 0°C. The reaction mixture was heated to rt and stirred for another 4 hours. Water was added and the aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate in heptane) to give methyl-3-(3-fluoro-2-pyridyl)-4, 5-dihydroisoxazole-5-carboxylate (10.6 g; 47.3 mmol; 68% yield).

For the preparation of (2Z)-3-fluoro-N-hydroxy-pyridine-2-carbohimidoyl chloride, see: WO 2006/114706, 2006, A1. LCMS: R _T = 0.89 min, m/z = 224.8 [M+H] ⁺ .

Stage 2: 3-((tert-butyldimethylsilyl)oxy)-5-(3-fluoropyridin-2-yl)pyrrolidin-2-one

Nickel(II) chloride hexahydrate (21.6 g; 89.2 mmol) and methyl 3-(3-fluoro-2-pyridyl)-4,5-dihydroisoxazole-5-carboxylate (10.0 g; 44.6 mmol) was dissolved in methanol (372 ml) and cooled to -30° C. under nitrogen. Sodium borohydride (8.79 g; 223 mmol) was added in portions over 10 minutes. The reaction mixture was then heated to rt and stirred for another 1 h. Ammonium hydroxide (100 ml) was added and the reaction mixture was allowed to stir at rt overnight. The precipitate was filtered off. The filtrate was concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 0.75 min, m/z = 196.8 [M+H] ⁺ . To a solution of the crude substrate, imidazole (9.11 g; 134 mmol) and tert-butyldimethylchlorosilane (13.9 g; 89.2 mmol) in dimethyl sulfoxide (89 ml) was added 4-dimethylaminopyridine (0.545 g; 4.46 mmol) at 40°C. After 24 h the reaction mixture was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4×200 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate in heptane) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-( 3-fluoro-2-pyridyl)pyrrolidin-2-one (9.6 g; 31 mmol; 69% yield).

¹ H NMR (400 MHz, chloroform-d) 1:1 mixture of diastereomers: δ 8.41-8.36 (m, 1H), 7.45-7.35 (m, 1H), 7.31-7.22 (m, 1H), 6.21 (s, 0 .5H), 5.87 (s, 0.5H), 5.18-5.10 (m, 0.5H), 4.90 (ddd, J=9.5; 6.3; 1.3 Hz, 0.5H), 4.59- 4.47 (m, 1H), 3.01-2.90 (m, 0.5H), 2.61 (ddd, J=13.0; 7.5; 3.7 Hz, 0.5H), 2.48 (ddd, J=13, 2; 8.1; 6.5 Hz, 0.5H), 2.21 (dt, J=12.3; 9.5 Hz, 0.5H), 0.93 (s, 4.5H), 0.91 (s, 4.5H ), 0.22–0.13 (m, 6Н). LCMS: R _T = 1.38 min, m/z = 311.0 [M+H] ⁺ .

Stage 3: ethyl 5-(3-fluoropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Sodium hydride (60% in oil; 0.390 g; 9.7 mmol) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-(3-fluoro-2-pyridyl)pyrrolidin-2-one (2.0 g; 6.4 mmol) in N,N-dimethylformamide (64 ml) at 0°C. After 30 minutes, O-diphenylphosphorylhydroxylamine (2.3 g, 9.7 mmol) was added. The reaction mixture was heated to rt and stirred for 16 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The crude residue was taken to the next reaction step without further purification. LCMS: R _T = 1.34 min, m/z = 326.0 [M+H] ⁺ and LCMS: R _T = 1.30 min, m/z = 326.0 [M+H] ⁺ . Ethyl 2-ethoxy-2-iminoacetate (2.50 g; 16 mmol) and the crude residue were dissolved in ethanol (23 ml) and the reaction mixture was heated at 90°C for 16 h. After cooling to rt, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude residue was taken to the next reaction step without further purification. LCMS: R _T = 1.38 min, m/z = 425.0 [M+H] ⁺ and LCMS: R _T = 1.34 min, m/z = 425.0 [M+H] ⁺ . To a solution of the crude residue in toluene (25 ml) was added p-toluenesulfonic acid monohydrate (1.5 g; 7.7 mmol). The reaction mixture was heated at 120° C. for 16 hours. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was taken to the next reaction step without further purification. LCMS: R _T = 1.55 min, m/z = 407.0 [M+H] ⁺ and LCMS: R _T = 1.50 min, m/z = 407.1 [M+H] ⁺ . To a solution of the crude residue in THF (21 ml) was added tetrabutylammonium fluoride (1.0 M solution in THF; 6.4 ml; 6.4 mmol) and the reaction mixture was heated at 40°C for 1 h. After cooling to rt, saturated aqueous ammonium chloride solution. The aqueous layer was extracted with isopropyl acetate (4×50 ml). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 10% methanol in dichloromethane) to give ethyl 5-(3-fluoro-2-pyridyl)-7-hydroxy -6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.800 g; 2.74 mmol; 42% yield). ¹ H NMR (400 MHz, chloroform-d) 1:1 mixture of diastereomers: δ 8.41-8.29 (m, 1H), 7.63-7.26 (m, 2H), 6.12 (dd, J=8.1; 4.4 Hz , 0.5H), 6.07 (d, J=8.2 Hz, 0.5H), 5.64 (dd, J=7.6; 4.0 Hz, 0.5H), 5.21 (d, J=6, 5 Hz, 0.5H), 4.51-4.38 (m, 2H), 3.45 (ddd, J=14.7; 8.3; 6.6 Hz, 0.5H), 3.29 (ddd, J=13.8 ; 7.5; 4.3 Hz, 0.5H), 3.10 (ddd, J=13.8; 8.1; 4.0 Hz, 0.5H), 2.74 (d, J=14.4 Hz, 0.5H), 1.40 (t, J=7.1 Hz, 3H). LCMS: R _T = 0.89 min, m/z = 292.9 [M+H] ⁺ .

Stage 4: ethyl 7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Diethylaminosulfur trifluoride (1.53 ml; 10.9 mmol) was added to a solution of ethyl 5-(3-fluoro-2-pyridyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazole-2-carboxylate (0.800 g; 2.74 mmol) in dichloromethane (27.4 ml) at rt. After 20 minutes, a saturated aqueous sodium bicarbonate solution was added. The aqueous layer was extracted with dichloromethane (4×30 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 10% DCM in methanol) to give ethyl 7-fluoro-5-(3-fluoro-2-pyridyl )-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.800 g; 2.72 mmol; 99% yield). LCMS: R _T = 1.01 min, m/z = 294.8 [M+H] ⁺ .

