Bicyclic ketone compounds and methods of use thereof

Abstract

The invention provides novel compounds having the general formula (I): (I) wherein R1, the A ring and the B ring are as described herein, pharmaceutical compositions including the compounds, and methods of using the compounds.

Description

[0001] BICYCLIC KETONE COMPOUNDS AND METHODS OF USE THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to inhibitors of RIPl kinase useful for treating diseases and disorders associated with inflammation, cell death and others.

[0004] BACKGROUND OF THE INVENTION

[0005] Receptor-interacting protein- 1 ("RIPl") kinase is a serine / threonine protein kinase. RIPl is a regulator of cell signaling that is involved, among other things, in the mediation of programmed cell death pathways, e.g., necroptosis. The best studied form of necroptotic cell death is initiated by TNFa (tumor necrosis factor), but necroptosis can also be induced by other members of the TNFa death ligand family (Fas and TRAIL / Apo2L), interferons, Toll-like receptors (TLRs) signaling and viral infection via the DNA sensor DAI (DNA-dependent activator of interferon regulatory factor) [1-3]. Binding of TNFa to the TNFRl (TNF receptor 1) prompts TNFRl trimerization and formation of an intracellular complex, Complex-I. TRADD (TNF receptor associated death domain protein) binds to the intracellular death domain of TNFRl and recruits the protein kinase RIPl (receptor-interacting protein 1) through the death domain present in both proteins [4]. Following initial recruitment into TNFRl -associated signaling complex, RIPl translocates to a secondary cytoplasmatic complex, Complex-II [5-7]. Complex-II is formed by the death domain containing protein FADD (Fas- associated Protein), RIPl, caspase-8 and cFLIP. If caspase-8 is not fully activated or its activity is blocked, the protein kinase RIP3 gets recruited to the complex, forming a necrosome, which will lead to necroptotic cell death initiation [8-10]. Once the necrosome is formed, RIPl and RIP3 engage in a series of auto and cross phosphorylation events that are essential for necroptotic cell death. Necroptosis can be completely blocked either by the kinase inactivating mutation in any of the two kinases, or chemically by RIPl kinase inhibitors (necrostatins), or RIP3 kinase inhibitors [11 -13]. Phosphorylation of RIP3 allows the binding and phosphorylation of pseudokinase MLKL (mixed lineage kinase domain-like), a key component of necroptotic cell death [14, 15].

[0006] Necroptosis has crucial pathophysiological relevance in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel diseases, retinal degeneration and a number of other common clinical disorders

[0016] . Therefore, selective inhibitors of RIPl kinase activity are therefore desired as a potential treatment of diseases mediated by this pathway and associated with inflammation and / or necroptotic cell death.

[0007] Inhibitors of RIPl kinase have been previously described. The first published inhibitor of RIPl kinase activity was necrostatin 1 (Nec-1)

[0017] . This initial discovery was followed by modified versions of Nec-1 with various abilities to block RIPl kinase activity [11, 18]. Recently, additional RIPl kinase inhibitors have been described that differ structurally from necrostatin class of compounds [19, 20, 21]. References cited above, each of which is hereby incorporated by reference in its entirety:

[0008] I) 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, M. C. and Vucic, D. (2015) Necroptosis: Pathway diversity and characteristics. Semin Cell Dev Biol. 39, 56-62.

[0011] 4) Chen, Z. J. (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 RIP 1 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

[0014] RIPl / caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Molecular cell. 43, 449-463.

[0015] 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) cIAPl and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 30, 689-700.

[0016] 8) Wang, L., Du, F. and Wang, X. (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 133, 693-703.

[0017] 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, 1 100-11 1 1. 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, 1 1 12-1 123.

[0018] I I) 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. 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.

[0020] 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.

[0021] 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.

[0022] 16) Linkermann, A. and Green, D. R. (2014) Necroptosis. The New England journal of medicine. 370, 455-465.

[0023] 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, 1 12-1 19.

[0024] 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.

[0025] 19) Harris, P. A., Bandyopadhyay, D., Berger, S. B., Campobasso, N., Capriotti, C. A., Cox, J. A., Dare, L., Finger, J. N., Hoffman, S. J., Kahler, K. M., Lehr, R., Lich, J. D., Nagilla, R., Nolte, R. T., Ouellette, M. T., Pao, C. S., Schaeffer, M. C, Smallwood, A., Sun, H. H., Swift, B. A., Totoritis, R. D., Ward, P., Marquis, R. W., Bertin, J. and Gough, P. J. (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243.

[0026] 20) Najjar, M., Suebsuwong, C, Ray, S. S., Thapa, R. J., Maki, J. L., Nogusa, S., Shah, S., Saleh, D., Gough, P. J., Bertin, J., Yuan, J., Balachandran, S., Cuny, G. D. and Degterev, A. (2015) Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1. Cell Rep. 21) International Patent Publication No. WO 2014 / 125444.

[0027] 22) International Patent Publication No. WO 2017 / 004500. SUMMARY OF THE INVENTION

[0028] Provided herein are compounds of formula I:

[0029] or pharmaceutically acceptable salts thereof, wherein

[0030] R1is selected from the group consisting of Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, phenyl, benzyl, 4 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R1is bound to the adjacent carbonyl by a carbon atom, and wherein R1is optionally substituted by one or two substituents selected from the group consisting of F, CI, Br, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(0)Ci-C6alkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 5 to 6 membered heteroaryl, and CH2-(5 to 6 membered heteroaryl); each RNis independently selected from the group consisting of H, Ci-C6alkyl, C3-C6cycloalkyl, d- C6alkoxy, and Ci-C6haloalkyl; or two RNmay together with the adjacent N form a 4-6 membered ring;

[0031] the A ring is a 5 membered heteroaryl having as the only heteroatoms, either (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom; wherein the A ring is bound to the adjacent carbonyl by a carbon atom; and

[0032] the B ring is a 4 to 8 membered cycloalkyl, or a 4 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is substituted according to (a), (b), or both (a) and (b):

[0033] (a) 1 to 2 substituents selected from the group consisting of halogen, deuterium, hydroxy, Q- C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, and cyano; wherein two Ci-C6alkyl substituents may together for a bridged or spirocyclic ring; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano, or a Ci-C6alkoxy, Ci-C6haloalkoxy or Ci-C6thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;

[0034] (b) 1 substituent selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, phenyl, benzyl, CH2-(C3-C6cycloalkyl), CH2CH2-(C3-C6cycloalkyl), 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 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.

[0035] 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.

[0036] 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.

[0037] Also provided herein are methods of treatment of diseases and disorders associated with inflammation, cell death, and others related to RIP1 kinase, as described further below.

[0038] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0039] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0040] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt thereof, or composition thereof according to any one of the embodiments provided herein, for the treatment of a disease or disorder 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0041] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of Parkinson's Disease, 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0042] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

[0043] DETAILED DESCRIPTION OF THE INVENTION

[0044] DEFINITIONS

[0045] As provided herein, all chemical formulae and generic chemical structures should be interpreted to provide proper valence and chemically stable bonds between atoms as understood by one of ordinary skill in the art. Where appropriate, substituents may be bonded to more than one adjacent atom (e.g., alkyl includes methylene where two bonds are present).

[0046] In the chemical formulae provided herein, "halogen" or "halo' refers to flurorine, chlorine, and bromine (i.e., F, CI, Br).

[0047] Alkyl, unless otherwise specifically defined, refers to an optionally substituted, straight-chain or branched Q-Cn alkyl group. In some embodiments, alkyl refers to a Ci-C6alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, ira-propyl, n-butyl, ira-butyl, teri-butyl, sec- butyl, n-pentyl, n-hexyl, n-heptyl, and n-oxtyl. Substituted alkyl groups provided herein are substituted by one or more substituents selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6cycloalkyl, phenyl, OH, C02H, C02(d-C4alkyl), NH2, NH(d-C4alkyl), N(d-C4alkyl)2, NH(C=0)d-C4alkyl, (C=0)NH(d-C4alkyl), (C=0)N(d-C4alkyl)2, S(d-C4alkyl), SO(d-C4alkyl), S02(d-C4alkyl), S02NH(d-C4alkyl), S02N(d-C4alkyl)2, and NHS02(d-C4alkyl). In some embodiments, the substituted alkyl group has 1 or 2 substituents. In some embodiments, the alkyl group is unsubstituted.

[0048] Cycloalkyl, unless otherwise specifically defined, refers to an optionally substituted C3-Ci2cycloalkyl group and includes fused, spirocyclic, and bridged bicyclic groups, wherein the substituents are selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6cycloalkyl, phenyl, OH, C02H, C02(d-C4alkyl), NH2, NH(d-C4alkyl), N(d-C4alkyl)2, NH(C=0)d-C4alkyl, (C=0)NH(d-C4alkyl), (C=0)N(d- C4alkyl)2, S(d-C4alkyl), SO(d-C4alkyl), S02(d-C4alkyl), S02NH(d-C4alkyl), S02N(d-C4alkyl)2, and NHS02(Ci-C4alkyl). In some embodiments, cycloalkyl refers to a C3-C6cycloalkyl group. In some embodiments, the C3-C6cycloalkyl group is optionally substituted with 1 to three halogen atoms. In some embodiments, the C3-C6cycloalkyl group is optionally substituted with 1 to three fluorine atoms. Exemplary C3-C6cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary C3-Ci2cycloalkyl groups further include bicyclo[3.1.0]hexyl, bicyclo[2.1.1 ]hexyl, cycloheptyl, bicycle[4.1.0]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl, bicyclo[2.2.1 ]heptanyl, bicycle[2.2.2]octanyl, adamantanyl, decalinyl, and spiro[5.4]decanyl. Where appropriate, cycloalkyl groups may be fused to other groups such that more than one chemical bond exists between the cycloalkyl group and another ring system (e.g., the C ring of formula I). In some embodiments, the cycloalkyl group is unsubstituted.

[0049] Haloalkyl, unless otherwise specifically defined, refers to a straight-chain or branched Q-C12alkyl group, wherein one or more hydrogen atoms are replaced by a halogen. In some embodiments, haloalkyl refers to a Ci-C6haloalkyl group. In some embodiments, 1 to 3 hydrogen atoms of the haloalkyl group are replaced by a halogen. In some embodiments, every hydrogen atom of the haloalkyl group is replaced by a halogen (e.g, trifluoromethyl). In some embodiments, the haloalkyl is as defined herein wherein the halogen in each instance is fluorine. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluromethyl, trifluoroethyl, and pentafluoroethyl.

[0050] Alkoxy, unless otherwise specifically defined, refers to a straight-chain or branched Q-C12alkyl group, wherein one or more oxygen atoms are present, in each instance between two carbon atoms. In some embodiments, alkoxy refers to a C\-C6alkoxy group. In some embodiments, Ci-C6alkoxy groups provided herein have one oxygen atom. Exemplary alkoxy groups include methoxy, ethoxy, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2CH2OCH2CH3, CH2OCH2CH2CH3, CH2CH2CH2OCH3, CH2OCH(CH3)2, CH2OC(CH3)3, CH(CH3)OCH3, CH2CH(CH3)OCH3, CH(CH3)OCH2CH3, CH2OCH2OCH3, CH2CH2OCH2CH2OCH3, and CH2OCH2OCH2OCH3.

[0051] Cycloalkoxy, unless otherwise specifically defined, refers to a C4-C10or a C4-C6alkoxy group as defined above wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0052] Haloalkoxy, unless otherwise specifically defined, refers to a Ci-C6haloalkyl group as defined above, wherein one or two oxygen atoms are present, in each instance between two carbon atoms. In some embodiments, Ci-C6haloalkoxy groups provided herein have one oxygen atom. Exemplary haloalkoxy groups include OCF3, OCHF2and CH2OCF3.

[0053] Thioalkyl, unless otherwise specifically defined, refers to a C1-C12or a Ci-C6alkoxy group as defined above wherein the oxygen atom is replaced by a sulfur atom. In some embodiments, thioalkyl groups may include sulfur atoms substituted by one or two oxygen atoms (i.e., alkylsulfones and alkylsulfoxides). Exemplary thioalkyl groups are those exemplified in the definition of alkoxy above, wherein each oxygen atom is replaced by a sulfur atom in each instance.

[0054] Thiocycloalkyl, unless otherwise specifically defined, refers to a C4-C10or a C4-C6thioalkyl group as defined above wherein the group is cyclic and contains one sulfur atom. In some embodiments, the sulfur atom of the thiocycloalkyl group is substituted by one or two oxygen atoms (i.e., a cyclic sulfone or sulfoxide). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1 ,1 -dioxothiolanyl, and 1 ,1 -dioxothianyl.

[0055] Heterocyclyl, unless otherwise specifically defined, referes to a single saturated or partially unsaturated 4 to 8 membered ring that has 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 multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems have from 7 to 12 atoms and are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, 7 or 8 membered rings) from about 1 to 7 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be C-branched (i.e., substituted by Ci-C4alkyl). The ring may be substituted with one or more (e.g., 1 , 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocyclyl group including a carbon atom and a nitrogen atom. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 ,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1 ,2- dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, spiro[cyclopropane-l ,1 '-isoindolinyl]-3'-one, isoindolinyl-1 -one, 2-oxa-6-azaspiro[3.3]heptanyl, 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, tetrhydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (lR,5S)-3-azabicyclo[3.2.1 ]octane, (l s,4s)-2- azabicyclo[2.2.2]octane, (lR,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

[0056] In some embodiments, the heterocyclyl is a C4-Ci0heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl group is neither bicyclic nor spirocyclic. In some embodiments, the heterocyclyl is a C5- C6heterocylcyl having 1 to 3 heteroatoms, wherein at least 2 are nitrogen if 3 heteroatoms are present.

[0057] Aryl, unless otherwise specifically defined, refers to a single all carbon aromatic ring or a multiple condensed all 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 radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Exemplary aryl groups include phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

[0058] Heteroaryl, unless otherwise specifically defined, refers to a 5 to 6 membered aromatic ring that has 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 multiple condensed ring systems having 8 to 16 atoms that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, "heteroaryl" includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro- 1,8 -naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has 1 to 15 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system. It is also to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-lH-indazole and 3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclo- penta[l ,2-c]pyrazole.

[0059] As used herein, the term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

[0060] As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0061] As used herein a wavy line " that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

[0062] As used herein, the term "C-linked" means that the group that the term describes is attached the remainder of the molecule through a ring carbon atom.

[0063] As used herein, the term "N-linked" means that the group that the term describes is attached to the remainder of the molecule through a ring nitrogen atom.

[0064] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0065] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0066] Stereochemical definitions and conventions used herein generally follow 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 invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0067] When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51 % the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 97%> the absolute stereoisomer depicted. In another embodiment, the compound may be at least 98%> the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99%> the absolute stereoisomer depicted.

[0068] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0069] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water. In some embodiments, a hydrate of a compound provided herein is a ketone hydrate.

[0070] As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4 edition, Wiley-Interscience, New York, 2006.

[0071] 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.

[0072] As used herein, the term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, 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, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0073] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in 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. In addition to salt forms, the present invention provides compounds which are in a prodrug form. As used herein the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0074] Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para- benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert- butylglycine.

[0075] Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester. As another example, compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl 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 functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci_6)alkanoyloxymethyl, l -((Ci_6)alkanoyloxy)ethyl, 1 -methyl- l-((Ci_6)alkanoyloxy)ethyl, (Ci_6)alkoxycarbonyloxymethyl, N-(Ci_6)alkoxycarbonylaminomethyl, succinoyl, (Ci_6)alkanoyl, alpha-amino(Ci_4)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)2, -P(0)(0(Ci_6)alkyl)2or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0076] Additionally, the present invention provides for metabolites of compounds of the invention. As used herein, a "metabolite" refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

[0077] Metabolite products typically are identified by preparing a radiolabelled (e.g.,14C or3H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg / kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC / MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

[0078] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0079] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.

[0080] The term "composition," as used herein, 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. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0081] The terms "treat" and "treatment" refer to both therapeutic treatment and / or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.

[0082] The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0083] The term "bioavailability" refers to the systemic availability (i.e., blood / plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.

[0084] INHIBITORS OF RIP1 KINASE

[0085] The present invention provides novel compounds having the general formula I:

[0086] or pharmaceutically acceptable salts thereof, wherein

[0087] R1is selected from the group consisting of Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, phenyl, benzyl, 4 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R1is bound to the adjacent carbonyl by a carbon atom, and wherein R1is optionally substituted by one or two substituents selected from the group consisting of F, CI, Br, Ci-C6alk l, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(0)Ci-C6alkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 5 to 6 membered heteroaryl, and CH2-(5 to 6 membered heteroaryl); each RNis independently selected from the group consisting of H, Ci-C6alkyl, C3-C6cycloalkyl, CrC6alkoxy, and Ci-C6haloalkyl; or two RNmay together with the adjacent N form a 4-6 membered ring;

[0088] the A ring is a 5 membered heteroaryl having as the only heteroatoms, either (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom; wherein the A ring is bound to the adjacent carbonyl by a carbon atom; and

[0089] the B ring is a 4 to 8 membered cycloalkyl, or a 4 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is substituted according to (a), (b), or both (a) and (b):

[0090] (a) 1 to 2 substituents selected from the group consisting of halogen, deuterium, hydroxy, Q- C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, and cyano; wherein two Ci-C6alkyl substituents may together for a bridged or spirocyclic ring; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano, or a Ci-C6alkoxy, Ci-C6haloalkoxy or Ci-C6thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;

[0091] (b) 1 substituent selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, phenyl, benzyl, CH2-(C3-C6cycloalkyl), CH2CH2-(C3-C6cycloalkyl), 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 5 to 6 membered heteroaryl ring is present it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Q-C4haloalkoxy, and cyano.

[0092] In another embodiment, provided herein are compounds of formula I:

[0093] or pharmaceutically acceptable salts thereof, wherein

[0094] R1is selected from the group consisting of Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, phenyl, benzyl, 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R1is bound to the adjacent carbonyl by a carbon atom, and wherein R1is optionally substituted by one or two substituents selected from the group consisting of F, CI, methyl, ethyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0095] each RNis independently selected from the group consisting of H, Q-Q alkyl, C3-C6cycloalkyl, CrC6alkoxy, and Ci-C6haloalkyl; or two RNmay together with the adjacent N form a 4-6 membered ring;

[0096] the A ring is a 5 membered heteroaryl having as the only heteroatoms, either (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom; wherein the A ring is bound to the adjacent carbonyl by a carbon atom; and

[0097] the B ring is a 4 to 8 membered cycloalkyl, or a 4 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is substituted according to (a), (b), or both (a) and (b):

[0098] (a) 1 to 2 substituents selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, and cyano; wherein two Ci-C6alkyl substituents may together for a bridged or spirocyclic ring; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano, or a Ci-C6alkoxy, Ci-C6haloalkoxy or Ci-C6thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;

[0099] (b) 1 substituent selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, phenyl, benzyl, CH2-(C3-C6cycloalkyl), CH2CH2-(C3-C6cycloalkyl), 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, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, cyano, and cyclopropyl.

[0100] In some embodiments, R1is selected from the group consisting of Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6haloalkyl, phenyl, benzyl, oxtetanyl, oxabicyclo[3.1.0]hexan-6-yl, thienyl and pyrazolyl; wherein R1is optionally substituted by: (i) one substituent selected from the group consisting of F, CI, methyl, hydroxyl, hydroxymethyl, cyano and trifluoromethyl, or (ii) two F substituents. In some of the above embodiments, R1is Q-Q alkyl. In some embodiments, R1is CrC4alkyl. In some embodiments, R1is C3-C5cycloalkyl. In some embodiments, R1is C3-C4cycloalkyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is CF3CH2. In some embodiments, R1is 2-propyl. In some embodiments, R1is tert- butyl. In some embodiments, R1is (2 -hydroxy)-2 -propyl. In some embodiments, R1is (2-cyano)-2- propyl. In some embodiments, R1is Ci-C6haloalkyl. In some embodiments, R1is Ci-C4haloalkyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is mono- or di-fluorocyclopropyl. In some embodiments, R1is 1 -fluorocyclopropyl. In some embodiments, R1is 2-fluorocyclopropyl. In some embodiments, R1is 2,2-difluorocyclopropyl. In some embodiments, R1is 1 - (trifluoromethyl)cyclopropyl. In some embodiments, R1is 1 -methylcyclopropyl. In some embodiments, R1is 1 -(hydroxymethyl)cyclopropyl. In some embodiments, R1is cyclobutyl. In some embodiments, R1is cyclopentyl. In some embodiments, R1is phenyl. In some embodiments, R1is benzyl. In some embodiments, R1is oxetan-3-yl. In some embodiments, R1is 3-methyloxetan-3-yl. In some embodiments, R1is oxabicyclo[3.1.0]hexan-6-yl. In some embodiments, R1is 2-pyridyl. In some embodiments, R1is l-methylpyrazol-4-yl. In some embodiments, R1is 2-thienyl.

[0101] In some embodiments, each RNis independently selected from the group consisting of H and Ci-C6alkyl. In some embodiments, each RNis a Ci-C4alkyl. In some embodiments, each RNis methyl.

[0102] In some embodiments of formula (I), R1is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0103]

[0104]

[0105] wherein

[0106] R2is selected from the group consisting of H, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 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, Q-C4 alkyl, C1-C4 haloalkyl, Q-C4 alkoxy, C1-C4 haloalkoxy, and cyano; and

[0107] R3aand R3bare selected as follows:

[0108] (i) one of R3aand R3bis H, and the other is selected from the group consisting of D, F, CI, OH, CN, C1-C4 alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and C1-C4haloalkoxy;

[0109] (ii) each of R3aand R3bis selected from the group consisting of D, F, CI, OH, CN and methyl, provided that R3aand R3bcannot both be OH or CN; or

[0110] (iii) R3aand R3btogether form cyclopropyl.

[0111] In some embodiments of formula (I), R1is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0112]

[0113] wherein

[0114] R3aand R3bare selected as follows: (i) one of Raand R is H, and the other is selected from the group consisting of D, F, CI, OH, CN, C1-C4alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and C1-C4haloalkoxy;

[0115] (ii) each of R3aand R3bis selected from the group consisting of D, F, CI, OH, CN and methyl, provided that R3aand R3bcannot both be OH or CN; or

[0116] (iii) R3aand R3btogether form cyclopropyl;

[0117] each R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy and Ci-C6haloalkoxy; and

[0118] m is 1, 2 or 3.

[0119] In some embodiments of formula (I), R1is as defined above, and the A ring and the B ring together are:

[0120]

[0121] wherein

[0122] each R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy and Ci-C6haloalkoxy; and

[0123] m is 1, 2 or 3.

[0124] In some embodiments of formula (I), R1is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0125]

[0126] wherein

[0127] R2is selected from the group consisting of H, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 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, Ci-C4alkyl, Ci-C4haloalkyl, Q-C4alkoxy, C1-C4haloalkoxy, and cyano;

[0128] R4aand R4bare selected as follows:

[0129] (i) one of R4aand R4bis H, and the other is selected from the group consisting of D, F, CI, OH, CN, C1-C4alkyl, Q-C4haloalkyl, cyclopropyl, Q-C4alkoxy and Q-C4haloalkoxy; or

[0130] (ii) each of R4aand R4bis selected from the group consisting of D, F, CI and methyl; and each R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy and Ci-C6haloalkoxy.

[0131] In some embodiments of formula (I), R1is as defined above, and the A ring and the B ring together are selected from the group consisting of:

[0132]

[0133] wherein

[0134] Raand R are selected as follows:

[0135] (i) one of R4aand R4bis H, and the other is selected from the group consisting of D, F, OH, CN, C1-C4alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and C1-C4haloalkoxy; or

[0136] (ii) each of Raand R is selected from the group consisting of D, F, CI and methyl; each R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, C1-C4 haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy; and

[0137] m is 1, 2 or 3.

[0138] In some of the above embodiments, R2is phenyl. In some embodiments, R2is mono- or difluorophenyl. In some embodiments, R2is mono- or dichlorophenyl. In some of the above embodiments, R2is pyridinyl. In some of the above embodiments, R2is chloro substituted pyridinyl. In some of the above embodiments, R2is fluoro substituted pyridinyl. In some of the above embodiments, R2is pyrazolyl. In some of the above embodiments, R2is 1 -methyl- lH-pyrazol-4-yl. In some of the above embodiments, R2is 4-chloro-l -methyl- lH-pyrazol-3-yl.

[0139] In some of the above embodiments, R3aand R3bare each H. In some of the above embodiments, R3ais H and R3bis F. In some of the above embodiments, R3ais H and R3bis CI. In some of the above embodiments, R3aand R3bare each F. In some of the above embodiments, R3aand R3bare each CI. In some of the above embodiments, R3aand R3bare each methyl. In some of the above embodiments, R3ais methyl and R3bis F. In some of the above embodiments, R3ais methyl and R3bis Cl. In some of the above embodiments, R3ais methyl and R3bis OH. In some of the above embodiments, R3ais methyl and R3bis CN. In some of the above embodiments, R3aand R3bare each D. In some of the above embodiments, R3ais H and R3bis D. In some of the above embodiments, R3ais D and R3bis F. In some of the above embodiments, R3ais D and R3bis CI. In some of the above embodiments, R3ais D and R3bis methyl.

[0140] In some of the above embodiments, R4aand R4bare each H. In some of the above embodiments one ofR4ais H and R4bis F. In some of the above embodiments one of R4ais H and R4bis methyl. In some of the above embodiments one ofR4ais H and R4bis Cl. In some of the above embodiments, R4aand R4bare each F. In some of the above embodiments, R4aand R4bare each D. In some of the above embodiments, R4ais H and R4bis D. In some of the above embodiments, R4ais D and R4bis F. In some of the above embodiments, R4ais D and R4bis CI.

[0141] In some of the above embodiments, R5is selected from the group consisting of H, F, CI, CH3, CH2CH3, OCH3, CF3, OCF3, CF2H, and OCF2H.

