Bicyclic ketone compounds and methods of use thereof

Abstract

The present invention relates to bicyclic ketone compounds and methods of use thereof. The present invention provides novel compounds having the general formula I: wherein R1, ring A, and ring B are as defined herein, pharmaceutical compositions comprising the compounds, and methods of using the compounds. # imgabs0 #

Description

[0001] This application is a divisional application of an application with a PCT international application date of July 12, 2018, PCT international application number PCT / EP2018 / 068998, Chinese national application number 201880046714.2, and invention name “Bicyclic Ketone Compounds and Methods of Use Thereof”. Field of the Invention

[0002] The present invention relates to organic compounds useful for treatment and / or prevention in mammals, and in particular to RIP1 kinase inhibitors useful for treating diseases and conditions associated with inflammation, cell death, and the like. Background of the Invention

[0004] Receptor interacting protein-1 ("RIP1") kinase is a serine / threonine protein kinase. RIP1 is a regulator of cellular signaling that is particularly involved in mediating programmed cell death pathways such as necroptosis. The best studied form of necrotic cell death is triggered by TNFα (tumor necrosis factor), but necroptosis can also be induced by other members of the TNFα family of death ligands (Fas and TRAIL / Apo2L), interferons, Toll-like receptor (TLR) signaling, and viral infection via the DNA sensor DAI (DNA-dependent activator of interferon regulatory factors) [1-3]. Binding of TNFα to TNFR1 (TNF receptor 1) leads to the trimerization of TNFR1 and the formation of the intracellular complex Complex-I. TRADD (TNF receptor-associated death domain protein) binds to the intracellular death domain of TNFR1 and recruits the protein kinase RIP1 (receptor interacting protein 1) through the death domains present in both proteins [4]. After initial recruitment to the signaling complex associated with TNFR1, RIP1 translocates to a secondary cytoplasmic complex, Complex-II[5-7]. Complex-II is formed by a death domain containing the proteins FADD (Fas-associated protein), RIP1, caspase-8, and cFLIP. If caspase-8 is not fully activated or its activity is blocked, the protein kinase RIP3 is recruited to the complex to form the necrosome, which initiates necrotic cell death[8-10]. Once the necrosome is formed, RIP1 and RIP3 participate in a series of autophosphorylation and cross-phosphorylation events that are essential for necrotic cell death. Necroptosis can be completely blocked by kinase-inactivating mutations in either of the two kinases, or chemically blocked by RIP1 kinase inhibitors (necrostatins) or RIP3 kinase inhibitors[11-13]. Phosphorylation of RIP3 allows the binding and phosphorylation of the pseudokinase MLKL (mixed lineage kinase domain-like), a key component of necrotic cell death [14,15].

[0005] Necroptosis has important pathophysiological implications in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel disease, retinal degeneration, and many other common clinical conditions.

[16] Therefore, selective inhibitors of RIP1 kinase activity are expected to be potential treatments for diseases mediated by this pathway and associated with inflammatory and / or necrotic cell death.

[0006] Inhibitors of RIP1 kinase have been described previously. The first published inhibitor of RIP1 kinase activity was necrostatin 1 (Nec-1)

[17] . This initial discovery was followed by improved versions of Nec-1 with varying abilities to block RIP1 kinase activity [11, 18]. More recently, additional RIP1 kinase inhibitors have been described that are structurally distinct from the necrostatin class of compounds [19, 20, 21].

[0007] Each of the above-cited documents is hereby incorporated by reference in its entirety:

[0008] 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.

[0009] 2) Newton, K. (2015) RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends in cell biology. 25, 347-353.

[0010] 3) de Almagro, MC and Vucic, D. (2015) Necroptosis: Pathway diversity and characteristics. Semin Cell Dev Biol. 39, 56-62.

[0011] 4)Chen, ZJ (2012) Ubiquitination in signaling to and activation of IKK. Immunological reviews. 246, 95-106.

[0012] 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.

[0013] 6) Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D. P., Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G., and Leverkus, M. (2011) cIAPs block Ripoptosome formation, a RIP1 / caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Molecular cell. 43, 449-463.

[0014] 7) Bertrand, M. J., Milutinovic, S., Dickson, K. M., Ho, W. C., Boudreault, A., Durkin, J., Gillard, J. W., Jaquith, J. B., Morris, S. J., and Barker, P. A. (2008) cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 30, 689-700.

[0015] 8) Wang, L., Du, F., and Wang, X. (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 133, 693-703.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 16) Linkermann, A. and Green, D. R. (2014) Necroptosis. The New England journal of medicine. 370, 455-465.

[0024] 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.

[0025] 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.

[0026] 19)Harris,PA,Bandyopadhyay,D.,Berger,SB,Campobasso,N.,Capriotti,CA,Cox,JA,Dare,L.,Finger,JN,Hoffman,SJ,Kahler,KM,Lehr,R.,Lich,JD,Nagilla,R ., Nolte, RT, Ouellette, MT, Pao, CS, Schaeffer, MC, Smallwood, A., Sun, HH, Swift, BA, Totoritis, RD, Ward, P., Marquis, RW, Bertin, J. and Gough, PJ (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243.

[0027] 20) Najjar, M., Suebsuwong, C., Ray, SS, Thapa, RJ, Maki, JL, Nogusa, S., Shah, S., Saleh, D., Gough, PJ, Bertin, J., Yuan, J., Balachandran, S., Cuny, GD and Degterev, A. (2015) Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1.Cell Rep.

[0028] 21) International Patent Publication No. WO 2014 / 125444.

[0029] 22) International Patent Publication No. WO 2017 / 004500. SUMMARY OF THE INVENTION

[0031] Provided herein are compounds of Formula I:

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein

[0034] R1 Selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4 to 8-membered heterocyclic group and 5 to 6-membered heteroaryl; wherein R 1 is connected to the adjacent carbonyl group through a carbon atom, and wherein R 1 Optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, hydroxy, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C1-C6 alkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl);

[0035] R N Each independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 haloalkyl; or two R N Can form a 4-6 membered ring together with the adjacent N;

[0036] Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatoms; wherein Ring A is linked to the adjacent carbonyl group through a carbon atom; and

[0037] Ring B is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclyl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein Ring B is substituted according to (a), (b), or both (a) and (b):

[0038] (a) 1 to 2 substituents selected from the group consisting of halogen, deuterium, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R N )2 and cyano; wherein the two C1-C6 alkyl substituents can together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 alkylthio group having an oxygen or sulfur atom directly bonded to the nitrogen atom;

[0039] (b) 1 substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R N )2, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6-membered heterocyclyl), CH2CH2-(4 to 6-membered heterocyclyl), 5 to 6-membered heteroaryl and CH2-(5 to 6-membered heteroaryl); wherein when a phenyl ring or a 5 to 6-membered heteroaryl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano and cyclopropyl.

[0040] Also provided herein are pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

[0041] Also provided herein are oral formulations of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

[0042] Also provided herein are methods of treating diseases and disorders associated with inflammation, cell death, etc., involving RIP1 kinase, as further described below.

[0043] Also provided herein are compounds of formula I or pharmaceutically acceptable salts thereof for use as therapeutically active substances.

[0044] Also provided herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, for use in treating a disease or condition selected from the group consisting of Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes, taupathies, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0045] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any embodiment provided herein, for use in treating a disease or condition selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, 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, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating disease.

[0046] Also provided herein are compounds of Formula I or pharmaceutically acceptable salts thereof for use in the preparation of a medicament for treating a disease or condition selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson-plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating disease.

[0047] Also provided herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, for use in treating a disease or condition 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

[0049] definition

[0050] As provided herein, all chemical formulae and general chemical structures should be interpreted as providing appropriate valences and chemically stable bonds between atoms, as understood by one of ordinary skill in the art. Where appropriate, a substituent may be bonded to more than one adjacent atom (e.g., an alkyl group includes a methylene group in which two bonds are present).

[0051] In the formulae provided herein, "halogen" or "halo" refers to fluorine, chlorine, and bromine (ie, F, Cl, Br).

[0052] Unless otherwise specified, an alkyl group refers to an optionally substituted linear or branched C1-C 12 Alkyl groups. In some embodiments, alkyl refers to C1-C6 alkyl groups. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl (oxtyl). The substituted alkyl groups provided herein are substituted with one or more substituents selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, OH, CO2H, CO2(C1-C4 alkyl), NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl)2, S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)2, and NHSO2(C1-C4 alkyl). In some embodiments, the substituted alkyl groups have 1 or 2 substituents. In some embodiments, the alkyl groups are unsubstituted.

[0053] Unless otherwise specifically defined, a cycloalkyl group refers to an optionally substituted C3-C 12 Cycloalkyl groups, and include fused, spiro and bridged bicyclic groups, wherein the substituents are selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, OH, CO2H, CO2(C1-C4 alkyl), NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl)2, S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)2 and NHSO2(C1-C4 alkyl). In some embodiments, cycloalkyl refers to a C3-C6 cycloalkyl group. In some embodiments, the C3-C6 cycloalkyl group is optionally substituted by 1 to three halogen atoms. In some embodiments, the C3-C6 cycloalkyl group is optionally substituted by 1 to three fluorine atoms. Exemplary C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Exemplary C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 12Cycloalkyl groups also include bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[4.1.0]heptyl, spiral[4.2]heptyl, cyclooctyl, spiral[4.3]octyl, spiral[5.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, decahydronaphthyl and spiral[5.4]decyl. Where appropriate, cycloalkyl groups can be fused with other groups so that there is more than one chemical bond between the cycloalkyl group and another ring system (e.g., the C ring of Formula I). ​​In some embodiments, the cycloalkyl group is unsubstituted.

[0054] Unless otherwise specified, a haloalkyl group refers to a linear or branched C1-C 12 Alkyl group, wherein one or more hydrogen atoms are replaced by halogen. In some embodiments, haloalkyl refers to C1-C6 haloalkyl group. In some embodiments, 1 to 3 hydrogen atoms in haloalkyl group are replaced by halogen. In some embodiments, each hydrogen atom in haloalkyl group is replaced by halogen (for example trifluoromethyl). In some embodiments, haloalkyl is as defined herein, wherein halogen is fluorine in each case. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and pentafluoroethyl.

[0055] Unless otherwise specified, alkoxy refers to a linear or branched C1-C 12 Alkyl group, wherein in each case there are one or more oxygen atoms between two carbon atoms.In some embodiments, alkoxy refers to C1-C6 alkoxy group.In some embodiments, C1-C6 alkoxy group provided herein has one oxygen atom.Exemplary alkoxy groups include methoxy, ethoxy, CHOCH3, CH2CH2OCH3, CHOCH2CH3, CH2CH2OCH2CH3, CHOCH2CH2CH3, CH2CH2CH2OCH3, CHOCH(CH3)2, CH2OC(CH3)3, CH(CH3)OCH3, CH2CH(CH3)OCH3, CH(CH3)OCH2CH3, CHOCH2OCH3, CH2CH2OCH2CH2OCH3 and CHOCH2OCH2OCH3.

[0056] Unless otherwise specified, cycloalkoxy refers to a C4-C 10 or a C4-C6 alkoxy group, wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0057] Unless otherwise specifically limited, haloalkoxy refers to a C1-C6 haloalkyl group as defined above, wherein one or two oxygen atoms are present between two carbon atoms in each case. In some embodiments, the C1-C6 haloalkoxy group provided herein has one oxygen atom. Exemplary haloalkoxy groups include OCF3, OCHF2, and CH2OCF3.

[0058] Unless otherwise specified, thioalkyl refers to a C1-C ... 12 or C1-C6 alkoxy groups. In some embodiments, alkylthio groups can include sulfur atoms substituted by one or two oxygen atoms (i.e., alkyl sulfones and alkyl sulfoxides). Exemplary alkylthio groups are those exemplified in the definition of alkoxy above, wherein each oxygen atom is replaced by a sulfur atom in each case.

[0059] Unless otherwise specified, thiocycloalkyl refers to a C4-C6 group as defined above wherein each group is cyclic and contains one sulfur atom. 10 or a C4-C6 alkylthio group. In some embodiments, the sulfur atom of the thiocycloalkyl group is substituted with one or two oxygen atoms (i.e., a cyclic sulfone or sulfoxide). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiolyl, and 1,1-dioxothiolyl.

[0060] Unless otherwise specifically limited, heterocyclic group refers to a single saturated or partially unsaturated 4 to 8-membered ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; The term also includes a polycondensed ring system having at least one such saturated or partially unsaturated ring, wherein the polycondensed ring system has 7 to 12 atoms and is further described below. Therefore, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6, 7 or 8-membered ring) having 1 to 7 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring can be C-branched (i.e., substituted by C1-C4 alkyl). The ring can be substituted by one or more (e.g., 1, 2 or 3) oxo groups, and sulfur and nitrogen atoms can also exist in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The rings of the poly-fused ring system can be connected to each other by fusion, spiro bonds and bridge bonds in the case of meeting the valence bond requirements. It should be understood that the individual rings of the poly-fused ring system can be connected in any order relative to each other. It should also be understood that the point of attachment of the poly-fused ring system (as defined above for heterocycle) can be located at any position of the poly-fused ring system. It should also be understood that the point of attachment of the heterocycle or heterocyclic poly-fused ring system can be at any suitable atom (including carbon atoms and nitrogen atoms) of the heterocyclyl group. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3,3] heptyl, imidazolidin-2-one, N-methylpiperidine, imidazolidine, pyrazolidine, 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.

[0061] In some embodiments, the heterocyclyl group is a C4-C5-C6-C7-C8-C6-C7-C8-C6-C7-C6 ... 10 Heterocyclyl. In some embodiments, the heterocyclyl group is neither bicyclic nor spirocyclic. In some embodiments, the heterocyclyl group is a C5-C6 heterocyclyl group having 1 to 3 heteroatoms, wherein if there are 3 heteroatoms, at least 2 are nitrogen.

[0062] Unless otherwise specifically limited, aryl refers to a single full carbon aromatic ring or a polycondensed full carbon ring system, wherein at least one of the rings is aromatic, and wherein the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms or 6 to 10 carbon atoms. Aryl includes a phenyl group. Aryl also includes a polycondensed ring system (for example, a ring system comprising 2, 3 or 4 rings) with about 9 to 20 carbon atoms, wherein at least one ring is aromatic, and wherein other rings can be aromatic or non-aromatic (i.e., carbocyclic rings). Such polycondensed ring systems are optionally substituted by one or more (for example, 1, 2 or 3) oxo groups on any carbocyclic ring portion of the polycondensed ring system. The rings of the polycondensed ring systems can be connected to each other by fusion, spiro bonds and bridge bonds when meeting the valence bond requirements. It should be understood that, as defined above, the connection point of the polycondensed ring system can be located at any position of the ring system, including the aromatic or carbocyclic ring portion of the ring. Exemplary aryl groups include phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0063] Unless otherwise specifically limited, heteroaryl refers to a 5- to 6-membered aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes a polycondensed ring system having 8 to 16 atoms having at least one such aromatic ring, the polycondensed ring system being as further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. Exemplary heteroaromatic ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems comprising 2 or 3 rings), wherein, as defined above, the heteroaryl group is fused to one or more rings selected from heteroaryl (to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl), thereby forming a polycondensed ring system. Thus, the heteroaryl group (single aromatic ring or polycondensed ring system) has 1 to 15 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portions of the condensed rings. The rings of the poly-fused ring systems can be connected to each other by fusion, spiro bonds and bridge bonds when meeting the valence bond requirements. It should be understood that the individual rings of the poly-fused ring systems can be connected in any order relative to each other. It should also be understood that the point of attachment of the poly-fused ring systems (as defined above for heteroaryl) can be located at any position of the poly-fused ring systems, including heteroaryl, heterocycle, aryl or carbocyclic moieties of the poly-fused ring systems. It should also be understood that the point of attachment of heteroaryl or heteroaryl poly-fused ring systems can be at any suitable atom (including carbon atoms and heteroatoms (e.g., nitrogen atoms)) of the heteroaryl or heteroaryl poly-fused ring systems. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thiazolyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclo-penta[1,2-c]pyrazole.

[0064] As used herein, the term "chiral" refers to molecules that have the property that their mirror image counterparts are non-superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image counterparts.

[0065] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0066] As used herein, a wavy line that intersects a bond in a chemical structure Indicates the point of attachment of a bond where the wavy bond meets the rest of the molecule in a chemical structure.

[0067] As used herein, the term "C-linked" means that the group such term describes is attached to the rest of the molecule through a ring carbon atom.

[0068] As used herein, the term "N-linked" means that the group such term describes is attached to the rest of the molecule through a ring nitrogen atom.

[0069] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical procedures, such as electrophoresis and chromatography.

[0070] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0071] The stereochemical definitions and conventions used herein generally follow those of S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention (including but not limited to diastereomers, enantiomers and rotamers, and mixtures thereof, such as racemic mixtures) are intended to form part of the present invention. Many organic compounds exist in optically active forms, that is, they are capable of rotating 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 about its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the rotation sign of the plane polarized light of the compound, wherein (-) or l mean that the compound is left-handed. The compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical, except that they are mirror images of each other. Concrete stereoisomers can also be referred to as enantiomers, and the mixture of such isomers is often referred to as an enantiomeric mixture. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric substances, without optical activity.

[0072] When the bonds in the compound formulas herein are drawn in a non-stereochemical manner (e.g., flat), the atoms connected by the bonds include all stereochemical possibilities. When the bonds in the compound formulas herein are drawn in a defined stereochemical manner (e.g., bold, bold-wedge, dashed, or dashed-wedge), it is understood that unless otherwise stated, the atoms connected by the stereochemical bonds are enriched in the absolute stereoisomers depicted. In one embodiment, the compound can be at least 51% of the absolute stereoisomers depicted. In another embodiment, the compound can be at least 80% of the absolute stereoisomers depicted. In another embodiment, the compound can be at least 90% of the absolute stereoisomers depicted. In another embodiment, the compound can be at least 95% of the absolute stereoisomers depicted. In another embodiment, the compound can be at least 97% of the absolute stereoisomers depicted. In another embodiment, the compound can be at least 98% of the absolute stereoisomers depicted. In another embodiment, the compound can be at least 99% of the absolute stereoisomers depicted.

[0073] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0074] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. In some embodiments, the hydrate of the compound provided herein is a ketohydrate.

[0075] As used herein, the term "protecting group" refers to a substituent that is generally used for blocking or protecting a particular functional group on a compound. For example, an "amino protecting group" is a substituent that is connected to an amino group of an amino functional group in a blocking or protecting compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects a hydroxy functional group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a protecting group of a carboxyl group that blocks or protects a carboxyl functional group. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(tosyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl etc. For a general description of protecting groups and their uses, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4th ed., Wiley-Interscience, New York, 2006.

[0076] As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0077] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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 aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, 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, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, etc.), and salts derived from relatively nontoxic organic acids (such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.). Also included are salts of amino acids (such as arginine, etc.), and salts of organic acids (such as glucuronic acid or galacturonic acid, etc.) (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compound to be converted into base addition salts or acid addition salts.

[0078] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0079] In addition to the salt form, the present invention also provides compounds in the form of prodrugs. As used herein, the term "prodrug" refers to compounds that are susceptible to chemical changes under physiological conditions to provide the compounds of this invention. In addition, prodrugs can be converted into compounds of this invention in an isolated environment by chemical or biochemical methods. For example, when prodrugs are placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, prodrugs can slowly be converted into compounds of this invention.

