HK40017913B - Bicyclic ketone compounds and methods of use thereof - Google Patents

Description

Bicyclic ketone compounds and their uses

Invention Field

This invention relates to organic compounds that can be used for treatment and/or prevention in mammals, and particularly to RIP1 kinase inhibitors that can be used to treat diseases and conditions associated with inflammation, cell death, etc.

Background of the Invention

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

Necrotic apoptosis has important pathophysiological significance in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel disease, retinal degeneration, and many other common clinical conditions[16]. Therefore, selective inhibitors of RIP1 kinase activity are expected to be a potential treatment for diseases mediated by this pathway and associated with inflammation and/or necrotic cell death.

Inhibitors of RIP1 kinase have been previously described. The first publicly disclosed inhibitor of RIP1 kinase activity was necrostatin 1 (Nec-1) [17]. Following this initial discovery were modified versions of Nec-1 with various abilities to block RIP1 kinase activity [11, 18]. More recently, other RIP1 kinase inhibitors have been described that are structurally different from necrostatin-like compounds [19, 20, 21].

Each of the references cited above is combined here in its entirety through citation:

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

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

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

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

5) O′Donnell, M.A., Legarda-Addison, D., Skountzos, P., Yeh, W.C. and Ting, A.T. (2007) Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-deathswitch in TNF signaling. Curr Biol. 17, 418-424.

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

7) Bertrand, M.J., Milutinovic, S., Dickson, K.M., Ho, W.C., Boudreault, A., Durkin, J., Gillard, J.W., Jaquith, J.B., Morris, S.J., and Barker, P.A. (200 8) cIAP1 andcIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 30, 689-700.

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

9) He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L. and Wang,

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

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

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

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

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

15) Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yah, J., Liu, W., Lei, X. and Wang, X. (2012) Mixed Line age Kinase Domain-like Protem MediatesNecrosis Signaling Downstream of RIP3 Kinase.Cell.148, 213-227.

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

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

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

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

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

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

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

Invention Overview

Compounds of Formula I are provided herein:

Or its medicinal salt, in which

^R1 is selected from the group consisting of: _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 - _C6 haloalkoxy, _C1 - _C6 alkyl-N( ^RN ) ₂ , phenyl, benzyl, 4- to 8-membered heterocyclic and 5- to 6-membered heteroaryl; wherein ^R1 is linked to an adjacent carbonyl group via a carbon atom, and wherein ^R1 is optionally substituted by one or two substituents selected from the group consisting of: F, Cl, Br, _C1 - _{C6 alkyl, C3-C6 cycloalkyl , C1} - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 - _C6 haloalkoxy, _C1 - _C6 alkyl-N( ^RN ) ₂ , hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O) _C1 -C _6- alkyl, phenyl, benzyl, CH _2- (C ₃ -C ₆ cycloalkyl), 5- to 6-membered heteroaryl and CH _2- (5- to 6-membered heteroaryl);

Each R ^{and N} is independently selected from the group consisting of: H, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, and _C1 - _C6 haloalkyl; or the two R and ^N can form a 4-6 membered ring together with the adjacent N;

Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatom; wherein ring A is connected to the adjacent carbonyl group via a carbon atom; and

The B ring is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group 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) One or two substituents selected from the group consisting of: halogen, deuterium, hydroxyl, _C1 - _C6 alkyl, _C1 -C6 haloalkyl, C3- _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, _C1 - _C6 alkylthio, _C1 - _C6 alkyl-N( ^RN ) ₂ and _{cyano; wherein the two C1-C6 alkyl substituents may} together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not halogen, cyano, or a _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, or C1 _{- C6} alkylthio with an oxygen or sulfur atom directly bonded to the nitrogen atom;

(b) One substituent selected from the group consisting of: _C1 - _C6 alkyl, _C1 -C6 haloalkyl, C3- _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, C1-C6 alkylthio, _{C1 - C6} alkyl-N( ^RN ) ₂ , phenyl, benzyl, _CH2- ( _C3 - _C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), _CH2- ( _4- to _6- membered heterocyclic), _CH2CH2- ( _4- to _6- membered heterocyclic), _5- to 6-membered heteroaryl, and _{CH2- ( 5-} to 6-membered heteroaryl); wherein, when a benzene ring or a 5- to 6-membered heteroaryl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, _C1 -C4 alkyl, _C1 -C4 haloalkyl, C1-C6 alkyl, C1- _{C6 alkyl} , _C1 -C6 alkyl, C1-C6 alkyl-N(RN) _2, phenyl, benzyl, CH2-( _C3- C6 cycloalkyl), ... ₄ -alkoxy, _C1 - _C4 haloalkoxy, cyano, and cyclopropyl.

Pharmaceutical compositions are also provided herein, comprising a compound of formula I or a pharmaceutical salt thereof, and one or more pharmaceutical carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

This document also provides oral formulations of compounds of Formula I or pharmaceutical salts thereof, as well as one or more pharmaceutical carriers or excipients suitable for oral delivery.

This article also provides methods for treating diseases and conditions related to inflammation, cell death, etc., involving RIP1 kinase, as further described below.

This document also provides compounds of formula I or their pharmaceutical salts, which are used as therapeutically active substances.

This document also provides compounds of Formula I or their pharmaceutical salts for the treatment of diseases or conditions 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, and stroke. roke, 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.

This document also provides compounds of Formula I according to any embodiment provided herein, or pharmaceutical salts thereof, or combinations thereof, for the treatment of diseases or conditions selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, tau proteinosis, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

This document also provides compounds of Formula I or pharmaceutical salts thereof for the preparation of medicaments for the treatment of diseases or conditions selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, tau proteinosis, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

This document also provides compounds of Formula I or their pharmaceutical salts for the treatment of diseases or conditions 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.

Invention Details

definition

As provided herein and as understood by one of ordinary skill in the art, all chemical formulas and general chemical structures should be interpreted as providing appropriate valences and chemically stable bonds between atoms. Where appropriate, substituents may be bonded to more than one adjacent atom (e.g., alkyl groups include methylene groups in which two bonds are present).

In the chemical formulas provided in this article, “halogen” or “halogenated” refers to fluorine, chlorine and bromine (i.e. F, Cl, Br).

Unless otherwise specified, alkyl means a _C1 - _C12 alkyl group that is optionally substituted, either straight-chain or branched. In some embodiments, alkyl means a _C1 - _C6 alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The substituted alkyl groups provided herein are substituted with one or more substituents selected from the group consisting of: halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, _C3 - _C6 cycloalkyl, phenyl, OH, _CO2H , _CO2 (C1-C4 alkyl), NH2, NH ( _C1 - _C4 alkyl), N ( _C1 - _C4 alkyl) ₂ , NH(C=O) _C1 - _C4 alkyl, (C=O)NH ( _C1 - _C4 alkyl), (C=O)N ( _C1 - _C4 alkyl) ₂ , S ( _C1 - _C4 alkyl), SO ( _{C1 -C4 alkyl} ), _SO2 ( _C1 - _C4 alkyl), _SO2NH ( _C1 - _C4 alkyl), _SO2N ( _{C1 - C4} alkyl) _2, and _NHSO2 ( _C1 - _C4 alkyl). In some embodiments, the substituted alkyl group has one or two substituents. In some embodiments, the alkyl group is unsubstituted.

Unless otherwise specified, cycloalkyl means optionally substituted _C3 - _C12 cycloalkyl groups, including fused, spirocyclic, and bridged bicyclic groups, wherein the substituents are selected from the group consisting of: halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, _C3 - _C6 cycloalkyl, phenyl, OH, _CO2H , _CO2 ( _C1 - _C4 alkyl), NH2, NH (C1-C4 alkyl), N ( _C1 - _C4 alkyl) ₂ , NH (C=O) _C1 - _C4 alkyl, (C=O)NH ( _{C1 - C4} alkyl), (C=O)N ( _C1 - _C4 alkyl) ₂ , S ( _C1 - _C4 alkyl), SO ( _C1 - _C4 alkyl), _SO2 ( _C1 - _C4 alkyl), _SO2NH ( _C1 - _C4 alkyl), _SO2N ( _C1 - _C4 alkyl) ₄ -alkyl) ₂ and NHSO ₂ ( _C1 - _C4 alkyl). In some embodiments, cycloalkyl refers to a _C3 - _C6 cycloalkyl group. In some embodiments, the _C3 - _C6 cycloalkyl group is optionally substituted with one to three halogen atoms. In some embodiments, the _C3 - _C6 cycloalkyl group is optionally substituted with one to three fluorine atoms. Exemplary _C3 - _C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Exemplary _C3 - _C12 cycloalkyl groups also include bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[4.1.0]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, decahydronaphthyl, and spiro[5.4]decyl. Where appropriate, the cycloalkyl group can be fused with other groups, such that there is more than one chemical bond between the cycloalkyl group and another ring system (e.g., the C ring of Formula I). In some embodiments, the cycloalkyl group is unsubstituted.

Unless otherwise specified, a haloalkyl group refers to a straight-chain or branched _C1 - _C12 alkyl group in which one or more hydrogen atoms are replaced by a halogen. In some embodiments, a haloalkyl group refers to a _C1 - _C6 haloalkyl group. In some embodiments, one to three hydrogen atoms in the haloalkyl group are replaced by a halogen. In some embodiments, each hydrogen atom in the haloalkyl group is replaced by a halogen (e.g., trifluoromethyl). In some embodiments, the haloalkyl group is as defined herein, wherein in each case the halogen is fluorine. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and pentafluoroethyl.

Unless otherwise specified, an alkoxy group refers to a straight-chain or branched _C1 - _C12 alkyl group, wherein in each case there are one or more oxygen atoms between two carbon atoms. In some embodiments, an alkoxy group refers to a _C1 - _C6 alkoxy group. In some embodiments, the _C1 - _C6 alkoxy group provided herein has one oxygen atom. _{Exemplary alkoxy} groups include methoxy _, ethoxy, _{CH2OCH3 , CH2CH2OCH3 , CH2OCH2CH3 , CH2CH2OCH2CH3 , CH2OCH2CH2CH3 , CH2CH2CH2OCH3 , CH2OCH ( CH3 ) 2 , CH2OC ( CH 3} ) ₃ , CH(CH ₃ )OCH ₃ , CH ₂ CH(CH ₃ )OCH ₃ , CH(CH ₃ )OCH ₂ CH ₃ , CH ₂ OCH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ and CH ₂ OCH ₂ OCH ₂ OCH ₃ .

Unless otherwise specified, cycloalkoxy means a _C4 - _C10 or _C4 - _C6 alkoxy group as defined above, wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxacyclobutyl, tetrahydrofuran, and tetrahydropyran.

Unless otherwise specified, a haloalkoxy group refers to a _C1 - _C6 haloalkyl group as defined above, wherein in each case there is one or two oxygen atoms between the two carbon atoms. In some embodiments, the _C1 - _C6 haloalkoxy groups provided herein have one oxygen atom. Exemplary haloalkoxy groups include _OCF3 , _{OCHF2 ,} and _CH2OCF3 .

Unless otherwise specified, thioalkyl refers to a _C1 - _C12 or _C1 - _C6 alkoxy group as defined above, in which an oxygen atom is replaced by a sulfur atom. In some embodiments, the thioalkyl group may include a sulfur atom replaced by one or two oxygen atoms (i.e., alkyl sulfones and alkyl sulfoxides). Exemplary thioalkyl groups are those exemplified in the above definition of alkoxy groups, wherein in each case each oxygen atom is replaced by a sulfur atom.

Unless otherwise specified, a thiocycloalkyl group refers to a _C4 - _C10 or _C4 - _C6 alkylthio group as defined above, wherein each group is cyclic and contains one sulfur atom. In some embodiments, the sulfur atom of the thiocycloalkyl group is replaced by one or two oxygen atoms (i.e., cyclic sulfones or sulfoxides). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiocyclopentyl, and 1,1-dioxothiocyclohexyl.

Unless otherwise specified, a heterocyclic group refers to a single saturated or partially unsaturated 4- to 8-membered ring having at least one atom other than carbon, wherein said atom is selected from the group consisting of oxygen, nitrogen, and sulfur; the term also includes polyfused ring systems having at least one such saturated or partially unsaturated ring, said polyfused ring systems having 7 to 12 atoms and are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, 7, or 8-membered ring) having 1 to 7 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be C-branched (i.e., substituted with _C1 - _C4 alkyl groups). The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. In a polyfused ring system, the rings can be connected to each other via fusion, spiking, and bridging, provided the valence requirements are met. It should be understood that the individual rings of a polyfused ring system can be connected relative to each other in any order. It should also be understood that the connection points in a polyfused ring system (as defined above for heterocycles) can be located anywhere within the polyfused ring system. Furthermore, it should be understood that the connection points in a heterocycle or a heterocyclic polyfused ring system can be located at any suitable atom (including carbon and nitrogen atoms) of the heterocyclic group. Exemplary heterocycles include, but are not limited to: aziridinyl, aziridinyl, pyrrolyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiaranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3] Heptyl, imidazolidin-2-one N-methylpiperidine, imidazolidin, pyrazolidine, butyrolactam, valproic acid, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrrololine, thiaran, pyranone, tetrahydrothiophene, quinine ring, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidone-2-one.

In some embodiments, the heterocyclic group is a _C4 - _C10 heterocyclic group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group is neither bicyclic nor spirocyclic. In some embodiments, the heterocyclic group is a _C5 - _C6 heterocyclic group having 1 to 3 heteroatoms, wherein if 3 heteroatoms are present, at least 2 are nitrogen atoms.

Unless otherwise specified, aryl refers to a single all-carbon aromatic ring or a polycyclic 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 phenyl groups. Aryl also includes polycyclic ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), wherein at least one ring is aromatic, and wherein the other rings may be aromatic or non-aromatic (i.e., carbon rings). Such polycyclic ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the polycyclic ring system. The rings of a polycyclic ring system can be connected to each other by fusion, spiro bonds, and bridging bonds, provided that valence requirements are met. It should be understood that, as defined above, the connection points of a polycyclic ring system can be located anywhere in the ring system, including the aromatic or carbon ring portions of the ring. Exemplary aryl groups include phenyl, indene, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracene, etc.

Unless otherwise specified, a heteroaryl refers to a 5- to 6-membered aromatic ring having at least one atom other than carbon, wherein said atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes polyfused ring systems having 8 to 16 atoms having at least one such aromatic ring, said polyfused ring systems being further described below. Thus, "heteroaryl" comprises a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polyfused ring systems (e.g., ring systems comprising 2 or 3 rings), wherein, as defined above, the heteroaryl group is fused with one or more rings selected from: a heteroaryl (to form, for example, naphridinyl, such as 1,8-naphridinyl), a heterocycle (to form, for example, 1,2,3,4-tetrahydronaphridinyl, such as 1,2,3,4-tetrahydro-1,8-naphridinyl), a carbocyclic ring (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and an aryl (to form, for example, indazole), thereby forming a polyfused ring system. Thus, a heteroaryl (single aromatic ring or polyfused ring system) has 1 to 15 carbon atoms and about 1 to 6 heteroatoms within the heteroaromatic ring. Such polyfused ring systems may optionally have one or more (e.g., 1, 2, 3, or 4) oxo groups substituted on the carbocyclic or heterocyclic portion of the fused ring. The rings of a polyfused ring system can be connected to each other by fusion, spiking, and bridging, provided that valence requirements are met. It should be understood that the individual rings of a polyfused ring system can be connected in any order relative to each other. It should also be understood that the connection points of a polyfused ring system (as defined above for heteroaryl groups) can be located anywhere within the polyfused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portion of the polyfused ring system. Furthermore, it should be understood that the connection points of a heteroaryl or heteroaryl polyfused ring system can be located at any suitable atom (including carbon atoms and heteroatoms (e.g., nitrogen atoms)) within the heteroaryl or heteroaryl polyfused ring system. Exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, indazole, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thionyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole.

As used herein, the term “chiral” refers to a molecule that has the property that its mirror-pairs cannot overlap, while the term “chiral” refers to a molecule that can overlap on its mirror-pairs.

As used herein, the term “stereoisomer” refers to compounds that have the same chemical composition but whose atoms or groups are arranged differently in space.

As used in this article, the wavy lines intersecting with bonds in the chemical structure indicate the connection points where the wavy bond intersects with the rest of the molecule.

As used herein, the term “C-linked” means that the group described by the term is linked to the rest of the molecule through a ring carbon atom.

As used herein, the term “N-linked” means that the group described by the term is linked to the rest of the molecule via a cyclic nitrogen atom.

A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

The stereochemical definitions and conventions used herein generally follow those of S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers and thus exist in various stereoisomeric forms. All stereoisomers of the compounds of this invention (including, but not limited to, diastereomers, enantiomers, and rotational isomers, and mixtures thereof, such as racemic mixtures) are intended to form part of this invention. Many organic compounds exist in an optically active form, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l, or (+) and (-), are used to indicate the rotation of a compound's plane-polarized light, where (-) or 1 indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when stereoselectivity or stereospecificity is no longer present in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that is not optically active.

When bonds in the structural formulas of compounds herein are drawn in a non-stereochemical manner (e.g., flat), the atoms bonded by that bond encompass all stereochemical possibilities. When bonds in the structural formulas of compounds herein are drawn in a defined stereochemical manner (e.g., bold, bold-wedge, dashed, or dashed-wedge), it should be understood that, unless otherwise stated, the atoms bonded by that stereochemical bond are abundant in the depicted absolute stereoisomers. In one embodiment, the compound may be at least 51% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 80% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 90% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 95% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 97% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 98% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 99% of the depicted absolute stereoisomers.

As used herein, the term "tautomer" or "tautomer form" refers to structural isomers of different energies that can interconvert through low energy barriers. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.

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

As used herein, the term "protecting group" refers to a substituent commonly used to block or protect a specific functional group on a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects an amino functional group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxyl group that blocks or protects a hydroxyl functional group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a protecting group of a carboxyl group that blocks or protects a carboxyl functional group. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, etc. For a general description of the protecting groups and their uses, see P.G.M. Wuts and T.W. Greene, Greene’s Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006.

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

As used herein, the term "pharmaceutical salt" means a salt comprising an active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents present on the compound described herein. When the compounds of the present invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base under pure (neat) conditions or in a suitable inert solvent. Examples of salts derived from pharmaceutical inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from medicinal organic bases include salts of the following: primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid under pure (neat) conditions or in a suitable inert solvent. Examples of pharmaceutical acid addition salts include those derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, etc.) and those derived from relatively non-toxic organic acids (such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.). Salts of amino acids (such as arginine) and salts of organic acids (such as glucuronic acid or galacturonic acid, etc.) are also included (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 functional groups, which allows the compound to be converted into a basic addition salt or an acid addition salt.

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

In addition to the salt form, the present invention also provides compounds in the form of prodrugs. As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of the present invention.

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

Other types of prodrugs are also included. For example, the free carboxyl group of the compounds of the present invention can be derived into an amide or alkyl ester. As another example, the compounds of the present invention containing a free hydroxyl group can be derived into prodrugs by converting the hydroxyl group into a group such as, but not limited to, phosphate esters, hemisuccinates, dimethylaminoacetate esters, or phosphoryloxymethoxycarbonyl groups, as described in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs containing hydroxyl and amino groups are also included, as are carbonate prodrugs containing hydroxyl groups, sulfonates, and sulfates. Prodrugs derived from hydroxyl groups into (acyloxy)methyl ethers and (acyloxy)ethyl ethers are also included, wherein the acyl group can be an alkyl ester optionally substituted with a group including but not limited to ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include replacing the hydrogen atom of an alcohol group with a group such as ( _C1-6 )alkanoyloxymethyl, 1-(( _C1-6 )alkanoyloxy)ethyl, 1-methyl-1-(( _C1-6 )alkanoyloxy)ethyl, ( _C1-6 )alkanoylcarbonyloxymethyl, N-( _C1-6 )alkanoylcarbonylaminomethyl, succinoyl, ( _C1-6 )alkanoyl, α-amino( _C1-4 )alkanoyl, aromatic acyl, and α-aminoyl or α-aminoyl-α-aminoyl, wherein each α-aminoyl group is independently selected from naturally occurring L-amino acids, P(O)(OH) ₂ , -P(O)(O( _C1-6 )alkyl) ₂ , or glycosyl (a group produced by removing the hydroxyl group from a sugar in the form of a hemiacetal).

For further examples of prodrug derivatives, see, for example, a) *Design of Prodrugs*, edited by H. Bundgaard (Elsevier, 1985) and *Methods in Enzymology*, Vol. 42, pp. 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”. The references to the citations of Prodrugs, H. Bundgaard, pp. 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) are all specifically incorporated herein by reference.

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

Metabolites are typically identified by preparing a radiolabeled (e.g., ^14C or ^3H ) isotope of the compound of the invention, administering it parenterally to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and isolating the metabolites from urine, blood, or other biological samples. These products are readily isolated because they are labeled (other methods use antibodies capable of binding to epitopes that survive in the metabolites). The metabolite structure is determined in a conventional manner, such as by MS, LC/MS, or NMR analysis. Typically, the metabolites are analyzed in the same manner as routine drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise found in vivo, they can be used in diagnostic tests for therapeutic administration of the compound of the invention.

Some compounds of the present invention may exist in both solvated and hydrated forms, including hydrated forms. Generally, the hydrated form is equivalent to the hydrated form and is intended to be included within the scope of the present invention. Some compounds of the present invention may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses contemplated by the present invention and are intended to fall within the scope of the present invention.

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

As used herein, the term "composition" is intended to include products containing specific amounts of specific ingredients, and any product produced directly or indirectly from a combination of specific amounts of specific ingredients. "Pharmaceutical" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipient.

The terms "treat" and "treatment" refer to therapeutic treatment and/or preventive treatment or preventive measures aimed at preventing or mitigating (alleviating) undesirable physiological changes or impairments, such as, for example, the development or spread of cancer. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, reduction of the severity of disease or condition, a stable (i.e., non-worsening) state of disease or condition, delay or slowing of disease progression, improvement or mitigation of disease state or condition, and relief (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolonged survival compared to expected survival without treatment. Those requiring treatment include those already suffering from the said disease or condition, those susceptible to the said disease or condition, or those for which the said disease or condition is to be prevented.

The terms "therapeutic effective amount" or "effective amount" mean the amount of the compound of the present invention that (i) treats or prevents a particular disease, condition, or symptom, (ii) weakens, improves, or eliminates one or more symptoms of a particular disease, condition, or symptom, or (iii) prevents or delays the occurrence of one or more symptoms of a particular disease, condition, or symptom described herein. For cancer treatment, efficacy can be measured, for example, by assessing time to progression (TTP) and/or determining response rate (RR).

The term "bioavailability" refers to the systemic utilization (i.e., blood/plasma level) of a given amount of drug administered to a patient. Bioavailability is an absolute term that measures the time (rate) and the total amount of drug from the administered dosage form to the systemic circulation.

RIP1 kinase inhibitors

This invention provides novel compounds having general formula I.

Or its medicinal salt, in which

^R1 is selected from the group consisting of: _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 - _C6 haloalkoxy, _C1 - _C6 alkyl-N( ^RN ) ₂ , phenyl, benzyl, 4- to 8-membered heterocyclic and 5- to 6-membered heteroaryl; wherein ^R1 is linked to an adjacent carbonyl group via a carbon atom, and wherein ^R1 is optionally substituted by one or two substituents selected from the group consisting of: F, Cl, Br, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 -C6 haloalkoxy, _{C1 -C6 alkyl} -N( ^RN ) ₂ , hydroxy, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O) _C1 -C _6- alkyl, phenyl, benzyl, CH _2- (C ₃ -C ₆ cycloalkyl), 5- to 6-membered heteroaryl and CH _2- (5- to 6-membered heteroaryl);

Each R ^{and N} is independently selected from the group consisting of: H, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, and _C1 - _C6 haloalkyl; or the two R and ^N can form a 4-6 membered ring together with the adjacent N;

Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatom; wherein ring A is connected to the adjacent carbonyl group via a carbon atom; and

The B ring is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group 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) One or two substituents selected from the group consisting of: halogen, deuterium, hydroxyl, _C1 - _C6 alkyl, _C1 -C6 haloalkyl, C3- _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, _C1 - _C6 alkylthio, _C1 - _C6 alkyl-N( ^RN ) ₂ and _{cyano; wherein two C1-C6 alkyl substituents may} together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not a halogen or cyano, or is not a _C1 - _C6 alkoxy, _C1 -C6 haloalkoxy or C1 _{- C6} alkylthio with an oxygen or sulfur atom directly bonded to the _nitrogen atom;

(b) One substituent selected from the group consisting of: _C1 - _C6 alkyl, C1-C6 haloalkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, C1-C6 alkylthio, _{C1 - C6} alkyl-N( ^RN ) ₂ , phenyl, benzyl, _CH2- ( _C3 - _C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), _CH2- ( _4- to _6- membered heterocyclic), _CH2CH2- ( _4- to _6- membered heterocyclic), _5- to 6-membered heteroaryl, and _{CH2- ( 5-} to 6-membered heteroaryl); wherein, when a benzene ring or a 5- to 6-membered heteroaryl ring is present, it may be substituented by 1 to 3 substituents selected from the group consisting of: halogen, _C1 -C4 alkyl, _C1 -C4 haloalkyl, C1-C6 alkyl, C1- _C6 alkyl, C1-C6 alkyl, C1- _C6 alkyl-N(RN) _2, phenyl, benzyl, CH2-( _C3- C6 cycloalkyl), ... ₄ -alkoxy, _C1 - _C4 haloalkoxy, and cyano.

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

Or its medicinal salt, in which

^R1 is selected from the group consisting of: _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 - _C6 haloalkoxy, _C1 - _C6 alkyl-N( ^RN ) ₂ , phenyl, benzyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl; wherein ^R1 is connected to the adjacent carbonyl group by a carbon atom, and wherein ^R1 is optionally substituted by one or two substituents selected from the group consisting of: F, Cl, methyl, ethyl, hydroxy, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

Each R ^{and N} is independently selected from the group consisting of: H, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, and _C1 - _C6 haloalkyl; or the two R and ^N can form a 4-6 membered ring together with the adjacent N;

Ring A is a 5-membered heteroaryl group having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom, or (iii) one nitrogen atom and one sulfur atom as the only heteroatom; wherein ring A is connected to the adjacent carbonyl group via a carbon atom; and

The B ring is a 4- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group 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) One or two substituents selected from the group consisting of: halogen, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C3 - _C6 cycloalkyl, C1-C6 alkoxy, _C1 - _C6 haloalkoxy, _C1 - _C6 alkylthio, _C1 - _C6 alkyl-N( ^RN ) ₂ and cyano; wherein two _{C1 - C6 alkyl} substituents may together form a bridged ring or a spiro ring; and wherein if the nitrogen atom in ring B is substituted, the substituent is not a halogen or a cyano or is not a _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy or C1 _{- C6} alkylthio with an oxygen or sulfur atom directly bonded to the nitrogen atom;

(b) One substituent selected from the group consisting of: _C1 - _C6 alkyl, C1-C6 haloalkyl, _C3 - _C6 cycloalkyl, C1-C6 alkoxy, C1- _C6 haloalkoxy, _C1 -C6 alkylthio, _C1 - _C6 alkyl-N(RN ₎₂ , phenyl, benzyl, CH2-(C3- _C6 cycloalkyl), CH2CH2-( _C3 -C6 cycloalkyl), CH2- ⁽ _4- to _6- membered heterocyclic), CH2CH2-( _4- to _6- membered heterocyclic), _5- to _6- membered heteroaryl, and _{CH2- ( 5-} to 6-membered heteroaryl); wherein, when a benzene ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, _C1 - _C4 alkyl, C1-C4 haloalkyl, C1- _C4 alkoxy, C1-C6 alkyl, C1-C6 alkyl-N(RN)2, phenyl, benzyl, _CH2- (C3-C6 cycloalkyl), _CH2- (C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclic), _CH2- (5- to 6-membered heteroaryl), CH2-(5- to 6-membered heteroaryl); wherein, when a benzene ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, _C1 - _C4 alkyl, C1-C4 haloalkyl, _C1 - _C4 alkoxy, C1-C6 alkyl-N(RN)2, phenyl, benzyl, CH2-( _C3 - _C6 cycloalkyl), ... ₁ -C ₄ -haloalkoxy, cyano, and cyclopropyl.

In some embodiments, ^R1 is selected from the group consisting of: _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 haloalkyl, phenyl, benzyl, oxacyclobutyl, oxabicyclo[3.1.0]hex-6-yl, thiophene, and pyrazolyl; wherein ^R1 is optionally substituted by: (i) a substituent selected from the group consisting of: F, C1, methyl, hydroxy, hydroxymethyl, cyano, and trifluoromethyl, or (ii) two F substituents. In some of the above embodiments, ^R1 is _C1 - _C6 alkyl. In some embodiments, ^R1 is _C1 - _C4 alkyl. In some embodiments, ^R1 is _C3 - _C5 cycloalkyl. In some embodiments, ^R1 is _C3 - _{C4 cycloalkyl} . In some embodiments, ^R1 is methyl. In some embodiments, ^R1 is ethyl. In some embodiments, ^R1 is _CF3CH2 . In some embodiments, ^R1 is 2-propyl. In some embodiments, ^R1 is tert-butyl. In some embodiments, ^R1 is (2-hydroxy)-2-propyl. In some embodiments, ^R1 is (2-cyano)-2-propyl. In some embodiments, ^R1 is a _C1 - _C6 haloalkyl. In some embodiments, ^R1 is a _C1 - _C4 haloalkyl. In some embodiments, ^R1 is cyclopropyl. In some embodiments, ^R1 is monofluorocyclopropyl or difluorocyclopropyl. In some embodiments, ^R1 is 1-fluorocyclopropyl. In some embodiments, ^R1 is 2-fluorocyclopropyl. In some embodiments, ^R1 is 2,2-difluorocyclopropyl. In some embodiments, ^R1 is 1-(trifluoromethyl)cyclopropyl. In some embodiments, ^R1 is 1-methylcyclopropyl. In some embodiments, ^R1 is 1-(hydroxymethyl)cyclopropyl. In some embodiments, ^R1 is cyclobutyl. In some embodiments, ^R1 is cyclopentyl. In some embodiments, ^R1 is phenyl. In some embodiments, ^R1 is benzyl. In some embodiments, ^R1 is oxacyclobut-3-yl. In some embodiments, ^R1 is 3-methyloxacyclobut-3-yl. In some embodiments, ^R1 is oxabicyclo[3.1.0]hex-6-yl. In some embodiments, ^R1 is 2-pyridyl. In some embodiments, ^R1 is 1-methylpyrazol-4-yl. In some embodiments, ^R1 is 2-thiophene.

In some embodiments, each ^RN is independently selected from the group consisting of H and _C1 - _C6 alkyl groups. In some embodiments, each ^RN is a _C1 - _C4 alkyl group. In some embodiments, each ^RN is a methyl group.

In some implementations of equation (I), ^R1 is as defined above, and rings A and B are selected from the group consisting of:

in

^R2 is selected from the group consisting of: H, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, _C1 -C6 alkylthio, phenyl, benzyl, _CH2- ( _C3 - _C6 cycloalkyl), _CH2CH2- (C3-C6 cycloalkyl), _CH2- ( _4- to _{6 -} membered heterocyclic), _CH2CH2- (4- to 6-membered heterocyclic), _5- to 6-membered heteroaryl _, and _CH2- (5- to 6-membered heteroaryl); wherein, when a benzene ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, _{C1 -C4 haloalkoxy} , and cyano; and

The choices for ^R3a and ^R3b are as follows:

(i) One of R ^3a and R ^3b is H, and the other is selected from the group consisting of: D, F, Cl, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, cyclopropyl, _C1 - _C4 alkoxy and _C1 - _C4 haloalkoxy;

(ii) Each of ^R3a and ^R3b is selected from the group consisting of: D, F, Cl, OH, CN, and methyl, provided that ^R3a and ^R3b cannot both be OH or CN; or

(iii) ^R3a and ^R3b together form a cyclopropyl group.

In some implementations of equation (I), ^R1 is as defined above, and rings A and B are selected from the group consisting of:

in

The choices for ^R3a and ^R3b are as follows:

(i) One of R ^3a and R ^3b is H, and the other is selected from the group consisting of: D, F, Cl, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, cyclopropyl, _C1 - _C4 alkoxy and _C1 - _C4 haloalkoxy;

(ii) Each of ^R3a and ^R3b is selected from the group consisting of: D, F, Cl, OH, CN, and methyl, provided that ^R3a and ^R3b cannot both be OH or CN; or

(iii) ^R3a and ^R3b together form a cyclopropyl group;

^R5 are each selected from the group consisting of: H, F, Cl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, and _C1 - _C6 haloalkoxy; and

m can be 1, 2, or 3.

In some implementations of equation (I), ^R1 is as defined above, and rings A and B together are:

in

^R5 are each selected from the group consisting of: H, F, Cl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, and _C1 - _C6 haloalkoxy; and

m can be 1, 2, or 3.

In some implementations of equation (I), ^R1 is as defined above, and rings A and B are selected from the group consisting of:

in

^R2 is selected from the group consisting of: H, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, C1- _C6 haloalkoxy, _C1 -C6 alkylthio, phenyl, benzyl, _CH2- ( _C3 - _C6 cycloalkyl), _CH2CH2- ( _C3 -C6 cycloalkyl), _CH2- ( _4- to _{6 -} membered heterocyclic), _CH2CH2- (4- to 6-membered heterocyclic), _5- to 6-membered heteroaryl _, and _CH2- (5- to 6-membered heteroaryl); wherein, when a benzene ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of _: halogen, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, _C1 - _C4 haloalkoxy, and cyano;

The choices for ^R4a and ^R4b are as follows:

(i) One of ^R4a and ^R4b is H, and the other is selected from the group consisting of: D, F, Cl, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, cyclopropyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; or

(ii) Each of ^R4a and ^R4b is selected from the group consisting of D, F, Cl, and methyl; and

^R5 are each selected from the group consisting of: H, F, Cl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy and _C1 - _C6 haloalkoxy.

In some implementations of equation (I), ^R1 is as defined above, and rings A and B are selected from the group consisting of:

in

The choices for ^R4a and ^R4b are as follows:

(i) One of ^R4a and ^R4b is H, and the other is selected from the group consisting of: D, F, Cl, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, cyclopropyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; or

(ii) Each of R ^4a and R ^4b is selected from the group consisting of D, F, Cl and methyl groups:

^R5 are each selected from the group consisting of: H, F, Cl, _C1 - _C6 alkyl, _C1 - _C4 haloalkyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; and

m can be 1, 2, or 3.

In some of the above embodiments, ^R2 is phenyl. In some embodiments, ^R2 is monofluorophenyl or difluorophenyl. In some embodiments, ^R2 is monochlorophenyl or dichlorophenyl. In some of the above embodiments, R2 is pyridyl. In some of the above embodiments, ^R2 is chlorinated pyridyl. In some of the above embodiments, ^R2 is fluorinated pyridyl. In some of the above embodiments, ^R2 is pyrazolyl. In some of the above embodiments, ^R2 is 1-methyl-1H-pyrazol-4-yl. In some of the above embodiments, ^R2 is 4-chloro-1-methyl-1H ^- pyrazol-3-yl.

In some of the above embodiments, ^R3a and ^R3b are each H. In some of the above embodiments, ^R3a is H and ^R3b is F. In some of the above embodiments, ^R3a is H and ^R3b is Cl. In some of the above embodiments, ^R3a and ^R3b are each F. In some of the above embodiments, ^R3a and ^R3b are each Cl. In some of the above embodiments, ^R3a and ^R3b are each methyl. In some of the above embodiments, ^R3a is methyl and ^R3b is F. In some of the above embodiments, ^R3a is methyl and ^R3b is Cl. In some of the above embodiments, ^R3a is methyl and ^R3b is OH. In some of the above embodiments, ^R3a is methyl and ^R3b is CN. In some of the above embodiments, ^R3a and ^R3b are each D. In some of the above embodiments, ^R3a is H and ^R3b is D. In some of the above embodiments, ^R3a is D and ^R3b is F. In some of the above embodiments, ^R3a is D and ^R3b is Cl. In some of the above embodiments, ^R3a is D and ^R3b is methyl.

In some of the above embodiments, ^R4a and ^R4b are each H. In some of the above embodiments, one of ^R4a is H and ^R4b is F. In some of the above embodiments, one of ^R4a is H and ^R4b is methyl. In some of the above embodiments, one of ^R4a is H and ^R4b is Cl. In some of the above embodiments, ^R4a and ^R4b are each F. In some of the above embodiments, ^R4a and ^R4b are each D. In some of the above embodiments, ^R4a is H and ^R4b is D. In some of the above embodiments, ^R4a is D and ^R4b is F. In some of the above embodiments, ^R4a is D and ^R4b is Cl.

In some of the above embodiments, ^R5 is selected from the group consisting of: H, F, Cl, _CH3 , _CH2CH3 , _OCH3 , _CF3 , _OCF3 , _CF2H and _{OCF2H .}

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

In another embodiment, compounds selected from the compounds in Table 1 below, or pharmaceutical salts thereof, are provided herein. In another embodiment, the compounds of Table 1 are provided herein with a _Ki of less than 100 nM in RIP1K biochemical or cell-based assays (including those described herein). In another embodiment, the compounds of Table 1 have a _Ki of less than 50 nM in RIP1K biochemical or cell-based assays (including those described herein). In yet another embodiment, the compounds of Table 1 have a _Ki of less than 25 nM in RIP1K biochemical or cell-based assays (including those described herein). In yet another embodiment, the compounds of Table 1 have a _Ki of less than 10 nM in RIP1K biochemical or cell-based assays (including those described herein).

In another embodiment, compounds selected from the compounds in Table 2 below, or pharmaceutical salts thereof, are provided herein. In another embodiment, the compounds in Table 2 are provided herein with a _Ki of less than 100 nM in RIP1K biochemical or cell-based assays (including those described herein). In another embodiment, the compounds in Table 2 have a _Ki of less than 50 nM in RIP1K biochemical or cell-based assays (including those described herein). In yet another embodiment, the compounds in Table 2 have a _Ki of less than 25 nM in RIP1K biochemical or cell-based assays (including those described herein). In yet another embodiment, the compounds in Table 2 have a _Ki of less than 10 nM in RIP1K biochemical or cell-based assays (including those described herein).

In some embodiments, individual stereoisomers of the compounds in Table 1 or Table 2 are provided herein, as characterized with reference to their chiral separation and resolution (e.g., as described in the examples by chiral SFC).

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

This document also provides oral formulations of compounds of Formula I as described in any of the above embodiments, or pharmaceutical salts thereof, and one or more pharmaceutical carriers or excipients suitable for oral delivery.

In some embodiments, the use herein of compounds of Formula I as described in any of the above embodiments or pharmaceutical salts thereof for the treatment of neurodegenerative diseases and conditions is provided. In some embodiments, the disease and condition to be treated is a synucleinic disease, such as Parkinson's disease, Lewy body dementia, multiple system atrophy, or Parkinson's plus syndrome. In some embodiments, the disease and condition to be treated is a tau disease, such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the disease and condition to be treated is a demyelinating disease, such as multiple sclerosis.

In some implementations, the disease and condition to be treated are other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Other exemplary neurodegenerative diseases to be treated as provided herein include, but are not limited to: intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

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

In some embodiments, the use herein of a compound of Formula I as described in any of the above embodiments or a pharmaceutical salt thereof for the treatment of inflammatory diseases and conditions is provided. In some embodiments, the disease or condition to be treated is selected from the group consisting of: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylitis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), and systemic lupus erythematosus. Sleucorrhea (SLE), Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver damage/diseases (non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis) Erosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity, kidney damage/injury (nephritis, renal transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia-reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome Ammatory 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 cystase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD). This includes conditions such as nicobstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-κ-B key regulator gene (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency (heme-oxidized IRP2 ubiquitin ligase-1 deficiency, also known as RBCK1), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases. (e diseases) (especially Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartic glycosaminoglycanuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, and fucoside storage disease. Dosis, Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile Free Sialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metachromatic leukodystrophy, Mucopolysaccharides Mucopolysaccharidose disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, osteogenesis imperfecta, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs familial amaurosis, and Wolman disease.

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

In some embodiments, methods are provided herein for treating or preventing diseases or conditions using a therapeutically effective amount of a compound of formula I or a pharmaceutical salt thereof, wherein the disease or condition is associated with inflammation and/or necrotizing apoptosis. In one embodiment, the disease or condition is selected from the specific diseases and conditions described herein.

In some embodiments, methods for inhibiting RIP1 kinase activity are provided herein by contacting cells with a compound of formula I or a pharmaceutical salt thereof.

Pharmaceutical composition and administration

This document provides pharmaceutical compositions or medicaments comprising the compounds of the present invention (or their stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutical salts, or prodrugs) and therapeutically inert carriers, diluents, or excipients, as well as methods for preparing such compositions and medicaments using the compounds of the present invention. In one example, a compound of formula I can be formulated by mixing it at ambient temperature, at a suitable pH, and with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used in galen formulations) to the desired purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but wherever preferred, the range is from about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

The composition is formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the etiology of the disease, the delivery site of the agent, the method of administration, the schedule of administration, and other factors known to the medical practitioner. In some embodiments, the "effective amount" of the compound to be administered will be determined by considerations that it is the minimum amount required to inhibit RIP1 kinase activity to provide a therapeutic effect in the mammal being treated. Furthermore, such an effective amount may be below amounts that would be toxic to normal cells or the mammal as a whole.