[0142] In some of the above embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0143] In another embodiment, provided herein is a compound selected from the compounds of

[0144] Table 1 below or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a compound of Table 1 having a K; of less than 100 nM in a RIPIK biochemical or cell-based assay, including as herein described. In another embodiment, the compound of Table 1 has a K; of less than 50 nM in a RIPIK biochemical or cell-based assay, including as herein described. In yet another embodiment, the compound of Table 1 has a K; of less than 25 nM in a RIPIK biochemical or cell-based assay, including as herein described. In yet another embodiment, the compound of Table 1 has a K; of less than 10 nM in a RIPIK biochemical or cell-based assay, including as herein described.

[0145] In another embodiment, provided herein is a compound selected from the compounds of Table 2 below or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a compound of Table 2 having a K; of less than 100 nM in a RIPIK biochemical or cell-based assay, including as herein described. In another embodiment, the compound of Table 2 has a K; of less than 50 nM in a RIPIK biochemical or cell-based assay, including as herein described. In yet another embodiment, the compound of Table 2 has a K; of less than 25 nM in a RIPIK biochemical or cell-based assay, including as herein described. In yet another embodiment, the compound of Table 2 has a K; of less than 10 nM in a RIPIK biochemical or cell-based assay, including as herein described.

[0146] In some embodiments, provided herein is a single stereoisomer of a compound of Table 1 or Table 2, as characterized by reference to its chiral separation and isolation (e.g., as described in the Examples by chiral SFC).

[0147] In some embodiments, provided herein are pharmaceutical compositions comprising a compound of formula I as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

[0148] Also provided herein are oral formulations of a compound of formula I as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

[0149] In some embodiments, provided herein are uses of a compound of formula I as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for the treatment of neurodegenerative diseases and disorders. In some embodiments, the diseases and disorders to be treated are synucleopathies such as Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes. In some embodiments, the diseases and disorders to be treated are taupathies such as Alzheimer's Disease and frontotemporal dementia. In some embodiments, the diseases and disorders to be treated are demyelination diseases such as multiple sclerosis.

[0150] In some embodiments, the diseases and disorders to be treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Additional exemplary neurodegenerative diseases to be treated 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, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0151] In some embodiments, the disease or disorder to be treated is Alzheimer's disease. In some embodiments, the disease or disorder to be treated is Parkinson's disease. In some embodiments, the disease or disorder to be treated is Huntington's disease. In some embodiments, the disease or disorder to be treated is multiple sclerosis. In some embodiments, the disease or disorder to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder to be treated is spinal muscular atrophy (SMA).

[0152] In some embodiments, provided herein are uses of a compound of formula I as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for the treatment of inflammatory diseases and disorders. In some embodiments, the disease or disorder to be treated is selected from the group consisting of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, 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 / diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage / injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. 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 I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO- deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma 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 infections and viral infections (such as tuberculosis and influenza), and Lysosomal storage diseases (particularly, Gaucher Disease, and including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl Ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease, Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile Free Sialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metachromatic Leukodystrophy, 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). In some embodiments, the disease or disorder to be treated is an inflammatory bowel disease. In some embodiments, the disease or disorder to be treated is Crohn's disease. In some embodiments, the disease or disorder to be treated is ulcerative colitis. In some embodiments, the disease or disorder to be treated is glaucoma. In some embodiments, the disease or disorder to be treated is psoriasis. In some embodiments, the disease or disorder to be treated is rheumatoid arthritis. In some embodiments, the disease or disorder to be treated is spondylarthritis. In some embodiments, the disease or disorder to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder to be treated is osteoarthritis.

[0153] In some embodiments, provided herein are methods for the treatment or prevention of a disease or disorder with a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and / or necroptosis. In some embodiments said disease or disorder is selected from the specific diseases and disorders recited herein.

[0154] 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.

[0155] PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

[0156] Provided herein are pharmaceutical compositions or medicaments containing the compounds of the invention (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof), and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula I are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0157] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. In some embodiments, the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit RIP1 kinase activity in order to provide a therapeutic effect in the mammal being treated. In addition, such an effective amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

[0158] In one example, the pharmaceutically effective amount of the compound of the invention administered intravenously or parenterally will be in the per dose range of about 0.1 to 100 mg / kg, alternatively about 0.1 to 20 mg / kg of patient body weight per day, or alternatively about 0.3 to 15 mg / kg / day.

[0159] In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg) of the compound of the invention. The daily does is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1 ,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0160] In some embodiments, a low dose of the compound of the invention is administered in order to provide therapeutic benefit while minimizing or preventing adverse effects.

[0161] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In specific embodiments, the compound of formula I is administered orally. In other specific embodiments, the compound of formula I is administered intravenously.

[0162] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0163] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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 formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0164] 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 and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are nontoxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0165] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn- protein complexes); and / or non-ionic surfactants such as TWEE ™, PLURONICS™ or polyethylene glycol (PEG). A active pharmaceutical ingredient of the invention (e.g., compound of formula I or an embodiment thereof) can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21stEdition, Lippincott Williams & Wilkins, Philidelphia, PA. Sustained-release preparations of a compound of the invention (e.g., compound of formula I or an embodiment thereof) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)- 3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposomally entrapped compounds, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030, 1980; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324A). Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.

[0166] In one example, compounds of formula I or an embodiment thereof may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula I (or an embodiment thereof) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula I or an embodiment thereof are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0167] 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, 25mg, 30mg, 50mg, 80mg, lOOmg, 150mg, 250mg, 300mg and 500mg) of the compound of the invention compounded with suitable amounts of anhydrous lactose, sodium croscarmellose, polyvinylpyrrolidone (PVP) K30, and magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.

[0168] Formulations of a compound of the invention (e.g., 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 oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables.

[0169] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time -release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL / hr can occur.

[0170] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.

[0171] The formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

[0172] An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula I, or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0173] When the binding target is located in the brain, certain embodiments of the invention provide for a compound of formula I (or an embodiment thereof) to traverse the blood-brain barrier. In these embodiments, the compounds provided herein exhibit sufficient brain penetration as potential therapeutics in neurological diseases. In some embodiments, brain penetration is assessed by evaluating free brain / plasma ratio (Bu / Pu) as measured in vivo pharmacokinetic studies in rodents or by other methods known to persons skilled in the art (see, e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008). Certain neurological diseases are associated with an increase in permeability of the blood- brain barrier, such that a compound of formula I (or an embodiment thereof) can be readily introduced to the brain. When the blood-brain barrier remains intact, several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods. Physical methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, circumventing the blood- brain barrier entirely, or by creating openings in the blood-brain barrier.

[0174] Circumvention 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. U.S.A. 91 :2076-2080, 1994), and implanting a delivery device in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

[0175] Methods of 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, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, e.g., 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).

[0176] Lipid-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating the a compound of formula I or I-I (or an embodiment thereof) in liposomes that are coupled to antibody binding fragments that bind to receptors 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 an embodiment thereof) in 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).

[0177] Receptor and channel-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase 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 a compound of formula I or I-I (or an embodiment thereof) with a transferrin and modulating activity of the one or more transferrin receptors (see, e.g., U.S. Patent Publication No. 2003 / 0129186), and cationizing the antibodies (see, e.g., U.S. Patent No. 5,004,697).

[0178] For intracerebral use, in certain embodiments, the compounds can be administered continuously by infusion into the fluid reservoirs of the CNS, although bolus injection may be acceptable. The inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration can be performed by use of an indwelling catheter and a continuous administration means such as a pump, or it can be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitors can be injected through chronically implanted cannulas or chronically infused with the help of osmotic minipumps. Subcutaneous pumps are available that deliver proteins through a small tubing to the cerebral ventricles. Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebro ventricular infusion through a totally implanted drug delivery system are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models for Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143, 1987.

[0179] INDICATIONS AND METHODS OF TREATMENT

[0180] The compounds of the invention inhibit RIP1 kinase activity. Accordingly, the compounds of the invention are useful for the treatment of diseases and disorders mediated by this pathway and associated with inflammation and / or necroptotic cell death.

[0181] In some embodiments, the disease or disorder to be treated is a neurodegenerative disease or disorder. In some embodiments, the diseases and disorders to be treated are synucleopathies such as Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes. In some embodiments, the diseases and disorders to be treated are taupathies such as Alzheimer's Disease and frontotemporal dementia. In some embodiments, the diseases and disorders to be treated are demyelination diseases such as multiple sclerosis.

[0182] In some embodiments, the diseases and disorders to be treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Additional exemplary neurodegenerative diseases to be treated 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, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0183] In some embodiments, the disease or disorder to be treated is Alzheimer's disease. In some embodiments, the disease or disorder to be treated is Parkinson's disease. In some embodiments, the disease or disorder to be treated is Huntington's disease. In some embodiments, the disease or disorder to be treated is multiple sclerosis. In some embodiments, the disease or disorder to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder to be treated is spinal muscular atrophy (SMA).

[0184] In some embodiments, the disease or disorder to be treated is an inflammatory disease or disorder. In some embodiments, the disease or disorder to be treated is selected from the group consisting of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, 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 / diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage / injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AKJ), 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 I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO- deficiency syndrome ( F-kappa-B essential modulator gene (also known as IKK gamma 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 infections and viral infections (such as tuberculosis and influenza), and Lysosomal storage diseases (particularly, Gaucher Disease, and including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl Ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease, Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile Free Sialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metachromatic Leukodystrophy, 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).

[0185] In some embodiments, the disease or disorder to be treated is an inflammatory bowel disease. In some embodiments, the disease or disorder to be treated is Crohn's disease. In some embodiments, the disease or disorder to be treated is ulcerative colitis. In some embodiments, the disease or disorder to be treated is glaucoma. In some embodiments, the disease or disorder to be treated is psoriasis. In some embodiments, the disease or disorder to be treated is rheumatoid arthritis. In some embodiments, the disease or disorder to be treated is spondylarthritis. In some embodiments, the disease or disorder to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder to be treated is osteoarthritis. In some embodiments, the method of treatment provided herein is the treatment of one or more symptoms of a disease or disorder listed above.

[0186] Also provided herein is the use of a compound of the invention in therapy. In some embodiments, provided herein is the use of a compound of the invention for the treatment or prevention of the above diseases and disorders. Also provided herein is the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of the above diseases and disorders.

[0187] Also provided herein is a method of treating a disease or disorder as provided above in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the mammal is a human.

[0188] Also provided herein is a method of treating a symptom of a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cysplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0189] Also provided herein is a method of treating a disease or disorder in a human patient in need of such treatment, said disease or disorder being selected from those provided above, wherein the method comprises orally administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as an orally acceptable pharmaceutical composition. COMBINATION THERAPY

[0190] Compounds of the invention may be combined with one or more other compounds of the invention or one or more other therapeutic agent as any combination thereof, in the treatment of the diseases and disorders provided herein. For example, a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents known to be useful for the treatment of a disease or disorder selected from those recited above.

[0191] As used herein "combination" refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agent. Unless the context makes clear otherwise, "combination" may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, "combination" may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, "combination" may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, "combination" may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.

[0192] In some embodiments, a compound provided herein may be combined with another therapeutically active agent as recited in WO 2016 / 027253, the contents of which are hereby incorporated by reference in their entirety. In such embodiments, the compound that inhibits RIP1 kinase in the combinations recited in WO 2016 / 027253 is replaced by a compound of formula I of the present disclosure.

[0193] In some embodiments, a compound provided herein may be combined with a DLK inhibitor for the treatment of neurodegenerative diseases and disorders, such as those listed elsewhere herein, and including but not limited to the following: Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes, Alzheimer's Disease, frontotemporal dementia, demyelination 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, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, and corticobasal degeneration. DLK inhibitors are described, for example, in WO 2013 / 174780, WO 2014 / 177524, WO 2014 / 177060, WO 2014 / 111496, WO 2015 / 091889 and WO 2016 / 142310.

[0194] EXAMPLES

[0195] The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

[0196] These examples serve to provide guidance to a skilled artisan to prepare and use the compounds, compositions and methods of the invention. While particular embodiment of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the inventions.

[0197] The chemical reactions in the examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non- exemplified compounds according to the invention can be successfully performed by modifications apparent to those skilled in the art, for example, by appropriately protecting interfering group, by utilizing other suitable reagents known in the art, for example, by appropriately protecting interfering groups by utilizing other suitable reagents known in the art other than those described, and / or by making routine modifications of reaction conditions.

[0198] In the examples below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and were used without further purification unless otherwise indicated. The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and / or heat dried.lR NMR spectra were obtained in deuterated CDC13, d6- DMSO, CH3OD or d6-acetone solvent solutions (reported in ppm) using or trimethylsilane (TMS) or residual non-deuterated solvent peaks as the reference standard. When peak multiplicities are reported, the following abbreviates are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, ar reported in Hz (Hertz).

[0199] All abbreviations used to describe reagents, reaction conditions or equipment are intended to be consistent with the definitions set forth in the following list of Abbreviations. The chemical names of discrete compounds of the invention were typically obtained using the structure naming feature of ChemDraw naming program.

[0200] Abbreviations

[0201] ACN Acetonitrile

[0202] Boc teri-Butoxycarbonyl

[0203] DAST Diethylaminosulfur trifluoride

[0204] DCE 1 ,2-dichloroethane

[0205] DCM Dichloromethane

[0206] DMF N,N-Dimethylformamide

[0207] DMSO Dimethyl sulfoxide

[0208] DPPH 2,2-Diphenyl-l -picrylhydrazyl

[0209] HPLC High Pressure Liquid Chromatography

[0210] LCMS Liquid Chromatography Mass Spectrometry

[0211] PCC Pyridinium chlorochromate RP Reverse phase

[0212] RT or RTRetention time

[0213] SEM 2-(Trimethylsilyl)ethoxymethyl

[0214] SFC Supercritical Fluid Chromatography

[0215] TFA Trifluoroacetic acid

[0216] THF Tetrahydrofuran

[0217] Synthetic Schemes

[0218] In addition to the specific synthetic methods of the examples below, additional compounds of the present invention may be prepared, for example, according to the following synthetic schemes.

[0219] After following steps 1-5 of Method 9 below, Scheme 1 is followed to prepare gem-difluroro moieties:

[0220] Scheme 1

[0221]

[0222] Scheme 2 is followed to prepare additional B ring diversity of compounds of formula I using a variety of nucleophiles including but not limited to halide and cyanide sources: Scheme 2

[0223]

[0224] trans mixture standard thionyl chloride

[0225] reaction conditions

[0226]

[0227] Scheme 3 is followed to prepare gem-dimethyl B ring substituted compounds of formula I: S

[0228]

[0229] The following intermediates used in the examples below were prepared according to the procedures described in WO 2017 / 004500 (the entirety of which is incorporated herein by reference):

[0230] If not stated in the specific method any utilized N-methoxy-N-methyl- alkyl, aryl, heteroaryl or heterocyclic carboxamide was prepared in the same manner as cis-2-fluoro-N-methoxy-N- methylcyclopropanecarboxamide in Method 5 below.

[0231] Method 1 : Compound Examples 1 & 2

[0232]

[0233] Example 1 Example 2

[0234] [(lS,2S)-2-nuorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl]methanone and [(lR,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone

[0235] To a cooled (-70 °C) solution of (5S,7S)-2-bromo-7-fluoro- 5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,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-butyllithium (2.5 M in hexanes, 0.64 mL, 1.60 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 20 - 45% / 0.225% HC1 in water). The racemic material was further separated by chrial SFC to afford arbitrarily assigned:

[0236] [(l S,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 1, retention time = 3.635 min) (4.0 mg, 2.5%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 3H), 7.30 - 7.28 (m, 2H), 6.20 - 6.18 (m, 0.5H), 6.06 - 6.04 (m, 0.5H), 5.65 - 5.64 (m, 1H), 5.04 - 5.02 (m, 0.5H), 4.90 - 4.87 (m, 0.5H), 3.80 - 3.74 (m, 1H), 3.25 - 3.21 (m, 1H), 2.88 - 2.81 (m, 1H), 2.03 - 1.96 (m, 1H), 1.34 - 1.28 (m, 1H). LCMS RT= 1.662 min, m / z = 290.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 1.662 min, ESI+ found [M+H] = 290.1. [(lR,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 2, retention time = 3.995 min) (15.9 mg, 10%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.30 - 7.28 (m, 2H), 6.21 - 6.18 (m, 0.5H), 6.06 - 6.05 (m, 0.5H), 5.66 - 5.65 (m, 1H), 5.05 - 5.04 (m, 0.5H), 4.90 - 4.87 (m, 0.5H), 3.82 - 3.74 (m, 1H), 3.23 - 3.20 (m, 1H), 2.88 - 2.82 (m, 1H), 2.02 - 1.96 (m, 1H), 1.34 - 1.30 (m, 1H). LCMS RT= 1.654 min, m / z = 290.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 1.654 min, ESI+ found [M+H] = 290.1.

[0237] SFC condition: Column: Chiralcel OD-3 150x4.6mm I.D., 3μιη Mobile phase: A: C02B:iso-propanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL / min Column temp. 35 °C.

[0238] Method 2: Compound Examples 3 & 4 Example 3 Example 4

[0239] [(lS,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone and [(lR,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone To a cooled (-70 °C) solution of (5R,7R)-2-bromo-7-fluoro- 5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,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 hexanes, 0.64 mL, 1.60 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%o / 0.05%o ammonia hydroxide in water) to afford [cis-2- fluorocyclopropyl] -[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazol-2- yl]methanone (35 mg, 22.5%o) as a pink solid. The racemic material was separated by chiral SFC to give arbitrarily assigned:

[0240] [(lS,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 1, Retention time = 4.787 min) (5.9 mg, 17%) as a white solid. Ή NMR (400 MHz, CDC13) δ 7.44 - 7.39 (m, 3H), 7.28 - 7.27 (m, 2H), 6.13 - 6.11 (m, 1H), 5.99 - 5.97 (m, 1H), 5.53 - 5.49 (m, 1H), 3.69 - 3.61 (m, 1H), 3.27 - 3.24 (m, 1H), 3.03 - 2.96 (m, 1H), 2.23 - 2.15 (m, 1H), 1.29 - 1.24 (m, 1H). LC-MS RT= 0.846 min, m / z = 289.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.846 min, ESI+ found [M+H] = 289.9.

[0241] [(lR,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 2, Retention time = 5.711 min) (11.7 mg, 33%o) as a white solid. ¾ NMR (400 MHz, CDC13) δ 7.44 - 7.37 (m, 3H), 7.28 - 7.27 (m, 2H), 6.13 - 6.11 (m, 1H), 5.99 - 5.97 (m, 1H), 5.53 - 5.50 (m, 1H), 3.69 - 3.63 (m, 1H), 3.27 - 3.23 (m, 1H), 3.03 - 2.96 (m, 1H), 2.23 - 2.16 (m, 1H), 1.29 - 1.24 (m, 1H). LC-MS RT= 0.849 min, m / z = 289.9 (M+H)+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.849 min, ESI+ found [M+H] = 289.9. SFC condition: Column: Chiralcel OD-3 150 X 4.6mm I.D., 3μηι Mobile phase: A: C02 B:iso- propanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL / min Column temp: 35 °C.

[0242] Chiral SFC purification and analytical conditions:

[0243] In the methods provided in the following table, Solvent A is carbon dioxide and Solbent B is 0.1 %>

[0244] NH4(aq) in CH3OH.

[0245] Ex. 6 / SP 6 Waters 15 15 220 Chiral- 40.0

[0246] Analytical UPC pak lG

[0247] Peak 1

[0248] 1.146 min

[0249] Ex. 37 / PIC 100 20 20 220 Chiral- 150 x 70 30 SP 37 Chiral pak 21.2 mm

[0250] Prep AD

[0251] Peak 1

[0252] Ex. 37 / Water 10 10 220 Chiral- 40 pak

[0253] SP 37 UPC

[0254] AD

[0255] Analytical

[0256] Peak 1

[0257] R.T = 0.427

[0258] min

[0259] Ex. 38 / PIC 100 20 20 220 Chiral- 150 x 70 40 pak

[0260] SP 38 Chiral 21.2 mm

[0261] AD

[0262] Prep

[0263] Peak 2

[0264] Ex. 38 / Water 10 10 220 Chiral- 40 pak

[0265] SP 38 UPC

[0266] AD

[0267] Analytical

[0268] Peak 2

[0269] 0.534 min

[0270] Ex. 39 / PIC 100 20 20 270 Chiral- 150 x 70 40 pak

[0271] SP 39 Chiral 21.2 mm

[0272] AD

[0273] Prep

[0274] Peak 2

[0275] Ex. 39 / Waters 20 20 254 Chiral- 40 pak

[0276] SP 39 UPC

[0277] AD

[0278] Analytical

[0279] Peak 2

[0280] R.T = 0.993

[0281] min Ex. 40 / PIC 100 20 20 270 Chiral- 150 x 70 40

[0282] pak

[0283] SP 40 Chiral 21.2 mm

[0284] AD

[0285] Prep

[0286] Peak 1

[0287] Ex. 40 / Waters 20 20 254 Chiral- 40

[0288] pak

[0289] SP 40 UPC

[0290] AD

[0291] Analytical

[0292] Peak 1

[0293] R.T = 0.861

[0294] min

[0295] Example 5

[0296] 2-hydroxy-2-methyl-l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl]propan-l-one

[0297] Arbitrarily assigned 2 -hydroxy-2 -methyl- 1 -[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l ,2-b] [l ,2,4]triazol-2-yl]propan-l -one (10.94 mg, 43% yield). ¾ NMR (400 MHz, DMSO- d6) δ 7.50 - 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-MS RT= 4.029 min, m / z = 290.1 (M+H)+.

[0298] Method SP 6 Example 6

[0299] 2-hydroxy-2-methyl-l-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl]propan-l-one

[0300] Arbitrarily assigned 2 -hydroxy-2 -methyl- 1 -[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l ,2-b] [1 ,2,4]triazol-2-yl]propan-l -one (11.1 mg, 43% yield). ¾ NMR (400 MHz, DMSO-d6) δ 7.47 - 7.31 (m, 3H), 7.30 - 7.12 (m, 2H), 6.37 - 6.01 (m, 1H), 5.82 - 5.53 (m, 1H), 5.23 (s, 1H), 2.85 - 2.59 (m, 1H), 1.52 - 1.47 (m, 6H).. LC-MS RT= 4.029 min, m / z = 290.1 (M+H)+. Method SP 37 Example 37

[0301] 2,2-dimethyl-l-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl]propan-l-one

[0302] Arbitrarily assigned 2,2-dimethyl-l -[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2- b][l,2,4]triazol-2-yl]propan-l-one (2.84 mg, 48% yield). LC-MS RT= 5.26 min, m / z = 288.1 (M+H)+.

[0303] Method SP 38 Example 38

[0304] 2,2-dimethyl-l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl]propan-l-one

[0305] Arbitrarily assigned 2,2-dimethyl-l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]propan-l-one (4.2 mg, 77% yield). LC-MS RT= 5.26 min, m / z = 288.1 (M+H)+.

[0306] Method SP 39 Example 39

[0307] (l-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0308] Arbitrarily assigned (1 -methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone (19.23 mg, 77% yield). ¾ NMR (400 MHz, DMSO-i / 6) δ 8.69 (s, 1H), 8.18 (d, J= 0.7 Hz, 1H), 7.48 - 7.34 (m, 3H), 7.30 - 7.22 (m, 2H), 6.43 - 6.09 (m, 1H), 5.88 - 5.62 (m, 1H), 3.93 (s, 3H), 3.87 - 3.58 (m, 1H). LC-MS RT= 3.99 min, m / z = 312.1 (M+H)+.

[0309] Method SP 40 Example 40

[0310] (l-methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone Arbitrarily assigned (1 -methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone (20.4 mg, 82% yield). ¾ NMR (400 MHz, DMSO-J6) δ 8.68 (s, 1H), 8.18 (s, 1H), 7.48 - 7.33 (m, 3H), 7.32 - 7.06 (m, 2H), 6.43 - 6.08 (m, 1H), 5.92 - 5.62 (m, 1H), 3.93 (s, 3H), 2.96 - 2.57 (m, 1H). LC-MS RT= 3.99 min, m / z = 312.1 (M+H)+.

[0311] Method 3

[0312] Example 7

[0313] 2-phenyl-l-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yljethanone

[0314] To a solution of ethyl [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylate (100 mg, 0.363 mmol) in tetrahydrofuran (2 mL) was added benzylmagnesium chloride (2 M 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 h and then quenched by addition of saturated aqueous 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 afford 2-phenyl-l-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]ethanone as a white solid (80 mg, 69% yield). LCMS RT= 5.24 min, m / z = 322.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.1% formic acid over 10 mins) retention time 5.24 min, ESI+ found [M+H] = 322.1

[0315] Method 4

[0316]

[0317] Example 8 Example 9

[0318] [(lS,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone and [(lR,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone

[0319] To a cooled (-70 °C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,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 hexanes, 0.64 mL, 1.60 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 35-65% / 0.05% ammonia hydroxide in water) to afford [trans-2-fluorocyclopropyl]- [(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b] [ l,2,4]triazol-2-yl]methanone (35 mg, 23%) as a pink solid. This racemic material was further separated by chiral SFC to give arbitrarily assigned: [(lS,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 1, Retention time = 2.836 min) (14.3 mg, 40%o) as a white solid. Ή NMR (400 MHz, CDC13) δ 7.43 - 7.39 (m, 3H), 7.28 - 7.27 (m, 2H), 6.13 - 5.97 (m, 1H), 5.54 - 5.51 (m, 1H), 5.02 - 4.84 (m, 1H), 3.69 - 3.53 (m, 2H), 3.03 - 2.97 (m, 1H), 1.70 - 1.63 (m, 2H). LC-MS RT= 0.866 min, m / z = 289.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.866 min, ESI+ found [M+H] = 289.9.

[0320] [(lR,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 2, Retention time = 3.725 min) (11.3 mg, 32%o) as a white solid. Ή NMR (400 MHz, CDC13) δ 7.43 - 7.39 (m, 3H), 7.28 - 7.27 (m, 2H), 6.12 - 5.97 (m, 1H), 5.54 - 5.50 (m, 1H), 5.03 - 4.87 (m, 1H), 3.69 - 3.51 (m, 2H), 3.04 - 2.97 (m, 1H), 1.70 - 1.62 (m, 2H). LC-MS RT= 0.865 min, m / z = 289.9 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.865 min, ESI+ found [M+H] = 289.9.