Stage 5: 7-fluoro-5-(3-fluoropyridin-2-yl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole-2-carboxamide

Lithium hydroxide monohydrate (1.20 g; 27 mmol) was added to a solution of ethyl 7-fluoro-5-(3-fluoro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazole-2-carboxylate (0.80 g; 2.7 mmol) in THF (9.1 ml), water (4.5 ml) and methanol (9.1 ml) at rt. After 1 h, the reaction mixture was neutralized with 1 M HCl solution (27 ml). The reaction mixture was extracted with isopropyl acetate (10×20 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next reaction step without further purification. LCMS: R _T = 0.83 min, m/z = 266.8 [M+H] ⁺ . To a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.790 g; 4.1 mmol), 1-hydroxybenzotriazole (0.370 g; 2.7 mmol), N,O-dimethylhydroxylamine hydrochloride (0.540 g; 5.4 mmol) and the crude residue in N,N-dimethylformamide (9.1 ml) were added triethylamine (1.5 ml; 11 mmol) at rt. After 2 hours the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0% to 10% methanol in dichloromethane) to give 7-fluoro-5-(3-fluoro-2-pyridyl)-N-methoxy-N-methyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.224 g; 0.724 mmol; 27% yield). LCMS: R _T = 0.85 min, m/z = 309.9 [M+H] ⁺ .

Stage 6: cyclopropyl ((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl)methanone and cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1 ,2,4]triazol-2-yl)methanone

Cyclopropyl magnesium bromide (0.5 M solution in THF; 5.7 ml; 2.85 mmol) was added to a solution of 7-fluoro-5-(3-fluoro-2-pyridyl)-N-methoxy-N-methyl-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.220 g; 0.711 mmol) in THF (2.4 ml) at -50°C. After 20 min, the reaction mixture was placed in a bath at rt and the contents of the reaction mixture were stirred for 3 min. Water was added and the reaction mixture was diluted with isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4×20 ml). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give, by convention, cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6.7 -dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (16.59 mg; 0.057 mmol; 8% yield) and cyclopropyl((5S,7R)-7 -fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone (23.7 mg ; 0.082 mmol; yield 12%).

Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2 -yl) methanone: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (dt, J=4.6; 1.5 Hz, 1H), 7.89 (ddd, J=10.0; 8.4; 1.3 Hz, 1H), 7.57 (dt, J=8.6; 4.4 Hz, 1H), 6.26 (ddd, J=56.6; 7.7; 2.7 Hz, 1H), 6.10- 5.99 (m, 1H), 3.74 (dddd, J=19.7; 14.7; 8.5; 7.7 Hz, 1H), 3.16-2.84 (m, 2H), 1.18-0.93 (m, 4H) . LCMS: R _T = 3.64 min, m/z = 291.1 [M+H] ⁺ .

Preparative SFC information: column: Chiralcel OJ, 5 μm (250 x 21.2 mm), mobile phase: carbon dioxide (A)/methanol (B), elution program: isocratic, 15% B; flow rate: 70 ml/min; column temperature: 35°C; wavelength: 261 nm.

Cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2 -yl) methanone: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (dt, J=4.6; 1.5 Hz, 1H), 7.89 (ddd, J=10.0; 8.5; 1.3 Hz, 1H), 7.56 (dt, J=8.6; 4.4 Hz, 1H), 6.58-6.32 (m, 2H), 3.55-3.19 (m, 2H), 2.95 (tt, J= 7.5, 4.9 Hz, 1H), 1.13-0.98 (m, 4H). LCMS: R _T = 3.82 min, m/z = 291.1 [M+H] ⁺ .

Preparative SFC information: column: Chiralcel OJ, 5 μm (250 x 21.2 mm), mobile phase: carbon dioxide (A)/methanol (B), elution program: isocratic, 15% B; flow rate: 70 ml/min; column temperature: 35°C; wavelength: 261 nm.

Method 118

Cyclopropyl ((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl) methanone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(1-methyl-1H-pyrazol- 4-yl) propane-1,3-dione

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 9.5 ml; 9.5 mmol) was added to a solution of methyl-5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole- 3-carboxylate (2.0 g; 5.9 mmol) and 1-(1-methylpyrazol-4-yl)ethanone (1.20 g; 9.5 mmol) in THF (40 ml) at 0°C. The reaction mixture was then heated to rt and stirred for 1 h. The reaction mixture was diluted with water and isopropyl acetate. A solution of 5% citric acid was added and the aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1 ,2,4-triazol-3-yl]-3-(1-methylpyrazol-4-yl)propan-1,3-dione (2.40 g; 5.60 mmol; 94% yield). LCMS: R _T = 1.57 min, m/z = 427.9 [M+H] ⁺ .

Step 2: 2-bromo-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazole

Sodium borohydride (3.30 g; 84 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(1-methylpyrazol-4 -yl)propan-1,3-dione (2.4 g; 5.6 mmol) in ethanol (110 ml) at rt. After 30 minutes, the reaction was quenched with saturated aqueous ammonium chloride and the volatiles were removed under reduced pressure. The crude residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 1.17 min, m/z = 431.9 [M+H] ⁺ . Trifluoroacetic acid (56 ml) and dichloromethane (56 ml) were added to the crude residue, and the reaction mixture was heated at 50° C. for 16 hours. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in dichloromethane and saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted with dichloromethane (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 0.82 min, m/z = 283.8 [M+H] ⁺ . To a solution of the crude residue in dichloromethane (56 ml) was added diethylaminosulfur trifluoride (3.1 ml; 22 mmol) at rt. After 20 minutes, sodium bicarbonate (5.0 g) was added to the reaction mixture. The reaction mixture was diluted with water and isopropyl acetate. Brine was added and the aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (50% to 100% isopropyl acetate in heptane) to give 2-bromo-7-fluoro-5-(1-methylpyrazol-4-yl) -6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.379 g; 1.32 mmol; 24% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) 1:1 mixture of diastereomers: δ 7.84 (s, 0.5H), 7.78 (s, 0.5H), 7.52 (d, J=0.8 Hz, 0, 5H), 7.45 (d, J=0.8 Hz, 0.5H), 6.33-6.03 (m, 1H), 5.88-5.74 (m, 0.5H), 5.63-5.51 (m, 0.5H), 3.83 (s, 1.5H), 3.82 (s, 1.5H), 3.65-3.47 (m, 0.5H), 3.25-3.00 (m, 1H), 2.81-2.64 (m, 0.5H). LCMS: R _T = 0.92 min, m/z = 285.8 [M+H] ⁺ .