In one instance, the effective dose of the compound of the present invention administered intravenously or parenterally will range from about 0.1 to 100 mg/kg, alternatively from about 0.1 to 20 mg/kg patient body weight/day, or alternatively from about 0.3 to 15 mg/kg/day.

In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg) of the compound of the present invention. In some embodiments, the daily dose is administered as a single daily dose or in divided doses twice to six times daily, or in a sustained-release form. In the case of a 70 kg adult, the total daily dose will typically be about 7 mg to about 1,400 mg. This dosage regimen can be adjusted to provide the best therapeutic response. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily.

In some embodiments, low doses of the compounds of the present invention are administered to provide therapeutic benefits while minimizing or preventing adverse reactions.

The compounds of the present invention can be administered by any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, intradural, and intranasal administration, as well as intralesional administration (if necessary for local treatment). Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In a specific embodiment, the compound of formula I is administered orally. In other specific embodiments, the compound of formula I is administered intravenously.

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

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

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 swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or excipient used will depend on the manner and purpose of applying the compounds of the present invention. Solvents are typically selected based on those considered by those skilled in the art to be generally safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof. Formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives to provide an elegant presentation of the medicine (i.e., the compounds of the present invention or pharmaceutical compositions thereof) or to aid in the preparation of a pharmaceutical product (i.e., a drug).

Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to recipients at the dosages and concentrations used and include: buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; and benzylthonium chloride. Chloride); phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other sugars, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; counterions that form salts, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEENTM, PLURONICS ^™ , or polyethylene glycol (PEG). The active pharmaceutical ingredient of the present invention (e.g., a compound of Formula I or an embodiment thereof) may also be encapsulated, for example, in microcapsules (e.g., hydroxymethyl cellulose microcapsules or gelatin microcapsules and poly(methyl methacrylate) microcapsules), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or macroemulsions prepared by coagulation techniques or interfacial polymerization, respectively. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005), 21st edition, Lippincott Williams & Wilkins, Philidelphia, PA.

Sustained-release formulations of the compounds of the present invention (e.g., compounds of Formula I or embodiments thereof) can be prepared. Suitable examples of sustained-release formulations include a semi-permeable matrix containing a solid hydrophobic polymer of Formula I or embodiments thereof, said matrix being in the form of a molded article (e.g., a film or microcapsule). Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT ^™ (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolideacetate), and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). The sustained-release composition also includes liposome-encapsulated compounds, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030, 1980; U.S. Patents 4,485,045 and 4,544,545; and EP 102,324A). Typically, the liposomes are small (approximately 200–800 Å) monolayers containing a lipid content greater than approximately 30 mol% cholesterol, the selected proportions being adjusted for optimal therapeutic use.

In one example, a compound of Formula I or an embodiment thereof may be formulated by mixing it at ambient temperature, at a suitable pH, and with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used in galen formulations) to the desired purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one example, a compound of Formula I (or a specific example thereof) is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula I or an embodiment thereof is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

An example of a suitable oral dosage form provided herein is a tablet containing about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg, and 500 mg) of the compound of the present invention mixed 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 PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

Formulations of the compounds of the present invention (e.g., compounds of Formula I or embodiments thereof) may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, in accordance with known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable carriers and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils can generally be used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid may also be used in the preparation of the injection.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of the active ingredient mixed with an appropriate and convenient amount of carrier material, said appropriate and convenient amount varying from about 5% to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable dosage. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per mL of solution so that an appropriate volume can be infused at a rate of about 30 mL/hour.

Preparations suitable for parenteral administration include: aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

The formulation can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier (e.g., water) for immediate use before injection. Temporary injectable solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets.

Therefore, one embodiment includes a pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof. Another embodiment includes a pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof, together with a pharmaceutical carrier or excipient.

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

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

Bypass methods include, but are not limited to: direct injection into the brain (see, for example, Papanastassiou et al., GeneTherapy 9:398-406, 2002), interstitial infusion/convection-enhanced delivery (see, for example, Bobo et al., Proc.Natl.Acad.Sci.USA91:2076-2080, 1994), and implantation of delivery devices in the brain (see, for example, Gill et al., Nature Med.9:589-595, 2003; and Gliadel Wafers ^™ , Guildford).

Methods for creating openings in a barrier include, but are not limited to, ultrasound (see, for example, U.S. Patent Publication No. 2002/0038086), osmotic pressure (e.g., by application 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 permeation by, for example, bradykinin or permeabilizer A-7 (see, for example, U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods for transporting compounds of formula I (or specific examples thereof) across the blood-brain barrier include, but are not limited to: encapsulating compounds of formula I or I-I (or specific examples thereof) in liposomes coupled to antibody-binding fragments of receptors on vascular endothelium that bind to the blood-brain barrier (see, for example, U.S. Patent Publication No. 2002/0025313), and coating compounds of formula I (or specific examples thereof) in low-density lipoprotein particles (see, for example, U.S. Patent Publication No. 2004/0204354) or apolipoprotein E (see, for example, U.S. Patent Publication No. 2004/0131692).

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

For intracerebral use, in some embodiments, the compound can be continuously administered via infusion into a fluid reservoir in the CNS, but bolus injection may be acceptable. Inhibitors can be administered into the ventricles or otherwise introduced into the CNS or cerebrospinal fluid. Administration can be made using indwelling catheters and continuous delivery methods (such as pumps), or via implantation (e.g., intracerebral implantation of a sustained-release carrier). More specifically, inhibitors can be administered via long-term implanted cannulas or via long-term infusion with the aid of osmotic micropumps. Subcutaneous pumps that deliver proteins to the ventricles via tubing are available. Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgery. Examples of suitable administration protocols and delivery systems involving subcutaneous pump devices or continuous intraventricular infusion via fully implanted drug delivery systems are those used to administer dopamine, dopamine agonists, and cholinergic agonists to patients with Alzheimer’s disease and animal models of Parkinson’s disease, such as those described in Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

Indications and treatment methods

The compounds of this invention inhibit RIP1 kinase activity. Therefore, the compounds of this invention can be used to treat diseases and conditions mediated by this pathway and associated with inflammation and/or necrotic cell death.

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

In some implementations, the disease and condition to be treated are other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Other exemplary neurodegenerative diseases to be treated as provided herein include, but are not limited to: intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

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

In some implementations, the disease or condition to be treated is an inflammatory disease or condition. In some implementations, the disease or condition to be treated is selected from the group consisting of: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylitis, gout, generalized juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver damage/disease (non-alcoholic fatty liver disease, alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), paracetamol). Aminophenol toxicity, hepatotoxicity), kidney damage/injury (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia-reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Bechtel disease, interleukin-1 Invertase (ICE, also known as cysteine-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-κ-B key regulator gene (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency (also known as RBCK1 heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (especially Gaucher disease, and including GM2 ganglioside storage diseases). Alpha-mannosinolate storage disease, aspartic glucosamineuria, cholesterol ester storage disease, chronic aminohexosidase A deficiency, cystine disease, Danon's disease, Fabry disease, Faber's disease, fucoside storage disease, galactosylsialic acid storage disease, GM1 ganglioside storage disease, mucolipid storage disease, infantile free sialic acid storage disease, juvenile aminohexosidase A deficiency, Krabby's disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharide storage disease, polysulfatase deficiency, Niemann-Pick disease, neuronal ceramide lipofuscin deposition disease, Pompeo's disease, osteogenesis imperfecta condensans, Sandhof's disease, Schindler's disease, sialic acid storage disease, familial amaurotic idiocy, and Wollman's disease.

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

In some implementations, the treatment methods provided herein are for treating one or more symptoms of the diseases or conditions listed above.

The use of the compounds of the present invention in treatment is also provided herein. In some embodiments, the use of the compounds of the present invention in treating or preventing the aforementioned diseases and conditions is provided herein. The use of the compounds of the present invention in the preparation of medicaments for treating or preventing the aforementioned diseases and conditions is also provided herein.

This document also provides methods for treating the diseases or conditions described above in mammals requiring such treatment, wherein said methods comprise 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.

This document also provides methods for treating symptoms of a disease or condition in mammals requiring such treatment, the disease or condition 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 the kidney, liver, and lungs, cysplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

This document also provides methods for treating diseases or conditions in human patients requiring such treatment, said diseases or conditions being selected from those provided above, wherein said methods comprise oral administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in an orally acceptable pharmaceutical composition.

Combination therapy

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

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

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

In some implementations, the compounds provided herein can be combined with DLK inhibitors for the treatment of neurodegenerative diseases and conditions, 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 syndrome, Alzheimer's disease, frontotemporal dementia, demyelinating diseases such as multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, and corticobasal degeneration. For example, DLK inhibitors are described in WO 2013/174780, WO 2014/177524, WO 2014/177060, WO 2014/111496, WO 2015/091889 and WO 2016/142310.

Example

The invention will be more fully understood by referring to the following embodiments. However, they should not be considered as limiting the scope of the invention.

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

The chemical reactions in the embodiments described can be readily modified to prepare many other compounds of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplary compounds of the present invention can be successfully carried out by modifications that are obvious to those skilled in the art, such as by appropriately protecting the interfering groups, by utilizing other suitable reagents known in the art, for example by appropriately protecting the interfering groups by utilizing other suitable reagents known in the art besides those described above, and/or by making conventional modifications to the reaction conditions.

In the examples below, all temperatures are given in degrees Celsius unless otherwise specified. Commercially available reagents, unless otherwise specified, are purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI, or Maybridge and used without further purification. The reactions listed below are typically carried out under positive pressure of nitrogen or argon or in anhydrous solvents using dried tubes (unless otherwise specified), and the reaction flasks are typically equipped with rubber septa for introducing substrates and reagents via syringe. Glassware is oven-dried and/or heat-dried. ^¹H NMR spectra are obtained in deuterated _CDCl₃ , _d⁶- DMSO, _CH₃OD , or _d⁶ -acetone solvent solutions using trimethylsilane (TMS) or residual non-deuterated solvent peaks as reference standards (reported in ppm). When reporting peak multiplicity, use the following abbreviations: s (single), d (double), t (triple), q (quartet), m (multiple), br (broadened), dd (double double), dt (double triple). When the coupling constant is given, it is reported in Hz (Hertz).

All abbreviations used to describe reagents, reaction conditions, or apparatus are intended to be consistent with the definitions listed below. The chemical names of discrete compounds of this invention are generally obtained using the structural nomenclature features of the ChemDraw nomenclature program.

abbreviation

ACN Acetonitrile

Boc tert-Butoxycarbonyl

DAST (diethylaminosulfonium trifluoride)

DCE 1,2-Dichloroethane

DCM (Dichloromethane)

DMF (N,N-dimethylformamide)

DMSO (Dimethyl sulfoxide)

DPPH 2,2-Diphenyl-1-picrylhydrazine

HPLC (High-Performance Liquid Chromatography)

LCMS (Liquid Chromatography-Mass Spectrometry)

PCC (Pyridium Chlorochromate)

RP (Inverted)

RT or R _T retention time

SEM 2-(trimethylsilyl)ethoxymethyl

SFC (Supercritical Fluid Chromatography)

TFA (trifluoroacetic acid)

THF (Tetrahydrofuran)

Synthesis scheme

In addition to the specific synthesis methods described in the following embodiments, other compounds of the present invention can be prepared according to the following synthesis schemes, for example.

After following steps 1-5 of Method 9, prepare the gem-difluorinated moiety according to Scheme 1:

Option 1

1) SFC separation of bromine enantiomers

2) As shown in the method, use Weinreb chemistry.

The diversity of other B-rings in compounds of formula I prepared according to scheme 2 using a variety of nucleophilic reagents (including but not limited to halide and cyanide sources):

Option 2

Compounds of formula I with β-dimethyl-B-ring substitution were prepared according to scheme 3:

Option 3

The following intermediates used in the following embodiments were prepared according to the procedure described in WO 2017/004500 (the entire contents of which are incorporated herein by reference):

If not specified in the specific method, any N-methoxy-N-methyl-alkyl, aryl, heteroaryl, or heterocyclic formamide may be prepared in the same manner as cis-2-fluoro-N-methoxy-N-methylcyclopropane formamide in Method 5 below.

Method 1: Compounds in Examples 1 and 2

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.64 mL, 1.60 mmol) was added dropwise to a cooled (-70 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) in tetrahydrofuran (12 mL) at a temperature of -70 °C. After addition, the mixture was stirred at -70 °C for 1 hour and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.225% HCl in water). The racemic material was further separated using a chiral SFC to obtain the definitively assigned:

[(1S,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 3.635 min) (4.0 mg, 2.5%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.39(m, 3H), 7.30-7.28(m, 2H), 6.20-6.18(m, 0.5H), 6.06-6.04(m, 0.5H), 5.65-5.64(m, 1H), 5.04-5.02(m, 0. 5H), 4.90-4.87(m, 0.5H), 3.80-3.74(m, 1H), 3.25-3.21(m, 1H), 2.88-2.81(m, 1H), 2.03-1.96(m, 1H), 1.34-1.28(m, 1H). LCMS R _T = 1.662 min, m/z = 290.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 1.662 min, ESI+ measured value [M+H] = 290.1.

[(1R,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 3.995 min) (15.9 mg, 10%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.38(m, 3H), 7.30-7.28(m, 2H), 6.21-6.18(m, 0.5H), 6.06-6.05(m, 0.5H), 5.66-5.65(m, 1H), 5.05-5.04(m, 0. 5H), 4.90-4.87(m, 0.5H), 3.82-3.74(m, 1H), 3.23-3.20(m, 1H), 2.88-2.82(m, 1H), 2.02-1.96(m, 1H), 1.34-1.30(m, 1H). LCMS R _T = 1.654 min, m/z = 290.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 1.654 min, ESI+ measured value [M+H] = 290.1.

SFC conditions: Column: Chiralcel OD-3 150×4.6mm ID3μm; Mobile phase: A: CO2 _, B: Isopropanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 2: Compound Examples 3 and 4

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.64 mL, 1.60 mmol) was added dropwise to a cooled (-70 °C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and cis-2-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (156.5 mg, 1.06 mmol) in tetrahydrofuran (10 mL) at a temperature of -70 °C. After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 30 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 35-65%/ammonium hydroxide in water) to give [cis-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (35 mg, 22.5%) as a pink solid. The racemic material was separated by chiral SFC to obtain the specifically attributed:

[(1S,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 4.787 min) (5.9 mg, 17%), is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.44-7.39(m, 3H), 7.28-7.27(m, 2H), 6.13-6.11(m, 1H), 5.99-5.97(m, 1H), 5.53-5.49(m, 1H) , 3.69-3.61(m, 1H), 3.27-3.24(m, 1H), 3.03-2.96(m, 1H), 2.23-2.15(m, 1H), 1.29-1.24(m, 1H). LC-MS R _T =0.846 min, m/z =289.9(M+H) ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.846 min, and the measured ESI+ value [M+H] = 289.9.

[(1R,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 5.711 min) (11.7 mg, 33%), is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.44-7.37(m, 3H), 7.28-7.27(m, 2H), 6.13-6.11(m, 1H), 5.99-5.97(m, 1H), 5.53-5.50(m, 1H) , 3.69-3.63(m, 1H), 3.27-3.23(m, 1H), 3.03-2.96(m, 1H), 2.23-2.16(m, 1H), 1.29-1.24(m, 1H). LC-MS R _T =0.849 min, m/z =289.9(M+H) ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.849 min, and the measured ESI+ value [M+H] = 289.9.

SFC conditions: Column: Chiralcel OD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Isopropanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Chiral SFC purification and analytical conditions:

In the methods provided in the table below, solvent A is carbon dioxide and solvent B is 0.1% _NH4 (aq) in _CH3OH .

Method SP5

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

2-Hydroxy-2-methyl-1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propyl-1-one (10.94 mg, 43% yield), specifically assigned. ^¹H 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 R _T =4.029 min, m/z =290.1(M+H) ⁺ .

Method SP6

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

2-Hydroxy-2-methyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propyl-1-one (11.1 mg, 43% yield), specifically assigned. ^¹H 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 R _T =4.029 min, m/z =290.1(M+H) ⁺ .

Method SP 37

2,2-Dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one

2,2-Dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (2.84 mg, 48% yield), specifically assigned. LC-MS R _{_T} = 5.26 min, m/z = 288.1 (M+H) ^⁺ .

Method SP 38

2,2-Dimethyl-1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one

2,2-Dimethyl-1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (4.2 mg, 77% yield), specifically assigned. LC-MS R _{_T} = 5.26 min, m/z = 288.1 (M+H) ^⁺ .

Method SP 39

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

Specifically assigned (1-methylpyrazol-4-yl)-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (19.23 mg, 77% yield). ^¹H NMR (400 MHz, DMSO- _d⁶ ) 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 =3.99min, m/z=312.1(M+H) ⁺ .

Method SP 40

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

Specifically assigned (1-methylpyrazol-4-yl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (20.4 mg, 82% yield). ^¹H NMR (400 MHz, DMSO- _d⁶ ) 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 =3.99min, m/z=312.1(M+H) ⁺ .

Method 3

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

Under nitrogen atmosphere, at -78 °C, benzyl magnesium chloride (2 M, in tetrahydrofuran, 0.20 mL, 0.400 mmol) was added to a solution of racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.363 mmol) in tetrahydrofuran (2 mL). After addition, the reaction mixture was stirred at -78 °C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (1 mL). The mixture was extracted with isopropyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% isopropyl acetate in heptane) to give 2-phenyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]acetone as a white solid (80 mg, 69% yield). LCMS R _{_T} = 5.24 min, m/z = 322.1 [M+H]^⁺. LCMS retention time (5-95% acetonitrile in water + 0.1% formic acid, within 10 min) was 5.24 min, ESI⁺ measured [M+H] = 322.1.

Method 4

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.64 mL, 1.60 mmol) was added dropwise to a cooled (-70 °C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and trans-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (156 mg, 1.06 mmol) in tetrahydrofuran (10 mL). After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 30 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 35-65%/ammonium hydroxide in water) to give [trans-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (35 mg, 23%) as a pink solid. This racemic material was further separated by chiral SFC to obtain the specifically assigned:

[(1S,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 2.836 min) (14.3 mg, 40%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) 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 R _{_T} = 0.866 min, m/z = 289.9 (M+H) ⁺ . LC-MS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) was 0.866 min, ESI+ measured value [M+H] = 289.9.

[(1R,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 3.725 min) (11.3 mg, 32%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) 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 R _{_T} = 0.865 min, m/z = 289.9 (M+H) ⁺ . LC-MS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) was 0.865 min, ESI+ measured value [M+H] = 289.9.

SFC conditions: Column: Chiralpak AD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min.

Method 5

(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[racemic-(1S,2S)-2-fluorocyclopropyl] methyl ketone

Step 1: cis-2-fluoro-N-methoxy-N-methylcyclopropaneformamide

A mixture of cis-2-fluorocyclopropanecarboxylic acid (500 mg, 4.80 mmol), N,O-dimethylhydroxylamine hydrochloride (610 mg, 6.25 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2375 mg, 6.25 mmol), and N,N-diisopropylethylamine (1552 mg, 12.0 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give cis-2-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (420 mg, 59%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.87-4.67 (m, 1H), 3.78 (s, 3H), 3.26 (s, 3H), 2.35-2.33 (m, 1H), 1.94-1.86 (m, 1H), 1.11-1.05 (m, 1H).

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.21 mL, 0.53 mmol) was added dropwise to a cooled (-78 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and cis-2-fluoro-N-methoxy-N-methylcyclopropaneformamide (52 mg, 0.35 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding 10 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/ammonium hydroxide in water 0.05%) to give (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[racemic-(1S,2S)-2-fluorocyclopropyl] methyl ketone (2.0 mg, 4%) as a pale yellow oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.37(m, 3H), 7.29-7.27(m, 2H), 6.19-6.18(m, 0.5H), 6.04-6.03(m, 0.5H), 5.67-5.61(m, 1H), 5.08 -4.89 (m, 1H), 3.81-3.70 (m, 1H), 3.26-3.16 (m, 1H), 2.91-2.75 (m, 1H), 2.07-1.90 (m, 1H), 1.36-1.29 (m, 1H). LCMS R _T =1.038 min, m/z =290.1[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 1.038 min, and the measured ESI+ value [M+H] was 290.1.

Method 6

(2,2-Difluorocyclopropyl)-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Step 1: 2,2-Difluoro-N-methoxy-N-methyl-cyclopropaneformamide

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

Step 2:

(2,2-Difluorocyclopropyl)-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.25 mL, 0.62 mmol) was added to a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-cyclopropaneformamide (59 mg, 0.35 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 35-65%/ammonium hydroxide in water) to give (2,2-difluorocyclopropyl)-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (10.6 mg, 19%) as a colorless oil. ^¹H NMR (400MHz, _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 R_{_T} = 0.875 min, m/z = 307.9 [M+H] ^⁺. LCMS (5–95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) retention time 0.875 min, ESI⁺ measured value [M+H] = 307.9.

Method 7

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

According to Method 3, phenyl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone was prepared from [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone was prepared from [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% isopropyl acetate in heptane) to give the final product (17 mg, 30%) as a white solid. 1H NMR (400MHz, 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, 1.9Hz, 1H), 5.78 (dddd, J=8.5, 6.5, 3.1Hz, 1H), 3.78 (dddd, J=25.8, 15.4, 8.5, 7.1Hz, 1H), 2.74 (dddd, J=26.7, 15.2, 3.2, 2.0Hz, 1H). LC-MS _RT =5.04min, m/z=308.1(M+H) ⁺ .

LCMS retention time (5-95% acetonitrile + 0.1% formic acid in water, within 10 minutes) was 5.04 min, and the measured ESI+ value [M+H] was 308.1.1.

Method 8

Step 1: (E)-Benzaldehyde oxime

Sodium carbonate (112.3 g, 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g, 508.9 mmol) were added to a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL). The reaction mixture was stirred at 25 °C for 3 hours 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 give crude (E)-benzaldehyde oxime as a colorless oil (51.0 g, 99%), which was used in the next step without further purification.

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

To a solution of (E)-benzaldehyde oxime (20.0 g, 165.1 mmol) in 1,4-dioxane (500 mL), methyl acrylate (14.2 g, 165.1 mmol), sodium iodide (24.7 g, 165.1 mmol), 2,6-dimethylpyridine (17.6 g, 165.1 mmol), and tert-butyl hypochlorite (17.9 g, 165.1 mmol) were added. The reaction mixture was stirred at 25 °C for 24 h, followed by concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g, 74%). LCMS R _{_T} = 0.871 min, m/z = 206.2 [M+H] ^⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.871 min, and the measured ESI+ value [M+H] = 206.2.

Step 3: 3-Hydroxy-5-phenyl-pyrrolidone-2-one

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

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

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

Cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one, as a colorless oil (12.4 g, 51%). ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.37–7.25 (m, 5H), 4.88–4.53 (m, 1H), 4.54–4.46 (m, 1H), 2.89–2.79 (m, 1H), 1.80–1.71 (m, 1H), 0.93–0.90 (m, 9H), 0.19–0.12 (m, 6H), and

trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one, as a colorless oil (9.3 g, 38%). ^¹H NMR (400 MHz, _CDCl₃ ) 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).

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

At 0 °C, sodium hydride (60%, 2.6 g, 64.1 mmol) was slowly added to a solution of cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one (12.4 g, 42.8 mmol) in N,N-dimethylformamide (400 mL). After addition, the mixture was stirred at 0 °C for 20 min, followed by the addition of O-(diphenylphosphoyl)hydroxylamine (14.9 g, 64.1 mmol). The reaction mixture was stirred at 25 °C for 16 h and then filtered. The filtrate was concentrated under reduced pressure to give crude cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one as a yellow oil (9.5 g, 73%), which was used in the next step without further purification. LCMS R _{_T} = 0.877 min, m/z = 307.0 [M+H] ^⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.877 min, and the measured ESI+ value [M+H] = 307.0.

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

To a solution of cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one (9.5 g, 31.0 mmol) in ethanol (250 mL), ethyl 2-ethoxy-2-imino-ethyl (6.7 g, 46.5 mmol) was added. The reaction mixture was stirred at 60 °C for 6 hours, followed by concentration under reduced pressure to give crude 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate as a yellow oil (10.6 g, 84%), which was used in the next step without further purification. LCMSR _T = 2.106 min, m/z = 406.2 [M+H] ⁺ . The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 2.106 min, and the measured ESI value [M+H] = 406.2.

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

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

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

A mixture of ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (3.1 g, 7.6 mmol) and tert-butylammonium fluoride (1.0 M, in THF, 7.6 mL, 7.6 mmol) in tetrahydrofuran (60 mL) was heated at 60 °C for 18 hours, followed by concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give ethyl cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate as a white solid (1.4 g, 69%). ¹ HNMR (400MHz, CDCl ₃ )δ7.39-7.32 (m, 5H), 5.73 (d, J = 3.5Hz, 1H), 5.50 (m, 1H), 4.41 (q, J = 7.1Hz, 2 H), 3.73-3.65 (m, 1H), 2.76 (td, J=4.5Hz, 13.9Hz, 1H), 1.35 (t, J=7.1Hz, 3H).

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

To a solution of cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (100 mg, 0.37 mmol) in dichloromethane (8 mL), diethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours, then quenched by adding water (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water (20 mL) and 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 give trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (30 mg, 30%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.40-7.37 (m, 3H), 7.14-7.12 (m, 2H), 6.14 (d, J=5.2Hz, 0.5H), 6.00 (d, J=5.2Hz, 0.5H), 5.7 4-5.71 (m, 1H), 4.51-4.45 (m, 2H), 3.42-3.35 (m, 1H), 3.07-2.96 (m, 1H), 1.42 (t, J=7.2Hz, 3H).

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

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

1-[racemic-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one

Ethyl magnesium bromide (3M, in THF, 0.03 mL, 0.10 mmol) was added to a cooled (-78 °C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (15 mg, 0.05 mmol) in tetrahydrofuran (10 mL). After addition, the mixture was stirred at -78 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 34-64%/0.05% hydrochloric acid in water) to give 1-[racemic-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (7.4 mg, 50%) as a white solid. ^¹H NMR (400MHz, _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 = 7.2Hz, 3H). LCMS R_{_T} = 0.840 min, m/z = 260.1 [M+H]^⁺. LCMS (5–95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) retention time 0.840 min, ESI⁺ measured value [M+H] = 260.1.

Method 9

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

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

p-Toluenesulfonic acid (17.1 g, 99.2 mmol) was slowly added to a solution of 3,5-dibromo-1h-1,2,4-triazole (150.0 g, 661.2 mmol) in tetrahydrofuran (1500 mL) at 0 °C, followed by the addition of 3,4-dihydro-2h-pyran (166.9 g, 1983.6 mmol). After the addition, the reaction mixture was heated at 70 °C for 3 hours and concentrated under reduced pressure. The residue was poured into water (500 mL) and the pH was adjusted to 9 by adding a saturated aqueous solution of 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 reduced pressure. The resulting crude product was washed with methanol (2 x 50 mL) and dried under reduced pressure to give crude 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (155 g, 75%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ5.49-5.46 (m, 1H), 4.12-3.99 (m, 1H), 3.72-3.61 (m, 1H), 2.38-2.26 (m, 1H), 2.18-2.07 (m, 1H), 1.98-1.90 (m, 1H), 1.78-1.60 (m, 3H).

Step 2: 1-Phenylacet-3-en-1-ol

Allyl magnesium chloride (2M, in THF, 858 mL, 1.72 mol) was added to a cooled (0°C) solution of benzaldehyde (130 g, 1.23 mol) in tetrahydrofuran (1000 mL) over 30 minutes. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was then quenched by adding 1000 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 1-phenylbut-3-en-1-ol (140 g, 77%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.37-7.34 (m, 4H), 7.29-7.26 (m, 1H), 5.83-5.75 (m, 1H), 5.21-5.08 (m, 2H), 4.76-4.69 (m, 1H), 2.55-2.45 (m, 2H), 2.12 (d, J=2.8Hz, 1H).

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

To a stirred solution of 1-phenyl-3-buten-1-ol (29.0 g, 195.7 mmol) in dichloromethane (400 mL), imidazole (27.0 g, 391.6 mmol) and tert-butyldimethylchlorosilane (39.0 g, 254.4 mmol) were added. After addition, the reaction mixture was stirred at 25 °C for 16 hours, and then quenched by adding 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 give tert-butyl-dimethyl-(1-phenylbut-3-enoxy)silane (43.0 g, 84%) as a colorless oil, which was used directly in the next step.

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

Osmium tetroxide (968 mg, 3.8 mmol) was added to a solution of tert-butyl-dimethyl-(1-phenylbut-3-enoxy)silane (50.0 g, 190.5 mmol) in tetrahydrofuran/water (600 mL, 1:1). After stirring at 15 °C for 30 min, sodium periodate (163 g, 762.0 mmol) was added in fractions over 2 hours. The resulting mixture was stirred at 30 °C for another 2 hours, and then quenched by adding cold, saturated aqueous solution of 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) and brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-phenyl-propanal (33.0 g, 65%) as a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.94 (t, J = 2.4 Hz, 1H), 7.48 (d, J = 4.2 Hz, 4H), 7.44-7.39 (m, 1H), 5.37-5.34 (m, 1H), 2.99-2.97 (m, 1H), 2.80-2.75 (m, 1H), 1.01 (s, 9H), 0.19 (s, 3H), 0.00 (s, 3H).

Step 5:

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

Under a nitrogen atmosphere, n _- butyllithium (2.5 M, in hexane, 55.0 mL, 137.5 mmol) was added dropwise to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (39.0 g, 125.4 mmol) in tetrahydrofuran (400 mL). The mixture was stirred at -78 °C for 30 min, and 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 the addition, the mixture was stirred at -78 °C for 1.5 h, and then quenched by adding saturated aqueous solution of 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 reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-phenylprop-1-ol (50.0 g, 80%) as a pale yellow oil.

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

To a stirred solution of 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-phenylprop-1-ol (50.0 g, 100.7 mmol) in dichloromethane (150 mL), trifluoroacetic acid (150 mL) was slowly added. The resulting mixture was stirred at 50 °C for 2 hours, and then concentrated under reduced pressure. The residue was adjusted to pH 9 with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-32% ethyl acetate in petroleum ether) to give trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-7-ol (5.5 g, 20%) as a yellow solid (a second fraction (8.5 g, 30%) was also given as a 4:3 mixture of the trans/cis products). ^¹H NMR (400MHz, _CDCl₃ ) 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 (5–95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.682 min, ESI⁺ measured value [M+H] = 279.8.

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

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

cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.31–7.24 (m, 3H), 7.17–7.07 (m, 2H), 5.97–5.77 (m, 1H), 5.37–5.27 (m, 1H), 3.52–3.37 (m, 1H), 2.84–2.70 (m, 1H). LCMS R _{_T} = 0.632 min, m/z = 281.9 [M+H] ^⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.632 min, and the measured ESI+ value [M+H] = 281.9.

trans-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ^¹H NMR (400MHz, _CDCl₃ ) δ 7.58–7.29 (m, 3H), 7.24–7.05 (m, 2H), 6.14–5.93 (m, 1H), 5.70–5.65 (m, 1H), 3.41–3.25 (m, 1H), 3.04–2.87 (m, 1H).

The racemic cis material was further separated by chiral SFC to obtain the definitively attributed:

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

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

SFC conditions: Column: Chiralpak AD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min.

Step 8: N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropaneformamide

A mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (400 mg, 2.60 mmol), N,O-dimethylhydroxylamine hydrochloride (329 mg, 3.37 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1283 mg, 3.37 mmol), and N,N-diisopropylethylamine (838 mg, 6.49 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 hours. 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, 0-25% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropaneformamide (330 mg, 64%) as a light-colored oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.74 (s, 3H), 3.29 (s, 3H), 1.37-1.17 (m, 4H).

Step 9:

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.1 mL, 0.25 mmol) was added to a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (70 mg, 0.35 mmol) in tetrahydrofuran (4 mL). After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (5 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (45-75% acetonitrile/0.05% ammonium hydroxide in water) to give specifically assigned (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(trifluoromethyl)cyclopropyl] ketone (14.1 mg, 23%) as a red solid. ^¹H NMR (400MHz, _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 R _{_T} = 0.933 min, m/z = 339.9 [M+H]^⁺. LC-MS (10–80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 min) retention time 0.933 min, ESI⁺ measured value [M+H] = 339.9.

Method 10

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

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

A mixture of 3-methyloxetane-3-carboxylic acid (300 mg, 2.58 mmol), N,O-dimethylhydroxylamine hydrochloride (328 mg, 3.36 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1277 mg, 3.36 mmol), and N,N-diisopropylethylamine (835 mg, 6.46 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give N-methoxy-N,3-dimethyloxetane-3-carboxamide (120 mg, 29.2%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) 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).

Step 2:

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.17 mL, 0.43 mmol) was added to a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (40 mg, 0.14 mmol) and N-methoxy-N,3-dimethyloxetane-3-carboxamide (45 mg, 0.28 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30-60%/ammonium hydroxide in water) to give (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3-methyloxetane-3-yl) ketone (11.5 mg, 27%) as a yellow oil. ^¹H NMR (400MHz, _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 R _{_T} = 0.816 min, m/z = 302.0 [M+H]^⁺. LCMS (5–95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.816 min, ESI⁺ measured value [M+H] = 302.0.

Method 11

(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[racemic-(1S,2R)-2-fluorocyclopropyl] methyl ketone

Step 1: trans-2-fluoro-N-methoxy-N-methyl-cyclopropaneformamide

A mixture of trans-2-fluorocyclopropane-1-carboxylic acid (100 mg, 0.96 mmol), N,O-dimethylhydroxylamine hydrochloride (122 mg, 1.25 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (475 mg, 1.25 mmol), and N,N-diisopropylethylamine (310 mg, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give trans-2-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (70 mg, 50%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) 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 _FR = 0.292 min, m/z = 148.1 [M+H] ^⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.292 min, and the measured ESI+ value [M+H] = 148.1.

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.07 mL, 0.18 mmol) was added to a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (40 mg, 0.14 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (42 mg, 0.28 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 20 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 35-65%/ammonium hydroxide in water) to give (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[racemic-(1S,2R)-2-fluorocyclopropyl] methyl ketone (3.3 mg, 7.6%) as a colorless oil. ^¹H NMR (400MHz, _CDCl₃ ) δ 7.42–7.37 (m, 3H), 7.28–7.27 (m, 2H), 6.13–5.97 (m, 1H), 5.54–5.52 (m, 1H), 5.03–4.85 (m, 1H), 3.71–3.51 (m, 2H), 3.04–2.94 (m, 1H), 1.70–1.62 (m, 2H). LCMS R_{_T} = 0.862 min, m/z = 289.9 [M+H] ^⁺. LCMS (5–95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.862 min, ESI⁺ measured value [M+H] = 289.9.

Method 12

1-(7-Phenylacetyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-1-one

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

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

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

To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (10.0 g, 80.6 mmol) in dichloromethane (300 mL), N-chlorosuccinimide (10.8 g, 80.6 mmol) was added. The mixture was stirred at 50 °C for 2 hours, followed by concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 3-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (8.0 g, 63%) as a white solid, which was used directly in the next step.

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

To a solution of 3-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (5.6 g, 35.3 mmol) in N,N-dimethylformamide (20 mL), N-iodosuccinimide (8.3 g, 37.1 mmol) was added. The mixture was heated at 60 °C for 3 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (5.3 g, 53%) as a pale yellow solid, which was used directly in the next step.

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

To a solution of 5.3 g (18.6 mmol) of 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-one in dichloromethane (20 mL), manganese dioxide (8.1 g, 93.2 mmol) was added. The mixture was heated at 40 °C for 5 hours and filtered. The filtrate was concentrated to dryness under reduced pressure to give crude 3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-one (3.2 g, 61%) as a brown solid, which was used directly in the next step.

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

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

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

Under a _nitrogen atmosphere, a mixture of N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl)amino]-4-methylbenzenesulfonamide (1.8 g, 3.88 mmol), phenylboronic acid (710 mg, 5.82 mmol), and potassium carbonate (1.6 g, 11.65 mmol) in 1,4-dioxane (40 mL) was heated at 110 °C for 18 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium (200 mg, 15%) as a light brown solid. LCMS R _T = 0.879 min, m/z = 334.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time: 0.879 min, ESI+ measured value [M+H] = 334.9.

Step 7: Methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate

Under CO (50 Psi), a mixture of 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200 mg, 0.58 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride 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 hours. The mixture was filtered through a diatomaceous earth stencil, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.4) to give methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (140 mg, 87%) as a light brown solid. LCMS R_{_T} = 0.676 min, m/z = 277.0 [M+H]^⁺ . LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min): 0.676 min, ESI⁺ measured value [M+H] = 277.0

Step 8: Methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate

A mixture of methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate (120 mg, 0.43 mmol) and palladium (10% on carbon, 103 mg, 0.10 mmol, 50% wet) in methanol (50 mL) was hydrogenated at 50 °C (40 psi) for 24 hours and then filtered. The filtrate was concentrated under reduced pressure to give crude methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate (100 mg, 95%) as a brown oil, which was used directly in the next step. ^¹H NMR (400 MHz, _CDCl₃ ) 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 R_{_T} = 0.513 min, m/z = 243.1 [M+H] ^⁺. LCMS (5–95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) retention time: 0.513 min, ESI⁺ measured value [M+H] = 243.1.

Step 9: 7-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-carboxylic acid

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

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

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

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

Ethyl magnesium bromide (3.0 M, in THF, 0.61 mL, 1.83 mmol) was added to a cooled (-70 °C) solution of _N -methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-carboxamide (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at -70 °C for 2 hours and then quenched by adding 3 mL of saturated aqueous ammonium chloride solution. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%/ammonium hydroxide in water) to give 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-1-one (4.6 mg, 9%) as a light brown solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.86 (s, 1H), 7.35-7.31 (m, 2H), 7.30-7.21 (m, 3H), 4.42-4.38 (m, 1H), 4.25-4.23 (m, 1H), 4.20-4.11 (m, 1H), 3.12-3.10 (m, 1H), 2.89-2.83 (m, 2H), 2.58-2.50 (m, 1H), 1.14-1.10 (m, 3H). LCMS R _T =0.634 min, m/z =241.1[M+H] ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.634 min, and the measured ESI+ value [M+H] = 241.1.

Method 13

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

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

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

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

Under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in THF, 0.2 mL, 0.10 mmol) was added to a cooled (-78 °C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (15 mg, 0.05 mmol) in tetrahydrofuran (10 mL). After addition, the mixture was stirred at -78 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (35-65% acetonitrile/0.05% hydrochloric acid in water) to give cyclopropyl-[racemic-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (7.6 mg, 50%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.40 (m, 3H), 7.30-7.26 (m, 2H), 6.29-6.26 (m, 0.5H), 6.14-6.12 (m, 0.5H), 5.92 -5.87 (m, 1H), 3.44-3.41 (m, 1H), 3.01-3.02 (m, 2H), 1.19-1.16 (m, 2H), 1.12-1.09 (m, 2H). LCMS R _T =0.849 min, m/z =272.0 [M+H] ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.849 min, and the measured ESI+ value [M+H] = 272.0.

Method 14

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

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

To a solution of propargyl-1-ol (30.0 g, 535.14 mmol) in toluene (300 mL), ethyl 2-diazoylacetate (67.2 g, 588.66 mmol) was added. The reaction mixture was stirred at 110 °C for 5 hours and cooled to room temperature. The crude product was collected by filtration and washed with 10% ethyl acetate (50 mL) in petroleum ether to give a mixture of ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (15.8 g, 17%) and ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (not separated, 1:3, 63.1 g, 69%) as a pale yellow solid, which was used as a mixture for the next step.

3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (major isomer): ^1H 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).

4-(hydroxymethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (minor isomer): ^1H 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).

Step 2: 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid ethyl ester and 4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid ethyl ester

A mixture of ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (3:1, 4.0 g, 23.5 mmol), (2-(chloromethoxy)ethyl)trimethylsilane (11.2 mL, 70.5 mmol) and cesium carbonate (45.9 g, 141.0 mmol) in acetone (100 mL) was stirred at 25 °C for 3 hours and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) to give ethyl 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (not separated, 3.7 g, 52%), which were used as a mixture for the next step. LC-MS R _{_T} = 0.855 min, m/2 = 322.9 (M+H) ^⁺. LC-MS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) 0.855 min, ESI⁺ measured [M+Na] = 322.9.

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

To a solution of ethyl 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (2.0 g, 6.66 mmol) in dichloromethane (100 mL), manganese dioxide (7.0 g, 80.52 mmol) was added. The mixture was stirred at 25 °C for 15 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give ethyl 5-formyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (700 mg, 35%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ10.02 (s, 1H), 7.38 (s, 1H), 5.94 (s, 2H), 4.40 (q, J=8.0Hz, 2H), 3.69-3 .60 (m, 2H), 1.40 (t, J=8.0Hz, 3H), 0.98-0.89 (m, 2H), 0.02-0.07 (m, 9H).