[0080] The prodrugs of the present invention include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently attached to a free amino group, a hydroxyl group, or a carboxylic acid group of a compound of the present invention via an amide or ester bond. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids (typically represented by three-letter symbols), and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodesmosine, γ-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylornithine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0081] Other types of prodrugs are also included. For example, the free carboxyl groups of the compounds of the present invention can be derived into amides or alkyl esters. As another example, compounds of the present invention containing free hydroxyl groups can be derived into prodrugs by converting the hydroxyl groups into groups such as, but not limited to, phosphates, hemisuccinates, dimethylaminoacetates, or phosphoryloxymethoxycarbonyl groups, as described in Fleisher, D. et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19: 115. Also included are carbamate prodrugs of hydroxyl and amino groups, as well as carbonate prodrugs, sulfonates, and sulfates of hydroxyl groups. Also included are derivatization of hydroxyl groups into (acyloxy)methyl ethers and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39: 10. More specific examples include prodrugs 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, succinyl, (C 1-6 ) alkanoyl, α-amino (C 1-4 )alkanoyl, aroyl and α-aminoacyl or α-aminoacyl-α-aminoacyl groups replace the hydrogen atoms of the alcohol group, wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C 1-6 )alkyl)2 or a glycosyl group (a group resulting from removal of a hydroxyl group of a saccharide in the hemiacetal form).

[0082] For additional examples of prodrug derivatives, see, e.g., a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", 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.

[0083] In addition, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced by the metabolism of a particular compound or its salt in vivo. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

[0084] Metabolites are typically identified by preparing radiolabeled (e.g., 14 C or 3H) isotope, which is administered parenterally to animals such as rats, mice, guinea pigs, monkeys or to humans in a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (usually about 30 seconds to 30 hours) and separation of its conversion products from urine, blood or other biological samples. These products are easy to separate because they are labeled (others are separated by using antibodies that can bind to epitopes that survive in metabolites). Metabolite structures are determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. Typically, metabolite analysis is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise found in vivo, they can be used in diagnostic tests for therapeutic administration of the compounds of the present invention.

[0085] Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Typically, 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. Typically, all physical forms are equivalent for the purposes contemplated by the present invention and are intended to fall within the scope of the present invention.

[0086] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (eg, separated enantiomers) are all intended to be encompassed within the scope of the present invention.

[0087] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0088] The terms "treat" and "treatment" refer to therapeutic and / or prophylactic treatments or preventative measures, wherein the purpose is to prevent or slow down (mitigate) an undesirable physiological change or disorder, such as the development or spread of, for example, cancer. For purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of a disease or condition, a stable (i.e., non-worsening) state of a disease or condition, a delay or slowing down of disease progression, an improvement or alleviation of a disease state or condition, and alleviation (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonged survival compared to the expected survival if not receiving treatment. Those requiring treatment include those already suffering from the disease or condition, as well as those susceptible to the disease or condition or those wherein the disease or condition is to be prevented.

[0089] The term "therapeutically effective amount" or "effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and / or determining response rate (RR).

[0090] The term "bioavailability" refers to the systemic availability (i.e., blood / plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that measures both the time (rate) and the total amount (extent) of drug that reaches the systemic circulation from an administered dosage form.

[0091] Inhibitors of RIP1 kinase

[0092] The present invention provides novel compounds having the general formula I,

[0093]

[0094] or a pharmaceutically acceptable salt thereof, wherein

[0095] R 1 Selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4 to 8-membered heterocyclic group and 5 to 6-membered heteroaryl; wherein R 1 is connected to the adjacent carbonyl group through a carbon atom, and wherein R 1 Optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, hydroxy, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C1-C6 alkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl);

[0096] R N Each independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 haloalkyl; or two R N Can form a 4-6 membered ring together with the adjacent N;

[0097] Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatoms; wherein Ring A is linked to the adjacent carbonyl group through a carbon atom; and

[0098] Ring B is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclyl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein Ring B is substituted according to (a), (b), or both (a) and (b):

[0099] (a) 1 to 2 substituents selected from the group consisting of halogen, deuterium, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R N )2 and cyano; wherein the two C1-C6 alkyl substituents can together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not halogen or cyano, or is not a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkylthio group having an oxygen or sulfur atom directly bonded to the nitrogen atom;

[0100] (b) one substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R N )2, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl and CH2-(5 to 6 membered heteroaryl); wherein when a benzene ring or a 5 to 6 membered heteroaryl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano.

[0101] In another embodiment, provided herein is a compound of Formula I:

[0102]

[0103] or a pharmaceutically acceptable salt thereof, wherein

[0104] R 1 Selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N)2, phenyl, benzyl, 4 to 6-membered heterocyclic group and 5 to 6-membered heteroaryl; wherein R 1 is connected to the adjacent carbonyl group through a carbon atom, and wherein R 1 Optionally substituted with one or two substituents selected from the group consisting of F, Cl, methyl, ethyl, hydroxy, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0105] R N Each independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 haloalkyl; or two R N Can form a 4-6 membered ring together with the adjacent N;

[0106] Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatoms; wherein Ring A is linked to the adjacent carbonyl group through a carbon atom; and

[0107] Ring B is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclyl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein Ring B is substituted according to (a), (b), or both (a) and (b):

[0108] (a) 1 to 2 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R N )2 and cyano; wherein the two C1-C6 alkyl substituents can together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not halogen or cyano or is not a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkylthio group having an oxygen or sulfur atom directly bonded to the nitrogen atom;

[0109] (b) one substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R N)2, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl and CH2-(5 to 6 membered heteroaryl); wherein when a benzene ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano and cyclopropyl.

[0110] In some embodiments, R 1 is selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl, benzyl, oxetanyl, oxabicyclo[3.1.0]hexan-6-yl, thienyl and pyrazolyl; wherein R 1 is optionally substituted with: (i) one substituent selected from the group consisting of F, Cl, methyl, hydroxy, hydroxymethyl, cyano, and trifluoromethyl, or (ii) two F substituents. In some of the above embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C4 alkyl. In some embodiments, R 1 is a C3-C5 cycloalkyl group. 1 is C3-C4 cycloalkyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is CF3CH2. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is (2-cyano)-2-propyl. In some embodiments, R 1 is C1-C6 haloalkyl. In some embodiments, R 1 is C1-C4 haloalkyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1is 1-(trifluoromethyl)cyclopropyl. In some embodiments, R 1 In some embodiments, R 1 is 1-(hydroxymethyl)cyclopropyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 1-methylpyrazol-4-yl. In some embodiments, R 1 It is 2-thienyl.

[0111] In some embodiments, R N Each is independently selected from the group consisting of H and C1-C6 alkyl. N In some embodiments, R N Each is a methyl group.

[0112] In some embodiments of Formula (I), R 1 is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0113]

[0114]

[0115] in

[0116] R 2is selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl and CH2-(5 to 6 membered heteroaryl); wherein when the phenyl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano; and

[0117] R 3a and R 3b The choices are as follows:

[0118] (i)R 3a and R 3b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0119] (ii)R 3a and R 3b Each of which is selected from the group consisting of: D, F, Cl, OH, CN and methyl, provided that R 3a and R 3b cannot both be OH or CN; or

[0120] (iii)R 3a and R 3b Together they form a cyclopropyl group.

[0121] In some embodiments of Formula (I), R 1 is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0122]

[0123] in

[0124] R 3a and R 3b The choices are as follows:

[0125] (i)R 3a and R 3b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0126] (ii)R 3a and R 3b Each of which is selected from the group consisting of: D, F, Cl, OH, CN and methyl, provided that R 3a and R 3b cannot both be OH or CN; or

[0127] (iii)R 3a and R 3b Together they form a cyclopropyl group;

[0128] R 5 are each selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0129] m is 1, 2, or 3.

[0130] In some embodiments of Formula (I), R 1 is as defined above, and Ring A and Ring B together are:

[0131]

[0132] in

[0133] R 5 are each selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0134] m is 1, 2, or 3.

[0135] In some embodiments of Formula (I), R 1 is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0136]

[0137]

[0138] in

[0139] R 2selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl and CH2-(5 to 6 membered heteroaryl); wherein when a phenyl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano;

[0140] R 4a and R 4b The choices are as follows:

[0141] (i)R 4a and R 4b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or

[0142] (ii)R 4a and R 4b Each of is selected from the group consisting of D, F, Cl and methyl; and

[0143] R 5 Each is selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0144] In some embodiments of Formula (I), R 1 is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0145]

[0146] in

[0147] R 4a and R 4b The choices are as follows:

[0148] (i)R 4a and R 4b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or

[0149] (ii)R4a and R 4b Each of which is selected from the group consisting of D, F, Cl and methyl:

[0150] R 5 are each selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; and

[0151] m is 1, 2, or 3.

[0152] In some of the above embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 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 fluoro-substituted pyridinyl. In some of the above embodiments, R 2 In some of the above embodiments, R 2 is 1-methyl-1H-pyrazol-4-yl. In some of the above embodiments, R 2 It is 4-chloro-1-methyl-1H-pyrazol-3-yl.

[0153] In some of the above embodiments, R 3a and R 3b Each is 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 In some of the above embodiments, R 3a and R 3b Each is F. In some of the above embodiments, R 3a and R 3b In some of the above embodiments, R 3a and R 3b 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 In some of the above embodiments, R 3a is methyl and R3b is CN. In some of the above embodiments, R 3a and R 3b Each is D. In some of the above embodiments, R 3a is H and R 3b is D. In some of the above embodiments, R 3a It is D and R 3b is F. In some of the above embodiments, R 3a It is D and R 3b is Cl. In some of the above embodiments, R 3a It is D and R 3b It's methyl.

[0154] In some of the above embodiments, R 4a and R 4b Each is H. In some of the above embodiments, R 4a One of them is H and R 4b is F. In some of the above embodiments, R 4a One of them is H and R 4b In some of the above embodiments, R 4a One of them is H and R 4b is Cl. In some of the above embodiments, R 4a and R 4b Each is F. In some of the above embodiments, R 4a and R 4b Each is D. In some of the above embodiments, R 4a is H and R 4b is D. In some of the above embodiments, R 4a It is D and R 4b is F. In some of the above embodiments, R 4a It is D and R 4b It's Cl.

[0155] In some of the above embodiments, R 5 Selected from the group consisting of: H, F, Cl, CH3, CH2CH3, OCH3, CF3, OCF3, CF2H and OCF2H.

[0156] In some of the above embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0157] In another embodiment, provided herein is a compound selected from the group consisting of compounds in Table 1 below, or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a compound selected from the group consisting of compounds in Table 1 below, or a pharmaceutically acceptable salt thereof. iIn another embodiment, the compounds of Table 1 have a K of less than 50 nM in a RIP1K biochemical assay or a cell-based assay (including as described herein). i In yet another embodiment, the compounds of Table 1 have a K of less than 25 nM in a RIP1K biochemical assay or a cell-based assay (including as described herein). i In yet another embodiment, the compounds of Table 1 have a K of less than 10 nM in a RIP1K biochemical assay or a cell-based assay (including as described herein). i .

[0158] In another embodiment, provided herein is a compound selected from the group consisting of compounds in Table 2 below, or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a compound selected from the group consisting of compounds in Table 2 below, or a pharmaceutically acceptable salt thereof. i In another embodiment, the compounds of Table 2 have a K of less than 50 nM in a RIP1K biochemical assay or a cell-based assay (including as described herein). i In yet another embodiment, the compounds of Table 2 have a K of less than 25 nM in a RIP1K biochemical assay or a cell-based assay (including as described herein). i In yet another embodiment, the compounds of Table 2 have a K of less than 10 nM in a RIP1K biochemical assay or a cell-based assay (including as described herein). i .

[0159] In some embodiments, individual stereoisomers of compounds of Table 1 or Table 2 are provided herein, as characterized by reference to their chiral separation and resolution (eg, as described in the Examples by chiral SFC).

[0160] In some embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as described in any of the above embodiments, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

[0161] Also provided herein are oral formulations of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described in any of the above embodiments, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

[0162] In some embodiments, there is provided herein the purposes of the compound of formula I as described in any of the above-mentioned embodiments or its pharmaceutically acceptable salt for the treatment of neurodegenerative diseases and illness. In some embodiments, disease to be treated and illness are synuclein diseases, such as Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's superposition syndrome. In some embodiments, disease to be treated and illness are tau diseases, such as Alzheimer's disease and frontotemporal dementia. In some embodiments, disease to be treated and illness are demyelinating diseases, such as multiple sclerosis (multiple sclerosis).

[0163] In some embodiments, the diseases and conditions 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 as provided herein include, but are not limited to, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating disease.

[0164] In some embodiments, the disease or condition to be treated is Alzheimer's disease. In some embodiments, the disease or condition to be treated is Parkinson's disease. In some embodiments, the disease or condition to be treated is Huntington's disease. In some embodiments, the disease or condition to be treated is multiple sclerosis. In some embodiments, the disease or condition to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition to be treated is spinal muscular atrophy (SMA).

[0165] In some embodiments, provided herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described in any of the above embodiments for treating inflammatory diseases and disorders. In some embodiments, the disease or condition to be 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), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, liver damage / disease (non-alcoholic fatty liver disease), steatohepatitis, alcoholic fatty liver, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity, kidney damage / injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS),SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington 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, Behcet'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 (TNFR-1), and pulmonary fibrosis. syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-κ-B key regulator gene (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency ((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (particularly Gaucher disease),These include GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, and Krabbe disease. disease, Lysosomal acid lipase deficiency, Metachromatic Leukodystrophy, Mucopolysaccharidoses disorders, Multiple sulfatase deficiency, Niemann-Pick disease, Neuronal Ceroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease, Schindler disease, Sialic Acid Storage Disease, Tay-Sachs, and Wolman disease.

[0166] In some embodiments, the disease or condition to be treated is inflammatory bowel disease. In some embodiments, the disease or condition to be treated is Crohn's disease. In some embodiments, the disease or condition to be treated is ulcerative colitis. In some embodiments, the disease or condition to be treated is glaucoma. In some embodiments, the disease or condition to be treated is psoriasis. In some embodiments, the disease or condition to be treated is rheumatoid arthritis. In some embodiments, the disease or condition to be treated is spondyloarthritis. In some embodiments, the disease or condition to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or condition to be treated is osteoarthritis.

[0167] In some embodiments, provided herein are methods for treating or preventing a disease or condition using a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disease or condition is associated with inflammation and / or necroptosis. In one embodiment, the disease or condition is selected from the specific diseases and conditions described herein.

[0168] In some embodiments, provided herein are methods of inhibiting RIP1 kinase activity by contacting a cell with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0169] Pharmaceutical compositions and administration

[0170] Provided herein are pharmaceutical compositions or medicines containing a compound of the present invention (or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs) and therapeutic inert carriers, diluents or excipients, and methods for preparing such compositions and medicines using the compounds of the present invention. In one example, the compound of Formula I can be prepared by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration for a galenic administration form) at ambient temperature, at a suitable pH and with the required purity. The pH of the preparation depends primarily on the specific purposes and the concentration of the compound, but no matter where, the preferred range is from about 3 to about 8. In one example, the compound of Formula I is prepared in acetate buffer at pH 5. In another embodiment, the compound of Formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0171] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the etiology of the condition, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to medical practitioners. In some embodiments, the "effective amount" of the compound to be administered will be determined by such considerations and is the minimum amount required to inhibit RIP1 kinase activity to provide a therapeutic effect in the mammal being treated. In addition, such an effective amount may be less than an amount that is toxic to normal cells or the mammal as a whole.

[0172] In one example, a pharmaceutically effective amount of a compound of the invention administered intravenously or parenterally will range from 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 per dose.

[0173] In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain 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 present invention. In certain embodiments, the daily dose is given as a single daily dose or in divided doses twice to six times a day or in a sustained release form. In the case of a 70 kg adult, the total daily dose will typically be about 7 mg to about 1,400 mg. The dosage regimen can be adjusted to provide the best therapeutic response. The compound can be administered in a regimen of 1 to 4 times a day, preferably once or twice a day.

[0174] In some embodiments, low doses of the compounds of the invention are administered to provide therapeutic benefit while minimizing or preventing adverse effects.

[0175] The compound of the present invention can be used by any suitable means, including oral, local (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal and intralesional (if needed for local treatment) use. Parenteral infusion includes 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.

[0176] The compounds of the present invention can be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0177] Typical formulations are prepared by mixing the compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (i.e., a drug).

[0178] Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent or excipient used will depend on the mode and purpose of applying the compound of the present invention. Solvents are usually selected based on solvents that are considered safe (GRAS) for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc., and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings and other known additives to provide an elegant presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to help prepare a pharmaceutical product (i.e., drug).

[0179] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include: buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride, and methylbenzyl ammonium chloride; 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 sugars including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TMOr polyethylene glycol (PEG). The active pharmaceutical ingredient of the present invention (e.g., a compound of Formula I or an embodiment thereof) can also be embedded in, for example, microcapsules (e.g., hydroxymethylcellulose microcapsules or gelatin microcapsules and poly (methyl methacrylate) microcapsules) prepared, for example, by coacervation technology or by interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such technology is disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21st edition, Lippincott Williams & Wilkins, Philidelphia, PA.

[0180] The sustained-release preparation of the compound of the present invention (for example, the compound of Formula I or its embodiment) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound of Formula I or its embodiment, and the matrix is ​​in the form of a shaped article (for example, a film or microcapsule). The example of sustained-release matrix includes polyesters, hydrogels (for example, poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactide (U.S. Patent number 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid (Sidman et al., Biopolymers 22:547,1983), non-degradable ethylene-vinyl acetate (Langer et al., J.Biomed.Mater.Res.15:167,1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM (injectable microspheres composed of a lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). Sustained-release compositions also include liposome-entrapped compounds, which 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; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Typically, the liposomes are small (about 200-800 angstroms) unilamellar types, in which the lipid content is greater than about 30 mol% cholesterol, the ratio selected being adjusted for optimal treatment.

[0181] In one example, the compound of formula I or its embodiment can be prepared by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration for the galenic administration form) at ambient temperature, at a suitable pH and with the required purity. The pH of the preparation depends primarily on the specific use and the concentration of the compound, but is preferably anywhere within the range of about 3 to about 8. In one example, the compound of formula I (or its specific examples) is prepared in acetate buffer at pH 5. In another embodiment, the compound of formula I or its embodiment is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0182] An example of a suitable oral dosage form provided herein is a tablet containing about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg, and 500 mg) of a compound of the invention mixed with appropriate amounts of anhydrous lactose, croscarmellose sodium, polyvinylpyrrolidone (PVP) K30, and magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0183] The preparation of the compound of the present invention (e.g., a compound of Formula I or an embodiment thereof) can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Among them, acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can generally be used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used for the preparation of injections.

[0184] The amount of the active component that can be combined with carrier material to produce single dosage form will change according to the host being treated and specific mode of administration.For example, it is intended that oral administration to people's time-release preparation can contain the active substance of about 1 to 1000mg mixed with the carrier material of appropriate and convenient amount, and the amount of described appropriate and aspect can change in about 5 to about 95% (weight: weight) of total composition.It is possible to prepare pharmaceutical composition to provide the dosage that can be easily measured.For example, it is intended that the aqueous solution of intravenous infusion can contain about 3 to 500 μ g active component / milliliter solution, so that the infusion of suitable volume can be carried out with the speed of about 30mL / hour.

[0185] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0186] The preparation can be packaged in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier (such as water) for injection immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the aforementioned type.

[0187] Thus, one embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0188] When the binding target is located in the brain, certain embodiments of the present invention provide compounds of Formula I (or specific examples thereof) to cross the blood-brain barrier. In these embodiments, the compounds provided herein exhibit sufficient brain penetration as potential therapeutic agents in neurological diseases. In some embodiments, free brain / plasma ratio (B) is measured by assessing the free brain / plasma ratio (B) as measured in rodent in vivo pharmacokinetic studies. u / P u ) or by other methods known to those skilled in the art (see, e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008).