Stage 3: cyclopropyl ((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl)methanone

Isopropyl magnesium chloride (2.0 M solution in THF; 2.0 ml; 3.97 mmol) was added to a solution of 2-bromo-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole (0.379 g; 1.32 mmol) and N-methoxy-N-methylcyclopropanecarboxamide (0.529 g; 3.97 mmol) in THF (13.2 ml) at 0°C. After 5 min the reaction mixture was heated to rt and stirred for another 1 h. Water was added and the reaction mixture was diluted with isopropyl acetate. Brine was added and the aqueous layer was extracted with isopropyl acetate (4×50 ml). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give, by convention, cyclopropyl((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl) -6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (44.23 mg; 0.161 mmol; 12% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, J=0.8 Hz, 1H), 7.48 (d, J=0.8 Hz, 1H), 6.21 (ddd, J=56.4 ; 7.0; 2.4 Hz, 1H), 5.66 (ddd, J=8.2; 6.0; 3.6 Hz, 1H), 3.81 (s, 3H), 3.73-3.55 (m, 1H) , 2.99 (tt, J=7.5; 4.9 Hz, 1H), 2.80 (dddd, J=26.4; 14.9; 3.7; 2.4 Hz, 1H), 1.14-0.95 (m , 4H). LCMS: R _T = 3.10 min, m/z = 276.1 [M+H] ⁺ .

Preparative SFC information: Column: Whelk-O1, 5 µm (150 x 21.2 mm), Mobile phase: Carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), Elution program: Isocratic, 35% IN; flow rate: 70 ml/min; column temperature: 40°C; wavelength: 220 nm.

Method 119

Cyclopropyl (7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(5-methylisoxazol-4-yl) propane-1,3-dione

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 7.1 ml; 7.1 mmol) was added to a solution of methyl-5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole- 3-carboxylate (1.5 g; 4.5 mmol) and 1-(5-methylisoxazol-4-yl)ethanone (0.890 g; 7.1 mmol) in THF (30 ml) at 0°C. After 5 min, the reaction mixture was heated to rt and stirred for another 30 min. Water was added and the reaction mixture was diluted with isopropyl acetate. A 10% aqueous citric acid solution was added to adjust the pH to 2. The aqueous layer was extracted with isopropyl acetate (2×200 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate in heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1 ,2,4-triazol-3-yl]-3-(5-methylisoxazol-4-yl)propan-1,3-dione (1.6 g; 3.7 mmol; 84% yield). LCMS: R _T = 1.35 min, m/z = 428.9 [M+H] ⁺ .

Step 2: cyclopropyl(7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone

Sodium borohydride (3.30 g; 84 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(5-methylisoxazol-4 -yl)propan-1,3-dione (2.4 g; 5.6 mmol) in ethanol (110 ml) at rt. After 30 minutes, the reaction was quenched with saturated aqueous ammonium chloride. Volatiles were removed under reduced pressure. The crude residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 1.27 min, m/z = 432.9 [M+H] ⁺ . Sulfuric acid (10 ml) was added to the crude residue and the reaction mixture was heated at 100° C. for 2 hours. After cooling to rt, the reaction mixture was diluted with water. Sodium hydroxide (3M solution in water) was added until the aqueous layer became basic. The aqueous layer was extracted with isopropyl acetate (3×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. To a solution of the crude residue in dichloromethane (8.4 ml) was added diethylaminosulfur trifluoride (0.470 ml; 3.37 mmol) at rt. After 20 min sodium bicarbonate (2.0 g) was added. The reaction mixture was diluted with water and isopropyl acetate. Brine was added and the aqueous layer was extracted with isopropyl acetate (4×20 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue (0.110 g; 0.383 mmol) was taken to the next reaction step without further purification. LCMS: R _T = 1.02 min, m/z = 286.8 [M+H] ⁺ . To a solution of the crude residue and N-methoxy-N-methylcyclopropanecarboxamide (0.153 g; 1.15 mmol) in THF (3.8 ml) was added isopropyl magnesium chloride (2.0 M in THF; 0.38 ml; 0.766 mmol) at 0 °C. After 5 min the reaction mixture was heated to rt and stirred for an additional 20 min. Water was added and the reaction mixture was diluted with isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4×20 ml). The combined organic layers were dried with sodium sulfate, concentrated and the crude residue was purified by preparative SFC to give the diastereomeric mixture cyclopropyl(7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)methanone (1.26 mg; 0.0046 mmol). LCMS: R _T = 3.63 min, m/z = 277.1 [M+H] ⁺ .

Preparative SFC information: column: Chiracel OX, 5 μm (150 x 21.2 mm), mobile phase: carbon dioxide (A)/methanol (B), elution program: isocratic, 20% B; flow rate: 70 ml/min; column temperature: 40°C; wavelength: 220 nm.

Method 120

((5S,7S)-5-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl)(cyclopropyl)methanone and ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7- dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl)methanone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-chloro-1-methyl- 1Н-pyrazol-3-yl)propan-1,3-dione

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 5.9 ml; 5.9 mmol) was added to a solution of methyl-5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole- 3-carboxylate (2.0 g; 5.9 mmol) and 1-(4-chloro-1-methyl-pyrazol-3-yl)ethanone (0.940 g; 5.9 mmol) in THF (40 ml) at 0 °C. After 5 min, the reaction mixture was heated to rt and stirred for another 30 min. Water was added and the reaction mixture was diluted with isopropyl acetate. A 10% aqueous citric acid solution was added to adjust the pH to 2. The aqueous layer was extracted with isopropyl acetate (2×200 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate in heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1 ,2,4-triazol-3-yl]-3-(4-chloro-1-methyl-pyrazol-3-yl)propan-1,3-dione (2.40 g; 5.19 mmol; 87% yield ). LCMS: R _T = 1.68 min, m/z = 461.9 [M+H] ⁺ .