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.853 min, and the measured ESI+ value [M+H] = 270.9.

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

Ethyl (E)-3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylate (310 mg, 1.15 mmol) and palladium (10% on carbon, 122 mg) in methanol (20 mL) were hydrogenated at 25 °C (15 psi) for 15 hours, and then filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 3-(3-hydroxy-3-phenylprop-1H-pyrazole-5-carboxylate) (314 mg, 99%) as a pale yellow oil. This crude product was used directly in the next step without further purification.

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

Sulfur dichloride (681 mg, 5.72 mmol) was added to a solution of ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate (314 mg, 1.14 mmol) in acetonitrile (5 mL). The mixture was heated at 65 °C for 15 hours and then concentrated under reduced pressure to give crude ethyl 3-(3-chloro-3-phenylpropyl)-1H-pyrazole-5-carboxylate (335 mg, 100%) as a yellow oil. This crude product was used directly in the next step without further purification. LC-MS R _{_T} = 0.861 min, m/z = 314.9 (M+H) ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.861 min, and the measured ESI+ value [M+H] = 314.9.

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

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

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

Ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (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) were stirred at 25 °C for 3 hours and then concentrated under reduced pressure. The residue was adjusted to pH 5 by adding 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) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (30 mg, 56%) as a yellow solid, which was used directly in the next step.

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

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

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

Under a nitrogen atmosphere, ethyl magnesium chloride (3.0 M, in THF, 0.07 mL, 0.21 mmol) was added dropwise to a cooled (-78 °C) solution of N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (24 mg, 0.09 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at -78 °C for 2 hours and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-yl)prop-1-one (13.0 mg, 61%) as a white solid. ^¹H NMR (400 MHz, _CD₃ OD) δ 7.39–7.30 (m, 3H), 7.11–7.09 (m, 2H), 6.60 (s, 1H), 5.54–5.50 (m, 1H), 3.11–3.01 (m, 3H), 2.95–2.89 (m, 2H), 2.52–2.48 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H). LC-MS R _{_T} = 1.858 min, m/z = 241.2 [M+H]^⁺. LC-MS (10–80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 min) retention time 1.858 min, ESI⁺ measured value [M+H] = 214.2.

Method 15

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

Under a nitrogen atmosphere, ethyl magnesium chloride (2M, in THF, 0.63 mL, 1.26 mmol) was added dropwise to a cooled (-78 °C) solution of 4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (200 mg, 0.63 mmol) in tetrahydrofuran (13 mL). After addition, the mixture was stirred at -78 °C for 2 hours, and then quenched by adding 20 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 1-[4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propyl-1-one (120 mg, 70%) as a white solid. This racemic material was further separated by chiral SFC to obtain the specifically assigned:

1-[(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propyl-1-one (peak 1, retention time = 2.979 min) (45.0 mg, 37%), a white solid. ^¹H 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 R _{_T} = 1.761 min, m/z = 275.2 [M+H] ^⁺ . The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 minutes) was 1.761 min, and the measured ESI value [M+H] = 275.2.

1-[(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propyl-1-one (peak 2, retention time = 3.234 min) (52 mg, 43%), a white solid. ^¹H 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-MSR _T = 1.755 min, m/z = 275.2 [M+H] ^⁺ . The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 minutes) was 1.752 min, and the measured ESI value [M+H] was 275.2.

SFC conditions: Column: ChiralPak AD-3 150×4.6mm ID3μm; Mobile phase: A: CO2 _, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃.

Method 16

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

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

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

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

Cesium carbonate (422 mg, 1.30 mmol) was added to a cooled (0 °C) solution of cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-oxo-propionitrile (140 mg, 0.52 mmol) in N,N-dimethylformamide (6 mL). After stirring for 30 min, iodomethane (2800 mg, 19.7 mmol) was added, and the reaction mixture was stirred at 0 °C for 4 h. The mixture was then quenched by adding cold, saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/ammonium hydroxide in water 0.05%) to give 3-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-3-oxopropionitrile (28.0 mg, 17%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.44-7.38(m, 3H), 7.27-7.25(m, 2H), 6.15-6.13(m, 0.5H), 6.01-5.99(m, 0.5H), 5.57-5.56 (m, 1H), 3.74-3.63 (m, 1H), 3.06-2.95 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H). LC-MS R _T =1.734 min, m/z =299.2[M+H] ⁺ . The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 minutes) was 1.734 min, and the measured ESI+ value [M+H] = 299.2.

Method 17

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

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

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

Step 2:

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

Under a nitrogen atmosphere, ethyl magnesium chloride (2.7 M, in THF, 0.54 mL, 1.47 mmol) was added dropwise to a cooled (-78 °C) solution of N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-carboxamide (100 mg, 0.37 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduced pressure to give crude 1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)prop-1-one (80 mg, 90%) as a light brown solid, which was further separated by chiral SFC to give the specifically attributed:

(R)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)prop-1-one (peak 1, retention time = 2.581 min) (25.4 mg, 32%), is a white solid. ^¹H 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 R _T = 0.843 min, m/z = 240.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.843 min, ESI+ measured value [M+H] = 240.9.

(S)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)prop-1-one (peak 2, retention time = 2.968 min) (22.7 mg, 28%), is a white solid. ^¹H 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 = 7.2 Hz, 3H). LCMS R _T = 0.838 min, m/z = 241.0 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.838 min, ESI+ measured value [M+H] = 241.0.

SFC conditions: Column: Chiralpak AD (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2O iPrOH; Start B15% End B15%; Flow rate (60mL/ _min ), column temperature 40℃.

Method 18

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

To a solution of 1-[cis-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-methyl-prop-1-one (50 mg, 0.18 mmol) in dimethyl sulfoxide (4 mL), add 1-bromo-2,5-pyrrolidone (33 mg, 0.18 mmol). Heat the mixture in air at 100 °C for 15 hours. The solvent was evaporated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 25-55%/ammonium hydroxide in water) and further purified by preparative TLC (ethyl acetate, _Rf = 0.6) to give 1-(racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxy-2-methyl-prop-1-one (48.6 mg, 91%) as a white solid. ^¹H NMR (400MHz, _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 R _{_T} = 0.771 min, m/z = 290.1 (M+H) ^. LC-MS (5–95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) retention time 0.771 min, ESI+ measured value [M+H] = 290.1.

Method 19

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

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

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

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

At 0 °C, diiodomethane (355 mg, 1.33 mmol) was added to a mixture of diethylzinc (123 mg, 1.00 mmol) and nickel chloride (8 mg, 0.07 mmol) in dichloromethane (5 mL). After stirring 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-1-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 adding cold, saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (25-55% acetonitrile/0.05% HCl in acetonitrile) to give (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl) ketone (3.0 mg, 3%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.41-7.37(m, 3H), 7.24-7.23(m, 2H), 6.15-6.13(m, 0.5H), 6.01-5.99(m, 0.5H), 5.60-5.59 (m, 1H), 3.76-3.68 (m, 1H), 2.84-2.74 (m, 1H), 1.82-1.76 (m, 2H), 1.41 (s, 3H), 0.97-0.92 (m, 2H). LC-MS R _T =1.068 min, m/z =286.1[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.068 min, and the measured ESI+ value [M+H] was 286.1.

Method 20

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

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

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

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

Under a nitrogen atmosphere, ethyl magnesium chloride (2.7 M, in THF, 0.39 mL, 1.04 mmol) was added dropwise to a cooled (-78 °C) solution of N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide (60 mg, 0.21 mmol) in tetrahydrofuran (6 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure to give a crude racemic product, which was further separated by chiral SFC to give the specifically attributed product:

1-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propyl-1-one (peak 1, retention time = 3.254 min) (11.5 mg, 21%), a white solid. ^¹H 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 R _{_T} = 1.026 min, m/z = 257.1 [M+H] ^⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.026 min, and the measured ESI+ value [M+H] was 257.1.

1-[(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propyl-1-one (peak 2, retention time = 4.381 min) (13.6 mg, 25%), is a white solid. ^¹H 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 R _T = 1.023 min, m/z = 257.1 [M+H] ⁺ LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid, within 2 minutes) retention time 1.023 min, ESI+ measured value [M+H] = 257.1.

SFC conditions: Column: OD (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2OEtOH ; Start B: 30%; End B: 30%; Flow rate (60mL/ _min ), column temperature 40℃.

Method 21

3,3,3-Trifluoro-1-(racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)prop-1-one

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

At 0 °C, triethylamine (165 mg, 1.63 mmol) and trimethylsilyl trifluoromethanesulfonate (254 mg, 1.14 mmol) were added to a solution of 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ethyl ketone (200 mg, 0.82 mmol) in 1,4-dioxane (6 mL). The mixture was stirred at 0 °C for 2 hours and quenched by adding cold, saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure to obtain crude 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)vinyloxy-trimethyl-silane (245 mg, 95%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.17-7.10(m, 3H), 6.98-6.96(m, 2H), 5.79-5.78(m, 0.5H), 5.65-5.64(m, 0.5H), 5.21- 5.17 (m, 2H), 4.40 (s, 1H), 4.49 (s, 1H), 3.37-3.27 (m, 1H), 2.66-2.56 (m, 1H), 0.03 (s, 9H).

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

A mixture of 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (418 mg, 1.32 mmol), 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)vinyloxy-trimethyl-silane (210 mg, 0.66 mmol) and cuprous thiocyanate (16 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 15 °C for 15 hours and then concentrated under reduced pressure. The residue was purified by RP-HPLC (25-55% acetonitrile/0.05% HCl in acetonitrile) to give 3,3,3-trifluoro-1-(racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)prop-1-one (31 mg, 15%) as a white solid. ^¹H NMR (400MHz, _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 R _{_T} = 1.072 min, m/z = 314.1 [M+H]^⁺. LC-MS (10–80% acetonitrile + 0.03% ammonium bicarbonate in water, within 2.0 min) retention time 1.072 min, ESI⁺ measured value [M+H] = 314.1.

Method 22

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

Under a nitrogen atmosphere, ethyl magnesium chloride (3.0 M, in THF, 0.58 mL, 1.74 mmol) was added dropwise to a cooled (-78 °C) solution of (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (200 mg, 0.78 mmol) in tetrahydrofuran (20 mL). After addition, the mixture was stirred at -78 °C for 2 hours, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. 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, 0-50% ethyl acetate in petroleum ether) to give 1-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (60 mg, 32%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.42-7.32 (m, 3H), 7.12-7.10 (m, 2H), 5.49 (dd, J = 5.6, 8.4 Hz, 1H), 3.31-3.21 (m, 1H), 3.17-3.01 (m, 4H), 2.72-2.64 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). LCMS R _T = 1.523 min, m/z = 242.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 min) retention time 1.523 min, ESI+ measured value [M+H] = 242.2.

Method 23

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

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

1-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propyl-1-one (peak 2, retention time = 3.038 min) (17 mg, 8%), is a white solid. ^¹H 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 R _T = 0.977 min, m/z = 260.1 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.977 min, ESI+ measured value [M+H] = 260.1.

SFC conditions: Column: OJ (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2OEtOH ; Start B: 20%; End B: 20%; Flow rate (60mL/ _min ), column temperature 40℃.

Method 24

1-[racemic-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one

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

Sulfuric acid (2.3 g, 23.12 mmol) was added to a solution of (E)-4-phenylbut-3-enoic acid (15.0 g, 92.48 mmol) in methanol (60 mL). The mixture was heated at 90 °C for 18 hours and then 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), saturated sodium bicarbonate aqueous solution (30 mL), and brine (30 mL), dried, and concentrated under reduced pressure to give crude (E)-4-phenylbut-3-enoic acid methyl ester (14.8 g, 91%) as a light-colored oil, which was used directly in the next step. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.39-7.21 (m, 5H), 6.54-6.45 (m, 1H), 6.35-6.25 (m, 1H), 3.72 (s, 3H), 3.30-3.25 (m, 2H).

Step 2: Methyl 2-(3-phenyloxacycloprop-2-yl)acetate

A solution of potassium persulfate triple salt (67.1 g, 109.2 mmol) in water (80 mL) was added dropwise to a mixture of (E)-4-phenylbut-3-enoate methyl ester (14.8 g, 84.0 mmol) and sodium bicarbonate (34.4 g, 409.0 mmol) in acetone (300 mL) at 0 °C. After addition, the resulting mixture was heated to 25 °C and stirred for 4 hours, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give methyl 2-(3-phenyloxacycloprop-2-yl)acetate (15.0 g, 93%) as a colorless oil. LC-MS R _{_T} = 0.799 min, m/z = 233.9 [M+H]^⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.799 min, and the measured ESI+ value [M+H] = 233.9.

Step 3: (racemic-3R,4S)-4-bromo-3-hydroxy-4-phenylbutyrate methyl ester

Lithium bromide (6.8 g, 78.0 mmol) and magnesium perchlorate (1.7 g, 78.0 mmol) were added to a solution of methyl 2-(3-phenyloxacycloprop-2-yl)acetate (15.0 g, 78.0 mmol) in acetonitrile (400 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h and diluted with dichloromethane (100 mL). The resulting mixture was washed with hydrochloric acid (1 N, 100 mL). The separated aqueous layer was washed with dichloromethane (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude (racemic-3R,4S)-4-bromo-3-hydroxy-4-phenylbutyrate methyl ester (20.0 g, 94%) as a colorless oil. The crude product was used in the next step without further purification. LC-MS R_{_T} = 0.610 min, m/z = 256.9 [M+H]^⁺. LC-MS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) was 0.610 min, ESI₊ measured value [M+H] = 256.9.

Step 4: (racemic-3R,4R)-4-azido-3-hydroxy-4-phenylbutyrate methyl ester

The compound of (racemic-3R,4S)-4-bromo-3-hydroxy-4-phenylbutyrate methyl ester (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 give crude (racemic-3R,4R)-4-azido-3-hydroxy-4-phenylbutyrate methyl ester (17.0 g, 99%) as a yellow oil. LC-MS R _{_T} = 0.978 min, m/z = 208.3 [M+H] ^⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.978 min, and the measured ESI+ value [M+H] = 208.3.

Step 5: (racemic-3R,4R)-4-amino-3-hydroxy-4-phenylbutyrate methyl ester

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

Step 6: cis-4-hydroxy-5-phenylpyrrolidone-2-one

A solution of (racemic-3R,4R)-4-amino-3-hydroxy-4-phenylbutyrate methyl ester (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, 0-5% methanol in dichloromethane) to give cis-4-hydroxy-5-phenylpyrrolidone-2-one (9.6 g, 76%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) 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 R _T =0.678 min, m/z =178.2[M+H] ⁺ .

The LCMS retention time (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.678 min, and the measured ESI+ value [M+H] = 178.2.

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

To a solution of cis-4-hydroxy-5-phenylpyrrolidone-2-one (9.6 g, 54.2 mmol) in dichloromethane (300 mL), imidazole (11.1 g, 162.5 mmol) and tert-butyldimethylsilyl chloride (16.3 g, 108.4 mmol) were added. 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, 0-50% ethyl acetate in petroleum ether) to give cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidone-2-one (10.0 g, 63%) as a white solid. LC-MS R _{_T} = 1.257 min, m/z = 292.3 [M+H] ^⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.257 min, and the measured ESI+ value [M+H] was 292.3.

Step 8: cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidine-2-one

Sodium hydride (60%, 2.1 g, 51.5 mmol) was added to a solution of cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidone-2-one (10.0 g, 34.3 mmol) in N,N-dimethylformamide (50 mL) at 0 °C. After stirring at 0 °C for 30 min, (aminooxy)diphenylphosphine oxide (12.0 g, 51.47 mmol) was added in portions. The resulting mixture was stirred at room temperature for 12 h and filtered. The filtrate was concentrated under reduced pressure to give crude cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidone-2-one (9.0 g, 86%) as a brown solid. This crude product was used in the next step without further purification. LC-MS R _{_T} = 1.225 min, m/z = 307.4 [M+H] ^⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.225 min, and the measured ESI+ value [M+H] was 307.4.

Step 9: Ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidine-1-yl)amino)-2-iminoethyl acetate

A mixture of cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidine-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 reduced pressure to give crude ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidine-1-yl)amino)-2-imino-acetate (10.0 g, 84%) as a brown oil. LC-MS R _{_T} = 1.128 min, m/z = 406.4 [M+H] ^⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.128 min, and the measured ESI+ value [M+H] was 406.4.

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

A mixture of ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetic acid (10.0 g, 24.7 mmol) and 4-methylbenzenesulfonic acid hydrate (4.7 g, 24.7 mmol) in toluene (300 mL) was heated at 120 °C for 16 hours, and then concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (5.5 g, 58%) as a brown oil. LC-MS R _{_T} = 1.345 min, m/z = 388.4 [M+H]^⁺. LC-MS retention time (10-80% acetonitrile in water + 0.03% trifluoroacetic acid, within 2.0 min) was 1.345 min, ESI⁺ measured [M+H] = 388.4.

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

To a solution of tetrabutylammonium fluoride (18.5 g, 70.9 mmol) in tetrahydrofuran (200 mL), ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (5.5 g, 14.2 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hours and diluted with ethyl acetate (300 mL). The compound was washed with water (50 mL) and 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, 0-50% ethyl acetate in petroleum ether) to give 1.8 g, 46% cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (46%) as a yellow solid. LC-MS R _{_T} = 1.036 min, m/z = 274.3 [M+H]^⁺. LC-MS retention time (0-60% acetonitrile in water + 0.03% trifluoroacetic acid, within 2.0 min) was 1.036 min, ESI⁺ measured [M+H] = 274.3.

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

At 25 °C, ethyl trifluoride (10.0 g, 62.0 mmol) was added dropwise to a solution of cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.0 g, 3.66 mmol) in dichloromethane (50 mL). The resulting mixture was stirred at 25 °C for 1 hour, and then quenched by slow addition of a saturated aqueous solution of 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, 0-40% ethyl acetate in petroleum ether) to give ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (400 mg, 40%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) 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 =0.958min, m/z=276.2[M+H] ⁺

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.958 min, and the measured ESI+ value [M+H] = 276.2.

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

Under a nitrogen atmosphere, ethyl magnesium chloride (3.0 M, 0.25 mL, 0.75 mmol in THF) was added dropwise to a cooled (-78 °C) solution of trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at -78 °C for 2 hours, and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 1-[racemic-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (13.6 mg, 45%) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.34-7.31(m, 3H), 6.90-6.87(m, 2H), 5.63-5.61(m, 0.5H), 5.59-5.57(m, 1H), 5.46-5.4 4 (m, 0.5H), 3.42-3.28 (m, 1H), 3.26-3.21 (m, 1H), 3.03-3.01 (m, 2H), 1.16 (t, J=7.2Hz, 3H). LCMS R _T =0.977 min, m/z =260.1[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.977 min, and the measured ESI+ value [M+H] = 260.1.

Method 25

(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl)methyl ketone

To a solution of 2-bromopyridine (435 mg, 2.76 mmol) in tetrahydrofuran (20 mL), n-butyllithium (2.5 M, in hexane, 1.10 mL, 2.76 mmol) was added at -78 °C. The mixture was then heated to 30 °C and stirred for 2 hours. The mixture was cooled to -78 °C, and cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (200 mg, 0.69 mmol) was added to tetrahydrofuran (5 mL). The reaction mixture was stirred at -78 °C for 6 hours and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55%/ammonium hydroxide in water 0.05%) to give (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl) methyl ketone (32.0 mg, 15%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.69-8.65(m, 1H), 8.00-7.90(m, 2H), 7.62-7.59(m, 1H), 7.42-7.30(m, 3H), 7.25-7.20(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 + 0.1% ammonia in water, within 3.0 minutes) retention time 1.510 min, ESI+ measured value [M+H] = 309.1.

Method 26

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

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

Under a nitrogen atmosphere, ethyl cyclopropyl magnesium bromide (0.5 M, in THF, 1.45 mL, 0.73 mmol) was added dropwise to a cooled (-78 °C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (4 mL). After addition, the mixture was stirred at -78 °C for 2 hours, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by RP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to give cis, racemic cyclopropyl-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (15 mg, 10%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.45-7.35(m, 3H), 7.27-7.25(m, 2H), 6.18-6.15(m, 0.5H), 6.05-6.00(m, 0.5H), 5.65-5.60(m, 1H), 3.77-3.65(m, 1H), 3.05-2.95(m, 1H), 2.90-2.70(m, 1H), 1.17-1.13(m, 2H), 1.10-1.05(m, 2H). LCMS R _T =1.031 min, m/z =272.3[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.031 min, and the measured ESI+ value [M+H] was 272.3.

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

Racemic cyclopropyl-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (100 mg, 0.37 mmol) was separated by chiral SFC to obtain the specifically assigned:

Cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 3.575 min) (25.5 mg, 24%) is a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.38 (m, 3H), 7.29-7.27 (m, 2H), 6.19 (d, J=5.6Hz, 0.5H), 6.05 (d, J=5.2Hz, 0.5H), 5 .66-5.62(m, 1H), 3.79-3.71(m, 1H), 3.05-3.02(m, 1H), 3.01-2.81(m, 1H), 1.29-1.09(m, 4H). LCMS R _T =0.816 min, m/z =271.9[M+H] ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.816 min, and the measured ESI+ value [M+H] = 271.9.

Cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 3.849 min) (18.5 mg, 17%), is a white solid. ^¹H 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 R _T = 0.817 min, m/z = 271.9 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.817 min, ESI+ measured value [M+H] = 271.9.

SFC conditions: Column: Chiralpak AD (250mm*30mm, 10μm); Conditions: 0.1% _NH3H2O iPrOH; Start B25% End B25%; Flow rate (60mL/ _min ), column temperature 40℃.

Method 27

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

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.611 min, and the measured ESI+ value [M+H] = 302.1.

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

A solution of cis-cyclopentyl(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol (100 mg, 0.33 mmol) in dichloromethane (15 mL) was mixed with manganese dioxide (288 mg, 3.32 mmol). The reaction mixture was stirred at 35 °C for 2 hours and then filtered through a diatomaceous earth stencil. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to give cyclopentyl-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (18.2 mg, 18%) as a white solid. ^¹H NMR (400MHz, _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 R_{_T} = 2.070 min, m/z = 300.2 [M+H]^⁺. LCMS (0–60% acetonitrile + 0.03% trifluoroacetic acid in water, within 3.0 min) retention time 2.070 min, ESI⁺ measured value [M+H] = 300.2.

Method 28

(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-thienyl)methyl ketone

To a cooled (-78°C) solution of 2-iodothiophene (289 mg, 1.38 mmol) in tetrahydrofuran (10 mL), n-butyllithium (2.5 M, in hexane, 0.55 mL, 1.38 mmol) was added dropwise under _a nitrogen atmosphere. The mixture was stirred at -78°C for 1 hour, and then cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.34 mmol) was added in tetrahydrofuran (2 mL). The mixture was stirred at -78°C for another 2 hours, and then quenched by adding saturated aqueous solution of 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 reduced pressure. The residue was purified by RP-HPLC (40-70% acetonitrile/0.05% hydrochloric acid in water) to give (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-thienyl) methyl ketone (15.6 mg, 14%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ8.50-8.49(m, 1H), 7.96-7.94(m, 1H), 7.49-7.35(m, 3H), 7.35-7.27(m, 2H), 7.26-7.20(m, 1H), 6.24-6.22(m, 0.5H), 6.10-6.08(m, 0.5H), 5.74-5.68(m, 1H), 3.86-3.72(m, 1H), 2.91-2.79(m, 1H). LCMS R _T =0.891 min, m/z =314.1[M+H] ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.891 min, and the measured ESI+ value [M+H] = 314.1.

Method 29

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

Under a _nitrogen atmosphere, cyclobutane bromide (0.5 mL, 5.85 mmol) was added dropwise to a mixture of magnesium (234 mg, 9.65 mmol), iodine (12 mg, 0.05 mmol), and 1,2-dibromoethane (0.1 mL, 0.10 mmol) in tetrahydrofuran (15 mL) under cooling (0 °C). The mixture was stirred at 35 °C for about 1 hour. The freshly prepared cyclobutyl magnesium bromide solution (1.0 mL, 0.39 mmol) was then added dropwise to a solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (28 mg, 0.10 mmol) in tetrahydrofuran (2 mL) under stirring and cooling (-78 °C). After addition, the mixture was stirred at -78°C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by RP-HPLC (acetonitrile 42-62%/0.05% hydrochloric acid in water) to give cyclobutyl-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (2 mg, 7%) as a white solid. ¹ HNMR (400MHz, CD ₃ OD) δ7.40-7.30(m, 3H), 7.25-7.21(m, 2H), 6.15-6.10(m, 0.5H), 6.01-5.95(m, 0.5H), 5.60-5.55(m, 1H), 4.15-4.07(m, 1H), 3.74-3.65(m, 1H), 2.80-2.70(m, 1H), 2.35-2.20(m, 3H), 2.20-2.15(m, 1H), 2.12-2.00(m, 1H), 1.90-1.85(m, 1H). LCMS R _T =0.883 min, m/z =286.0[M+H] ⁺ . LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.883 min, and the measured ESI+ value [M+H] was 286.0.

Method 30

1-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-prop-1-one

Under a nitrogen atmosphere, tert-butyllithium (1.3 M, in pentane, 0.17 mL, 0.22 mmol) was added dropwise to a cooled (-78 °C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at -78 °C for 2 hours, and then quenched by adding 10 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by RP-HPLC (acetonitrile 45-75%/0.05% hydrochloric acid in water) to give 1-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-prop-1-one (12.7 mg, 40%) as a white solid. ^¹H NMR (400MHz, _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 R_{_T} = 0.907 min, m/z = 288.0 [M+H] ^⁺. LCMS (5–95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) retention time 0.907 min, ESI⁺ measured value [M+H] = 288.0.

Method 31

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

Under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 mL in THF, 1.1 mL, 2.20 mmol) was added dropwise to a cooled (-78 °C) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (200 mg, 0.73 mmol) in 10 mL of tetrahydrofuran. After addition, the mixture was stirred at -78 °C for 2 hours, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by RP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to give racemic 1-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-prop-1-one (6.9 mg, 3.4%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.46-7.36(m, 3H), 7.28-7.26(m, 2H), 6.18-6.16(m, 0.5H), 6.05-6.02(m, 0.5H), 5.65-5.61(m, 1H) , 3.78-3.72 (m, 1H), 3.64-3.61 (m, 1H), 2.87-2.76 (m, 1H), 1.19 (d, J=7.2Hz, 3H), 1.17 (d, J=6.8Hz, 3H). LCMS R _T =1.971 min, m/z =274.2[M+H] ⁺ . The LCMS retention time (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water, within 3.0 minutes) was 1.971 min, and the measured ESI+ value [M+H] = 274.2.

Method 32

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

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

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

Under a nitrogen atmosphere, ethyl magnesium bromide (3.0 M, in THF, 0.1 mL, 0.30 mmol) was added dropwise to a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (30 mg, 0.10 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at 30 °C for about 3 hours, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by RP-HPLC (acetonitrile 25-55%/ammonium hydroxide in water 0.05%) to give 1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (6.3 mg, 23%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.38-7.35(m, 3H), 7.25-7.23(m, 2H), 6.15-6.13(m, 0.5H), 6.01-5.99(m, 0.5H), 5.59- 5.53 (m, 1H), 3.77-3.67 (m, 1H), 3.05-2.99 (m, 2H), 2.84-2.73 (m, 1H), 1.13 (t, J=7.2Hz, 3H). LCMS R _T =1.038 min, m/z =260.2[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.038 min, and the measured ESI+ value [M+H] = 260.2.

Step 2:

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

Racemic 1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propyl-1-one (220 mg) was separated by chiral SFC to obtain the specifically attributed:

1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (peak 1, retention time = 2.265 min) (78 mg, 35%, 88% ee) is a pale yellow oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.32(m, 3H), 7.27-7.23(m, 2H), 6.17-6.14(m, 0.5H), 6.02-6.00(m, 0.5H), 5.65- 5.58 (m, 1H), 3.84-3.64 (m, 1H), 3.06-3.00 (m, 2H), 2.88-2.69 (m, 1H), 1.13 (t, J=7.2Hz, 3H). LCMS R _T =0.822 min, m/z =260.0[M+H] ⁺ . LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.822 min, and the measured ESI+ value [M+H] was 260.0.

1-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (peak 2, retention time = 2.382 min) (80 mg, 35%, 91% ee) is a pale yellow oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.32(m, 3H), 7.27-7.23(m, 2H), 6.17-6.14(m, 0.5H), 6.02-6.00(m, 0.5H), 5.65- 5.58 (m, 1H), 3.84-3.64 (m, 1H), 3.06-3.00 (m, 2H), 2.88-2.69 (m, 1H), 1.13 (t, J=7.2Hz, 3H). LCMS R _T =0.817 min, m/z =260.0[M+H] ⁺ . LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.817 min, and the measured ESI+ value [M+H] = 260.0.

SFC conditions: Column: AS (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2OEtOH ; Start B 20% End B 20%; Flow rate (60mL/ _min ), column temperature 40℃.

Method 33

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

Under a nitrogen atmosphere, tert-butyllithium (1.3 M, in hexane, 1.45 mL, 1.89 mmol) was added dropwise to a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (137 mg, 0.47 mmol) and 1-methyl-4-iodo-1h-pyrazole (393 mg, 1.89 mmol) in tetrahydrofuran (10 mL) at a temperature of -70 °C. The mixture was stirred at -70 °C for 1 hour and then quenched by adding 10 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 27-57%/0.05% hydrochloric acid in water) to give cis, racemic (1-methylpyrazol-4-yl)-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (53.4 mg, 36%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ8.61 (s, 1H), 8.24 (s, 1H), 7.46-7.34 (m, 3H), 7.32-7.25 (m, 2H), 6.22-6.19 (m, 0.5H), 6.08-6.05(m, 0.5H), 5.72-5.65(m, 1H), 3.93(s, 3H), 3.85-3.70(m, 1H), 2.90-2.75(m, 1H). LCMS R _T =0.791 min, m/z =311.9[M+H] ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.791 min, and the measured ESI+ value [M+H] = 311.9.

Method 34

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

Step 1: (E)-Benzaldehyde oxime

Sodium carbonate (112.3 g, 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g, 508.9 mmol) were added to a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL). The reaction mixture was stirred at 25 °C for 3 hours 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 give crude (E)-benzaldehyde oxime as a colorless oil (51.0 g, 99%), which was used in the next step without further purification.

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

To a solution of (E)-benzaldehyde oxime (20.0 g, 165.1 mmol) in 1,4-dioxane (500 mL), methyl acrylate (14.2 g, 165.1 mmol), sodium iodide (24.7 g, 165.1 mmol), 2,6-dimethylpyridine (17.6 g, 165.1 mmol), and tert-butyl hypochlorite (17.9 g, 165.1 mmol) were added. The reaction mixture was stirred at 25 °C for 24 h, followed by concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g, 74%). LCMS R _{_T} = 0.871 min, m/z = 206.2 [M+H] ^⁺ . LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.871 min, and the measured ESI+ value [M+H] = 206.2.

Step 3: 3-Hydroxy-5-phenyl-pyrrolidone-2-one

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

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

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

cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one (12.4 g, 51%). ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.37–7.25 (m, 5H), 4.88–4.53 (m, 1H), 4.54–4.46 (m, 1H), 2.89–2.79 (m, 1H), 1.80–1.71 (m, 1H), 0.93–0.90 (m, 9H), 0.19–0.12 (m, 6H), and

trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidine-2-one, as a colorless oil (9.3 g, 38%). ^¹H NMR (400 MHz, _CDCl₃ ) 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).

Step 5: trans-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidine-2-one

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

Step 6: Ethyl trans-2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidine-1-yl)amino)-2-iminoethyl acetate

To a solution of trans-1-amino-3-[tert-butyl(dimethyl)silyl)oxy-5-phenyl-pyrrolidine-2-one (7.0 g, 22.8 mmol) in ethanol (150 mL), ethyl 2-ethoxy-2-imino-ethyl (6.63 g, 45.7 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h, followed by concentration under reduced pressure to give crude trans-2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidine-1-yl)amino)-2-imino-ethyl acetate (8.50 g, 92%) as a yellow oil, which was used in the next step without further purification. _{LCMSR T} = 2.154 min, m/z = 406.3 [M+H] ⁺ . The LCMS retention time (0 to 60% acetonitrile + 0.03% trifluoroacetic acid in water, within 3.0 min) was 2.143 min, and the measured ESI+ value [M+H] = 406.3.

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

To a solution of ethyl 2-[[trans-3-[tert-butyl(dimethyl)silyl)oxy-2-oxo-5-phenyl-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (8.5 g, 21.0 mmol) in toluene (100 mL), p-toluenesulfonic acid (4.4 g, 25.2 mmol) was added. The reaction mixture was stirred at 120 °C for 16 h, followed by concentration under reduced pressure to give crude trans-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (7.5 g, 92.3%) as a yellow oil, which was used in the next step without further purification. LCMS R _{_T} = 1.022 min, m/z = 374.2 [M+H] ^⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.022 min, and the measured ESI+ value [M+H] was 374.2.

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

To a solution of trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (7.0 g, 18.06 mmol) in tetrahydrofuran (120 mL), tetrabutylammonium fluoride (1 N, in THF, 18.06 mL, 18.06 mmol) was added. The reaction mixture was stirred at 40 °C for 3 hours, followed by concentration under reduced pressure to give crude trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.5 g, 57%) as a yellow oil, which was used in the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ ): δ7.39-7.35(m, 3H), 7.14-7.12(m, 2H), 5.73-5.70(m, 1H), 5.54-5.51(m, 1H ), 4.47-4.40 (m, 2H), 3.24-3.21 (m, 1H), 3.05-3.00 (m, 1H), 1.41-1.36 (m, 3H).

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

At 0 °C, diethylaminosulfonate trifluoride (176.9 mg, 1.10 mmol) was added to a solution of trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.37 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at 0 °C for 2 hours, followed by quenching with the 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) and 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 give cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (54 mg, 54%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.44-7.31 (m, 3H), 7.25-7.17 (m, 2H), 6.09 (dd, J=1.4Hz, 7.2Hz, 1H), 5.95 (dd, J=1.4Hz, 7.2Hz, 1 H), 5.52-5.47(m, 1H), 4.53-4.37(m, 2H), 3.74-3.54(m, 1H), 3.05-2.82(m, 1H), 1.48-1.33(m, 3H).

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

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

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

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

A mixture of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (350 mg, 1.42 mmol), 1-hydroxybenzotriazole (201 mg, 1.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (407 mg, 2.12 mmol), and N,O-dimethylhydroxylamine hydrochloride (180 mg, 1.84 mmol) in N,N-dimethylformamide (10 mL) was stirred at 20 °C for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.7) to give cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (225 mg, 54.7%) as a white solid. ¹ HNMR (400MHz, CDCl ₃ )δ7.41-7.35(m, 3H), 7.26-7.22(m, 2H), 6.09-6.07(m, 0.5H), 5.96-5.93(m, 0.5H), 5.4 9-5.46 (m, 1H), 3.78 (s, 3H), 3.66-3.59 (m, 1H), 3.55-3.35 (brs, 3H), 2.99-2.88 (m, 1H). LCMS R _T =0.564 min, m/z =291.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.564 min, and the measured ESI+ value [M+H] = 291.1.

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

Under a nitrogen atmosphere, methyl magnesium bromide (3.0 M, in THF, 0.1 mL, 0.30 mmol) was added dropwise to a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (30 mg, 0.10 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at 30 °C for about 3 hours, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried under reduced pressure and concentrated. The residue was purified by RP-HPLC (acetonitrile 25-55%/ammonium hydroxide in water 0.05%) to give 1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]acetone (4 mg, 15%) as a white solid. ^¹H 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 R _T = 0.954 min, m/z = 246.2 [M+H] ⁺ . LCMS (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) retention time 0.954 min, ESI+ measured value [M+H] = 246.2.

Method 35

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.64 mL, 1.60 mmol) was added dropwise to a cooled (-70 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (157 mg, 1.06 mmol) in tetrahydrofuran (10 mL) of 10 mL. After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 30 mL of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 37-67%/ammonium hydroxide in water 0.05%) to give [trans-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (25 mg, 16%) as a deep red solid. This material was further separated by chiral SFC to obtain the specifically assigned:

[(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 3.130 min) (11.2 mg, 44%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.51-7.33(m, 3H), 7.30-7.28(m, 2H), 6.21-6.03(m, 1H), 5.68-5.64(m, 1H), 5.02-4.94(m, 1H), 4.84-4 .80 (m, 1H), 3.84-3.70 (m, 1H), 3.47-3.44 (m, 1H), 2.90-2.78 (m, 1H), 1.73-1.62 (m, 1H), 1.60-1.52 (m, 1H). LCMS R _T =1.765 min, m/z =290.1[M+H] ⁺ . LCMS (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 2.0 minutes) retention time 1.765 min, ESI+ measured value [M+H] = 290.1.

[(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 3.464 min) (10.2 mg, 40%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.51-7.33(m, 3H), 7.32-7.20(m, 2H), 6.21-6.04(m, 1H), 5.70-5.62(m, 1H), 5.00-4.82(m, 1H) ), 3.83-3.70(m, 1H), 3.47-3.42(m, 1H), 2.90-2.77(m, 1H), 1.74-1.63(m, 1H), 1.60-1.52(m, 1H). LCMS R _T =1.756 min, m/z =290.1[M+H] ⁺ . The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 2.0 minutes) was 1.756 min, and the measured ESI+ value [M+H] = 290.1.

SFC conditions: Column: Chiralcel OD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2 _, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min.

Method 36

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

Step 1: 1-Fluoro-N-methoxy-N-methylcyclopropaneformamide

A mixture of 1-fluorocyclopropanecarboxylic acid (150 mg, 1.44 mmol), N,N-diisopropylethylamine (465 mg, 3.60 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (712 mg, 1.87 mmol), and N,O-dimethylhydroxylamine hydrochloride (183 mg, 1.87 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 1-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (140 mg, 66%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.75 (s, 3H), 3.26 (s, 3H), 1.31-1.21 (m, 4H).

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.21 mL, 0.53 mmol) was added dropwise to a cooled (-78 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and 1-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (52 mg, 0.35 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding 10 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.05% HCl in water) to give a crude product (20 mg). The crude product was further purified by preparative TLC (in 30% ethyl acetate in petroleum ether, _Rf = 0.3) to give (1-fluorocyclopropyl)(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (10.2 mg, 19%), as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.41-7.37(m, 3H), 7.23-7.21(m, 2H), 6.09-6.07(m, 0.5H), 5.96-5.93(m, 0.5H), 5.51- 5.50 (m, 1H), 3.67-3.58 (m, 1H), 3.00-2.90 (m, 1H), 1.92-1.88 (m, 2H), 1.62-1.58 (m, 2H). LCMS R _T =1.726 min, m/z =290.1[M+H] ⁺ .

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

Method 37

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.34 mL, 0.85 mmol) was added dropwise to a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (80 mg, 0.28 mmol) and N-methoxy-N,3-dimethyloxetane-3-carboxamide (90 mg, 0.57 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding 10 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30-60%/ammonium hydroxide in water) to give [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(3-methyloxetane-3-yl) ketone (16.3 mg, 19%) as a pink solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.37(m, 3H), 7.25-7.23(m, 2H), 6.17-6.15(m, 0.5H), 6.03-6.01(m, 0.5H), 5.65-5.62 (m, 1H), 5.09-5.02 (m, 2H), 4.52-4.26 (m, 2H), 3.78-3.70 (m, 1H), 2.86-2.76 (m, 1H), 1.74 (s, 3H). LCMS R _T =0.675 min, m/z =302.1[M+H] ⁺ . LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes): 0.675 min, ESI+ measured value [M+H] = 302.1.

Method 38

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

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

A mixture of N,O-dimethylhydroxylamine hydrochloride (252 mg, 2.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (396 mg, 2.07 mmol), 3-methyloxetane-3-carboxylic acid (200 mg, 1.72 mmol), 1-hydroxybenzotriazole (140 mg, 1.03 mmol), and N,N-diisopropylethylamine (556 mg, 4.31 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 12 hours. 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) and brine (20 mL), dried, and concentrated under reduced pressure to give crude N-methoxy-N,3-dimethyloxetane-3-carboxamide (270 mg, 98%) as a colorless oil. The crude product was used in the next step without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.96–4.93 (m, 2H), 4.29–4.27 (m, 2H), 3.66 (s, 3H), 3.18 (s, 3H), 1.66 (s, 3H).

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.43 mL, 1.06 mmol) was added dropwise to a cooled (-78 °C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) and N-methoxy-N,3-dimethyloxetane-3-carboxamide (113 mg, 0.71 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding 10 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30-60%/ammonium hydroxide in water) to give [(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(3-methyloxetane-3-yl) ketone (13.6 mg, 13%) as a pink solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.37(m, 3H), 7.25-7.23(m, 2H), 6.17-6.15(m, 0.5H), 6.03-6.01(m, 0.5H), 5.65-5.62 (m, 1H), 5.09-5.02 (m, 2H), 4.52-4.26 (m, 2H), 3.78-3.70 (m, 1H), 2.86-2.76 (m, 1H), 1.74 (s, 3H). LCMS R _T =0.678 min, m/z =302.1[M+H] ⁺ . LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes): 0.678 min, ESI+ measured value [M+H] = 302.1.