[0189] Certain neurological diseases are associated with increased permeability of the blood-brain barrier, making it possible for compounds of Formula I (or specific examples thereof) to be easily introduced into the brain. When the blood-brain barrier remains intact, there are several methods known in the art for transporting molecules across the blood-brain barrier, including but not limited to physical methods, lipid-based methods, and receptor- and channel-based methods. Physical methods for transporting compounds of Formula I (or specific examples thereof) across the blood-brain barrier include but are not limited to completely bypassing the blood-brain barrier, or bypassing the blood-brain barrier by creating openings in the blood-brain barrier.

[0190] Bypass methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion / convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of delivery devices in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers TM , Guildford.

[0191] Methods for creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002 / 0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, EA, Implication of the Blood-Brain Barrier and its Manipulation, Vols. 1 and 2, Plenum Press, NY, 1989)), and permeabilization by, for example, bradykinin or permeabilizer A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0192] Lipid-based methods for transporting a compound of Formula I (or a specific embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating a compound of Formula I or II (or a specific embodiment thereof) in liposomes coupled to an antibody binding fragment that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Publication No. 2002 / 0025313), and coating a compound of Formula I (or a specific embodiment thereof) on low-density lipoprotein particles (see, e.g., U.S. Patent Publication No. 2004 / 0204354) or apolipoprotein E (see, e.g., U.S. Patent Publication No. 2004 / 0131692).

[0193] Receptor and channel-based methods for transporting compounds of Formula I (or specific embodiments thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase the permeability of the blood-brain barrier (see, e.g., U.S. Patent Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, e.g., U.S. Patent Publication No. 2005 / 0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Publication No. 2003 / 0073713); coating compounds of Formula I or II (or specific embodiments thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. Patent Publication No. 2003 / 0129186), and cationizing antibodies (see, e.g., U.S. Patent No. 5,004,697).

[0194] For use in the brain, in certain embodiments, the compound can be continuously administered by being infused into the fluid reservoir of the CNS, but a bolus injection may be acceptable. The inhibitor can be administered to the ventricle or otherwise introduced into the CNS or spinal fluid. It can be administered by using an indwelling catheter and a continuous administration mode (such as a pump), or it can be administered by implanting (e.g., implanting a sustained-release carrier in the brain). More specifically, the inhibitor can be injected by a long-term implanted cannula or infused for a long time with the help of an osmotic micropump. It is available for a subcutaneous pump that delivers protein to the ventricle by a tubule. A highly precise pump can be refilled by the skin, and its delivery rate can be set without the need for surgery. Examples of suitable administration regimens and delivery systems involving a subcutaneous pump device or continuous intraventricular infusion via a fully implanted drug delivery system are those used to administer dopamine, dopamine agonists, and cholinergic agonists to patients with Alzheimer's disease and animal models of Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

[0195] Indications and treatments

[0196] The compounds of the present invention inhibit RIP1 kinase activity. Therefore, the compounds of the present invention are useful in treating diseases and conditions mediated by this pathway and associated with inflammation and / or necrotic cell death.

[0197] In some embodiments, the disease or condition to be treated is a neurodegenerative disease or condition. In some embodiments, the disease and condition to be treated is a synuclein disease, such as Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome. In some embodiments, the disease and condition to be treated is a tau disease, such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the disease and condition to be treated is a demyelinating disease, such as multiple sclerosis.

[0198] In some embodiments, the diseases and conditions 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 as provided herein include, but are not limited to, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating disease.

[0199] In some embodiments, the disease or condition to be treated is Alzheimer's disease. In some embodiments, the disease or condition to be treated is Parkinson's disease. In some embodiments, the disease or condition to be treated is Huntington's disease. In some embodiments, the disease or condition to be treated is multiple sclerosis. In some embodiments, the disease or condition to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition to be treated is spinal muscular atrophy (SMA).

[0200] In some embodiments, the disease or condition to be treated is an inflammatory disease or condition. In some embodiments, the disease or condition to be 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 juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver damage / disease (non-alcoholic fatty liver disease, alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetylcholinesterase inhibitors (ACE), lipopolysaccharide (PLA), lipopolysaccharide (LPI ... toxicity, hepatotoxicity), renal impairment / injury (nephritis, renal transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia-reperfusion injury of solid 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 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet'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-deficiency syndrome (F-κ-B key regulator gene (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency ((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (particularly Gaucher disease, and including GM2 gangliosidosis , alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0201] In some embodiments, the disease or condition to be treated is inflammatory bowel disease. In some embodiments, the disease or condition to be treated is Crohn's disease. In some embodiments, the disease or condition to be treated is ulcerative colitis. In some embodiments, the disease or condition to be treated is glaucoma. In some embodiments, the disease or condition to be treated is psoriasis. In some embodiments, the disease or condition to be treated is rheumatoid arthritis. In some embodiments, the disease or condition to be treated is spondyloarthritis. In some embodiments, the disease or condition to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or condition to be treated is osteoarthritis.

[0202] In some embodiments, the methods of treatment provided herein treat one or more symptoms of the diseases or conditions listed above.

[0203] Also provided herein are uses of the compounds of the present invention in therapy. In some embodiments, provided herein are uses of the compounds of the present invention for treating or preventing the aforementioned diseases and conditions. Also provided herein are uses of the compounds of the present invention in the preparation of medicaments for treating or preventing the aforementioned diseases and conditions.

[0204] Also provided herein are methods of treating a disease or condition as provided above in a mammal in need of such treatment, wherein the method comprises administering to the 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.

[0205] Also provided herein are methods of treating a symptom of a disease or condition selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of the kidney, liver and lung, cysplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0206] Also provided herein are methods of treating a disease or condition selected from those provided above in a human patient in need of such treatment, wherein the method comprises orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in an orally acceptable pharmaceutical composition.

[0207] Combination therapy

[0208] In the treatment of diseases and conditions provided herein, the compounds of the present invention can be combined with one or more other compounds of the present invention or one or more other therapeutic agents as any combination thereof. For example, the compounds of the present invention can be administered simultaneously, sequentially, or separately in combination with other therapeutic agents known to be useful for treating a disease or condition selected from those described above.

[0209] As used herein, "combination" refers to any mixture or arrangement of one or more compounds of the present invention and one or more other compounds of the present invention or one or more additional therapeutic agents. Unless the context otherwise explains, "combination" may include simultaneous or sequential delivery of a compound of the present invention and one or more therapeutic agents. Unless the context otherwise explains, "combination" may include a dosage form of a compound of the present invention and another therapeutic agent. Unless the context otherwise explains, "combination" may include a route of administration of a compound of the present invention and another therapeutic agent. Unless the context otherwise explains, "combination" may include a formulation of a compound of the present invention and another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0210] In some embodiments, the compounds provided herein can be combined with another therapeutically active agent described in WO 2016 / 027253 (the contents of which are incorporated herein by reference in their entirety). In such embodiments, the compound that inhibits RIP1 kinase in the combination described in WO 2016 / 027253 is replaced by a compound of Formula I of the present disclosure.

[0211] In some embodiments, the compounds provided herein can be used in combination with a DLK inhibitor to treat neurodegenerative diseases and disorders, such as those listed elsewhere herein, and including, but not limited to, the following: Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson plus syndrome, Alzheimer's disease, frontotemporal dementia, demyelinating diseases such as multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophies, 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. Example

[0212] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the invention.

[0213] These examples are intended to provide guidance to those skilled in the art for preparing and using the compounds, compositions and methods of the invention. While specific embodiments of the invention have been described, it will be appreciated by those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0214] The chemical reactions in the examples can be readily adapted to prepare numerous other compounds of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds of the invention can be successfully performed by modifications readily apparent to one skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art, e.g., by appropriately protecting interfering groups with other suitable reagents known in the art in addition to those described above, and / or by making routine modifications to the reaction conditions.

[0215] In the following examples, unless otherwise noted, all temperatures are given in degrees Celsius. Unless otherwise noted, commercially available reagents are purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and are used without further purification. Conventionally, the reaction listed below is carried out in anhydrous solvents under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise noted), and reaction flasks are typically equipped with rubber septa for introducing substrate and reagent by syringe. Glassware is oven-dried and / or hot-dry.1 HNMR spectra were obtained in deuterated CDCl3, d6-DMSO, CH3OD, or d6-acetone solvent solutions using trimethylsilane (TMS) or the residual non-deuterated solvent peak as a reference standard (reported in ppm). When peak multiplicities are 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). When coupling constants are given, they are reported in Hz (Hertz).

[0216] All abbreviations used to describe reagents, reaction conditions, or apparatus are intended to be consistent with the definitions listed in the following abbreviation list.The chemical names of the discrete compounds of the invention are generally derived using the structure naming feature of the ChemDraw naming program.

[0217] abbreviation

[0218] ACN acetonitrile

[0219] Boc tert-Butoxycarbonyl

[0220] DAST Diethylaminosulfur trifluoride

[0221] DCE 1,2-dichloroethane

[0222] DCM dichloromethane

[0223] DMF N,N-dimethylformamide

[0224] DMSO dimethyl sulfoxide

[0225] DPPH 2,2-Diphenyl-1-picrylhydrazyl

[0226] HPLC High-pressure liquid chromatography

[0227] LCMS liquid chromatography mass spectrometry

[0228] PCC Pyridinium Chlorochromate

[0229] RP Inverter

[0230] RT or R T Retention time

[0231] SEM 2-(trimethylsilyl)ethoxymethyl

[0232] SFC Supercritical Fluid Chromatography

[0233] TFA trifluoroacetic acid

[0234] THF Tetrahydrofuran

[0235] Synthesis scheme

[0236] In addition to the specific synthetic methods of the following examples, additional compounds of the present invention can be prepared, for example, according to the following synthetic schemes.

[0237] After following steps 1-5 of Method 9 below, the gem-bisfluoro moiety was prepared according to Scheme 1:

[0238] Solution 1

[0239]

[0240] 1) SFC separation of bromine enantiomeric mixtures

[0241] 2) Weinreb chemistry as shown in Methods, using

[0242]

[0243] Additional B-ring diversity of compounds of Formula I were prepared according to Scheme 2 using a variety of nucleophiles, including but not limited to halide and cyanide sources:

[0244] Option 2

[0245]

[0246] The compounds of formula I substituted with a dimethyl B ring were prepared according to Scheme 3:

[0247] Option 3

[0248]

[0249] The following intermediates used in the following examples were prepared according to the procedures described in WO 2017 / 004500 (the entire contents of which are incorporated herein by reference):

[0250]

[0251] If not indicated in a specific method, any N-methoxy-N-methyl-alkyl, aryl, heteroaryl or heterocyclic carboxamide utilized was prepared in the same manner as cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide in Method 5 below.

[0252] Method 1: Compound Examples 1 and 2

[0253]

[0254] [(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

[0255] 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) was added n-butyl lithium (2.5 M in hexane, 0.64 mL, 1.60 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by addition of a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 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). The racemic material was further separated by chiral SFC to give the arbitrarily assigned:

[0256] [(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%) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ7.44–7.39(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 =1.662min, m / z=290.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 1.662 min, ESI+ found [M+H] = 290.1.

[0257] [(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%) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ7.44–7.38(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 =1.654min, m / z=290.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 1.654 min, ESI+ found [M+H] = 290.1.

[0258] SFC conditions: column: Chiralcel OD-3 150×4.6 mm ID3 μm; mobile phase: A: CO2 B: isopropanol (0.05% DEA); gradient: 5% to 40% B, 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes; flow rate: 2.5 mL / min; column temperature 35°C.

[0259] Method 2: Compound Examples 3 and 4

[0260]

[0261] [(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

[0262] 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) was added n-butyllithium (2.5 M in hexane, 0.64 mL, 1.60 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -70 ° C. for 1 hour and then quenched by addition of a saturated aqueous solution of ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 material was separated by chiral SFC to give the unequivocally assigned:

[0263] [(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%) was obtained as a white solid. 1 H NMR (400MHz, CDCl3) δ7.44–7.39(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-MSR T =0.846min,m / z=289.9(M+H) + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.846 min, ESI+ found [M+H] = 289.9.

[0264] [(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 (400MHz, CDCl3) δ7.44–7.37(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-MSR T =0.849min, m / z=289.9(M+H) + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.849 min, ESI+ found [M+H] = 289.9.

[0265] SFC conditions: column: Chiralcel OD-3 150×4.6 mm ID3 μm; mobile phase: A: CO2B: isopropanol (0.05% DEA); gradient: 5% to 40% B, 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes; flow rate: 2.5 mL / min; column temperature: 35°C.

[0266] Chiral SFC purification and analysis conditions:

[0267] In the methods provided in the table below, solvent A is carbon dioxide and solvent B is 0.1% NH4(aq) in CH3OH.

[0268]

[0269]

[0270]

[0271] Method SP 5

[0272]

[0273] 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

[0274] 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) was assigned unconditionally.1 H NMR(400MHz,DMSO-d6)δ7.50–7.33(m,2H),7.29–7.14(m,2H),6.40–6.05(m,1H ),5.81–5.63(m,1H),5.23(s,1H),2.98–2.56(m,1H),1.51(s,3H),1.48(s,3H). LC-MSR T =4.029min,m / z=290.1(M+H) + .

[0275] Method SP 6

[0276]

[0277] 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

[0278] 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) was assigned unconditionally. 1 H NMR(400MHz,DMSO-d6)δ7.47–7.31(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-MSR T =4.029min,m / z=290.1(M+H) + .

[0279] Method SP 37

[0280]

[0281] 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

[0282] 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) was assigned unequivocally. LC-MS R T=5.26min, m / z=288.1(M+H) + .

[0283] Method SP 38

[0284]

[0285] 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

[0286] 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) was assigned unequivocally. LC-MS R T =5.26min, m / z=288.1(M+H) + .

[0287] Method SP 39

[0288]

[0289] (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

[0290] Unequivocally assigned (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 (400MHz, DMSO-d6) δ8.69 (s, 1H), 8.18 (d, J = 0.7Hz, 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-MSR T =3.99 min, m / z=312.1 (M+H) + .

[0291] Method SP 40

[0292]

[0293] (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

[0294] Unequivocally assigned (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(400MHz,DMSO-d6)δ8.68(s,1H),8.18(s,1H),7.48–7.33(m,3H),7.32–7.0 6(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-MSR T =3.99 min, m / z=312.1 (M+H) + .

[0295] Method 3

[0296]

[0297] 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

[0298] To a solution of [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (100 mg, 0.363 mmol) in tetrahydrofuran (2 mL) was added benzylmagnesium chloride (2M in tetrahydrofuran, 0.20 mL, 0.400 mmol) at -78 ° C under nitrogen. After addition, the reaction mixture was stirred at -78 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (1 mL). The mixture was extracted with isopropyl acetate (3 x 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 =5.24min, m / z=322.1[M+H] +LCMS (5 to 95% acetonitrile + 0.1% formic acid in water over 10 minutes) retention time 5.24 min, ESI+ found [M+H] = 322.1

[0299] Method 4

[0300]

[0301] [(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

[0302] 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) was added n-butyllithium (2.5 M in hexane, 0.64 mL, 1.60 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 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. The racemic material was further separated by chiral SFC to give the unequivocally assigned:

[0303] [(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%) was obtained as a white solid. 1H NMR (400MHz, CDCl3) δ7.43–7.39(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,1H),3.69-3.53(m,2H),3.03–2.97(m,1H),1.70–1.63(m,2H). LC-MSR T =0.866min, m / z=289.9(M+H) + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.866 min, ESI+ found [M+H] = 289.9.

[0304] [(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%) was obtained as a white solid. 1 H NMR (400MHz, CDCl3) δ7.43–7.39(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,1H),3.69–3.51(m,2H),3.04–2.97(m,1H),1.70–1.62(m,2H). LC-MSR T =0.865min,m / z=289.9(M+H) + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.865 min, ESI+ found [M+H] = 289.9.

[0305] SFC conditions: column: Chiralpak AD-3 150×4.6 mm ID 3 μm; mobile phase: A: CO 2 B: methanol (0.05% DEA); gradient: 5% to 40% B, 5 minutes, and hold at 40%, 2.5 minutes, then 5% B, 2.5 minutes, flow rate: 2.5 mL / min.

[0306] Method 5

[0307]

[0308] (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

[0309]

[0310] Step 1: cis-2-Fluoro-N-methoxy-N-methylcyclopropanecarboxamide

[0311] By cis-2-fluorocyclopropanecarboxylic acid (500mg, 4.80mmol), N, O-dimethylhydroxylamine hydrochloride (610mg, 6.25mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2375mg, 6.25mmol) and N, N-diisopropylethylamine (1552mg, 12.0mmol) in N, N-dimethylformamide (15mL) mixture was stirred at 25 DEG C for 12 hours.Mixture is poured in water (10mL) and extracted with ethyl acetate (3x10mL).The organic layer merged is washed with water (2x 10mL), brine (20mL), and is under reduced pressure concentrated. 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-methyl-cyclopropanecarboxamide (420 mg, 59%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.87–4.67(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).

[0312]

[0313] 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

[0314] Under a nitrogen atmosphere, to a cooling (-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), n-butyllithium (2.5 M in hexane, 0.21 mL, 0.53 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (10 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 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 a light yellow oil. 1 HNMR(400MHz,CD3OD)δ7.44–7.37(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, 1H),5.08–4.89(m,1H),3.81–3.70(m,1H),3.26–3.16(m,1H),2.91–2.75(m,1H),2.07–1.90(m,1H),1.36–1.29(m,1H). LCMS R T =1.038min, m / z=290.1[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 1.038 min, ESI+ found [M+H] = 290.1.

[0315] Method 6

[0316]

[0317] (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

[0318]

[0319] Step 1: 2,2-Difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

[0320] By 2,2-difluorocyclopropanecarboxylic acid (300mg, 2.46mmol), N, O-dimethylhydroxylamine hydrochloride (312mg, 3.19mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1214mg, 3.19mmol) and N, N-diisopropylethylamine (794mg, 6.14mmol) in N, N-dimethylformamide (15mL) mixture was stirred at 25 DEG C for 12 hours.Mixture is poured in water (10mL) and extracted with ethyl acetate (3x10mL).The organic layer merged is washed with water (2x 10mL), brine (20mL), and is under reduced pressure concentrated. 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 =0.427min, m / z=166.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.427 min, ESI+ found [M+H] = 166.1.

[0321]

[0322] Step 2:

[0323] (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

[0324] To a cooled (-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 in hexane, 0.25 mL, 0.62 mmol) under a nitrogen atmosphere. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 (400MHz, CD3OD) δ7.44–7.39(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 =0.875min,m / z=307.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.875 min, ESI+ found [M+H] = 307.9.

[0325] Method 7

[0326]

[0327] Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0328] Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone was prepared from [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester 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. 1H NMR (400MHz, DMSO-d6) δ8.20–8.12(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 ,7.2,1.9Hz,1H),5.78(dddd,J=8.5,6.5,3.1Hz,1H),3.78(dddd,J=25.8,15.4,8.5,7.1Hz,1H),2.74(dddd,J=26.7,15.2,3.2,2.0Hz,1H). LC-MSR T =5.04min, m / z=308.1(M+H) + .