Step 2: ((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b] [1,2,4]triazol-2-yl)(cyclopropyl)methanone and ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6 ,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl)methanone

Sodium borohydride (3.10 g; 78 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(4-chloro-1 -methyl-pyrazol-3-yl)propan-1,3-dione (2.4 g; 5.2 mmol) in ethanol (100 ml) at rt. After 30 minutes, the reaction was quenched with saturated aqueous ammonium chloride. Volatiles were removed under reduced pressure. The residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. Sulfuric acid (10 ml) was added to the crude residue and the reaction mixture was heated at 100° C. for 2 hours. After cooling to rt, the reaction mixture was diluted with water. Sodium hydroxide (3M solution in water) was added until the aqueous layer became basic. The aqueous layer was extracted with isopropyl acetate (3×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification.

To a solution of the crude residue in dichloromethane (26 ml) was added diethylaminosulfur trifluoride (1.5 ml; 10 mmol) at rt. After 20 min sodium bicarbonate (2.0 g) was added. The reaction mixture was diluted with water and isopropyl acetate. Brine was added and the aqueous layer was extracted with isopropyl acetate (4×50 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue (0.40 g; 1.25 mmol) was taken to the next reaction step without further purification. To a solution of the crude residue and N-methoxy-N-methylcyclopropanecarboxamide (0.498 g; 3.74 mmol) in THF (12.5 ml) was added isopropylmagnesium chloride (2.0 M solution in THF; 1.2 ml; 2.50 mmol ) at 0°С. After 5 min, the reaction mixture was heated to rt and stirred for another 20 min. Water was added and the reaction mixture was diluted with isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4×20 ml). The combined organic layers were dried with sodium sulfate, concentrated and the crude residue was purified by preparative SFC to give, as tentatively indicated, ((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)- 7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl)methanone (8.4 mg; 0.027 mmol) and ((5S ,7R)-5-(4-chloro-1-methyl-1Н-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl)(cyclopropyl)methanone (38.8 mg; 0.125 mmol).

((5S,7S)-5-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl)(cyclopropyl)methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 6.23 (ddd, J=56.8; 7.8; 3.3 Hz, 1H), 5.70 (ddd, J=8, 4; 6.5; 5.0 Hz, 1H), 3.82 (s, 3H), 3.72 (ddt, J=16.3; 14.6; 8.1 Hz, 1H), 3.02-2.82 (m, 2H ), 1.14-0.99 (m, 4H). LCMS: R _T = 3.86 min, m/z = 310.0 [M+H] ⁺ .

Preparative SFC information: column: Chiralpak IB-N, 5 µm (150 x 21.2 mm), mobile phase: carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), elution program: isocratic, 20 % IN; flow rate: 70 ml/min; column temperature: 40°C; wavelength: 225 nm.

((5S,7R)-5-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl)(cyclopropyl)methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 6.58-6.22 (m, 1H), 6.04 (ddd, J=7.4; 6.1; 3.1 Hz, 1H) , 3.81 (s, 3H), 3.46-3.21 (m, 2H), 2.97 (tt, J=7.6; 4.8 Hz, 1H), 1.14-1.00 (m, 4H). LCMS: R _T = 4.01 min, m/z = 310.0 [M+H] ⁺ .

Preparative SFC information: column: Chiralpak IB-N, 5 µm (150 x 21.2 mm), mobile phase: carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), elution program: isocratic, 20 % IN; flow rate: 70 ml/min; column temperature: 40°C; wavelength: 225 nm.

Method 121

Cyclopropyl ((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(3-methoxyphenyl)propan-1, 3-dione

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 14 mL; 14 mmol) was added to a solution of methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-carboxylate ( 3.00 g; 8.9 mmol) and 1-(3-methoxyphenyl)ethanone (2.0 ml; 14 mmol) in THF (59 ml) at 0°C. After 5 min, the reaction mixture was heated to rt and stirred for another 30 min. Water was added and the reaction mixture was diluted with isopropyl acetate. A 10% aqueous citric acid solution was added to adjust the pH to 2. The aqueous layer was extracted with isopropyl acetate (2×200 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1 ,2,4-triazol-3-yl]-3-(3-methoxyphenyl)propan-1,3-dione (4.10 g; 9.02 mmol; 100% yield; product contained an impurity of 1-(3-methoxyphenyl )ethenone). LCMS: R _T = 1.80 min, m/z = 453.9 [M+H] ⁺ .

Stage 2: 2-bromo-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Sodium borohydride (5.30 g; 140 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(3-methoxyphenyl)propane -1,3-dione (4.1 g; 9.0 mmol) in ethanol (180 ml) at rt. After 30 minutes, a saturated aqueous ammonium chloride solution was added. Volatiles were removed under reduced pressure. The crude residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 1.40 min, m/z = 357.9 [M+H] ⁺ . Sulfuric acid (10 ml) was added to a solution of the crude residue, and the reaction mixture was heated at 100°C for 2 hours. After cooling to rt, the reaction mixture was diluted with water. Sodium hydroxide (3M solution in water) was added until the aqueous layer became basic. The aqueous layer was extracted with isopropyl acetate (3×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was taken to the next step without further purification. LCMS: R _T = 1.02 min, m/z = 309.8 [M+H] ⁺ . To a solution of the crude residue in dichloromethane (89 ml) was added diethylaminosulfur trifluoride (2.50 ml; 17.9 mmol) at rt. After 20 min sodium bicarbonate (5.0 g) was added. The reaction mixture was diluted with water and isopropyl acetate. Brine was added and the aqueous layer was extracted with isopropyl acetate (4×100 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give 2-bromo-7-fluoro-5-(3-methoxyphenyl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg; 0.160 mmol; 1.79% yield). ¹ H NMR (400 MHz, chloroform-d) δ 7.35-7.26 (m, 1H), 6.90 (ddd, J=8.3; 2.5; 0.9 Hz, 1H), 6.83 (dd, J=7 .6; 1.6 Hz, 1H), 6.76 (t, J=2.1 Hz, 1H), 5.97 (ddd, J=56.0; 7.14 1.8 Hz, 1H), 5.39 (t, J=9.1 Hz, 1H), 3.79 (s, 3H), 3.64-3.46 (m, 1H), 2.96-2.80 (m, 1H). LCMS: R _T = 1.16 min, m/z = 311.8 [M+H] ⁺ .

Step 3: cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- silt) methanone

Isopropyl magnesium chloride (2.0 M solution in THF; 0.24 ml; 0.481 mmol) was added dropwise over 15 min to a solution of (5S,7S)-2-bromo-7-fluoro-5-(3-methoxyphenyl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg; 0.160 mmol) and N-methoxy-N-methylcyclopropanecarboxamide (64 mg; 0.481 mmol) in THF (1 .6 ml) at 0°C. The reaction mixture was then allowed to stir at this temperature for 1 hour. A saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with isopropyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give, by convention, cyclopropyl-[(5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (2.35 mg; 0.0078 mmol; 5% yield). LCMS: R _T = 4.92 min, m/z = 302.1 [M+H] ⁺ .