Method 39

3-Oxabicyclo[3.1.0]hex-6-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

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

A mixture of 3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (trans, 300 mg, 2.34 mmol), N,O-dimethylhydroxylamine hydrochloride (297 mg, 3.04 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1157 mg, 3.04 mmol), and N,N-diisopropylethylamine (756 mg, 5.85 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide (180 mg, 45%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) 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).

Step 2: 3-oxabicyclo[3.1.0]hex-6-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.21 mL, 0.53 mmol) was added dropwise to a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide (61 mg, 0.35 mmol) in tetrahydrofuran (2 mL) at a temperature of -70 °C. After addition, the mixture was stirred at -70 °C for 1 hour and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30-60%/ammonium hydroxide in water) to give 3-oxabicyclo[3.1.0]hex-6-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (2.2 mg, 3.9%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.43-7.39(m, 3H), 7.27-7.26(m, 2H), 6.12-5.96(m, 1H), 5.53-5.49(m, 1H), 4.02-3.99(m, 2H) , 3.82-3.80(m, 2H), 3.70-3.61(m, 1H), 3.07-3.05(m, 1H), 3.02-2.95(m, 1H), 2.45-2.43(m, 2H). LCMS R _T =0.821 min, m/z =313.9[M+H] ⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.821 min, and the measured ESI+ value [M+H] = 313.9.

Method 40

Oxacyclobut-3-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

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

A mixture of oxetane-3-carboxylic acid (300 mg, 2.94 mmol), 1,1'-carbonyldiimidazole (524 mg, 3.23 mmol), and N,O-dimethylhydroxylamine hydrochloride (286 mg, 2.94 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) and 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. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.92-4.89 (m, 2H), 4.80-4.76 (m, 2H), 4.19-4.13 (m, 1H), 3.63 (s, 3H), 3.21 (s, 3H).

Step 2: Oxalide-3-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.16 mL, 0.40 mmol) was added dropwise to a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (38 mg, 0.13 mmol) and N-methoxy-N-methyloxetane-3-carboxamide (39 mg, 0.27 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at -70 °C for 1 hour, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 25-55%/ammonium hydroxide in water) to give oxetane-3-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (6.3 mg, 15.5%) as a white solid. ^¹H NMR (400MHz, _CDCl₃ ) δ 7.43–7.40 (m, 3H), 7.27–7.23 (m, 2H), 6.11–5.95 (m, 1H), 5.50–5.49 (m, 1H), 4.97–4.90 (m, 4H), 4.72–4.68 (m, 1H), 3.68–3.59 (m, 1H), 3.03–2.92 (m, 1H). LCMS R_{_T} = 0.782 min, m/z = 287.9 [M+H] ^⁺. LCMS (5–95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.782 min, ESI⁺ measured value [M+H] = 287.9.

Method 41

[1-(hydroxymethyl)cyclopropyl]-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

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

To a solution of 1-(hydroxymethyl)cyclopropanecarboxylic acid (200 mg, 1.72 mmol) in dichloromethane (5 mL), tert-butyldimethylchlorosilane (532 mg, 3.53 mmol) and imidazole (240 mg, 3.53 mmol) were added. The mixture was stirred at 25 °C for 5 hours, then quenched by adding 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 sodium hydroxide (138 mg, 3.44 mmol) was added. The resulting mixture was stirred at 25 °C for 10 hours, then adjusted to pH 4 by adding citric acid. The solution was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried and concentrated under reduced pressure to obtain crude 1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropanecarboxylic acid (400 mg, 100%) as a colorless oil.

Step 2:

1-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropaneformamide

A mixture of 1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropanecarboxylic acid (400 mg, 1.74 mmol), N,O-dimethylhydroxylamine hydrochloride (423 mg, 4.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (499 mg, 2.6 mmol), 1-hydroxybenzotriazole (235 mg, 1.74 mmol), and N,N-diisopropylethylamine (1.23 mL, 6.95 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 18 hours. The resulting mixture was 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, 0-30% ethyl acetate in petroleum ether) to give 1-[[tert-butyl(dimethyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropaneformamide (200 mg, 42%) as a colorless oil. LCMS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min): 0.848 min, ESI+ measured [M+H] = 274.1.

Step 3:

(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone

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

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

A mixture of [1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (34 mg, 0.08 mmol) and 2,2,2-trifluoroacetic acid (0.50 mL) in dichloromethane (3 mL) was stirred at 20 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by RP-HPLC (30-60% acetonitrile/0.05% ammonium hydroxide in water) to give [1-(hydroxymethyl)cyclopropyl]-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (4.1 mg, 16%) as a light brown oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.37(m, 3H), 7.27-7.25(m, 2H), 6.17-6.15(m, 0.5H), 6.03-6.01(m, 0.5H), 5.63-5.61(m, 1H), 3.96-3.85(m, 2H), 3.77-3.71(m, 1H), 2.86-2.75(m, 1H), 1.71-1.67(m, 2H), 1.10-1.07(m, 2H). LCMS R _T =0.648 min, m/z =302.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.648 min, and the measured ESI+ value [M+H] = 302.1.

Method 42

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

Step 1: 2,2-Difluoro-N-methoxy-N-methylcyclopropaneformamide

A mixture of 2,2-difluorocyclopropanecarboxylic acid (1.00 g, 8.19 mmol), N,N-diisopropylethylamine (2646 mg, 20.5 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (4.05 g, 10.6 mmol), and N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (30 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methylcyclopropaneformamide (700 mg, 52%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.77 (s, 3H), 3.26 (s, 3H), 2.96-2.91 (m, 1H), 2.16-2.12 (m, 1H), 1.69-1.65 (m, 1H).

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 1.28 mL, 3.19 mmol) was added dropwise to a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (300 mg, 1.06 mmol) and 2,2-difluoro-N-methoxy-N-methyl-cyclopropaneformamide (351 mg, 2.13 mmol) in tetrahydrofuran (15 mL) of 1.28 mL. After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.225% HCl in water) to give (2,2-difluorocyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (120 mg, 37%) as a white solid. This material was further separated by chiral SFC to obtain the specifically assigned:

((1S)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (peak 1, retention time = 2.069 min) (35.0 mg, 29%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.42-7.38(m, 3H), 7.31-7.29(m, 2H), 6.21-6.19(m, 0.5H), 6.07-6.05(m, 0.5H), 5.68 -5.66 (m, 1H), 3.85-3.76 (m, 2H), 2.86-2.83 (m, 1H), 2.32-2.28 (m, 1H), 1.96-1.93 (m, 1H). LCMS R _T =1.834 min, m/z =308.1[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes): 1.834 min, ESI+ measured value [M+H] = 308.1.

((1R)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (peak 2, retention time = 3.055 min) (35.0 mg, 29%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.45-7.41(m, 3H), 7.30-7.28(m, 2H), 6.21-6.19(m, 0.5H), 6.07-6.05(m, 0.5H), 5.66 -5.65 (m, 1H), 3.87-3.74 (m, 2H), 2.89-2.79 (m, 1H), 2.33-2.28 (m, 1H), 1.98-1.97 (m, 1H). LCMS R _T =1.822 min, m/z =308.1[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes): 1.822 min, ESI+ measured value [M+H] = 308.1.

SFC conditions: Chiralcel OD-3 column, 150×4.6mm ID3μm; mobile phase: A: CO2 _, B: isopropanol (0.05% DEA), gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; flow rate: 2.5 mL/min; column temperature: 35℃.

Method 43

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 1.28 mL, 3.19 mmol) was added dropwise to a cooled (-78 °C) solution of 1-fluoro-N-methoxy-N-methyl-cyclopropaneformamide (313 mg, 2.13 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (300 mg, 1.06 mmol) in tetrahydrofuran (30 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding 20 mL of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.05% HCl in water) and then by preparative TLC (30% ethyl acetate in petroleum ether, _Rf = 0.3) to give (1-fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (80 mg, 25%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.40-7.37(m, 3H), 7.23-7.21(m, 2H), 6.09-6.07(m, 0.5H), 5.96-5.94(m, 0.5H), 5.51- 5.49 (m, 1H), 3.67-3.58 (m, 1H), 3.00-2.90 (m, 1H), 1.92-1.88 (m, 2H), 1.62-1.60 (m, 2H). LCMS R _T =1.736 min, m/z =290.1[M+H] ⁺ . LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes): 1.736 min, ESI+ measured value [M+H] = 290.1.

Method 44

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

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

Under a nitrogen atmosphere at 0 °C, allyl magnesium bromide (1.0 M, in tetrahydrofuran, 150.0 mL, 150.0 mmol) was added to a solution of 2-fluorobenzaldehyde (15.0 g, 120.86 mmol) in tetrahydrofuran (250 mL). After addition, the mixture was heated to 25 °C and stirred for 2 hours, then quenched by adding saturated aqueous solution of 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 reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 1-(2-fluorophenyl)but-3-en-1-ol (6.0 g, 24%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.49-7.27(m, 1H), 7.29-7.12(m, 2H), 7.05-7.00(m, 1H), 5.89-5.80(m, 1H) , 5.20-5.13(m, 2H), 5.15-5.07(m, 1H), 2.66-2.55(m, 1H), 2.57-5.48(m, 1H).

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

To a solution of 1-(2-fluorophenyl)but-3-en-1-ol (6.0 g, 36.1 mmol) in dichloromethane (50 mL), imidazole (4.9 g, 72.2 mmol) and tert-butyldimethylchlorosilane (7.1 g, 146.9 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h and quenched by the 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 give tert-butyl-[1-(2-fluorophenyl)but-3-enoxy]-dimethyl-silane (8.5 g, 84%) as a light-colored oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.60-7.36(m, 1H), 7.34-7.18(m, 2H), 7.13-7.02(m, 1H), 5.97-5.85(m, 1H) , 5.21-5.07(m, 3H), 2.60-2.48(m, 2H), 0.99(s, 9H), 0.15(s, 3H), 0.00(s, 3H).

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

Osmium tetroxide (0.15 g, 0.6 mmol) was added to a solution of tert-butyl-[1-(2-fluorophenyl)but-3-enoxy]-dimethyl-silane (8.50 g, 30.3 mmol) in water (100 mL) and tetrahydrofuran (100 mL). After stirring at 25 °C for 30 min, sodium periodate (25.90 g, 121.2 mmol) was added in fractions over 2 hours. The resulting mixture was stirred at 25 °C for 2 hours and quenched by adding cold, saturated aqueous solution of 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) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g, 64%) as a black oil. ¹ H NMR (400MHz, CDCl ₃ )δ9.84-9.77(m, 1H), 7.53-7.51(m, 1H), 7.31-7.24(m, 1H), 7.21-7.13(m, 1H), 7.09-6.98(m, 1H), 5. 58-5.55 (m, 1H), 2.85-2.80 (m, 1H), 2.74-2.64 (m, 1H), 0.92-0.85 (m, 9H), 0.09 (s, 3H), -0.09 (s, 3H).

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 8.6 mL, 21.4 mmol) was added to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (6.3 g, 20.1 mmol) in tetrahydrofuran (50 mL). The mixture was stirred at -78 °C for 30 min, and 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 the addition, the mixture was stirred at -78 °C for 1.5 h, and then quenched by adding saturated aqueous solution of 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 reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)prop-1-ol (8.0 g, 80%) as a yellow oil. This was used as is in the next step.

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

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

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.505 min, and the measured ESI+ value [M+H] = 298.1.

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

To a solution of 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (750 mg, 2.52 mmol) in toluene (20 mL), diethylaminosulfur trifluoride (1.62 g, 10.06 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour, and then slowly added to ice water (20 mL) at 0 °C. The mixture was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give racemic-(5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (250 mg, 33%) as a pale yellow solid. ^¹H NMR (400 MHz, _CDCl₃ ) 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] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.112 min, and the measured ESI+ value [M+H] = 300.0.

The cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

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

SFC conditions: Column: ChiralPak AD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

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

Under a nitrogen atmosphere at -78°C, n-butyllithium (2.5 M, in hexane, 0.27 mL, 0.67 mmol) was added to a solution of (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.33 mmol) and N-methoxy-N-methyl-cyclopropaneformamide (86 mg, 0.67 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at -78°C for 2 hours and quenched by adding saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (35-65% acetonitrile/0.05% ammonium hydroxide in water) to give cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (7.2 mg, 7%) as a yellow solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.47-7.41(m, 1H), 7.25-7.18(m, 2H), 7.16-7.13(m, 1H), 6.22-6.06(m, 1H), 5.92-5.88(m, 1H ), 3.85-3.78(m, 1H), 3.08-3.02(m, 1H), 2.93-2.78(m, 1H), 1.22-1.17(m, 2H), 1.15-1.09(m, 2H). LCMS R _T =1.043 min, m/z =290.2[M+H] ⁺ .

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

Method 45

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

At -78°C under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 0.72 mL, 0.36 mmol) was added dropwise to a solution of (5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at -78°C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (40-50% acetonitrile/0.05% ammonium hydroxide in water) to give cyclopropyl-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (50 mg, 51%) as a white solid (80% ee). Further purification of the product by chiral SFC yielded specifically assigned (S)-cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (17.5 mg, 34%) as a brown oil. ¹ H NMR (400MHz, CD ₃ OD)δ7.44-7.35(m,1H),7.23-7.16(m,3H),5.81-5.77(m,1H),3.37-3.29(m,1H),3.21-3 .03 (m, 2H), 2.99-2.93 (m, 1H), 2.77-2.65 (m, 1H), 1.16-1.09 (m, 2H), 1.09-1.00 (m, 2H). LC-MS R _T =0.699 min, m/z =272.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.699 min, and the measured ESI+ value [M+H] = 272.1.

SFC conditions: Column: ChiralPak AD-3 150×4.6mm ID3μm; Mobile phase: A: CO2 _, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5-5 min, and hold at 40%, 3 min, then 5% B, 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃.

Method 46

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

At -78 °C, n-butyllithium (2.5 M, in hexane, 0.26 mL, 0.64 mmol) was added dropwise to a solution of 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (76 mg, 0.43 mmol) and (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg, 0.21 mmol) in tetrahydrofuran (13 mL). After addition, the mixture was stirred at -78 °C for 2 hours and quenched by adding saturated aqueous solution of 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 (20-45% acetonitrile/0.225% hydrochloric acid in water) to give (3,3-difluorocyclobutyl)-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (11.0 mg, 16%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.38(m, 3H), 7.29-7.27(m, 2H), 6.19-6.17(m, 0.5H), 6.05-6.03(m, 0. 5H), 5.64-5.63(m, 1H), 3.94-3.93(m, 1H), 3.79-3.75(m, 1H), 2.90-2.82(m, 5H). LCMS R _T =1.904 min, m/z =322.1[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 1.904 min, and the measured ESI value [M+H] was 322.1.

Method 47

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

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

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

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.774 min, and the measured ESI+ value [M+H] = 303.1.

The racemic material (950 mg, 3.17 mmol) was further separated by chiral SFC to obtain the specifically assigned:

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

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

SFC conditions: Column: OJ (250mm*50mm, 10um); Mobile phase: A: CO2 _, B: 0.1% _{NH3 H2O} EtOH; Gradient: 20% to 20% B; Flow rate: 180mL/min, Column temperature: 40℃.

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

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

[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2-fluorocyclopropyl] methyl ketone (peak 1, retention time = 2.365 min) (15.1 mg, 30%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.49-7.44(m, 3H), 7.33-7.30(m, 2H), 5.99-5.92(m, 1H), 5.02-5.00(m, 0.5H), 4.86-4.82(m, 0.5H), 3.89-3 .86 (m, 1H), 3.51-3.47 (m, 1H), 3.34-3.33 (m, 0.5H), 3.32-3.22 (m, 0.5H), 1.78-1.70 (m, 1H), 1.63-1.57 (m, 1H). LC-MS R _T =0.822 min, m/z =308.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.822 min, and the measured ESI+ value [M+H] was 308.0.

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

¹ H NMR (400MHz, CD ₃ OD) δ7.47-7.43(m, 3H), 7.31-7.29(m, 2H), 5.98-5.94(m, 1H), 5.05-4.99(m, 0.5H), 4.86-4.83(m, 0. 5H), 3.91-3.86(m, 1H), 3.47-3.45(m, 1H), 3.34-3.26(m, 1H), 1.74-1.68(m, 1H), 1.62-1.56(m, 1H). LC-MS R _T =0.818 min, m/z =308.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.818 min, and the measured ESI+ value [M+H] = 308.1.

SFC conditions: Column: AD (250mm*30mm, 5μm); Mobile phase: A: CO2 _, B: 0.1% NH3 _H2O EtOH; Gradient: 20% to 20% B; Flow rate: 50mL/min; _Column temperature: 40℃.

Method 48

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

At -78°C under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 2.6 mL, 1.3 mmol) was added to a solution of 7,7-difluoro-N-methoxy-N-methyl-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.32 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at -78°C for 2 hours and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give cyclopropyl-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (60 mg, 64%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) 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).

The racemic compound was further separated by a chiral SFC to obtain the definitively assigned:

Cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 2.971 min) (22.4 mg, 37%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.45–7.41 (m, 3H), 7.23–7.21 (m, 2H), 5.73–5.68 (m, 1H), 3.75–3.70 (m, 1H), 3.31–3.19 (m, 1H), 3.09–3.04 (m, 1H), 1.37–1.32 (m, 2H), 1.14–1.09 (m, 2H). LCMS R _T =1.238 min, m/z =290, 2[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 1.238 min, and the ESI ⁺ measured value [M+H] = 290.2.

Cyclopropyl-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 2.677 min) (24.7 mg, 41%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.45–7.41 (m, 3H), 7.23–7.20 (m, 2H), 5.72–5.68 (m, 1H), 3.81–3.66 (m, 1H), 3.28–3.21 (m, 1H), 3.09–3.05 (m, 1H), 1.37–1.27 (m, 2H), 1.17–1.05 (m, 2H). LCMS R _T =1.239 min, m/z =290.2[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 1.239 min, and the ESI ⁺ measured value [M+H] = 290.2.

SFC conditions: Column: Chiralcel OJ (250mm*30mm, 5μm); Mobile phase: A: CO2 _, B: Ethanol (0.1% _NH3H2O ); Gradient: 25% to 25% B, 5 min: 2.5 mL/ _min ; Column temperature: 35℃.

Method 49

(2,2-Difluorospiro[2,3]hex-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone

Step 1: 1,1-Difluoro-N-methoxy-N-methylspiro[2,3]hexane-5-carboxamide

A mixture of 1-hydroxybenzotriazole (83 mg, 0.62 mmol), N,O-dimethylhydroxylamine hydrochloride (180 mg, 1.85 mmol), 2,2-difluorospiro[2.3]hexane-5-carboxylic acid (200 mg, 1.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 mmol), and N,N-diisopropylethylamine (478 mg, 3.70 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 12 hours 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, 0-30% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (130 mg, 51%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.67 (s, 3H), 3.65-3.51 (m, 1H), 3.21 (s, 3H), 2.78-2.68 (m, 1H), 2.57-2.47 (m, 1H), 2.48-2.37 (m, 1H), 2.28-2.17 (m, 1H), 1.32-1.13 (m, 2H).

Step 2: (2,2-Difluorospiro[2,3]hex-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in n-hexane, 0.28 mL, 0.71 mmol) was added to a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-spiro[2,3]hexane-5-carboxamide (73 mg, 0.35 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at -78 °C for 2 hours and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 47-77%/0.2% formic acid in water) to give (2,2-difluorospiro[2.3]hex-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (10.8 mg, 17%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.38(m, 3H), 7.28-7.26(m, 2H), 6.18-6.02(m, 1H), 5.64-5.62(m, 1H), 4.24-4 .08(m, 1H), 3.87-3.64(m, 1H), 2.91-2.74(m, 1H), 2.68-2.28(m, 4H), 1.32-1.23(m, 2H). LCMS R _T =1.281 and 1.298 min, m/z=348.1[M+H] ⁺ .

LCMS retention times (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 1.281 and 1.298 min, with an ESI+ measured value [M+H] = 348.1.

Method 50

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

Step 1: Ethyl 4-(2-chlorophenyl)-4-oxobutyrate

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

Step 2: (2-(2-chlorophenyl)-5-oxopyrrolidone-1-yl)tert-butyl carbamate

To a solution of ethyl 4-(2-chlorophenyl)-4-oxo-butyrate (10.0 g, 41.55 mmol) in acetic acid (33 mL) and tetrahydrofuran (100 mL), tert-butyl hydrazide (11.0 g, 83.10 mmol) was added. The mixture was stirred at 85 °C for 12 hours, and sodium cyanoborohydride (7.8 g, 124.65 mmol) was added. The resulting mixture was stirred at 85 °C for another 12 hours and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated sodium carbonate (80 mL) and 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, 20-50% ethyl acetate in petroleum ether) to give N-[2-(2-chlorophenyl)-5-oxo-pyrrolidine-1-yl]carbamate tert-butyl ester (5.0 g, 39%) as a pale yellow oil. LCMS R _{_T} = 0.840 min, m/z = 255.0 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.840 min, and the measured ESI+ value [M-55] was 255.0.

Step 3: 1-Amino-5-(2-chlorophenyl)pyrrolidine-2-one

A solution of N-[2-(2-chlorophenyl)-5-oxo-pyrrolidine-1-yl]carbamate tert-butyl ester (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 filter cake was washed with ethyl acetate (20 mL) and dissolved in water (20 mL). The solution was adjusted to pH 9 by adding a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (4 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-amino-5-(2-chlorophenyl)pyrrolidine-2-one (3.3 g, 97%) as a white solid. LCMSR _T = 0.615 min, m/z = 211.0 [M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.615 min, and the measured ESI+ value [M+H] = 211.0.

Step 4: 1-Amino-5-(2-chlorophenyl)pyrrolidine-2-one

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

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.675 min, and the measured ESI+ value [M+H] was 310.0.

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

A mixture of ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (4.8 g, 15.5 mmol) and phosphoryl chloride (21.4 g, 139.5 mmol) was stirred at 100 °C for 3 hours 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, 0-40% ethyl acetate in petroleum ether) to give ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.0 g, 66%) as a brown oil. LCMS R _T =0.741 min, m/z =292.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.741 min, and the measured ESI+ value [M+H] = 292.1.

The above racemic material (1.0 g, 3.43 mmol) was further separated by SFC to obtain the specifically attributed:

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

SFC conditions: Column: AD-3 (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2OEtOH ; Start B 30% End B 30%; Flow rate (60mL/ _min ), column temperature 40℃.

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.642 min, and the measured ESI+ value [M+H] = 264.0.

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

A mixture of 1-hydroxybenzotriazole (215 mg, 1.59 mmol), N,O-dimethylhydroxylamine hydrochloride (194 mg, 1.99 mmol), (S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (350 mg, 1.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (305 mg, 1.59 mmol), and N,N-diisopropylethylamine (515 mg, 3.98 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 12 hours. The reaction mixture 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, 10-35% ethyl acetate in petroleum ether) to give (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (300 mg, 74%) as a colorless oil. LCMS R _{_T} = 0.700 min, m/z = 307.0 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.700 min, and the measured ESI+ value [M+H] was 307.0.

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

To a cooled (0°C) solution of (S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (20 mg, 0.07 mmol) in tetrahydrofuran (5 mL), ethyl magnesium bromide (1.0 M, in hexane, 0.42 mL, 0.42 mmol) was added. The mixture was stirred at 0–5°C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 32-62%/0.2% formic acid in water) to give 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one (5.7 mg, 31%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.52-7.50 (m, 1H), 7.38-7.33 (m, 2H), 6.96-6.94 (m, 1H), 5.99-5.96 (m, 1H), 3.40-3. 33 (m, 1H), 3.14-3.11 (m, 2H), 3.07-3.03 (m, 2H), 2.68-2.65 (m, 1H), 1.18 (d, J=7.2Hz, 3H). LCMS R _T =1.185 min, m/z =276.1[M+H] ⁺ .

LCMS (10-80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) retention time: 1.185 min; ESI+ measured value [M+H] = 276.1.

Method 51

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

Step 1: 1-(ethoxycarbonyl)cyclopropanecarboxylic acid

Sodium hydroxide (2.1 g, 53.7 mmol) was added to a mixture of diethyl 1,1-cyclopropanedicarboxylate (10.0 g, 53.7 mmol) in ethanol (70 mL) and water (35 mL). 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 adding 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. ¹ H NMR (400MHz, CDCl ₃ ) δ 12.86 (br s, 1H), 4.31-4.17 (m, 2H), 1.87-1.81 (m, 2H), 1.77-1.69 (m, 2H), 1.32-1.24 (m, 3H).

Step 2: Ethyl 1-(hydroxymethyl)cyclopropanecarboxylate

Isobutyl chloroformate (8.12 mL, 62.6 mmol) was added dropwise 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) at 0 °C. After addition, the reaction was stirred at 0 °C for 1 hour and filtered. The filtrate was then added to a mixture of sodium borohydride (1.6 g, 41.7 mmol) in tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture was stirred at 0 °C for 1 hour and quenched by the 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, 0-30% ethyl acetate in petroleum ether) to give ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (3.8 g, 63%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.17-4.08 (m, 2H), 3.62 (s, 2H), 1.29-1.21 (m, 5H), 0.87-0.84 (m, 2H).

Step 3: 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylic acid ethyl ester

Imidazole (1.4 g, 20.81 mmol) and tert-butyldiphenylchlorosilane (3.8 g, 13.87 mmol) were added to a stirred solution of 1-(hydroxymethyl)cyclopropane-1-carboxylate (1.0 g, 6.94 mmol) in N,N-dimethylformamide (20 mL) at 0 °C. The mixture was stirred at 25 °C for 18 hours and then 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, 0-20% ethyl acetate in petroleum ether) to give 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylate (2.3 g, 87%) as a colorless oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.70-7.61(m, 4H), 7.46-7.35(m, 6H), 4.15-4.06(m, 2H), 3.85(s, 2H) , 1.23 (t, J=7.0Hz, 3H), 1.17-1.11 (m, 2H), 1.04 (s, 9H), 0.93-0.87 (m, 2H).

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

Ethyl 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylate (1.0 g, 2.61 mmol) and lithium hydroxide monohydrate (438 mg, 10.46 mmol) in tetrahydrofuran (16 mL), methanol (16 mL), and water (8 mL) were stirred at 25 °C for 18 hours. The organic solvent was removed under reduced pressure. The aqueous residue was washed with ethyl acetate (15 mL) and adjusted to pH 3 at 0 °C by adding aqueous hydrochloric acid (4 M). 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 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg, 100%) as a viscous, pale white solid. This crude product was used in the next step without further purification.

Step 5: 1-(((tert-butyldiphenylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropaneformamide

A mixture of 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg, 2.68 mmol), N,O-dimethylhydroxylamine hydrochloride (523 mg, 5.36 mmol), N,N-diisopropylethylamine (1.43 mL, 8.04 mmol), 1-hydroxybenzotriazole (217 mg, 1.61 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (771 mg, 4.02 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 18 hours. 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 give 1-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropaneformamide (700 mg, 66%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.68–7.63 (m, 4H), 7.42–7.25 (m, 6H), 3.79 (s, 2H), 3.62 (s, 3H), 3.23 (s, 3H), 1.04–0.99 (m, 9H), 0.75–0.71 (m, 2H).

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

At -78 °C under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 0.43 mL, 1.06 mmol) was added dropwise to a mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) and 1-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N-methylcyclopropaneformamide (282 mg, 0.71 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.4) to give [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (60 mg, 31%) as a light brown oil.

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

To a solution of [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (60 mg, 0.11 mmol) in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 0.17 mL, 0.17 mmol) was added. The mixture was stirred at 25 °C for 3 hours and then 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%/ammonium hydroxide in water 0.05%) to give the specifically assigned [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (7.8 mg, 18%) as a light brown oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.38(m, 3H), 7.30-7.26(m, 2H), 6.19-6.16(m, 0.5H), 6.05-6.02(m, 0.5H), 5.65-5.61(m, 1H), 3.97-3.85(m, 2H), 3.84-3.68(m, 1H), 2.87-2.80(m, 1H), 1.72-1.67(m, 2H), 1.11-1.08(m, 2H). LC-MS R _T =0.695 min, m/z =302.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.695 min, and the measured ESI+ value [M+H] was 302.1.

Method 52

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

Step 1: 3,3-Difluoro-N-methoxy-N-methylcyclobutane formamide

A mixture of 1-hydroxybenzotriazole (297 mg, 2.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (845 mg, 4.41 mmol), 3,3-difluorocyclobutanecarboxylic acid (500 mg, 3.67 mmol), N,O-dimethylhydroxylamine hydrochloride (537 mg, 5.51 mmol), and N,N-diisopropylethylamine (1187 mg, 9.18 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 5 hours 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) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 3,3-difluoro-N-methoxy-N-methyl-cyclobutaneformamide (430 mg, 65%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.67 (s, 3H), 3.33-3.22 (m, 1H), 3.20 (s, 3H), 2.93-2.78 (m, 2H), 2.76-2.64 (m, 2H).

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

To a solution of 3,3-difluoro-N-methoxy-N-methylcyclobutanecarboxamide (76 mg, 0.43 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg, 0.21 mmol) in tetrahydrofuran (13 mL), n-butyllithium (2.5 M, in hexane, 0.26 mL, 0.64 mmol) was added dropwise. After addition, the mixture was stirred at -78 °C for 2 hours and quenched by adding saturated aqueous solution of 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%/0.225% hydrochloric acid in water) to give (3,3-difluorocyclobutyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (12.4 mg, 18%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.39(m, 3H), 7.30-7.28(m, 2H), 6.20-6.17(m, 0.5H), 6.06-6.03(m, 0. 5H), 5.66-5.64(m, 1H), 3.97-3.80(m, 1H), 3.78-3.74(m, 1H), 2.91-2.83(m, 5H). LCMS R _T =1.241 min, m/z =322.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.241 min, and the measured ESI+ value [M+H] was 322.2.

Method 53

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

Step 1: N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropaneformamide

A mixture of 1-hydroxybenzotriazole (149 mg, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (423 mg, 2.21 mmol), 2-(pyridin-2-yl)cyclopropanecarboxylic acid (300 mg, 1.84 mmol), N,O-dimethylhydroxylamine hydrochloride (269 mg, 2.76 mmol), and N,N-diisopropylethylamine (594 mg, 4.60 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 16 hours 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) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide (300 mg, 79%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) 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).

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in n-hexane, 0.64 mL, 1.6 mmol) was added to a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and N-methoxy-N-methyl-2-(2-pyridyl)cyclopropanecarboxamide (219 mg, 1.06 mmol) in 3 mL of 2-methyltetrahydrofuran. The mixture was stirred at -78 °C for about 30 min and quenched by adding saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 32-62%/ammonium hydroxide in water 0.05%) to give the specifically assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(2-pyridyl)cyclopropyl] ketone (11.0 mg, 6%) as a pale pink solid. ¹ H NMR (400MHz, CD ₃ OD) δ8.39-8.37(m, 1H), 7.69-7.65(m, 1H), 7.42-7.31(m, 4H), 7.27-7.17(m, 3H), 6.18-6.02(m, 1H) ), 5.65-5.61(m, 1H), 3.83-3.67(m, 1H), 3.56-3.51(m, 1H), 2.88-2.73(m, 2H), 1.86-1.79(m, 2H). LCMS R _T =0.745 min, m/z =348.9[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 0.745 min, and the measured ESI value [M+H] was 348.9.

Method 54

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

At 0 °C under a nitrogen atmosphere, isopropyl magnesium bromide (3.0 M, in tetrahydrofuran, 0.85 mL, 2.55 mmol) was added dropwise to a solution of trans-N-methoxy-N,2-dimethyl-cyclopropaneformamide (137 mg, 0.96 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (180 mg, 0.64 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of 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 (in 30% ethyl acetate in petroleum ether, _Rf = 0.2) to give specifically attributed [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-methylcyclopropyl] ketone (trans-mixture methylcyclopropyl mixture) (80 mg, 44%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.42-7.37(m, 3H), 7.28-7.26(m, 2H), 6.20-6.16(m, 0.5H), 6.05-6.02(m, 0.5H), 5.65-5.63(m, 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 R _T =0.793 min, m/z =286.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.793 min, and the measured ESI+ value [M+H] = 286.1.

Method 55

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hexyl-5-yl methyl ketone

Step 1: N-methoxy-N-methyl-spiro[2,3]hexane-5-carboxamide

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

Step 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hexyl-5-yl methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.21 mL, 0.42 mmol) was added dropwise to a solution of N-methoxy-N-methyl-spiro[2,3]hexane-5-carboxamide (43 mg, 0.25 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of 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 residue was purified by RP-HPLC (water (0.05% ammonium hydroxide v/v) - acetonitrile 45-70%) to give the specifically assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hex-5-yl methyl ketone (42 mg, 75%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.42-7.37(m, 3H), 7.27-7.23(m, 2H), 6.10-5.94(m, 1H), 5.50-5.47(m, 1H), 4.32-4.26(m, 1H), 3.67-3. 60 (m, 1H), 3.01-2.70 (m, 1H), 2.65-2.57 (m, 2H), 2.31-2.26 (m, 2H), 0.51-0.47 (m, 2H), 0.43-0.40 (m, 2H). LC-MS _RT =0.904min, m/z=312.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.904 min, and ESI ⁺ measured value [M+H] = 312.0.

Method 56

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

Under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 4.24 mL, 2.12 mmol) was added to a cooled (-78 °C) solution of (5S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.33 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at -78 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 38-68%/0.2% formic acid in water) to give cyclopropyl-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (23.5 mg, 25%) as a colorless oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.51 (d, J=1.6Hz, 1H), 7.49-7.33 (m, 2H), 6.96 (d, J=7.6Hz, 1H), 6.00-5.96 (m, 1H), 3.45-3.36 (m , 1H), 3.15-3.10(m, 2H), 3.05-2.98(m, 1H), 2.70-2.60(m, 1H), 1.20-1.15(m, 2H), 1.11-1.07(m, 2H). LCMS R _T =1.187 min, m/z =288.1[M+H] ⁺ .

LCMS retention time (10-80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.187 min, and the measured ESI+ value [M+H] = 288.1.

Method 57

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

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

A mixture of racemic-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (800 mg, 3.25 mmol), N,O-dimethylhydroxylamine hydrochloride (412 mg, 4.22 mmol), N,N-diisopropylethylamine (1.34 mL, 8.12 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (V) (1.6 g, 4.22 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25 °C for 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 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 column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give racemic (4S,6S)-4-fluoro-N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (800 mg, 85%) as a white solid. LCMS RT = 0.707 min, m/z = 290.1 [M+H]+.

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.707 min, and the measured ESI+ value [M+H] = 290.1.

Step 2: Cyclopropyl-[racemic-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] methyl ketone

Under a nitrogen atmosphere, cyclopropyl magnesium bromide (0.5 M, in tetrahydrofuran, 1.5 mL, 0.75 mmol) was added to a cooled (0 °C) solution of racemic (4S,6S)-4-fluoro-N-methoxy-N-methyl-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (40 mg, 2.77 mmol). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give cyclopropyl-[racemic-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] methyl ketone (28.6 mg, 75%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.41-7.36(m, 3H), 7.27-6.90(m, 2H), 6.93(s, 1H), 6.09-5.92(m, 1H), 5.53-5.49 (m, 1H), 3.58-3.47 (m, 1H), 2.97-2.79 (m, 2H), 1.22-1.19 (m, 2H), 0.99-0.96 (m, 2H). LCMS R _T =0.870 min, m/z =270.9[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.870 min, and the measured ESI+ value [M+H] = 270.9.

Step 3: Cyclopropyl-[(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] methyl ketone (G03280299)

Cyclopropyl-[racemic-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] methyl ketone (600 mg, 2.22 mmol, from another scale-up batch) was further separated by chiral SFC to obtain the specifically assigned:

Cyclopropyl-[(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] methyl ketone (peak 1, retention time = 3.306 min) (250 mg, 41.7%) is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.39-7.37(m, 3H), 7.23-7.21(m, 2H), 6.93(d, J=2.8Hz, 1H), 6.09-6.07(m, 0.5H), 5.95-5.93(m, 0.5H), 5.5 1-5.49 (m, 1H), 3.54-3.45 (m, 1H), 2.96-2.92 (m, 1H), 2.85-2.82 (m, 1H), 1.23-1.20 (m, 2H), 0.99-0.96 (m, 2H). LCMS R _T =0.883 min, m/z =271.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.883 min, and the measured ESI+ value [M+H] was 271.0.

SFC conditions: Column: OD-H (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2OEtOH ; Start B 30% End B 30%; Flow rate (60mL/ _min ), column temperature 40℃.

Method 58

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

Step 1: 1-(fluoromethyl)-N-methoxy-N-methyl-cyclopropaneformamide

A mixture of 1-(fluoromethyl)cyclopropanecarboxylic acid (543 mg, 4.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1057 mg, 5.52 mmol), 1-hydroxybenzotriazole (372 mg, 2.76 mmol), N,O-dimethylhydroxylamine hydrochloride (897 mg, 9.19 mmol), and N,N-diisopropylethylamine (594 mg, 4.60 mmol) in dichloromethane (15 mL) was stirred at 30 °C for 18 hours and quenched by the addition of water (10 mL). The separated organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 1-(fluoromethyl)-N-methoxy-N-methylcyclopropaneformamide (135 mg, 18%) as a brown oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.63-4.47 (m, 2H), 3.74 (s, 3H), 3.26 (s, 3H), 1.30-1.23 (m, 2H), 0.95-0.85 (m, 2H).

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

At -78 °C, n-butyllithium (2.5 M, in hexane, 0.3 mL, 0.75 mmol) was added dropwise to a solution of 1-(fluoromethyl)-N-methoxy-N-methylcyclopropaneformamide (80 mg, 0.50 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (70 mg, 0.25 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at -78 °C for 1 hour, and then quenched by adding saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.4) to give specifically attributed [1-(fluoromethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (15.6 mg, 20%) as a brown oil. ¹ H NMR (400MHz, CD ₃ OD) δ7.43-7.33(m, 3H), 7.26-7.23(m, 2H), 6.17-6.12(m, 0.5H), 6.01-5.98(m, 0.5H), 5.62-5.60(m, 1H), 4.83 -4.76 (m, 1H), 4.73-4.63 (m, 1H), 3.76-3.65 (m, 1H), 2.85-2.77 (m, 1H), 1.86-1.79 (m, 2H), 1.23-1.16 (m, 2H). LC-MS R _T =1.188 min, m/z =304.2[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 1.188 min, and the measured ESI+ value [M+H] was 304.2.

Method 59

(3,3-Difluorobicyclo[3.1.0]hex-6-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

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

To a solution of 3-cyclopenten-1-ol (10.0 g, 118.88 mmol) in tetrahydrofuran (130 mL), imidazole (16.0 g, 237.76 mmol) and tert-butyldimethylchlorosilane (23.0 g, 154.54 mmol) were added. After addition, the reaction mixture was stirred at 30 °C for 16 h and quenched by adding water (100 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, 0-3% ethyl acetate in petroleum ether) to give tert-butyl-cyclopenten-1-yloxy-dimethylsilane (22.0 g, 93%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 5.61 (s, 2H), 4.49-4.44 (m, 1H), 2.54-2.48 (m, 2H), 2.24-2.19 (m, 2H), 0.82 (s, 9H), 0.02 (s, 6H).

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

To a solution of tert-butyl-cyclopent-3-en-1-yloxy-dimethyl-silane (20.0 g, 100.82 mmol) in dichloromethane (160 mL), ethyl diazonylacetate (13.8 g, 120.98 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give ethyl 3-[tert-butyl(dimethyl)silyl]oxydicyclo[3.1.0]hexane-6-carboxylate (15.0 g, 52%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ4.49-4.44(m, 2H), 2.53-2.48(m, 2H), 2.24-2.19(m, 2H), 1.65-1.24(m, 2H), 1.25-1.22(m, 2H), 0.83(s, 9H), 0.00(s, 6H).

Step 3: Ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate

To a solution of ethyl 3-[tert-butyl(dimethyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylate (15.0 g, 52.73 mmol) in tetrahydrofuran (200 mL), tetrabutylammonium fluoride (20.7 g, 79.09 mmol) was added. The reaction mixture was stirred at 50 °C for 12 hours and diluted with water (200 mL). The mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate (8.8 g, 98%) as a yellow oil.

Step 4: Ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate

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

Step 5: Ethyl 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylate

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

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

A solution of lithium hydroxide monohydrate (330 mg, 7.89 mmol) in water (7 mL) was added to a solution of ethyl 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid (500 mg, 2.63 mmol) in tetrahydrofuran (24 mL). The mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure. The aqueous residue was adjusted to pH 3 at 0 °C by adding an aqueous solution of hydrochloric acid (4 M). 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 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid (250 mg, 59%) as a colorless oil.

Step 7: 3,3-Difluoro-N-methoxy-N-methylbicyclo[3.1.0]hexane-6-carboxamide

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

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.522 min, and the measured ESI+ value [M+H] = 206.1.