[0321] SFC condition: Column: Chiralpak AD-3 150 X 4.6mm I.D., 3μιη Mobile phase: A: C02 B:methanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL / min.

[0322] Example 10

[0323] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-[rac-(lS,2S)-2- fluorocyclopropyl] methanone

[0324] Step 1: cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide

[0325] A mixture of cis-2-fluorocyclopropanecarboxylic acid (500 mg, 4.80 mmol), Ν,Ο- dimethylhydroxylamme hydrochloride (610 mg, 6.25 mmol), l -[bis(dimethylamino)methylene]-lH- l ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2375 mg, 6.25 mmol) and N,N- diisopropylethylamine (1552 mg, 12.0 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give cis-2-fluoro-N-methoxy-N -methyl - cyclopropanecarboxamide (420 mg, 59%) as a colorless oil. ¾ NMR (400 MHz, CDC13) δ 4.87 - 4.67 (m, 1H), 3.78 (s, 3H), 3.26 (s, 3H), 2.35 - 2.33 (m, 1 H), 1.94 - 1.86 (m, 1H), 1.11 - 1.05 (m, 1H).

[0326]

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

[0328] To a cooled (-78 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[l,2- b] [l ,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) was added n- butyllithium (2.5 M in hexanes, 0.21 mL, 0.53 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by RP- HPLC (acetonitrile 30-60%o / 0.05%i ammonia hydroxide in water) to afford (rac-(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazol-2-yl)-[rac-(l S,2S)-2- fluorocyclopropyl]methanone (2.0 mg, 4%) as a light yellow oil. H NMR (400 MHz, CD3OD) δ 7.44 - 7.37 (m, 3H), 7.29 - 7.27 (m, 2H), 6.19 - 6.18 (m, 0.5H), 6.04 - 6.03 (m, 0.5H), 5.67 - 5.61 (m, 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 RT= 1.038 min, m / z = 290.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 1.038 min, ESI+ found [M+H] = 290.1.

[0329] Example 11

[0330] (2,2-difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone

[0331] Step 1 : 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

[0332] A mixture of 2,2-difluorocyclopropanecarboxylic acid (300 mg, 2.46 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (312 mg, 3.19 mmol), l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (1214 mg, 3.19 mmol) and N,N- diisopropylethylamine (794 mg, 6.14 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20%o ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methyl- cyclopropanecarboxamide (200 mg, 49%o) as colorless oil. LCMS RT= 0.427 min, m / z = 166.1 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time found [M+H] = 166.1.

[0333]

[0334] Step 2:

[0335] (2,2-difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone

[0336] To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l,2- b][l,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 hexanes, 0.25 mL, 0.62 mmol) under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 35-65% / 0.05%o ammonia hydroxide in water) to afford (2,2-difluorocyclopropyl)-(rac- (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl)methanone (10.6 mg, 19 %) as colorless oil. Ή NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 3H), 7.30 - 7.29 (m, 2H), 6.21 - 6.05 (m, 1H), 5.69 - 5.64 (m, 1H), 3.84 - 3.74 (m, 2H), 2.90 - 2.82 (m, 1H), 2.32 - 2.27 (m, 1H), 1.97 - 1.90 (m, 1H). LCMS RT= 0.875 min, m / z = 307.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.875 min, ESI+ found [M+H] = 307.9.

[0337] Method 7

[0338] Example 12

[0339] phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yljmethanone

[0340] Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone was prepared from ethyl [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole- 2-carboxylate and phenylmagnesium according to Method 3. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100%o isopropyl acetate in heptane) to afford final product (17 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.12 (m, 2H), 7.74 - 7.65 (m, 1H), 7.61 - 7.52 (m, 2H), 7.48 - 7.33 (m, 3H), 7.32 - 7.24 (m, 2H), 6.28 (ddd, J = 56.4, 7.2, 1.9 Hz, 1H), 5.78 (ddd, J = 8.5, 6.5, 3.1 Hz, 1H), 3.78 (dddd, J = 25.8, 15.4, 8.5, 7.1 Hz, 1H), 2.74 (dddd, J = 26.7, 15.2, 3.2, 2.0 Hz, 1H). LC-MS RT= 5.04 min, m / z = 308.1 (M+H)+.

[0341] LCMS (5 to 95%o acetonitrile in water + 0.1%o formic acid over 10 mins) retention time 5.04 min, ESI+ found [M+H] = 308.1.1

[0342] Method 8

[0343]

[0344] Step 1 : (ii)-benzaldehyde oxime

[0345] To a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL) was added sodium carbonate (112.3 g, 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g, 508.9 mmol). The reaction mixture was stirred at 25 °C for 3 h and filtered. The filtrate was concentrated under reduced pressure and the residue was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude (£) -benzaldehyde oxime as colorless oil 51.0 g, 99%), used in the next step without further purification.

[0346] Step 2: methyl 3-phenyl-4, 5-dihydroisoxazole-5-carboxylate

[0347] To a solution of (^-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 hypochlorous acid tert-butyl ester (17.9 g, 165.1 mmol). The reaction mixture was stirred at 25 °C for 24 h and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20%o ethyl acetate in petroleum ether) to afford methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g, 74%). LCMS RT= 0.871 min, m / z = 206.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 2.0 mins) retention time 0.871 min, ESI+ found [M+H] =206.2.

[0348] Step 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one

[0349] A mixture of methyl 3-phenyl-4, 5-dihydroisoxazole-5-carboxylate (25.0 g, 121.8 mmol) and palladium (10%o on carbon, 2.5 g) in ethanol (800 mL) was hydrogenated (50 psi) at 25 °C for 2 h and then filtered and the filtrate was concentrated under reduced pressure to afford crude 3-hydroxy-5- phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%), used in the next step without further purification. LCMS RT= 0.270 min, m / z = 177.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03 % trifluoacetic acid over 1.5 mins) retention time 0.270 min, ESI+ found [M+H] =177.8.

[0350] Step 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one & ira«s-3-[tert- butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

[0351] To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol) in dichloromethane (300 mL) was added tert-butyldimethylchlorosilane (19.1 g, 126.9 mmol) and imidazole (1 1.5 g, 169.3 mmol). The reaction mixture was stirred at 25 °C for 16 h and subsequently 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 afford c*s-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrroUdin-2-one as a colorless oil (12.4 g, 51 %). ¾ NMR (400 MHz, CDC13) δ 7.37 - 7.25 (m, 5H), 4.88 - 4.53 (m, 1H), 4.54 - 4.46 (m, 1H), 2.89 - 2.79 (m, 1H), 1.80 - 1.71 (m, 1H), 0.93 - 0.90 (m, 9H), 0.19 - 0.12 (m, 6H) and ira«s-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g, 38%). ¾ NMR (400 MHz, CDC13) δ 7.44 - 7.34 (m, 2H), 7.29 - 7.24 (m, 3H), 4.87 - 4.80 (m, 1H), 4.44- 4.41 (m, 1H), 2.45 - 2.37 (m, 1H), 2.27 - 2.22 (m, 1H), 0.93 - 0.90 (m, 9H), 0.16 - 0.13 (m, 6H).

[0352]

[0353] Step 5: cis-l-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

[0354] To a solution of c«-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 42.8 mmol) in NN-dimethylformamide (400 mL) was slowly added sodium hydride (60%, 2.6 g, 64.1 mmol) at 0 °C. After addition, the mixture was stirred at 0 °C for 20 min and subsequently O- (diphenylphosphoryl)hydroxylamine (14.9 g, 64.1mmol) was added. The reaction mixture was stirred at 25 °C for 16 h and then filtered. The filtrate was concentrated under reduced pressure to afford the crude c«-l -amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a yellow oil (9.5 g, 73%), used in the next step without further purification. LCMS RT= 0.877 min, m / z = 307.0 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time found [M+H] =307.0.

[0355] Step 6: ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-l-yl]amino]-2- imino-acetate

[0356] To a solution of c«-l-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 h and subsequently concentrated under reduced pressure to afford crude ethyl 2-[[cw-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-l -yl]amino]-2- imino-acetate as a yellow oil (10.6 g, 84%), used in the next step without further purification. LCMS RT= 2.106 min, m / z =406.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1% ammonia water over 3.0 mins) retention time 2.106 min, ESI+ found [M+H] =406.2.

[0357]

[0358] Step 7: ethyl cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylate

[0359] To a solution of ethyl 2-[[c«-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-l-yl]amino]- 2-imino-acetate (10.6 g, 26.1 mmol) in toluene (200 mL) was added p-toluenesulfonic acid (4.5 g, 26.1 mmol). The reaction mixture was heated at 120 °C for 24 h and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 80%o ethyl acetate in petroleum ether) to afford ethyl czs-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl- 6,7-dihydro-5H-pyrrolo[l ,2-b][l,2,4]triazole-2-carboxylate as a white solid (6.5 g, 64%), used as is in the next step.

[0360]

[0361] Step 8: ethyl c*s-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylate

[0362] A mixture of ethyl 2-[[cw-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-l-yl]amino]-2- imino-acetate (3.1 g, 7.6 mmol) and ieri-butylammonium fluoride (1.0 M in THF, 7.6 mL, 7.6 mmol) in tetrahydrofuran (60 mL) was heated at 60 °C for 18 h and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100%o ethyl acetate in petroleum ether) to give ethyl czs-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxylate as white solid (1.4 g, 69%). ¾ NMR (400 MHz, CDC13) 57.39 - 7.32 (m, 5H), 5.73 (d, J = 3.5 Hz, 1H), 5.50 (m, 1H), 4.41 (q, J

[0363] = 4.5 Hz, 13.9 Hz, 1H), 1.35 (t, J= 7.1 Hz, 3H).

[0364]

[0365] Step 1 : iraws-ethyl 7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylate To a solution of c«-ethyl-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole-2- carboxylate (100 mg, 0.37 mmol) in dichloromethane (8 mL) was added diethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then quenched by addition of water (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf= 0.5) to afford ira«s-ethyl-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylate (30 mg, 30%) as light yellow oil. ¾ NMR (400 MHz, CDC13) δ 7.40 - 7.37 (m, 3H), 7.14 - 7.12 (m, 2H), 6.14 (d, J= 5.2 Hz, 0.5H), 6.00 (d, J = 5.2 Hz, 0.5H), 5.74 - 5.71 (m, 1H), 4.51 - 4.45 (m, 2H), 3.42 - 3.35 (m, 1H), 3.07 - 2.96 (m, 1H), 1 = 7.2 Hz, 3H).

[0366]

[0367] Step 2: ira«s-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylic acid

[0368] To a solution of ?ran5-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole-2- carboxylate (30 mg, 0.11 mol) in tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide monohydrate (14 mg, 0.33 mmol). The reaction mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by addition of hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude ira«s-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylic acid as white solid (13 mg, 48%o), used in the next step without further purification. l-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l-one

[0369] To a cooled (-78 °C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl- 6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazole-2-carboxamide (15 mg, 0.05 mmol) in tetrahydrofuran (10 mL) was added ethylmagnesium bromide (3 M in THF, 0.03 mL, 0.10 mmol) under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and quenched by addition of saturated aqueous 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 reduce pressure. The residue was purified by RP-HPLC (acetonitrile 34-64% / 0.05%> hydrochloride in water) to afford 1- [rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazol-2-yl]propan-l -one (7.4 mg, 50%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.30 - 7.26 (m, 2H), 6.27 - 6.26 (m, 0.5H), 6.14 - 6.12 (m, 0.5H), 5.87 - 5.84 (m, 1H), 3.44 - 3.41 (m, 1H), 3.12 -3.02 (m, 3H), 1.16 (t, J = 7.2 Hz, 3H). LCMS RT= 0.840 min, m / z = 260.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.840 min, ESI+ found [M+H] = 260.1.

[0370] Method 9

[0371] Example 14

[0372] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-[l- (trifluoromethyl)cyclopropyl]methanone

[0373] N-N

[0374] Step 1 : 3t,5-dib>romo-l-(tetrahydro-2H-pyran-2-yl)-lH-l,2,4-triazole

[0375] To a solution of 3,5-dibromo-lh-l,2,4-triazole (150.0 g, 661.2 mmol) in tetrahydrofuran (1500 mL) was slowly added p-toluenesulfonic acid (17.1 g, 99.2 mmol), followed by 3,4-dihydro-2h-pyran (166.9 g, 1983.6 mmol) at 0 °C. After addition, the reaction mixture was heated at 70 °C for 3 h and concentrated under reduced pressure. The residue was poured into water (500 mL) and adjusted to pH = 9 by addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure. The resulting crude product was washed with methanol (2 x 50 mL), dried under reduced pressure to give crude 3,5-dibromo-l-tetrahydropyran-2-yl-l,2,4-triazole (155 g, 75%) as a white solid. Ή NMR (400 MHz, CDC13) δ 5.49 - 5.46 (m, 1H), 4.12 - 3.99 (m, 1H), 3.72 - 3.61 (m, 1H), 2.38 - 2.26 (m, 1H), 2.18 - 2.07 (m, 1H), 1.98 - 1.90 (m, 1H), 1.78 - 1.60 (m, 3H).

[0376] Step 2: l-phenylbut-3-en-l-ol

[0377] To a cooled (0 °C) solution of benzaldehyde (130 g, 1.23 mol) in tetrahydrofuran (1000 mL) was added allylmagnesium chloride (2 M in THF, 858 mL, 1.72 mol) over 30 min. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched by addition of saturated aqueous ammonium chloride (1000 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give l-phenylbut-3-en-l-ol (140 g, 77%) as a light yellow oil. Ή NMR (400 MHz, CDC13) δ 7.37 - 7.34 (m, 4H), 7.29 - 7.26 (m, 1H), 5.83 - 5.75

[0378] (m, 2H), 4.76 - 4.69 (m, 1H), 2.55 - 2.45 (m, 2H), 2.12 (d, J= 2.8 Hz, 1H).

[0379]

[0380] Step 3: tert-butyldimethyl((l-phenylbut-3-en-l-yl)oxy)silane

[0381] To a stirred solution of l -phenyl-3-buten-l-ol (29.0 g, 195.7 mmol) in dichloromethane (400 mL) was added imidazole (27.0 g, 391.6 mmol) and tert-butyldimethylchlorosilane (39.0 g, 254.4 mmol). After addition, the reaction mixture was stirred at 25 °C for 16 h and then quenched by addition of water (200 mL). The mixture was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to afford tert-butyl-dimethyl-(l-phenylbut-3-enoxy)silane (43.0 g , 84%) as colorless oil, used as is in the next step.

[0382]

[0383] Step 4: 3-((tert-butyldimethylsilyl)oxy)-3-phenylpropanal

[0384] To a solution of tert-butyl-dimethyl-(l-phenylbut-3-enoxy)silane (50.0 g, 190.5 mmol) in tetrahydrofuran / water (600 mL, 1 :1) was added osmium tetraoxide (968 mg, 3.8 mmol). After stirring for 30 min at 15 °C, sodium periodate (163 g, 762.0 mmol) was added in small portions over 2 h. The resulting mixture was stirred for another 2 h at 30 °C and then quenched by addition of cold saturated aqueous sodium thiosulfate (500 mL). The mixture was stirred for 30 min and then extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 3-[tert-butyl(dimethyl)silyl]oxy-3-phenyl-propanal (33.0 g, 65%) as yellow oil. ¾ NMR (400 MHz, CDC13) δ 9.94 (t, J = 2.4 Hz, 1H), 7.48 (d, J = 4.2 Hz, 4H), 7.44 - 7.39 (m, 1H), - 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).

[0385]

[0386] Step 5:

[0387] l-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-l,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)- 3-phenylpropan-l-ol

[0388] To a cooled (-78 °C) solution of 3,5-dibromo-l-tetrahydropyran-2-yl-l,2,4-triazole (39.0 g, 125.4 mmol) in tetrahydrofuran (400 mL) was added n-butyllithium (2.5 M in hexanes, 55.0 mL, 137.5 mmol) dropwise under N2atmosphere. The mixture was stirred at -78 °C for 30 min, then a solution of 3 -[tert-butyl(dimethyl)silyl]oxy-3 -phenyl -propanal (33.0 g, 124.2 mmol) in tetrahydrofuran (50 mL) was added dropwise. After addition, the mixture was stirred at -78 °C for 1.5 h and then quenched by addition of saturated aqueous ammonium chloride (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5%> ethyl acetate in petroleum ether) to afford l -(3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-l,2,4-triazol-5-yl)-3- ((tert-butyldimethylsilyl)oxy)-3-phenylpropan-l- ol (50.0 g, 80%) as light yellow oil.

[0389]

[0390] Step 6: trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-7-ol

[0391] To a stirred solution of l-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH- l,2,4-triazol-5-yl)-3-((tert- butyldimethylsilyl)oxy)-3-phenylpropan-l-ol (50.0 g, 100.7 mmol) in dichloromethane (150 mL) was slowly added trifluoroacetic acid (150 mL). The resulting mixture was heated at 50 °C for 2 h and then concentrated under reduced pressure. The residue was adjusted to pH = 9 with saturated aqueous 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 afford trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo [l,2-b] [l,2,4]triazol-7-ol (5.5 g, 20%o) as a yellow solid (A second fraction (8.5 g, 30%o) was also obtained as a 4:3 mixture of trans / cis products). H NMR (400 MHz, CDC13) δ 7.46 - 7.32 (m, 3H), 7.15 (d, J= 7.6 Hz, 2H), 5.65 (t, J= 6.6 Hz, 1H), 5.50 (br s, 1H), 5.45 (d, J= 6.4 Hz, 1H), 3.19 - 3.11 (m, 1H), 3.01 - 2.92 (m, 1H). LCMS RT = 0.682 min, m / z = 279.8 [M +H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoroacetic acid over 1.5 mins) retention time 0.682 min, ESI+found = 279.8.

[0392]

[0393] Step 7: (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole and (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole

[0394] To a stirred solution of trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-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 h and then slowly added into stirred aqueous saturated sodium bicarbonate (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%o ethyl acetate in petroleum ether) to afford racemic cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[ l,2-b] [l,2,4]triazole (1.5 g, 49%o) as a light yellow solid and racemic trans-2-bromo-7-fluoro-5-phenyl -6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazole (650 mg, 21%>) as a white solid. cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole: ¾ NMR (400 MHz, CDC13) δ 7.31 - 7.24 (m, 3H), 7.17 - 7.07 (m, 2H), 5.97 - 5.77 (m, 1H), 5.37 - 5.27 (m, 1H), 3.52 - 3.37 (m, 1H), 2.84 - 2.70 (m, 1H). LCMS RT= 0.632 min, m / z = 281.9 [M +H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoroacetic acid over 1.5 mins) retention time 0.632 min, ESI+found [M +H] = 281.9. trans-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole: ¾ NMR (400 MHz, CDCI3) δ 7.58 - 7.29 (m, 3H), 7.24 - 7.05 (m, 2H), 6.14 - 5.93 (m, 1H), 5.70 - 5.65 (m, 1H), 3.41 - 3.25 (m, 1H), 3.04 - 2.87 (m, 1H).

[0395] The racemic cis material was further separated by chiral SFC to give arbitrarily assigned: (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole (Peak 1 , retention time = 2.963 min) (350 mg, 44%) as a white solid.

[0396] (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole (Peak 2, retention time = 3.174 min) (350 mg, 44%o) as a white solid.

[0397] SFC condition: Column: Chiralpak AD-3 150 X 4.6mm I.D., 3μηι Mobile phase: A: C02 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL / min.

[0398] Step 8: N-methoxy-N-methyl-l-(trifluoromethyl)cyclopropanecarboxamide

[0399] A mixture of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (400 mg, 2.60 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (329 mg, 3.37 mmol), l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1283 mg, 3.37mmol) and N,N- diisopropylethylamine (838 mg, 6.49 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25%o ethyl acetate in petroleum ether) to give N-methoxy-N -m ethyl- 1- (trifluoromethyl)cyclopropanecarboxamide (330 mg, 64%) as a light oil. ¾ NMR (400 MHz, CDC13)

[0400] (s, 3H), 1.37 - 1.17 (m, 4H).

[0401]

[0402] Step 9:

[0403] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-[l- (trifluoromethyl)cyclopropyl] methanone

[0404] To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l,2- b][l,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 hexanes, 0.1 mL, 0.25 mmol) under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (5 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC ((acetonitrile 45-75% / 0.05% ammonia hydroxide in water)) to afford arbitrarily assigned (rac- (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-[l - (trifluoromethyl)cyclopropyl]methanone (14.1 mg, 23%) as a red solid. H NMR (400 MHz, CD3OD) δ 7.43 - 7.35 (m, 3H), 7.24 - 7.22 (m, 2H), 6.15 - 5.99 (m, 1H), 5.61 - 5.60 (m, 1H), 3.77 - 3.68 (m, 1H), 2.84 - 2.77 (m, 1H), 2.27 - 2.17 (m, 2H), 1.60 - 1.55 (m, 2H). LC-MS RT= 0.933 min, m / z = 339.9 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 mins) retention time 0.933 min, ESI+ found [M+H] = 339.9.

[0405]

[0406] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-(3- methyloxetan-3-yl)methanone

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

[0408] A mixture of 3-methyloxetane-3-carboxylic acid (300 mg, 2.58 mmol), N,0-dimethylhydroxylamine hydrochloride (328 mg, 3.36 mmol), l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3 -oxide hexafluorophosphate (1277 mg, 3.36 mmol) and N,N-diisopropylethylamine (835 mg, 6.46 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50%o ethyl acetate in petroleum ether) to give N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (120 mg, 29.2%o) as a colorless oil. 'H NMR (400 MHz, CDC13) δ 4.97 (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] Step 2:

[0410] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-(3- methyloxetan-3-yl)methanone

[0411] To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l,2- b][l,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 hexanes, 0.17 mL, 0.43 mmol) under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05%o ammonia hydroxide in water) to afford (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2- yl)-(3-methyloxetan-3-yl)methanone (11.5 mg, 27 %>) as a yellow oil. H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.26 - 7.23 (m, 2H), 6.17 - 6.01 (m, 1H), 5.65 - 5.63 (m, 1H), 5.08 - 5.03 (m, 2H), 4.52 - 4.48 (m, 2H), 3.78 - 3.70 (m, 1H), 2.86 - 2.76 (m, 1H), 1.75 (s, 3H). LCMS RT= 0.816 min, m / z = 302.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.816 min, ESI+ found [M+H] = 302.0.

[0412] Method 11

[0413] Example 16

[0414] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-[rac-(lS,2R)-2- fluorocyclopropyl] methanone mixture

[0415] Step 1 : trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

[0416] A mixture of trans-2-fluorocyclopropane-l-carboxylic acid (100 mg, 0.96 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (122 mg, 1.25 mmol), l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (475 mg, 1.25 mmol) and N,N- diisopropylethylamine (310 mg, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give trans-2-fluoro-N-methoxy-N-methyl- cyclopropanecarboxamide (70 mg, 50%) as colorless oil. H NMR (400 MHz, CDC13) δ 4.89 - 4.71 (m, 1H), 3.79 (s, 3H), 3.21 (s, 3H), 2.62 - 2.60 (m, 1H), 1.48 - 1.35 (m, 2H). LCMS RT= 0.292 min, m / z = 148.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.292 min, ESI+ found [M+H] = 148.1.

[0417]

[0418] Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-[rac- (1 S,2R)-2-fluorocyclopropyl] methanone

[0419] To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole (40 mg, 0.14 mmol) and trans-2-fluoro-N-methoxy-N-methyl- cyclopropanecarboxamide (42 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in hexanes, 0.07 mL, 0.18 mmol) under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%o / 0.05%o ammonia hydroxide in water) to afford (rac-(5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l ,2-b] [ l,2,4]triazol-2-yl)-[rac-( l S,2R)-2-fluorocyclopropyl]methanone (3.3 mg, 7.6%) as colorless oil. Ή NMR (400 MHz, CDC13) δ 7.42 - 7.37 (m, 3H), 7.28 - 7.27 (m, 2H), 6.13 - 5.97 (m, 1H), 5.54 - 5.52 (m, 1H), 5.03 - 4.85 (m, 1H), 3.71 - 3.51 (m, 2H), 3.04 - 2.94 (m, 1H), 1.70 - 1.62 (m, 2H). LCMS RT= 0.862 min, m / z = 289.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.862 min, ESI+ found [M+H] = 289.9.

[0420] Example 17

[0421] l-(7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-2-yl)propan-l-one Step 1: 6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-ol

[0422] To a solution of imidazole (40.0 g, 587.5 mmol), acetic acid (1.8 mL), and 1,4-dioxane (600 mL) was added acrolein (58.8 mL, 881.3 mmol). The resulting mixture was stirred at 110 °C for 24 h and cooled to 0 °C. The resulting solid was collected by filtration, washed with petroleum ether (200 mL) to afford crude 6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-ol (50.0 g, 69%) as a white solid. Used as is in the next step.

[0423] Step 2: 3-chloro-6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-ol

[0424] To a solution of 6,7-dihydro-5H-pyrrolo[l,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 h and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 3-chloro- 6,7-dihydro-5H-pyrrolo[l ,2-a]imidazol-7-ol (8.0 g, 63%o) as a white solid, used as is in the next step.

[0425] Step 3: 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-ol

[0426] To a solution of 3-chloro-6,7-dihydro-5H-pyrrolo[l,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 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10%o methanol in dichloromethane) to afford 3-chloro- 2-iodo-6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-ol (5.3 g, 53%o) as light yellow solids, used as is in the next step.

[0427] Step 4: 3-chloro-2-iodo-5H-pyrrolo[l,2-a]imidazol-7(6H)-one

[0428] To a solution of 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[l,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 h and filtered. The filtrate was concentrated to dryness under reduced pressure to afford crude 3-chloro-2-iodo-5,6-dihydropyrrolo[l,2-a]imidazol-7-one (3.2 g, 61%o) as a brown solid, used as is in the next step.