Preparative SFC information: column: Cellulose-1, 5 μm (150 x 21.2 mm), mobile phase: carbon dioxide (A)/methanol (B), elution program: isocratic, 15% B; flow rate: 70 ml/min; column temperature: 40°C; wavelength: 220 nm.

Method 122

Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl) methanone

Stage 1: methyl 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-oxo-propanoate

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 194 ml; 194 mmol) was added to a solution of methyl 3-bromo-1H-1,2,4-triazole-5-carboxylate (20.0 g; 97 .1 mmol) and methyl acetate (15.5 ml; 194 mmol) in THF (324 ml) at -20°C. After the addition was complete, the reaction mixture was allowed to warm to rt and stirred overnight. The pH of the reaction mixture was adjusted to pH 1 by adding a 10% aqueous citric acid solution. The aqueous layer was extracted with isopropyl acetate (3×200 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give methyl-3-(3-bromo-1H-1,2,4 -triazol-5-yl)-3-oxo-propanoate (15.4 g; 62.1 mmol; 64.0% yield). LCMS: R _T = 0.91 min, m/z = 247.7 [M+H] ⁺ .

Step 2: 2-bromo-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

Piperidinium acetate (0.250 g; 1.6 mmol) was added to a solution of methyl 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-oxo-propanoate (2.00 g; 8 .1 mmol) and 3-fluoro-5-(trifluoromethyl)benzaldehyde (1.2 ml; 8.1 mmol) in benzene (8.1 ml). The reaction vessel was equipped with a Dean-Stark trap and a reflux condenser and the reaction mixture was heated at reflux for 3 hours. After cooling to rt, the reaction mixture was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (3×50 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give methyl 2-bromo-5-[3-fluoro-5-( trifluoromethyl)phenyl]-7-hydroxy-5H-pyrrolo[1,2-b][1,2,4]triazole-6-carboxylate (0.60 g; 1.4 mmol; 18% yield) which was used immediately in the next reaction step. LCMS: R _T = 1.28 min, m/z = 421.8 [M+H] ⁺ .

To a solution of the crude residue in dimethyl sulfoxide (4.7 ml) and water (0.47 ml) was added sodium chloride (0.830 g; 14 mmol). The reaction mixture was then heated at 120° C. for 15 min, after which the reaction vessel was placed in a water bath at rt and sodium borohydride (0.270 g; 7.1 mmol) was added. After 10 minutes, a saturated aqueous ammonium chloride solution was added and the reaction mixture was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (3×20 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give 2-bromo-5-[3-fluoro-5-(trifluoromethyl) phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (0.320 g; 0.874 mmol; 61% yield). ¹ H NMR (400 MHz, chloroform-d) 3:1 mixture of diastereomers: δ 7.45 (s, 1H), 7.39-7.25 (m, 2H), 5.46-5.35 (m, 2H), 3.63-3.49 (m, 0.75 H), 3.18 (ddd, J=14.3; 7.5; 2.5 Hz, 0.25 N), 2.90 (ddd, J=14.2; 7.1; 6.1 Hz, 0.25H) , 2.66 (ddd, J=14.5; 3.9; 3.0 Hz, 0.75H). LCMS: R _T = 1.19 min, m/z = 365.8 [M+H] ⁺ .

Step 3: 2-bromo-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Diethylaminosulfur trifluoride (0.230 ml; 1.75 mmol) was added to a solution of 2-bromo-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-7-ol (0.320 g; 0.874 mmol) in dichloromethane (17.5 ml) at 40°C. After 10 minutes, a saturated aqueous sodium bicarbonate solution was added. The reaction mixture was diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×20 ml). The combined organic layers were dried using sodium sulfate, concentrated and the crude residue was purified by flash column chromatography (silica; 0% to 100% isopropyl acetate in heptane) to give 2-bromo-7-fluoro-5-[3-fluoro-5 -(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.250 g; 0.679 mmol; 78% yield). ¹ H NMR (400 MHz, chloroform-d) 3:1 mixture of diastereomers: δ 7.42-7.33 (m, 1H), 7.27 (d, J=12.2 Hz, 1H), 7.15-7.04 (m, 1H), 6.14-5.88 (m, 1H), 5.72 (td, J=6.8; 3.6 Hz, 0.75H), 5.60-5.44 (m, 0.25H), 3.70-3.52 (m, 0.25H), 3.41 (dddd, J=22.4; 15.3; 7.0; 1.3 Hz, 0.75H), 3.01-2.80 (m, 1H). LCMS: R _T = 1.35 min, m/z = 367.7 [M+H] ⁺ .

Step 4: cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2 ,4]triazol-2-yl)methanone

Isopropyl magnesium chloride (2.0 M solution in THF; 1.0 ml; 2.04 mmol) was added dropwise over 15 min to a solution of N-methoxy-N-methylcyclopropanecarboxamide (0.271 g; 2.04 mmol) and 2-bromo -7-fluoro-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.250 g; 0.679 mmol ) in THF (6.8 ml) at 0°C. After 1 h, a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with isopropyl acetate (2×20 ml). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give, by convention, cyclopropyl-[7-fluoro-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (3.47 mg; 0.0097 mmol; 1.4% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.76 (dt, J=8.8; 2.1 Hz, 1H), 7.61 (s, 1H), 7.47 (dt, J=9.4; 1, 9 Hz, 1H), 6.26 (ddd, J=56.2; 7.0; 2.1 Hz, 1H), 5.89 (ddd, J=8.9; 6.2; 3.4 Hz, 1H), 3.86-3.66 (dddd, J=25.2; 15.4; 8.5; 7.1 Hz, 1H), 3.09-2.93 (m, 1H), 2.83 (dddd, J=26.1; 15.2 ; 3.4; 2.2 Hz, 1H), 1.16-0.99 (m, 4H). LCMS: R _T = 5.51 min, m/z = 358.1 [M+H] ⁺ .

Preparative SFC Information: Column: Whelk-O1, 5 µm (150 x 21.2 mm), Mobile phase: Carbon dioxide (A)/Methanol (B), Elution program: Isocratic, 20% B; flow rate: 70 ml/min; column temperature: 40°C; wavelength: 220 nm.