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

At -78°C under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.37 mL, 0.74 mmol) was added dropwise to a solution of 3,3-difluoro-N-methoxy-N-methyl-bicyclo[3.1.0]hexane-6-carboxamide (102 mg, 0.50 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (70 mg, 0.25 mmol) in tetrahydrofuran (10 mL). After addition, the mixture was stirred at -78°C for 2 hours and quenched by adding saturated aqueous solution of 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%/0.225% hydrochloric acid in water) to give (3,3-difluoro-6-bicyclo[3.1.0]hexyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (11 mg, 13%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.40(m, 3H), 7.29-7.27(m, 2H), 6.19-6.16(m, 0.5H), 6.05-6.02(m, 0.5H), 5.65-5.64(m, 1H), 3.79 -3.73 (m, 1H), 3.03-3.02 (m, 1H), 2.90-2.80 (m, 1H), 2.54-2.30 (m, 2H), 2.30-2.25 (m, 2H), 2.20-2.18 (m, 2H). LCMS R _T =1.255 min, m/z =348.2[M+H] ⁺ .

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

Method 60

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

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

A mixture of N,O-dimethylhydroxylamine hydrochloride (4.42 g, 45.30 mmol), N,N-diisopropylethylamine (10.2 mL, 56.94 mmol), 4,4,4-trifluorobut-2-enoic acid (5.00 g, 35.70 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.21 g, 42.84 mmol) in dichloromethane (50 mL) was stirred at 0 °C for 5 hours. The mixture was washed with brine (2 x 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give (E)-4,4,4-trifluoro-N-methoxy-N-methyl-but-2-enoamide (2.50 g, 38%) as a colorless oil. LC-MS _RT =0.522min, m/z=184.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.522 min, and the measured ESI+ value [M+H] was 184.1.

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.722 min, and the measured ESI+ value [M+H] = 197.9.

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

At 0 °C under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 1.06 mL, 2.13 mmol) was added to a solution of N-methoxy-N-methyl-2-(trifluoromethyl)cyclopropaneformamide (98 mg, 0.50 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at 25 °C for 16 hours and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) to give [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(trifluoromethyl)cyclopropyl] ketone (30 mg, 24%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.45-7.39(m, 3H), 7.32-7.29(m, 2H), 6.22-6.05(m, 1H), 5.70-5.65(m, 1H), 3.84-3 .71 (m, 1H), 3.41-3.37 (m, 1H), 2.90-2.79 (m, 1H), 2.45-2.40 (m, 1H), 1.53-1.46 (m, 2H). LC-MS _RT =0.904min, m/z=339.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.904 min, and the measured ESI+ value [M+H] was 339.9.

Method 61

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

Step 1: 6,6-Difluoro-N-methoxy-N-methylbicyclo[3.1.0]hexane-3-carboxamide

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

LCMS retention times (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 0.540 and 0.572 min, and the measured ESI+ value [M+H] was 206.0.

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

At -78°C under nitrogen, isopropyl magnesium chloride (2.0 M, 0.16 mL, 0.32 mmol) was added to a solution of 6,6-difluoro-N-methoxy-N-methyl-bicyclo[3.1.0]hexane-3-carboxamide (33 mg, 0.16 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (30 mg, 0.11 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at -78°C for 2 hours and then quenched by adding saturated aqueous solution of ammonium chloride (15 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (40%-70% acetonitrile/0.05% ammonium hydroxide in water) to give (6,6-difluoro-3-bicyclo[3.1.0]hexyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (3.9 mg, 11%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.42-7.39(m, 3H), 7.26-7.23(m, 2H), 6.12-5.94(m, 1H), 5.52-5.48(m, 1H), 4.19-4.15(m, 0.5H) , 3.88-3.85(m, 0.5H), 3.68-3.59(m, 1H), 3.02-2.91(m, 1H), 2.39-2.30(m, 4H), 2.08-2.04(m, 2H). LCMS R _T =0.896 min, m/z =347.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.896 min, and the measured ESI+ value [M+H] = 347.9.

Method 63

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

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.748 min, and the measured ESI+ value [M+H] = 294.0.

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

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

The cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

Cyclopropyl-[(5S,7S)-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 4.247 min) (29.8 mg, 16%), is a yellow solid. ^¹H NMR (400 MHz, _CD₃OD ) δ 7.40–7.31 (m, 5H), 5.56–5.52 (m, 1H), 4.94–4.92 (m, 1H), 3.67–3.59 (m, 4H), 3.02–3.01 (m, 1H), 2.62–2.57 (m, 1H), 1.17–1.15 (m, 2H), 1.10–1.07 (m, 2H). LCMS R _T =0.709 min, m/z =284.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.709 min, and the measured ESI+ value [M+H] = 284.1.

SFC conditions: Column: Lux Cellulose-2 150×4.6mm ID3μm; Mobile phase: 40% ethanol (0.05% DEA) in _CO2 ; Flow rate: 2.5mL/min; Column temperature: 40℃.

Method 64

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

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

At 0 °C under nitrogen atmosphere, allyl magnesium chloride (1.82 M, in tetrahydrofuran, 288.0 mL, 523.73 mmol) was added to a solution of 4-fluorobenzaldehyde (50.0 g, 402.87 mmol) in tetrahydrofuran (500 mL). The reaction mixture was heated to 25 °C and stirred for 2 hours, then quenched by adding 200 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(4-fluorophenyl)but-3-en-1-ol (66.8 g, 99%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.32-7.28(m, 2H), 7.04-7.00(m, 2H), 5.80-5.73(m, 1H), 5.17-5.12(m, 2H), 4.70-4.67(m, 1H), 2.48-2.46(m, 2H), 2.44-2.31(m, 1H).

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

To a solution of 1-(4-fluorophenyl)but-3-en-1-ol (66.8 g, 401.95 mmol) in dichloromethane (500 mL), imidazole (54.7 g, 803.9 mmol) and tert-butylchlorodimethylsilane (72.7 g, 482.34 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours and diluted with water (500 mL). The resulting mixture was extracted with dichloromethane (2 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude tert-butyl-[1-(4-fluorophenyl)but-3-enoxy]-dimethylsilane (111.0 g, 98%) as a light-colored oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.41-7.37(m, 2H), 7.14-7.10(m, 2H), 5.92-5.85(m, 1H), 5.15-5.11(m, 2H) , 4.81-4.79 (m, 1H), 2.58-2.45 (m, 2H), 1.01 (s, 9H), 0.15 (s, 3H), 0.00 (s, 3H).

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

Osmium tetroxide (0.5 g, 1.97 mmol) was added to a solution of tert-butyl-[1-(4-fluorophenyl)but-3-enoxy]-dimethyl-silane (110.0 g, 392.23 mmol) in water (500 mL) and tetrahydrofuran (500 mL). After stirring at 25 °C for 30 min, sodium periodate (335.6 g, 1568.90 mmol) was added in fractions over 2 hours, and the resulting mixture was stirred at 25 °C for another 2 hours. The mixture was quenched by adding cold, saturated aqueous solution of sodium thiosulfate (500 mL). The mixture was stirred for 30 min and then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-2% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(4-fluorophenyl)propanal (70.0 g, 63%) as a yellow oil. ^¹H NMR (400 Hz, _CDCl₃ ) δ 9.95-9.90 (m, 1H), 7.48-7.44 (m, 2H), 7.19-7.15 (m, 2H), 5.37-5.34 (m, 1H), 3.02-2.95 (m, 1H), 2.79-2.77 (m, 1H), 1.01 (s, 9H), 0.19 (s, 3H), 0.00 (s, 3H).

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

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

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

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

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.679 min, and the measured ESI+ value [M+H] = 300.0.

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

To a cooled (0°C) solution of 2-bromo-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (6.0 g, 20.13 mmol) in dichloromethane (50 mL), diethylaminosulfur trifluoride (10.7 mL, 80.51 mmol) in dichloromethane (8 mL) was added. After stirring for 30 minutes, the mixture was poured into ice water (100 mL). The resulting mixture was 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, 0-12% ethyl acetate in petroleum ether) to give cis-2-bromo-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (2.1 g, 35%) as a pale yellow solid. ^¹H NMR ( _CDCl₃ , 400 MHz) δ 7.26-7.23 (m, 2H), 7.12-7.08 (m, 2H), 6.07-5.91 (m, 1H), 5.45-5.42 (m, 1H), 3.64-3.52 (m, 1H), 2.92-2.85 (m, 1H).

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.733 min, and the measured ESI+ value [M+H] = 290.1.

The cis mixture was further separated into independently attributed components by chiral SFC:

Cyclopropyl-[(5S,7S)-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 3.981 min) (71 mg, 39%), is a white solid. ^¹H NMR (400 MHz, _CD₃OD ) δ 7.36–7.32 (m, 2H), 7.19–7.14 (m, 2H), 6.20–6.04 (m, 1H), 5.65–5.65 (m, 1H), 3.83–3.69 (m, 1H), 3.10–2.97 (m, 1H), 2.89–2.77 (m, 1H), 1.20–1.09 (m, 4H). LCMS R _T =0.833 min, m/z =289.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.833 min, and the measured ESI+ value [M+H] = 289.9.

Also collected was the 5R,7R-isomer (peak 1, retention time = 3.439 min) (65 mg, 36%), which was a white solid.

SFC conditions: Column: ChiralPak AD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃.

Method 65

2-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl)cyclopropanecarboxylate

Step 1: 2-Bromo-1-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ethyl ketone

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.771 min, and the ESI ⁺ measured value [M+H] = 326.0.

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

To a mixture of 2-bromo-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]acetone (120 mg, 0.37 mmol) in tetrahydrofuran (2 mL) and dimethyl sulfoxide (0.5 mL), 1,4-diazabicyclo[2.2.2.]octane (53 mg, 0.48 mmol) was added. After stirring at 20 °C for 30 min, sodium carbonate (76 mg, 0.72 mmol) and acrylonitrile (6.2 mL, 94.23 mmol) were added to the mixture. The resulting mixture was stirred at 90 °C for 20 h and diluted with ethyl acetate (40 mL). The solution was washed with water (2 x 20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (water (0.05% ammonium hydroxide v/v) - acetonitrile 30-60%) to specifically assigned 2-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropaneformitrile (3 mg, 3%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.46-7.42(m, 3H), 7.31-7.27(m, 2H), 6.15-5.99(m, 1H), 5.56-5.53(m, 1H), 3.72-3. 67 (m, 2H), 3.07-3.03 (m, 1H), 2.21-2.08 (m, 1H), 1.75-1.70 (m, 1H), 1.68-1.57 (m, 1H). LCMS R _T =0.818 min, m/z =296.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.771 min, and the ESI ⁺ measured value [M+H] = 296.9.

Method 66

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

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

To a mixture of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1000 mg, 3.57 mmol) and triethylamine (1083 mg, 10.71 mmol) in dichloromethane (50 mL), tert-butyldimethylsilyltrifluoromethanesulfonate (1415 mg, 5.35 mmol) was added. The mixture was stirred at 25 °C for 14 hours and diluted with water (50 mL). The resulting solution 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, 0-30% ethyl acetate in petroleum ether) to give:

(trans)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (870 mg, 62%), is a yellow solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.41–7.36 (m, 5H), 5.31–5.28 (m, 1H), 5.26–5.23 (m, 1H), 3.47–3.40 (m, 1H), 2.58–2.52 (m, 1H), 0.99 (s, 9H), 0.23 (s, 3H), 0.20 (s, 3H).

(cis)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (430 mg, 31%), is a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.49–7.35 (m, 3H), 7.11–7.10 (m, 2H), 5.61–5.58 (m, 1H), 5.33–5.30 (m, 1H), 3.00–2.96 (m, 1H), 2.90–2.83 (m, 1H), 0.93 (s, 9H), 0.23 (s, 3H), 0.19 (s, 3H).

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

At 0 °C under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 1.41 mL, 2.81 mmol) was added to a solution of N-methoxy-N-methylcyclopropaneformamide (242 mg, 1.88 mmol) and (cis)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (370 mg, 0.94 mmol) in tetrahydrofuran (2 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) to give [cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (220 mg, 61%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.36-7.34(m, 5H), 5.39-5.36(m, 1H), 5.29-5.28(m, 1H), 3.54-3.48(m, 1H), 3.08-3.05(m, 1H) , 2.65-2.61(m, 1H), 1.30-1.28(m, 2H), 1.07-1.02(m, 2H), 0.91(s, 9H), 0.24(s, 3H), 0.22(s, 3H).

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

At 25°C, tetrabutylammonium fluoride (1.0 M, 2.09 mL, 2.09 mmol) was added to a solution of [cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (200 mg, 0.52 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 25°C for 14 hours and diluted with dichloromethane (30 mL). The resulting mixture was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-90% ethyl acetate in petroleum ether) to give cyclopropyl-[cis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (95 mg, 67%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.42-7.36 (m, 5H), 5.46-5.40 (m, 2H), 4.79-4.78 (d, 1H), 3.64-3.58 (m, 1H), 3.00-2.98 (m, 1H), 2.81-2.76 (m, 1H), 1.31-1.27 (m, 2H), 1.07-1.03 (m, 2H).

The cis mixture was further separated by a chiral SFC to obtain the arbitrarily attributed [agent/substrate].

Cyclopropyl-[(5S,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 3.345 min) (22.2 mg, 24%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.43–7.36 (m, 5H), 5.44–5.41 (m, 2H), 4.81 (s, 1H), 3.65–3.60 (m, 1H), 2.99–2.96 (m, 1H), 2.82–2.76 (m, 1H), 1.30–1.29 (m, 2H), 1.06–1.03 (m, 2H). LCMS R _T =2.061 min, m/z =270.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 7.0 min) was 2.061 min, and the measured ESI+ value [M+H] = 270.2.

Cyclopropyl-[(5R,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 3.975 min) (32.2 mg, 35%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.43–7.34 (m, 5H), 5.44–5.39 (m, 2H), 3.65–3.57 (m, 1H), 3.07–3.00 (m, 1H), 2.79–2.74 (m, 1H), 1.31–1.28 (m, 2H), 1.07–1.04 (m, 2H). LCMS R _T =0.896 min, m/z =270.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.896 min, and the measured ESI+ value [M+H] = 270.2.

SFC conditions: Column: OD (250mm*30mm, 5μm); Mobile phase: A: CO2 _, B: 0.1% _NH3H2OEtOH ; Gradient: 40% B _; Flow rate: 60mL/min; Column temperature: 40℃.

Method 67

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

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

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

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 1.008 min, and the measured ESI+ value [M+H] was 384.2.

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

To a solution of [trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (50 mg, 0.13 mmol) in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 0.52 mL, 0.52 mmol) was added. The mixture was stirred at 25 °C for 14 hours and diluted with dichloromethane (20 mL). The solution was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (2.5% methanol in dichloromethane, _Rf = 0.5) to give cyclopropyl-[(trans)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (20 mg, 57%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.43-7.38(m, 3H), 7.19-7.17(m, 2H), 5.76-5.73(m, 1H), 5.54-5.52(m, 1H) , 3.29-3.25(m, 1H), 3.03-3.00(m, 2H), 1.31-1.28(m, 2H), 1.06-1.03(m, 2H).

The trans mixture (70 mg, from another batch) was further separated by chiral SFC to obtain the arbitrarily assigned:

Cyclopropyl-[(5S,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 3.515 min) (10.5 mg, 15%) is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.44-7.38(m, 3H), 7.20-7.18(m, 2H), 5.76-5.73(m, 1H), 5.70-5.62(m, 1H), 5.52-5. 49 (m, 1H), 3.29-3.25 (m, 1H), 3.01-2.96 (m, 2H), 1.32-1.26 (m, 2H), 1.06-1.04 (m, 2H). LCMS R _T =0.906 min, m/z =270.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.906 min, and the measured ESI+ value [M+H] = 270.2.

Cyclopropyl-[(5R,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 3.729 min) (17.0 mg, 24%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.44–7.38 (m, 3H), 7.20–7.18 (m, 2H), 5.76–5.73 (m, 1H), 5.65 (brs, 1H), 5.51–5.50 (m, 1H), 3.28–3.25 (m, 1H), 3.01–2.96 (m, 2H), 1.32–1.26 (m, 2H), 1.06–1.04 (m, 2H). LCMS R _T =0.905 min, m/z =270.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.905 min, and the measured ESI+ value [M+H] = 270.2.

SFC conditions: Column: ChiralPak AD-3 150×4.6mm ID3μm; Mobile phase: A: CO2 _, B: IPA (0.05% DEA); Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min; Flow rate: 25 mL/min; Column temperature: 40℃.

Method 68

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

The racemic [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-methylcyclopropyl] ketone (trans mixture LHS) (80 mg) was further separated by chiral SFC to obtain the specifically assigned:

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S)-2-methylcyclopropyl] methyl ketone (peak 1, retention time = 3.714 min) (28 mg, 35%, ee: 96.1%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.45-7.38(m, 3H), 7.29-7.26(m, 2H), 6.19-6.17(m, 0.5H), 6.05-6.03(m, 0.5H), 5.67-5.62(m, 1H), 3.81- 3.71 (m, 1H), 2.89-2.75 (m, 2H), 1.62-1.54 (m, 1H), 1.45-1.39 (m, 1H), 1.18 (d, J=6.4Hz, 3H), 0.99-0.96 (m, 1H). LC-MS R _T =0.756 min, m/z =286.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.756 min, and the measured ESI+ value [M+H] = 286.1.

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2R)-2-methylcyclopropyl] ketone (peak 2, retention time = 3.901 min) (48 mg, 60%, ee: 86%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.40(m, 3H), 7.29-7.27(m, 2H), 6.20-6.16(m, 0.5H), 6.06-6.02(m, 0.5H), 5.67-5.61(m, 1H), 3.79- 3.73 (m, 1H), 2.89-2.74 (m, 2H), 1.64-1.60 (m, 1H), 1.44-1.39 (m, 1H), 1.17 (d, J=6.0Hz, 3H), 1.00-0.95 (m, 1H). LC-MS R _T =0.757 min, m/z =286.1[M+H] ⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.757 min, and the measured ESI+ value [M+H] = 286.1.

SFC conditions: Column: AD (250mm*30mm, 5μm); Mobile phase: A: CO2 _, B: 0.1% _{NH3 H2O} EtOH; Gradient: 25% to 25% B; Flow rate: 50mL/min; Column temperature: 40℃.

Method 69

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.739 min, and the measured ESI+ value [M+H] = 308.1.

The above trans mixture was further separated by a chiral SFC to obtain the definitively attributed:

[(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 2.773 min) (48.1 mg, 45%), is a white solid. ¹ HNMR (400MHz, CD ₃ OD) δ7.48-7.42 (m, 1H), 7.25-7.13 (m, 3H), 6.22-6.06 (m, 1H), 5.93-5.89 (m, 1H), 5.01-4.87 (m, 0.5H), 4.85-4 .82(m, 0.5H), 3.88-3.75(m, 1H), 3.51-3.42(m, 1H), 2.93-2.81(m, 1H), 1.75-1.64(m, 1H), 1.62-1.54(m, 1H). LC-MS R _T =0.852 min, m/z =308.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.852 min, and ESI ⁺ measured value [M+H] = 308.0.

SFC conditions: Column: Chiralcel OD-3 150×4.6mm I.D. 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃

A larger batch of the trans mixture (215 mg, 0.70 mmol) was separated by chiral SFC to obtain:

[(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 2.445 min) (19.5 mg, 9%), is a white solid. ¹ HNMR (400MHz, CDCl ₃ )δ7.40-7.38(m, 1H), 7.18-7.15(m, 2H), 6.98-6.97(m, 1H), 6.13-6.11(m, 0.5H), 5.99-5.98(m, 0.5H), 5.87-5.85(m, 1H) , 5.05-5.04(m, 0.5H), 4.89-4.88(m, 0.5H), 3.73-3.67(m, 1H), 3.58-3.54(m, 1H), 3.01-2.95(m, 1H), 1.72-1.65(m, 2H). LC-MSR _T =1.763min, m/z=308.1(M+H) ⁺ .

LCMS (10-80% acetonitrile + 0.1% ammonia in water, within 3.0 min) retention time 1.763 min, ESI ⁺ measured value [M+H] = 308.1. Note: Under AD SFC conditions, the 1R,2S-isomer is peak 2 (retention time = 2.728 min).

SFC conditions: Column: Daicel Chiralpak AD-H (250mm*30mm, 5μm); Mobile phase: A: CO2, B: ethanol (0.1% _{NH3H2O methanol} ); Gradient: 15% to 15% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 70

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

The racemic [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-methylcyclopropyl] ketone (trans mixture LHS) (80 mg) was further separated by chiral SFC to obtain the specifically assigned:

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S)-2-methylcyclopropyl] methyl ketone (peak 1, retention time = 3.714 min) (28 mg, 35%, ee: 96.1%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.45-7.38(m, 3H), 7.29-7.26(m, 2H), 6.19-6.17(m, 0.5H), 6.05-6.03(m, 0.5H), 5.67-5.62(m, 1H), 3.81- 3.71 (m, 1H), 2.89-2.75 (m, 2H), 1.62-1.54 (m, 1H), 1.45-1.39 (m, 1H), 1.18 (d, J=6.4Hz, 3H), 0.99-0.96 (m, 1H). LC-MS R _T =0.756 min, m/z =286.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.756 min, and the measured ESI+ value [M+H] = 286.1.

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2R)-2-methylcyclopropyl] ketone (peak 2, retention time = 3.901 min) (48 mg, 60%, ee: 86%), is a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.44-7.40(m, 3H), 7.29-7.27(m, 2H), 6.20-6.16(m, 0.5H), 6.06-6.02(m, 0.5H), 5.67-5.61(m, 1H), 3.79- 3.73 (m, 1H), 2.89-2.74 (m, 2H), 1.64-1.60 (m, 1H), 1.44-1.39 (m, 1H), 1.17 (d, J=6.0Hz, 3H), 1,00-0.95 (m, 1H). LC-MS R _T =0.757 min, m/z =286.1[M+H] ⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.757 min, and the measured ESI+ value [M+H] = 286.1.

SFC conditions: Column: AD (250mm*30mm, 5μm); Mobile phase: A: CO2 _, B: 0.1% _{NH3 H2O} EtOH; Gradient: 25% to 25% B; Flow rate: 50mL/min; Column temperature: 40℃.

Method 71

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

Step 1: Ethyl 3-ethyl-4,5-dihydroisoxazole-5-carboxylate

At 25°C, a solution of 1-nitropropane (15.1 mL, 168.37 mmol) was added to a solution of ethyl acrylate (89.6 mL, 841.85 mmol), di-tert-butyl dicarbonate (58.0 mL, 252.55 mmol), and 4-dimethylaminopyridine (2.1 g, 16.84 mmol) in acetonitrile (50 mL). The mixture was stirred at 25°C for 5 hours and quenched by adding saturated ammonium chloride solution (80 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 3-ethyl-4,5-dihydroisoxazol-5-carboxylate (25.5 g, 88%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.94-4.86 (m, 1H), 4.24-4.13 (m, 2H), 3.21-3.14 (m, 2H), 2.40-2.29 (m, 2H), 1.30-1.24 (m, 3H), 1.16-1.11 (m, 3H)

Step 2: 5-Ethyl-3-hydroxy-pyrrolidone-2-one

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

Step 3: 3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidine-2-one

To a solution of 5-ethyl-3-hydroxypyrrolidone-2-one (11.0 g, 85.17 mmol) in dichloromethane (200 mL), imidazole (11.6 g, 170.33 mmol) and tert-butyldimethylchlorosilane (19.2 g, 127.75 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidone-2-one (10.0 g, 48%) as a colorless oil.

Step 4: 1-Amino-3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidine-2-one

Sodium hydride (60%, 2.5 g, 61.62 mmol) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidine-2-one (10.0 g, 41.08 mmol) in N,N-dimethylformamide (200 mL). After stirring at 0 °C for 20 min, O-(diphenylphosphoyl)hydroxylamine (14.4 g, 61.62 mmol) was added to the mixture, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidine-2-one (10.0 g, 94%) as a yellow oil. LCMS RT = 1.130 min, m/z = 259.2 [M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.130 min, and the measured ESI+ value [M+H] = 259.2.

Step 5: 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate

A mixture of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-pyrrolidine-2-one (10.0 g, 38.7 mmol) and 2-ethoxy-2-imino-ethyl acetate (14.0 g, 96.74 mmol) in ethanol (250 mL) was stirred at 90 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (13.0 g, 94%) as a yellow oil. LCMS RT = 1.148 min, m/z = 358.3 [M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.148 min, and the measured ESI+ value [M+H] was 358.3.

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

A mixture of ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (13.0 g, 36.36 mmol) and p-toluenesulfonic acid (7.5 g, 43.63 mmol) in toluene (250 mL) was stirred at 120 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (12.0 g, 97%) as a yellow oil. LCMS RT = 0.823 min, m/z = 340.2 [M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.823 min, and the measured ESI+ value [M+H] = 340.2.

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

To a solution of 7-[tert-butyl(dimethyl)silyl]oxy-5-ethyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (12.0 g, 35.35 mmol) in tetrahydrofuran (200 mL), tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 35.35 mL, 35.35 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours and concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to give trans-5-ethyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (2.3 g, 29%) as a pale red oil (together with the cis isomer (2.8 g, 35%)). ¹ H NMR (400MHz, CDCl ₃ )δ5.32-5.27(m, 1H), 4.49-4.43(m, 3H), 3.24-3.17(m, 1H), 2.41-2.36(m, 1H), 2. 21-2.12 (m, 1H), 1.94-1.84 (m, 1H), 1.36 (t, J=7.2Hz, 3H), 1.03 (t, J=7.2Hz, 3H).

Step 8:

cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

At 0 °C, diethylaminosulfonate trifluoride (6.6 g, 40.85 mmol) was added dropwise to a solution of trans-5-ethyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.3 g, 10.21 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at 0 °C for 2 hours and quenched by adding saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (800 mg, 34%) as a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 6.00-5.78 (m, 1H), 4.53-4.37 (m, 3H), 3.35-3.16 (m, 1H), 2.69-2.54 (m, 1H), 2.13-2.05 (m, 1H), 1.98-1.91 (m, 1H), 1.43 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H).

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

Ethyl cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (200 mg, 0.88 mmol) was added to a mixture of tetrahydrofuran (3 mL), water (2 mL), and methanol (1 mL) with lithium hydroxide monohydrate (148 mg, 3.52 mmol). The mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. The residue was diluted with ice water (20 mL) and adjusted to pH 3 by adding aqueous hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure to give crude cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (150 mg, 86%) as a yellow oil.

Step 10: cis-5-ethyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide, cis mixture

A mixture of cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (100 mg, 0.50 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), N,N-diisopropylethylamine (0.21 mL, 1.26 mmol), N,O-dimethylhydroxylamine hydrochloride (74 mg, 0.75 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.60 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in petroleum ether) to give cis-5-ethyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (120 mg, 99%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ5.99-5.79(m, 1H), 4.40-4.39(m, 1H), 3.84(s, 3H), 3.43(s, 3H), 3.36-3.16(m, 1 H), 2.67-2.54(m, 1H), 2.14-2.03(m, 1H), 1.97-1.90(m, 1H), 1.07-1.03(m, 3H)LCMS R _T =0.481 min, m/z =243.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.481 min, and the measured ESI+ value [M+H] = 243.1.

Step 11: Cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, under nitrogen atmosphere, cyclopropyl magnesium bromide (0.5 M, in tetrahydrofuran, 2.0 mL, 1.0 mmol) was added to a solution of cis-5-ethyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.41 mmol). After addition, the mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.4) to give cyclopropyl-[cis-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (80 mg, 87%) as a yellow oil. This cis mixture was further separated by chiral SFC to give the specifically assigned:

Cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 3.928 min) (22.5 mg, 28%), as an orange solid (the (5S,7R)-isomer was also collected as peak 2 (retention time = 4.391 min, 18.8 mg, 22%)). ¹ H NMR (400MHz, CD ₃ OD) δ6.09-5.89 (m, 1H), 4.55-4.45 (m, 1H), 3.43-3.36 (m, 1H), 3.15-3.06 (m, 1H), 2.67-2. 53 (m, 1H), 2.09-1.93 (m, 2H), 1.23-1.18 (m, 2H), 1.17-1.11 (m, 2H), 1.05 (t, J=7.2Hz, 3H). LCMS R _T =0.770 min, m/z =224.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.770 min, and the measured ESI+ value [M+H] was 224.0.

SFC conditions: Column: Chiralcel IC 100×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA); Gradient: 5% to 40% B, 3.5 min, and hold at 40%, 2.5 min, then 5% B, 1.5 min; Flow rate: 3 mL/min; Column temperature: 40℃.

Method 72

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

Step 1: Ethyl 3-propyl-4,5-dihydroisoxazole-5-carboxylate

At 25°C, a solution of 1-nitrobutane (2.01 mL, 19.39 mmol) was added to a solution of ethyl acrylate (10.32 mL, 96.97 mmol), di-tert-butyl dicarbonate (6.68 mL, 29.09 mmol), and 4-dimethylaminopyridine (0.24 g, 1.94 mmol) in acetonitrile (20 mL). After addition, the mixture was stirred at 25°C for 5 hours and quenched by adding saturated ammonium chloride solution (80 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel, eluting with silica gel (100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 3-propyl-4,5-dihydroisoxazol-5-carboxylate (3.2 g, 89%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ4.98-4.93(m, 1H), 4.27-4.20(m, 2H), 3.21-3.18(m, 2H), 2.37-2.33(m, 2H), 1.64-1.58(m, 2H), 1.33-1.28(m, 3H), 0.98-0.94(m, 3H).

Step 2: Hydroxy-5-propyl-pyrrolidone-2-one

A mixture of ethyl 3-propyl-4,5-dihydroisoxazole-5-carboxylate (8.0 g, 43.19 mmol) and palladium (10% on carbon, 3.3 g) in ethanol (200 mL) was stirred at 40 °C for 16 hours under a hydrogen atmosphere (50 psi) and filtered. The filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-propyl-pyrrolidine-2-one (6.1 g, 99%) as a pale yellow oil. LCMS R _{_T} = 0.263 min, m/z = 144.3 [M+H] ^⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.263 min, and the measured ESI+ value [M+H] = 144.3.

Step 3: 3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidine-2-one

To a solution of 3-hydroxy-5-propyl-pyrrolidone-2-one (6.1 g, 42.60 mmol) in dichloromethane (200 mL), imidazole (5.8 g, 85.21 mmol) and tert-butyldimethylchlorosilane (9.6 g, 63.91 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidone-2-one (7.5 g, 68%) as a yellow oil. LCMS R _{_T} = 1.474 min, m/z = 258.2 [M+H] ^⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.474 min, and the measured ESI+ value [M+H] = 258.2.

Step 4: 1-Amino-3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidine-2-one

Sodium hydride (60%, 1.6 g, 40.79 mmol, 60%) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidine-2-one (7.0 g, 27.19 mmol) in N,N-dimethylformamide (200 mL). After stirring at 0 °C for 20 min, O-(diphenylphosphoyl)hydroxylamine (9.5 g, 40.79 mmol) was added to the mixture, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidine-2-one (6.8 g, 92%) as a yellow oil. This crude product was used in the next step without further purification. LCMS R _{_T} = 0.766 min, m/z = 273.3 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.766 min, and the measured ESI+ value [M+H] = 273.3.

Step 5: 2-[[3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-propyl-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate

A mixture of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-propyl-pyrrolidine-2-one (6.6 g, 24.22 mmol) and 2-ethoxy-2-imino-ethyl acetate (8.8 g, 60.56 mmol) in ethanol (100 mL) was stirred at 90 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 2-[[3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-propyl-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (9.0 g, 100%) as a yellow oil. LCMS R _{_T} = 1.192 min, m/z = 372.3 [M+H] ^⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.192 min, and the measured ESI+ value [M+H] was 372.3.

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

A mixture of ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-propyl-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (9.0 g, 24.22 mmol) and p-toluenesulfonic acid (6.3 g, 36.33 mmol) in toluene (150 mL) was stirred at 120 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (8.3 g, 97%) as a yellow oil. LCMS R _T = 0.803 min, m/z = 240.2 [M-TBS] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.803 min, and the measured ESI+ value [M-TBS] was 240.2.

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

To a solution of 7-[tert-butyl(dimethyl)silyl]oxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (8.30 g, 23.48 mmol) in tetrahydrofuran (150 mL), tetrabutylammonium fluoride (11.74 mL, 11.74 mmol) in tetrahydrofuran was added. The reaction mixture was stirred at 40 °C for 15 hours and concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in petroleum ether) to give ethyl trans-7-hydroxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.0 g, 18%) as a yellow oil (together with an equal amount of the cis product): ^¹H NMR (400 MHz, CDCl₃ ₎ )δ5.33-5.31(m, 1H), 4.64-4.63(m, 1H), 4.46-4.40(m, 2H), 2.87-2.85(m, 1H) , 2.70-2.66 (m, 1H), 2.66-2.06 (m, 1H), 1.63-1.33 (m, 6H), 0.96-0.92 (m, 3H).

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

At 0 °C, diethylaminosulfonate trifluoride (2.2 g, 13.37 mmol) was added to a solution of trans-7-hydroxy-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (800 mg, 3.34 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 0 °C for 2 hours and quenched by adding saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to give cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (270 mg, 34%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ5.99-5.78(m, 1H), 4.53-4.40(m, 3H), 3.34-3.15(m, 1H), 2.70-2.54(m, 1H), 2.14-2.0 2 (m, 1H), 1.91-1.78 (m, 1H), 1.63-1.50 (m, 1H), 1.46-1.41 (m, 4H), 0.98 (t, J=7.2Hz, 3H).

Step 9: cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Ethyl cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (260 mg, 1.08 mmol) and lithium hydroxide monohydrate (135 mg, 3.23 mmol) in tetrahydrofuran (2 mL), water (1 mL), and methanol (0.5 mL) were stirred at 25 °C for 4 hours and then concentrated under reduced pressure. The residue was diluted with ice water (20 mL) and adjusted to pH 3 by adding aqueous hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure to give crude cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (225 mg, 98%) as a yellow solid.

Step 10: Cyclopropyl-[cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

A mixture of cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (200 mg, 0.94 mmol), 1-hydroxybenzotriazole (63 mg, 0.47 mmol), N,O-dimethylhydroxylamine hydrochloride (137 mg, 1.41 mmol), N,N-diisopropylethylamine (0.39 mL, 2.35 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg, 1.13 mmol) was stirred at 25 °C for 3 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in petroleum ether) to give cis-7-fluoro-N-methoxy-N-methyl-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (180 mg, 75%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ6.00-5.76(m, 1H), 4.51-4.37(m, 1H), 3.84(s, 3H), 3.43(s, 2H), 3.33-3.17(m, 1H), 2.70-2.53(m, 1 H), 2.11-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.66-1.53 (m, 1H), 1.51-1.38 (m, 1H), 0.98 (t, J=7.2Hz, 3H).

Step 11: Cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C under nitrogen atmosphere, cyclopropyl magnesium bromide (0.5 M, in tetrahydrofuran, 3.21 mL, 1.61 mmol) was added to a solution of cis-7-fluoro-N-methoxy-N-methyl-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (170 mg, 0.66 mmol). After addition, the mixture was stirred at 0 °C for 1 hour and quenched by adding saturated ammonium chloride aqueous solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf = 0.4) to give cyclopropyl-[cis-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (100 mg, 64%) as a colorless oil. The cis mixture was further separated by chiral SFC to give the specifically assigned:

Cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 3.997 min) (40.0 mg, 40%) is a colorless oil. ¹ H NMR (400MHz, CD ₃ OD) δ6.07-5.91 (m, 1H), 4.59-4.53 (m, 1H), 3.42-3.33 (m, 1H), 3.11-3.07 (m, 1H), 2.67-2.52 (m, 1H), 2.02-1. 98 (m, 1H), 1.91-1.80 (m, 1H), 1.69-1.57 (m, 1H), 1.52-1.38 (m, 1H), 1.23-1.11 (m, 4H), 1.01 (t, J=7.2Hz, 3H). LCMS R _T =0.972 min, m/z =238.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 0.972 min, and the measured ESI+ value [M+H] = 238.2.

SFC conditions: Column: Chiralcel IC 100×4.6mm I.D, 3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA); Gradient: 5% to 40% B, 3.5 min, and hold at 40%, 2.5 min, then 5% B, 1.5 min; Flow rate: 3 mL/min; Column temperature: 40℃.

Note: The 5S,7R-isomer was also collected as a colorless oil. (Peak 2, retention time = 4.420 min) (42.0 mg, 42%)

Method 73

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

Step 1: 1-(2,6-Difluorophenyl)but-3-en-1-ol

Under a nitrogen atmosphere at 0 °C, allyl magnesium bromide (1.0 M, in tetrahydrofuran, 760.0 mL, 760.0 mmol) was added dropwise to a solution of 2,6-difluorobenzaldehyde (90.0 g, 633.36 mmol) in tetrahydrofuran (2000 mL). The mixture was heated to 25 °C and stirred for 2 hours, then quenched by adding a saturated aqueous solution of ammonium chloride (2000 mL). The resulting mixture was extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-(2,6-difluorophenyl)but-3-en-1-ol (116 g, 99%) as a colorless oil.

Step 2: tert-butyl((1-(2,6-difluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a solution of 1-(2,6-difluorophenyl)but-3-en-1-ol (116.0 g, 629.82 mmol) in dichloromethane (2000 mL), imidazole (85.8 g, 1259.60 mmol) and tert-butyldimethylchlorosilane (113.9 g, 755.78 mmol) were added. The reaction mixture was stirred at 25 °C for 4 hours and filtered. The filtrate was washed with water (2 x 2000 mL), a saturated aqueous solution of sodium bicarbonate (2 x 2000 mL), and brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude tert-butyl-[1-(2,6-difluorophenyl)but-3-enoxy]-dimethyl-silane (180.0 g, 96%) as a pale yellow oil.

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,6-difluorophenyl)propanal

Osmium tetroxide (0.88 g, 3.45 mmol) was added to a solution of tert-butyl-[1-(2,6-difluorophenyl)but-3-enoxy]-dimethyl-silane (180.0 g, 603.14 mmol) in water (1000 mL) and tetrahydrofuran (1000 mL). After stirring at 15 °C for 30 min, sodium periodate (516.0 g, 2412.6 mmol) was added in small portions over 2 hours. The resulting mixture was stirred at 25 °C for another 2 hours and quenched by adding cold, saturated aqueous solution of sodium thiosulfate (300 mL). The mixture was stirred for 30 min and extracted with ethyl acetate (3 x 2000 mL). The combined organic layers were washed with water (2000 mL) and brine (2000 mL), dried with sodium sulfate, and concentrated under reduced pressure to give crude product 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl)propanal (180.0 g, 99%), which was a yellow oil.

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(2,6-difluorophenyl)prop-1-ol

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 268.8 mL, 672.09 mmol) was slowly added to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (190.0 g, 610.99 mmol) in tetrahydrofuran (2000 mL). The mixture was stirred at -78 °C for 30 min, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl)propionaldehyde (177.0 g, 589.17 mmol) in tetrahydrofuran (100 mL) was added dropwise. After the addition, the mixture was stirred at -78 °C for 1.5 h and quenched by adding saturated aqueous solution of ammonium chloride (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 2000 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-12% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl)prop-1-ol (160 g, 49%) as a yellow oil.

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

A mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,6-difluorophenyl)prop-1-ol (80.0 g, 150.24 mmol), trifluoroacetic acid (400 mL, 600.95 mmol), and trifluoromethanesulfonic acid (40 mL, 600.95 mmol) was stirred at 50 °C for 12 h and concentrated under reduced pressure. The residue was adjusted to pH 9 by adding a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (2 x 700 mL). The combined organic layers were washed with water (2 x 300 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether (80 mL) to give crude 2-bromo-5-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (40 g, 84%) as a white solid. LCMS R _{_T} = 0.694 and 0.711 min, m/z = 317.9 [M+H] ^⁺ .

LCMS retention times (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 0.694 and 0.711 min, and the measured ESI+ value [M+H] was 317.9.

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

To a cooled (0°C) solution of 2-bromo-5-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.5 g, 4.75 mmol) in dichloromethane (30 mL), diethylaminosulfur trifluoride (2.5 mL, 18.98 mmol) was added. The mixture was stirred at 0°C for 1 hour and quenched at 0°C by adding 100 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-12% ethyl acetate in petroleum ether) to give cis-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.25 g, 16%) as a pale yellow solid. LCMS R _{_T} = 0.808 min, m/z = 319.9 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.808 min, and the measured ESI+ value [M+H] was 319.9.

The cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

(5S,7S)-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 3.293 min) (115 mg, 46%), is a pale yellow solid.

SFC conditions: ChiralPak AD-3 150×4.6mm I.D.3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min. Flow rate: 2.5 mL/min; Column temperature: 40℃.

Step 7: Cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.36 mL, 0.72 mmol) was added to a solution of (5S,7S)-2-bromo-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (115 mg, 0.36 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (93 mg, 0.72 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 37-67%/ammonium hydroxide in water 0.05%) to give cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (32.6 mg, 29%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.54-7.48 (m, 1H), 7.10-7.06 (m, 2H), 6.24-6.21 (m, 0.5H), 6.10-6.07 (m, 0.5H), 5.98 -5.94 (m, 1H), 3.89-3.81 (m, 1H), 3.03-2.91 (m, 2H), 1.18-1.16 (m, 2H), 1.11-1.08 (m, 2H). LCMS R _T =0.740 min, m/z =308.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.740 min, and the measured ESI+ value [M+H] was 308.1.