[0329] LCMS (5 to 95% acetonitrile + 0.1% formic acid in water over 10 minutes) retention time 5.04 min, ESI+ found [M+H] = 308.1.1

[0330] Method 8

[0331]

[0332] Step 1: (E)-Benzaldehyde oxime

[0333] To the solution of benzaldehyde (45.0g, 424.1mmol) in ethanol (100mL), sodium carbonate (112.3g, 1060.1mmol) and hydroxylamine hydrochloride (35.3g, 508.9mmol) are added. Reactant mixture is stirred 3 hours and filtered at 25 ℃. Filtrate is concentrated under reduced pressure, and residue is diluted with water (50mL). Gained mixture is extracted with ethyl acetate (3x 150mL). The organic layer merged is washed with salt water (60mL), dried over anhydrous sodium sulfate, and under reduced pressure concentrated to obtain rough (E)-benzaldehyde oxime, which is colorless oil (51.0g, 99%), which is used for next step without further purification.

[0334]

[0335] Step 2: Methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate

[0336] 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 (24.7 g, 165.1 mmol), 2,6-lutidine (17.6 g, 165.1 mmol) and tert-butyl hypochlorite (17.9 g, 165.1 mmol). The reaction mixture was stirred at 25 ° C for 24 hours 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 =0.871min, m / z=206.2[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.871 min, ESI+ found [M+H] = 206.2.

[0337]

[0338] Step 3: 3-Hydroxy-5-phenyl-pyrrolidin-2-one

[0339] A mixture of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (25.0 g, 121.8 mmol) and palladium (10% on carbon, 2.5 g) in ethanol (800 mL) was hydrogenated (50 psi) at 25° C. for 2 hours, then filtered, and the filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%), which was used in the next step without further purification. LCMS R T =0.270min,m / z=177.8[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.270 min, ESI+ found [M+H] = 177.8.

[0340]

[0341] Step 4: cis-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one and trans-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

[0342] To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol) in dichloromethane (300 mL) was added tert-butyldimethylsilyl chloride (19.1 g, 126.9 mmol) and imidazole (11.5 g, 169.3 mmol). The reaction mixture was stirred at 25 ° C for 16 hours 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

[0343] cis-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (12.4 g, 51%). 1 H NMR (400MHz, CDCl3) δ7.37–7.25(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

[0344] trans-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g, 38%). 1 H NMR (400MHz, CDCl3) δ7.44–7.34(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).

[0345]

[0346] Step 5: cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

[0347] At 0 ° C, to a solution of cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 42.8 mmol) in N,N-dimethylformamide (400 mL), sodium hydride (60%, 2.6 g, 64.1 mmol) was slowly added. After addition, the mixture was stirred at 0 ° C for 20 minutes, followed by the addition of O-(diphenylphosphoryl)hydroxylamine (14.9 g, 64.1 mmol). The reaction mixture was stirred at 25 ° C for 16 hours and then filtered. The filtrate was concentrated under reduced pressure to give 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 =0.877min, m / z=307.0[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.877 min, ESI+ found [M+H] = 307.0.

[0348]

[0349] Step 6: Ethyl 2-[[cis-3-[tert-Butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetic acid

[0350] To a solution of cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (9.5 g, 31.0 mmol) in ethanol (250 mL) was added 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-pyrrolidin-1-yl]amino]-2-imino-acetate as a yellow oil (10.6 g, 84%), which was used in the next step without further purification. LCMSR T =2.106min, m / z=406.2[M+H] + LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 2.106 min, ESI+ found [M+H] = 406.2.

[0351]

[0352] Step 7: cis-7-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0353] 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 hours 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 directly in the next step.

[0354]

[0355] Step 8: cis-7-Hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0356] A mixture of ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate (3.1 g, 7.6 mmol) and tert-butylammonium fluoride (1.0 M in THF, 7.6 mL, 7.6 mmol) in tetrahydrofuran (60 mL) was heated at 60° C. for 18 hours 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 HNMR (400MHz, CDCl3) δ7.39–7.32(m,5H),5.73(d,J=3.5Hz,1H),5.50(m,1H),4.41(q,J =7.1Hz,2H),3.73–3.65(m,1H),2.76(td,J=4.5Hz,13.9Hz,1H),1.35(t,J=7.1Hz,3H).

[0357]

[0358] Step 1: trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0359] To a solution of cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (100 mg, 0.37 mmol) in dichloromethane (8 mL) at 0 ° C, diethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and then quenched by adding water (20 mL). The mixture was extracted with dichloromethane (3x 20 mL). The combined organic layer was 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 trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (30 mg, 30%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.40–7.37(m,3H),7.14–7.12(m,2H),6.14(d,J=5.2Hz,0.5H),6.00(d,J=5.2Hz,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=7.2Hz,3H).

[0360]

[0361] Step 2: trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

[0362] To a solution of trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (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 hours and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by adding hydrochloric acid (2N). The mixture was extracted with ethyl acetate (3x 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.

[0363] 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

[0364] To a cooling (-78 DEG 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) under a nitrogen atmosphere was added ethylmagnesium bromide (3 M in THF, 0.03 mL, 0.10 mmol). After addition, the mixture was stirred at -78 DEG C for 1 hour and quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 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 (400MHz, CD3OD) δ7.44–7.38(m,3H),7.30–7.26(m,2H),6.27–6.26(m,0.5H),6.14–6.1 2(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=7.2Hz,3H). LCMS R T =0.840min,m / z=260.1[M+H] +LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.840 min, ESI+ found [M+H] = 260.1.

[0365] Method 9

[0366]

[0367] (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

[0368]

[0369] Step 1: 3,5-Dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

[0370] At 0 ° C to 3,5-dibromo-1h-1,2,4-triazole (150.0g, 661.2mmol) in tetrahydrofuran (1500mL), p-toluenesulfonic acid (17.1g, 99.2mmol) was slowly added, followed by 3,4-dihydro-2h-pyrans (166.9g, 1983.6mmol). After addition, the reaction mixture was heated at 70 ° C for 3 hours and concentrated under reduced pressure. The residue was poured into water (500mL) and adjusted to pH=9 by adding a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3x 400mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was washed with methanol (2 x 50 mL) and dried under reduced pressure to give crude 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (155 g, 75%) as a white solid. 1 H NMR(400MHz, CDCl3)δ5.49–5.46(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).

[0371]

[0372] Step 2: 1-phenylbut-3-en-1-ol

[0373] In 30 minutes, to the cooling (0 ℃) solution of benzaldehyde (130g, 1.23mol) in tetrahydrofuran (1000mL), add allyl magnesium chloride (2M, in THF, 858mL, 1.72mol).After adding, the reaction mixture is warmed to room temperature and stirred for 2 hours.Then by adding saturated aqueous solution of ammonium chloride (1000mL) with mixture quencher, and extract with ethyl acetate (3x 500mL).The organic layer merged is dried over sodium sulfate, and under reduced pressure concentrated.Resistates is passed through column chromatography purification (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether), obtain 1-phenyl but-3-ene-1-ol (140g, 77%), be light yellow oily thing. 1 H NMR (400MHz, CDCl3) δ7.37–7.34(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=2.8Hz,1H).

[0374]

[0375] Step 3: tert-Butyldimethyl((1-phenylbut-3-en-1-yl)oxy)silane

[0376] To the stirred solution of 1-phenyl-3-butene-1-ol (29.0g, 195.7mmol) in dichloromethane (400mL), imidazoles (27.0g, 391.6mmol) and tert-butyldimethylchlorosilane (39.0g, 254.4mmol) were added. After the addition, the reaction mixture was stirred at 25 ℃ for 16 hours, then quenched by adding water (200mL). The mixture was extracted with dichloromethane (2x 200mL). The organic layer merged was washed with salt water (100mL), dried over sodium sulfate, and under reduced pressure concentrated. Residue was passed through column chromatography purification (silica gel, 100-200 mesh, 100% petroleum ether), tert-butyl-dimethyl-(1-phenyl but-3-enyloxy) silane (43.0g, 84%) was obtained, which was a colorless oil that was directly used in the next step.

[0377]

[0378] Step 4: 3-((tert-Butyldimethylsilyl)oxy)-3-phenylpropanal

[0379] To tert-butyl-dimethyl-(1-phenyl but-3-enyloxy) silane (50.0g, 190.5mmol) in tetrahydrofuran / water (600mL, 1:1), add osmium tetroxide (968mg, 3.8mmol).After stirring at 15 ℃ for 30 minutes, in 2 hours, divide several small portions and add sodium periodate (163g, 762.0mmol).Gained mixture is stirred for another 2 hours at 30 ℃, then quenched by adding cold sodium thiosulfate saturated aqueous solution (500mL).Mixture is stirred 30 minutes, then extracted with ethyl acetate (3x 400mL).The organic layer merged is washed with water (200mL), salt solution (200mL), dried over sodium sulfate, and under reduced pressure concentrated. 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-phenyl-propionaldehyde (33.0 g, 65%) as a yellow oil. 1 H NMR(400MHz, CDCl3) δ9.94(t,J=2.4Hz,1H),7.48(d,J=4.2Hz,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).

[0380]

[0381] Step 5:

[0382] 1-(3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-phenylpropan-1-ol

[0383] To a cooling (-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) under N2 atmosphere, n-butyl lithium (2.5 M in hexane, 55.0 mL, 137.5 mmol) was added dropwise. The mixture was stirred at -78 ° C for 30 minutes, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-phenyl-propionaldehyde (33.0 g, 124.2 mmol) in tetrahydrofuran (50 mL) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1.5 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined 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 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.

[0384]

[0385] Step 6: trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

[0386] 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) was slowly added trifluoroacetic acid (150 mL). The resulting mixture was stirred at 50 ° C for 2 hours and then concentrated under reduced pressure. The residue was adjusted to pH = 9 with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 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 (a second fraction (8.5 g, 30%) was also obtained as a 4:3 mixture of trans / cis products). 1H NMR (400MHz, CDCl3) δ7.46–7.32(m,3H),7.15(d,J=7.6Hz,2H),5.65(t,J=6.6Hz,1H),5.50(br s,1H),5.45(d,J=6.4Hz,1H),3.19–3.11(m,1H),3.01–2.92(m,1H). LCMS RT=0.682min,m / z=279.8[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.682 min, ESI+ found [M+H] = 279.8.

[0387]

[0388] 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

[0389] To a stirred solution of trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-7-ol (3.0 g, 10.71 mmol) in dichloromethane (60 mL) was slowly added diethylaminosulfur trifluoride (7.8 g, 48.19 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2.5 hours and then slowly added to a stirred saturated aqueous sodium bicarbonate solution (100 mL) at 0°C. The mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. 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 a 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.

[0390] cis-2-Bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: 1H NMR (400MHz, CDCl3) δ7.31–7.24(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 =0.632min, m / z=281.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.632 min, ESI+ found [M+H] = 281.9.

[0391] trans-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: 1 H NMR (400MHz, CDCl3) δ7.58–7.29(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).

[0392] The racemic cis material was further separated by chiral SFC to give the arbitrarily assigned:

[0393] (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.

[0394] (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.

[0395] SFC conditions: column: Chiralpak AD-3 150×4.6 mm ID 3 μm; mobile phase: A: CO 2 B: ethanol (0.05% DEA); gradient: 5% to 40% B, 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes; flow rate: 2.5 mL / min.

[0396]

[0397] Step 8: N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide

[0398] By 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 (1283mg, 3.37mmol) and N, N-diisopropylethylamine (838mg, 6.49mmol) in N, N-dimethylformamide (15mL) mixture was stirred at 25 DEG C for 12 hours.Mixture was diluted with water (20mL), and extracted with ethyl acetate (3x30mL).The organic layer merged was washed with salt water (20mL), 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 light oil. 1 HNMR (400MHz, CDCl3) δ3.74(s,3H),3.29(s,3H),1.37–1.17(m,4H).

[0399]

[0400] Step 9:

[0401] (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

[0402] Under nitrogen atmosphere, to a cooled (-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-butyllithium (2.5 M in hexane, 0.1 mL, 0.25 mmol). After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (5 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 unconditionally assigned (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. 1H NMR (400MHz, CD3OD) δ7.43–7.35(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-MSR T =0.933min, m / z=339.9[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 0.933 min, ESI+ found [M+H] = 339.9.

[0403] Method 10

[0404]

[0405] (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

[0406]

[0407] Step 1: N-methoxy-N,3-dimethyl-oxetane-3-carboxamide

[0408] By 3-methyloxetane-3-formic acid (300mg, 2.58mmol), N, O-dimethylhydroxylamine hydrochloride (328mg, 3.36mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1277mg, 3.36mmol) and N, N-diisopropylethylamine (835mg, 6.46mmol) in N, N-dimethylformamide (15mL) mixture was stirred at 25 DEG C for 12 hours.Mixture is poured in water (10mL) and extracted with ethyl acetate (3x10mL).The organic layer merged is washed with water (2x 10mL), brine (20mL), and is under reduced pressure concentrated. 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 a colorless oil. 1H NMR (400MHz, CDCl3) δ4.97 (d, J = 6.4 Hz, 2H), 4.30 (d, J = 6.4 Hz, 2H), 3.67 (s, 3H), 3.19 (s, 3H), 1.67 (s, 3H).

[0409]

[0410] Step 2:

[0411] (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

[0412] Under nitrogen atmosphere, to a cooled (-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 in hexane, 0.17 mL, 0.43 mmol). After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by adding saturated aqueous ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 a yellow oil. 1 H NMR (400MHz, CD3OD) δ7.43–7.37(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 =0.816min, m / z=302.0[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.816 min, ESI+ found [M+H] = 302.0.

[0413] Method 11

[0414]

[0415] (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

[0416]

[0417] Step 1: trans-2-Fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

[0418] By trans-2-fluorocyclopropane-1-formic acid (100mg, 0.96mmol), N, O-dimethylhydroxylamine hydrochloride (122mg, 1.25mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (475mg, 1.25mmol) and N, N-diisopropylethylamine (310mg, 2.40mmol) in DMF (5mL) stirred 12 hours at 25 DEG C.Mixture is poured in water (10mL) and extracted with ethyl acetate (3x 10mL).The organic layer merged is washed with water (2x 10mL), salt solution (20mL), and is under reduced pressure concentrated. 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 (400MHz, CDCl3) δ4.89–4.71(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 =0.292min, m / z=148.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.292 min, ESI+ found [M+H] = 148.1.

[0419]

[0420] 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

[0421] To a cooled (-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) under a nitrogen atmosphere was added n-butyllithium (2.5 M in hexane, 0.07 mL, 0.18 mmol). After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 HNMR(400MHz, CDCl3)δ7.42–7.37(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 =0.862min, m / z=289.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.862 min, ESI+ found [M+H] = 289.9.

[0422] Method 12

[0423]

[0424] 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one

[0425]

[0426] Step 1: 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0427] 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 hours and cooled to 0 ° C. The resulting solid was collected by filtration and washed with petroleum ether (200 mL) to give crude 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-7-ol (50.0 g, 69%) as a white solid. It was used directly in the next step.

[0428]

[0429] Step 2: 3-Chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0430] 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 directly in the next step.

[0431]

[0432] Step 3: 3-Chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0433] To a solution of 3-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (5.6 g, 35.3 mmol) in N,N-dimethylformamide (20 mL) was added N-iodosuccinimide (8.3 g, 37.1 mmol). The mixture was heated at 60°C for 3 hours 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]imidazol-7-ol (5.3 g, 53%) as a light yellow solid, which was used directly in the next step.

[0434]

[0435] Step 4: 3-Chloro-2-iodo-5H-pyrrolo[1,2-a]imidazol-7(6H)-one

[0436] To a solution of 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (5.3 g, 18.6 mmol) in dichloromethane (20 mL) was added manganese dioxide (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 was used directly in the next step.

[0437]

[0438] Step 5: N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methyl-benzenesulfonamide

[0439] A mixture of 4-methylbenzenesulfonylhydrazide (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 hours 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 light green solid, which was used directly in the next step.

[0440]

[0441] Step 6: 3-Chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0442] Under N2 atmosphere, a mixture of N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methyl-benzenesulfonamide (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 hours. 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 =0.879min, m / z=334.9[M+H] +LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time: 0.879 min, ESI+ found [M+H] = 334.9.

[0443]

[0444] Step 7: 3-Chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid methyl ester

[0445] Under CO (50Psi), a mixture of 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200mg, 0.58mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (24mg, 0.03mmol) and triethylamine (0.4mL, 2.9mmol) in N,N-dimethylformamide (24mL) / methanol (8mL) was heated at 90°C for 18 hours. 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 =0.676min, m / z=277.0[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 minutes) retention time: 0.676 min, ESI+ found [M+H] = 277.0

[0446]

[0447] Step 8: 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid methyl ester

[0448] 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% wet) in methanol (50 mL) was hydrogenated (40 psi) at 50° C. for 24 hours 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 directly in the next step. 1HNMR(400MHz, CDCl3)δ7.85–7.60(m,1H),7.40–7.25(m,4H),4.70–4.55(m,1H),4.40 –4.15(m,2H),3.89(s,3H),3.30–3.20(m,1H),2.75–2.70(m,1H),1.70–1.60(m,1H). LCMS R T =0.513min, m / z=243.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time: 0.513 min, ESI+ found [M+H] = 243.1.

[0449]

[0450] Step 9: 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid

[0451] A mixture of 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid methyl ester (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. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and adjusted to pH=3 by adding 2M HCl. 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 directly in the next step.

[0452]

[0453] Step 10: N-methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide

[0454] 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 hours. 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 =0.506min, m / z=272.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time: 0.506 min, ESI+ found [M+H] = 272.1.

[0455]

[0456] Step 11: 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one

[0457] To a cooled (-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) under N2 atmosphere was added ethylmagnesium bromide (3.0 M in THF, 0.61 mL, 1.83 mmol). After addition, the mixture was stirred at -70 ° C for 2 hours and then quenched by addition of a saturated aqueous solution of ammonium chloride (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. 1H NMR(400MHz,CD3OD)δ7.86(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 =0.634min, m / z=241.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.634 min, ESI+ found [M+H] = 241.1.

[0458] Method 13

[0459]

[0460] Cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0461]

[0462] Step 1: trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0463] 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 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 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.

[0464]

[0465] Step 2: Cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0466] Under a nitrogen atmosphere, to a cooling (-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), cyclopropylmagnesium bromide (0.5 M in THF, 0.2 mL, 0.10 mmol) was added. After addition, the mixture was stirred at -78 ° C for 1 hour and quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 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 (400MHz, CD3OD) δ7.44–7.40(m,3H),7.30–7.26(m,2H),6.29–6.26(m,0.5H),6.14–6.12(m,0.5 H),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 =0.849min, m / z=272.0[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.849 min, ESI+ found [M+H] = 272.0.

[0467] Method 14

[0468]

[0469] 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one

[0470]

[0471] Step 1: Ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate

[0472] To the solution of propan-2-alkynes-1-alcohol (30.0g, 535.14mmol) in toluene (300mL), add ethyl 2-diazoacetate (67.2g, 588.66mmol).Reactant mixture was stirred 5 hours at 110 ℃, and was cooled to room temperature.Crude product was collected by filtration, and 10% ethyl acetate (50mL) was used in the washing of petroleum ether to obtain a mixture of 4-(hydroxymethyl)-1H-pyrazoles-5-ethyl formate (15.8g, 17%) and 3-(hydroxymethyl)-1H-pyrazoles-5-ethyl formate (not separated, 1:3, 63.1g, 69%), which is a light yellow solid. It is used for next step as a mixture.

[0473] Ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (major isomer): 1 H NMR (DMSO-d6) 12.60 (1H, s, broad); 6.70 (1H, s); 4.70 (1H, s); 4.35 (2H, q, J = 7.0 Hz); 4.45 (1H, s, broad); 1.25 (3H, t, J = 7.0 Hz).

[0474] Ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (minor isomer): 1 H NMR (DMSO-d6) 12.60 (1H, s, broad); 7.65 (1H, s); 4.75 (1H, s); 4.35 (2H, q, J = 7.0 Hz); 4.13 (1H, s, broad); 1.25 (3H, t, J = 7.0 Hz).