[0429] Step 5: N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[l,2-a]imidazol-7-ylidene)amino]-4-methyl- benzenesulfonamide

[0430] A mixture of 4-methylbenzenesulfonohydrazide (2.1 g, 11.3 mmol) and 3-chloro-2-iodo-5,6- dihydropyrrolo[l,2-a]imidazol-7-one (3.2 g, 11.3 mmol) in ethanol (70 mL) was heated at 90 °C for 7 h and cooled to 15 °C. The resulting solid was collected by filtration and dried under reduced pressure to afford crude N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[l,2-a]imidazol-7- ylidene)amino]-4-methyl-benzenesulfonamide (2.8 g, 54%) as a pale green solid, used as is in the next step.

[0431] Step 6: 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole

[0432] A mixture of N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[l,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 h under N2atmosphere. 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%o ethyl acetate in petroleum ether) to afford 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a] imidazole (200 mg, 15%) as a light brown solid. LCMS RT= 0.879 min, m / z = 334.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time: 0.879 min, ESI+ found = 334.9.

[0433]

[0434] Step 7: methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2- carboxylate

[0435] A mixture of 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (200 mg, 0.58 mmol), l,l '-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (24 mg, 0.03 mmol) and triethylamine (0.4 mL, 2.9 mmol) in N,N-dimethylformamide (24 mL) / methanol (8 mL) was heated at 90 °C for 18 h under CO (50 Psi). 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%o ethyl acetate in petroleum ether, Rf= 0.4) to afford methyl 3-chloro-7- phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2- carboxylate (140 mg, 87%) as a light brown solid. LCMS RT= 0.676 min, m / z = 277.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time: 0.676 min, ESI+ found [M+H] = 277.0

[0436]

[0437] Step 8: methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2-carboxylate

[0438] A mixture of methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a] imidazole-2-carboxylate (120 mg, 0.43 mmol) and palladium (10%o on carbon, 103 mg, 0.10 mmol, 50%o wet) in methanol (50 mL) was hydrogenated (40 psi) at 50 °C for 24 h and then filtered. The filtrate was concentrated under reduced pressure to afford crude methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-a] imidazole-2- carboxylate (100 mg, 95%o) as brown oil, used as is in the next step. ¾ NMR (400MHz, CDC13) δ 7.85 - 7.60 (m, 1H), 7.40 - 7.25 (m, 4H), 4.70 - 4.55 (m, 1H), 4.40 - 4.15 (m, 2H), 3.89 (s, 3H), 3.30 - 3.20 (m, 1H), 2.75 - 2.70 (m, 1H), 1.70 - 1.60 (m, 1H). LCMS RT= 0.513 min, m / z = 243.1 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time:

[0439] [M+H] = 243.1.

[0440]

[0441] Step 9: 7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2-carboxylic acid

[0442] A mixture of methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2- carboxylate (100 mg, 0.41 mmol) and lithium hydroxide monohydrate (118 mg, 2.89 mmol) in tetrahydrofuran (2 mL), water (1 mL) and methanol (2 mL) was heated at 25 °C for 18 h. Sodium hydroxide (100 mg) was added and the mixture was heated at 40 °C for another 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and adjusted to pH = 3 by addition of 2 M HC1. The resulting mixture was lyophilized to dryness to afford the crude 7-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-a]imidazole-2-carboxylic acid (94 mg, 99%o) as a white solid, used as is in the next step.

[0443]

[0444] Step 10: N-methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole -2- carboxamide A mixture of 7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-2-carboxylic acid (60 mg, 0.26 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (77 mg, 0.79 mmol), triethylamine (0.11 mL, 0.79 mmol), l-[bis(dimethylamino)methylene] -lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (105 mg, 0.28 mmol) in N,N-dimethylformamide (4 mL) was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf= 0.5) to afford N-methoxy-N-methyl -7-phenyl-6,7- dihydro-5H-pyrrolo[l,2-a]imidazole-2-carboxamide (70 mg, 98%) as a white solid. LCMS RT= 0.506 min, m / z = 272.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time: 0.506 min, ESI+ found [M+H] = 272.1.

[0445]

[0446] Step 11: l-(7-phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-2-yl)propan-l-one

[0447] To a cooled (-70 °C) solution of N-methoxy-N-methyl-7-phenyl-6,7-dihydro- 5H-pyrrolo[l,2- a]imidazole-2-carboxamide (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added ethylmagnesium bromide (3.0 M in THF, 0.61 mL, 1.83 mmol) under N2atmosphere. After addition, the mixture was stirred at -70 °C for 2 h and then quenched by addition of saturated aqueous ammonium chloride (3 mL). The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%o / 0.05%o ammonia hydroxide in water) to afford l -(7- phenyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazol -2-yl)propan-l-one (4.6 mg, 9%>) as a light brown solid. ¾ NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.35 - 7.31 (m, 2H), 7.30 - 7.21 (m, 3H), 4.42 - 4.38 (m, 1H), 4.25 - 4.23 (m, 1H), 4.20 - 4.11 (m, 1H), 3.12 - 3.10 (m, 1H), 2.89 - 2.83 (m, 2H), 2.58 - 2.50 (m, 1H), 1.14 - 1.10 (m, 3H). LCMS RT= 0.634 min, m / z = 241.1 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.634 min, ESI+ found [M+H] = 241.1. Method 13

[0448] Example 18

[0449] cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yljmethanone

[0450] Step 1 : trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide

[0451] A mixture of trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4] triazole-2-carboxylic acid (50 mg, 0.20 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 1 -hydro xybenzotriazole (5 mg, 0.04 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (12 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20 °C for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf= 0.7) to afford trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7- dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazole-2-carboxamide (30 mg, 51 %) as a white solid.

[0452]

[0453] Step 2: cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol- 2-yl]methanone

[0454] To a cooled (-78 °C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl- 6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazole-2-carboxamide (15 mg, 0.05 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (0.5 M in THF, 0.2 mL, 0.10 mmol) under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and quenched by addition of saturated aqueous 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 reduce pressure. The residue was purified by RP-HPLC (acetonitrile 35-65% / 0.05%o hydrochloride in water) to afford cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (7.6 mg, 50%) as a white solid. H NMR (400 MHz, CD3OD) δ 7.44 - 7.40 (m, 3H), 7.30 - 7.26 (m, 2H), 6.29 - 6.26 (m, 0.5H), 6.14 - 6.12 (m, 0.5H), 5.92 - 5.87 (m, 1H), 3.44 - 3.41 (m, 1H), 3.01 - 3.02 (m, 2H), 1.19 - 1.16 (m, 2H), 1.12 - 1.09 (m, 2H). LCMS RT= 0.849 min, m / z = 272.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.849 min, ESI+ found [M+H] = 272.0.

[0455] Method 14 Example 19

[0456] l-(6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)propan-l-one

[0457] Step 1: ethyl 3-(hydroxymethyl)-lH-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-lH- pyrazole-5-carboxylate

[0458] To a solution of prop-2-yn-l -ol (30.0 g, 535.14 mmol) in toluene (300 mL) was added ethyl 2- diazoacetate (67.2 g, 588.66 mmol). The reaction mixture was stirred at 110 °C for 5 h and cooled to room temperature. The crude product was collected by filtration and washed with 10% ethyl acetate in petroleum ether (50 mL) to afford a mixture of ethyl 4-(hydroxymethyl)-lH-pyrazole-5-carboxylate (15.8 g, 17%) and ethyl 3-(hydroxymethyl)-lH-pyrazole-5-carboxylate (not separable, 1 :3, 63.1 g, 69%) as light yellow solids, used as mixture in the next step. ethyl 3-(hydroxymethyl)-lH-pyrazole-5-carboxylate (major isomer): ¾ 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). ethyl 4-(hydroxymethyl)-lH-pyrazole-5-carboxylate (minor isomer)::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).

[0459]

[0460] Step 2:ethyl 3-(hydroxymethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole -5-carboxylate and ethyl 4-(hydroxymethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazole-5-carboxylate

[0461] A mixture of ethyl 3-(hydroxymethyl)-lH-pyrazole -5-carboxylate and ethyl 4-(hydroxymethyl)-lH- pyrazole-5-carboxylate (3 :1 , 4.0 g, 23.5 mmol), (2-(chloromethoxy)ethyl)trimethylsilane (11.2 mL, 70.5 mmol) and cesium carbonate (45.9 g, 141.0 mmol) in acetone (100 mL) was stirred at 25 °C for 3 h and then filtered. The filtrate was concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40%o ethyl acetate in petroleum ether) to afford ethyl 3-(hydroxymethyl)-l-((2-(trimethylsilyl) ethoxy)methyl)-lH-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5-carboxylate (not separable, 3.7g, 52%), used as mixture in the next step. LC-MS RT= 0.855 min, m / z = 322.9 (M+H)+. LCMS (5 to 95%> acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.855 min, ESI+ found [M+Na] = 322.9.

[0462] Step 3: Ethyl 3-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5-carboxylate

[0463] To a solution of ethyl 3-(hydroxymethyl)-l-((2-(trimethylsilyl)ethoxy)methyl) -lH-pyrazole-5- carboxylate and ethyl 4-(hydroxymethyl)-l -((2-(trimethylsilyl)ethoxy) methyl)-lH-pyrazole-5- carboxylate (2.0 g, 6.66 mmol) in dichloromethane (100 mL) was added manganese dioxide (7.0 g, 80.52 mmol). The mixture was stirred at 25 °C for 15 h and filtered. The filtrate was concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20%o ethyl acetate in petroleum ether) to afford ethyl 5-formyl-2-(2-trimethylsilyl ethoxymethyl)pyrazole-3-carboxylate (700 mg, 35%) as colorless oil. ¾ NMR (400MHz, CDC13) δ 10.02 (s, 1H), 7.38 (s, 1H), 5.94 (s, 2H), 4.40 (q, J= 8.0 Hz, 2H), 3.69 - 3.60 (m, 2H), 1.40 (t, J= 8.0 Hz, 3H), 0.98 - 0.89 (m, 2H), 0.02 - 0.07 (m, 9H).

[0464]

[0465] Step 4: (E)-ethyl 3-(3-oxo-3-phenylprop-l-en-l-yl)-lH-pyrazole-5-carboxylate

[0466] To a solution of ethyl 5-formyl-2-(2-trimethylsilylethoxymethyl) pyrazole-3-carboxylate (700 mg, 2.35 mmol) in dichloromethane (100 mL) was added trimethyl((l-phenylvinyl)oxy)silane (499 mg, 2.59 mmol) and titanium tetrachloride (875 mg, 4.61 mmol). The mixture was stirred at 40 °C for 48 h and then quenched by addition of water (50 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30%o ethyl acetate in petroleum ether) to afford (E)-ethyl 3-(3-oxo-3-phenylprop-l-en-l-yl)-lH-pyrazole-5- carboxylate (310 mg, 49%) as a yellow solid. LC-MS RT= 0.853 min, m / z = 270.9 (M+H)+.

[0467] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.853min, ESI+ found [M+H] = 270.9.

[0468] Step 5: ethyl 3-(3-hydroxy-3-phenylpropyl)-lH-pyrazole-5-carboxylate

[0469] A mixture of (E)-ethyl 3-(3-oxo-3-phenylprop-l-en-l-yl)-lH-pyrazole-5-carboxylate (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 h and then filtered. The filtrate was concentrated under reduce pressure to afford crude ethyl 3-(3-hydroxy -3-phenylpropyl)-lH-pyrazole-5-carboxylate (314 mg, 99%) as light yellow oil. This crude was used directly in next step without further purification.

[0470]

[0471] Step 6: ethyl 3-(3-chloro-3-phenylpropyl)-lH-pyrazole-5-carboxylate

[0472] To a solution of ethyl 3-(3-hydroxy-3-phenylpropyl)-lH-pyrazole-5-carboxylate (314 mg, 1.14 mmol) in acetonitrile (5 mL) was added sulfurous dichloride (681 mg, 5.72 mmol). The mixture was heated at 65 °C for 15 h and then concentrated under reduced pressure to afford crude ethyl 3-(3-chloro-3- phenyl-propyl)-lH-pyrazole -5-carboxylate (335 mg, 100%) as yellow oil. This crude was used directly in next step without further purification. LC-MS RT= 0.861 min, m / z = 314.9 (M+H)+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.861min, ESI+ found [M+H] = 314.9.

[0473]

[0474] Step 7: ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate

[0475] A mixture of ethyl 3-(3-chloro-3-phenyl-propyl)-lH-pyrazole-5-carboxylate (335 mg, 1.14 mmol) and cesium carbonate (3.0 g, 9.21 mmol) in acetonitrile (20 mL) was stirred at 15 °C for 15 h and then filtered. The filtrate was concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25%o ethyl acetate in petroleum ether) to afford ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate (120 mg, 41%) as light yellow oil. LC-MS RT= 0.824 min, m / z = 279.0 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.824 min, ESI+ found [M+H] = 279.0.

[0476] Step 8: 6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid

[0477] A mixture of ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate (60 mg, 0.23 mmol) and lithium hydroxide monohydrate (50 mg, 1.2 mmol) in tetrahydrofuran (5 mL), methanol (5 mL) and water (2 mL) was stirred at 25 °C for 3 h and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by additional of hydrochloric acid (2 N). 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 afford crude 6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b] pyrazole-2-carboxylic acid (30 mg, 56%) as a yellow solid, used as is in the next step.

[0478]

[0479] Step 9: N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxamide

[0480] A mixture of 6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid (30 mg, 0.13 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (17 mg, 0.17 mmol), l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (65 mg, 0.17 mmol), N,N- diisopropylethylamine (42 mg, 0.33 mmol) in tetrahydrofuran (5 mL) was stirred at 25 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50%o ethyl acetate in petroleum ether) to afford N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo [l,2-b]pyrazole-2-carboxamide (25 mg, 70%) as a white solid. LC-MS RT= 0.952 min, m / z = 272.1 (M+H)+. LCMS (10 to 80% acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 0.952 min, ESI+ found

[0481]

[0482] Step 10: l-(6-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)propan-l-one

[0483] To a cooled (-78 °C) solution of N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazole-2-carboxamide (24 mg, 0.09 mmol) in tetrahydrofuran (5 mL) was added ethylmagnesium chloride (3.0 M in THF, 0.07 mL, 0.21 mmol) dropwise under a nitrogen atmosphere. The mixture was stirred at -78°C for 2 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford l-(6-phenyl-5,6- dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)propan-l-one (13.0 mg, 61 %) as a white solid.1H NMR (400 MHz, CD3OD) δ 7.39 - 7.30 (m, 3H), 7.11 - 7.09 (m, 2H), 6.60 (s, 1H), 5.54 - 5.50 (m, 1H), 3.11 - 3.01 (m, 3H), 2.95 - 2.89 (m, 2H), 2.52 - 2.48 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H). LC-MS RT= 1.858 min, m / z = 241.2 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o ammonium bicarbonate over 3.0 mins) retention time 1.858 min, ESI+ found [M+H] = 214.2.

[0484]

[0485] Example 20 Example 21

[0486] l-[(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-yl]propan-l-one and 1- [(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4]oxazin-2-yl]propan-l-one

[0487] To a cooled (-78 °C) solution of 4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4]oxazine-2- carboxylate (200 mg, 0.63 mmol) in tetrahydrofuran (13 mL) was added ethylmagnesium chloride (2 M in THF, 0.63 mL, 1.26 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30%o ethyl acetate in petroleum ether) to give l-[4-(2-fluorophenyl)- 6,7-dihydro-4H-pyrazolo[5,l -c] [l,4]oxazin-2-yl]propan-l -one (120 mg, 70%o) as a white solid. This racemic material was further separated by chiral SFC to afford arbitrarily assigned:

[0488] 1 -[(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,l -c] [1 ,4]oxazin-2-yl]propan-l -one (Peak 1 , retention time = 2.979 min) (45.0 mg, 37%) as a white solid. Η NMR (400 MHz, CD3OD) δ 7.40 - 7.34 (m, 2H), 7.16 - 7.14 (m, 2H), 6.22 (s, 1H), 6.07 (s, 1H), 4.42 - 4.18 (m, 4H), 2.96 - 2.92 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). LC-MS RT= 1.761 min, m / z = 275.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03%o ammonium bicarbonate over 3.0 mins) retention time 1.761 min, ESI+ found [M+H] = 275.2. l-[(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5, l-c] [l,4]oxazin-2-yl]propan-l-one (Peak 2, retention time = 3.234 min) (52 mg, 43%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.40 - 7.34 (m, 2H), 7.16 - 7.14 (m, 2H), 6.22 (s, 1H), 6.08 (s, 1H), 4.41 - 4.15 (m, 4H), 3.00 - 2.92 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). LC-MSRT= 1.755 min, m / z = 275.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03%o ammonium bicarbonate over 3.0 mins) retention time 1.752 min, ESI+ found [M+H] = 275.2.

[0489] SFC condition: Column: ChiralPak AD-3 150x4.6mm I.D., 3μηι Mobile phase: A: C02B:Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min Flow rate: 2.5 mL / min, Column temperature: 40 °C .

[0490] Example 22

[0491] 3-(rac-(5S,7S)-7-fluoro-5^henyl-6 -dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-2,2-dimethyl- 3-oxo-propanenitrile

[0492]

[0493] Step 1 : cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-3- oxopropanenitrile

[0494] To a cooled (-78 °C) solution of acetonitrile (298 mg, 7.27 mmol) in tetrahydrofuran (15 mL) was added potassium t-butoxide (611.4 mg, 5.45 mmol). After stirring for 30 min, ethyl cis-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole -2-carboxylate (500 mg, 1.82 mmol) in tetrahydrofuran (5 mL) was added dropwise. After addition, the mixture was stirred at -78 °C for 2 h and then quenched by slow addition of cold saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure to give crude cis-3-(7-fluoro-5-phenyl -6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-3-oxo-propanenitrile (150 mg, 31%o) as a white solid, used as is in the next step.

[0495] Step 2: 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-2,2- dimethyl-3-oxo-propanenitrile

[0496] To a cooled (0 °C) solution of cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol- 2-yl)-3-oxo-propanenitrile (140 mg, 0.52 mmol) in N,N-dimethylformamide (6 mL) was added cesium carbonate (422 mg, 1.30 mmol). After stirred for 30 min, iodomethane (2800 mg, 19.7 mmol) was added and the reaction mixture was stirred at 0 °C for 4 h. The mixture was then quenched by addition of cold saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hyfroxide in water) to afford 3-(rac- (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-2,2-dimethyl-3-oxo- propanenitrile (28.0 mg, 17%) as a white solid. ¾ NMR (400 MHz, CDC13) δ 7.44 - 7.38 (m, 3H), 7.27 - 7.25 (m, 2H), 6.15 - 6.13 (m, 0.5H), 6.01 - 5.99 (m, 0.5H), 5.57 - 5.56 (m, 1H), 3.74 - 3.63 (m, 1H), 3.06 - 2.95 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H). LC-MS RT= 1.734 min, m / z = 299.2 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o ammonium bicarbonate over 3.0 mins) retention time 1.734 min, ESI+ found [M+H] = 299.2.

[0497]

[0498] Example 23 Example 24

[0499] l-[(4S)-4-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl]propan-l-one and l-[(4R)-4- phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl]propan-l-one

[0500]

[0501] Step 1: N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2- carboxamide A mixture of 4-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid (93 mg, 0.41 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (80 mg, 0.81 mmol), l-[bis(dimethylamino)methylene]- l H-l,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 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (10% methanol in dichloromethane, Rf= 0.7) to afford N-methoxy-N-methyl -4-phenyl-5,6- dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxamide (100 mg, 91%) as a colorless oil. LCMS RT= 0.593 min, m / z = 272.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.593 min, ESI+ found [M+H] = 272.1.

[0502]

[0503] Step 2:

[0504] l-[(4S)-4-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl]propan-l-one and l-[(4R)-4- phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl]propan-l-one

[0505] To a cooled (-78 °C) solution of N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H- pyrrolo[l,2- b]pyrazole-2-carboxamide (100 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added ethylmagnesium chloride (2.7 M in THF, 0.54 mL, 1.47 mmol) dropwise under nitrogen atmosphere.

[0506] After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 15 mL).

[0507] The combined organic layers were concentrated under reduce pressure to afford crude 1 -(4-phenyl- 5,6-dihydro-4H-pyrrolo[l ,2-b]pyrazol-2-yl)propan-l-one (80 mg, 90%o) as a light brown solid which was further separated by chiral SFC to afford arbitrarily assigned:

[0508] (R)-l-(4-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)propan-l-one (Peak 1, retention time = 2.581 min) (25.4 mg, 32%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.32 - 7.21 (m, 5H), 6.43 (s, 1H), 4.50 - 4.37 (m, 1H), 4.36 - 4.33 (m, 1H), 4.24 - 4.22 (m, 1H), 3.13 - 3.10 (m, 1H), 2.99 - 2.95 (m, 2H), 2.57 - 2.53 (m, 1H), 1.15 (t, J= 7.2 Hz, 3H). LCMS RT= 0.843 min, m / z = 240.9 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.843 min, ESI+ found [M+H] = 240.9. (S)-l-(4-phenyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)propan-l-one (Peak 2, retention time = 2.968 min) (22.7 mg, 28%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.35 - 7.22 (m, 5H), 6.43 (s, 1H), 4.51 - 4.38 (m, 1H), 4.37 - 4.33 (m, 1H), 4.25 - 4.22 (m, 1H), 3.14 - 3.12 (m, 1H), 3.02 - 2.96 (m, 2H), 2.58 - 2.54 (m, 1H), 1.16 (t, J= 12 Hz, 3H). LCMS RT= 0.838min, m / z = 241.0 [M + H] . LCMS (5 to 95% acetonitrile in water + 0.03%> trifluoacetic acid over 1.5 mins) retention time 0.838 min, ESI+ found [M+H] = 241.0.

[0509] SFC condition: Column: Chiralpak AD (250mm*30mm, 5μιη); Condition: 0.1 %NH3H2O iPrOH; Begin B 15% End B 15%; Flow Rate (60 mL / min), Column temperature 40 °C.

[0510] Method 18

[0511]

[0512] 1- (rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-2-hydroxy-2- methyl-propan-l-one

[0513] To a solution of l -[cis-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l ,2,4]triazol-2-yl]-

[0514] 2- methyl-propan-l -one (50 mg, 0.18 mmol) in dimethyl sulfoxide (4 mL) was added l -bromo-2,5- pyrrolidinedione (33 mg, 0.18 mmol). The mixture was heated at 100 °C for 15 h under air. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%o / 0.05%o ammonia hydroxide in water) and further by preparative TLC (ethyl acetate, Rf= 0.6) to afford l -(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2- b] [l ,2,4]triazol -2-yl)-2-hydroxy-2-methyl-propan-l-one (48.6 mg, 91 %o) as a white solid.lH NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.27 - 7.25 (m, 2H), 6.20 - 6.03 (m, 1H), 5.66 - 5.57 (m, 1H), 3.79 - 3.71 (m, 1H), 2.87 - 2.77 (m, 1H), 1.60 (s, 3H), 1.56 (s, 3H). LC-MS RT= 0.771 min, m / z = 290.1 (M+H)+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.771 min, ESI+ found [M+H] = 290.1.

[0515] Method 19

[0516]

[0517] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-(l- methylcyclopropyl)methanone

[0518] Step 1: cis-l-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl) -2- methylprop-2-en-l-one

[0519] A mixture of cis-l-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][ 1,2,4] triazol-2-yl)propan-l-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 min 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-l -one (52 mg, 41%) as a white solid. LC-MS RT= 1.020 min, m / z = 272.1 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03%o trifluoroacetic acid over 2 mins) retention time 1.020 min, ESI+ found [M+H] =

[0520]

[0521] Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-(l- methylcyclopropyl)methanone

[0522] To a mixture of diethylzinc (123 mg, 1.00 mmol) and nickel chloride (8 mg, 0.07 mmol) in dichloromethane (5 mL) was added diiodomethane (355 mg, 1.33 mmol) at 0 °C. After stirred for 30 min, 1 -(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1 ,2-b] [1 ,2,4]triazol-2-yl)-2-methyl-prop-2-en-l - one (90 mg, 0.33 mmol) was added and the reaction mixture was stirred at 0 °C for 2 h. The mixture was quenched by addition of cold saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 25-55%o / 0.05%o HCl in acetonitrile) to afford (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-( l - methylcyclopropyl)methanone (3.0 mg, 3%) as a white solid. H NMR (400 MHz, CD3OD) δ 7.41 - 7.37 (m, 3H), 7.24 - 7.23 (m, 2H), 6.15 - 6.13 (m, 0.5H), 6.01 - 5.99 (m, 0.5H), 5.60 - 5.59 (m, 1H), 3.76 - 3.68 (m, 1H), 2.84 - 2.74 (m, 1H), 1.82 - 1.76 (m, 2H), 1.41 (s, 3H), 0.97 - 0.92 (m, 2H). LCMS RT= 1.068 min, m / z = 286.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid over 2 mins) retention time 1.068 min, ESI+ found [M+H] = 286.1.

[0523] Example 27 Example 28

[0524] l-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-yl]propan-l-one & l-[(4R)-4- phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4]oxazin-2-yl]propan-l-one

[0525]

[0526] Step 1: N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c][l,4] oxazine-2- carboxamide

[0527] A mixture of 4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazine-2-carboxylic acid (156 mg, 0.64 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (125 mg, 1.28 mmol), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (291.42 mg, 0.77 mmol) and triethylamine (258 mg, 2.55 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15 °C for 2 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (10% methanol in dichloromethane, Rf= 0.7) to afford N-methoxy-N-methyl-4- phenyl-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazine-2-carboxamide (80 mg, 43.6%) as colorless oil.