Method 74

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

Step 1: 1-Cyano-N-methoxy-N-methyl-cyclopropaneformamide

A mixture of 1-cyanocyclopropanecarboxylic acid (500 mg, 4.5 mmol), 1-hydroxybenzotriazole (365 mg, 2.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.4 mmol), N,O-dimethylhydroxylamine hydrochloride (878 mg, 9.0 mmol), and N,N-diisopropylethylamine (0.8 mL, 4.5 mmol) in dichloromethane (40 mL) was stirred at 25 °C for 16 hours and quenched by the addition of water (100 mL). The resulting 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, 50% to 60% ethyl acetate in petroleum ether) to give 1-cyano-N-methoxy-N-methyl-cyclopropaneformamide (410 mg, 59%) as a yellow oil.

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

Under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 1.06 mL, 2.13 mmol) was added dropwise to a cooled (0 °C) mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (200 mg, 0.71 mmol) and 1-cyano-N-methoxy-N-methyl-cyclopropaneformamide (164 mg, 1.06 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at 25 °C for 3 hours, and then quenched by adding 10 mL of saturated aqueous ammonium chloride solution. 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 RP-HPLC (acetonitrile 35-65%/ammonium hydroxide in water 0.05%) to give 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropaneformitrile (20 mg, 9.2%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.43-7.40(m, 3H), 7.78-7.27(m, 2H), 6.15-5.99(m, 1H), 5.57-5.55(m, 1H) , 3.69-3.61(m, 1H), 3.06-2.96(m, 1H), 2.10-2.03(m, 2H), 1.84-1.81(m, 2H). LCMS R _T =0.813 min, m/z =296.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.813 min, and the measured ESI+ value [M+H] = 296.9.

Method 75

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,2]pent-2-yl-methyl ketone

Step 1: N-methoxy-N-methylspiro[2,2]pentane-1-carboxamide

A mixture of spiro[2,2]pentane-2-carboxylic acid (0.5 g, 4.46 mmol), N,O-dimethylhydroxylamine hydrochloride (0.65 g, 6.69 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.70 g, 4.46 mmol), and N,N-diisopropylethylamine (1.44 g, 11.15 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 5 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure to give crude N-methoxy-N-methyl-spiro[2,2]pentane-2-carboxamide (690 mg, 100%) as a colorless oil. The crude product is used in the next step without further purification.

LC-MS R _T =0.638 min, m/z =156.1[M+H] ⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.638 min, and the measured ESI+ value [M+H] = 156.1.

Step 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,2]pent-2-yl-methyl ketone

At 0 °C under a nitrogen atmosphere, isopropyl magnesium bromide (3.0 M, in 2-methyltetrahydrofuran, 0.71 mL, 2.13 mmol) was added to a mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) and N-methoxy-N-methyl-spiro[2,2]pentane-2-carboxamide (110 mg, 0.71 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at 0 °C for 2 hours and quenched by adding saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (40-70% acetonitrile/0.05% ammonium hydroxide in water) to give the specifically assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,2]pent-2-yl methyl ketone (18.6 mg, 18%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.41-7.33(m, 3H), 7.29-7.23(m, 2H), 6.09-5.93(m, 1H), 5.52-5.44(m, 1H), 3.68-3.60(m, 1H), 3.40-3.36(m, 1H) , 3.01-2.89 (m, 1H), 1.88-1.82 (m, 1H), 1.63-1.61 (m, 1H), 1.05-0.97 (m, 2H), 0.95-0.89 (m, 1H), 0.88-0.83 (m, 1H). LC-MS R _T =0.786 min, m/z =298.1[M+H] ⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.786 min, and the measured ESI+ value [M+H] = 298.1.

Method 76

[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hexyl-2-yl-methyl ketone

Step 1: N-methoxy-N-methylspiro[2,3]hexane-1-carboxamide

A mixture of spiro[2,3]hexane-2-carboxylic acid (300 mg, 2.38 mmol), N,O-dimethylhydroxylamine hydrochloride (464 mg, 4.76 mmol), N,N-diisopropylethylamine (922 mg, 7.13 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (949 mg, 2.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at 20 °C for 2 hours. The mixture was then poured into water (60 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with water (2 x 20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude N-methoxy-N-methyl-spiro[2,3]hexane-2-carboxamide (400 mg, 99%) as a pale yellow oil, which was used in the next step without further purification. LC-MS R _{_T} = 0.725 min, m/z = 170.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.725 min, and the measured ESI+ value [M+H] = 170.2.

Step 2: [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hex-2-yl-methyl ketone

At 0 °C under a nitrogen atmosphere, isopropyl magnesium bromide (3.0 M, in 2-methyltetrahydrofuran, 0.71 mL, 2.13 mmol) was added dropwise to a solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) and N-methoxy-N-methyl-spiro[2,3]hexane-2-carboxamide (120 mg, 0.71 mmol) in tetrahydrofuran (2 mL). After addition, the mixture was stirred at 0 °C for 2 hours and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (45-75% acetonitrile/0.05% ammonium hydroxide in water) to give the specifically assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hex-2-yl methyl ketone (21.6 mg, 19%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.42-7.38(m, 3H), 7.29-7.26(m, 2H), 6.11-5.95(m, 1H), 5.51-5.48(m, 1H), 3.69-3.60(m, 1H), 3.10-3.03(m, 1H) , 3.02-2.90 (m, 1H), 2.38-2.13 (m, 4H), 2.08-1.99 (m, 1H), 1.98-1.89 (m, 1H), 1.56-1.52 (m, 1H), 1.29-1.24 (m, 1H). LC-MS R _T =0.821 min, m/z =312.1[M+H] ⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.821 min, and the measured ESI+ value [M+H] = 312.1.

Method 77

[1-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone

Step 1: N-methoxy-N-methyl-1-(2-pyridyl)cyclopropaneformamide

A mixture of 1-(2-pyridyl)cyclopropanecarboxylic acid (200 mg, 1.23 mmol), N,N-diisopropylethylamine (475 mg, 3.68 mmol), 1-hydroxybenzotriazole (198 mg, 1.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (282 mg, 1.47 mmol), and N,O-dimethylhydroxylamine hydrochloride (179 mg, 1.84 mmol) in dichloromethane (10 mL) was stirred at 30 °C for 18 hours and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-1-(2-pyridyl)cyclopropanecarboxamide (200 mg, 79%) as a white solid. LC-MS R _{_T} = 0.733 min, m/z = 207 (M+H) ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.733 min, and ESI ⁺ measured value [M+H] = 207.

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

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.4 mL, 0.80 mmol) was added dropwise to a solution of N-methoxy-N-methyl-1-(2-pyridyl)cyclopropanecarboxamide (55 mg, 0.27 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (5 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (water (0.05% ammonium hydroxide v/v) - acetonitrile 35-65%) to give specifically assigned [1-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (15.4 mg, 24%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ8.42-8.40(m, 1H), 7.50-7.47(m, 1H), 7.34-7.32(m, 3H), 7.26-7.10(m, 1H), 7.06-7.02(m, 3H), 6.00-5.83(m, 1H) , 5.40-5.35 (m, 1H), 3.60-3.49 (m, 1H), 2.92-2.81 (m, 1H), 2.02-1.90 (m, 1H), 1.83-1.78 (m, 2H), 1.60-1.50 (m, 1H). LCMS R _T =1.678 min, m/z =349.2[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 1.678 min, and the ESI ⁺ measured value [M+H] = 349.2.

Method 78

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

Step 1: 1-Cyclopropyl-N-methoxy-N-methyl-cyclopropaneformamide

A mixture of 1-cyclopropylcyclopropanecarboxylic acid (500 mg, 3.96 mmol), 1-hydroxybenzotriazole (321 mg, 2.38 mmol), N,O-dimethylhydroxylamine hydrochloride (773 mg, 7.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (912 mg, 4.76 mmol), and N,N-diisopropylethylamine (512 mg, 3.96 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 18 hours and quenched by the addition of water (10 mL). The separated organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 50-60% ethyl acetate in petroleum ether) to give 1-cyclopropyl-N-methoxy-N-methyl-cyclopropaneformamide (370 mg, 55%) as a yellow oil.

Step 2: (1-Cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 3.57 mL, 7.15 mmol) was added dropwise to a solution of 1-cyclopropyl-N-methoxy-N-methyl-cyclopropanecarboxamide (340 mg, 2.01 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (288 mg, 1.02 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether, _Rf = 0.6) to give (1-cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (100 mg, 31%) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.40-7.36(m, 3H), 7.24-7.22(m, 2H), 6.09-5.91(m, 1H), 5.52-5.45(m, 1H), 3.69-3.54(m, 1H), 2.99-2. 86 (m, 1H), 1.88-1.83 (m, 1H), 1.54-1.50 (m, 2H), 0.78-0.76 (m, 2H), 0.43-0.39 (m, 2H), 0.07-0.03 (m, 2H). LC-MS R _T =0.816 min, m/z =312.1[M+H] ⁺ .

LCMS (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 minutes) retention time 1.935 min, ESI+ measured value [M+H] = 312.2.

Method 79

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

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

At -78°C under a nitrogen atmosphere, allyl magnesium chloride (2.0 M, in tetrahydrofuran, 448.1 mL, 896.35 mmol) was added to a solution of 2-chlorobenzaldehyde (90.0 g, 640.25 mmol) in tetrahydrofuran (1000 mL). The resulting mixture was heated to 25°C and stirred for 1 hour, then quenched by adding 100 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2-chlorophenyl)but-3-en-1-ol (116.0 g, 99%) as a yellow oil.

Step 2: tert-butyl-[1-(2-chlorophenyl)but-3-enoxy]-dimethyl-silane

To a solution of 1-(2-chlorophenyl)but-3-en-1-ol (116.0 g, 634.55 mmol) in dichloromethane (1.5 L), imidazole (86.4 g, 1269.1 mmol) and tert-butyldimethylchlorosilane (124.3 g, 824.9 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h and quenched by the addition of water (1 L). The mixture was extracted with ethyl acetate (2 x 1 L). The combined organic layers were washed with brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure to give crude tert-butyl-[1-(2-chlorophenyl)but-3-enoxy]-dimethyl-silane (188.0 g, 99%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )7.59-7.54(m, 1H), 7.31-7.23(m, 2H), 7.20-7.14(m, 1H), 5.92-5.79(m, 1H), 5.17-5.12(m, 1H), 5.0 7-5.00 (m, 2H), 2.49-2.42 (m, 1H), 2.40-2.32 (m, 1H), 0.89 (s, 9H), 0.05 (s, 3H), -0.10--0.13 (m, 3H).

Step 3: 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propanal

Osmium tetroxide (0.04%, in water, 41.55 mL, 6.65 mmol) was added to a solution of tert-butyl-[1-(2-chlorophenyl)but-3-enoxy]-dimethyl-silane (188.0 g, 633.19 mmol) in water (1.0 L) and tetrahydrofuran (1.0 L). After stirring at 15 °C for 30 min, sodium periodate (541.7 g, 2532.8 mmol) was added in fractions over 2 hours. The resulting mixture was stirred at 30 °C for another 2 hours and quenched by adding cold, saturated aqueous solution of sodium thiosulfate (500 mL). The mixture was stirred for 30 min and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propanal (189.0 g, 99%) as a colored oil. ^¹H NMR (400 MHz, _CDCl₃ ) 9.84-9.81 (m, 1H), 7.63-7.59 (m, 1H), 7.35-7.28 (m, 2H), 7.25-7.19 (m, 1H), 5.66-5.62 (m, 1H), 2.76-2.69 (m, 2H), 0.89 (s, 9H), 0.09 (s, 3H), -0.10 (s, 3H).

Step 4: 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)prop-1-ol

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 278.2 mL, 695.6 mmol) was slowly added to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (194.6 g, 626.04 mmol) in tetrahydrofuran (1100 mL). The mixture was stirred at -78 °C for 30 min, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)propanal (189.0 g, 632.4 mmol) in tetrahydrofuran (400 mL) was added dropwise. After the addition, the mixture was stirred at -78 °C for 2 h, and then quenched by adding 200 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (2 x 800 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2-chlorophenyl)prop-1-ol (202.0 g, 60%) as a yellow oil. LC-MS R _{_T} = 2.657 min, m/z = 446.1 [M+H] ^⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 minutes) was 2.657 min, and the measured ESI+ value [M+H] = 446.1.

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

A mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6-trifluorophenyl)prop-1-ol (50.0 g, 94.17 mmol) and trifluoroacetic acid (280.7 mL, 3766.8 mmol) was stirred at 55 °C for 16 h and concentrated under reduced pressure. The residue was adjusted to pH 9 by adding a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 2-bromo-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-7-ol (9.2 g, 31%) as a white solid. ¹ H NMR (400MHz, CD ₃ Cl) δ 7.48-7.41 (m, 1H), 7.34-7.27 (m, 2H), 7.10-6.79 (m, 1H), 6.08-5.83 (m, 1H), 5.70-5.53 (m, 1H), 5.41 (br s, 1H), 3.74-3.57 (m, 0.5H), 3.35-3.21 (m, 0.5H), 2.99-2.84 (m, 1H), 2.67-2.52 (m, 0.5H). LC-MSR _T =0.614min, m/z=314.0[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.614 min, and the measured ESI+ value [M+H] = 314.0.

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

To a cooled (0°C) solution of 2-bromo-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (5.2 g, 16.53 mmol) in dichloromethane (80 mL), diethylaminosulfur trifluoride (8.8 mL, 66.12 mmol) in dichloromethane (20 mL) was added. The reaction mixture was stirred at 0°C for 1 hour and quenched at 0°C by adding 300 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-12% ethyl acetate in petroleum ether) to give 2-bromo-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (3.9 g, 75%) as a deep yellow oil.

Step 7: Cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 5.5 mL, 11.06 mmol) was added dropwise to a mixture of N-methoxy-N-methyl-cyclopropaneformamide (402 mg, 3.11 mmol), 2-bromo-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (500 mg, 1.58 mmol) in tetrahydrofuran (30 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (in 20% ethyl acetate in petroleum ether, _Rf = 0.5) to give [5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (250 mg, 52%) as a white solid. LC-MS R _{_T} = 0.685 min, m/z = 306.1 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.685 min, and the measured ESI+ value [M+H] = 306.1.

The above cis/trans mixture was further separated by chiral SFC to obtain the definitively attributed:

Cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 2.509 min) (50.6 mg, 12%) is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.45-7.43(m, 1H), 7.34-7.28(m, 1H), 7.26-7.24(m, 1H), 6.76-6.72(m, 1H), 6.10-6.06(m, 0.5H), 6.01-5.95(m, 1H) , 5.95-5.93(m, 0.5H), 3.78-3.62(m, 1H), 3.12-3.04(m, 1H), 2.93-2.80(m, 1H), 1.37-1.32(m, 2H), 1.14-1.09(m, 2H). LC-MS R _T =1.049 min, m/z =306.1[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.049 min, and the measured ESI+ value [M+H] was 306.1.

Cyclopropyl-[(5R,7R)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 4, retention time = 3.571 min) (65.6 mg, 15%) is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.47-7.43(m, 1H), 7.34-7.26(m, 1.5H), 7.25-7.22(m, 0.5H), 6.76-6.72(m, 1H), 6.10-6.06(m, 0.5H), 6.01-5.96(m, 1 H), 5.95-5.93(m, 0.5H), 3.78-3.62(m, 1H), 3.12-3.04(m, 1H), 2.93-2.80(m, 1H), 1.37-1.32(m, 2H), 1.14-1.08(m, 2H). LC-MS R _T =0.776 min, m/z =306.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.776 min, and the measured ESI+ value [M+H] = 306.1.

Note: Peak 1 and Peak 3 are trans isomers.

SFC method: Column: Chiralcel OJ-3 150×4.6mm ID3μm; Mobile phase: A: _CO2 B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 80

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

Step 1: 1-(2,5-Difluorophenyl)but-3-en-1-ol

Under a nitrogen atmosphere at 0 °C, allyl magnesium bromide (2.0 M, in tetrahydrofuran, 49.3 mL, 98.5 mmol) was added to a solution of 2,5-difluorobenzaldehyde (10.0 g, 70.4 mmol) in tetrahydrofuran (20 mL). After addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched by adding 10 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,5-difluorophenyl)but-3-en-1-ol (11.0 g, 85%) as a yellow oil.

Step 2: tert-butyl((1-(2,5-difluorophenyl)but-3-en-1-yl)oxy)dimethylsilane

To a solution of 1-(2,5-difluorophenyl)but-3-en-1-ol (11.0 g, 59.7 mmol) in dichloromethane (200 mL), imidazole (8.1 g, 119.5 mmol) and tert-butyldimethylchlorosilane (11.7 g, 77.6 mmol) were added. After addition, the reaction mixture was stirred at 25 °C for 16 hours and quenched by adding water (100 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 to give crude tert-butyl-[1-(2,5-difluorophenyl)but-3-enoxy]-dimethyl-silane (17.0 g, 95%) as a light-colored oil.

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,5-difluorophenyl)propanal

Osmium tetroxide (80.0 mg, 0.33 mmol) was added to a solution of tert-butyl-[1-(2,5-difluorophenyl)but-3-enoxy]-dimethyl-silane (17.0 g, 57.0 mmol) in tetrahydrofuran/water (100 mL, 1:1). After stirring at 15 °C for 30 min, sodium periodate (48.7 g, 227.9 mmol) was added in fractions over 2 hours, and the resulting mixture was stirred at 30 °C for another 2 hours. The mixture was quenched by adding cold, saturated aqueous solution of sodium thiosulfate (100 mL). The mixture was stirred for 30 min and then extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,5-difluorophenyl)propionaldehyde (10.8 g, 63%) as a pale yellow oil.

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 16.1 mL, 40.3 mmol) was slowly added to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (11.4 g, 36.6 mmol) in tetrahydrofuran (80 mL). The mixture was stirred at -78 °C for 30 min, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propionaldehyde (10.8 g, 36.0 mmol) in tetrahydrofuran (100 mL) was added dropwise. After the addition, the mixture was stirred at -78 °C for 1.5 h and quenched by adding saturated aqueous solution of ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,5-difluorophenyl)prop-1-ol (10.0 g, 52%) as a yellow oil.

Step 5: 2-Bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

To a solution of 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,5-difluorophenyl)prop-1-ol (3.96 g, 8.83 mmol) in trifluoroacetic acid (25 mL, 88.3 mmol), trifluoromethanesulfonic acid (2.5 mL, 8.83 mmol) was added. The resulting mixture was stirred at 60 °C for 2 hours and concentrated under reduced pressure. The residue was adjusted to pH 9 by adding a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 100-200 mesh, 50-60% ethyl acetate in petroleum ether) to give a crude product, which was washed with methyl tert-butyl ether (20 mL) to give 2-bromo-5-(2,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.1 g, 39%) as a brown solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.11-7.03 (m, 1H), 6.98-6.75 (m, 1H), 5.84-5.68 (m, 1H), 5.47-5.30 (m, 2H), 3.64-3.18 (m, 1H), 3.02-2.63 (m, 1H). LCMSR _T =0.727min, m/z=318.0[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.727 min, and the measured ESI+ value [M+H] = 318.0.

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

At 0 °C, diethylaminosulfonate trifluoride (10.2 g, 63.3 mmol) was added dropwise to a solution of 2-bromo-5-(2,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (5.0 g, 15.8 mmol) in toluene (50 mL). The reaction mixture was stirred at 0 °C for 16 hours, and then slowly added to a saturated aqueous solution of sodium bicarbonate (100 mL) at 0 °C. The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give racemic-(5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (1.3 g, 26%) as a brown solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.15-7.05 (m, 2H), 6.72-6.68 (m, 1H), 6.07-5.91 (m, 1H), 5.78-5.74 (m, 1H), 3.68-3.55 (m, 1H), 2.90-2.79 (m, 1H). LCMS R _T =0.821 min, m/z =317.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.821 min, and the measured ESI+ value [M+H] = 317.9.

The cis mixture (500 mg, 1.7 mmol) was further separated by a chiral SFC to obtain the arbitrarily assigned:

(5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.600 min) (220 mg, 44%), is a brown solid. (Together with the 5R,7R-isomer (peak 1, retention time = 2.295 min) (220 mg, 44%)).

SFC conditions: Column: ChiralPak IC-3 150×4.6mm ID3μm. Mobile phase: A: _CO2 , B: ethanol (0.05% DEA). Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min. Flow rate: 2.5 mL/min. Column temperature: 40℃.

Step 7: Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.31 mL, 0.63 mmol) was added dropwise to a mixture of (5S,7S)-2-bromo-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.31 mmol), N-methoxy-N-methyl-cyclopropaneformamide (81 mg, 0.63 mmol), and acetic acid (3 mL) in tetrahydrofuran. The mixture was stirred at 0 °C for 0.5 h and quenched by adding 10 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC to give cyclopropyl-[(5S,7S)-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (22.1 mg, 23%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.28-7.17(m, 2H), 6.93-6.88(m, 1H), 6.22-6.06(m, 1H), 5.90-5.86(m, 1H), 3.88-3 .74 (m, 1H), 3.09-3.02 (m, 1H), 2.93-2.82 (m, 1H), 1.21-1.18 (m, 2H), 1.15-1.11 (m, 2H). LCMS R _T =1.007 min, m/z =308.1[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.007 min, and the measured ESI+ value [M+H] was 308.1.

Method 81

Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: 1-(2,3,6-trifluorophenyl)but-3-en-1-ol

At 0 °C under a nitrogen atmosphere, allyl magnesium bromide (2.5 M, in hexane, 93.7 mL, 187.4 mmol) was added to a solution of 2,3,6-trifluorobenzaldehyde (25.0 g, 156.2 mmol) in tetrahydrofuran (350 mL). The resulting mixture was heated to 25 °C and stirred for 1 hour, then quenched by adding saturated aqueous solution of ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,3,6-trifluorophenyl)but-3-en-1-ol (30 g, 95%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.01-7.17(m, 1H), 6.79-6.92(m, 1H), 5.72-5.91(m, 1H), 5.07-5.26(m, 3H), 2.74-2.88(m, 1H), 2.65-2.69(m, 1H), 2.44(s, 1H).

Step 2: tert-butyldimethyl((1-(2,3,6-trifluorophenyl)but-3-en-1-yl)oxy)silane

To a solution of 1-(2,3,6-trifluorophenyl)but-3-en-1-ol (30.0 g, 148.4 mmol) in dichloromethane (250 mL), imidazole (20.2 g, 296.8 mmol) and tert-butyldimethylchlorosilane (29.1 g, 192.9 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h, and then quenched by adding water (100 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 to give crude tert-butyl-dimethyl-[1-(2,3,6-trifluorophenyl)but-3-enoxy]silane (46.0 g, 98%) as a pale yellow oil. ¹ HNMR (400MHz, CDCl ₃ )δ7.26(s, 1H), 7.07-6.95(m, 1H), 6.97-6.77(m, 1H), 5.58-5.82(m, 1H), 4.97-5.11(m, 3H), 2. 84-2.64(m, 1H), 2.62-2.44(m, 1H), 0.83-0.86(m, 9H), 0.03-0.07(m, 3H), -0.17--0.13(m, 3H).

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,3,6-trifluorophenyl)propanal

Osmium tetroxide (0.5 g, 1.97 mmol) was added to a solution of tert-butyl-dimethyl-[1-(2,3,6-trifluorophenyl)but-3-enoxy]silane (5.0 g, 15.8 mmol) in water (30 mL) and tetrahydrofuran (30 mL). After stirring at 15 °C for 30 min, sodium periodate (13.5 g, 63.2 mmol) was added in small portions over 2 hours. The resulting mixture was stirred at 30 °C for another 2 hours, and then quenched by adding cold, saturated aqueous solution of sodium thiosulfate (300 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 (200 mL) and brine (200 mL), dried with sodium sulfate, and concentrated under reduced pressure to give crude product 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6-trifluorophenyl)propionaldehyde (5 g, 99%), which was a yellow oil.

Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(2,3,6-trifluorophenyl)prop-1-ol

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 38.0 mL, 95.0 mmol) was added to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (26.9 g, 86.4 mmol) in tetrahydrofuran (300 mL). The mixture was stirred at -78 °C for 30 min, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6-trifluorophenyl)propionaldehyde (27.0 g, 84.8 mmol) in tetrahydrofuran (100 mL) was added dropwise. After the addition, the mixture was stirred at -78 °C for 1.5 h and quenched by adding saturated aqueous solution of ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(2,3,6-trifluorophenyl)prop-1-ol (23 g, 49%) as a yellow oil.

Step 5: 2-Bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,6-trifluorophenyl)prop-1-ol (22.9 g, 41.6 mmol) and trifluoromethanesulfonic acid (12.2 mL, 138.4 mmol) in dichloromethane (200 mL) was heated at 55 °C for 4 days and concentrated under reduced pressure. The residue was diluted with water (100 mL) and adjusted to pH 9 with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 2-bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (9.2 g, 66%) as a yellow solid. LCMS R _{_T} = 0.873 and 0.897 min, m/z = 334.0/336.0 [M+H] ^⁺ .

LCMS retention times (10–80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) were 0.873 and 0.897 min, respectively. ESI+ measured values [M+H] = 334.0/336.0

Step 6: Racemic-(5S,7S)-2-bromo-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a cooled (0°C) solution of 2-bromo-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (9.2 g, 27.5 mmol) in toluene (100 mL), diethylaminosulfonate trifluoride (14.6 mL, 110.2 mmol) in toluene (4 mL) was added. The reaction mixture was stirred at 0°C for 1 hour, and then slowly added to a saturated aqueous solution of sodium bicarbonate (100 mL) at 0°C. The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-12% ethyl acetate in petroleum ether) to give racemic-(5S,7S)-2-bromo-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (1.8 g, 19%) as a pale yellow solid.

Step 7: Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

To a cooled (0°C) solution of N-methoxy-N-methyl-cyclopropaneformamide (188 mg, 1.47 mmol) and racemic-(5S,7S)-2-bromo-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.72 mmol) in tetrahydrofuran (10 mL), magnesium isopropyl chloride (2.0 M, in tetrahydrofuran, 0.73 mL, 1.46 mmol) was added. The mixture was stirred at 0°C for 1 hour and quenched by adding water (30 mL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give cyclopropyl-[racemic-(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (95 mg, 40%) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.25-7.16(m, 1H), 6.92-6.89(m, 1H), 6.23-5.96(m, 1H), 5.91-5.77(m, 1H) , 3.87-3.72(m, 1H), 3.14-2.97(m, 2H), 1.37-1.27(m, 2H), 1.14-1.03(m, 2H). LCMS R _T =0.655 min, m/z =326.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.655 min, and the measured ESI+ value [M+H] = 326.1.

The cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 2.856 min) (40 mg, 42%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.24–7.20 (m, 1H), 6.93–6.90 (m, 1H), 6.19–6.03 (m, 1H), 5.86–5.83 (m, 1H), 3.84–3.74 (m, 1H), 3.10–3.04 (m, 2H), 1.34–1.31 (m, 2H), 1.13–1.08 (m, 2H). LCMS R _T =0.864 min, m/z =325.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.864 min, and the measured ESI+ value [M+H] = 325.9.

SFC conditions: Column: Chiralcel OJ-3 150×4.6mm ID3μm. Mobile phase: A: CO2 _; B: ethanol (0.05% DEA). Gradient: 5% to 40% B, 5 min, then hold at 40%, 2.5 min, then 5% B, 2.5 min. Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 82

Cyclopropyl-[(5S,7S)-7-deuterated-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: cis-2-bromo-7-deutero-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole

To a cooled (0°C) solution of trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (400 mg, 1.42 mmol) in toluene (10 mL), diethylaminosulfur trifluoride (917 mg, 5.69 mmol) was added. The mixture was stirred at 0°C for 1 hour and quenched at 0°C by the addition of saturated sodium bicarbonate (30 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-12% ethyl acetate in petroleum ether) to give cis-2-bromo-7-deuterated-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (0.22 g, 55%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.43-7.38 (m, 3H), 7.27-7.24 (m, 2H), 5.47-5.42 (m, 1H), 3.63-3.51 (m, 1H), 2.94-2.84 (m, 1H).

Step 2: Cyclopropyl-[(5S,7S)-7-deuterated-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C under nitrogen, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.74 mL, 1.48 mmol) was added to a solution of cis-2-bromo-7-deuterated-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (210 mg, 0.74 mmol) and N-methoxy-N-methylcyclopropaneformamide (192 mg, 1.48 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 44-74%/ammonium hydroxide in water 0.05%) to give cyclopropyl-[cis-7-deuteron-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (55 mg, 27%) as a white solid. LCMS R _{_T} = 0.646 min, m/z = 273.2 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes): 0.646 min, ESI+ measured value [M+H] = 273.2.

The above cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

Cyclopropyl-[(5S,7S)-7-deuterated-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 4.354 min) (16.6 mg, 29%), is a white solid. ^¹H NMR (400 MHz, _CD₃OD ) δ 7.45–7.38 (m, 3H), 7.29–7.27 (m, 2H), 5.67–5.63 (m, 1H), 3.80–3.70 (m, 1H), 3.05–3.02 (m, 1H), 2.88–2.80 (m, 1H), 1.19–1.16 (m, 2H), 1.12–1.09 (m, 2H). LCMS R _T =0.738 min, m/z =273.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes): 0.738 min, ESI+ measured value [M+H] = 273.1.

SFC conditions: Column: Daicel Chiralpak AD-H (250mm*30mm, 5μm) ID 5μm; Mobile phase: A: CO2 B: Ethanol (0.1% _{NH3 H2O} IPA); Gradient: 30% to 30% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 83

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

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

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.739 min, and the measured ESI+ value [M+H] = 308.1.

The above trans mixture was further separated by a chiral SFC to obtain the definitively attributed:

[(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 2.773 min) (48.1 mg, 45%), is a white solid. ¹ HNMR (400MHz, CD ₃ OD) δ7.48-7.42 (m, 1H), 7.25-7.13 (m, 3H), 6.22-6.06 (m, 1H), 5.93-5.89 (m, 1H), 5.01-4.87 (m, 0.5H), 4.85-4 .82(m, 0.5H), 3.88-3.75(m, 1H), 3.51-3.42(m, 1H), 2.93-2.81(m, 1H), 1.75-1.64(m, 1H), 1.62-1.54(m, 1H). LC-MS R _T =0.852 min, m/z =308.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.852 min, and ESI ⁺ measured value [M+H] = 308.0.

The 1S,2R isomers were not separated.

SFC conditions: Column: Chiralcel OD-3 150×4.6mm I.D. 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃

A larger batch of the trans mixture (215 mg, 0.70 mmol) was separated by chiral SFC to obtain the specifically attributed:

[(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 2.445 min) (19.5 mg, 9%), is a white solid. ¹ HNMR (400MHz, CDCl ₃ )δ7.40-7.38(m, 1H), 7.18-7.15(m, 2H), 6.98-6.97(m, 1H), 6.13-6.11(m, 0.5H), 5.99-5.98(m, 0.5H), 5.87-5.85(m, 1H) , 5.05-5.04(m, 0.5H), 4.89-4.88(m, 0.5H), 3.73-3.67(m, 1H), 3.58-3.54(m, 1H), 3.01-2.95(m, 1H), 1.72-1.65(m, 2H). LC-MSR _T =1.763min, m/z=308.1(M+H) ⁺ .

LCMS (10-80% acetonitrile + 0.1% ammonia in water, within 3.0 min) retention time 1.763 min, ESI ⁺ measured value [M+H] = 308.1. Note: Under AD SFC conditions, the 1R,2S-isomer is peak 2 (retention time = 2.728 min).

SFC conditions: Column: Daicel Chiralpak AD-H (250mm*30mm, 5μm); Mobile phase: A: CO2, B: ethanol (0.1% _{NH3H2O methanol} ); Gradient: 15% to 15% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 84

Racemic-(1R,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxylonitrile

Step 1: trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid

A solution of sodium hydroxide (429 mg, 10.74 mmol) in water (3 mL) was added to a solution of diethyl trans-cyclopropane-1,2-dicarboxylate (2000 mg, 10.74 mmol) in ethanol (26 mL). The mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure. The aqueous residue was adjusted to pH 3 at 0 °C by adding an aqueous solution of hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give trans-2-ethoxycarbonylcyclopropanecarboxylic acid (820 mg, 48%) as a white solid. LCMS R _{_T} = 0.430 min, m/z = 159.1 [M+H]^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.430 min, and the measured ESI+ value [M+H] was 159.1.

Step 2: Ethyl trans-2-(methoxy(methyl)carbamoyl)cyclopropanecarboxylate

A mixture of 1-hydroxybenzotriazole (684 mg, 5.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1164 mg, 6.07 mmol), trans-2-ethoxycarbonylcyclopropanecarboxylic acid (800 mg, 5.06 mmol), N,O-dimethylhydroxylamine hydrochloride (740 mg, 7.59 mmol), and N,N-diisopropylethylamine (1634 mg, 12.65 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 16 hours and diluted with water (20 mL). The reaction mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give ethyl trans-2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate (600 mg, 59%) as a pale yellow oil. LCMS R _{_T} = 0.525 min, m/z = 202.2 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.525 min, and the measured ESI+ value [M+H] = 202.2.

Step 3: Ethyl trans-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl)cyclopropanecarboxylate

At 0 °C under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 2.84 mL, 5.67 mmol) was added dropwise to a solution of trans-2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate (571 mg, 2.84 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (400 mg, 1.42 mmol) in tetrahydrofuran (13 mL). After addition, the mixture was stirred at 0 °C for 2 hours and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The resulting 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 column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) to give ethyl trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxylate (350 mg, 72%) as a pale yellow oil. LCMS R _{_T} = 0.693 min, m/z = 344.1 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.693 min, and the measured ESI+ value [M+H] = 344.1.

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

A solution of lithium hydroxide (42 mg, 1.75 mmol) in water (2 mL) was added to a solution of trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxylate (100 mg, 0.29 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure. The aqueous residue was adjusted to pH 3 at 0 °C by adding aqueous hydrochloric acid (4 M). The mixture was then 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 trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxylic acid (90 mg, 98%) as a white solid. LCMS R _{_T} = 0.590 min, m/z = 316.2 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.590 min, and the measured ESI+ value [M+H] was 316.2.

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

A mixture of 1-hydroxybenzotriazole (34 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49 mg, 0.25 mmol), ammonium chloride (27 mg, 0.51 mmol), N,N-diisopropylethylamine (98 mg, 0.76 mmol), and trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropanecarboxylic acid (80 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25 °C for 18 hours and diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in methanol) to give trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxamide (75 mg, 94%) as a white solid. LCMS R _{_T} = 0.555 min, m/z = 315.1 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.555 min, and the measured ESI+ value [M+H] was 315.1.

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

Triethylamine (62 mg, 0.62 mmol) and trifluoroacetic anhydride (87 mg, 0.41 mmol) were added to a solution of trans-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropaneformamide (65 mg, 0.21 mmol) in 1,4-dioxane (3 mL). The reaction was stirred at 25 °C for 2 h and diluted with water (15 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (15-45% acetonitrile/0.05% ammonium hydroxide in water) to give specifically attributed racemic-(1R,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropaneformitrile (24.0 mg, 38%) as a white solid. ¹ HNMR (400MHz, CD ₃ OD) δ7.45-7.39(m, 3H), 7.32-7.30(m, 2H), 6.22-6.20(m, 0.5H), 6.08-6.06(m, 0.5H), 5.70-5.67(m, 1H), 3.81-3.75(m, 1H), 3.62-3.31(m, 1H), 2.90-2.75(m, 1H), 2.28-2.24(m, 1H), 1.68-1.63(m, 2H). LCMS R _T =0.957 min, m/z =297.2[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 2.0 minutes) was 0.957 min, and the measured ESI value [M+H] = 297.2.

Method 85

Cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: 1-(2,3-difluorophenyl)but-3-en-1-ol

Allyl magnesium chloride (2.0 M, in tetrahydrofuran, 46.0 mL, 92.0 mmol) was added to a cooled (0 °C) solution of 2,3-difluorobenzaldehyde (10.0 g, 70.4 mmol) in tetrahydrofuran (100 mL) over 30 minutes. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hours, then quenched by adding 100 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(2,3-difluorophenyl)but-3-en-1-ol (12.9 g, 99%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.27-7.24 (m, 1H), 7.11-7.06 (m, 2H), 5.87-5.77 (m, 1H), 5.20-5.08 (m, 3H), 2.62-2.47 (m, 2H).

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

To a stirred solution of 1-(2,3-difluorophenyl)but-3-en-1-ol (12.9 g, 70.6 mmol) in dichloromethane (20 mL), imidazole (9.6 g, 141.2 mmol) and tert-butyldimethylchlorosilane (12.8 g, 84.7 mmol) were added. After addition, the reaction mixture was stirred at 25 °C for 16 hours and quenched by adding water (100 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 to give crude tert-butyl-[1-(2,3-difluorophenyl)but-3-enoxy]-dimethyl-silane (21.0 g, 99%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.25-7.22 (m, 1H), 7.08-7.03 (m, 2H), 5.82-5.75 (m, 1H), 5.10-4.99 (m, 3H), 2.49-2.42 (m, 2H), 0.89 (s, 9H), 0.67 (s, 3H), -0.08 (s, 3H).

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(3,4-difluorophenyl)propanal

Osmium tetroxide (0.1 g, 0.39 mmol) was added to a solution of tert-butyl-[1-(2,3-difluorophenyl)but-3-enoxy]-dimethyl-silane (21.0 g, 70.4 mmol) in tetrahydrofuran/water (200 mL, 1:1). After stirring at 15 °C for 30 min, sodium periodate (60.2 g, 281.5 mmol) was added in fractions over 2 hours. The resulting mixture was stirred at 30 °C for another 2 hours, and then quenched by adding cold, saturated aqueous solution of sodium thiosulfate (300 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 (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-3% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propionaldehyde (15.0 g, 71%) as a yellow oil.

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

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in hexane, 22.0 mL, 54.9 mmol) was added dropwise to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (15.7 g, 50.4 mmol) in tetrahydrofuran (150 mL). The mixture was stirred at -78 °C for 30 min, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)propionaldehyde (15.0 g, 49.9 mmol) in tetrahydrofuran (20 mL) was added dropwise. After the addition, the mixture was stirred at -78 °C for 1.5 h, and then quenched by adding saturated aqueous solution of ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-12% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3-difluorophenyl)prop-1-ol (12.0 g, 45%) as a yellow oil.

Step 5: 2-Bromo-5-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A solution of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,4-difluorophenyl)prop-1-ol (56.0 g, 105.2 mmol) in trifluoroacetic acid (150 mL) was heated at 55 °C for 16 h and concentrated under reduced pressure. The residue was adjusted to pH 9 by adding a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 2-bromo-5-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (22.0 g, 66%) as a white solid.

Step 6: (5S,7S)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (5R,7R)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

At 0 °C, diethylaminosulfonate trifluoride (45.9 g, 284.7 mmol) was slowly added to a stirred solution of 2-bromo-5-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (30.0 g, 94.9 mmol) in toluene (200 mL). The reaction mixture was stirred at 0 °C for 16 hours, and then slowly added to a stirred solution of saturated sodium bicarbonate (200 mL) at 0 °C. The mixture was extracted with dichloromethane (3 x 150 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give cis-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole. This cis material was further separated by chiral SFC to obtain the specifically assigned:

(5S,7S)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 1, retention time = 2.828 min) (1.1 g, 3.7%), is a white solid, and (5R,7R)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.935 min) (1.1 g, 3.7%), is a white solid.

SFC conditions: Column: Chiral Cel OJ-H 150×4.6mm ID5μm; Mobile phase: A: CO2 _, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃.

Step 7: Cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.47 mL, 0.94 mmol) was added dropwise to a solution of (5S,7S)-2-bromo-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.47 mmol) and N-methoxy-N-methyl-cyclopropaneformamide (122 mg, 0.94 mmol) in tetrahydrofuran (3 mL). After addition, the mixture was stirred at 0 °C for 0.5 h and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (40-70% acetonitrile/0.225% formic acid in water) to give cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (49.1 mg, 34%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.22-7.16(m, 1H), 7.14-7.08(m, 1H), 6.75-6.72(m, 1H), 6.13-6.10(m, 0.5H), 5.99-5.96(m, 0.5H), 5.88- 5.84 (m, 1H), 3.74-3.67 (m, 1H), 3.09-3.04 (m, 1H), 2.99-2.92 (m, 1H), 1.36-1.31 (m, 2H), 1.14-1.09 (m, 2H). LC-MS _RT =0.666min, m/z=308.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.666 min, and the measured ESI+ value [M+H] = 308.1.