Method 123

(1-((1H-Pyrazol-1-yl)methyl)cyclopropyl)(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone

(1-((1H-Pyrazol-1-yl)methyl)cyclopropyl)(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl ) methanone was prepared from (1R,2R)-2-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid according to methods 2 and 3. The crude residue was further purified by preparative HPLC (Gemini-NX C18, 50 x 30 mm, 5 μm ; 20-60% of a mixture of 0.1% formic acid in water/acetonitrile) to give the final product (20.2 mg; 32%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.57 (d, J=2.2 Hz, 1H), 7.44-7.30 (m, 4H), 7.26-7.18 (m, 2H), 6.16 (d, J =2.2 Hz, 1H), 5.60 (dd, J=8.3; 5.8 Hz, 1H), 4.63 (q, J=14.4 Hz, 2H), 3.22-2.81 (m, 2H), 2.61-2.28 (m, 1H), 1.70-1.53 (m, 2H), 1.35-1.13 (m, 3H). LCMS: R _T = 4.31 min, m/z = 334.2 (M+H) ⁺ . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid for 10 min): retention time 4.31 min, ESI+: detected [M+H] = 334.2.

Additional conditions for purification by SFC and analysis

SFC 1

Cyclopropyl ((4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) methanone

For conventionally designated as cyclopropyl ((4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanone (7.9 mg; yield 55%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46-7.28 (m, 3H), 7.28-7.07 (m, 2H), 6.94 (d, J=2.6 Hz, 1H), 6.34-5.96 (m , 1Н), 5.88-5.51 (m, 1Н), 2.94-2.75 (m, 1Н), 2.76-2.55 (m, 1Н), 2.07 (s, 1Н), 1.04-0.74 (m, 4Н). LC-MS: R _T = 5.11 min, m/z = 271.1 (M+H) ⁺ .

SFC 2

[rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1S,2S)-2-(trifluoromethyl)cyclopropyl]methanone

For conventionally designated as [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] -[rac-(1S,2S)-2-(trifluoromethyl)cyclopropyl]methanone (4.2 mg; 31% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59-7.08 (m, 5H), 6.50-6.06 (m, 1H), 5.93-5.55 (m, 1H), 3.76-3.25 (m, 1H), 2.58 (d, J=2.5 Hz, 1H), 1.88-1.15 (m, 2H). LC-MS: R _T = 5.36 min, m/z = 340.1 (M+H) ⁺ .

SFC3

[rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1R,2R)-2-(trifluoromethyl)cyclopropyl]methanone

For conventionally designated as [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] -[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]methanone (12.2 mg; 89% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50-7.13 (m, 5H), 6.51-6.05 (m, 1H), 5.93-5.49 (m, 1H), 3.90-3.54 (m, 1H), 2.84 -2.59 (m, 1H), 2.62-2.53 (m, 1H), 2.07 (s, 1H), 1.64-1.26 (m, 2H). LC-MS: R _T = 5.40 min, m/z = 340.1 (M+H) ⁺ .

SFC 4

[rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (2S)-spiro[2.2]pentan-2-yl]methanone

For conventionally designated as [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] -[rac-(2S)-spiro[2.2]pentan-2-yl]methanone (3.2 mg; 39% yield). LC-MS: R _T = 4.95 min, m/z = 298.1 (M+H) ⁺ .

SFC5

[rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (2R)-spiro[2.2]pentan-2-yl]methanone

For conventionally designated as [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] -[rac-(2R)-spiro[2.2]pentan-2-yl]methanone (x mg; x% yield). LC-MS: R _T = 4.94 min, m/z = 298.1 (M+H).

RIP1 kinase inhibition assays (biochemical analysis)

Compounds of the present invention were tested for their ability to inhibit RIP1K activity as described below.

Enzymatic analysis. The ability of the receptor-interacting protein-1 (RIPK1) protein kinase to catalyze the hydrolysis of adenosine 5'-triphosphate (ATP) was monitored using the Transcreener ADP (adenosine-5'-diphosphate) assay (BellBrook Labs). Purified human RIP1 kinase domain (2-375) (50 nM) derived from the expression system of baculovirus-infected insect cells was incubated with test compounds for 2 hours in 50 mM Hepes (4-(2-hydroxyethyl)-1) based buffer. -piperazineethanesulfonic acid) (pH 7.5) containing 30 mM MgCl ₂ , 1 mM dithiothreitol, 50 μM ATP, 0.002% Brij-35 and 0.5% dimethyl sulfoxide (DMSO). Reactions were quenched by adding 1X Buffer B from BellBrooks (20 mM Hepes (pH 7.5), 40 mM EDTA and 0.02% Brij-35) additionally containing 12 mM EDTA and anti-ADP2 antibody (55 µg/ ml) and a 4 nM AlexaFluor® 633 ADP indicator. The antibody-bound indicator is displaced by the ADP formed in the reaction involving RIP1K, which causes a decrease in fluorescence polarization (FP), which is measured using a laser with excitation at a wavelength of 633 nm using the M1000 microplate reader for reading FP. The relative activity was plotted against the concentration of the test compound. Using the Genedata Screener software (Genedata; Basel, Switzerland), data were fitted to the Morrison equation to determine the apparent tight-binding inhibition constant (K _i ^app ) (Williams, JW and Morrison, JF (1979) The kinetics of reversible tight-binding inhibition Methods Enzymol., 63: 437-67). The following equation was used to calculate the relative activity and K _i ^app :

where [E] _T and [I] _T are the total concentrations of active enzyme and test compound, respectively.

Exemplary compounds of the present invention are shown in Tables 1 and 2 along with their physicochemical characteristics and in vitro inhibition of RIP1 kinase activity. The "method" in the first column of each table refers to the synthetic method(s) used to prepare each compound as shown in the examples above. In some examples, retention times (min) on chiral columns are given for some stereoisomers. Unless otherwise indicated, the stereochemical configuration shown for each structure is the relative configuration of the individual stereo isomer, and the absolute configuration indicated (i.e., "R" and/or "S") is by convention. In some embodiments, where the described method involves separation of stereoisomers, an individual stereoisomer of a compound from Table 1 or Table 2 is provided.

All US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference in their entirety.

While the above invention has been described in some detail for ease of understanding, it will be apparent that, in practice, some changes and modifications may be made within the scope of the appended claims. Accordingly, the described embodiments are to be considered illustrative and not restrictive, and the invention is not to be limited to the details set forth herein, but may be modified within the scope and equivalents of the appended claims.