[0528]

[0529] Step 2: l-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-yl]propan-l-one & 1- [(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4]oxazin-2-yl]propan-l-one

[0530] To a cooled (-78 °C) solution of N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H- pyrazolo[5,l- c][l,4]oxazine-2-carboxamide (60 mg, 0.21 mmol) in tetrahydrofuran (6 mL) was added dropwise with ethylmagnesiumchloride (2.7 M in THF, 0.39 mL, 1.04 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure to afford crude racemic product, which was further separated by chiral SFC to afford arbitrarily assigned: l-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l -c] [l,4]oxazin-2-yl]propan-l-one (Peak 1, retention time = 3.254 min) (11.5 mg, 21%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.39 - 7.37 (m, 5H), 6.21 (s, 1H), 5.82 (s, 1H), 4.42 - 4.36 (m, 2H), 4.30 - 4.28 (m, 1H), 4.21 - 4.18 (m, 1H), 3.00 - 2.95 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). LCMS RT= 1.026 min, m / z = 257.1 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2 mins) retention time 1.026 min, ESI+ found [M+H] = 257.1. l-[(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4]oxazin-2-yl]propan-l-one (Peak 2, retention time = 4.381 min) (13.6 mg, 25%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.39 - 7.37 (m, 5H), 6.21 (s, 1H), 5.82 (s, 1H), 4.42 - 4.36 (m, 2H), 4.31 - 4.25 (m, 1H), 4.21 - 4.19 (m, 1H), 3.00 - 2.92 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). LCMS RT= 1.023 min, m / z = 257.1 [M + H]+LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2 mins) retention time 1.023 min, ESI+ found [M+H] = 257.1.

[0531] SFC condition: Column: OD (250mm*30mm^m); Condition: 0.1 %NH3H2O EtOH; Begin B: 30% ; End B: 30%o; Flow Rate(60 mL / min), Column temperature 40 °C.

[0532] Method 21

[0533] Example 29

[0534] 3,3,3-trffluoro-l-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yl)propan-l-one

[0535]

[0536] Step 1: l-cis-7-fluoro-5-phenyl-2-(l-((trimethylsilyl)oxy)vinyl)-6,7-dihydro-5H- pyrrolo [1,2- b][l,2,4]triazole

[0537] To a solution of l-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4] triazol-2-yl)ethanone (200 mg, 0.82 mmol) in 1,4-dioxane (6 mL) was added triethylamine (165 mg, 1.63 mmol) and trimethylsilyl trifluoromethanesulfonate (254 mg, 1.14 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h and quenched by addition of cold saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure to give crude l -(cis-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l ,2-b] [l ,2,4]triazol-2-yl)vinyloxy-trimethyl-silane (245 mg, 95%) as light yellow oil.lH NMR (400 MHz,CDCl3) δ 7.17 - 7.10 (m, 3 H), 6.98 - 6.96 (m, 2 H), 5.79 - 5.78 (m, 0.5 H), 5.65 - 5.64 (m, 0.5 H), 5.21 - 5.17 (m, 2 H), 4.40 (s, 1 H), 4.49 (s, 1 H), 3.37 - 3.27 (m, 1 H), 2.66 - 2.56 (m, 1 H), 0.03 (s, 9 H).

[0538]

[0539] Step 2: 3,3,3-trffluoro-l-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2- b][l,2,4]triazol-2-yl)propan-l-one

[0540] A mixture of l -trifuloromethyl-l ,2-benziodoxol-3(lH)-one (418 mg, 1.32 mmol), l -(cis-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l ,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 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55% / 0.05%o HC1 in acetonitrile) to afford 3,3,3-trifluoro-l -(rac-(5R,7R)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazol-2-yl)propan-l -one (31mg, 15%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.40 - 7.37 (m, 3H), 7.28 - 7.26 (m, 2H), 6.19 - 6.17 (m, 0.5H), 6.05 - 6.03 (m, 0.5H), 5.65 - 5.63 (m, 1H), 4.09 - 4.01 (m, 2H), 3.78 - 3.29 (m, 1H), 2.89 - 2.77 (m, 1H). LC-MS RT= 1.072 min, m / z = 314.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 2.0 mins) retention time 1.072 min, ESI+ found [M+H] = 314.1.

[0541] Example 30

[0542] l-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l-one

[0543] To a cooled (-78°C) solution of ethyl (S)-5-phenyl-6,7-dihydro-5H-pyrrolo [l ,2-b][l ,2,4]triazole-2- carboxylate (200 mg, 0.78 mmol) in tetrahydrofuran (20 mL) was added ethylmagnesium chloride (3.0 M in THF, 0.58 mL, 1.74 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 1- [(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4] triazol-2-yl]propan-l-one (60 mg, 32%) as a white solid. Ή NMR (400 MHz, CDC13) δ 7.42 - 7.32 (m, 3H), 7.12 - 7.10 (m, 2H), 5.49 (dd, J = 5.6, 8.4 Hz, 1H), 3.31 - 3.21 (m, 1H), 3.17 - 3.01 (m, 4H), 2.72 - 2.64 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). LCMS RT= 1.523 min, m / z = 242.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1% ammonia water over 3.0 mins) retention time 1.523 min, ESI+ found [M+H] = 242.2.

[0544] Example 31

[0545] l-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l-one

[0546] To a cooled (-70 °C) solution of ethyl 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylate (496 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was added ethylmagnesium chloride (2.7 M in THF, 1.33 mL, 3.6 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous 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 reduce pressure to afford crude racemic product, which was further purified by chiral SFC and RP-HPLC (acetonitrile 25-55%o / 0.05%o ammonia hydroxide in water) to afford arbitrarily assigned:

[0547] l-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l ,2-b] [ l,2,4]triazol-2-yl]propan-l-one (Peak 2, retention time = 3.038 min) (17 mg, 8%) as white solids. ¾ NMR (400 MHz, CD3OD) δ 7.45 - 7.35 (m, 1H), 7.20 - 7.12 (m, 3H), 5.80 - 5.75 (m, 1H), 3.30 - 3.28 (m, 1H), 3.15 - 3.05 (m, 2H), 3.01 - 2.97 (m, 2H), 2.72 - 2.66 (m, 1H), 1.12 (t, J =7.2 Hz, 3H). LCMS RT= 0.977 min, m / z = 260.1 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.977 min, ESI+ found [M+H] = 260.1.

[0548] SFC condition: Column: OJ(250mm*30mm^m); Condition: 0.1%NH3H2O EtOH; Begin B: 20% ; End B: 20%o; Flow Rate(60 mL / min), Column temperature 40 °C.

[0549] o-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l-one

[0550] Step 1 : (E)-methyl 4-phenylbut-3-enoate

[0551] To a solution of (E)-4-phenylbut-3-enoic acid (15.0 g, 92.48 mmol) in methanol (60 mL) was added sulfuric acid (2.3 g, 23.12 mmol). The mixture was heated at 90 °C for 18 h and cooled. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water (30 mL), aqueous saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried and concentrated under reduce pressure to afford crude methyl (E)-4- phenylbut-3-enoate (14.8 g, 91%) as light oil, used as is in the next step. ¾ NMR (400MHz, CDC13) - 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).

[0552] Step 2: methyl 2-(3-phenyloxiran-2-yl)acetate

[0553] To a mixture of methyl (E)-4-phenylbut-3-enoate (14.8 g, 84.0 mmol) and sodium bicarbonate (34.4 g, 409.0 mmol) in acetone (300 mL) was added a solution of potassium monoper sulfate triple salt (67.1 g, 109.2 mmol) in water (80 mL) dropwise at 0 °C. After addition, the resulting mixture was allowed to warm to 25 °C and stirred for 4 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to afford methyl 2-(3-phenyloxiran-2-yl) acetate (15.0 g, 93%) as colorless oil. LC-MS RT= 0.799 min, m / z = 233.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.799 min, ESI+ found [M+H] = 233.9.

[0554] Step 3: methyl (rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate

[0555] To a solution of methyl 2-(3-phenyloxiran-2-yl)acetate (15.0 g, 78.0 mmol) in acetonitrile (400 mL) was added lithium bromide (6.8 g, 78.0 mmol) and magnesium perchlorate (1.7 g, 78.0 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h and diluted with dichloromethane (100 mL). The resulting mixture was washed with hydrochloric acid (IN, 100 mL). The separated aqueous layer was washed with dichloromethane (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure to give crude methyl (rac-3R,4S)-4-bromo-3-hydroxy-4- phenylbutanoate (20.0 g, 94%) as colorless oil. The crude was used in the next step without further purification. LC-MS RT= 0.610 min, m / z = 256.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03 % trifluoacetic acid over 1.5 mins) retention time 0.610 min, ESI+ found [M+H] = 256.9.

[0556] Step 4: methyl (rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate

[0557] A mixture of methyl (rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate (20.0 g, 73.2 mmol) and sodium azide (14.3 g, 219.7 mmol) in N,N-dimethylformamide (500 mL) was stirred at 20 °C for 16 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude methyl (rac-3R,4R)-4-azido-3-hydroxy -4- phenylbutanoate (17.0 g, 99%) as yellow oil. LC-MS RT= 0.978 min, m / z = 208.3 [M + H]+.

[0558] LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time

[0559] [M+H] = 208.3.

[0560] Step 5: methyl (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate

[0561] A mixture of methyl (rac-3R,4R)-4-azido-3 -hydroxy -4-phenylbutanoate (17.0 g, 72.3 mmol) and palladium (10%o on carbon, 7.7 g) in ethyl acetate (800 mL) was hydrogenated (15 psi) at 25 °C for 24 h and then filtered. The filtrate was concentrated under reduced pressure to give crude methyl (rac- 3R,4R)-4-amino -3-hydroxy-4-phenylbutanoate (15.0 g, 99%o) as colorless oil. The crude was used in the next step without further purification. LC-MS RT= 0.315 min, m / z = 210.2 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 0.315 min, ESI+ found [M+H] = 210.2.

[0562] Step 6: cis-4-hydroxy-5-phenylpyrrolidin-2-one

[0563] A solution of methyl (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate (15.0 g, 71.7 mmol) in methanol (200 mL) was heated at 50 °C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5%> methanol in dichloromethane) to afford cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g, 76%o) as a white solid. ¾ NMR (400 MHz, CDC13) δ 7.45 - 7.26 (m, 5H), 6.39 (br s, 1H), 4.89 - 4.87 (m, 1H), 4.66 - 4.48 (m, 1H), 2.80 - 2.62 (m, 1H), 2.53 - 2.30 (m, 1H). LC-MS RT= 0.678 min, m / z = 178.2 [M + H]+.

[0564] LCMS (0 to 60%o acetonitrile in water + 0.03 %> trifluoacetic acid over 2.0 mins) retention time 0.678 min, ESI+ found [M+H] = 178.2.

[0565] Step 7 : cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

[0566] To a solution of cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g, 54.2 mmol) in dichloromethane (300 mL) was added imidazole (11.1 g, 162.5 mmol) and tert-butyldimethylsilyl chloride (16.3 g, 108.4 mmol). The resulting mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford cis-4-((tert-butyldimethylsilyl)oxy)-5-phenyl pyrrolidin-2-one (10.0 g, 63%) as a white solid. LC-MS RT= 1.257 min, m / z = 292.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 1.257 min, ESI+ found [M+H] = 292.3.

[0567] Step 8: cis-l-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

[0568] 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) was added sodium hydride (60%o, 2.1 g, 51.5 mmol) at 0 °C. After stirring at 0 °C for 30 min, (aminooxy)diphenylphosphine oxide (12.0 g, 51.47 mmol) was added portion-wise. The resulting mixture was stirred at room temperature for 12 h and filtered. The filtrate was concentrated under reduced pressure to give crude cis-l-amino-4-((tert-butyldimethylsilyl)oxy)- 5-phenylpyrrolidin-2-one (9.0 g, 86%o) as a brown solid. This crude was used in the next step without further purification. LC-MS RT= 1.225 min, m / z = 307.4 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 1.225 min, ESI+ found [M+H] = 307.4.

[0569]

[0570] Step 9: ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin -l-yl)amino) -2- imino acetate

[0571] A mixture of cis-l-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (9.0 g, 29.4 mmol) and ethyl 2-ethoxy-2-imino-acetate (21.3 g, 146.8 mmol) in toluene (500 mL) was heated at 90 °C for 18 h and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were concentrated under reduce pressure to afford crude ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy) -5-oxo-2- phenylpyrrolidin-l-yl)amino)-2-iminoacetate (10.0 g, 84%) as a brown oil. LC-MS RT= 1.128 min, m / z = 406.4 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 2.0 in, ESI+ found [M+H] = 406.4.

[0572]

[0573] Step 10: ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylate

[0574] A mixture of ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2 -phenyl pyrrolidin-l-yl)amino)-2- iminoacetate (10.0 g, 24.7 mmol) and 4-methylbenzenesulfonic acid hydrate (4.7 g, 24.7 mmol) in toluene (300 mL) was heated at 120 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20%o ethyl acetate in petroleum ether) to afford ethyl cis-6-((tert-butyldimethylsilyl)oxy) -5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylate (5.5 g, 58%) as brown oil. LC-MS RT= 1.345 min, m / z = 388.4 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time

[0575] [M+H] = 388.4.

[0576]

[0577] Step 11 : ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [1,2,4] triazole-2- carboxylate

[0578] To a solution of tetrabutylammonium fluoride (18.5 g, 70.9 mmol) in tetrahydrofuran (200 mL) was added ethyl cis-6-((tert-butyldimethylsilyl)oxy) -5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylate (5.5 g, 14.2 mmol). The resulting mixture was stirred at 25 °C for 16 h and diluted with ethyl acetate (300 mL). The mixture was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50%o ethyl acetate in petroleum ether) to afford ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l ,2,4]triazole-2- carboxylate (1.8 g, 46%) as a yellow solid. LC-MS RT= 1.036 min, m / z = 21 A3 [M + H]+. LCMS (0 to 60%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 1.036 min, ESI+ found [M+H] = 274.3.

[0579] rans m x ure

[0580] Step 12: ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [1,2,4] triazole-2- carbox late

[0581] To a solution of ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2- carboxylate (1.0 g, 3.66 mmol) in dichloromethane (50 mL) was added diethylaminosulfur trifluoride (10.0 g, 62.0 mmol) dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 h and then quenched by slow addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylate (400 mg, 40%) as a white solid. Ή NMR (400MHz, CDC13) δ 7.41 - 7.24 (m, 3H), 6.92 - 6.89 (m, 2H), 5.70 - 5.55 (m, 1H), 5.62 - 5.48 (m, 1H), 4.49 - 4.34 (m, 2H), 3.52 - 3.35 (m, 1H), 3.35 - 3.15 (m, 1H), 1.40 - 1.36 (m, 3H). LC-MS RT= 0.958 min, m / z = 276.2 [M + H]+

[0582] LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 0.958

[0583] ] = 276.2.

[0584]

[0585] Step 13: l-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yl]propan-l-one

[0586] To a cooled (-78°C) solution of ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2- b][l,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) in tetrahydrofuran (5 mL) was added ethylmagnesium chloride (3.0 M in THF, 0.25 mL, 0.75 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50%o ethyl acetate in petroleum ether) to afford arbitrarily assigned l-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2- b][l,2,4]triazol-2-yl]propan-l-one (13.6 mg, 45%) as a yellow solid. Ή NMR (400 MHz, CDC13) δ 7.34 - 7.31 (m, 3H), 6.90 - 6.87 (m, 2H), 5.63 - 5.61 (m, 0.5H), 5.59 - 5.57 (m, 1H), 5.46 - 5.44 (m,

[0587] 0.5H), 3.42 - 3.28 (m, 1H), 3.26 - 3.21 (m, 1H), 3.03 - 3.01 (m, 2H), 1.16 (t, J= 7.2 Hz, 3H). LCMS RT= 0.977 min, m / z = 260.1 [M + H] . LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 2.0 mins) retention time 0.977 min, ESI+ found [M+H] = 260.1.

[0588] Example 33

[0589] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-(2- pyridyl)methanone

[0590] To a solution of 2-bromopyridine (435 mg, 2.76 mmol) in tetrahydrofuran (20 mL) was added n- butyllithium (2.5 M in hexanes, 1.10 mL, 2.76 mmol) at -78 °C. After addition, the mixture was allowed to warm to 30 °C and stirred for 2 h. The mixture was cooled to -78 °C and cis-7-fluoro-N- methoxy-N-methyl -5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l,2,4]triazole-2-carboxamide (200 mg, 0.69 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at -78 °C for 6 h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 25-55%o / 0.05%o ammonia hydroxide in water) to afford (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl)-(2-pyridyl)methanone (32.0 mg, 15%) as a white solid. H NMR (400 MHz, DMSO-i / 6) δ 8.69 - 8.65 (m, 1H), 8.00 - 7.90 (m, 2H), 7.62 - 7.59 (m, 1H), 7.42 - 7.30 (m, 3H), 7.25 - 7.20 (m, 2H), 6.30 - 6.22 (m, 0.5H), 6.18 - 6.14 (m, 0.5H), 5.75 - 5.55 (m, 1H), 3.77 - 3.67 (m, 1H), 2.74 - 2.45 (m, 1H). LCMS: RT= 1.510 min, m / z = 309.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1 %> ammonia water over 3.0 mins) retention time 1.510 min, ESI+ found [M+H] = 309.1.

[0591] Method 26

[0592]

[0593] Example 34 Example 35 cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yl]methanone and cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0594] Example 42

[0595] Step 1 : cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol- 2-yl)methanone

[0596] To a cooled (-78 °C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2- b][l,2,4]triazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (4 mL) was added cyclopropylmagnesium bromide (0.5 M in THF, 1.45 mL, 0.73 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h, and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hydroxide in water) to afford cis racemic cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [1,2,4] triazol-2-yl)methanone (15 mg, 10%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.45 - 7.35 (m, 3H), 7.27 - 7.25 (m, 2H), 6.18 - 6.15 (m, 0.5H), 6.05 - 6.00 (m, 0.5H), 5.65 - 5.60 (m, 1H), 3.77 - 3.65 (m, 1H), 3.05 - 2.95 (m, 1H), 2.90 - 2.70 (m, 1H), 1.17 - 1.13 (m, 2H), 1.10 - 1.05 (m, 2H). LCMS RT= 1.031 min, m / z = 272.3 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 2.0 mins) retention time 1.031 min, ESI+ found [M+H] = 272.3.

[0597]

[0598] Step 2: cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [1,2,4] triazol-2- yljmethanone and cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0599] The 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 afford arbitrarily assigned: cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-^

[0600] (Peak 1, retention time = 3.575 min) (25.5 mg, 24%) as a white solid.

[0601] Ή NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.29 - 7.27 (m, 2H), 6.19 (d, J = 5.6 Hz, 0.5H), 6.05 (d, J= 5.2 Hz, 0.5H), 5.66 - 5.62 (m, 1H), 3.79 - 3.71 (m, 1H), 3.05 - 3.02 (m, 1H), 3.01 - 2.81 (m, 1H), 1.29 - 1.09 (m, 4H). LCMS RT= 0.816 min, m / z = 271.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.816 min, ESI+ found [M+H] = 271.9. cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H^yrrolo[l,2-b][l ,2,4]triazol-2-yl]methanone (Peak 2, retention time = 3.849 min) (18.5 mg, 17%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.44 - 7.27 (m, 5H), 6.20 - 6.17 (m, 0.5H), 6.06 - 6.03 (m, 0.5H), 5.66 - 5.64 (m, 1H), 3.79 - 3.71 (m, 1H), 3.05 - 3.02 (m, 1H), 3.01 - 2.81 (m, 1H), 1.19 - 1.09 (m, 4H). LCMS RT= 0.817 min, m / z = 271.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.817 min, ESI+ found [M+H] = 271.9.

[0602] SFC condition: Column: Chiralpak AD (250 mm*30 mm, 10 μιη); Condition: 0.1%NH3H2O iPrOH; Begin B 25%o End B 25%o; Flow Rate (60 mL / min), Column temperature 40 °C.

[0603] Method 27

[0604] Example 36

[0605] cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yl)methanone

[0606]

[0607] Step 1: cyclopentyl-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol -2- yl)methanol

[0608] Cyclopentylmagnesium bromide (1 M in THF, 0.73 mL, 0.73 mmol) was added dropwise to a stirred and cooled (-78 °C) solution of cis-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole-2- carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere. After addition, the mixture was stirred at 25 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure to afford crude cis-cyclopentyl(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl)methanol (100 mg, 91%) as a white solid. LCMS RT= 0.611 min, m / z = 302.1 [M + H]+.

[0609] LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.611 min, ESI+ found [M+H] = 302.1.

[0610]

[0611] Step 2: cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol- 2-yl)methanone

[0612] To a solution of cis-cyclopentyl(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [l,2-b][l,2,4]triazol-2- yl)methanol (100 mg, 0.33 mmol) in dichloromethane (15 mL) was added manganese dioxide (288 mg, 3.32 mmol). The reaction mixture was stirred at 35 °C for 2 h and then filtered through a short pad of Celite. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (40%> ethyl acetate in petroleum ether) to afford cyclopentyl-(rac-(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)methanone (18.2 mg, 18%o) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.44 - 7.40 (m, 3H), 7.28 - 7.26 (m, 2H), 6.19 - 6.17 (m, 0.5H), 6.05 - 6.03 (m, 0.5H), 5.64 - 5.63 (m, 1H), 3.89 - 3.68 (m, 2H), 2.88 - 2.75 (m, 1H), 2.02 - 1.60 (m, 8H). LCMS RT= 2.070 min, m / z = 300.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoacetic acid over 3.0 mins) retention time 2.070 min, ESI+ found [M+H] = 300.2.

[0613] Method 28

[0614] Example 41

[0615] (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)-(2- thienyl)methanone

[0616] To a cooled (-78 °C) solution of 2-iodothiophene (289 mg, 1.38 mmol) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (2.5 M in hexanes, 0.55 mL, 1.38 mmol) under N2atmosphere. The mixture was stirred at -78 °C for 1 h, then cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7- dihydro-5H-pyrrolo[l,2-b] [l,2,4] triazole-2-carboxamide (100 mg, 0.34 mmol) in tetrahydrofuran (2 mL) was added. The mixture was stirred at -78 °C for another 2 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 40-70% / 0.05% hydrochloride in water) to afford (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[ l,2-b] [l,2,4]triazol-2-yl)-(2- thienyl)methanone (15.6 mg, 14%) as a white solid. H NMR (400 MHz, CD3OD) δ 8.50 - 8.49 (m, 1H), 7.96 - 7.94 (m, 1H), 7.49 - 7.35 (m, 3H), 7.35 - 7.27 (m, 2H), 7.26 - 7.20 (m, 1H), 6.24 - 6.22 (m, 0.5H), 6.10 - 6.08 (m, 0.5H), 5.74 - 5.68 (m, 1H), 3.86 - 3.72 (m, 1H), 2.91 - 2.79 (m, 1H). LCMS RT= 0.891 min, m / z = 314.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.891 min, ESI+ found [M+H] = 314.1.

[0617] Method 29

[0618]

[0619] cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yljmethanone

[0620] To a cooled (0 °C) mixture of magnesium (234 mg, 9.65 mmol), iodine (12 mg, 0.05 mmol), 1,2- dibromoethane (0.1 mL, 0.10 mmol) in tetrahydrofuran (15 mL) was added dropwise with bromocyclobutane (0.5 mL, 5.85 mmol) under N2atmosphere. The mixture was stirred at 35 °C for about lh. The above freshly prepared cyclobutylmagnesium bromide solution (1.0 mL, 0.39 mmol) was added dropwise to a stirred and cooled (-78 °C) solution of c«-7-fluoro-N-methoxy-N-methyl-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxamide (28 mg, 0.10 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at -78 °C for 1 h, and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 42-62%o / 0.05%o hydrochloride in water) to afford cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l,2-b] [ l,2,4]triazol-2- yl]methanone (2 mg, 7%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.40 - 7.30 (m, 3H), 7.25 - 7.21 (m, 2H), 6.15 - 6.10 (m, 0.5H), 6.01 - 5.95 (m, 0.5H), 5.60 - 5.55 (m, 1H), 4.15 - 4.07 (m, 1H), 3.74 - 3.65 (m, 1H), 2.80 - 2.70 (m, 1H), 2.35 - 2.20 (m, 3H), 2.20 - 2.15 (m, 1H), 2.12 - 2.00 (m, 1H), 1.90 - 1.85 (m, 1H). LCMS RT= 0.883 min, m / z = 286.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.883 min, ESI+ found [M+H] = 286.0.

[0621] Method 30

[0622] Example 44

[0623] l-(rac-(5S,7S)-7-fluoro-5^henyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-2,2-dimethyl- propan-l-one

[0624] To a cooled (-78 °C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2- b][l,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) in tetrahydrofuran (3 mL) was added tert- butyllithium (1.3 M in pentane, 0.17 mL, 0.22 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h, and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 45-75% / 0.05% hydrochloride in water) to afford l-(rac-(5S,7S)- 7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-2,2-dimethyl-propan-l-one (12.7 mg, 40%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.42 - 7.36 (m, 3H), 7.36 - 7.23 (m, 2H), 6.16 - 6.13 (m, 0.5H), 6.02 - 5.99 (m, 0.5H), 5.65 - 5.61 (m, 1H), 3.77 - 3.68 (m, 1H), 2.85 - 2.73 (m, 1H), 1.35 (s, 9H). LCMS RT= 0.907 min, m / z = 288.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.907 min, ESI+ found [M+H] = 288.0.

[0625] Method 31

[0626] Example 45

[0627] l-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-2-methyl- propan-l-one

[0628] To a cooled (-78 °C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2- b][l,2,4]triazole-2-carboxylate (200 mg, 0.73 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride (2.0 mL in THF, 1.1 mL, 2.20 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h, and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hydroxide in water) to afford racemic l-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4] triazol-2-yl)-2- methyl-propan-l-one (6.9 mg, 3.4%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.46 - 7.36 (m, 3H), 7.28 - 7.26 (m, 2H), 6.18 - 6.16 (m, 0.5H), 6.05 - 6.02 (m, 0.5H), 5.65 - 5.61 (m, 1H), 3.78 - 3.72 (m, 1H), 3.64 - 3.61 (m, 1H), 2.87 - 2.76 (m, 1H), 1.19 (d, J= 7.2 Hz, 3H), 1.17 (d, J= 6.8 Hz, 3H). LCMS RT= 1.971 min, m / z = 274.2 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoacetic acid over 3.0 mins) retention time 1.971 min, ESI+ found [M+H] = 274.2.