Method 86

Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: 1-(2,3,5-trifluorophenyl)but-3-en-1-ol

At 25 °C, tetrabutylammonium iodide (4.6 g, 12.49 mmol) and potassium allyl trifluoroborate (40.7 g, 137.42 mmol) were added to a solution of 2,3,5-trifluorobenzaldehyde (20.0 g, 124.93 mmol) in dichloromethane (120 mL) and water (120 mL). The mixture was stirred at 25 °C for 2 hours and extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure to give crude 1-(2,3,5-trifluorophenyl)but-3-en-1-ol (29.0 g, 100%) as a yellow oil.

Step 2: tert-butyldimethyl((1-(2,3,5-trifluorophenyl)but-3-en-1-yl)oxy)silane

To a mixture of 1-(2,3,5-trifluorophenyl)but-3-en-1-ol (20.5 g, 101.4 mmol) and imidazole (13.8 g, 202.7 mmol) in dichloromethane (120 mL), tert-butyldimethylchlorosilane (19.9 g, 131.9 mmol) was added. The mixture was stirred at 35 °C for 16 hours and diluted with dichloromethane (50 mL). The mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give tert-butyldimethyl((1-(2,3,5-trifluorophenyl)but-3-en-1-yl)oxy)silane (28.0 g, 87%) as a colorless oil.

Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2,3,5-trifluorophenyl)propanal

A mixture of tert-butyl-dimethyl-[1-(2,3,5-trifluorophenyl)but-3-enoxy]silane (5.0 g, 15.8 mmol) and osmium tetroxide (5.0 g, 19.7 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was stirred at 20 °C for 0.5 h, followed by the addition of sodium periodate (13.5 g, 63.2 mmol) in three portions over 0.5 h. After the addition, the reaction mixture was stirred at 20 °C for 3 h and quenched by the addition of a saturated aqueous solution of sodium thiosulfate (30 mL). The solids were removed by filtration. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)propanal (1.6 g, 32%) as a brown oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.78 (t, J = 2.2 Hz, 1H), 7.04-7.01 (m, 1H), 6.87-6.83 (m, 1H), 5.56-5.53 (m, 1H), 2.85-2.79 (m, 1H), 2.71-2.66 (m, 1H), 0.89 (s, 1H), 0.11 (s, 1H), -0.05 (s, 1H).

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

At -78°C under nitrogen, n-butyllithium (2.5 M, in hexane, 2.1 mL, 5.2 mmol) was added dropwise to a mixture of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (1.6 g, 5.2 mmol) in tetrahydrofuran (20 mL). After addition, the mixture was stirred at -78°C for 0.5 h, and a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)propionaldehyde (1.5 g, 4.71 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was stirred at -78°C for 4 h and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)prop-1-ol (1.78 g, 69%) as a yellow gel. LCMS R _{_T} = 1.056 min, m/z = 466.0 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 1.056 min, and the measured ESI+ value [M+H] was 466.0.

Step 5: 2-Bromo-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A solution of 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(2,3,5-trifluorophenyl)prop-1-ol (1.8 g, 3.2 mmol) in trifluoroacetic acid (250 mL, 32.3 mmol) was stirred at 50 °C for 1 hour, followed by the addition of trifluoromethanesulfonic acid (1 mL, 3.2 mmol). The resulting mixture was stirred at 50 °C for 3 hours, followed by concentration under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and adjusted to pH 8 by adding an aqueous solution of sodium hydroxide (20%). The separated organic layers were washed with water (2 x 50 mL) and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 40-60% ethyl acetate in petroleum ether) to give the crude product. The crude product was washed with methyl tert-butyl ether (20 mL) to give 2-bromo-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (0.55 g, 51%), as a brown solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.01–6.94 (m, 1H), 6.980–6.56 (m, 1H), 5.88–5.60 (m, 2H), 5.47–5.40 (m, 1H), 3.66–3.22 (m, 1H), 3.01–3.64 (m, 1H).

Step 6: (5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a mixture of 2-bromo-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (550 mg, 1.65 mmol) in toluene (10 mL), diethylaminosulfonium trifluoride (1.06 g, 6.6 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 16 hours, and then quenched by adding saturated aqueous sodium bicarbonate solution (50 mL). The resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 15-20% ethyl acetate in petroleum ether) to give racemic-(5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (197 mg, 36%) as a brown solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.00-6.95 (m, 1H), 6.52-6.48 (m, 1H), 6.08-5.92 (m, 1H), 5.81-5.77 (m, 1H), 3.71-3.57 (m, 1H), 2.90-2.80 (m, 1H).

The racemic compound was further separated by a chiral SFC to obtain the definitively assigned:

(5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.866 min) (80 mg, 41%), is a brown solid (together with the 5R,7R-isomer (peak 1, retention time = 2.345 min) (80 mg, 41%)).

SFC conditions: Column: Chiralpak IC-3 150×4.6mm ID, 3μm. Mobile phase: A: _CO2 , B: isopropanol (0.05% DEA). Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min. Flow rate: 2.5 mL/min. Column temperature: 35℃.

Step 7: Cyclopropyl-((5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 0.24 mL, 0.48 mmol) was added dropwise to a mixture of (5S,7S)-2-bromo-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (80 mg, 0.24 mmol), N-methoxy-N-methyl-cyclopropaneformamide (62 mg, 0.48 mmol), in tetrahydrofuran (3 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70/0.05% ammonium hydroxide in water) to give cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (11 mg, 14%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.29-7.26(m, 1H), 6.78-6.75(m, 1H), 6.23-6.06(m, 1H), 5.96-5.93(m, 1H ), 3.88-3.80(m, 1H), 3.07-3.04(m, 1H), 2.96-2.89(m, 1H), 1.22-1.11(m, 4H). LCMS R _T =1.029 min, m/z =326.2[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 1.029 min, and the measured ESI+ value [M+H] was 326.2.

Method 87

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

Step 1: (1E)-2-methylpropanal oxime

Hydroxylamine hydrochloride (231.3 g, 3328.3 mmol) and sodium carbonate (587.9 g, 5547.1 mmol) were added to a solution of isobutyraldehyde (200.0 g, 2773.5 mmol) in water (2.0 L). After addition, the reaction mixture was stirred at 20 °C for 4 hours and filtered. The filtrate was extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L), dried over sodium sulfate, and concentrated under reduced pressure to give crude (1E)-2-methylpropionaldehyde oxime (220 g, 91%) as a colorless oil.

Step 2: Methyl 3-isopropyl-4,5-dihydroisoxazole-5-carboxylate

At 25°C, pyridine (9.73 mL, 120.5 mmol) and (1E)-2-methylpropionaldehyde oxime (175.0 g, 2008.7 mmol) were added to a solution of n-chlorosuccinimide (268.2 g, 2008.7 mmol) in chloroform (1500 mL). After stirring at 25°C for 0.5 hours, a solution of methyl acrylate (227.2 mL, 2506.9 mmol) and triethylamine (292.4 mL, 2109.2 mmol) in chloroform (100 mL) was added dropwise over 30 minutes at 25°C. The reaction mixture was stirred at 25°C for 16 hours and diluted with dichloromethane (1000 mL). The separated organic layer was washed with water (3 x 500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give methyl 3-isopropyl-4,5-dihydroisoxazole-5-carboxylate (240 g, 70%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.98-4.93 (m, 1H), 3.76 (s, 3H), 3.21-3.19 (m, 2H), 2.75-2.66 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H).

Step 3: 3-Hydroxy-5-isopropyl-pyrrolidone-2-one

A mixture of methyl 3-isopropyl-4,5-dihydroisoxazole-5-carboxylate (240.0 g, 1402 mmol) and palladium (10% on carbon, 14.9 g) in ethanol (2 L) was hydrogenated at 45 °C (50 psi) for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-isopropyl-pyrrolidine-2-one (70 g, 35%) as a white solid.

Step 4: 3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidine-2-one

To a mixture of 3-hydroxy-5-isopropylpyrrolidone-2-one (49.0 g, 342.2 mmol) and imidazole (69.9 g, 1026.7 mmol) cooled (0 °C) in dichloromethane (1120 mL), tert-butyldimethylchlorosilane (77.4 g, 513.3 mmol) was added. After addition, the mixture was stirred at 25 °C for 16 hours and then poured into water (1000 mL). The separated organic layer was washed with brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-isopropylpyrrolidone-2-one (35.0 g, 40%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.63 (s, 1H), 4.32-4.28 (m, 1H), 3.17-3.11 (m, 1H), 2.46-2.40 (m, 1H), 1.66-1.60 (m, 2H), 0.92-0.89 (m, 14H), 0.15 (d, J = 10.4Hz, 6H).

Step 5: 1-Amino-3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidine-2-one

Sodium hydride (60%, 1.2 g, 29.13 mmol) was added to a cooled (0 °C) solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidine-2-one (5.0 g, 19.42 mmol) in N,N-dimethylformamide (200 mL). After addition, the mixture was stirred at 0 °C for 30 min, followed by the addition of o-(diphenylphosphoyl)hydroxylamine (6.8 g, 29.13 mmol). The resulting mixture was stirred at 20 °C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidine-2-one (5.3 g, 100%)) as a yellow oil. LCMS R _{_T} = 1.178 min, m/z = 273.3 [M+H]^⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2 minutes) was 1.178 min, and the measured ESI+ value [M+H] was 273.3.

Step 6: 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate

To a solution of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-pyrrolidine-2-one (5.28 g, 19.38 mmol) in ethanol (250 mL), ethyl 2-ethoxy-2-imino-ethyl (8.44 g, 58.14 mmol) was added. The reaction mixture was stirred at 90 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl (7.10 g, 98%) as a yellow oil. LCMS R _{_T} = 0.948 min, m/z = 372.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.948 min, and the measured ESI+ value [M+H] = 372.2.

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

To a solution of ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (7.1 g, 19.11 mmol) in toluene (140 mL), p-toluenesulfonic acid monohydrate (4.4 g, 22.93 mmol) was added. The reaction mixture was stirred at 120 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give ethyl 7-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (6.6 g, 98%) as a yellow oil. LCMS R _{_T} = 0.952 min, m/z = 354.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.952 min, and the measured ESI+ value [M+H] = 354.2.

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

At 25 °C, tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 18.67 mL, 18.67 mmol) was added to a solution of 7-[tert-butyl(dimethyl)silyl]oxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (6.6 g, 18.67 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 40 °C for 16 hours and concentrated. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% ethyl acetate in petroleum ether) to give 2.8 g, 62.7% cis-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester, as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ )δ5.34-5.31(m, 1H), 4.47-4.43(m, 2H), 4.26-4.24(m, 1H), 3.14-3.09(m, 1H), 2. 48-2.42 (m, 2H), 1.43-1.39 (m, 3H), 1.07 (d, J=7.2Hz, 3H), 0.92 (d, J=7.2Hz, 3H).

Step 8: Ethyl trans-5-isopropyl-7-(4-nitrobenzoyl)oxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Diisopropyl azodicarbonate (5.0 mL, 25.08 mmol) was added to a mixture of cis-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.0 g, 8.36 mmol), 4-nitrobenzoic acid (2.1 g, 12.54 mmol), and triphenylphosphine (6.6 g, 25.08 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-17% ethyl acetate in petroleum ether) to give ethyl trans-5-isopropyl-7-(4-nitrobenzoyl)oxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.5 g, 77%) as a yellow solid.

Step 9: Ethyl trans-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of potassium carbonate (1.23 g, 8.88 mmol) and trans-5-isopropyl-7-(4-nitrobenzoyl)oxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.3 g, 5.92 mmol) in ethanol (10 mL)/tetrahydrofuran (5 mL)/water (5 mL) was stirred at 25 °C for 1 hour and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude trans-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.10 g, 78%) as a colorless oil.

Step 10: Ethyl cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

At 0 °C under a nitrogen atmosphere, diethylaminosulfonate trifluoride (2.23 mL, 16.72 mmol) was added to a mixture of trans-7-hydroxy-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.0 g, 4.18 mmol) in dichloromethane (20 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous sodium bicarbonate solution (200 mL). The solution was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 7% ethyl acetate in petroleum ether) to give cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (550 mg, 55%) as a colorless oil.

Step 11: cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (550 mg, 2.28 mmol) and lithium hydroxide hydrate (191 mg, 4.56 mmol) in methanol (10 mL)/tetrahydrofuran (5 mL)/water (5 mL) was stirred at 20 °C for 1 hour and concentrated under reduced pressure. The residue was diluted with water (20 mL) and washed with ethyl acetate (20 mL). The aqueous phase was adjusted to pH 6 by adding hydrochloric acid (1 M) and then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure to give crude cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (420 mg, 86%) as a colorless oil.

Step 12: cis-7-fluoro-5-isopropyl-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxylic acid (420 mg, 1.97 mmol), N,N-diisopropylethylamine (1.05 mL, 5.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (453 mg, 2.36 mmol), 1-hydroxybenzotriazole (160 mg, 1.18 mmol), and N,O-dimethylhydroxylamine hydrochloride (384 mg, 3.94 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 16 hours and quenched by the addition of water (20 mL). The mixture was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 50-60%) to give cis-7-fluoro-5-isopropyl-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (200 mg, 40%) as a yellow oil. LCMS R _{_T} = 0.692 min, m/z = 257.1 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.692 min, and the measured ESI+ value [M+H] = 257.1.

Step 13: Cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 1.0 mL, 0.50 mmol) was added to a cooled (0 °C) solution of cis-7-fluoro-5-isopropyl-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (200 mg, 0.78 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at 25 °C for 1 hour and quenched by adding 20 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in petroleum ether) to give cyclopropyl.[cis-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (100 mg, 52%) as a white solid. This cis mixture was further separated by chiral SFC to give the specifically assigned:

Cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 5.136 min) (24 mg, 23%) is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ5.99-5.83(m, 1H), 4.39-4.34(m, 1H), 3.22-3.18(m, 1H), 3.12-3.08(m, 1H), 2.72-2.62(m, 1H), 2. 42-2.38 (m, 1H), 1.34-1.33 (m, 2H), 1.13-1.10 (m, 2H), 1.08 (d, J=6.8Hz, 3H), 0.94 (d, J=6.8Hz, 3H). LCMS R _T =0.822 min, m/z =238.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.822 min, and the measured ESI+ value [M+H] was 238.0.

SFC conditions: Column: Lux 3u Cellulose-2 150x4.6mm; Mobile phase: A: CO2 _, B: Methanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 88

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

Step 1: (E)-Cyclopropane-formaldehyde oxime

Sodium carbonate (166.3 g, 1569.4 mmol) and hydroxylamine hydrochloride (59.5 g, 856.04 mmol) were added to a solution of cyclopropaneformaldehyde (50.0 g, 713.37 mmol) in ethanol (500 mL). The reaction mixture was stirred at 25 °C for 3 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water (1000 mL) and extracted with ethyl acetate (3 x 600 mL). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude (E)-cyclopropaneformaldehyde oxime (40 g, 66%) as a colorless oil.

Step 2: Methyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate

A mixture of pyridine (2.85 mL, 35.25 mmol), N-chlorosuccinimide (78.5 g, 587.54 mmol), and (E)-cyclopropaneformaldehyde oxime (50 g, 587.54 mmol) in chloroform (500 mL) was stirred at 25 °C for 2 hours, followed by the addition of a solution of methyl acrylate (66.45 mL, 733.25 mmol) and triethylamine (85.35 mL, 615.75 mmol) in chloroform (100 mL). The reaction mixture was stirred at 25 °C for 12 hours and quenched by the addition of water (200 mL). The resulting mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate (75.0 g, 76%) as a colorless oil.

Step 3: 5-Cyclopropyl-3-hydroxy-pyrrolidone-2-one

A mixture of methyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate (35.0 g, 206.88 mmol) and platinum oxide (6.1 g, 26.89 mmol) in ethylene glycol (300 mL) was stirred at 25 °C for 48 hours under a hydrogen atmosphere (30 psi) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give 5-cyclopropyl-3-hydroxy-pyrrolidine-2-one (15.5 g, 53%) as a colorless oil. LCMSR _T = 0.297 min, m/z = 142.1 [M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 0.297 min, and the measured ESI+ value [M+H] = 142.1.

Step 4: 3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidine-2-one

To a mixture of 5-cyclopropyl-3-hydroxypyrrolidone-2-one (13.0 g, 92.09 mmol) and imidazole (18.8 g, 276.26 mmol) cooled (0 °C) in dichloromethane (150 mL), tert-butyldimethylchlorosilane (20.8 g, 138.13 mmol) was added. The mixture was stirred at 25 °C for 16 hours, then washed with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidone-2-one (10.2 g, 43%) as a colorless oil.

Step 5: 1-Amino-3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidine-2-one

Sodium hydride (60%, in mineral oil, 2.4 g, 59.9 mmol) was added to a cooled (0 °C) solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidine-2-one (10.2 g, 39.93 mmol) in N,N-dimethylformamide (150 mL). The mixture was stirred at 0 °C for 30 min, and then O-(diphenylphosphoyl)hydroxylamine (14.0 g, 59.9 mmol) was added. The resulting mixture was stirred at 10 °C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give crude (1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidine-2-one (10.5 g, 97%) as a yellow oil. LCMS R _T = 0.810 min, m/z = 271.2 [M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.8 to 10 minutes, and the measured ESI+ value [M+H] was 271.2.

Step 6: 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate

A mixture of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-pyrrolidine-2-one (10.5 g, 38.83 mmol) and 2-ethoxy-2-imino-ethyl acetate (14.1 g, 97.06 mmol) in ethanol (150 mL) was stirred at 90 °C for 12 hours and concentrated under reduced pressure to give crude 2-[[3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (10.0 g, 70%) as a yellow oil. LCMS R _{_T} = 0.804 min, m/z = 370.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.804 min, and the measured ESI+ value [M+H] = 370.2.

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

To a solution of (2Z)-2-amino-2-[3-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-2-oxo-pyrrolidine-1-yl]imino-ethyl acetate (10.0 g, 27.06 mmol) in toluene (120 mL), p-toluenesulfonic acid (5.6 g, 32.47 mmol) was added. The reaction mixture was stirred at 120 °C for 16 h and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were concentrated under reduced pressure to give crude 7-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (9.5 g, 99%) as a red oil. LCMS R _T =0.928 min, m/z =352.2[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.928 min, and the measured ESI+ value [M+H] = 352.2.

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

To a solution of 7-[tert-butyl(dimethyl)silyl]oxy-5-cyclopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (9.5 g, 27.03 mmol) in tetrahydrofuran (100 mL), tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 27.0 mL, 27.0 mmol) was added. The reaction mixture was stirred at 40 °C for 12 hours and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give ethyl 5-cyclopropyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.2 g, 34%) as a yellow oil. LCMS R _{_T} = 0.521 min, m/z = 238.1 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.521 min, and the measured ESI+ value [M+H] = 238.1.

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

To a cooled (0°C) solution of ethyl 5-cyclopropyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (2.0 g, 8.43 mmol) in dichloromethane (20 mL), diethylaminosulfur trifluoride (3.26 mL, 25.29 mmol) was added. The reaction mixture was stirred at 0°C for 12 hours and quenched by adding water (5.0 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (220 mg, 11%) as a yellow oil. LCMS R _{_T} = 0.701 min, m/z = 240.1 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.701 min, and the measured ESI+ value [M+H] was 240.1.

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

A mixture of lithium hydroxide monohydrate (105 mg, 2.51 mmol) and cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (200 mg, 0.84 mmol) in ethanol (0.50 mL)/water (0.50 mL)/tetrahydrofuran (0.50 mL) was stirred at 25 °C for 2 hours and concentrated under reduced pressure. The aqueous residue was adjusted to pH 7 by adding aqueous hydrochloric acid (1 M) and concentrated under reduced pressure to give crude cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (175 mg, 99%) as a yellow oil. LCMS R _T =0.452 min, m/z =212.1 [M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.452 min, and the measured ESI+ value [M+H] = 212.1.

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

A mixture of cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxylic acid (175 mg, 0.83 mmol), 1-hydroxybenzotriazole (56 mg, 0.41 mmol), N,O-dimethylhydroxylamine hydrochloride (121 mg, 1.24 mmol), N,N-diisopropylethylamine (0.34 mL, 2.07 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190.6 mg, 0.99 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 16 hours and quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (3 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 column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in petroleum ether) to give cis-5-cyclopropyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (75 mg, 36%) as a colorless oil. LCMS R _{_T} = 0.604 min, m/z = 255.1 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.604 min, and the measured ESI+ value [M+H] = 255.1.

Step 12: Cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 1.24 mL, 0.62 mmol) was added to a cooled (0 °C) solution of cis-5-cyclopropyl-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (65 mg, 0.26 mmol) in tetrahydrofuran (5 mL). After addition, the mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (3 mL). The resulting mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.4) to give cyclopropyl-[cis-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (50 mg, 83%) as a yellow oil. LCMS R _{_T} = 0.676 min, m/z = 236.1 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.676 min, and the measured ESI+ value [M+H] = 236.1.

The cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

Cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 2.841 min) (3.1 mg, 6%), is a colorless oil. ^¹H NMR (400 MHz, _CD₃OD ) δ 6.05–5.89 (m, 1H), 4.02–3.95 (m, 1H), 3.51–3.35 (m, 1H), 3.14–3.10 (m, 1H), 2.78–2.70 (m, 1H), 1.26–1.12 (m, 5H), 0.79–0.67 (m, 3H), 0.58–0.52 (m, 1H). LCMS R _T =0.677 min, m/z =236.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.677 min, and the measured ESI+ value [M+H] = 236.1.

SFC conditions: Column: DAICL CHIRALPAK IC (250 mm * 30 mm, 5 μm); Mobile phase: A: CO2, B: 0.1% NH3H2O IPA; Start with 40% B, end with 40% B; Gradient time: Gradient: 40% to 40% B, 5 min, and hold at 40%, 2.5 min; Flow rate: 60 mL/min; Column temperature: 35℃.

Method 89

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

Nickel (10 mg, 0.17 mmol) was added to a solution of cyclopropyl-[(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (50 mg, 0.17 mmol) in methanol (2.0 mL). The mixture was stirred at 20 °C for 2 hours under a hydrogen atmosphere (15 psi) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (water (0.05% ammonium hydroxide v/v)-acetonitrile: 33-63%) to give specifically attributed cyclopropyl-[(5S,7S)-7-deuterated-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (14.8 mg, 33%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.41-7.36(m, 3H), 7.14-7.11(m, 2H), 5.52-5.48(m, 1H), 3.28-3.21(m, 1H) , 3.06-3.00(m, 2H), 2.70-2.65(m, 1H), 1.30-1.27(m, 2H), 1.06-1.03(m, 2H). LCMS R _T =1.551 min, m/z =255.1[M+H] ⁺ .

LCMS (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) retention time 1.551 min, ESI ⁺ measured value [M+H] = 255.1.

Method 90

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

Step 1: 1-Nitrobut-2-ol

At 25°C, propionaldehyde (50.0 g, 860.9 mmol) was added to a mixture of nitromethane (52.6 g, 860.9 mmol), hexadecyltrimethylammonium chloride (27.6 g, 86.1 mmol), and sodium hydroxide (34.4 g, 860.9 mmol) in water (2.5 L). The mixture was stirred at 25°C for 4 hours, then sodium chloride (700 g) was added, and the mixture was extracted with ethyl acetate (2 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-nitrobut-2-ol (80.0 g, 78%) as a light brown oil. The crude product was used directly in the next step without further purification.

Step 2: tert-butyldimethyl((1-nitrobut-2-yl)oxy)silane

At 25°C under nitrogen, tert-butyldimethylchlorosilane (53.2 g, 352.6 mmol) was added to a stirred solution of 1-nitrobut-2-ol (40.0 g, 335.8 mmol) and imidazole (48.0 g, 705.2 mmol) in N,N-dimethylformamide (300 mL). After addition, the reaction mixture was stirred at 25°C for 5 hours. The mixture was then diluted with water (400 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give tert-butyl-dimethyl-[1-(nitromethyl)propoxy]silane (28.0 g, 36%) as a light brown oil.

Step 3:

3-(1-((tert-butyldimethylsilyl)oxy)propyl)-4,5-dihydroisoxazole-5-carboxylic acid methyl ester

To a mixture of methyl acrylate (54.4 mL, 599.9 mmol), di-tert-butyl dicarbonate (39.3 g, 179.9 mmol), and 4-dimethylaminopyridine (1.5 g, 12.0 mmol) in acetonitrile (500 mL), a solution of tert-butyl-dimethyl-[1-(nitromethyl)propoxy]silane (28.0 g, 119.9 mmol) in acetonitrile (10 mL) was added. The mixture was stirred at 25 °C for 5 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give methyl 3-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-4,5-dihydroisoxazole-5-carboxylate (17.0 g, 47%) as a brown oil.

Step 4: 5-(1-((tert-butyldimethylsilyl)oxy)propyl)-3-hydroxypyrrolidine-2-one

A mixture of ethyl 3-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-4,5-dihydroisoxazol-5-carboxylate (17.0 g, 53.89 mmol) and palladium (10% on carbon, 3.0 g) in ethanol (500 mL) was stirred at 40 °C for 48 hours under a hydrogen atmosphere (50 psi) and filtered. The filtrate was concentrated under reduced pressure to give crude 5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-3-hydroxy-pyrrolidine-2-one (12.0 g, 82%) as a white solid.

Step 5: 3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)pyrrolidine-2-one

To a solution of 5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-3-hydroxy-pyrrolidone-2-one (8.8 g, 32.2 mmol) in dichloromethane (440 mL), tetrabutylammonium bromide (519 mg, 1.6 mmol), sodium hydroxide aqueous solution (30%, 60 mL), and benzyl bromide (8.3 g, 48.3 mmol) were added. After addition, the mixture was stirred at 40 °C for 18 hours. The mixture was then poured into water (200 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 80% ethyl acetate in petroleum ether) to give 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]pyrrolidine-2-one (6.8 g, 58%) as a colorless oil.

Step 6: 1-Amino-3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)pyrrolidine-2-one

At 0 °C, sodium hydride (6.80 g, 18.7 mmol) was added to a solution of 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]pyrrolidine-2-one (6.80 g, 18.7 mmol) in N,N-dimethylformamide (150 mL). After stirring at 25 °C for 20 min, o-(diphenylphosphoyl)hydroxylamine (6.50 g, 28.1 mmol) was added to the mixture, and stirring was continued at 25 °C for another 18 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]pyrrolidine-2-one (7.10 g, 100%) as a pale yellow solid. LC-MS R _T =0.876 min, m/z =379.3[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.876 min, and the measured ESI+ value [M+H] = 379.3.

Step 7: Ethyl 2-((3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)-2-oxopyrrolidine-1-yl)amino)-2-iminoethyl acetate

A mixture of 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl)oxypropyl]pyrrolidine-2-one (1.87 g, 4.94 mmol) and 2-ethoxy-2-imino-ethyl acetate (1.79 g, 12.35 mmol) in ethanol (25 mL) was stirred at 90 °C for 33 h and concentrated under reduced pressure to give crude 2-((3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)-2-oxopyrrolidine-1-yl)amino)-2-iminoethyl acetate (2.36 g, 99%) as a yellow oil. The crude product was used in the next step without further purification. LC-MS R _{_T} = 1.037 and 1.061 min, m/z = 478.2 [M+H] ^⁺ .

LCMS retention times (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 1.037 and 1.061 min, and the measured ESI+ value [M+H] was 478.2.

Step 8: 7-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)propyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

To a solution of 2-[[3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (2.2 g, 4.61 mmol) in toluene (50 mL), p-toluenesulfonic acid monohydrate (1.1 g, 5.53 mmol) was added. The reaction mixture was stirred at 120 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (0.9 g, 43%) as a colorless oil. LC-MS _RT =0.935min, m/z=460.3[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.935 min, and the measured ESI+ value [M+H] was 460.3.

Step 9: 7-(benzyloxy)-5-(1-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

To a solution of 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxypropyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxylic acid ethyl ester (800 mg, 1.74 mmol) in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 5.22 mL, 5.22 mmol) was added. The mixture was stirred at 25 °C for 18 hours and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 7-benzyloxy-5-(1-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (70 mg, 93%) as a brown oil. This crude product was used in the next step without further purification.

Step 10: 7-(benzyloxy)-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

At 0 °C, ethyl 7-benzyloxy-5-(1-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (600 mg, 1.74 mmol) and sodium bicarbonate (584 mg, 6.95 mmol) in dichloromethane (20 mL) were added with Desmartin oxidant (1473 mg, 3.47 mmol). The reaction mixture was stirred at 0 °C for 40 min and then quenched by adding 20 mL of saturated aqueous sodium sulfite solution. The separated organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (in 50% ethyl acetate in petroleum ether, _Rf = 0.3) to give ethyl 7-benzyloxy-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (590 mg, 99%) as a light brown oil. LC-MS R _{_T} = 0.834 min, m/z = 344.1 [M+H] ^⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.834 min, and the measured ESI+ value [M+H] = 344.1.

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

A mixture of ethyl 7-benzyloxy-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (450 mg, 1.31 mmol) in 2,2,2-trifluoroacetic acid (20 mL) was heated at 120 °C for 3 hours and concentrated under reduced pressure. The residue was redissolved in dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (15 mL), and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate in petroleum ether, _Rf = 0.3) to give ethyl 7-hydroxy-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (220 mg, 66%) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ )δ5.43-5.39 (m, 1H), 5.25-5.21 (m, 1H), 4.50-4.43 (m, 2H), 3.05-3.01 (m, 2H), 2.75-2.55 (m, 2H), 1.44-1.40 (m, 3H), 1.13-1.08 (m, 3H). LC-MS R _T =0.530 and 0.564 min, m/z=254.1[M+H] ⁺ .

LCMS retention times (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 0.530 and 0.564 min, with an ESI+ measured value [M+H] = 254.1.

Step 12: Ethyl cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of ethyl 7-hydroxy-5-propionyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (220 mg, 0.87 mmol) and diethylaminosulfur trifluoride (140 mg, 0.87 mmol) was stirred at 10 °C for 2 hours, and then quenched by adding saturated aqueous sodium bicarbonate solution (15 mL). The resulting mixture was extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (in 50% ethyl acetate in petroleum ether, _Rf = 0.4 (for the cis isomer) and _Rf = 0.6 (for the trans isomer) to give trans-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ethyl ester (60 mg, 25%) and cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate ethyl ester (60 mg, 25%), both of which were brown oils.

Step 13: cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

Ethyl cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (55 mg, 0.20 mmol) was added to a solution of tetrahydrofuran (2 mL), ethanol (2 mL), and water (0.5 mL). Lithium hydroxide monohydrate (83 mg, 1.98 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours and then concentrated under reduced pressure. The residue was diluted with ice water (20 mL) and adjusted to pH 3 by adding aqueous hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure to give crude cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (40 mg, 81%) as a light pink solid.

Step 14: cis-5-(1,1-difluoropropyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of cis-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxylic acid (40 mg, 0.16 mmol), N,O-dimethylhydroxylamine hydrochloride (31 mg, 0.32 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazololo[4,5-b]pyridinium 3-oxide hexafluorophosphate (64 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.48 mmol) in N,N-dimethylformamide (1 mL) was stirred at 20 °C for 2 hours and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.3) to give cis-5-(1,1-difluoropropyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (27 mg, 58%) as a colorless oil. LC-MS R _{_T} = 0.714 min, m/z = 293.1 [M+H] ^⁺ .

LCMS retention time (5-95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.714 min, and the measured ESI+ value [M+H] = 293.1.

Step 15: Cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 0.92 mL, 0.46 mmol) was added to a solution of cis-5-(1,1-difluoropropyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (27 mg, 0.09 mmol) in tetrahydrofuran (0.5 mL). After addition, the mixture was stirred at 0 °C for 1 hour and quenched by adding methanol (10 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.6) to give cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (cis mixture) (9.9 mg, 35%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD)δ5.97-5.80(m,1H),4.90-4.78(m,1H),3.45-3.25(m,1H),3.05-2.95(m,1H) ), 2.95-2.75(m, 1H), 2.28-2.00(m, 2H), 1.20-1.11(m, 2H), 1.07-0.98(m, 5H). LC-MS _RT =0.766min, m/z=274.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.766 min, and the measured ESI+ value [M+H] = 274.1.

Step 16: Cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[(5R,7R)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (58 mg) was separated by chiral SFC to obtain the specifically assigned methyl ketone.

Cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 5.085 min) (8.2 mg, 14%) is a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ6.02-5.84(m, 1H), 4.71-4.66(m, 1H), 3.33-3.23(m, 1H), 3.19-3.07(m, 2H), 2.34-2.26(m, 1H), 2.18-2.01(m, 1H), 1.35-1.25(m, 2H), 1.18(s, 1H), 1.17-1.15(m, 2H), 1.14-1.11(m, 2H). LC-MS R _T =0.818 min, m/z =273.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.818 min, and the measured ESI+ value [M+H] = 273.9.

Cyclopropyl-[(5R,7R)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 3.815 min) (13.9 mg, 23%) is a white solid. ¹ H NMR (400MHz, CDCl3) δ6.04-5.81 (m, 1H), 4.69-4.61 (m, 1H), 3.43-3.23 (m, 1H), 3.20-3.00 (m, 2H), 2.43 -2.22(m, 1H), 2.20-2.00(m, 1H), 1.35-1.25(m, 2H), 1.18(s, 1H), 1.16-1.15(m, 2H), 1.15-1.12(m, 2H). LC-MS R _T =0.815 min, m/z =273.9[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.815 min, and the measured ESI+ value [M+H] = 273.9.

Method 91

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

Step 1: Methyl 2-cyclopropyloxacyclopropane-2-carboxylate

Cyclopropane formaldehyde (35.0 g, 499.36 mmol) was added to a mixture of sodium methoxide (40.5 g, 749.04 mmol) and methanol (250 mL) at -10 °C, followed by dropwise addition of methyl chloroacetate (81.3 g, 749.04 mmol) over 2 hours. After addition, the mixture was stirred at 25 °C for 16 hours and quenched by the addition of acetic acid. The resulting mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude methyl 2-cyclopropyloxetane-2-carboxylate as a brown oil. The oil was distilled under reduced pressure to give methyl 2-cyclopropyloxetane-2-carboxylate (38 g, 53%) as a colorless oil.

Step 2: (Z)-2-Cyclopropylacetaldehyde oxime

2-Cyclopropyloxecyclopropane-2-carboxylate (59.0 g, 415.05 mmol) was added to a solution of sodium hydroxide (19.9 g, 498.07 mmol) in water (70 mL) over 2 hours at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour, and hydroxylamine sulfate (37.5 g, 228.28 mmol) was added over 30 minutes at 25 °C. The mixture was stirred at 25 °C for 2 hours and diluted with water (300 mL). The solution was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 50% ethyl acetate in petroleum ether) to give (Z)-2-cyclopropylacetaldehyde oxime (23.5 g, 57%) as a white solid. LC-MS _RT =0.265min, m/z=100.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.265 min, and the measured ESI+ value [M+H] = 100.1.

Step 3: Methyl 3-(cyclopropylmethyl)-4,5-dihydroisoxazole-5-carboxylate

A solution of pyridine (0.85 mL, 10.59 mmol), N-chlorosuccinimide (28.3 g, 211.84 mmol), and (Z)-2-cyclopropylacetaldehyde oxime (21.0 g, 211.84 mmol) in chloroform (200 mL) was stirred at 25 °C for 2 hours. Then, a solution of methyl acrylate (23.96 mL, 264.38 mmol) and triethylamine (30.77 mL, 222.01 mmol) in chloroform (30 mL) was added. The mixture was stirred at 25 °C for 16 hours and diluted with water (300 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give methyl 3-(cyclopropylmethyl)-4,5-dihydroisoxazole-5-carboxylate (21.0 g, 54%) as a colorless oil. LC-MS R _{_T} = 0.565 min, m/z = 184.1 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.565 min, and the measured ESI+ value [M+H] was 184.1.

Step 4: 5-(cyclopropylmethyl)-3-hydroxypyrrolidone-2-one

Methyl 3-(cyclopropylmethyl)-4,5-dihydroisoxazole-5-carboxylate (18.0 g, 98.25 mmol) was stirred in a mixture of methanol and palladium (10.5 g on carbon) at 25 °C for 16 h under hydrogen (15 psi) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give 5-(cyclopropylmethyl)-3-hydroxy-pyrrolidine-2-one (6.2 g, 41%) as a colorless oil. LC-MSR _T = 0.272 min, m/z = 165.2 [M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.272 min, and the measured ESI+ value [M+H] = 165.2.

Step 5: 3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)pyrrolidine-2-one

To a solution of 5-(cyclopropylmethyl)-3-hydroxypyrrolidine-2-one (5.7 g, 36.73 mmol) and imidazole (5.5 g, 80.80 mmol) in dichloromethane (50 mL), tert-butyldimethylchlorosilane (11.1 g, 73.46 mmol) was added. The mixture was stirred at 20 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidine-2-one (7.7 g, 78%) as a white solid. LC-MS R _{_T} = 0.872 min, m/z = 270.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.872 min, and the measured ESI+ value [M+H] = 270.2.

Step 6: 1-Amino-3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)pyrrolidone-2-one

Sodium hydride (60%, 1.6 g, 40.08 mmol) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidine-2-one (7.2 g, 26.72 mmol) in N,N-dimethylformamide (10 mL). After stirring at 0 °C for 30 min, O-(diphenylphosphoyl)hydroxylamine (9.3 g, 40.08 mmol) was added, and the mixture was stirred at 10 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidine-2-one (7.5 g, 99%) as a yellow oil. LC-MS R _{_T} = 0.772 min, m/z = 285.2 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.772 min, and the measured ESI+ value [M+H] was 285.2.

Step 7: (Z)-2-amino-2-((3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)-2-oxopyrrolidone-1-yl)imino)ethyl acetate

A mixture of 1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)pyrrolidine-2-one (7.1 g, 24.96 mmol) and 2-ethoxy-2-imino-ethyl acetate (9.1 g, 62.4 mmol) in ethanol (150 mL) was stirred at 90 °C for 12 hours and concentrated under reduced pressure to give crude (Z)-2-amino-2-((3-((tert-butyldimethylsilyl)oxy)-5-(cyclopropylmethyl)-2-oxopyrrolidine-1-yl)imino)ethyl acetate (9.2 g, 96%) as a yellow oil. LC-MS R _{_T} = 0.783 min, m/z = 384.3 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.783 min, and the measured ESI+ value [M+H] = 384.3.

Step 8: ethyl 5-(cyclopropylmethyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of (Z)-2-amino-2-[3-[tert-butyl(dimethyl)silyl]oxy-5-(cyclopropylmethyl)-2-oxo-pyrrolidine-1-yl]imino-ethyl acetate (9.2 g, 23.99 mmol) and p-toluenesulfonic acid (5.0 g, 28.78 mmol) in toluene (100 mL) was stirred at 120 °C for 16 h and diluted with water (200 mL). The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were concentrated under reduced pressure to give crude ethyl 5-(cyclopropylmethyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (4.9 g, 82%) as a red oil. LC-MS R _{_T} = 0.540 min, m/z = 252.2 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.540 min, and the measured ESI+ value [M+H] = 252.2.

Step 9: Ethyl cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 5-(cyclopropylmethyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.0 g, 11.98 mmol) in dichloromethane (150 mL), diethylaminosulfur trifluoride (5.8 g, 35.94 mmol) was added. The mixture was stirred at 0 °C for 16 hours and quenched by adding saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give ethyl trans-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (650 mg, 21%) and ethyl cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (850 mg, 28%), both as yellow oils. (TLC: 33% ethyl acetate in petroleum ether, _Rf = 0.35 (for the cis isomer) and _Rf = 0.85 (for the trans isomer)).

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

A mixture of ethyl cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (750 mg, 2.96 mmol) and lithium hydroxide monohydrate (1.2 g, 29.61 mmol) in ethanol (3 mL) and water (1 mL) was stirred at 20 °C for 16 h and concentrated under reduced pressure. The residue was diluted with ice water (2 mL) and adjusted to pH 3 by adding hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (660 mg, 99%) as a clear oil. LC-MS R _T =0.491 min, m/z =226.2[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.491 min, and the measured ESI+ value [M+H] = 226.2.

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

A mixture of cis-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxylic acid (660 mg, 3.11 mmol), N,N-diisopropylethylamine (3.32 mL, 18.65 mmol), N,O-dimethylhydroxylamine hydrochloride (606 mg, 6.22 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazololo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1536 mg, 4.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 3 hours and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude cis-5-(cyclopropylmethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (670 mg, 80%) as a brown solid. LC-MS R _{_T} = 0.706 min, m/z = 269.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.706 min, and the measured ESI+ value [M+H] = 269.2.

Step 12: Cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 3.35 mL, 1.68 mmol) was added to a solution of cis-5-(cyclopropylmethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (150 mg, 0.56 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at 0 °C for 5 hours and quenched by adding water (5 mL). The resulting mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.225% formic acid in water) and further purified by chiral SFC to give the definitively attributed:

Cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 3.498 min) (13.6 mg, 9.5%) is a colorless oil. ¹ H NMR (400MHz, CD ₃ OD) δ6.02-6.00(m, 0.5H), 5.88-5.86(m, 0.5H), 4.60-4.55(m, 1H), 3.37-3.23(m, 1H), 3.05-3.01(m, 1H), 2.75-2.60(m, 1H), 2.00-1.95(m, 1H), 1.68-1.65(m, 1H), 1.16-1.06(m, 4H), 0.90-0.77(m, 1H), 0.49-0.47(m, 2H), 0.10-0.02(m, 2H). LC-MS R _T =0.635 min, m/z =250.2[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.635 min, and the measured ESI+ value [M+H] = 250.2.