[0475]

[0476] Step 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

[0477] 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 hours 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 (not separated, 3.7 g, 52%), which were used as a mixture in the next step. LC-MS R T =0.855min,m / z=322.9(M+H) + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.855 min, ESI+ found [M+Na] = 322.9.

[0478]

[0479] Step 3: Ethyl 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

[0480] 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 hours 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. 1H NMR (400MHz, CDCl3) δ10.02(s,1H),7.38(s,1H),5.94(s,2H),4.40(q,J=8.0Hz,2H ),3.69–3.60(m,2H),1.40(t,J=8.0Hz,3H),0.98–0.89(m,2H),0.02–0.07(m,9H).

[0481]

[0482] Step 4: (E)-3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0483] To a solution of 5-formyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-ethyl formate (700mg, 2.35mmol) in dichloromethane (100mL), trimethyl((1-phenylvinyl)oxy)silane (499mg, 2.59mmol) and titanium tetrachloride (875mg, 4.61mmol) were added. The mixture was stirred at 40°C for 48 hours, then quenched by adding water (50mL). The resulting mixture was extracted with dichloromethane (3x 50mL). The combined organic layer 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 obtain (E)-3-(3-oxo-3-phenylprop-1-ene-1-yl)-1H-pyrazole-5-ethyl formate (310mg, 49%), which was a yellow solid. LC-MS R T =0.853min,m / z=270.9(M+H) + .

[0484] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.853 min, ESI+ found [M+H] = 270.9.

[0485]

[0486] Step 5: Ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate

[0487] A mixture of (E)-3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (310 mg, 1.15 mmol) and palladium (10% on carbon, 122 mg) in methanol (20 mL) was hydrogenated (15 psi) at 25° C. for 15 hours and then filtered. The filtrate was concentrated under reduced pressure to give crude 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylic acid ethyl ester (314 mg, 99%) as a light yellow oil.

[0488] The crude material was used directly in the next step without further purification.

[0489]

[0490] Step 6: Ethyl 3-(3-chloro-3-phenylpropyl)-1H-pyrazole-5-carboxylate

[0491] To a solution of 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylic acid ethyl ester (314 mg, 1.14 mmol) in acetonitrile (5 mL) was added sulfur dichloride (681 mg, 5.72 mmol). The mixture was heated at 65 ° C for 15 hours and then concentrated under reduced pressure to give crude 3-(3-chloro-3-phenyl-propyl)-1H-pyrazole-5-carboxylic acid ethyl ester (335 mg, 100%) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS R T =0.861min, m / z=314.9(M+H) + .

[0492] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.861 min, ESI+ found [M+H] = 314.9.

[0493]

[0494] Step 7: Ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate

[0495] A mixture of 3-(3-chloro-3-phenyl-propyl)-1H-pyrazole-5-carboxylic acid ethyl ester (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 hours 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 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid ethyl ester (120 mg, 41%) as a light yellow oil. LC-MS R T =0.824min, m / z=279.0(M+H) + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.824 min, ESI+ found [M+H] = 279.0.

[0496]

[0497] Step 8: 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

[0498] A 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 hours and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by adding hydrochloric acid (2N). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over 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 directly in the next step.

[0499]

[0500] Step 9: N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

[0501] By 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (30mg, 0.13mmol), N, O-dimethylhydroxylamine hydrochloride (17mg, 0.17mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (65mg, 0.17mmol), N, N-diisopropylethylamine (42mg, 0.33mmol) in tetrahydrofuran (5mL) was stirred at 25 DEG C for 2 hours.The mixture was diluted with water (20mL) and extracted with ethyl acetate (3x15mL).The combined organic layer 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 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 =0.952min,m / z=272.1(M+H) + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.952 min, ESI+ found [M+H] = 272.1.

[0502]

[0503] Step 10: 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one

[0504] Under a nitrogen atmosphere, ethyl magnesium chloride (3.0 M in THF, 0.07 mL, 0.21 mmol) was added dropwise to a cooled (-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) under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 2 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 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. 1H NMR (400MHz, CD3OD) δ7.39–7.30(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=7.2Hz,3H). LC-MSR T =1.858min, m / z=241.2[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.858 min, ESI+ found [M+H] = 214.2.

[0505] Method 15

[0506]

[0507] 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

[0508] To a cooled (-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 ethylmagnesium chloride (2M in THF, 0.63 mL, 1.26 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 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. The racemic material was further separated by chiral SFC to give the unequivocally assigned:

[0509] 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. 1H NMR (400MHz, CD3OD) δ7.40–7.34(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=7.2Hz,3H). LC-MSR T =1.761min, m / z=275.2[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.761 min, ESI+ found [M+H] = 275.2.

[0510] 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 (400MHz, CD3OD) δ7.40–7.34(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=7.2Hz,3H). LC-MSR T =1.755min, m / z=275.2[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.752 min, ESI+ found [M+H] = 275.2.

[0511] SFC conditions: column: ChiralPak AD-3 150×4.6mm ID3μm; mobile phase: A: CO2B: ethanol (0.05% DEA); gradient: 5% to 40% B, 5.5 minutes, and hold at 40% for 3 minutes, then 5% B for 1.5 minutes; flow rate: 2.5mL / min, column temperature: 40°C.

[0512] Method 16

[0513]

[0514] 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-propionitrile

[0515]

[0516] Step 1: cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-oxopropionitrile

[0517] To a cooling (-78 DEG 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, cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (500 mg, 1.82 mmol) in tetrahydrofuran (5 mL) was added dropwise. After addition, the mixture was stirred at -78 DEG C for 2 hours and then quenched by slowly adding a cold saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 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]triazol-2-yl)-3-oxo-propionitrile (150 mg, 31%) as a white solid, which was used directly in the next step.

[0518]

[0519] 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-propionitrile

[0520] To a cooling (0 ° C) solution of cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-yl)-3-oxo-propionitrile (140 mg, 0.52 mmol) in N,N-dimethylformamide (6 mL), cesium carbonate (422 mg, 1.30 mmol) was added. After stirring for 30 minutes, iodomethane (2800 mg, 19.7 mmol) was added, and the reaction mixture was stirred at 0 ° C for 4 hours. The mixture was then quenched by adding a cold saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (3x15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by 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-propionitrile (28.0 mg, 17%) as a white solid. 1H NMR (400MHz, CDCl3) δ7.44–7.38(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-MSR T =1.734min, m / z=299.2[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.734 min, ESI+ found [M+H] = 299.2.

[0521] Method 17

[0522]

[0523] 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

[0524]

[0525] Step 1: N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

[0526] 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 =0.593min, m / z=272.1[M+H] +LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.593 min, ESI+ found [M+H] = 272.1.

[0527]

[0528] Step 2:

[0529] 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

[0530] Under a nitrogen atmosphere, to a cooled (-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 ethyl magnesium chloride (2.7 M in THF, 0.54 mL, 1.47 mmol) dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 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 separated by chiral SFC to give the following:

[0531] (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 (400MHz, CD3OD) δ7.32–7.21(m,5H),6.43(s,1H),4.50–4.37(m,1H),4.36–4.33(m,1H),4.2 4–4.22(m,1H),3.13–3.10(m,1H),2.99–2.95(m,2H),2.57–2.53(m,1H),1.15(t,J=7.2Hz,3H). LCMS R T =0.843min, m / z=240.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.843 min, ESI+ found [M+H] = 240.9.

[0532] (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 (400MHz, CD3OD) δ7.35–7.22(m,5H),6.43(s,1H),4.51–4.38(m,1H),4.37–4.33(m,1H),4.2 5–4.22(m,1H),3.14–3.12(m,1H),3.02–2.96(m,2H),2.58–2.54(m,1H),1.16(t,J=7.2Hz,3H). LCMS R T =0.838min, m / z=241.0[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.838 min, ESI+ found [M+H] = 241.0.

[0533] SFC conditions: column: Chiralpak AD (250 mm*30 mm, 5 μm); condition: 0.1% NH3H2OiPrOH; start B15% and end B15%; flow rate (60 mL / min), column temperature 40°C.

[0534] Method 18

[0535]

[0536] 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

[0537] 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 hours under 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) and further purified by preparative TLC (ethyl acetate, R f=0.6) to give 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 (48.6 mg, 91%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.43–7.37(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-MSR T =0.771min,m / z=290.1(M+H) + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.771 min, ESI+ found [M+H] = 290.1.

[0538] Method 19

[0539]

[0540] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone

[0541]

[0542] 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-one

[0543] 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) was heated at 100° C. for 30 minutes under microwave conditions. 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=1.020min, m / z=272.1[M+H] + LCMS (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water over 2 minutes) retention time 1.020 min, ESI+ found [M+H] = 272.1.

[0544]

[0545] 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

[0546] At 0 DEG C, to the mixture of diethylzinc (123mg, 1.00mmol) and nickelous chloride (8mg, 0.07mmol) in dichloromethane (5mL), diiodomethane (355mg, 1.33mmol) is added. After stirring for 30 minutes, 1- (7- fluoro- 5- phenyl -6,7- dihydro -5H- pyrrolo- [1,2-b] [1,2,4] triazole -2- bases) -2- methyl -prop- 2- ene- 1- ketone (90mg, 0.33mmol) is added, and the reaction mixture is stirred at 0 DEG C for 2 hours. By adding cold ammonium chloride saturated aqueous solution (10mL) the mixture is quenched, and extracted with ethyl acetate (3x 15mL). The organic layer combined is concentrated under reduced pressure. The residue was purified by 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 (400MHz, CD3OD) δ7.41–7.37(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-MSR T =1.068min, m / z=286.1[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2 minutes) retention time 1.068 min, ESI+ found [M+H] = 286.1.

[0547] Method 20

[0548]

[0549] 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

[0550]

[0551] Step 1: N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide

[0552] 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 hours 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.

[0553]

[0554] 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

[0555] Under a nitrogen atmosphere, to a cooled (-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 ethylmagnesium chloride (2.7 M in THF, 0.39 mL, 1.04 mmol) dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure to give a crude racemic product, which was further separated by chiral SFC to give the following:

[0556] 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(400MHz,CD3OD)δ7.39–7.37(m,5H),6.21(s,1H),5.82(s,1H),4.42–4.36(m,2 H), 4.30–4.28 (m, 1H), 4.21–4.18 (m, 1H), 3.00–2.95 (m, 2H), 1.13 (t, J = 7.2Hz, 3H). LCMS R T =1.026min, m / z=257.1[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2 minutes) retention time 1.026 min, ESI+ found [M+H] = 257.1.

[0557] 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(400MHz,CD3OD)δ7.39–7.37(m,5H),6.21(s,1H),5.82(s,1H),4.42–4.36(m,2 H), 4.31–4.25 (m, 1H), 4.21–4.19 (m, 1H), 3.00–2.92 (m, 2H), 1.13 (t, J = 7.2Hz, 3H). LCMS R T =1.023min, m / z=257.1[M+H] +LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2 minutes) retention time 1.023 min, ESI+ found [M+H] = 257.1.

[0558] SFC conditions: column: OD (250 mm*30 mm, 5 μm); condition: 0.1% NH 3 H 2 O EtOH; start B: 30%; end B: 30%; flow rate (60 mL / min), column temperature 40°C.

[0559] Method 21

[0560]

[0561] 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

[0562]

[0563] 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

[0564] At 0 ° C, to 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) solution, triethylamine (165 mg, 1.63 mmol) and trimethylsilyl trifluoromethanesulfonate (254 mg, 1.14 mmol) were added. The mixture was stirred at 0 ° C for 2 hours and quenched by adding a cold saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 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]triazol-2-yl)vinyloxy-trimethyl-silane (245 mg, 95%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.17–7.10(m,3H),6.98–6.96(m,2H),5.79–5.78(m,0.5H),5.65–5.64(m,0.5 H),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).

[0565]

[0566] 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

[0567] 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-trimethyl-silane (210 mg, 0.66 mmol) and cuprous thiocyanate (16 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 15 °C for 15 hours and then concentrated under reduced pressure. The residue was purified by 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 (400MHz, CD3OD) δ7.40–7.37(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-MSR T =1.072min, m / z=314.1[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 2.0 minutes) retention time 1.072 min, ESI+ found [M+H] = 314.1.

[0568] Method 22

[0569]

[0570] 1-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one Under nitrogen atmosphere, to a cooled (-78 ° C) solution of (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (200 mg, 0.78 mmol) in tetrahydrofuran (20 mL), ethyl magnesium chloride (3.0 M in THF, 0.58 mL, 1.74 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride solution (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 (400MHz, CDCl3) δ7.42–7.32(m,3H),7.12–7.10(m,2H),5.49(dd,J=5.6,8.4Hz, 1H),3.31–3.21(m,1H),3.17–3.01(m,4H),2.72–2.64(m,1H),1.21(t,J=7.2Hz,3H). LCMSR T =1.523min, m / z=242.2[M+H] + LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 1.523 min, ESI+ found [M+H] = 242.2.

[0571] Method 23

[0572]

[0573] 1-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0574] Under a nitrogen atmosphere, to a cooling (-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), ethyl magnesium chloride (2.7 M in THF, 1.33 mL, 3.6 mmol) was added dropwise. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a crude racemic product, which was further purified by chiral SFC and RP-HPLC (acetonitrile 25-55% / 0.05% ammonium hydroxide in water) to give:

[0575] 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 (400MHz, CD3OD) δ7.45–7.35(m,1H),7.20–7.12(m,3H),5.80–5.75(m,1H),3.30–3.2 8(m,1H),3.15–3.05(m,2H),3.01–2.97(m,2H),2.72–2.66(m,1H),1.12(t,J=7.2Hz,3H). LCMS R T =0.977min, m / z=260.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.977 min, ESI+ found [M+H] = 260.1.

[0576] SFC conditions: column: OJ (250 mm*30 mm, 5 μm); condition: 0.1% NH 3 H 2 O EtOH; start B: 20%; end B: 20%; flow rate (60 mL / min), column temperature 40°C.

[0577] Method 24

[0578]

[0579] 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

[0580]

[0581] Step 1: (E)-4-phenylbut-3-enoic acid methyl ester

[0582] To (E)-4-phenyl but-3-enoic acid (15.0g, 92.48mmol) in methanol (60mL) solution, add sulfuric acid (2.3g, 23.12mmol).Mixture was heated 18 hours and cooled at 90 ℃.Mixture was diluted with water (20mL), and extracted with dichloromethane (3x 50mL).The organic layer washed with water (30mL), saturated sodium bicarbonate aqueous solution (30mL), salt solution (30mL) merged, dry, and under reduced pressure concentrate to obtain rough (E)-4-phenyl but-3-enoic acid methyl esters (14.8g, 91%), which is a light oily substance, which is directly used in the next step. 1 H NMR (400MHz, CDCl3) δ7.39–7.21(m,5H),6.54–6.45(m,1H),6.35–6.25(m,1H),3.72(s,3H),3.30–3.25(m,2H).

[0583]

[0584] Step 2: Methyl 2-(3-phenyloxirane-2-yl)acetate

[0585] To a mixture of (E)-4-phenylbut-3-enoic acid methyl ester (14.8 g, 84.0 mmol) and sodium bicarbonate (34.4 g, 409.0 mmol) in acetone (300 mL) was added dropwise a solution of potassium monopersulfate triple salt (67.1 g, 109.2 mmol) in water (80 mL) at 0°C. After addition, the resulting mixture was warmed to 25°C and stirred for 4 hours, 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 2-(3-phenyloxacycloprop-2-yl)acetic acid methyl ester (15.0 g, 93%) as a colorless oil. LC-MS R T =0.799min, m / z=233.9[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.799 min, ESI+ found [M+H] = 233.9.

[0586]

[0587] Step 3: Methyl (rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutyrate

[0588] To a solution of 2-(3-phenyloxacyclopropyl-2-yl)methyl acetate (15.0g, 78.0mmol) in acetonitrile (400mL) at 0°C, lithium bromide (6.8g, 78.0mmol) and magnesium perchlorate (1.7g, 78.0mmol) were added. The mixture was stirred at 20°C for 12 hours and diluted with dichloromethane (100mL). The resulting mixture was washed with hydrochloric acid (1N, 100mL). The separated aqueous layer was washed with dichloromethane (3x 100mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude (racemic-3R, 4S)-4-bromo-3-hydroxy-4-phenylbutyric acid methyl esters (20.0g, 94%), which were colorless oils. The crude product was used for the next step without further purification. LC-MS R T =0.610min, m / z=256.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.610 min, ESI+ found [M+H] = 256.9.

[0589]

[0590] Step 4: (rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutyric acid methyl ester

[0591] The compound of (racemic-3R, 4S)-4-bromo-3-hydroxy-4-phenylbutyric acid methyl ester (20.0g, 73.2mmol) and sodium azide (14.3g, 219.7mmol) in N, N-dimethylformamide (500mL) was stirred at 20 ° C for 16 hours. The mixture was diluted with water (500mL) and extracted with ethyl acetate (3x 300mL). The combined organic layer was washed with brine (150mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (racemic-3R, 4R)-4-azido-3-hydroxy-4-phenylbutyric acid methyl ester (17.0g, 99%) as a yellow oil. LC-MS R T =0.978min, m / z=208.3[M+H] + .

[0592] LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.978 min, ESI+ found [M+H] = 208.3.

[0593]

[0594] Step 5: (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutyric acid methyl ester

[0595] A mixture of (rac-3R, 4R)-4-azido-3-hydroxy-4-phenylbutyric acid methyl ester (17.0 g, 72.3 mmol) and palladium (10% on carbon, 7.7 g) in ethyl acetate (800 mL) was hydrogenated (15 psi) at 25 ° C for 24 hours and then filtered. The filtrate was concentrated under reduced pressure to give crude (rac-3R, 4R)-4-amino-3-hydroxy-4-phenylbutyric acid methyl ester (15.0 g, 99%) as a colorless oil. The crude product was used in the next step without further purification. LC-MS R T =0.315min, m / z=210.2[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.315 min, ESI+ found [M+H] = 210.2.

[0596]

[0597] Step 6: cis-4-hydroxy-5-phenylpyrrolidin-2-one

[0598] A solution of methyl (rac-3R, 4R)-4-amino-3-hydroxy-4-phenylbutyrate (15.0 g, 71.7 mmol) in methanol (200 mL) was heated at 50° C. for 16 hours 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 (400MHz, CDCl3) δ7.45–7.26(m,5H),6.39(br s,1H),4.89–4.87(m,1H),4.66–4.48(m,1H),2.80–2.62(m,1H),2.53–2.30(m,1H). LC-MSR T =0.678min, m / z=178.2[M+H] + .

[0599] LCMS (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.678 min, ESI+ found [M+H] = 178.2.

[0600]

[0601] Step 7: cis-4-((tert-Butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

[0602] To a solution of cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g, 54.2 mmol) in dichloromethane (300 mL) were 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 hours 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 =1.257min, m / z=292.3[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.257 min, ESI+ found [M+H] = 292.3.

[0603]

[0604] Step 8: cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

[0605] To a solution of cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (10.0 g, 34.3 mmol) in N,N-dimethylformamide (50 mL) at 0 ° C, sodium hydride (60%, 2.1 g, 51.5 mmol) was added. After stirring at 0 ° C for 30 minutes, (aminooxy)diphenylphosphine oxide (12.0 g, 51.47 mmol) was added portionwise. 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. The crude product was used for the next step without further purification. LC-MS R T =1.225min, m / z=307.4[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.225 min, ESI+ found [M+H] = 307.4.