[0629]

[0630] Example 46 Example 47

[0631] Example 49

[0632] l-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]propan-l-one and l-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]propan-l-one

[0633]

[0634] Step 1: l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl]propan-l-one

[0635] To a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl- 6,7-dihydro-5H- pyrrolo[l,2-b][ 1,2,4] triazole-2-carboxamide (30 mg, 0.10 mmol) in tetrahydrofuran (3 mL) was added ethylmagnesium bromide (3.0 M in THF, 0.1 mL, 0.30 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at 30 °C for about 3 h, and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 25-55% / 0.05% ammonia hydroxide in water) to afford 1 -[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazol-2-yl]propan-l - one (6.3 mg, 23%) as a white solid. Ή NMR (400 MHz, CD3OD) δ 7.38 - 7.35 (m, 3H), 7.25 - 7.23 (m, 2H), 6.15 - 6.13 (m, 0.5H), 6.01 - 5.99 (m, 0.5H), 5.59 - 5.53 (m, 1H), 3.77 - 3.67 (m, 1H), 3.05 - 2.99 (m, 2H), 2.84 - 2.73 (m, 1H), 1.13 (t, J= 7.2 Hz, 3H). LCMS RT= 1.038 min, m / z = 260.2 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time

[0636] = 260.2.

[0637]

[0638] Step 2:

[0639] l-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]propan-l-one and l-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]propan-l-one

[0640] The racemic l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4] triazol-2- yl]propan-l -one (220 mg) was separated by chiral SFC to afford arbitrarily assigned: l-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l -one (peak 1, retention time = 2.265 min) (78 mg, 35%, 88%ee) as light yellow oil. ¾ NMR (400 MHz, CD3OD) δ 7.43 - 7.32 (m, 3H), 7.27 - 7.23 (m, 2H), 6.17 - 6.14 (m, 0.5H), 6.02 - 6.00 (m, 0.5H), 5.65 - 5.58 (m, 1H), 3.84 - 3.64 (m, 1H), 3.06 - 3.00 (m, 2H), 2.88 - 2.69 (m, 1H), 1.13 (t, J = 12 Hz, 3H). LCMS RT= 0.822 min, m / z = 260.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.822 min, ESI+ found [M+H] = 260.0.

[0641] 1 -[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazol-2-yl]propan-l -one (peak 2, retention time = 2.382 min) (80 mg, 35%, 91%ee) as light yellow oil. ¾ NMR (400 MHz, CD3OD) δ 7.43 - 7.32 (m, 3H), 7.27 - 7.23 (m, 2H), 6.17 - 6.14 (m, 0.5H), 6.02 - 6.00 (m, 0.5H), 5.65 - 5.58 (m, 1H), 3.84 - 3.64 (m, 1H), 3.06 - 3.00 (m, 2H), 2.88 - 2.69 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H). LCMS RT= 0.817 min, m / z = 260.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.817 min, ESI+ found [M+H] = 260.0. SFC condition: Column: AS (250mm*30mm,5 μιη); Condition: 0.1%NH3H2O EtOH; Begin B 20% End B 20%o; Flow Rate (60 mL / min), Column temperature 40 °C. Method 33

[0642] Example 48

[0643] (l-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl]methanone

[0644] To a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl- 6,7-dihydro-5H- pyrrolo[l ,2-b] [l ,2,4]triazole-2-carboxamide (137 mg, 0.47 mmol) and l -methyl-4-iodo-lh-pyrazole (393 mg, 1.89 mmol) in tetrahydrofuran (10 mL) was added dropwise tert-butyllithium (1.3 M in hexane, 1.45 mL, 1.89 mmol) under a nitrogen atmosphere. The mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 27- 57% / 0.05% hydrochloride in water) to afford cis racemic (l -methylpyrazol-4-yl)-[rac-(5R,7R)-7- fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazol-2-yl]methanone (53.4 mg, 36%) as a white solid.!H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.24 (s, 1H), 7.46 - 7.34 (m, 3H), 7.32 - 7.25 (m, 2H), 6.22 - 6.19 (m, 0.5H), 6.08 - 6.05 (m, 0.5H), 5.72 - 5.65 (m, 1H), 3.93 (s, 3H), 3.85 - 3.70 (m, 1H), 2.90 - 2.75 (m, 1H). LCMS RT= 0.791 min, m / z = 31 1.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.791 min, ESI+ found [M+H] = 31 1.9. Method 34 Example 50

[0645] l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-

[0646] Step 1 : (£)-benzaldehyde oxime

[0647] To a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL) was added sodium carbonate (1 12.3 g, 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g, 508.9 mmol). The reaction mixture was stirred at 25 °C for 3 h and filtered. The filtrate was concentrated under reduced pressure and the residue was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude (£)-benzaldehyde oxime as colorless oil 51.0 g, 99%), used in the next step without further purification.

[0648] Step 2: methyl 3-phenyl-4, 5-dihydroisoxazole-5-carboxylate

[0649] To a solution of (iT)-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 hypochlorous acid tert-butyl ester (17.9 g, 165.1 mmol). The reaction mixture was stirred at 25 °C for 24 h and subsequently 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 afford methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g, 74%). LCMS RT= 0.871 min, m / z = 206.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 2.0 mins) retention time 0.871 min, ESI+ found [M+H] =206.2.

[0650]

[0651] Step 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one

[0652] A mixture of methyl 3-phenyl-4, 5-dihydroisoxazole-5-carboxylate (25.0 g, 121.8 mmol) and palladium (10%o on carbon, 2.5 g) in ethanol (800 mL) was hydrogenated (50 psi) at 25 °C for 2 h and then filtered and the filtrate was concentrated under reduced pressure to afford crude 3-hydroxy-5- phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%), used in the next step without further purification. LCMS RT= 0.270 min, m / z = 177.8 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03 % trifluoacetic acid over 1.5 mins) retention time 0.270 min, ESI+ found [M+H] =177.8.

[0653]

[0654] Step 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one & ira«s-3-[tert- butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

[0655] To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol) in dichloromethane (300 mL) was added tert-butyldimethylchlorosilane (19.1 g, 126.9 mmol) and imidazole (11.5 g, 169.3 mmol). The reaction mixture was stirred at 25 °C for 16 h and subsequently 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 afford arbitrarily assigned: c«-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 51%). H NMR (400 MHz, CDC13) δ 7.37 - 7.25 (m, 5H), 4.88 - 4.53 (m, 1H), 4.54 - 4.46 (m, 1H), 2.89 - 2.79 (m, 1H), 1.80 - 1.71 (m, 1H), 0.93 - 0.90 (m, 9H), 0.19 - 0.12 (m, 6H) and

[0656] ?ran5-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g, 38%). Ή NMR (400 MHz, CDC13) δ 7.44 - 7.34 (m, 2H), 7.29 - 7.24 (m, 3H), 4.87 - 4.80 (m, 1H), 4.44- 4.41 (m, 1H), 2.45 - 2.37 (m, 1H), 2.27 - 2.22 (m, 1H), 0.93 - 0.90 (m, 9H), 0.16 - 0.13 (m, 6H).

[0657]

[0658] Step 5: ira«s-l-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

[0659] To a solution of ?an5-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g, 24.0 mmol) in NN-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 min. Then o-(diphenylphosphoryl)hydroxylamine (8.40 g, 36.03 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford trans -l -amino-3-[tert- butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g, 95.1%) as a yellow oil, use in the next step without further purification. LCMS RT= 0.775 min, m / z = 307.0 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.775 min, ESI+ found [M+H] = 307.0.

[0660]

[0661] Step 6: trans-ethyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-l-yl)amino)-2- imino acetate

[0662] To a solution of ?ran5-l-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 h and subsequently concentrated under reduced pressure to afford crude trans-ethyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-l-yl)amino)- 2-iminoacetate (8.50 g, 92%) as a yellow oil, used in the next step without further purification. LCMS RT= 2.154 min, m / z = 406.3 [M + H]+. LCMS (0 to 60% acetonitrile in water + 0.03% trifluoacetic acid over 3.0 mins) retention time 2.143 min, ESI+ found [M+H] = 406.3.

[0663]

[0664] Step 7: iraws-ethyl 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylate

[0665] To a solution of ethyl 2-[[?ran5-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-l- yl]amino]-2-imino-acetate (8.5 g, 21.0 mmol) in toluene (100 mL) was added / ?-toluenesulfonic acid (4.4 g, 25.2 mmol). The reaction mixture was stirred at 120 °C for 16 h and subsequently concentrated under reduced pressure to afford crude trans-ethyl 7-((tert-butyldimethylsilyl)oxy)-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (7.5 g, 92.3%o) as a yellow oil, used in the next step without further purification. LCMS RT= 1.022 min, m / z = 374.2 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2 mins) retention time 1.022

[0666] ] = 374.2.

[0667]

[0668] Step 8: iraws-ethyl 7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylate

[0669] To a solution of ethyl Zran5-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxylate (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 h and subsequently concentrated under reduced pressure to afford crude trans-ethyl 7- hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (3.5 g, 57%o) as a yellow oil, used in the next step without further purification.:H NMR (400 MHz, CDC13): δ 7.39 - 7.35 (m, 3H), 7.14 - 7.12 (m, 2H), 5.73 - 5.70 (m, 1H), 5.54 - 5.51 (m, 1H), 4.47 - 4.40 (m, 2H), 3.24 - 3.21 (m, 1H), 3.05 - 3.00 (m, 1H), 1.41 - 1.36 (m, 3H).

[0670] Step 9: cis-ethyl 7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate

[0671] To a solution of trans-ethyl 7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole-2- carboxylate (100 mg, 0.37 mmol) in dichloromethane (8 mL) was added diethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and subsequently quenched by addition of water (20 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf= 0.5) to afford czs-ethyl-7- fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (54 mg, 54%) as a light yellow oil. Ή NMR (400MHz, CDC13) δ 7.44 - 7.31 (m, 3H), 7.25 - 7.17 (m, 2H), 6.09 (dd, J= 1.4 Hz, 7.2 Hz, 1H), 5.95 (dd, J = 1.4 Hz, 7.2 Hz, 1H), 5.52 - 5.47(m, 1H), 4.53 - 4.37 (m, 2H), 3.74 - - 2.82 (m, 1H), 1.48 - 1.33 (m, 3H).

[0672]

[0673] Step 10: cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylic acid

[0674] To a solution of c«-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole-2- carboxylate (54 mg, 0.20mol) in tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide monohydrate (25 mg, 0.59 mmol). The reaction mixture was stirred at 25 °C for 2 h and subsequently concentrated under reduced pressure. The residue was adjusted to pH = 5 by addition of hydrochloric acid (2 N). 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 afford crude czs-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (45 mg, 93%o) as a white solid, used in the next step without further purification.

[0675] l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]ethanone

[0676]

[0677] Step 11: cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxamide

[0678] A mixture of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazole -2-carboxylic acid (350 mg, 1.42 mmol), 1 -hydro xybenzotriazole (201 mg, 1.49 mmol), l -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (407 mg, 2.12 mmol), N,0-dimethylhydroxylamine hydrochloride (180 mg, 1.84 mmol) in N,N-dimethylformamide (10 mL) stirred at 20 °C for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf= 0.7) to afford cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7- dihydro-5H-pyrrolo[l ,2-b] [l ,2,4] triazole-2-carboxamide (225 mg, 54.7%o) as a white solid. ¾ NMR (400 MHz, CDC13) δ 7.41 - 7.35 (m, 3H), 7.26 - 7.22 (m, 2H), 6.09 - 6.07 (m, 0.5H), 5.96 - 5.93 (m, 0.5H), 5.49 - 5.46 (m, 1H), 3.78 (s, 3H), 3.66 - 3.59 (m, 1H), 3.55 - 3.35 (brs, 3H), 2.99 - 2.88 (m, 1H). LCMS RT= 0.564 min, m / z = 291.1 [M + H]+.

[0679] LCMS (5 to 95%o acetonitrile in water + 0.03 %> trifluoacetic acid over 1.5 mins) retention time 0.564

[0680] H] = 291.1.

[0681]

[0682] Step 12: l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yljethanone

[0683] To a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl- 6,7-dihydro-5H- pyrrolo[l ,2-b] [ 1 ,2,4] triazole-2-carboxamide (30 mg, 0.10 mmol) in tetrahydrofuran (3 mL) was added methylmagnesium bromide (3.0 M in THF, 0.1 mL, 0.30 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at 30 °C for about 3 h, and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried and concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 25-55 % / 0.05% ammonia hydroxide in water) to afford l-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]ethanone (4 mg, 15%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.41 - 7.35 (m, 3H), 7.26 - 7.24 (m, 2H), 6.16 - 6.14 (m, 0.5H), 6.01 - 6.00 (m, 0.5H), 5.62 - 5.58 (m, 1H), 3.77 - 3.68 (m, 1H), 2.85 - 2.74 (m, 1H), 2.55 (s, 3H). LCMS RT= 0.954 min, m / z = 246.2 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 0.954 min, ESI+ found [M+H] = 246.2.

[0684]

[0685] Example 51 Example 52

[0686] [(lS,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone and [(lR,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone

[0687] To a cooled (-70 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[l,2- b][l,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) was added n-butyllithium (2.5 M in hexanes, 0.64 mL, 1.60 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h then quenched by addition of saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure. The residue was purified by RP-HPLC (acetonitrile 37-67%o / 0.05%i ammonia hydroxide in water) to give [trans-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone ( 25 mg, 16%) as a deep red solid. This material was further separated by chiral SFC to afford arbitrarily assigned:

[0688] [(l S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone (Peak 1, Retention time = 3.130 min) (11.2 mg, 44%o) as a white solid. Ή NMR (400MHz, CD3OD) δ 7.51 - 7.33 (m, 3H), 7.30 - 7.28 (m, 2H), 6.21 - 6.03 (m, 1H), 5.68 - 5.64 (m, 1H), 5.02 - 4.94 (m, 1H), 4.84 - 4.80 (m, 1H), 3.84 - 3.70 (m, 1H), 3.47 - 3.44 (m, 1H), 2.90 - 2.78 (m, 1H), 1.73 - 1.62 (m, 1H), 1.60 - 1.52 (m, 1H). LCMS RT= 1.765 min, m / z = 290.1 [M + H] . LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 2.0 mins) retention time 1.765 min, ESI+ found [M+H] = 290.1.

[0689] [(lR,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2- b][l ,2,4]triazol-2-yl]methanone (Peak 2, Retention time = 3.464 min) (10.2 mg, 40%o) as a white solid. Ή NMR (400MHz, CD3OD) δ 7.51 - 7.33 (m, 3H), 7.32 - 7.20 (m, 2H), 6.21 - 6.04 (m, 1H), 5.70 - 5.62 (m, 1H), 5.00 - 4.82 (m, 1H), 3.83 - 3.70 (m, 1H), 3.47 - 3.42 (m, 1H), 2.90 - 2.77 (m, 1H), 1.74 - 1.63 (m, 1H), 1.60 - 1.52 (m, 1H). LCMS RT= 1.756 min, m / z = 290.1 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.03%o ammonium bicarbonate over 2.0 mins) retention time 1.756 min, ESI+ found [M+H] = 290.1.

[0690] SFC condition: Column: Chiralcel OD-3 150 x 4.6mm I.D., 3μηι Mobile phase: A: C02B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL / min.

[0691] Example 53

[0692] (l-fluorocyclopropyl)(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl) methanone

[0693] Step 1 : 1-fluoro-N-methoxy-N-methylcyclopropanecarboxamide

[0694] A mixture of 1 -fluorocyclopropanecarboxylic acid (150 mg, 1.44 mmol), N,N-diisopropylethylamine (465 mg, 3.60 mmol), l -[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (712 mg, 1.87 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (183 mg, 1.87 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20%o ethyl acetate in petroleum ether) to give 1 -fluoro-N-methoxy-N-methyl- cyclopropanecarboxamide (140 mg, 66%) as a colorless oil. ¾ NMR (400 MHz, CDC13) δ 3.75 (s, 3H), 3.26 (s, 3H), 1.31 - 1.21 (m, 4H).

[0695] c s m x ure

[0696] Step 2: (l-fluorocyclopropyl)(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone

[0697] To a cooled (-78 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[l,2- b][l,2,4]triazole (50 mg, 0.18 mmol) and 1-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (52 mg, 0.35 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (2.5 M in hexanes, 0.21 mL, 0.53 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 20 - 45% / 0.05% HC1 in water) to give the crude product (20 mg). This crude was further purified by preparative TLC (30%o ethyl acetate in petroleum ether, Rf= 0.3) to give (l -fluorocyclopropyl)(rac- (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)methanone (10.2 mg, 19%) as a light yellow oil. Ή NMR (400 MHz, CDC13) δ 7.41 - 7.37 (m, 3H), 7.23 - 7.21 (m, 2H), 6.09 - 6.07 (m, 0.5H), 5.96 - 5.93 (m, 0.5H), 5.51 - 5.50 (m, 1H), 3.67 - 3.58 (m, 1H), 3.00 - 2.90 (m, 1H), 1.92 - 1.88 (m, 2H), 1.62 - 1.58 (m, 2H). LCMS RT= 1.726 min, m / z = 290.1 [M + H]+. LCMS (10 to 80%o acetonitrile in water + 0.1%o ammonia water over 3.0 mins) retention time: 1.726 min, ESI+ found [M+H] = 290.1.

[0698] Example 54

[0699] ((5S,7S)-7-fluoro-5-phenyl-6,7-dihy dro-5H-pyrrolo [1 ,2-b] [1 ,2,4] triazol-2-yl)(3-methyloxetan-3- yl)methanone

[0700] To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2- b][l,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) was added n-butyllithium (2.5 M in hexanes, 0.34 mL, 0.85 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05%o ammonia hydroxide in water) to afford [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]-(3-methyloxetan-3-yl)methanone (16.3 mg, 19%>) as a pink solid. ¾ NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.25 - 7.23 (m, 2H), 6.17 - 6.15 (m, 0.5H), 6.03 - 6.01 (m, 0.5H), 5.65 - 5.62 (m, 1H), 5.09 - 5.02 (m, 2H), 4.52 - 4.26 (m, 2H), 3.78 - 3.70 (m, 1H), 2.86 - 2.76 (m, 1H), 1.74 (s, 3H). LCMS RT= 0.675 min, m / z = 302.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time: 0.675 min, ESI+ found [M+H] = 302.1.

[0701] Method 38

[0702] Example 55

[0703] ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)(3-methyloxetan-3- yl)methanone

[0704]

[0705] Step 1 : N-methoxy-N,3-dimethyloxetane-3-carboxamide

[0706] A mixture of Ν,Ο-dimethylhydroxylamine hydrochloride (252 mg, 2.58 mmol), l -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (396 mg, 2.07 mmol), 3-methyloxetane-3- carboxylic acid (200 mg, 1 .72 mmol), 1 -hydro xybenzotriazole (140 mg, 1.03 mmol) and N,N- diisopropylethylamine (556 mg, 4.31 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL), dried and concentrated under reduced pressure to give crude N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (270 mg, 98%o) as a colorless oil. This crude was used in the next step without further purification.

[0707] ¾ NMR (400 MHz, CDC13) δ 4.96 - 4.93 (m, 2H), 4.29 - 4.27 (m, 2H), 3.66 (s, 3H), 3.18 (s, 3H),

[0708] 1.66 (s, 3H).

[0709] Step 2: ((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2 -yl)(3- methyloxetan-3-yl)methanone

[0710] To a cooled (-78 °C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,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-butyllithium (2.5 M in hexanes, 0.43 mL, 1.06 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05%o ammonia hydroxide in water) to afford [(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]-(3-methyloxetan-3-yl)methanone (13.6 mg, 13%) as a pink solid. ¾ NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.25 - 7.23 (m, 2H), 6.17 - 6.15 (m, 0.5H), 6.03 - 6.01 (m, 0.5H), 5.65 - 5.62 (m, 1H), 5.09 - 5.02 (m, 2H), 4.52 - 4.26 (m, 2H), 3.78 - 3.70 (m, 1H), 2.86 - 2.76 (m, 1H), 1.74 (s, 3H). LCMS RT= 0.678 min, m / z = 302.1 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time: 0.678 min, ESI+ found [M+H] = 302.1.

[0711] Method 39

[0712] Example 56

[0713] 3-oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- -yl]methanone

[0714]

[0715] Step 1 : N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide A mixture of 3-oxabicyclo[3.1.0]hexane-6-carboxylicacid (trans, 300 mg, 2.34 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (297 mg, 3.04 mmol), l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1157 mg, 3.04 mmol) and N,N- diisopropylethylamine (756 mg, 5.85 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-3- oxabicyclo[3.1.0]hexane-6-carboxamide (180 mg, 45%) as a colorless oil. ¾ NMR (400 MHz, CDC13) δ 3.95 - 3.93 (m, 2H), 3.80 - 3.78 (m, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 2.17 - 2.09 (m, 3H).

[0716]

[0717] trans LHS

[0718] Step 2: 3-oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone

[0719] To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,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 hexanes, 0.21 mL, 0.53 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%o / 0.05%o ammonia hydroxide in water) to afford 3-oxabicyclo[3.1.0]hexan-6-yl- [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone (2.2 mg, 3.9%) as a white solid. Ή NMR (400 MHz, CDC13) δ 7.43 - 7.39 (m, 3H), 7.27 - 7.26 (m, 2H), 6.12 - 5.96 (m, 1H), 5.53 - 5.49 (m, 1H), 4.02 - 3.99 (m, 2H), 3.82 - 3.80 (m, 2H), 3.70 - 3.61 (m, 1H), 3.07 - 3.05 (m, 1H), 3.02 - 2.95 (m, 1H), 2.45 - 2.43 (m, 2H). LCMS RT= 0.821 min, m / z = 313.9 [M + H]+. LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.821 min, ESI+ found [M+H] = 313.9.

[0720] Method 40

[0721] cis mixture Example 57

[0722] oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2- yljmethanone

[0723] Step 1: N-methoxy-N-methyl-oxetane-3-carboxamide

[0724] A mixture of oxetane-3-carboxylic acid (300 mg, 2.94 mmol), Ι,Γ-carbonyldiimidazole (524 mg, 3.23 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (286 mg, 2.94 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate in petroleum ether, Rf= 0.3) to give N-methoxy-N-methyl- oxetane-3-carboxamide (60 mg, 14%) as a colorless oil. H NMR (400 MHz, CDC13) δ 4.92 - 4.89 (m, 2H), 4.80 - 4.76 (m, 2H), 4.19 - 4.13 (m, 1H), 3.63 (s, 3H), 3.21 (s, 3H).

[0725]

[0726] cis mixture

[0727] Step 2: oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol- 2-yl]methanone

[0728] To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,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) was added n-butyllithium (2.5 M in hexanes, 0.16 mL, 0.40 mmol) dropwise under nitrogen atmosphere. After addition, the mixture was stirred at -70 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%o / 0.05%o ammonia hydroxide in water) to afford 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. H NMR (400 MHz, CDC13) δ 7.43 - 7.40 (m, 3H), 7.27 - 7.23 (m, 2H), 6.11 - 5.95 (m, 1H), 5.50 - 5.49 (m, 1H), 4.97 - 4.90 (m, 4H), 4.72 - 4.68 (m, 1H), 3.68 - 3.59 (m, 1H), 3.03 - 2.92 (m, 1H). LCMS RT= 0.782 min, m / z = 287.9 [M + H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.782 min, ESI+ found [M+H] = 287.9.

[0729] Example 58

[0730] [l-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0731] Step 1 : l-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropanecarboxylic acid

[0732] To a solution of l-(hydroxymethyl)cyclopropanecarboxylic acid (200 mg, 1.72 mmol) in dichloromethane (5 mL) was added tert-butyldimethylchlorosilane (532 mg, 3.53 mmol) and imidazole (240 mg, 3.53 mmol). The mixture was stirred at 25 °C for 5 h and then quenched by addition of water (10 mL). The mixture was extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (6 mL) / water (6 mL) and added sodium hydroxide (138 mg, 3.44 mmol). The resulting mixture was stirred at 25 °C for 10 h and then adjusted to pH = 4 by addition of citric acid. The solution was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried and concentrated under reduced pressure to afford crude l-[[tert- butyl(dimethyl)silyl]oxymethyl] cyclopropanecarboxylic acid (400 mg, 100%) as a colorless oil.

[0733] Step 2 :

[0734] l-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methyl cyclopropane carboxamide

[0735] A mixture of l-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropanecarboxylic acid (400 mg, 1.74 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (423 mg, 4.34 mmol), l -(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 h. The resulting mixture was partitioned between water (30 mL) and dichloromethane (30 mL). The separated organic layer was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford l -[[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%o trifluoacetic acid over 1.5 mins) retention

[0736] [M+H] = 274.1.

[0737]

[0738] Step 3:

[0739] (l-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)[rac-(5S,7S)-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone

[0740] To a cooled (-78 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H -pyrrolo[l,2- b] [l ,2,4]triazole (60 mg, 0.21 mmol) and l -[[tert-butyl(dimethyl)silyl] oxymethyl]-N-methoxy-N- methyl-cyclopropanecarboxamide (116 mg, 0.43 mmol) in tetrahydrofuran (2 mL) was added n- butyllithium (2.5 M in hexanes, 0.26 mL, 0.64 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by preparative TLC (50%o ethyl acetate in petroleum ether, Rf= 0.4) to afford [l -[[tert- butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[c«-7- fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2- b][l ,2,4]triazol-2-yl]methanone (34 mg, 38%o) as a light brown oil.

[0741]

[0742] Step 4: [l-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7- dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone

[0743] A mixture of [l -[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[rac-(5S,7S) -7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazol-2-yl]methanone (34 mg, 0.08 mmol) and 2,2,2- trifluoroacetic acid (0.50 mL) in dichloromethane (3 mL) was stirred at 20 °C for 2 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%o / 0.05%o ammonia hydroxide in water) to afford [l -(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro- 5-phenyl-6,7- dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazol-2-yl]methanone (4.1 mg, 16%) as a light brown oil. Ή NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.27 - 7.25 (m, 2H), 6.17 - 6.15 (m, 0.5H), 6.03 - 6.01 (m, 0.5H), 5.63 - 5.61 (m, 1H), 3.96 - 3.85 (m, 2H), 3.77 - 3.71 (m, 1H), 2.86 - 2.75 (m, 1H), 1.71 - 1.67 (m, 2H), 1.10 - 1.07 (m, 2H). LCMS RT= 0.648min, m / z = 302.1 [M + H]+.