Claims (226)

1. Compound of formula (I)

where R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ alkyl-N(R ^N ) ₂ , phenyl, benzyl, 4-8 membered heterocyclyl and 5-6 membered heteroaryl; wherein R ¹ is bonded to the adjacent carbonyl via a carbon atom, and wherein R ¹ is optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ alkyl-N (R ^N ) ₂ , hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C (O) C ₁ -C ₆ alkyl, phenyl, benzyl, CH ₂ -(C ₃ -C ₆ cycloalkyl), 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); each ^RN is independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl; or two ^RN together with the adjacent N atom may form a 4-6 membered ring; Ring A and Ring B are jointly selected from the group consisting of:

where R ² is selected from the group consisting of C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thioalkyl, phenyl, benzyl, CH groups ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ - (4-6-membered heterocyclyl), CH ₂ CH ₂ - (4-6-membered heterocyclyl) , 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, in the case of the presence of a phenyl ring or a 5-6-membered heteroaryl ring, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, cyclopropyl and cyano; And R ^3a and R ^3b are selected as follows: (1) one of R ^3a and R ^3b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy; (2) each of R ^3a and R ^3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, with the proviso that R ^3a and R ^3b cannot both be OH or CN; or (3) R ^3a and R ^3b together form cyclopropyl. 2. A compound according to claim 1, wherein Ring A and Ring B are jointly selected from the group consisting of:

where R ² is selected from the group consisting of C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thioalkyl, phenyl, benzyl, CH groups ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ CH ₂ - (C ₃ -C ₆ cycloalkyl), CH ₂ - (4-6-membered heterocyclyl), CH ₂ CH ₂ - (4-6-membered heterocyclyl) , 5-6 membered heteroaryl and CH ₂ -(5-6 membered heteroaryl); however, in the case of the presence of a phenyl ring or a 5-6-membered heteroaryl ring, it may be substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and cyano; And R ^4a and R ^4b are selected as follows: (1) one of R ^4a and R ^4b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy; or (2) each of R ^4a and R ^4b is selected from the group consisting of D, F, Cl and methyl. 3. A compound according to claim 1 or 2 wherein R ² is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl and dichlorophenyl. 4. A compound according to claim 1 or 2, wherein ring A and ring B are jointly selected from the group consisting of:

where R ^3a and R ^3b are selected as follows: (1) one of R ^3a and R ^3b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C _{1 -4} alkyl, C _{1 -4} haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy; (2) each of R ^3a and R ^3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, with the proviso that R ^3a and R ^3b cannot both be OH or CN; or (3) R ^3a and R ^3b together form cyclopropyl; each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy; And m is 1, 2, or 3. 5. The compound according to claim 1 or 2, where ring A and ring B together represent:

where each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy; And m is 1, 2, or 3. 6. A compound according to claim 1 or 2 wherein R ² is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl and dichlorophenyl. 7. A compound according to claim 1 or 2, wherein ring A and ring B are jointly selected from the group consisting of:

where R ^4a and R ^4b are selected as follows: (1) one of R ^4a and R ^4b is H and the other is selected from the group consisting of F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, C ₁ -C ₄ alkoxy and C ₁ -C ₆ haloalkoxy; or (2) each of R ^4a and R ^4b is selected from the group consisting of F, Cl and methyl; each R ⁵ is selected from the group consisting of H, F, Cl, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy; And m is 1, 2, or 3. 8. Compound, where the compound is selected from the group consisting of: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ((1R,2R) -2-fluorocyclopropyl) methanone; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1S,2S) -2-fluorocyclopropyl) methanone; ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2R) -2-fluorocyclopropyl) methanone; ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1S,2S) -2-fluorocyclopropyl) methanone; 2-hydroxy-2-methyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]propan-1-one; 2-hydroxy-2-methyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]propan-1-one; 2-phenyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl]ethanone; ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2S) -2-fluorocyclopropyl) methanone; ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1S,2R) -2-fluorocyclopropyl) methanone; (7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2S)-2- fluorocyclopropyl] methanone; (2,2-difluorocyclopropyl)-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone; phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; 1-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-she; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1- (trifluoromethyl)cyclopropyl]methanone; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3- methyloxetan-3-yl) methanone; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac- (1S,2R)-2-fluorocyclopropyl]methanone; 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one; cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one; 1-[rac-(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one; 1-[rac-(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one; 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2 ,2-dimethyl-3-oxo-propanenitrile; (S)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one; (R)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one; 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2 -hydroxy-2-methyl-propan-1-one; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1- methyl cyclopropyl) methanone; 1-[rac-(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one; 1-[rac-(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one; 3,3,3-trifluoro-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]propan-1-one; 1-[rac-(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one; 1-[rac-(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1- she; 1-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-she; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2- pyridyl) methanone; cyclopropyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone; 2,2-dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]propan-1-one; 2,2-dimethyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]propan-1-one; (1-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; (1-methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2- thienyl) methanone; cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; 1-(7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-propan-1 -she; 1-(7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-propan-1-one ; 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-she; 1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-she; (1-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan- 1-she; 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2S) -2-fluorocyclopropyl) methanone; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1S,2R) -2-fluorocyclopropyl) methanone; (1-fluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl) methanone; (3-methyloxetan-3-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; (3-methyloxetan-3-yl)-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; 3-oxabicpo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone; oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; [1-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone; [(1R)-2,2-difluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; [(1S)-2,2-difluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; (1-fluorocyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone; cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone; cyclopropyl-[rac-(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; (3,3-difluorocyclobutyl)-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; [(1S,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2- fluorocyclopropyl] methanone; [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S)-2- fluorocyclopropyl] methanone; cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; [(1R,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; (2,2-difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone; 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one; [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone; (3,3-difluorocyclobutyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; [2-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(1S ,2S)-2-methylcyclopropyl]methanone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexane -5-yl-methanone; cyclopropyl-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[rac-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone; [1-(fluoromethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl] methanone; (3,3-difluoro-6-bicyclo[3.1.0]hexanyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl]methanone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(trifluoromethyl )cyclopropyl]methanone; (6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][ 1,2,4]triazol-2-yl]methanone; 2-[1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropyl ]acetonitrile; cyclopropyl-[(5S,7S)-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7S)-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone; 2-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]-cyclopropanecarbonitrile ; cyclopropyl-[(5S,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S )-2-methylcyclopropyl]methanone; [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2R )-2-methylcyclopropyl]methanone; cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarbonitrile; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.2]pentane -2-yl-methanone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexane -2-yl-methanone; [1-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole -2-yl]methanone; (1-cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone; cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone; cyclopropyl-[(5S,7S)-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; cyclopropyl-[(5S,7S)-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone; rac-(1R,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carbonyl]cyclopropanecarbonitrile; cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; cyclopropyl-[(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone; cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7S)-7-deutero-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S)-7,7-dideutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5R,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[rac-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; cyclopropyl-[rac-(5S,7S)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[rac-(5S,7R)-7-chloro-7-deutero-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; cyclopropyl-[rac-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone; 2-[(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile; (1-ethylcyclopropyl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-tetrahydropyran-4 -yl-methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-tetrahydropyran-3 -yl-methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (2R)-pyrrolidin-2-yl]methanone; (2-methyltetrahydrofuran-2-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-tetrahydrofuran-3 -yl-methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (3S)-tetrahydrofuran-3-yl]methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (3R)-tetrahydrofuran-3-yl]methanone; 3-methoxy-2,2-dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]propan-1-one; rac-(2S)-3,3,3-trifluoro-2-hydroxy-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazol-2-yl]propan-1-one; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (3R)-3-methyltetrahydrofuran-3-yl]methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (3S)-3-methyltetrahydrofuran-3-yl]methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]methanone; ((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)methanone; ((1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5Н-pyrrolo[1, 2-b][1,2,4]triazol-2-yl)methanone; 1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2 -(trifluoromethoxy)ethanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]methanone; cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone; (S)-cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone; cyclopropyl ((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone ; cyclopropyl-[rac-(5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; cyclopropyl-[rac-(5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; cyclopropyl ((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2 -yl) methanone; cyclopropyl ((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2 -yl) methanone; cyclopropyl ((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl)methanone; cyclopropyl (7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone; ((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl)(cyclopropyl)methanone; ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl)(cyclopropyl)methanone; cyclopropyl ((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone ; cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl) methanone; (5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(pyrazol-1-ylmethyl)cyclopropyl]methanone; cyclopropyl ((4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1S,2S)-2-(trifluoromethyl) cyclopropyl] methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (1R,2R)-2-(trifluoromethyl)cyclopropyl]methanone; [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (2S)-spiro[2.2]pentan-2-yl]methanone; And [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac- (2R)-spiro[2.2]pentan-2-yl]methanone. 9. A compound, where the compound is selected from the group consisting of: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2R) -2-fluorocyclopropyl) methanone; phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1- methylcyclopropyl) methanone; cyclopropyl ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone; [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone; cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl] methanone; cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methanone; cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; And cyclopropyl ((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone . 10. A compound wherein the compound is ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2- yl)((1R,2R)-2-fluorocyclopropyl)methanone. 11. A compound wherein the compound is phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone. 12. A compound wherein the compound is (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl)-(1-methylcyclopropyl) methanone. 13. A compound wherein the compound is cyclopropyl-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl) methanone. 14. A compound wherein the compound is [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-b][1,2,4]triazol-2-yl]methanone. 15. A compound wherein the compound is cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1, 2,4]triazol-2-yl]methanone. 16. A compound wherein the compound is cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2, 4]triazol-2-yl]methanone. 17. A compound wherein the compound is cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-yl]methanone. 18. A compound wherein the compound is cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4 ]triazol-2-yl)methanone. 19. The compound of claim 1, wherein the selected compound is a compound having RIP1 (receptor-interacting protein-1) kinase inhibitory activity with a K ₁ less than 100 nM. 20. Pharmaceutical composition for inhibiting the activity of RIP1 kinase, containing an effective amount of the compound according to any one of paragraphs. 1-19 and a therapeutically inert carrier. 21. Connection according to any one of paragraphs. 1-19 for use as a therapeutically active substance. 22. The use of a compound according to any one of paragraphs. 1-19 for the treatment of a disease or disorder associated with RIP1 kinase activity selected from the group consisting of Parkinson's disease, Lewy body dementia, multiple system atrophy, parkinsonism-plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, osteoarthritis, kidney damage/injury (due to nephritis, kidney transplant, surgery, administration of nephrotoxic drugs), acute kidney injury (AKI), transplant rejection, ischemic/reperfusion injury to whole organs, sepsis, and systemic inflammatory response syndrome (SIRS). 23. The use of a compound according to any one of paragraphs. 1-19 for the preparation of a medicament for the treatment of a disease or disorder associated with RIP1 kinase activity selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, parkinsonism-plus syndrome, tauopathy, Alzheimer's disease, fronto -temporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy , peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, osteoarthritis, kidney injury/injury (due to nephritis , kidney transplantation, surgery, administration of nephrotoxic drugs), acute kidney injury (AKI), transplant rejection, ischemic/reperfusion injury to whole organs, sepsis, and systemic inflammatory response syndrome (SIRS). 24. Use according to claim 22 or 23, wherein the disease or disorder associated with RIP1 kinase activity is inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, or osteoarthritis . 25. Use according to claim 22 or 23, where the disease or disorder associated with RIP1 kinase activity is kidney damage/damage (as a result of nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs), acute kidney injury (AKI) , transplant rejection, ischemic/reperfusion injury to whole organs, sepsis, or systemic inflammatory response syndrome (SIRS). 26. A method of treating a disease or disorder associated with RIP1 kinase activity in humans, comprising administering to a person in need thereof an effective amount of a compound according to any one of paragraphs. 1-19, wherein the disease or disorder is selected from the group consisting of Parkinson's disease, Lewy body dementia, multiple system atrophy, parkinsonism-plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy , primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, intracerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, congenital muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, osteoarthritis, kidney damage/injury (from nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs ), acute kidney injury (AKI), transplant rejection, ischemic/reperfusion injury to whole organs, sepsis, and systemic inflammatory response syndrome (SIRS). 27. The method of claim 26, wherein the disease or disorder associated with RIP1 kinase activity is inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, or osteoarthritis. 28. The method of claim 26, wherein the disease or disorder associated with RIP1 kinase activity is kidney damage/damage (due to nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs), acute kidney injury (AKI), rejection transplant, ischemic/reperfusion injury of whole organs, sepsis or systemic inflammatory response syndrome (SIRS).