[0606]

[0607] Step 9: cis-ethyl 2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate

[0608] A mixture of cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (9.0 g, 29.4 mmol) and 2-ethoxy-2-imino-ethyl acetate (21.3 g, 146.8 mmol) in toluene (500 mL) was heated at 90 ° C for 18 hours and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were concentrated under reduced pressure to give crude cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoethyl acetate (10.0 g, 84%) as a brown oil. LC-MS R T =1.128min, m / z=406.4[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.128 min, ESI+ found [M+H] = 406.4.

[0609]

[0610] Step 10: cis-6-((tert-Butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0611] A mixture of cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetic acid ethyl ester (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 hours 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 cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (5.5 g, 58%) as a brown oil. LC-MS R T =1.345min, m / z=388.4[M+H] +LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.345 min, ESI+ found [M+H] = 388.4.

[0612]

[0613] Step 11: cis-6-Hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0614] To a solution of tetrabutylammonium fluoride (18.5 g, 70.9 mmol) in tetrahydrofuran (200 mL) was added cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (5.5 g, 14.2 mmol). The resulting mixture was stirred at 25 ° C for 16 hours and diluted with ethyl acetate (300 mL). The compound 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 cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (1.8 g, 46%) as a yellow solid. LC-MS R T =1.036min, m / z=274.3[M+H] + LCMS (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.036 min, ESI+ found [M+H] = 274.3.

[0615]

[0616] Step 12: trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0617] At 25 ° C, to cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (1.0 g, 3.66 mmol) in dichloromethane (50 mL), trifluorinated diethylamino sulfide (10.0 g, 62.0 mmol) was added dropwise. The resulting mixture was stirred at 25 ° C for 1 hour, then quenched by slowly adding a saturated aqueous solution of sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was 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 trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (400 mg, 40%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.41–7.24(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-MSR T =0.958min, m / z=276.2[M+H] +

[0618] LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.958 min, ESI+ found [M+H] = 276.2.

[0619]

[0620] Step 13: 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

[0621] Under a nitrogen atmosphere, to a cooling (-78 ° C) solution of trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (30 mg, 0.11 mmol) in tetrahydrofuran (5 mL), ethyl magnesium chloride (3.0 M in THF, 0.25 mL, 0.75 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 2 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to provide unconditionally assigned 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 (400MHz, CDCl3) δ7.34–7.31(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 =0.977min, m / z=260.1[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.977 min, ESI+ found [M+H] = 260.1.

[0622] Method 25

[0623]

[0624] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl)methanone

[0625] At -78 ° C, to a solution of 2-bromopyridine (435mg, 2.76mmol) in tetrahydrofuran (20mL), n-butyl lithium (2.5M in hexane, 1.10mL, 2.76mmol) was added. After addition, the mixture was warmed 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 (200mg, 0.69mmol) in tetrahydrofuran (5mL) was added. The reaction mixture was stirred at -78 ° C for 6 hours and quenched by adding a saturated aqueous solution of ammonium chloride (10mL). The mixture was extracted with ethyl acetate (2x10mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by 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-pyridinyl)methanone (32.0 mg, 15%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.69–8.65(m,1H),8.00–7.90(m,2H),7.62–7.59(m,1H),7.42–7.30(m,3H),7.25–7.2 0(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 =1.510min,m / z=309.1[M+H] + LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 1.510 min, ESI+ found [M+H] = 309.1.

[0626] Method 26

[0627]

[0628] 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

[0629]

[0630] Step 1: Cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0631] Under a nitrogen atmosphere, to a cooling (-78 ° C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (100 mg, 0.36 mmol) in tetrahydrofuran (4 mL), cyclopropylmagnesium bromide (0.5 M in THF, 1.45 mL, 0.73 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 2 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by 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 (400MHz, CD3OD) δ7.45–7.35(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 =1.031min, m / z=272.3[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.031 min, ESI+ found [M+H] = 272.3.

[0632]

[0633] Step 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

[0634] 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 separated by chiral SFC to give the unequivocally assigned:

[0635] 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.

[0636] 1 H NMR (400MHz, CD3OD) δ7.44–7.38(m,3H),7.29–7.27(m,2H),6.19(d,J=5.6Hz,0.5H),6.05(d,J=5.2Hz, 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 =0.816min, m / z=271.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.816 min, ESI+ found [M+H] = 271.9.

[0637] 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 (400MHz, CD3OD) δ7.44–7.27(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 =0.817min, m / z=271.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.817 min, ESI+ found [M+H] = 271.9.

[0638] SFC conditions: column: Chiralpak AD (250 mm*30 mm, 10 μm); condition: 0.1% NH 3 H 2 O iPrOH; start B 25% end B 25%; flow rate (60 mL / min), column temperature 40° C.

[0639] Method 27

[0640]

[0641] Cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0642]

[0643] Step 1: Cyclopentyl-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol

[0644] Under a nitrogen atmosphere, cyclopentylmagnesium bromide (1M in THF, 0.73mL, 0.73mmol) is added dropwise to a solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100mg, 0.36mmol) in tetrahydrofuran (10mL) stirred and cooled (-78°C). After addition, the mixture is stirred at 25°C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (20mL). The mixture is extracted with ethyl acetate (2x 10mL). The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give crude cis-cyclopentyl (7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-yl) methanol (100mg, 91%) as a white solid. LCMS R T =0.611min, m / z=302.1[M+H] + .

[0645] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.611 min, ESI+ found [M+H] = 302.1.

[0646]

[0647] Step 2: Cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0648] To cis-cyclopentyl (7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole-2-yl) methanol (100 mg, 0.33 mmol) in dichloromethane (15 mL), manganese dioxide (288 mg, 3.32 mmol) was added. The reaction mixture was stirred at 35 ° C for 2 hours and then filtered through a short pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to give cyclopentyl-(racemic-(5S, 7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole-2-yl) ketone (18.2 mg, 18%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.44–7.40(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 =2.070min,m / z=300.2[M+H] + LCMS (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water over 3.0 minutes) retention time 2.070 min, ESI+ found [M+H] = 300.2.

[0649] Method 28

[0650]

[0651] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-thienyl)methanone

[0652] To a cooling (-78 DEG C) solution of 2-iodothiophene (289 mg, 1.38 mmol) in tetrahydrofuran (10 mL) under N2 atmosphere, n-butyl lithium (2.5 M in hexane, 0.55 mL, 1.38 mmol) was added dropwise. The mixture was stirred at -78 DEG C for 1 hour, followed by addition of 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 DEG C for another 2 hours, then quenched by addition of a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 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 (400MHz, CD3OD) δ8.50–8.49(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 =0.891min, m / z=314.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.891 min, ESI+ found [M+H] = 314.1.

[0653] Method 29

[0654]

[0655] Cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0656] To a cooled (0°C) mixture of magnesium (234 mg, 9.65 mmol), iodine (12 mg, 0.05 mmol), and 1,2-dibromoethane (0.1 mL, 0.10 mmol) in tetrahydrofuran (15 mL) under N2 atmosphere was added bromocyclobutane (0.5 mL, 5.85 mmol) dropwise. The mixture was stirred at 35°C for approximately 1 hour. The freshly prepared cyclobutylmagnesium bromide solution (1.0 mL, 0.39 mmol) was added dropwise to a 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). In the mixture of 4-nitro-1-oxo-2-nitro-4-nitro-5-nitro-6-nitro-7-nitro-1,2-dextrose-5-nitropropene-2 ​​... 1 HNMR(400MHz,CD3OD)δ7.40–7.30(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 =0.883min,m / z=286.0[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.883 min, ESI+ found [M+H] = 286.0.

[0657] Method 30

[0658]

[0659] 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

[0660] Under a nitrogen atmosphere, to a cooling (-78 ° C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (30 mg, 0.11 mmol) in tetrahydrofuran (3 mL), tert-butyl lithium (1.3 M in pentane, 0.17 mL, 0.22 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 2 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by 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(400MHz,CD3OD)δ7.42–7.36(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 =0.907min, m / z=288.0[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.907 min, ESI+ found [M+H] = 288.0.

[0661] Method 31

[0662]

[0663] 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

[0664] Under a nitrogen atmosphere, to a cooling (-78 ° C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (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. After addition, the mixture was stirred at -78 ° C for 2 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by 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 (400MHz, CD3OD) δ7.46–7.36(m,3H),7.28–7.26(m,2H),6.18–6.16(m,0.5H),6.05–6.02(m,0.5H),5.65–5.6 1(m,1H),3.78–3.72(m,1H),3.64–3.61(m,1H),2.87–2.76(m,1H),1.19(d,J=7.2Hz,3H),1.17(d,J=6.8Hz,3H). LCMS R T =1.971min, m / z=274.2[M+H] + LCMS (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water over 3.0 minutes) retention time 1.971 min, ESI+ found [M+H] = 274.2.

[0665] Method 32

[0666]

[0667]

[0668] 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one, and

[0669] 1-[(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0670]

[0671] Step 1: 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

[0672] Under a nitrogen atmosphere, to a cooling (-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), ethylmagnesium bromide (3.0 M in THF, 0.1 mL, 0.30 mmol) was added dropwise. After addition, the mixture was stirred at 30 ° C for about 3 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by 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 HNMR(400MHz,CD3OD)δ7.38–7.35(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=7.2Hz,3H). LCMS R T =1.038min, m / z=260.2[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.038 min, ESI+ found [M+H] = 260.2.

[0673]

[0674] Step 2:

[0675] 1-[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one and 1-[(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0676] Racemic 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 (220 mg) was separated by chiral SFC to give the unequivocally assigned:

[0677] 1-[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (peak 1, retention time = 2.265 min) (78 mg, 35%, 88% ee) was obtained as a light yellow oil. 1 H NMR (400MHz, CD3OD) δ7.43–7.32(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=7.2Hz,3H). LCMS R T =0.822min, m / z=260.0[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.822 min, ESI+ found [M+H] = 260.0.

[0678] 1-[(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (peak 2, retention time = 2.382 min) (80 mg, 35%, 91% ee) was obtained as a light yellow oil. 1 H NMR (400MHz, CD3OD) δ7.43–7.32(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=7.2Hz,3H). LCMS R T =0.817min, m / z=260.0[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.817 min, ESI+ found [M+H] = 260.0.

[0679] SFC conditions: column: AS (250 mm*30 mm, 5 μm); condition: 0.1% NH 3 H 2 O EtOH; start B 20% end B 20%; flow rate (60 mL / min), column temperature 40°C.

[0680] Method 33

[0681]

[0682] (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

[0683] Under a nitrogen atmosphere, 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) was added tert-butyl lithium (1.3 M in hexane, 1.45 mL, 1.89 mmol) dropwise. The mixture was stirred at -70 ° C for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by 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 (400MHz, CD3OD) δ8.61(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,1H),2.90–2.75(m,1H). LCMS R T =0.791min, m / z=311.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.791 min, ESI+ found [M+H] = 311.9.

[0684] Method 34

[0685]

[0686] 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone

[0687]

[0688] Step 1: (E)-Benzaldehyde oxime

[0689] To the solution of benzaldehyde (45.0g, 424.1mmol) in ethanol (100mL), sodium carbonate (112.3g, 1060.1mmol) and hydroxylamine hydrochloride (35.3g, 508.9mmol) are added. Reactant mixture is stirred 3 hours and filtered at 25 ℃. Filtrate is concentrated under reduced pressure, and residue is diluted with water (50mL). Gained mixture is extracted with ethyl acetate (3x 150mL). The organic layer merged is washed with salt water (60mL), dried over anhydrous sodium sulfate, and under reduced pressure concentrated to obtain rough (E)-benzaldehyde oxime, which is colorless oil (51.0g, 99%), which is used for next step without further purification.

[0690]

[0691] Step 2: Methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate

[0692] 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 (24.7 g, 165.1 mmol), 2,6-lutidine (17.6 g, 165.1 mmol) and tert-butyl hypochlorite (17.9 g, 165.1 mmol). The reaction mixture was stirred at 25 ° C for 24 hours 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 =0.871min, m / z=206.2[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.871 min, ESI+ found [M+H] = 206.2.

[0693]

[0694] Step 3: 3-Hydroxy-5-phenyl-pyrrolidin-2-one

[0695] A mixture of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (25.0 g, 121.8 mmol) and palladium (10% on carbon, 2.5 g) in ethanol (800 mL) was hydrogenated (50 psi) at 25° C. for 2 hours, then filtered, and the filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%), which was used in the next step without further purification. LCMS R T =0.270min,m / z=177.8[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.270 min, ESI+ found [M+H] = 177.8.

[0696]

[0697] Step 4: cis-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one and trans-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

[0698] To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol) in dichloromethane (300 mL) was added tert-butyldimethylsilyl chloride (19.1 g, 126.9 mmol) and imidazole (11.5 g, 169.3 mmol). The reaction mixture was stirred at 25° C. for 16 hours 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 the unequivocally assigned:

[0699] cis-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 51%). 1 HNMR (400 MHz, CDCl3) δ7.37–7.25 (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

[0700] trans-3-[tert-Butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g, 38%). 1 H NMR (400MHz, CDCl3) δ7.44–7.34(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).

[0701]

[0702] Step 5: trans-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

[0703] 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) was added sodium hydride (1.44 g, 36.0 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 20 minutes. 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%) as a yellow oil, which was used in the next step without further purification. LCMS R T =0.775min,m / z=307.0[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.775 min, ESI+ found [M+H] = 307.0.

[0704]

[0705] Step 6: Ethyl trans-2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetate

[0706] To a solution of trans-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g, 22.8 mmol) in ethanol (150 mL) was added ethyl 2-ethoxy-2-imino-acetate (6.63 g, 45.7 mmol). The reaction mixture was stirred at 60° C. for 16 hours and then concentrated under reduced pressure to give crude trans-2-(3-((tert-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. LCMSR T =2.154min, m / z=406.3[M+H] + LCMS (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water over 3.0 minutes) retention time 2.143 min, ESI+ found [M+H] = 406.3.

[0707]

[0708] Step 7: trans-7-((tert-Butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0709] To a solution of ethyl 2-[[trans-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetic acid (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 hours and then concentrated under reduced pressure to give crude trans-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 =1.022min, m / z=374.2[M+H] + .

[0710] LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2 minutes) retention time 1.022 min, ESI+ found [M+H] = 374.2.

[0711]

[0712] Step 8: trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0713] To a solution of trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (7.0 g, 18.06 mmol) in tetrahydrofuran (120 mL) was added tetrabutylammonium fluoride (1 N in THF, 18.06 mL, 18.06 mmol). The reaction mixture was stirred at 40 ° C for 3 hours and then concentrated under reduced pressure to give crude trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (3.5 g, 57%) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ7.39–7.35(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).

[0714]

[0715] Step 9: cis-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0716] At 0 ° C, to a solution of trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (100 mg, 0.37 mmol) in dichloromethane (8 mL), trifluorodiethylaminosulfur (176.9 mg, 1.10 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and then quenched by adding water (20 mL). The resulting mixture was extracted with dichloromethane (3x 20 mL). The combined organic layer was 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-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (54 mg, 54%) as a light yellow oil. 1H NMR (400MHz, CDCl3) δ7.44–7.31(m,3H),7.25–7.17(m,2H),6.09(dd,J=1.4Hz,7.2Hz,1H),5.95(dd,J=1.4Hz ,7.2Hz,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).

[0717]

[0718] Step 10: cis-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

[0719] 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 hours and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by adding hydrochloric acid (2N). The resulting mixture was extracted with ethyl acetate (3 x 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.

[0720]

[0721] 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone

[0722]

[0723] 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

[0724] 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 HNMR(400MHz, CDCl3)δ7.41–7.35(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 =0.564min, m / z=291.1[M+H] + .

[0725] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.564 min, ESI+ found [M+H] = 291.1.

[0726]

[0727] 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

[0728] Under a nitrogen atmosphere, to a cooling (-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), methylmagnesium bromide (3.0 M in THF, 0.1 mL, 0.30 mmol) was added dropwise. After addition, the mixture was stirred at 30 ° C for about 3 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by 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 (400MHz, CD3OD) δ7.41–7.35(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 =0.954min, m / z=246.2[M+H] + LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.954 min, ESI+ found [M+H] = 246.2.

[0729] Method 35

[0730]

[0731] [(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

[0732] Under a nitrogen atmosphere, to a cooling (-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-butyl lithium (2.5 M in hexane, 0.64 mL, 1.60 mmol) was added dropwise. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by 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 material was further separated by chiral SFC to give the unequivocally assigned:

[0733] [(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%) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ7.51–7.33(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 =1.765min, m / z=290.1[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 2.0 minutes) retention time 1.765 min, ESI+ found [M+H] = 290.1.

[0734] [(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 (400MHz, CD3OD) δ7.51–7.33(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,1H). LCMS R T =1.756min, m / z=290.1[M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 2.0 minutes) retention time 1.756 min, ESI+ found [M+H] = 290.1.

[0735] SFC conditions: column: Chiralcel OD-3 150×4.6 mm ID 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); gradient: 5% to 40% B, 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes; flow rate: 2.5 mL / min.

[0736] Method 36

[0737]

[0738] (1-Fluorocyclopropyl)(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0739]

[0740] Step 1: 1-Fluoro-N-methoxy-N-methylcyclopropanecarboxamide

[0741] By 1-fluorocyclopropanecarboxylic acid (150mg, 1.44mmol), N, N-diisopropylethylamine (465mg, 3.60mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (712mg, 1.87mmol) and N, O-dimethylhydroxylamine hydrochloride (183mg, 1.87mmol) mixture in N, N-dimethylformamide (5mL) was stirred at 25 DEG C for 12 hours.Reactant mixture is diluted with ammonium chloride saturated aqueous solution (15mL), and extracted with ethyl acetate (3x 20mL).The organic layer merged is washed with water (2x 20mL), salt solution (20mL), and is under reduced pressure concentrated. 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 (400MHz, CDCl3) δ3.75(s,3H),3.26(s,3H),1.31–1.21(m,4H).

[0742]

[0743] Step 2: (1-Fluorocyclopropyl)(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0744] Under a nitrogen atmosphere, to a cooling (-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), n-butyllithium (2.5 M in hexane, 0.21 mL, 0.53 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 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 a crude product (20 mg). The crude material 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 (400MHz, CDCl3) δ7.41–7.37(m,3H),7.23–7.21(m,2H),6.09–6.07(m,0.5H),5.96–5.93(m,0.5 H),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 =1.726min, m / z=290.1[M+H] + .

[0745] LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time: 1.726 min, ESI+ found [M+H] = 290.1.

[0746] Method 37

[0747]

[0748] ((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

[0749] 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) under a nitrogen atmosphere was added n-butyl lithium (2.5 M in hexane, 0.34 mL, 0.85 mmol) dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by addition of a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 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.1 H NMR (400MHz, CD3OD) δ7.43–7.37(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 =0.675min,m / z=302.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time: 0.675 min, ESI+ found [M+H] = 302.1.

[0750] Method 38

[0751]

[0752] ((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

[0753]

[0754] Step 1: N-methoxy-N,3-dimethyloxetane-3-carboxamide

[0755] By N, O-dimethylhydroxylamine hydrochloride (252mg, 2.58mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (396mg, 2.07mmol), 3-methyloxetane-3-carboxylic acid (200mg, 1.72mmol), 1-hydroxybenzotriazole (140mg, 1.03mmol) and N, N-diisopropylethylamine (556mg, 4.31mmol) in dichloromethane (10mL) was stirred at 25 ℃ for 12 hours. The reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (3x 15mL). The combined organic layer was washed with water (2x 10mL), brine (20mL), dried, and concentrated under reduced pressure to give crude N-methoxy-N, 3-dimethyl-oxetane-3-carboxamide (270mg, 98%) as a colorless oil. The crude material was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ4.96–4.93(m,2H),4.29–4.27(m,2H),3.66(s,3H),3.18(s,3H),1.66(s,3H).