[0744] LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.648 min, ESI+ found [M+H] = 302.1.

[0745]

[0746] Example 59 Example 60

[0747] ((lS)-2,2-dffluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone and ((lR)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl- pyrrolo[l,2-b][l,2,4]triazol-2-yl)methanone

[0748] Step 1 : 2,2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide

[0749] A mixture of 2,2-difluorocyclopropanecarboxylic acid (1.00 g, 8.19 mmol), N,N- diisopropylethylamine (2646 mg, 20.5 mmol), l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (4.05 g, 10.6 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (1.04 g, 10.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (30 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20%o ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide (700 mg, 52%o) as a colorless oil. ¾ NMR (400 MHz, CDC13) δ 3.77 (s, 3 H), 3.26 (s, 3 H), 2.96 - 2.91 (m, 1 H),

[0750] 1.69-

[0751] Step 2 : ((1 S)-2,2-dffluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo [1,2- b] [l,2,4]triazol-2-yl)methanone and ((lR)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)methanone To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2- b] [l,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-butyllithium (2.5 M in hexanes, 1.28 mL, 3.19 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 20-45% / 0.225% HC1 in water) to give (2,2-difluorocyclopropyl)-[(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone (120 mg, 37%o) as a white solid. This material was further separated by chiral SFC to afford arbitrarily assigned:

[0752] ((l S)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone (peak 1, retention time = 2.069 min) (35.0 mg, 29%o) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.42 - 7.38 (m, 3H), 7.31 - 7.29 (m, 2H), 6.21 - 6.19 (m, 0.5H), 6.07

[0753] - 6.05 (m, 0.5H), 5.68 - 5.66 (m, 1H), 3.85 - 3.76 (m, 2H), 2.86 - 2.83 (m, 1H), 2.32 - 2.28 (m, 1H), 1.96 - 1.93 (m, 1H). LCMS RT= 1.834min, m / z = 308.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1 %> ammonia water over 3.0 mins) retention time: 1.834 min, ESI+ found [M+H] = 308.1.

[0754] ((lR)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone (peak 2, retention time = 3.055 min) (35.0 mg, 29%o) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.45 - 7.41 (m, 3H), 7.30 - 7.28 (m, 2H), 6.21 - 6.19 (m, 0.5H), 6.07

[0755] - 6.05 (m, 0.5H), 5.66 - 5.65 (m, 1H), 3.87 - 3.74 (m, 2H), 2.89 - 2.79 (m, 1H), 2.33 - 2.28 (m, 1H), 1.98 - 1.97 (m, 1H). LCMS RT=1.822 min, m / z = 308.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1 %> ammonia water over 3.0 mins) retention time: 1.822 min, ESI+ found [M+H] = 308.1. SFC conditions: Column Chiralcel OD-3 150x4.6mm I.D., 3μηι Mobile phase: A: C02B:iso- propanol (0.05% DEA), Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL / min, Column temp.: 35 °C.

[0756] Method 43 Example 61

[0757] (l-fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl)methanone

[0758] To a cooled (-78 °C) solution of 1 -fluoro-N-methoxy-N -methyl-cyclopropane carboxamide (313 mg, 2.13 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl -6,7-dihydro-5H-pyrrolo[l ,2-b][l,2,4]triazole (300 mg, 1.06 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (2.5 M in hexanes, 1.28 mL, 3.19 mmol) dropwise under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 20 -

[0759] 45% / 0.05% HC1 in water), and then by preparative TLC (30% ethyl acetate in petroleum ether, Rf= 0.3) to give (l-fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl)methanone (80 mg, 25%) as a light yellow oil. ¾ NMR (400 MHz, CDC13) δ 7.40 - 7.37 (m, 3H), 7.23 - 7.21 (m, 2H), 6.09 - 6.07 (m, 0.5H), 5.96 - 5.94 (m, 0.5H), 5.51 - 5.49 (m, 1H), 3.67 - 3.58 (m, 1H), 3.00 - 2.90 (m, 1H), 1.92 - 1.88 (m, 2H), 1.62 - 1.60 (m, 2H). LCMS RT= 1.736min, m / z = 290.1 [M + H]+. LCMS (10 to 80% acetonitrile in water + 0.1% ammonia water over 3.0 mins) retention time: 1.736 min, ESI+ found [M+H] = 290.1.

[0760] Method 44

[0761] Example 62

[0762] cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b] [1,2,4] triazol-2- yljmethanone

[0763]

[0764] Step 1: l-(2-fluorophenyl)but-3-en-l-ol

[0765] To a solution of 2-fluorobenzaldehyde (15.0 g, 120.86 mmol) in tetrahydrofuran (250 mL) was added allylmagnesium bromide (1.0 M in tetrahydrofuran, 150.0 mL, 150.0 mmol) at 0 °C under nitrogen atmosphere. After addition, the mixture was allowed to warm to 25 °C and stirred for 2 h before quenched by addition of saturated aqueous ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to afford l-(2-fluorophenyl)but-3- en-l-ol (6.0 g, 24%) as a yellow oil. Ή NMR (400MHz, CDC13) δ 7.49 - 7.27 (m, 1H), 7.29 - 7.12 (m, 2H), 7.05 - 7.00 (m, 1H), 5.89 - 5.80 (m, 1H), 5.20 - 5.13 (m, 2H), 5.15 - 5.07 (m, 1H), 2.66 - 2.55 (m, 1H), 2.57 - 5.48 (m, 1H).

[0766]

[0767] Step 2 : tert-butyl((l-(2-fluorophenyl)but-3-en-l-yl)oxy)dimethylsilane

[0768] To a solution of l-(2-fluorophenyl)but-3-en-l-ol (6.0 g, 36.1 mmol) in dichloromethane (50 mL) was added imidazole (4.9 g, 72.2 mmol) and tert-butyldimethylchlorosilane (7.1 g, 146.9 mmol). The reaction mixture was stirred at 25 °C for 16 h and quenched by addition of water (100 mL). The mixture was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to afford tert-butyl-[l-(2-fluorophenyl)but-3-enoxy]-dimethyl-silane (8.5 g, 84%o) as a light oil. Ή NMR (400MHz, CDC13) δ 7.60 - 7.36 (m, 1H), 7.34 - 7.18 (m, 2H), 7.13 - 7.02 (m, 1H), 5.97 - 5.85 (m, 1H), 5.21 - 5.07 (m, 3H), 2.60 - 2.48 (m, 2H), 0.99 (s, 9H), 0.15 (s, 3H), 0.00 (s, 3H).

[0769]

[0770] Step 3 : 3-((tert-butyldimethylsilyl)oxy)-3-(2-fluorophenyl)propanal To a solution of tert-butyl-[l-(2-fluorophenyl)but-3-enoxy]-dimethyl-silane (8.50 g, 30.3 mmol) in water (100 mL) and tetrahydrofuran (100 mL) was added osmium tetroxide (0.15 g, 0.6 mmol). After stirred for 30 min at 25 °C, sodium periodate (25.90 g, 121.2 mmol) was added in small portions over 2 h. The resulting mixture was stirred for 2 h at 25 °C and quenched by addition of cold saturated aqueous sodium thiosulfate (100 mL). The mixture was stirred for 30 min and then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to5%o ethyl acetate in petroleum ether) to afford 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g, 64%) as a black oil. Ή NMR (400MHz, CDC13) δ 9.84 - 9.77 (m, 1H), 7.53 - 7.51 (m, 1H), 7.31 - 7.24 (m, 1H), 7.21 - 7.13 (m, 1H), 7.09 - 6.98 (m, 1H), 5.58 - 5.55 (m, 1H), 2.85 - 2.80 (m, 1H), 2.74 - 2.64 (m, 1H), 0.92 - 0.85 (m, 9H), 0.09 (s, 3H), -0.09 (s, 3H).

[0771]

[0772] Step 4: l-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-l,2,4-triazol-5-yl)-3-((tert- butyldimethylsilyl)oxy)-3-(2-fluorophenyl)propan-l-ol

[0773] To a cooled (-78 °C) solution of 3,5-dibromo-l-tetrahydropyran-2-yl-l,2,4-triazole (6.3 g, 20.1 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (2.5 M in hexanes, 8.6 mL, 21.4 mmol) under nitrogen atmosphere. The mixture was stirred at -78 °C for 30 min, then a solution of 3-[tert- butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g, 19.5 mmol) in tetrahydrofuran (25 mL) was added dropwise. After addition, the mixture was stirred at -78 °C for 1.5 h and then quenched by addition of saturated aqueous ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10%o ethyl acetate in petroleum ether) to afford l-(5-bromo-2-tetrahydropyran-2- yl-l,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propan-l-ol (8.0 g, 80%o) as a yellow oil. Used as is in the next step.

[0774]

[0775] Step 5: 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-7-ol

[0776] A mixture of l -(5-bromo-2-tetrahydropyran-2-yl-l,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl] oxy- 3-(2-fluorophenyl)propan-l-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 h and concentrated under reduced pressure. The residue was adjusted to pH = 9 by addition of saturated aqueous 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%o ethyl acetate in petroleum ether) to afford 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-7-ol (2.0 g, 43%) as a light yellow solid. LCMS RT= 0.505 min, m / z = 298.1 [M+H]+.

[0777] LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 0.505 + found [M+H] =298.1.

[0778]

[0779] Step 6: (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole

[0780] To a solution of 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b] [ l,2,4]triazol-7-ol (750 mg, 2.52 mmol) in toluene (20 mL) was added diethylaminosulfur trifluoride (1.62 g, 10.0 6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then slowly added into ice water (20 mL) at 0 °C. The mixture was 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 15% ethyl acetate in petroleum ether) to afford rac-(5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l ,2-b] [ l,2,4]triazole (250 mg, 33%) as a light yellow solid. ¾ NMR (400MHz, CDC13) δ 7.40 - 7.27 (q, J= 6.6 Hz, 1H), 7.20 - 7.10 (m, 2H), 7.01 - 6.97 (m, 1H), 6.10 - 5.89 (m, 1H), 5.84 - 5.75 (m, 1H), 3.70 - 3.53 (m, 1H), 2.96 - 2.75 (m, 1H). LCMS RT= 1.112 min, m / z = 300.0 [M+H]+.

[0781] LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2.0 mins) retention time 1.112 min, ESI+ found [M+H] =300.0.

[0782] This cis mixture was further separated by chiral SFC to afford arbitrarily assigned:

[0783] (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazole (Peak 2, retention time = 3.408 min ) (100 mg, 40%o) as a white solid. (The 5R,7R-isomer was also collected (Peak 1, retention time = 3.139 min ) (100 mg, 40%)).

[0784] SFC condition : Column: ChiralPak AD-3 150x4.6mm I.D., 3μιη mobile phase: A: C02 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL / min Column temp.: 35°C .

[0785] Step 7: cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0786] To a solution of (5SJS)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole (100 mg, 0.33 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (86 mg, 0.67 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 0.27 mL, 0.67 mmol) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h and quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35- 65% / 0.05% ammonium hydroxide in water) to afford arbitrarily assigned cyclopropyl-[(5S,7S)-7- fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl] methanone (7.2 mg, 7%) as a yellow solid. Ή NMR (400 MHz, CD3OD) δ 7.47 - 7.41 (m, 1H), 7.25 - 7.18 (m, 2H), 7.16 - 7.13 (m, 1H), 6.22 - 6.06 (m, 1H), 5.92 - 5.88 (m, 1H), 3.85 - 3.78 (m, 1H), 3.08 - 3.02 (m, 1H), 2.93 - 2.78 (m, 1H), 1.22 - 1.17 (m, 2H), 1.15 - 1.09 (m, 2H). LCMS RT= 1.043 min, m / z = 290.2 [M+H]+.

[0787] LCMS (10 to 80% acetonitrile in water + 0.03% ammonium bicarbonate over 3.0 mins) retention time 1.043 min, ESI+ found [M+H] = 290.2.

[0788] 63

[0789] (S)-cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl) methanone

[0790] To a solution of ethyl (5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole-2- carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (3 mL) was added cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 0.72 mL, 0.36 mmol) dropwise under nitrogen atmosphere at -78 °C. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting 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 RP-HPLC (acetonitrile 40-50%o / 0.05%o ammonia hydroxide in water) to afford cyclopropyl-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H- pyrrolo[l,2-b] [l,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 arbitrarily assigned (S)-cyclopropyl(5-(2-fluorophenyl)-6,7- dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)methanone (17.5 mg, 34%) as a brown oil. ¾ NMR (400 MHz, CD3OD) δ 7.44 - 7.35 (m, 1H), 7.23 - 7.16 (m, 3H), 5.81 - 5.77 (m, 1H), 3.37 - 3.29 (m, 1H), 3.21 - 3.03 (m, 2H), 2.99 - 2.93 (m, 1H), 2.77 - 2.65 (m, 1H), 1.16 - 1.09 (m, 2H), 1.09 - 1.00 (m, 2H). LC-MS RT= 0.699 min, m / z = 272.1 [M+H]+.

[0791] LCMS (5 to 95%o acetonitrile in water + 0.03 %> trifluoacetic acid over 1.5 mins) retention time 0.699 min, ESI+ found [M+H] = 272.1.

[0792] SFC condition: Column: ChiralPak AD-3 150x4.6mm I.D., 3μηι Mobile phase: A: C02B: Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min Flow rate: 2.5 mL / min Column temp: 40 °C.

[0793] Method 46

[0794] Example 64

[0795] (3,3-dffluorocyclobutyl)((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4] triazol- 2-yl)methanone

[0796] To a solution of 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (76 mg, 0.43 mmol) and (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole (60 mg, 0.21 mmol) in tetrahydrofuran (13 mL) was added n-butyllithium (2.5 M in hexanes, 0.26 mL, 0.64 mmol) dropwise at -78 °C. After addition, the mixture was stirred at -78 °C for 2 h and quenched by addition of saturated aqueous ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 20 - 45%ο / 0.225%ο hydrochloric acid in water) to give arbitrarily assigned (3,3-difluorocyclobutyl)-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone (11.0 mg, 16%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.43 - 7.38 (m, 3H), 7.29 - 7.27 (m, 2H), 6.19 - 6.17 (m, 0.5H), 6.05 - 6.03 (m, 0.5H), 5.64 - 5.63 (m, 1H), 3.94 - 3.93 (m, 1H), 3.79 - 3.75 (m, 1H), 2.90 - 2.82 (m, 5H). LCMS RT= 1.904 min, m / z = 322.1 [M+H]+.

[0797] LCMS (10 to 80%o acetonitrile in water + 0.1%o ammonia water over 3.0 mins) retention time 1.904 min, ESI+ found [M+H] =322.1. Examples 66 and 67

[0798] [(5S)-7,7-dffluoro-5-phenyl-5,6-dihydropyrrolo[l,2-b][l,2,4]triazol-2-yl]-[(lS,2R)-2- fluorocyclopropyl]methanone & [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo [1,2- b][l,2,4]triazol-2-yl]-[(lR,2S)-2-fluorocyclopropyl]methanone

[0799]

[0800] Step 1 : 2-bromo-5-phenyl-5H-pyrrolo[l,2-b] [1,2,4] triazol-7(6H)-one To a solution of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b][l,2,4]triazol-7-ol (2.0 g, 7.14 mmol) in dichloromethane (100 mL) was added pyridinium chlorochromate (1.7 g, 7.85 mmol). The mixture was stirred at 20 °C for 18 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 2-bromo-5-phenyl-5,6-dihydropyrrolo[l,2-b][l,2,4]triazol- -one (1.8 g, 88%) as a white solid. Used as is in the next step.

[0801]

[0802] Step 2: (S)-2-bromo-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole

[0803] To a cooled solution of 2-bromo-5-phenyl-5,6-dihydropyrrolo[l,2-b][l,2,4]triazol-7-one (1.7 g, 6.11 mmol) in dichloromethane (80 mL) was added diethylaminosulfur trifluoride (7.88 mL, 61.13 mmol) at 0 °C. After stirred at 25 °C for 2 h, 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%o ethyl acetate in petroleum ether) to afford racemic 2-bromo-7,7-difluoro-5- phenyl-5,6-dihydropyrrolo[l,2-b][l ,2,4]triazole (1.5 g, 82%) as a pink solid. LC-MS RT= 0.774 min, m / z = 303.1 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03% trifluoacetic acid over 1.5 mins) retention time 0.774 min, ESI+ found [M+H] = 303.1.

[0804] The racemic material (950 mg, 3.17 mmol) was further separated by chiral SFC to give arbitrarily assigned:

[0805] (5R)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l ,2-b] [ l ,2,4]triazole (Peak 1 , retention time = 2.308 min) (410 mg, 43%o) as a light brown solid.

[0806] (5S)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l ,2-b] [l ,2,4]triazole (Peak 2, retention time = 2.614 min) (440 mg, 46%>) as a light brown solid.

[0807] SFC condition: Column: OJ (250mm*50mm,10um); Mobile phase: A: C02B: 0.1 %NH3H2O EtOH Gradient: from 20%o to20%o of B; Flow rate: 180mL / min, Column temperature:40 °C.

[0808]

[0809] Step 3: [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l,2-b] [l,2,4]triazol-2-yl]-[(lS,2R)-2- fluorocyclopropyl]methanone and [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo [1,2- b][l,2,4]triazol-2-yl]-[(lR,2S)-2-fluorocyclopropyl]methanone

[0810] To a mixture of (5S)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l ,2-b] [l ,2,4]triazole (200 mg, 0.67 mmol) and ?ran5-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (196 mg, 1.33 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 0.8 mL, 2.0 mmol) dropwise under nitrogen atmosphere at -78 °C. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated to dryness under reduce pressure to give the crude product, which was purified by RP-HPLC (acetonitrile 45- 75%o / 0.05%o ammonia hydroxide in water) to afford the [(5S)-7,7-difluoro-5-phenyl-5,6- dihydropyrrolo[l,2-b] [l ,2,4]triazol-2-yl]-[trans-2-fluoro cyclopropyl]methanone (50 mg, 24%) as brown oil. This racemic material was separated by chiral SFC to give arbitrarily assigned:

[0811] [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l ,2-b][l ,2,4]triazol-2-yl]-[(l S,2R)-2-fluoro cyclopropyl]methanone (Peak 1 , retention time = 2.365 min) (15.1 mg, 30%o) as a white solid.lH NMR (400 MHz, CD3OD) δ 7.49 - 7.44 (m, 3H), 7.33 - 7.30 (m, 2H), 5.99 - 5.92 (m, 1H), 5.02 - 5.00 (m, 0.5H), 4.86 - 4.82 (m, 0.5H), 3.89 - 3.86 (m, 1H), 3.51 - 3.47 (m, 1H), 3.34 - 3.33 (m, 0.5H), 3.32 - 3.22 (m, 0.5H), 1.78 - 1.70 (m, 1H), 1.63 - 1.57 (m, 1H). LC-MS RT= 0.822 min, m / z = 308.0 [M+H]+. LCMS (5 to 95% acetonitrile in water + 0.03%> trifluoacetic acid over 1.5 mins) retention time 0.822 min, ESI+ found [M+H] = 308.0.

[0812] [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyr^

[0813] cyclopropyl]methanone (Peak 2, retention time = 3.163 min) (13.6 mg, 27%o) as a white solid.

[0814] ¾ NMR (400 MHz, CD3OD) δ 7.47 - 7.43 (m, 3H), 7.31 - 7.29 (m, 2H), 5.98 - 5.94 (m, 1H), 5.05 - 4.99 (m, 0.5H), 4.86 - 4.83 (m, 0.5H), 3.91 - 3.86 (m, 1H), 3.47 - 3.45 (m, 1H), 3.34 - 3.26 (m, 1H), 1.74 - 1.68 (m, 1H), 1.62 - 1.56 (m, 1H). LC-MS RT= 0.818 min, m / z = 308.1 [M+H]+.

[0815] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.818 min, ESI+ found [M+H] = 308.1.

[0816] SFC condition: Column: Column: AD (250ιηηι*30ηιηι,5μηι); Mobile phase: A: C02B:0.1%NH3H2O EtOH; Gradient: from 20%o to 20%o of B; Flow rate: 50mL / min Column temperature:40 °C.

[0817] Example 68

[0818] cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l,2-b] [l,2,4]triazol-2-yl] methanone and cyclopropyl-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l,2-b][l,2,4]triazol-2-yl] methanone

[0819] To a solution of 7,7-difluoro-N-methoxy-N-methyl-5-phenyl-5,6-dihydropyrrolo[l,2- b] [l,2,4]triazole-2-carboxamide (100 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 2.6 mL, 1.3 mmol) at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30%o ethyl acetate in petroleum ether) to afford cyclopropyl-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone (60 mg, 64%) as a white solid. ¾ NMR (400MHz, CDC13) δ 7.38 - 7.31 (m, 3H), 7.16 - 7.11 (m, 2H), 5.66 - 5.60 (m, 1H), 3.73 - 3.61 (m, 1H), 3.23 - 3.11 (m, 1H), 3.00 - 2.96 (m, 1H), 1.31 - 1.19 (m, 2H), 1.11 - 0.96 (m, 2H).

[0820] This racemate was further separated by chiral SFC to give arbitrarily assigned: cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l ,2-b] [1 ,2,4]triazol-2-yl]methanone (peak 2, retention time = 2.971 min) (22.4 mg, 37%) as a white solid. H NMR (400 MHz, CDC13) δ 7.45 - 7.41 (m, 3H), 7.23 - 7.21 (m, 2H), 5.73 - 5.68 (m, 1H), 3.75 - 3.70 (m, 1H), 3.31 - 3.19 (m, 1H), 3.09 - 3.04 (m, 1H), 1.37 - 1.32 (m, 2H), 1.14 - 1.09 (m, 2H). LCMS RT= 1.238 min, m / z =290.2 [M+H]+.

[0821] LCMS (10 to 80%o acetonitrile in water + 0.1%o ammonia water over 3.0 mins) retention time 1.238 min, ESf found [M+H] =290.2. cyclopropyl-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[l,2-b] [ l,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.677 min) (24.7 mg, 41%) as a white solid. ¾ NMR (400MHz, CDC13) δ 7.45 - 7.41 (m, 3H), 7.23 - 7.20 (m, 2H), 5.72 - 5.68 (m, 1H), 3.81 - 3.66 (m, 1H), 3.28 - 3.21 (m, 1H), 3.09 - 3.05 (m, 1H), 1.37 - 1.27 (m, 2H), 1.17 - 1.05 (m, 2H). LCMS RT= 1.239 min, m / z =290.2 [M+H]+.

[0822] LCMS (10 to 80%o acetonitrile in water + 0.1%o ammonia water over 3.0 mins) retention time 1.239 min, ESf found [M+H] =290.2.

[0823] SFC condition: Column: Chiralcel OJ(250mm*30mm^m) Mobile phase: A: C02B:ethanol (0.1 %NH3H2O) Gradient: from 25% to 25% of B in 5 min : 2.5mL / min Column temp.: 35°C Method 49

[0824] Example 70

[0825] (2,2-difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0826]

[0827] Step 1 : l,l-difluoro-N-methoxy-N-methylspiro[2.3]hexane-5-carboxamide

[0828] A mixture of 1 -hydro xybenzotriazole (83 mg, 0.62 mmol), N,0-dimethylhydroxylamine hydrochloride (180 mg, 1.85 mmol), 2,2-difluorospiro[2.3]hexane-5-carboxylic acid (200 mg, 1.23 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (284 mg, 1.48 mmol) and N,N- diisopropylethylamme (478 mg, 3.70 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 12 h and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 2,2-difluoro-N-methoxy-N-methyl-spiro[2.3]hexane-5- carboxamide (130 mg, 51%) as a colorless oil. ¾ NMR (400MHz, CDC13) δ 3.67 (s, 3H), 3.65 - 3 (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 1H), 1.32 - 1.13 (m, 2H).

[0829]

[0830] Step 2: (2,2-dffluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone

[0831] To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole (50 mg, 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-spiro[2.3]hexane-5- carboxamide (73 mg, 0.35 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in n- hexane, 0.28 mL, 0.71 mmol) under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting 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 47-77%o / 0.2% formic acid in water) to afford (2,2-difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone (10.8 mg, 17%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.43 - 7.38 (m, 3H), 7.28 - 7.26 (m, 2H), 6.18 - 6.02 (m, 1H), 5.64 - 5.62 (m, 1H), 4.24 - 4.08 (m, 1H), 3.87 - 3.64 (m, 1H), 2.91 - 2.74 (m, 1H), 2.68 - 2.28 (m, 4H), 1.32 - 1.23 (m, 2H). LCMS RT= 1.281&1.298 min, m / z = 348.1 [M + H]+.

[0832] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 1.281&1.298 min, ESI+ found [M+H] = 348.1

[0833] Example 71

[0834] l-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l-one

[0835] Stepl : ethyl 4-(2-chlorophenyl)-4-oxobutanoate

[0836] To a solution of 2-chloroacetophenone (100.0 g, 646.87 mmol), l,3-dimethyl-3,4,5,6-tetrahydro- 2(lh)-pyrimidinone (156.4 mL, 1293.70 mmol) in tetrahydrofuran (500 mL) was added [bis(trimethylsilyl)amino]lithium (1.0 M in tetrahydrofuran, 711.6 mL, 711.56 mmol) at - 60 °C. The mixture was stirred at - 60 °C for 100 min and ethyl bromoacetate (143.5 mL, 1293.7 mmol) was added rapidly. The resulting mixture was allowed to warm to 25 °C and stirred for 15 h. The reaction was quenched by addition of water (400 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were 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 the ethyl 4-(2-chlorophenyl)-4-oxo-butanoate (50.0 g, 32%) as a colorless oil. Used as is in the next step.