[0756]

[0757] 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

[0758] Under nitrogen atmosphere, 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) was added n-butyl lithium (2.5 M in hexane, 0.43 mL, 1.06 mmol) dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 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. 1 H NMR (400MHz, CD3OD) δ7.43–7.37(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 =0.678min,m / z=302.1[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time: 0.678 min, ESI+ found [M+H] = 302.1.

[0759] Method 39

[0760]

[0761] 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

[0762]

[0763] Step 1: N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0764] By 3-oxabicyclo [3.1.0] hexane-6-carboxylic acid (trans, 300mg, 2.34mmol), N, O-dimethylhydroxylamine hydrochloride (297mg, 3.04mmol), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (1157mg, 3.04mmol) and N, N-diisopropylethylamine (756mg, 5.85mmol) in N, N-dimethylformamide (15mL) mixture was stirred at 25 DEG C for 12 hours.Reactant mixture is diluted with water (30mL), and extracted with ethyl acetate (3x 15mL).The organic layer merged is washed with water (2x 10mL), brine (20mL), and is 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 (400MHz, CDCl3) δ3.95–3.93(m,2H),3.80–3.78(m,2H),3.73(s,3H),3.20(s,3H),2.17–2.09(m,3H).

[0765]

[0766] Step 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

[0767] Under nitrogen atmosphere, to a cooled (-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 n-butyllithium (2.5 M in hexane, 0.21 mL, 0.53 mmol) dropwise. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by addition of saturated aqueous ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 (400MHz, CDCl3) δ7.43–7.39(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 =0.821min, m / z=313.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.821 min, ESI+ found [M+H] = 313.9.

[0768] Method 40

[0769]

[0770] 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

[0771]

[0772] Step 1: N-methoxy-N-methyl-oxetane-3-carboxamide

[0773] By oxetane-3-formic acid (300mg, 2.94mmol), 1,1'-carbonyldiimidazole (524mg, 3.23mmol) and N, the mixture of O-dimethylhydroxylamine hydrochloride (286mg, 2.94mmol) in dichloromethane (8mL) was stirred at 25 DEG C for 12 hours.The reaction mixture is diluted with water (20mL), and extracted with ethyl acetate (3x 15mL).The organic layer merged is washed with water (2x 10mL), brine (20mL), and is concentrated under reduced pressure.The residue is passed through preparative TLC purification (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 (400MHz, CDCl3) δ4.92–4.89(m,2H),4.80–4.76(m,2H),4.19–4.13(m,1H),3.63(s,3H),3.21(s,3H).

[0774]

[0775] Step 2: 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

[0776] Under nitrogen atmosphere, to a cooled (-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), n-butyllithium (2.5 M in hexane, 0.16 mL, 0.40 mmol) was added dropwise. After addition, the mixture was stirred at -70 ° C for 1 hour and then quenched by addition of saturated aqueous ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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. 1H NMR (400MHz, CDCl3) δ7.43–7.40(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 =0.782min, m / z=287.9[M+H] + LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water over 1.5 minutes) retention time 0.782 min, ESI+ found [M+H] = 287.9.

[0777] Method 41

[0778]

[0779] [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

[0780]

[0781] Step 1: 1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropanecarboxylic acid

[0782] To a solution of 1-(hydroxymethyl)cyclopropanecarboxylic acid (200mg, 1.72mmol) in dichloromethane (5mL), tert-butyldimethylsilyl chloride (532mg, 3.53mmol) and imidazole (240mg, 3.53mmol) were added. The mixture was stirred at 25°C for 5 hours, then quenched by adding water (10mL). The mixture was extracted with dichloromethane (2x 10mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (6mL) / water (6mL), and sodium hydroxide (138mg, 3.44mmol) was added. The resulting mixture was stirred at 25°C for 10 hours, then adjusted to pH=4 by adding citric acid. The solution was extracted with ethyl acetate (2x 20mL). 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.

[0783]

[0784] Step 2:

[0785] 1-(((tert-Butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropanecarboxamide

[0786] A 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) was stirred at 25 ° C for 18 hours. The resulting mixture was distributed 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-[[tert-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 over 1.5 minutes) retention time: 0.848 min, ESI+ found [M+H] = 274.1.

[0787]

[0788] Step 3:

[0789] (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

[0790] Under a nitrogen atmosphere, to a cooling (-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), n-butyllithium (2.5 M in hexane, 0.26 mL, 0.64 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R f=0.4) to give [1-[[tert-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 a light brown oil.

[0791]

[0792] 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

[0793] 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 hours and then concentrated under reduced pressure. The residue was purified by 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 a light brown oil. 1 H NMR (400MHz, CD3OD) δ7.43–7.37(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 =0.648min, m / z=302.1[M+H] + .

[0794] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.648 min, ESI+ found [M+H] = 302.1.

[0795] Method 42

[0796]

[0797] ((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

[0798]

[0799] Step 1: 2,2-Difluoro-N-methoxy-N-methylcyclopropanecarboxamide

[0800] By 2,2-difluorocyclopropanecarboxylic acid (1.00g, 8.19mmol), N, N-diisopropylethylamine (2646mg, 20.5mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (4.05g, 10.6mmol), N, O-dimethylhydroxylamine hydrochloride (1.04g, 10.7mmol) in N, N-dimethylformamide (10mL) mixture was stirred at 25 DEG C for 12 hours.Reactant mixture is diluted with ammonium chloride saturated aqueous solution (20mL), and extracted with ethyl acetate (3x 20mL).The combined organic layer is washed with water (2x 20mL), brine (30mL), 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 (400MHz, CDCl3) δ3.77(s,3H),3.26(s,3H),2.96–2.91(m,1H),2.16-2.12(m,1H),1.69-1.65(m,1H).

[0801]

[0802] 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

[0803] 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) was added n-butyl lithium (2.5 M in hexane, 1.28 mL, 3.19 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by addition of a saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 material was further separated by chiral SFC to give the unequivocally assigned:

[0804] ((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 (peak 1, retention time = 2.069 min) (35.0 mg, 29%) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ7.42–7.38(m,3H),7.31–7.29(m,2H),6.21–6.19(m,0.5H),6.07–6.05(m,0.5 H),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 =1.834min, m / z=308.1[M+H] + LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time: 1.834 min, ESI+ found [M+H] = 308.1.

[0805] ((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 (peak 2, retention time = 3.055 min) (35.0 mg, 29%) was obtained as a white solid. 1H NMR (400MHz, CD3OD) δ7.45–7.41(m,3H),7.30–7.28(m,2H),6.21–6.19(m,0.5H),6.07–6.05(m,0.5 H),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 =1.822min, m / z=308.1[M+H] + LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time: 1.822 min, ESI+ found [M+H] = 308.1.

[0806] SFC conditions: column Chiralcel OD-3 150×4.6mm ID3μm; mobile phase: A: CO2B: isopropanol (0.05% DEA), gradient: 5% to 40% B, 5 minutes, and hold at 40%, 2.5 minutes, then 5% B, 2.5 minutes, flow rate: 2.5mL / min, column temperature: 35℃.

[0807] Method 43

[0808]

[0809] (1-Fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0810] Under nitrogen atmosphere, to a cooled (-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), n-butyllithium (2.5 M in hexane, 1.28 mL, 3.19 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by addition of saturated aqueous ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 by preparative TLC (30% ethyl acetate in petroleum ether, R f=0.3) to give (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. 1 H NMR (400MHz, CDCl3) δ7.40–7.37(m,3H),7.23–7.21(m,2H),6.09–6.07(m,0.5H),5.96–5.94(m,0.5 H),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 =1.736min, m / z=290.1[M+H] + LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time: 1.736 min, ESI+ found [M+H] = 290.1.

[0811] Method 44

[0812]

[0813] Cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0814]

[0815] Step 1: 1-(2-Fluorophenyl)but-3-en-1-ol

[0816] At 0 DEG C under nitrogen atmosphere, to a solution of 2-fluorobenzaldehyde (15.0g, 120.86mmol) in tetrahydrofuran (250mL), allylmagnesium bromide (1.0M, in tetrahydrofuran, 150.0mL, 150.0mmol) was added. After addition, the mixture was warmed to 25 DEG C and stirred for 2 hours, then quenched by adding a saturated aqueous solution of ammonium chloride (100mL). The resulting mixture was extracted with ethyl acetate (2x100mL). The combined 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 5% ethyl acetate in petroleum ether) to obtain 1-(2-fluorophenyl) but-3-ene-1-ol (6.0g, 24%), which was a yellow oil. 1H NMR (400MHz, CDCl3) δ7.49–7.27(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).

[0817]

[0818] Step 2: tert-Butyl((1-(2-fluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

[0819] To the solution of 1-(2-fluorophenyl) but-3-ene-1-ol (6.0g, 36.1mmol) in dichloromethane (50mL), imidazoles (4.9g, 72.2mmol) and tert-butyldimethylchlorosilane (7.1g, 146.9mmol) were added. The reaction mixture was stirred at 25 ℃ for 16 hours and quenched by adding water (100mL). The mixture was extracted with dichloromethane (2x 100mL). The organic layer merged was washed with salt water (100mL), dried over sodium sulfate, and under reduced pressure concentrated. Residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether), to obtain tert-butyl-[1-(2-fluorophenyl) but-3-eneoxy]-dimethyl-silane (8.5g, 84%), which was a light oil. 1 H NMR (400MHz, CDCl3) δ7.60–7.36(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).

[0820]

[0821] Step 3: 3-((tert-Butyldimethylsilyl)oxy)-3-(2-fluorophenyl)propanal

[0822] To tert-butyl-[1-(2-fluorophenyl) but-3-enyloxy]-dimethyl-silane (8.50g, 30.3mmol) in water (100mL) and tetrahydrofuran (100mL), add osmium tetroxide (0.15g, 0.6mmol). After stirring at 25 ℃ for 30 minutes, sodium periodate (25.90g, 121.2mmol) was added in several small portions within 2 hours. The gained mixture was stirred at 25 ℃ for 2 hours, and quenched by adding a cold saturated aqueous solution of sodium thiosulfate (100mL). The mixture was stirred for 30 minutes, then extracted with ethyl acetate (3x 200mL). The combined organic layer was washed with water (50mL), salt solution (50mL), 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 (400MHz, CDCl3) δ9.84–9.77(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).

[0823]

[0824] 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

[0825] Under a nitrogen atmosphere, n-butyl lithium (2.5M in hexane, 8.6mL, 21.4mmol) was added to a cooling (-78°C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (6.3g, 20.1mmol) in tetrahydrofuran (50mL). The mixture was stirred at -78°C for 30 minutes, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5g, 19.5mmol) in tetrahydrofuran (25mL) was added dropwise. After addition, the mixture was stirred at -78°C for 1.5 hours and then quenched by adding a saturated aqueous solution of ammonium chloride (50mL). The resulting mixture was extracted with ethyl acetate (2x100mL). The combined 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 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. This was used as is in the next step.

[0826]

[0827] Step 5: 2-Bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

[0828] A mixture of 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, 15.55 mmol) and trifluoroacetic acid (30.0 mL) in dichloromethane (3.0 mL) was stirred at 50 ° C for 5 hours and concentrated under reduced pressure. The residue was adjusted to pH = 9 by adding a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to 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 =0.505min,m / z=298.1[M+H] + .

[0829] LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 0.505 min, ESI+ found [M+H] = 298.1.

[0830]

[0831] Step 6: (5S,7S)-2-Bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

[0832] To a solution of 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-7-ol (750 mg, 2.52 mmol) in toluene (20 mL) at 0 ° C, diethylaminosulfur trifluoride (1.62 g, 10.06 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour and then slowly added to ice water (20 mL) at 0 ° C. The mixture was extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 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(400MHz, CDCl3)δ7.40–7.27(q,J=6.6Hz,1H),7.20–7.10(m,2H),7.01–6.97(m ,1H),6.10–5.89(m,1H),5.84–5.75(m,1H),3.70–3.53(m,1H),2.96–2.75(m,1H). LCMS R T =1.112min, m / z=300.0[M+H] + .

[0833] LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2.0 minutes) retention time 1.112 min, ESI+ found [M+H] = 300.0.

[0834] The cis mixture was further separated by chiral SFC to give the arbitrarily assigned:

[0835] (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. (Also collected was the 5R,7R-isomer (peak 1, retention time = 3.139 min) (100 mg, 40%).

[0836] SFC conditions: column: ChiralPak AD-3 150×4.6 mm ID3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); gradient: 5% to 40% B, 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes; flow rate: 2.5 mL / min; column temperature: 35°C.

[0837]

[0838] Step 7: Cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0839] At -78 ° C under a nitrogen atmosphere, to (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) solution, n- butyl lithium (2.5 M in hexane, 0.27 mL, 0.67 mmol) was added. The mixture was stirred at -78 ° C for 2 hours and quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35-65% / 0.05% ammonium hydroxide in water) to give unambiguously assigned 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. 1H NMR (400MHz, CD3OD) δ7.47–7.41(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 =1.043min, m / z=290.2[M+H] + .

[0840] LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.043 min, ESI+ found [M+H] = 290.2.

[0841] Method 45

[0842]

[0843] (S)-Cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0844] At -78 ° C, under a nitrogen atmosphere, to a solution of (5S) -5- (2- fluorophenyl) -6,7- dihydro -5H- pyrrolo [1,2-b] [1,2,4] triazole -2- carboxylic acid ethyl ester (100 mg, 0.36 mmol) in tetrahydrofuran (3 mL), cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 0.72 mL, 0.36 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 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 by chiral SFC to give unambiguously assigned (S)-cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (17.5 mg, 34%) as a brown oil. 1H NMR (400MHz, CD3OD) δ7.44–7.35(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-MSR T =0.699min, m / z=272.1[M+H] + .

[0845] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.699 min, ESI+ found [M+H] = 272.1.

[0846] SFC conditions: column: ChiralPak AD-3 150×4.6 mm ID3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); gradient: 5% to 40% B, 5.5 minutes, and hold at 40% for 3 minutes, then 5% B for 1.5 minutes; flow rate: 2.5 mL / min; column temperature: 40°C.

[0847] Method 46

[0848]

[0849] (3,3-Difluorocyclobutyl)((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0850] At -78 ° C, to 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), n-butyl lithium (2.5 M in hexane, 0.26 mL, 0.64 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 2 hours and quenched by adding a saturated aqueous solution of ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 20-45% / 0.225% hydrochloric acid in water) to give unambiguously assigned (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 (400MHz, CD3OD) δ7.43–7.38(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 =1.904min, m / z=322.1[M+H] + .

[0851] LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 1.904 min, ESI+ found [M+H] = 322.1.

[0852] Method 47

[0853]

[0854] [(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

[0855]

[0856] Step 1: 2-Bromo-5-phenyl-5H-pyrrolo[1,2-b][1,2,4]triazol-7(6H)-one

[0857] To a solution of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-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 hours 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]triazole-7-one (1.8 g, 88%) as a white solid. It was used directly in the next step.

[0858]

[0859] Step 2: (S)-2-Bromo-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

[0860] At 0 ° C, to a cooled solution of 2-bromo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7-one (1.7 g, 6.11 mmol) in dichloromethane (80 mL), trifluorodiethylaminosulfur (7.88 mL, 61.13 mmol) was added. After stirring at 25 ° C for 2 hours, the mixture was poured into ice water (10 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 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 =0.774min, m / z=303.1[M+H] + .

[0861] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.774 min, ESI+ found [M+H] = 303.1.

[0862] The racemic material (950 mg, 3.17 mmol) was further separated by chiral SFC to give the unequivocally assigned:

[0863] (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.

[0864] (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.

[0865] SFC conditions: column: OJ (250 mm*50 mm, 10 um); mobile phase: A: CO2 B: 0.1% NH3H2O ​​EtOH; gradient: 20% to 20% B; flow rate: 180 mL / min, column temperature: 40°C.

[0866]

[0867] 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

[0868] 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) at -78 ° C. under a nitrogen atmosphere, n-butyllithium (2.5 M in hexane, 0.8 mL, 2.0 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C. for 1 hour and then quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated to dryness under reduced pressure to give the 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. The racemic material was separated by chiral SFC to give the following unequivocally assigned product:

[0869] [(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 (400MHz, CD3OD) δ7.49–7.44(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-MSR T =0.822min, m / z=308.0[M+H] + .

[0870] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.822 min, ESI+ found [M+H] = 308.0.

[0871] [(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.

[0872] 1 H NMR (400MHz, CD3OD) δ7.47–7.43(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-MSR T =0.818min,m / z=308.1[M+H] + .

[0873] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.818 min, ESI+ found [M+H] = 308.1.

[0874] SFC conditions: Column: AD (250 mm*30 mm, 5 μm); mobile phase: A: CO2 B: 0.1% NH3H2O ​​EtOH; gradient: 20% to 20% B; flow rate: 50 mL / min; column temperature: 40°C.

[0875] Method 48

[0876]

[0877] 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

[0878] At -78 ° C, under a nitrogen atmosphere, 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), cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 2.6 mL, 1.3 mmol) was added. The mixture was stirred at -78 ° C for 2 hours and quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to 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 HNMR(400MHz, CDCl3)δ7.38–7.31(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).

[0879] The racemate was further separated by chiral SFC to give the arbitrarily assigned:

[0880] 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. 1H NMR (400MHz, CDCl3) δ7.45–7.41(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 =1.238min, m / z=290.2[M+H] + .

[0881] LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 1.238 min, ESI + Found [M+H] = 290.2.

[0882] 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 (400MHz, CDCl3) δ7.45–7.41(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 =1.239min, m / z=290.2[M+H] + .

[0883] LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 1.239 minutes, ESI + Found [M+H] = 290.2.

[0884] SFC conditions: column: Chiralcel OJ (250 mm*30 mm, 5 μm); mobile phase: A: CO2B: ethanol (0.1% NH3H2O); gradient: 25% to 25% of B, 5 minutes: 2.5 mL / min; column temperature: 35°C.

[0885] Method 49

[0886]

[0887] (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

[0888]

[0889] Step 1: 1,1-Difluoro-N-methoxy-N-methylspiro[2.3]hexane-5-carboxamide

[0890] By 1-hydroxybenzotriazole (83mg, 0.62mmol), N, O-dimethylhydroxylamine hydrochloride (180mg, 1.85mmol), 2,2-difluorospiro [2.3] hexane-5-formic acid (200mg, 1.23mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284mg, 1.48mmol) and N, N-diisopropylethylamine (478mg, 3.70mmol) mixture in dichloromethane (10mL) was stirred 12 hours at 25 DEG C, and diluted with water (30mL).Mixture is extracted with ethyl acetate (3x 15mL).The organic layer merged is washed with salt water (20mL), and is under reduced pressure concentrated. 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 (400MHz, CDCl3) δ3.67(s,3H),3.65–3.51(m,1H),3.21(s,3H),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).

[0891]

[0892] 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

[0893] Under nitrogen atmosphere, to (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- formamide (73 mg, 0.35 mmol) in tetrahydrofuran (10 mL) cooling (-78 ° C) solution, n-butyl lithium (2.5 M in n-hexane, 0.28 mL, 0.71 mmol) was added. The mixture was stirred at -78 ° C for 2 hours and quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 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 HNMR(400MHz,CD3OD)δ7.43–7.38(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 1.298min, m / z=348.1[M+H] + .