[0837]

[0838] Step2 : tert-butyl (2-(2-chlorophenyl)-5-oxopyrrolidin-l-yl)carbamate

[0839] To a solution of ethyl 4-(2-chlorophenyl)-4-oxo-butanoate (10.0 g, 41.55 mmol) in acetic acid (33 mL) and tetrahydrofuran (100 mL) was added tert-butyl hydrazinecarboxylate (11.0 g, 83.10 mmol). The mixture was stirred 85 °C for 12 h and added sodium cyanoborohydride (7.8 g, 124.65 mmol). The resulting mixture was stirred at 85 °C for another 12 h and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated sodium carbonate (80 mL), hydrochloric acid (2 M, 80 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 20 to 50%o ethyl acetate in petroleum ether) to afford tert-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-l-yl]carbamate (5.0 g, 39%o) as a light yellow oil. LCMS RT= 0.840 min, m / z = 255.0 [M + H]+.

[0840] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.840 min, ESI+ found [M-55] = 255.0.

[0841] Step3: l-amino-5-(2-chlorophenyl)pyrrolidin-2-one

[0842] A solution of tert-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-l-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 h and filtered. The filtered cake was washed with ethyl acetate (20 mL) and dissolved in water (20 mL). The solution was adjusted to pH = 9 by addition of 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 afford crude l-amino-5-(2- chlorophenyl)pyrrolidin-2-one (3.3 g, 97%) as a white solid. LCMS RT= 0.615 min, m / z = 211.0 [M + H]+.

[0843] LCMS (5 to 95% acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.615

[0844] = 211.0.

[0845]

[0846] Step4: l-amino-5-(2-chlorophenyl)pyrrolidin-2-one

[0847] A mixture of l-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 h and concentrated under reduced pressure to give crude ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-l-yl]amino]-2- imino-acetate (4.8 g, 99%) as a brown oil. LCMS RT= 0.675 min, m / z = 310.0 [M + H]+.

[0848] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.675

[0849] = 310.0.

[0850]

[0851] Step5: (S)-ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate

[0852] A mixture of ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-l-yl]amino]-2-imino-acetate (4.8 g, 15.5 mmol) and phosphorus oxychloride (21.4 g, 139.5 mmol) was stirred at 100 °C for 3 h and cooled to 25 °C. The mixture was carefully poured into water (100 mL) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l ,2-b] [l,2,4]triazole-2-carboxylate (3.0 g, 66%) as a brown oil. LCMS RT= 0.741 min, m / z = 292.1 [M + H]+.

[0853] LCMS (5 to 95% acetonitrile in water + 0.03%> trifluoacetic acid over 1.5 mins) retention time 0.741 min, ESI+ found [M+H] = 292.1.

[0854] The above racemic material (1.0 g, 3.43 mmol) was further separated by SFC to afford arbitartily assigned:

[0855] (S)-ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l ,2-b] [l,2,4]triazole-2-carboxylate (peak 2, retention time = 4.11 1 min) (400 mg, 40%) and (R)-ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H- pyrrolo[l ,2-b] [l ,2,4]triazole-2-carboxylate (peak 1 , retention time = 3.762 min) (400 mg, 40%o), both as yellow solids.

[0856] SFC condition: Column: AD-3 (250mm*30mm,5 μιη); Condition: 0.1 %NH3H2O EtOH; Begin B 30% End B 30%o; Flow Rate (60 mL / min), Column temperature 40 °C.

[0857]

[0858] Step 6: (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxylic acid

[0859] A mixture of ethyl (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l ,2-b] [l,2,4]triazole-2-carboxylate (400 mg, 1.37 mmol) and lithium hydroxide monohydrate (287 mg, 6.86 mmol) in ethanol (2 mL), water (2mL) and tetrahydrofuran (2 mL) was stirred at 25 °C for 12 h and concentrated under reduced pressure. The residue was diluted with ice water (2 mL) and adjusted to pH = 3 by addition of hydrochloric acid (2 M). The solid product was collected by filtration and washed with acetonitrile to afford crude (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l ,2-b][l ,2,4]triazole-2-carboxylic acid (350 mg, 97%) as a white solid. LCMS RT= 0.642 min, m / z = 264.0 [M + H]+.

[0860] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.642 min, ESI+ found [M+H] = 264.0.

[0861]

[0862] Step 7: (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide A mixture of 1 -hydro xybenzotriazole (215 mg, 1.59 mmol), N,0-dimethylhydroxylamine hydrochloride (194 mg, 1.99 mmol), (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylic acid (350 mg, 1.33 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydro chloride (305 mg, 1.59 mmol) and N,N-diisopropylethylamine (515 mg, 3.98 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 12 h. The reaction was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (2 x 25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 10 to 35% ethyl acetate in petroleum ether) to afford (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazole-2-carboxamide (300 mg, 74%) as a colorless oil. LCMS RT= 0.700 min, m / z = 307.0 [M + H]+.

[0863] LCMS (5 to 95%o acetonitrile in water + 0.03%o trifluoacetic acid over 1.5 mins) retention time 0.700 min, ESI+ found [M+H] = 307.0.

[0864]

[0865] Step 8: l-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]propan-l- one

[0866] To a cooled (0 °C) solution of (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H- pyrrolo[l,2-b] [l,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 h and quenched by addition of saturated aqueous 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 afford l-[(5S)-5-(2-chlorophenyl)-6,7- dihydro-5H-pyrrolo[l ,2-b] [1 ,2,4]triazol-2-yl]propan-l -one (5.7 mg, 31 %) as a white solid. ¾ NMR (400MHz, CD3OD) δ 7.52 - 7.50 (m, 1H), 7.38 - 7.33 (m, 2H), 6.96 - 6.94 (m, 1H), 5.99 - 5.96 (m, 1H), 3.40 - 3.33 (m, 1H), 3.14 - 3.11 (m, 2H), 3.07 - 3.03 (m, 2H), 2.68 - 2.65 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H). LCMS RT= 1.185 min, m / z = 276.1 [M + H]+.

[0867] LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2 mins) retention time 1.185 min, ESI+ found [M+H] = 276.1

[0868] Method 51 Example 72

[0869] [l-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0870] Step 1: l-(ethoxycarbonyl)cyclopropanecarboxylic acid

[0871] 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 h and diluted with ethyl acetate (60 mL). The organic layer was discarded. The aqueous phase was adjusted to pH = 3 by addition of aqueous hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 1- ethoxycarbonylcyclopropanecarboxylic acid (6.6 g, 78%) as a colorless oil. ¾ NMR (400MHz, CDC13) δ 12.86 (br s, 1H), 4.31 - 4.17 (m, 2H), 1.87 - 1.81 (m, 2H), 1.77 - 1.69 (m, 2H), 1.32 - 1.24

[0872]

[0873] Step 2: ethyl l-(hydroxymethyl)cyclopropanecarboxylate

[0874] To a mixture of 1 -ethoxycarbonylcyclopropanecarboxylic acid (6.6 g, 41.7 mmol) and triethylamine (6.98 mL, 50.1 mmol) in tetrahydrofuran (60 mL) was added isobutyl chloroformate (8.12 ml, 62.6 mmol) dropwise at 0 °C. After addition, the reaction was stirred at 0 °C for 1 h and filtered. The filtrate was then added to a mixture of sodium borohydride (1.6 g, 41.7 mmol) in tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture was stirred at 0 °C for 1 h and quenched by addition of 10% acetic acid (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30%o ethyl acetate in petroleum ether) to give ethyl 1- (hydroxymethyl)cyclopropanecarboxylate (3.8 g, 63 %>) as a colorless oil. ¾ NMR (400MHz, CDC13) δ 4.17 - 4.08 (m, 2H), 3.62 (s, 2H), 1.29 - 1.21 (m, 5H), 0.87 - 0.84 (m, 2H).

[0875] Step 3: ethyl l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylate

[0876] To stirred solution of ethyl 1 -(hydro xymethyl)cyclopropane-l-carboxylate (1.0 g, 6.94 mmol) in N,N- dimethylformamide (20 mL) was added imidazole (1.4 g, 20.81 mmol) and tert- butyldiphenylchlorosilane (3.8 g, 13.87 mmol) at 0 °C. The mixture was stirred at 25 °C for 18 h and poured into water (30 mL). The solution was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford ethyl l-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopro panecarboxylate (2.3 g, 87%) as a colorless oil. ¾ NMR (400MHz, CD3OD) δ 7.70 - 7.61 (m, 4H), 7.46 - 7.35 (m, 6H), 4.15 - 4.06 (m, 2H), 3.85 (s, 2H), 1.23 (t, J= 7.0 Hz, 3H), 1.17 - 1.11 (m, 2H), 1.04 (s, 9H), 0.93 - 0.87 (m, 2H).

[0877]

[0878] Step 4: l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylic acid

[0879] A mixture of ethyl l-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylate (1.0 g, 2.61 mmol) and lithium hydroxide monohydrate (438 mg, 10.46 mmol) in tetrahydrofuran (16 mL), methyl alcohol (16 mL) and water (8 mL) was stirred at 25 °C for 18 h. The organic solvent was removed under reduced pressure. The aqueous residue was washed with ethyl acetate (15 mL) and adjusted to pH = 3 by addition of aqueous hydrochloric acid (4 M) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude l-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclopropane carboxylic acid (950 mg, 100%o) as a light stick white solid. This crude was used in next step without further purification.

[0880] Step 5: l-(((tert-butyldiphenylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropanecar boxamide

[0881] A mixture of l-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg, 2.68 mmol), N,0-dimethylhydroxylamine hydrochloride (523 mg, 5.36 mmol), N,N-diisopropylethylamine (1.43 mL, 8.04 mmol), 1 -hydro xybenzotriazole (217 mg, 1.61 mmol) and l-(3-dimethylaminopropyl)- 3-ethylcarbodiimidehydrochloride (771 mg, 4.02 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 18 h. The resulting mixture was poured into water (20 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (15% ethyl acetate in petroleum ether, Rf= 0.4) to afford l-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N- methyl-cyclopropanecarboxamide (700 mg, 66%) as a colorless oil. ¾ NMR (400MHz, CDC13) δ

[0882] 7.68 - 7.63(m, 4H), 7.42 - 7.25 (m, 6H), 3.79 (s, 2H), 3.62 (s, 3H), 3.23 (s, 3H), 1.04 - 0.99 (m, 9H), 0.75 - 0.71 (m, 2H).

[0883]

[0884] Step 6: (l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7- dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)methanone

[0885] To a mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole (100 mg, 0.35 mmol) and l-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N-methyl- cyclopropanecarboxamide (282 mg, 0.71 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexanes, 0.43 mL, 1.06 mmol) dropwise under nitrogen atmosphere at -78 °C. After addition, the mixture was stirred at -78 °C for 1 h and then quenched by addition of saturated aqueous 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%o ethyl acetate in petroleum ether, Rf= 0.4) to afford [l-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]methanone (60 mg, 31%) as a light brown oil.

[0886] Step 7: [l-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]methanone

[0887] To a solution of [l-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[l ,2-b] [ l,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 h 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%o ammonia hydroxide in water) to afford arbitrarily assigned [ 1 -(hydroxymethyl)cyclopropyl] -[(5 S,7S)-7-fluoro-5 -phenyl-6,7-dihydro-5H-pyrrolo [ 1 ,2- b] [l,2,4]triazol-2-yl]methanone (7.8 mg, 18%) as a light brown oil. ¾ NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.30 - 7.26 (m, 2H), 6.19 - 6.16 (m, 0.5H), 6.05 - 6.02 (m, 0.5H), 5.65 - 5.61 (m, 1H), 3.97 - 3.85 (m, 2H), 3.84 - 3.68 (m, 1H), 2.87 - 2.80 (m, 1H), 1.72 - 1.67 (m, 2H), 1.11 - 1.08 (m, 2H). LC-MS RT= 0.695 min, m / z = 302.1 [M+H]+.

[0888] LCMS (5 to 95%o acetonitrile in water + 0.03 %> trifluoacetic acid over 1.5 mins) retention time 0.695 min, ESI+ found [M+H] = 302.1.

[0889] Method 52

[0890] Example 73

[0891] (3,3-dffluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4] triazol- 2-yl)methanone

[0892]

[0893] Step 1: 3,3-difluoro-N-methoxy-N-methylcyclobutanecarboxamide

[0894] A mixture of 1 -hydroxybenzotriazole (297 mg, 2.20 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydro chloride (845 mg, 4.41 mmol), 3,3-difluorocyclobutanecarboxylic acid (500 mg, 3.67 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (537 mg, 5.51 mmol) and N,N- diisopropylethylamine (1187 mg, 9.18 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 5 h and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 3,3- difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (430 mg, 65%) as a colorless oil. ¾ NMR (400MHz, CDC13) δ 3.67 (s, 3H), 3.33 - 3.22 (m, 1H), 3.20 (s, 3H), 2.93 - 2.78 (m, 2H), 2.76 - 2.64 (m, 2H).

[0895]

[0896] Step 2: (3,3-difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl)methanone

[0897] 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[l,2-b] [l,2,4]triazole (60 mg, 0.21 mmol) in tetrahydrofuran (13 mL) was added n-butyllithium (2.5 M in hexanes, 0.26 mL, 0.64 mmol) dropwise at -78 °C. After addition, the mixture was stirred at -78 °C for 2 h and quenched by addition of saturated aqueous ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 20 - 45%ο / 0.225%ο hydrochloric acid in water) to give arbitrarily assigned (3,3-difluorocyclobutyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]methanone (12.4 mg, 18%) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 3H), 7.30 - 7.28 (m, 2H), 6.20 - 6.17 (m, 0.5H), 6.06 - 6.03 (m, 0.5H), 5.66 - 5.64 (m, 1H), 3.97 - 3.80 (m, 1H), 3.78 - 3.74 (m, 1H), 2.91 - 2.83 (m, 5H). LCMS RT= 1.241 min, m / z = 322.2 [M+H]+.

[0898] LCMS (10 to 80%o acetonitrile in water + 0.03%o trifluoacetic acid over 2 mins) retention time 1.241 min, ESI+ found [M+H] = 322.2.

[0899] Method 53 Example 74 ((5S,7S)-7-fluoro-5-phenyl-6,7-dihy dro-5H-pyrrolo [1 ,2-b] [1 ,2,4] triazol-2-yl)(2-(pyridin-2- yl)cyclopropyl)methanone

[0900]

[0901] Step 1 : N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide

[0902] A mixture of 1 -hydro xybenzotriazole (149 mg, 1.10 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydro chloride (423 mg, 2.21 mmol), 2-(pyridin-2-yl)cyclopropanecarboxylic acid (300 mg, 1.84 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (269 mg, 2.76 mmol) and N,N- diisopropylethylamine (594 mg, 4.60 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 16 h and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-2-(pyridin-2- yl)cyclopropanecarboxamide (300 mg, 79%) as a colorless oil. ¾ NMR (400 MHz, CDC13) δ 8.47 - 8.43 (m, 1H), 7.57 - 7.51 (m, 1H), 7.27 - 7.22 (m, 1H), 7.10 - 7.02 (m, 1H), 3.68 (s, 3H), 3.21 (s, 3H), 2.76 (s, 1H), 2.61 - 2.52 (m, 1H), 1.63 - 1.55 (m, 2H).

[0903]

[0904] Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl)(2-(pyridin- 2-yl)cyclopropyl)methanone

[0905] To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole (150 mg, 0.53 mmol) and N-methoxy-N-methyl-2-(2- pyridyl)cyclopropanecarboxamide (219 mg, 1.06 mmol) in 2-Methyltetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in n-hexane, 0.64 mL, 1.6 mmol) under nitrogen atmosphere. The mixture was stirred at -78 °C for about 30 min and quenched by 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 reduce pressure. The residue was purified by RP-HPLC (acetonitrile 32 - 62%o / 0.05%i ammonia hydroxide in water) to give arbitrarily assigned [(5S,7S)-7- fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]-[2-(2-pyridyl)cyclopropyl] methanone (11.0 mg, 6%) as a faint pink solid. ¾ NMR (400 MHz, CD3OD) δ 8.39 - 8.37 (m, 1H), 7.69 - 7.65 (m, 1H), 7.42 - 7.31 (m, 4H), 7.27 - 7.17 (m, 3H), 6.18 - 6.02 (m, 1H), 5.65 - 5.61 (m, 1H), 3.83 - 3.67 (m, 1H), 3.56 - 3.51 (m, 1H), 2.88 - 2.73 (m, 2H), 1.86 - 1.79 (m, 2H). LCMS RT= 0.745 min, m / z = 348.9 [M + H]+.

[0906] LCMS (10 to 80% acetonitrile in water + 0.1%o ammonia water over 3.0 mins) retention time 0.745 min, ESI+ found [M+H] =348.9.

[0907] Example 75

[0908] [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]-[rac-(lS,2S)-2- methylcyclopropyl] methanone

[0909] To a solution of trans-N-methoxy-N,2-dimethyl-cyclopropanecarboxamide (137 mg, 0.96 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole (180 mg, 0.64 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium bromide (3.0 M in tetrahydrofuran, 0.85 mL, 2.55 mmol) dropwise under nitrogen atmosphere at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h and quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting solution was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30%o ethyl acetate in petroleum ether, Rf= 0.2) to afford arbitrarily assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l ,2-b] [l,2,4]triazol-2-yl]-[rac-(l S,2S)-2- methylcyclopropyl]methanone (trans mixture methylcyclopropyl mixture) (80 mg, 44%o) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.42 - 7.37 (m, 3H), 7.28 - 7.26 (m, 2H), 6.20 - 6.16 (m, 0.5H), 6.05 - 6.02 (m, 0.5H), 5.65 - 5.63 (m, 1H), 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-MS RT= 0.793 min, m / z = 286.1 [M+H]+.

[0910] LCMS (5 to 95%o acetonitrile in water + 0.03 %> trifluoacetic acid over 1.5 mins) retention time 0.793 min, ESI+ found [M+H] = 286.1.

[0911] Method 55

[0912] Example 76 [(5S,7S)-7-fluoro-5-phenyl-6,7-dih dro-5H-pyrrolo [1 ,2-b] [1 ,2,4] triazol-2-yl] -spiro [2.3] hexan-5- yl-methanone

[0913]

[0914] Step 1 : N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide

[0915] A mixture of spiro[2.3]hexane-5-carboxylic acid (150 mg, 1.19 mmol), N,N-diisopropylethylamine (0.5 mL, 2.97 mmol), 1-hydroxybenzotriazole (96.4 mg, 0.71 mmol) and Ν,Ο- dimethylhydroxylamine hydrochloride (174 mg, 1.78 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 16 h and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl- spiro[2.3]hexane-5-carboxamide (170 mg, 84%) as a colorless oil. ¾ NMR (400 MHz, CDC13) δ 3.66 (s, 3H), 3.20 (s, 3H), 2.60 - 2.54 (m, 2H), 2.17 - 2.12 (m, 2H), 0.50 - 0.40 (m, 4H).

[0916]

[0917] Step 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-2-yl]- spiro[2.3]hexan-5-yl-methanone

[0918] To a solution of N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (43 mg, 0.25 mmol), (5S,7S)- 2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l ,2,4]triazole (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.21 mL, 0.42 mmol) dropwise at 0°C. The mixture was stirred at 0 °C for 1 h and quenched by addition of saturated aqueous ammonium chloride (5 mL). The solution was then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resid...

Claims

A compound of formula (I):or pharmaceutically acceptable salts thereof, whereinR1is selected from the group consisting of Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, phenyl, benzyl, 4 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R1is bound to the adjacent carbonyl by a carbon atom, and wherein R1is optionally substituted by one or two substituents selected from the group consisting of F, CI, Br, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(0)Ci-C6alkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 5 to 6 membered heteroaryl, and CH2-(5 to 6 membered heteroaryl); each RNis independently selected from the group consisting of H, Ci-C6alkyl, C3-C6cycloalkyl, d- C6alkoxy, and Ci-C6haloalkyl; or two RNmay together with the adjacent N form a 4-6 membered ring;the A ring is a 5 membered heteroaryl having as the only heteroatoms, either (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom; wherein the A ring is bound to the adjacent carbonyl by a carbon atom; andthe B ring is a 4 to 8 membered cycloalkyl, or a 4 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is substituted according to (a), (b), or both (a) and (b):(a) 1 to 2 substituents selected from the group consisting of halogen, deuterium, hydroxy, Q- C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, and cyano; wherein two Ci-C6alkyl substituents may together for a bridged or spirocyclic ring; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano, or a Ci-C6alkoxy, Ci-C6haloalkoxy or Ci-C6thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;(b) 1 substituent selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, phenyl, benzyl, CH2-(C3-C6cycloalkyl), CH2CH2-(C3-C6cycloalkyl), 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 5 to 6 membered heteroaryl ring is present it may be substituted by 1 to 3 substituents selected from thegroup consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, Q-C4 alkoxy, C1-C4 haloalkoxy, cyano, and cyclopropyl.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-N(RN)2, phenyl, benzyl, 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R1is bound to the adjacent carbonyl by a carbon atom, and wherein R1is optionally substituted by one or two substituents selected from the group consisting of F, CI, methyl, ethyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy.each RNis independently selected from the group consisting of H, Ci-C6alkyl, C3-C6cycloalkyl, d- C6alkoxy, and Ci-C6haloalkyl; or two RNmay together with the adjacent N form a 4-6 membered ring;the A ring is a 5 membered heteroaryl having as the only heteroatoms, either (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom; wherein the A ring is bound to the adjacent carbonyl by a carbon atom; andthe B ring is a 4 to 8 membered cycloalkyl, or a 4 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is substituted according to (a), (b), or both (a) and (b):(a) 1 to 2 substituents selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, Ci-C6alkyl-N(RN)2, and cyano; wherein two Ci-C6alkyl substituents may together for a bridged or spirocyclic ring; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano, or a Ci-C6alkoxy, Ci-C6haloalkoxy or Ci-C6thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;(b) 1 substituent selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, C\-C6alkyl-N(RN)2, phenyl, benzyl, CH2-(C3-C6cycloalkyl), CH2CH2-(C3-C6cycloalkyl), 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, Q-C4 alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, and cyano.

3. A compound of 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:whereinR2is selected from the group consisting of H, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 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, Ci-C4alkyl, Ci-C4haloalkyl, Q-C4 alkoxy, C1-C4 haloalkoxy, and cyano; andR3aand R3bare selected as follows:(i) one of Raand R is H, and the other is selected from the group consisting of D, F, CI, OH, CN, C1-C4alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and C1-C4haloalkoxy;(ii) each of R3aand R3bis selected from the group consisting of D, F, CI, OH, CN and methyl, provided that R3aand R3bcannot both be OH or CN; or(iii) R3aand R3btogether form cyclopropyl.

4. A compound of 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:whereinR2is selected from the group consisting of H, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6thioalkyl, phenyl, benzyl, CH2-(C3-C6cycloalkyl), 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 itmay be substituted by 1 to 3 substituents selected from the group consisting of halogen, Ci-C4alkyl, C1-C4 haloalkyl, Q-C4alkoxy, C1-C4haloalkoxy, and cyano; andR4aand R4bare selected as follows:(i) one of R4aand R4bis H, and the other is selected from the group consisting of D, F, CI, OH, CN, C1-C4alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and C1-C4haloalkoxy; or(ii) each of R4aand R4bis selected from the group consisting of D, F, CI and methyl.

5. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl and dichlorophenyl.

6. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are selected from the group consisting of:R3aand R3bare selected as follows:(i) one of R3aand R3bis H, and the other is selected from the group consisting of D, F, CI, OH, CN, C1-C4alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and C1-C4haloalkoxy;(ii) each of R3aand R3bis selected from the group consisting of D, F, CI, OH, CN and methyl, provided that R3aand R3bcannot both be OH or CN; or(iii) R3aand R3btogether form cyclopropyl;each R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy and Ci-C6haloalkoxy; andm is 1, 2 or 3.

7. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are:whereineach R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy and Ci-C6haloalkoxy; andm is 1, 2 or 3.

8. A compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl and dichlorophenyl.

9. A compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are selected from the group consisting of:whereinR4aand R4bare selected as follows:(i) one of R4aand R4bis H, and the other is selected from the group consisting of F, CI, OH, CN, Ci-C4alkyl, C1-C4haloalkyl, cyclopropyl, C1-C4alkoxy and Q-C4 haloalkoxy; or(ii) each of R4aand R4bis selected from the group consisting of F, CI and methyl;each R5is selected from the group consisting of H, F, CI, Ci-C6alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy; andm is 1, 2 or 3.

10. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1 or Table 2.

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound selected is a compound having a RIP1 kinase inhibitory activity K; of less than 100 nM.

12. A pharmaceutical composition comprising a compound in accordance with any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

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

14. A compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

15. The use of a compound or composition according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

16. The use of a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of Parkinson's Disease, 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

17. The use of a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondylarthritis, juvenile idiopathic arthritis, and osteoarthritis.

18. A method for the treatment of a disease or disorder in a human, the method comprising administration to the human of an effective treatment amount of a compound or composition according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is 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, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

19. A method for the treatment of a disease or disorder in a human, the method comprising administration to the human of an effective treatment amount of a compound or composition according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder 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 osteoarthritis20. The method of claim 1 8, wherein the disease or disorder is Alzheimer's disease.

21. The method of claim 1 8, wherein the disease or disorder is multiple sclerosis.

22. The method of claim 1 8, wherein the disease or disorder is Parkinson's disease.

23. The method of claim 1 8, wherein the disease or disorder is amyotrophic lateral sclerosis.

24. The method of claim 1 8, wherein the disease or disorder is Huntington's disease.

25. The method of claim 1 8, wherein the disease or disorder is spinal muscular atrophy.

26. The method of claim 1 9, wherein the disease or disorder is an inflammatory bowel disease.

27. The method of claim 1 9, wherein the disease or disorder is Crohn's disease.

28. The method of claim 1 9, wherein the disease or disorder ulcerative colitis.

29. The method of claim 1 9, wherein the disease or disorder is psoriasis.

30. The method of claim 1 9, wherein the disease or disorder is psoriatic arthritis.

31. The method of claim 1 9, wherein the disease or disorder is rheumatoid arthritis.

32. The method of claim 1 9, wherein the disease or disorder is spondyloarthritis.

33. The method of claim 1 9, wherein the disease or disorder is juvenile idiopathic arthritis.