[0894] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 1.281 and 1.298 min, ESI+ found [M+H] = 348.1

[0895] Method 50

[0896]

[0897] 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0898]

[0899] Step 1: Ethyl 4-(2-chlorophenyl)-4-oxobutanoate

[0900] At -60 ° C, 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), [bis (trimethylsilyl) amino] lithium (1.0 M in tetrahydrofuran, 711.6 mL, 711.56 mmol) was added. The mixture was stirred at -60 ° C for 100 minutes, and ethyl bromoacetate (143.5 mL, 1293.7 mmol) was quickly added. The mixture was warmed to 25 ° C and stirred for 15 hours. The reaction was quenched by adding water (400 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layer was washed with water (2 x 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 4-(2-chlorophenyl)-4-oxo-butyric acid ethyl ester (50.0 g, 32%) as a colorless oil which was used directly in the next step.

[0901]

[0902] Step 2: tert-Butyl (2-(2-chlorophenyl)-5-oxopyrrolidin-1-yl)carbamate

[0903] To a solution of 4-(2-chlorophenyl)-4-oxo-butyric acid ethyl ester (10.0g, 41.55mmol) in acetic acid (33mL) and tetrahydrofuran (100mL), t-butyl hydrazinecarboxylate (11.0g, 83.10mmol) was added. The mixture was stirred at 85°C for 12 hours, and sodium cyanoborohydride (7.8g, 124.65mmol) was added. The resulting mixture was stirred at 85°C for another 12 hours, and concentrated under reduced pressure. The residue was diluted with water (100mL) and extracted with ethyl acetate (3x 80mL). The combined organic layer was washed with saturated sodium carbonate (80mL), hydrochloric acid (2M, 80mL), 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 tert-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (5.0 g, 39%) as a light yellow oil. LCMS R T =0.840min,m / z=255.0[M+H] + .

[0904] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.840 min, ESI+ found [M-55] = 255.0.

[0905]

[0906] Step 3: 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one

[0907] 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 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 solution was adjusted to pH = 9 by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane (4 x 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. LCMSR T =0.615min, m / z=211.0[M+H] + .

[0908] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.615 min, ESI+ found [M+H] = 211.0.

[0909]

[0910] Step 4: 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one

[0911] A mixture of 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one (3.3 g, 15.67 mmol) and ethyl 2-ethoxy-2-imino-acetate (4.6 g, 31.33 mmol) in ethanol (50 mL) was stirred at 70° C. for 18 hours 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 =0.675min,m / z=310.0[M+H] + .

[0912] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.675 min, ESI+ found [M+H] = 310.0.

[0913]

[0914] Step 5: (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

[0915] A mixture of 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]amino]-2-imino-ethyl acetate (4.8g, 15.5mmol) and phosphorus oxychloride (21.4g, 139.5mmol) was stirred at 100°C for 3 hours and cooled to 25°C. The mixture was carefully poured into water (100mL) and extracted with ethyl acetate (3x 50ml). 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 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (3.0g, 66%) as a brown oil. LCMS R T =0.741min, m / z=292.1[M+H] + .

[0916] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.741 min, ESI+ found [M+H] = 292.1.

[0917] The racemic material (1.0 g, 3.43 mmol) was further separated by SFC to give the arbitrarily assigned:

[0918] (S)-5-(2-Chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (peak 2, retention time = 4.111 min) (400 mg, 40%) and (R)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (peak 1, retention time = 3.762 min) (400 mg, 40%), both as yellow solids.

[0919] SFC conditions: column: AD-3 (250 mm*30 mm, 5 μm); condition: 0.1% NH 3 H 2 O EtOH; start B 30% end B 30%; flow rate (60 mL / min), column temperature 40°C.

[0920]

[0921] Step 6: (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

[0922] A mixture of (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (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) was stirred at 25 ° C for 12 hours and concentrated under reduced pressure. The residue was diluted with ice water (2 mL) and adjusted to pH = 3 by adding hydrochloric acid (2M). The solid product 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 =0.642min, m / z=264.0[M+H] + .

[0923] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.642 min, ESI+ found [M+H] = 264.0.

[0924]

[0925] Step 7: (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0926] By 1-hydroxybenzotriazole (215mg, 1.59mmol), N, O-dimethylhydroxylamine hydrochloride (194mg, 1.99mmol), (S) -5- (2- chlorophenyl) -6,7- dihydro -5H- pyrrolo [1,2-b] [1,2,4] triazole -2- carboxylic acid (350mg, 1.33mmol), 1- (3- dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (305mg, 1.59mmol) and N, N- diisopropylethylamine (515mg, 3.98mmol) mixture in dichloromethane (8mL) was stirred at 25 DEG C for 12 hours.The reaction was diluted with water (15mL), and extracted with ethyl acetate (3x 15mL).The organic layer merged was washed with salt water (2x 25mL), 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 =0.700min,m / z=307.0[M+H] + .

[0927] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.700 min, ESI+ found [M+H] = 307.0.

[0928]

[0929] Step 8: 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0930] 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 in hexane, 0.42 mL, 0.42 mmol). The mixture was stirred at 0-5 ° C for 1 hour and quenched by adding a saturated aqueous solution of ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (2 x 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 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 (400MHz, CD3OD) δ7.52–7.50(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=7.2Hz,3H). LCMS R T =1.185min,m / z=276.1[M+H] + .

[0931] LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid over 2 minutes) retention time 1.185 min, ESI+ found [M+H] = 276.1

[0932] Method 51

[0933]

[0934] [1-(Hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0935]

[0936] Step 1: 1-(Ethoxycarbonyl)cyclopropanecarboxylic acid

[0937] 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 was stirred at 25 ° C for 16 hours and diluted with ethyl acetate (60 mL). The organic layer was discarded. The aqueous phase was adjusted to pH = 3 by adding aqueous hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (3x80 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 (400MHz, CDCl3) δ12.86(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).

[0938]

[0939] Step 2: Ethyl 1-(hydroxymethyl)cyclopropanecarboxylate

[0940] At 0 ° C to 1-ethoxycarbonyl cyclopropanecarboxylic acid (6.6g, 41.7mmol) and triethylamine (6.98mL, 50.1mmol) in tetrahydrofuran (60mL), isobutyl chloroformate (8.12ml, 62.6mmol) was added dropwise. After addition, the reaction was stirred at 0 ° C for 1 hour and filtered. The filtrate was then added to a mixture of sodium borohydride (1.6g, 41.7mmol) in tetrahydrofuran (40mL) and water (10mL). The resulting mixture was stirred at 0 ° C for 1 hour and quenched by adding 10% acetic acid (20mL). The mixture was extracted with ethyl acetate (3x 30mL). The combined organic layer was washed with brine (30mL), 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 (400MHz, CDCl3) δ4.17–4.08(m,2H),3.62(s,2H),1.29–1.21(m,5H),0.87–0.84(m,2H).

[0941]

[0942] Step 3: Ethyl 1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylate

[0943] At 0 ℃ to 1-(hydroxymethyl) cyclopropane-1-ethyl formate (1.0g, 6.94mmol) in N, N-dimethylformamide (20mL) stirring solution, add imidazoles (1.4g, 20.81mmol) and tert-butyldiphenylchlorosilane (3.8g, 13.87mmol). The mixture was stirred at 25 ℃ for 18 hours and poured into water (30mL). The solution was extracted with dichloromethane (3x20mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to obtain 1-[[tert-butyl (diphenyl) silyl] oxymethyl] cyclopropanecarboxylic acid ethyl ester (2.3g, 87%), which is a colorless oil. 1 H NMR (400MHz, CD3OD) δ7.70–7.61(m,4H),7.46–7.35(m,6H),4.15–4.06(m,2H),3.8 5(s,2H),1.23(t,J=7.0Hz,3H),1.17–1.11(m,2H),1.04(s,9H),0.93–0.87(m,2H).

[0944]

[0945] Step 4: 1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylic acid

[0946] By 1-[[tert-butyl (diphenyl) silyl] oxymethyl] cyclopropanecarboxylic acid ethyl ester (1.0g, 2.61mmol) and lithium hydroxide monohydrate (438mg, 10.46mmol) in tetrahydrofuran (16mL), methanol (16mL) and water (8mL) mixture is stirred at 25 ℃ for 18 hours.Organic solvent is removed under reduced pressure.Aqueous residue is washed with ethyl acetate (15mL), and is adjusted to pH=3 by adding aqueous hydrochloric acid solution (4M) at 0 ℃.Gained mixture is extracted with ethyl acetate (3x 15mL).The organic layer merged is washed with brine (10mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain crude 1-[[tert-butyl (diphenyl) silyl] oxymethyl] cyclopropanecarboxylic acid (950mg, 100%), which is a sticky light white solid.This crude thing is used for next step without further purification.

[0947]

[0948] Step 5: 1-(((tert-Butyldiphenylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropanecarboxamide

[0949] By 1-[[tert-butyl (diphenyl) silyl] oxymethyl] cyclopropanecarboxylic acid (950mg, 2.68mmol), N, O-dimethylhydroxylamine hydrochloride (523mg, 5.36mmol), N, N-diisopropylethylamine (1.43mL, 8.04mmol), 1-hydroxybenzotriazole (217mg, 1.61mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (771mg, 4.02mmol) mixture in dichloromethane (20mL) was stirred at 25 ℃ for 18 hours.Gained mixture is poured in water (20mL) and extracted with dichloromethane (3x 10mL).The organic layer merged is dried over sodium sulfate, and is under reduced pressure concentrated.By residue by preparative TLC purifying (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 (400MHz, CDCl3) δ7.68–7.63(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).

[0950]

[0951] Step 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

[0952] At -78 ° C, under a nitrogen atmosphere, 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 1- [[tert-butyl (diphenyl) silyl] oxymethyl] -N- methoxy -N- methyl - cyclopropanecarboxamide (282 mg, 0.71 mmol) in tetrahydrofuran (2 mL), n-butyl lithium (2.5 M in hexane, 0.43 mL, 1.06 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 1 hour and then quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 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-[[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, 31%) as a light brown oil.

[0953]

[0954] 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

[0955] 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 in tetrahydrofuran, 0.17 mL, 0.17 mmol). The mixture was stirred at 25 ° C for 3 hours and poured into water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 by RP-HPLC (acetonitrile 25-55% / 0.05% ammonium hydroxide in water) to give unambiguously assigned [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 a light brown oil. 1 H NMR (400MHz, CD3OD) δ7.44–7.38(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-MSR T =0.695min, m / z=302.1[M+H] + .

[0956] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.695 min, ESI+ found [M+H] = 302.1.

[0957] Method 52

[0958]

[0959] (3,3-Difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0960]

[0961] Step 1: 3,3-Difluoro-N-methoxy-N-methylcyclobutanecarboxamide

[0962] By 1-hydroxybenzotriazole (297mg, 2.20mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (845mg, 4.41mmol), 3,3-difluorocyclobutanecarboxylic acid (500mg, 3.67mmol), N, O-dimethylhydroxylamine hydrochloride (537mg, 5.51mmol) and N, N-diisopropylethylamine (1187mg, 9.18mmol) mixture in dichloromethane (8mL) was stirred 5 hours at 25 DEG C, and diluted with water (20mL).Gained mixture is extracted with ethyl acetate (3x 20mL).The organic layer merged is washed with water (2x 20mL), brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 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 (400MHz, CDCl3) δ3.67(s,3H),3.33–3.22(m,1H),3.20(s,3H),2.93–2.78(m,2H),2.76–2.64(m,2H).

[0963]

[0964] Step 2: (3,3-Difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0965] 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) at -78 ° C, n-butyllithium (2.5 M in hexane, 0.26 mL, 0.64 mmol) was added dropwise. After addition, the mixture was stirred at -78 ° C for 2 hours and quenched by adding a saturated aqueous solution of ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 20-45% / 0.225% hydrochloric acid in water) to give unambiguously assigned (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 (400MHz, CD3OD) δ7.44–7.39(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,1H),3.97–3.80(m,1H),3.78–3.74(m,1H),2.91–2.83(m,5H). LCMS R T =1.241min, m / z=322.2[M+H] + .

[0966] LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water over 2 minutes) retention time 1.241 min, ESI+ found [M+H] = 322.2.

[0967] Method 53

[0968]

[0969] ((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

[0970]

[0971] Step 1: N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide

[0972] By 1-hydroxybenzotriazole (149mg, 1.10mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (423mg, 2.21mmol), 2-(pyridin-2-yl)cyclopropanecarboxylic acid (300mg, 1.84mmol), N, O-dimethylhydroxylamine hydrochloride (269mg, 2.76mmol) and N, N-diisopropylethylamine (594mg, 4.60mmol) mixture in dichloromethane (10mL) was stirred at 25 DEG C for 16 hours, and diluted with water (20mL).Gained mixture is extracted with ethyl acetate (3x 20mL).The organic layer merged is washed with water (20mL), salt solution (20mL), and is under reduced pressure concentrated. 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%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ8.47–8.43(m,1H),7.57–7.51(m,1H),7.27–7.22(m,1H),7.10–7. 02(m,1H),3.68(s,3H),3.21(s,3H),2.76(s,1H),2.61–2.52(m,1H),1.63–1.55(m,2H).

[0973]

[0974] 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

[0975] Under a nitrogen atmosphere, to a cooling (-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-butyl lithium (2.5 M in n-hexane, 0.64 mL, 1.6 mmol). The mixture was stirred at -78 ° C for about 30 minutes and quenched by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 32-62% / 0.05% ammonium hydroxide in water) to give unequivocally assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(2-pyridinyl)cyclopropyl]methanone (11.0 mg, 6%) as a light pink solid. 1 H NMR (400MHz, CD3OD) δ8.39–8.37(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 =0.745min,m / z=348.9[M+H] + .

[0976] LCMS (10 to 80% acetonitrile + 0.1% ammonia in water over 3.0 minutes) retention time 0.745 min, ESI+ found [M+H] = 348.9.

[0977] Method 54

[0978]

[0979] [(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

[0980] At 0 ° C, under a nitrogen atmosphere, to 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) was added dropwise isopropylmagnesium bromide (3.0 M in tetrahydrofuran, 0.85 mL, 2.55 mmol). After addition, the mixture was stirred at 0 ° C for 1 hour and quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The resulting solution was extracted with ethyl acetate (2 x 15 mL). The combined organic layer was 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 the unconditionally assigned [(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 methylcyclopropyl mixture) (80 mg, 44%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.42–7.37(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,1 H),3.78–3.68(m,1H),2.83–2.75(m,2H),1.59–1.52(m,1H),1.45–1.37(m,1H),1.19–1.14(m,3H),1.01–0.91(m,1H). LC-MSR T =0.793min, m / z=286.1[M+H] + .

[0981] LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid over 1.5 minutes) retention time 0.793 min, ESI+ found [M+H]...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4 to 8-membered heterocyclic group and 5 to 6-membered heteroaryl; wherein R 1 is connected to the adjacent carbonyl group through a carbon atom, and wherein R 1 Optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, hydroxy, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C1-C6 alkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl); R N Each independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 haloalkyl; or two R N Can form a 4-6 membered ring with the adjacent N; Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatoms; wherein Ring A is linked to the adjacent carbonyl group through a carbon atom; and Ring B is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclyl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein Ring B is substituted according to (a), (b) or both (a) and (b): (a) 1 to 2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R) N )2 and cyano; wherein the two C1-C6 alkyl substituents may together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not halogen or cyano, or is not a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkylthio group having an oxygen or sulfur atom directly bonded to the nitrogen atom; (b) 1 substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R) N )2, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclyl), CH2CH2-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl and CH2-(5- to 6-membered heteroaryl); wherein when a benzene ring or a 5- to 6-membered heteroaryl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano and cyclopropyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl; wherein R 1 is connected to the adjacent carbonyl group through a carbon atom, and wherein R 1 Optionally substituted with one or two substituents selected from the group consisting of F, Cl, methyl, ethyl, hydroxy, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy. R N Each independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 haloalkyl; or two R N Can form a 4-6 membered ring with the adjacent N; Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatoms; wherein Ring A is linked to the adjacent carbonyl group through a carbon atom; and Ring B is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclyl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein Ring B is substituted according to (a), (b) or both (a) and (b): (a) 1 to 2 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R) N )2 and cyano; wherein the two C1-C6 alkyl substituents may together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not halogen or cyano, or is not a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkylthio group having an oxygen or sulfur atom directly bonded to the nitrogen atom; (b) 1 substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkyl-N(R) N )2, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclyl), CH2CH2-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl and CH2-(5- to 6-membered heteroaryl); wherein when a benzene ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are selected from the group consisting of: Where R 2 is selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl and CH2-(5 to 6 membered heteroaryl); wherein when a benzene ring is present, it may be substituted with 1 to 3 substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano; and R 3a and R 3b The choices are as follows: (i)R 3a and R 3b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; (ii) R 3a and R 3b Each of is selected from the group consisting of D, F, Cl, OH, CN and methyl, provided that R 3a and R 3b cannot both be OH or CN; or (iii) R 3a and R 3b Together they form a cyclopropyl group.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are selected from the group consisting of: in R 2 is selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl and CH2-(5 to 6 membered heteroaryl); wherein when a benzene ring is present, it may be substituted with 1 to 3 substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano; and R 4a and R 4b The choices are as follows: (i)R 4a and R 4b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or (ii) R 4a and R 4b Each of which is selected from the group consisting of D, F, Cl and methyl.

5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl and dichlorophenyl.

6. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Ring A and Ring B together are selected from the group consisting of: in R 3a and R 3b The choices are as follows: (i)R 3a and R 3b one of which is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; (ii) R 3a and R 3b Each of is selected from the group consisting of D, F, Cl, OH, CN and methyl, provided that R 3a and R 3b cannot both be OH or CN; or (iii) R 3a and R 3b together they form a cyclopropyl group; R 5 are each selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and m is 1, 2, or 3.

7. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Ring A and Ring B together are: in R 5 are each selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and m is 1, 2, or 3.

8. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl and dichlorophenyl.

9. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein Ring A and Ring B together are selected from the group consisting of: in R 4a and R 4b The choices are as follows: (i)R 4a and R 4b one of which is H, and the other is selected from the group consisting of F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or (ii) R 4a and R 4b Each of which is selected from the group consisting of F, Cl and methyl; R 5 are each selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; and m is 1, 2, or 3.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1 or Table 2.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the selected compound has RIP1 kinase inhibitory activity K i Compounds at less than 100 nM.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

14. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating disease.

15. Use of a compound or composition according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for treating a disease or condition selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating disease.

16. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or condition selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating disease.

17. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or condition 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.

18. A method for treating a disease or condition in a human, the method comprising administering to the human an effective therapeutic amount of a compound or composition according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating disease.

19. A method for treating a disease or condition in a human, the method comprising administering to the human an effective therapeutic amount of a compound or composition according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is 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.

20. The method of claim 18, wherein the disease or condition is Alzheimer's disease.

21. The method of claim 18, wherein the disease or condition is multiple sclerosis.

22. The method of claim 18, wherein the disease or condition is Parkinson's disease.

23. The method of claim 18, wherein the disease or condition is amyotrophic lateral sclerosis.

24. The method of claim 18, wherein the disease or disorder is Huntington's disease.

25. The method of claim 18, wherein the disease or condition is spinal muscular atrophy.

26. The method of claim 19, wherein the disease or disorder is inflammatory bowel disease.

27. The method of claim 19, wherein the disease or condition is Crohn's disease.

28. The method of claim 19, wherein the disease or condition is ulcerative colitis.

29. The method of claim 19, wherein the disease or condition is psoriasis.

30. The method of claim 19, wherein the disease or condition is psoriatic arthritis.

31. The method of claim 19, wherein the disease or condition is rheumatoid arthritis.

32. The method of claim 19, wherein the disease or condition is spondyloarthritis.

33. The method of claim 19, wherein the disease or condition is juvenile idiopathic arthritis.

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