The 5S,7R-isomer (peak 1, retention time = 3.041 min) (13.5 mg, 9%) was also obtained as a colorless oil.

SFC conditions: Column: ChiralPak AD-3 150×4.6mm ID3μm; Mobile phase: A: CO2 _, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min; Flow rate: 25 mL/min; Column temperature: 40℃.

SFC conditions: Column: Lux Cellulose-2 150×4.6mm I.D.3μm, Mobile phase: A: CO2 B: Ethanol (0.05% DEA), Gradient: 5% to 40% B, 5.5 min, and hold at 40%, 3 min, then 5% B, 1.5 min, Flow rate: 2.5 mL/min, Column temperature: 40℃.

Method 92

Cyclopropyl-[(5S)-7,7-dideuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: Cyclopropyl-[(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[(5R,7R)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Cyclopropyl-[racemic-(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (350 mg, from another scale-up batch) was isolated by chiral SFC to the specifically assigned:

Cyclopropyl-[(5R,7R)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1: retention time = 3.132 min, 100 mg, 10%) and cyclopropyl-[(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2: retention time = 4.124 min, 100 mg, 10%) were both white solids.

SFC conditions: Column: OJ-H (250mm*30mm, 10μm); Conditions: 0.1% _NH3H2OEtOH ; Start B 30% End B 30%; Flow rate (80mL/ _min ), column temperature 40℃.

Step 2: Cyclopropyl-[(5S)-7,7-dideuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

A solution of cyclopropyl-[(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (40 mg, 0.14 mmol) and zinc (40 mg, 0.61 mmol) in formic acid- _D2 (2.0 mL, 0.14 mmol) was stirred at 20 °C for 48 hours. The mixture was diluted with ethyl acetate (20 mL), washed with water (2 x 10 mL), and concentrated under reduced pressure. The residue was purified by RP-HPLC (0.05% ammonium hydroxide v/v-acetonitrile 36-66%) to give cyclopropyl-[(5S)-7,7-dideuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (13.2 mg, 36%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.41-7.36(m, 3H), 7.14-7.11(m, 2H), 5.52-5.48(m, 1H), 3.28-3.21(m, 1H) , 3.04-3.00 (m, 1H), 2.70-2.65 (m, 1H), 1.30-1.27 (m, 2H), 1.06-1.03 (m, 2H). LCMS R _T =1.549 min, m/z =256.2[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.1% ammonia in water, within 3.0 minutes) was 1.549 min, and the ESI ⁺ measured value [M+H] = 256.2.

Method 93

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

A mixture of thionyl chloride (441 mg, 3.71 mmol) and cyclopropyl-[trans-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (400 mg, 1.49 mmol) was stirred at 0 °C for 0.5 h and quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give cyclopropyl-[cis-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (220 mg, 52%) as a yellow solid. LC-MS RT=0.692min, m/z=288.1[M+H]+.

LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) retention time 0.692 min, [M+H] = 288.1.

The cis mixture was further separated by a chiral SFC to obtain the definitively attributed:

Cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 1, retention time = 3.711 min) (72.9 mg, 33%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.43–7.39 (m, 2H), 7.33–7.28 (m, 3H), 5.56–5.51 (m, 1H), 5.40–5.35 (m, 1H), 3.95–3.88 (m, 1H), 3.07–2.99 (m, 2H), 1.34–1.31 (m, 2H), 1.11–1.07 (m, 2H). LCMS R _T =1.034 min, m/z =288.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.034 min, and the measured ESI+ value [M+H] = 288.2.

Cyclopropyl-[(5R,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 3.949 min) (84.6 mg, 38%), is a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.43–7.39 (m, 2H), 7.33–7.28 (m, 3H), 5.56–5.51 (m, 1H), 5.40–5.35 (m, 1H), 3.96–3.86 (m, 1H), 3.10–2.99 (m, 2H), 1.35–1.28 (m, 2H), 1.10–1.06 (m, 2H). LCMS R _T =1.033 min, m/z =288.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.033 min, and the measured ESI+ value [M+H] = 288.2.

SFC method: Column: Chiralcel OJ-3 150×4.6mm ID3μm; Mobile phase: A: _CO2 B: Ethanol (0.05% DEA); Gradient: 5% to 40% B, 5 min, and hold at 40%, 2.5 min, then 5% B, 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.

Method 94

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

Step 1: [racemic-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethylsilane

A mixture of racemic (5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (800 mg, 2.86 mmol), imidazole (389 mg, 5.71 mmol), and tert-butyldimethylchlorosilane (646 mg, 4.28 mmol) in dichloromethane (20 mL) was stirred at 15 °C for 1.5 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give [racemic-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (900 mg, 80%) as a colorless oil.

Step 2: Cyclopropyl-[(racemic-5S,7S)-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 3.42 mL, 6.85 mmol) was added dropwise to a solution of N-methoxy-N-methyl-cyclopropaneformamide (589 mg, 4.56 mmol) and [racemic-(5S,7S)-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (900 mg, 2.28 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0 °C for 1 hour and diluted with ethyl acetate (100 mL). The separated organic layer was washed with saturated aqueous ammonium chloride solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give cyclopropyl-[(racemic-5S,7S)-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (450 mg, 51%) as a colorless oil. LCMS R _{_T} = 1.016 min, m/z = 384.3 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 1.016 min, and the measured ESI+ value [M+H] = 384.3.

Step 3: Cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

To a solution of cyclopropyl-[(racemic-5S,7S)-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (450 mg, 1.17 mmol) in dichloromethane (10 mL), thionyl chloride (0.43 mL, 5.87 mmol) was added. The mixture was stirred at 25 °C for 40 hours and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give cyclopropyl-[racemic-(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (200 mg, 59%) as a colorless oil. LCMS RT = 0.803 min, m/z = 288.2 [M+H]+

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.803 min, and the measured ESI+ value [M+H] = 288.2.

The racemic compound was further separated by a chiral SFC to obtain the definitively assigned:

Cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone (peak 2, retention time = 4.690 min) (60 mg, 40%), is a white solid. ^¹H NMR (400 MHz, _CD₃OD ) δ 7.45–7.38 (m, 3H), 7.34–7.32 (m, 2H), 5.85 (t, J = 7.2 Hz, 1H), 5.69–5.67 (m, 1H), 3.40–3.31 (m, 2H), 3.03–3.00 (m, 1H), 1.19–1.16 (m, 2H), 1.11–1.08 (m, 2H). LCMS R _T =1.028 min, m/z =288.2[M+H] ⁺ .

LCMS retention time (10 to 80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) was 1.028 min, and the measured ESI+ value [M+H] = 288.2.

SFC conditions: Column: Chiralcel OJ-H 100×4.6mm I.D.3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA); Gradient: 30% to 30% B; Temperature: 40℃.

Method 95

Cyclopropyl-[racemic-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: Ethyl 3-chloro-2-vinylpyridine

A mixture of 2-bromo-3-chloropyridine (62.5 g, 324.78 mmol), potassium vinyltrifluoroborate (47.9 g, 357.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.2 g, 16.24 mmol), and sodium bicarbonate (68.2 g, 811.94 mmol) in 1,4-dioxane (600 mL) and water (150 mL) was stirred at 100 °C for 24 hours and concentrated under reduced pressure. The residue was diluted with petroleum ether (500 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give 3-chloro-2-vinylpyridine (40.0 g, 88%) as a green oil. LCMS R _T =0.554 min, m/z =140.1/142.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.554 min, and the measured ESI+ values [M+H] were 140.1 and 142.1.

Step 2: 3-Chloropyridine formaldehyde

Osmium tetroxide (0.89 g, 3.51 mmol) was added to a solution of 3-chloro-2-vinylpyridine (35.0 g, 250.75 mmol) in water (200 mL) and tetrahydrofuran (200 mL). The black solution was stirred at 25 °C for 30 min, and sodium periodate (214.5 g, 1003 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h and quenched by adding a saturated aqueous solution of sodium sulfite (200 mL). The solution was extracted with ethyl acetate (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, 0-10% ethyl acetate in petroleum ether) to give 3-chloropyridine-2-carboxaldehyde (18.5 g, 52%) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.45-10.18 (m, 1H), 8.73-8.70 (m, 1H), 7.86-7.84 (m, 1H), 7.48-7.44 (m, 1H).

Step 3: 1-(3-chloropyridin-2-yl)but-3-en-1-ol

At 0 °C, allyl magnesium bromide (1.0 M, in n-hexane, 162.2 mL, 162.2 mmol) was added dropwise over 30 minutes to a solution of 3-chloropyridin-2-carboxaldehyde (18.5 g, 130.7 mmol) in tetrahydrofuran (200 mL). After addition, the reaction was heated to 20 °C and stirred for 2 hours. The mixture was quenched by adding 100 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (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, 0-30% ethyl acetate in petroleum ether) to give 1-(3-chloro-2-pyridyl)but-3-en-1-ol (10.0 g, 42%) as a colorless oil. LCMSR _T =0.524min, m/z=184.1/186.1[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) was 0.524 min, and the measured ESI+ values [M+H] were 184.1 and 186.1.

Step 4: 2-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-3-chloropyridine

To a solution of 1-(3-chloro-2-pyridyl)but-3-en-1-ol (10.0 g, 54.46 mmol) in dichloromethane (100 mL), imidazole (7.4 g, 108.91 mmol) and tert-butyldimethylchlorosilane (12.3 g, 81.69 mmol) were added. The reaction mixture was stirred at 10 °C for 16 h and diluted with water (50 mL). The separated organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give tert-butyl-[1-(3-chloro-2-pyridyl)but-3-enoxy]-dimethyl-silane (10 g, 62%) as a light-colored oil.

Step 5: 3-((tert-butyldimethylsilyl)oxy)-3-(3-chloropyridin-2-yl)propionaldehyde

Osmium tetroxide (0.11 g, 0.44 mmol) was added to a solution of tert-butyl-[1-(3-chloro-2-pyridyl)but-3-enoxy]-dimethyl-silane (10.0 g, 33.57 mmol) in water (100 mL) and tetrahydrofuran (100 mL). After stirring at 15 °C for 30 min, sodium periodate (28.7 g, 134.27 mmol) was added to the mixture in portions over 30 min, and the mixture was stirred at 25 °C for another 2 h. The mixture was quenched by adding a saturated aqueous solution of sodium sulfite (1.50 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propionaldehyde (6.5 g, 65%) as a yellow oil. LCMS R _{_T} = 0.719 min, m/z = 300.1/302.1 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.719 min, and the measured ESI+ values [M+H] were 300.1 and 302.1.

Step 6: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(3-chloropyridin-2-yl)prop-1-ol

Under a nitrogen atmosphere, n-butyllithium (2.5 M, in n-hexene, 9.97 mL, 24.93 mmol) was added dropwise to a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (8.1 g, 26.01 mmol) in tetrahydrofuran (50 mL). The mixture was stirred at -78 °C for 30 min, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)propionaldehyde (6.5 g, 21.68 mmol) in tetrahydrofuran (15 mL) was added. The resulting mixture was stirred at -78 °C for 1.5 h and quenched by adding saturated aqueous solution of ammonium chloride (50 mL). The solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridinyl)prop-1-ol (10.0 g, 87%) as a yellow oil. LCMS R _{_T} = 0.941 min, m/z = 533.2 [M+H] ^⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.941 min, and the measured ESI+ value [M+H] = 533.2.

Step 7: 2,2-Dimethylpropionic acid [1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(3-chloropyridin-2-yl)propyl] ester

To a mixture of 4-dimethylaminopyridine (321 mg, 2.63 mmol), 1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridyl)prop-1-ol (14.0 g, 26.32 mmol), and triethylamine (7.01 mL, 52.64 mmol) in dichloromethane (100 mL), tertivalyl chloride (4.8 g, 39.48 mmol) was added. The mixture was stirred at 20 °C for 2 hours and quenched by adding water (50 mL). The solution was 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, 0-20% ethyl acetate in petroleum ether) to give 2,2-dimethylpropionic acid [1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridinyl)propyl] ester (12.5 g, 77%) as a colorless oil.

Step 8: 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloropyridin-2-yl)-3-hydroxypropyl 2,2-dimethylpropionic acid

A mixture of 2,2-dimethylpropionic acid [1-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3-chloro-2-pyridinyl)propyl] ester (12.0 g, 19.48 mmol) and p-toluenesulfonic acid (4.0 g, 23.37 mmol) in methanol (100 mL) was stirred at 50 °C for 2 h, and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give 2,2-dimethylpropionic acid [1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro-2-pyridinyl)-3-hydroxy-propyl] ester (6.8 g, 83%) as a white solid. LCMS R _T =0.760 and 0.768 min, m/z=417.1/419.0[M+H] ⁺ .

LCMS retention times (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 0.760 and 0.768 min, with measured ESI+ values [M+H] = 417.1 and 419.0.

Step 9: Racemic 2,2-dimethylpropionic acid [(5S,7S)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl] ester

A solution of diisopropyl azodicarbonate (3.6 g, 17.81 mmol) in tetrahydrofuran (50 mL) was added to a mixture of 2,2-dimethylpropionic acid [1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro-2-pyridinyl)-3-hydroxy-propyl] ester (6.2 g, 14.84 mmol) and triphenylphosphine (4.7 g, 17.81 mmol) in tetrahydrofuran (50 mL). The mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give racemic 2,2-dimethylpropionic acid [(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl] ester (2.3 g, 39%) as a colorless oil. LCMSR _T = 0.753 and 0.781 min, m/z = 399.0/401.0 [M+H] ⁺ .

LCMS retention times (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) were 0.753 and 0.781 min, with ESI+ measured values [M+H] = 399.0 and 401.0.

Step 10: Racemic-(5S,7S)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of racemic 2,2-dimethylpropionic acid [(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl] ester (2.3 g, 5.75 mmol) and lithium hydroxide monohydrate (2.4 g, 57.55 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at 25 °C for 12 h and then extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give racemic (5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.7 g, 94%) as a white solid. LCMS R _T =0.639 min, m/z =315.0/317.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.639 min, and the measured ESI+ values [M+H] were 315.0 and 317.0.

Step 11: Racemic-4-nitrobenzoic acid (5S,7R)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-7-yl ester

At 0 °C, under a nitrogen atmosphere, diisopropyl azodicarbonate (0.77 mL, 4.75 mmol) was added dropwise to a mixture of triphenylphosphine (1.25 g, 4.75 mmol), racemic-(5S,7S)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (1.2 g, 3.80 mmol), and 4-nitrobenzoic acid (790 mg, 4.75 mmol) in tetrahydrofuran (5 mL). The solution was stirred at 0°C for 12 hours and filtered to obtain crude racemic 4-nitrobenzoic acid [(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl] ester (1.6 g, 91%), which was a white solid.

Step 12: Racemic-(5S,7R)-2-bromo-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of potassium carbonate (713 mg, 5.16 mmol) and racemic 4-nitrobenzoic acid [(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl] ester (1.6 g, 3.44 mmol) in methanol (5 mL) and water (5 mL) was stirred at 70 °C for 1 hour and concentrated under reduced pressure. The residue was diluted with water (10 mL) and filtered. The solid product was washed with acetonitrile (5 mL) to give crude racemic 4-(5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (800 mg, 74%) as a white solid. LCMSR _T =0.649min, m/z=315.0/317.0[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.649 min, and the measured ESI+ values [M+H] were 315.0 and 317.0.

Step 13: Racemic-(5S,7R)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

At 0 °C, tert-butyldimethylchlorosilane (251 mg, 1.66 mmol) was added to a mixture of racemic (5S,7R)-2-bromo-5-(3-chloro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (350 mg, 1.11 mmol), imidazole (151 mg, 2.22 mmol), and dichloromethane (20 mL). The mixture was stirred at 0 °C for 1 hour and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give racemic-(5S,7R)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (450 mg, 94%) as a white solid. ¹ H NMR (400MHz, CDCl3) δ8.43-8.41(m, 1H), 7.73(d, J=8.4Hz, 1H), 7.25-7.21(m, 1H), 6.22-6.19(m , 1H), 5.49-5.46 (m, 1H), 3.12-3.08 (m, 1H), 2.97-2.93 (m, 1H), 0.95 (s, 9H), 0.24-0.19 (m, 6H).

Step 14: Racemic-((5S,7R)-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone

At 0 °C, a solution of racemic-(5S,7R)-2-bromo-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (450 mg, 1.05 mmol) and N-methoxy-N-methylcyclopropaneformamide (270 mg, 2.09 mmol) in tetrahydrofuran (20 mL) was added, along with magnesium isopropyl chloride (2.0 M, in tetrahydrofuran, 2.62 mL, 5.23 mmol). After addition, the reaction mixture was stirred at 0 °C for 1 hour and quenched by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give racemic-((5S,7R)-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone (125 mg, 28%) as a colorless oil. ¹ H NMR (400MHz, CDCl3) δ8.41-8.40 (m, 1H), 7.75-7.73 (m, 1H), 7.24-7.22 (m, 1H), 6.28-6.25 (m, 1H), 5.53-5.50 (m, 1H), 3.15-3 .12 (m, 1H), 3.10-3.06 (m, 1H), 3.04-3.02 (m, 1H), 1.06-1.04 (m, 2H), 0.96 (s, 9H), 0.91-0.86 (m, 2H), 0.25 (d, J=6.8Hz, 6H). LCMS _RT =0.857 min, m/z=419.1[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.857 min, and the measured ESI+ value [M+H] = 419.1.

Step 15: Racemic-((5S,7R)-5-(3-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone

A mixture of racemic-((5S,7R)-7-((tert-butyldimethylsilyl)oxy)-5-(3-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone (120 mg, 0.29 mmol) and hydrochloric acid (4.0 M, in methanol, 3.60 mL, 14.40 mmol) in methanol (10 mL) was stirred at 20 °C for 1 hour, and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH 7 by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were concentrated under reduced pressure to obtain crude racemic-((5S,7R)-5-(3-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone (52 mg, 60%) as a yellow solid. LCMS R _{_T} = 0.567 min, m/z = 305.0 [M+H] ^⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.567 min, and the measured ESI+ value [M+H] was 305.0.

Step 16: Cyclopropyl-[racemic-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

At 0 °C, a mixture of racemic -((5S,7R)-5-(3-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone (90 mg, 0.28 mmol) in dichloromethane (2 mL) was added, along with diethylaminosulfur trifluoride (40 mg, 0.25 mmol). The mixture was stirred for 1 hour and then quenched by adding water (5 mL). The resulting mixture was extracted with dichloromethane (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 32-62/ammonium hydroxide in water 0.05%) to give cyclopropyl-[racemic-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (G03345456) (15.0 mg, 28.7%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ8.45 (d, J=4.8Hz, 1H), 7.97-7.95 (m, 1H), 7.42-7.38 (m, 1H), 6.24-6.03 (m, 2H), 3.83-3.72(m, 1H), 3.04-2.89(m, 2H), 1.18-1.15(m, 2H), 1.11-1.08(m, 2H). LCMSR _T =0.780min, m/z=306.9[M+H] ⁺ .

LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.780 min, and the measured ESI+ value [M+H] was 306.9.

The cis mixture was further separated by SFC to obtain the arbitrarily attributed:

Cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (G03348054) (peak 1, retention time = 3.920 min) (5.2 mg, 34%) is a white solid. ¹ HNMR (400MHz, CDCl ₃ )δ8.47(d, J=4.8Hz, 1H), 7.79-7.76(m, 1H), 7.29-7.27(m, 1H), 6.14-6.12(m, 1H), 6.11-6.10(m, 0.5 H), 5.99-5.98(m, 0.5H), 3.71-3.64(m, 1H), 3.13-3.02(m, 2H), 1.34-1.32(m, 2H), 1.11-1.08(m, 2H). LCMS _RT =0.617 min, m/z=307.0[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.617 min, and the measured ESI+ value [M+H] = 307.0.

SFC conditions: Column: OJ-H (250mm*30mm, 5μm); Conditions: 0.1% _NH3H2OEtOH ; Start B 35% End B 35%; Flow rate (50mL/ _min ), column temperature 40℃.

Method 96

Cyclopropyl-[racemic-(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol

Sodium borodeide (1.4 g, 32.36 mmol) was added to a solution of 2-bromo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-one (3.0 g, 10.79 mmol) in methanol (100 mL). The mixture was stirred at 20 °C for 1 hour and concentrated under reduced pressure. The residue was diluted with water (50 mL), aqueous hydrochloric acid (1.0 M, 2 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (3.0 g, 99%) as a yellow solid. LCMS R _T =0.681 min, m/z =283.0[M+H] ⁺ .

The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.681 min, and the measured ESI+ value [M+H] = 283.0.

Step 2: 4-Nitrobenzoic acid [trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl] ester

At 0 °C under nitrogen atmosphere, diisopropyl azodicarbonate (1.5 g, 7.21 mmol) was added dropwise to a mixture of 4-nitrobenzoic acid (1.0 g, 6.24 mmol), triphenylphosphine (1.9 g, 7.21 mmol), and cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (1.4 g, 4.8 mmol) in tetrahydrofuran (20 mL). The mixture was stirred for 1.5 hours and filtered. The solid was washed with tetrahydrofuran (10 mL) and methyl tert-butyl ether (10 mL) to give 4-nitrobenzoic acid [trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl] ester (800 mg, 39%), as a white solid. LCMS R _{_T} = 0.904 min, m/z = 432.0 [M+H]^⁺. LCMS retention time (in water, 5 to 95% acetonitrile + 0.03% trifluoroacetic acid, within 1.5 min) was 0.904 min, ESI⁺ measured [M+H] = 432.0.

Step 3: trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol

A mixture of potassium carbonate (514 mg, 3.72 mmol) and 4-nitrobenzoic acid [trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl] ester (800 mg, 1.86 mmol) in methanol (10 mL)/water (5 mL) was stirred at 25 °C for 16 hours and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-35% ethyl acetate in petroleum ether) to give trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (300 mg, 57%) as a pale yellow solid. LCMS R _{_T} = 0.689 min, m/z = 281.0 [M+H]^⁺. LCMS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) was 0.689 min, ESI⁺ measured [M+H] = 281.0.

Step 4: [trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethylsilane

To a solution of trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (300 mg, 1.07 mmol) and imidazole (145 mg, 2.13 mmol) in dichloromethane (20 mL), tert-butyldimethylchlorosilane (241 mg, 1.6 mmol) was added. The mixture was stirred at 25 °C for 18 hours and diluted with water (30 mL). The solution was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give [trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethylsilane 350 mg, 83%) as a yellow oil. LCMS R _{_T} = 0.931 min, m/z = 397.1 [M+H]^⁺. LCMS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) was 0.931 min, ESI⁺ measured [M+H] = 397.1.

Step 5: [trans-7-[tert-butyl(dimethyl)silyl]oxy-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone

At 0 °C under a nitrogen atmosphere, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 1.33 mL, 2.66 mmol) was added to a solution of N-methoxy-N-methyl-cyclopropaneformamide (457 mg, 3.54 mmol) and [trans-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (350 mg, 0.89 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give [trans-7-[tert-butyl(dimethyl)silyl]oxy-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (200 mg, 59%) as a yellow oil. LCMS R _{_T} = 0.935 min, m/z = 385.3 [M+H] ^⁺. LCMS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) was 0.935 min, ESI⁺ measured [M+H] = 385.3.

Step 6: Cyclopropyl-[racemic-(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

To a mixture of [trans-7-[tert-butyl(dimethyl)silyl]oxy-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (200 mg, 0.52 mmol) in dichloromethane (3 mL), thionyl chloride (0.19 mL, 2.6 mmol) and 2 drops of dimethylformamide were added. The mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was first purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether), and then purified by RP-HPLC (acetonitrile 54-84/0.05% ammonium hydroxide in water) to give cyclopropyl-[racemic-(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (35.0 mg, 23%) as a yellow solid. ^¹H NMR (400MHz, _CD₃OD ) δ 7.46–7.38 (m, 3H), 7.33–7.31 (m, 2H), 5.69–5.65 (m, 1H), 4.02–3.96 (m, 1H), 3.07–2.99 (m, 1H), 2.91–2.86 (m, 1H), 1.21–1.16 (m, 2H), 1.13–1.09 (m, 2H). LCMS R _{_T} = 1.033 min, m/z = 289.1 [M+H] ^⁺. LCMS (10–80% acetonitrile in water + 0.03% trifluoroacetic acid, within 2.0 min) retention time 1.033 min, ESI⁺ measured value [M+H] = 289.1.

Method 97

Cyclopropyl-[racemic-(5S,7R)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: [cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethylsilane

A solution of cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-ol (1.5 g, 5.34 mmol) and imidazole (726 mg, 10.67 mmol) in dichloromethane (50 mL) was mixed with tert-butyldimethylchlorosilane (1.2 g, 8.00 mmol). The mixture was stirred at 15 °C for 16 hours and diluted with water (20 mL). The resulting mixture was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give [cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethylsilane (1.8 g, 85%) as a colorless oil. LCMS R _{_T} = 1.029 min, m/z = 395.1 [M+H]^⁺. LCMS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) was 1.029 min, ESI⁺ measured [M+H] = 395.1.

Step 2: [cis-7-[tert-butyl(dimethyl)silyl]oxy-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in tetrahydrofuran, 6.83 mL, 13.66 mmol) was added dropwise to a solution of N-methoxy-N-methyl-cyclopropaneformamide (1.2 g, 9.10 mmol) and [cis-2-bromo-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl]oxy-tert-butyl-dimethyl-silane (1.8 g, 4.55 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at 0 °C for 1.5 h and quenched by adding saturated aqueous solution of ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give [cis-7-[tert-butyl(dimethyl)silyl]oxy-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (450 mg, 26%) as a colorless oil. LCMS R _{_T} = 1.030 min, m/z = 384.2 [M+H] ^⁺. LCMS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) was 1.030 min, ESI⁺ measured [M+H] = 384.2.

Step 3: Cyclopropyl-[racemic-(5S,7R)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

To a mixture of [cis-7-[tert-butyl(dimethyl)silyl]oxy-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (450 mg, 1.17 mmol) in dichloromethane (4 mL), thionyl chloride (1.47 mL, 20.23 mmol) was added. The mixture was stirred at 25 °C for 25 hours and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was first purified by column chromatography on silica gel (solvent gradient: 0-30% ethyl acetate in petroleum ether), and then purified by RP-HPLC (acetonitrile 40-70/0.05% ammonium hydroxide in water) to give specifically assigned cyclopropyl-[racemic-(5S,7R)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (110 mg, 32.2% yield) as a white solid. ^¹H NMR (400MHz, _CD₃OD ) δ 7.74–7.69 (m, 3H), 7.63–7.61 (m, 2H), 6.14 (t, J = 6.8 Hz, 1H), 3.73–3.62 (m, 2H), 3.61–3.59 (m, 1H), 1.48–1.45 (m, 2H), 1.40–1.37 (m, 2H). LCMS R_{_T} = 1.033 min, m/z = 289.2 [M+H]^⁺. LCMS (10–80% acetonitrile + 0.03% trifluoroacetic acid in water, within 2.0 min) retention time 1.033 min, ESI⁺ measured value [M+H] = 289.2.

Method 98

Cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: 1-Nitroprop-2-ol

To a cooled (0°C) solution of acetaldehyde (45.9 mL, 819.13 mmol) and nitromethane (44.4 mL, 819.13 mmol) in water (1000 mL) in sodium hydroxide (32.8 g, 819.13 mmol), cetyltrimethylammonium chloride (26.2 g, 81.91 mmol) was added. The reaction mixture was stirred at 15°C for 16 hours and adjusted to pH 7 by adding acetic acid. The mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-nitropropane-2-ol (61.0 g, 71%) as a light brown oil.

Step 2: tert-butyl-dimethyl-(1-methyl-2-nitro-ethoxy)silane

At 0 °C, tert-butyldimethylchlorosilane (104.9 g, 696.55 mmol) was added to a mixture of imidazole (83.0 g, 1219 mmol) and 1-nitroprop-2-ol (61.0 g, 580.45 mmol) in dichloromethane (1.00 L). The mixture was stirred at 20 °C for 16 h and diluted with water (200 mL). The solution was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give tert-butyl-dimethyl-(1-methyl-2-nitro-ethoxy)silane (115.0 g, 90%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.53-4.68 (m, 1H), 4.24-4.53 (m, 2H), 1.25-1.32 (m, 3H), 0.87-0.90 (m, 9H), 0.07-0.12 (m, 6H).

Step 3: 3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dihydroisoxazol-5-carboxylic acid ethyl ester

At 20°C, tert-butyl-dimethyl-(1-methyl-2-nitro-ethoxy)silane (100.0 g, 455.89 mmol) was added to a mixture of ethyl acrylate (242.6 mL, 2279.5 mmol), di-tert-butyl dicarbonate (157.1 mL, 683.84 mmol), and 4-dimethylaminopyridine (5.6 g, 45.59 mmol) in acetonitrile (1 L). The mixture was stirred at 20°C for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dihydroisoxazole-5-carboxylate (40.0 g, 29%) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ )δ4.89-5.07(m, 1H), 4.66-4.84(m, 1H), 4.16-4.33(m, 2H), 3.21-3.41(m, 2H) , 1.32-1.37(m, 3H), 1.26-1.30(m, 3H), 0.86-0.87(m, 9H), 0.03-0.10(m, 6H).

Step 4: 5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3-hydroxypyrrolidine-2-one

A mixture of 3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dihydroisoxazol-5-carboxylate (40.0 g, 132.69 mmol) and palladium (10% on carbon, 7.06 g) in ethanol (1.0 L) was hydrogenated at 40 °C (50 psi) for 48 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3-hydroxy-pyrrolidine-2-one (37.0 g, 92%) as a white solid.

Step 5: 3-Benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidine-2-one

To a solution of 5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3-hydroxypyrrolidine-2-one (31.2 g, 120.27 mmol) in dichloromethane (500 mL), tetrabutylammonium bromide (1.94 g, 6.01 mmol), sodium hydroxide (30% in water, 80.2 g, 601.34 mmol), and benzyl bromide (30.9 g, 180.4 mmol) were added. The mixture was stirred at 40 °C for 18 hours and cooled to 25 °C. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-80% ethyl acetate in petroleum ether) to give 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidine-2-one (22.0 g, 52%) as a colorless oil. LC-MSR _T = 0.957 min, m/z = 350.2 [M+H] ⁺ . LCMS (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) retention time 0.957 min, ESI+ measured value [M+H] = 350.2.

Step 6: 1-Amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidine-2-one

At 0 °C, sodium hydride (60%, in mineral oil, 3.78 g, 94.41 mmol) was added to a solution of 3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidine-2-one (22.0 g, 62.94 mmol) in N,N-dimethylformamide (400 mL). After stirring at 20 °C for 30 minutes, 19.1 g (81.82 mmol) of to-(diphenylphosphoyl)hydroxylamine was added. The mixture was stirred at 20 °C for 18 hours and filtered. The filtrate was concentrated under reduced pressure to give crude 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidine-2-one (22.9 g, 99%) as a brown oil.

Step 7: Ethyl 2-((3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopyrrolidine-1-yl)amino)-2-iminoethyl

A mixture of 1-amino-3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidine-2-one (22.0 g, 60.4 mmol) and 2-ethoxy-2-imino-ethyl acetate (20.3 mL, 150.9 mmol) in ethanol (220 mL) was stirred at 90 °C for 33 h and concentrated under reduced pressure to give crude 2-((3-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopyrrolidine-1-yl)amino)-2-iminoethyl acetate (27.9 g, 99%) as a yellow oil. LC-MS R _{_T} = 0.840 min, m/z = 365.3 [M+15] ^⁺ . LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.840 min, and the measured ESI+ value [M+15] was 365.3.

Step 8: 7-Benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

To a solution of 2-[[3-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-oxo-pyrrolidine-1-yl]amino]-2-imino-ethyl acetate (27.0 g, 58.2 mmol) in toluene (500 mL), p-toluenesulfonic acid monohydrate (13.3 g, 69.9 mmol) was added. The reaction mixture was stirred at 130 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (11.2 g, 43%) as a yellow oil. LC-MS R_{_T} = 1.029 min, m/z = 446.3 [M+H]^⁺. LC-MS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) was 1.029 min, ESI₊ measured value [M+H] = 446.3.

Step 9: 7-Benzyloxy-5-(1-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

To a solution of 7-benzyloxy-5-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (5.1 g, 11.44 mmol) in tetrahydrofuran (100 mL), tetrabutylammonium fluoride (1.0 M, in tetrahydrofuran, 34.33 mL, 34.33 mmol) was added. The mixture was stirred at 25 °C for 18 hours and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with aqueous hydrochloric acid (1N, 15 mL) and brine (50 mL), dried with sodium sulfate, and concentrated under reduced pressure to give crude 7-benzyloxy-5-(1-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (3.8 g, 100%) as a brown oil.

Step 10: Ethyl 5-acetyl-7-benzyloxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a cooled (0°C) solution of 7-benzyloxy-5-(1-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (3.8 g, 11.44 mmol) in dichloromethane (25 mL), sodium bicarbonate (3.8 g, 45.75 mmol) and Desmartin oxidant (9.7 g, 22.87 mmol) were added. The mixture was stirred at 0°C for 2 hours and filtered. The filtrate was diluted with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.5) to give ethyl 5-acetyl-7-benzyloxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.5 g, 40%) as a light brown oil. LC-MS R _{_T} = 0.655 min, m/z = 330.2 [M+H]^⁺. LC-MS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) retention time 0.655 min, ESI⁺ measured [M+H] = 330.2.

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

A mixture of 5-acetyl-7-benzyloxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.5 g, 4.6 mmol) in 2,2,2-trifluoroacetic acid (3 mL) was heated at 120 °C for 3 h and concentrated under reduced pressure. The residue was purified by preparative TLC (5% methanol and 45% ethyl acetate in petroleum ether, _Rf = 0.2) to give 5-acetyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (350 mg, 32%) as a light brown oil. LC-MS R _{_T} = 0.278 min, m/z = 240.2 [M+H] ^⁺ . The LCMS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 minutes) was 0.278 min, and the measured ESI+ value [M+H] = 240.2.

Step 12: cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

A mixture of ethyl 5-acetyl-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (350 mg, 1.46 mmol) and diethylaminosulfonium trifluoride (5.0 mL, 1.46 mmol) in dichloromethane (10 mL) was stirred at 10 °C for 2 hours and quenched by adding ice-cold saturated aqueous solution of sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, _Rf = 0.4) to give cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (37 mg, 10%) as a colorless oil. LC-MS R _{_T} = 0.694 min, m/z = 264.1 [M+H]^⁺. LC-MS retention time (5-95% acetonitrile in water + 0.03% trifluoroacetic acid, within 1.5 min) was 0.694 min, ESI⁺ measured [M+H] = 264.1.

Step 13: cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester (27 mg, 0.10 mmol) and lithium hydroxide monohydrate (22 mg, 0.51 mmol) in methanol (0.7 mL)/water (0.7 mL)/tetrahydrofuran (0.7 mL) was stirred at 10 °C for 2 hours and concentrated under reduced pressure. The residue was diluted with ice water (2 mL) and adjusted to pH 4 by adding aqueous hydrochloric acid (1 M). The mixture was concentrated under reduced pressure to dryness to give crude cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid with lithium chloride salt (28 mg, 98%).

Step 14: cis-5-(1,1-difluoroethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of cis-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carboxylic acid (28 mg, 0.12 mmol), N,O-dimethylhydroxylamine hydrochloride (23 mg, 0.24 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazololo[4,5-b]pyridinium 3-oxide hexafluorophosphate (48 mg, 0.13 mmol), and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in N,N-dimethylformamide (2 mL) was stirred at 20 °C for 3 hours and concentrated under reduced pressure. The residue was purified by preparative TLC (70% ethyl acetate in petroleum ether, _Rf = 0.3) to give cis-5-(1,1-difluoroethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (15 mg, 45%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 6.05–5.73 (m, 1H), 4.62 (br s, 1H), 3.86–3.82 (m, 3H), 3.54–3.21 (m, 5H), 3.14–2.99 (m, 1H), 1.96–1.75 (m, 3H).

Step 15: Cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Under a nitrogen atmosphere, cyclopropylmagnesium bromide (0.5 M, in tetrahydrofuran, 0.5 mL, 0.25 mmol) was added dropwise to a cooled (0 °C) solution of cis-5-(1,1-difluoroethyl)-7-fluoro-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (10 mg, 0.04 mmol) in tetrahydrofuran (1 mL). After stirring at 0 °C for 1 hour, the mixture was quenched by adding 0.5 mL of saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The residue was redissolved in dichloromethane (50 mL), filtered to remove solids, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 36-66%/ammonium hydroxide in water 0.05%) to give cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone (2.2 mg, 23%) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 6.00–5.84 (m, 1H), 4.75–4.55 (m, 1H), 3.38–3.29 (m, 1H), 3.18–2.99 (m, 2H), 1.86 (t, J = 19.2 Hz, 3H), 1.36–1.33 (m, 2H), 1.16–1.12 (m, 2H). LC-MS R_{_T} = 0.828 min, m/z = 259.9 [M+H]^⁺. LC-MS retention time (5 to 95% acetonitrile + 0.03% trifluoroacetic acid in water, within 1.5 min) was 0.828 min, ESI₊ measured value [M+H] = 259.9.

Method 99

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

Under a nitrogen atmosphere, a mixture of [(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-cyclopropyl-methyl ketone (40 mg, 0.13 mmol), potassium hexacyanoferrate(II) trihydrate (28 mg, 0.07 mmol), potassium acetate (2 mg, 0.02 mmol), t-BuXPhos Phos palladium(II) methanesulfonate biphenyl-2-amine (10 mg, 0.01 mmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.01 mmol) in water (5 mL) and 1,4-dioxane (5 mL) was stirred at 100 °C for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (40-70/ _0.04 % _NH3H2O in water + 10mM _NH4HCO3 ) to give 2-[(5S,7S) _-2- (cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile (6.1 mg, 16%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.79-7.76 (m, 1H), 7.64-7.60 (m, 1H), 7.53-7.50 (m, 1H), 7.01 (d, J=8.0Hz, 1H), 6.15-6.12 (m, 0.5H), 6.00- 5.98 (m, 1.5H), 3.90-3.74 (m, 1H), 3.10-3.06 (m, 1H), 2.99-2.85 (m, 1H), 1.39-1.33 (m, 2H), 1.17-1.09 (m, 2H). LC-MS R _T =0.915 min, m/z =397.2[M+H] ⁺ .

The LCMS retention time (10 to 80% acetonitrile + 0.03% ammonium bicarbonate in water, within 3.0 minutes) was 0.915 min, and the measured ESI+ value [M+H] = 397.2.

Method 100

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

Step 1: 1-Ethyl-N-methoxy-N-methylcyclopropane-1-carboxamide

Method 5 was used to prepare 1-ethylcyclopropanecarboxylic acid. The crude reaction mixture was purified by rapid column chromatography (silica gel, 0-100% isopropyl acetate/heptane) to give 1-ethyl-N-methoxy-N-methylcyclopropane-1-carboxamide (435 mg, 63% yield). ^¹H NMR (400 MHz, chloroform-d) δ 3.71 (s, 3H), 3.24 (s, 3H), 1.60 (q, J = 7.4 Hz, 2H), 0.97 (d, J = 2.0 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H), 0.59-0.52 (m, 2H). LCMS R _{_T} = 0.92 min, m/z = 157.9 [M+H] ^⁺ . LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 minutes) was 0.92 min, and the measured ESI+ value [M+H] = 157.9.

Step 2: (1-Ethylcyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl ketone

Method 2 was used to prepare 1-ethyl-N-methoxy-N-methylcyclopropane-1-carboxamide. The crude reaction mixture was purified by RP-HPLC (30-70% acetonitrile/0.1% formic acid in water, 10 min) to give (1-ethylcyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (134 mg, 72% yield). ^¹H NMR (400 MHz, DMSO- _d6) )δ7.46-7.34(m, 3H), 7.25-7.19(m, 2H), 6.20(ddd, J=56.5, 7.1, 1.9Hz, 1H), 5.69 (dddd, J=8.5, 6.6, 3.0Hz, 1H), 3.72 (dddd, J=26.1, 15.4, 8.5, 7.1Hz, 1H), 2.68 (dddd, J=26.6, 15.3, 3.1, 1.9Hz, 1H), 1.73 (qd, J=7.2, 1.7Hz, 2H), 1.58 ( dq, J=4.4, 1.7, 1.2Hz, 2H), 0.93 (q, J=3.2, 2.6Hz, 2H), 0.86 (t, J=7.3Hz, 3H). LCMS R _T = 5.29 min, m/z = 300.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 5.29 min, ESI+ measured value [M+H] = 300.1.

Method 101

((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone

Step 1: N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide

Method 5 was used to prepare the mixture from tetrahydropyran-4-carboxylic acid. The crude reaction mixture was purified by rapid column chromatography (silica gel, 0-100% isopropyl acetate/heptane) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (721 mg, quantitative yield). ^¹H NMR (400 MHz, chloroform-d) δ 4.08–3.95 (m, 2H), 3.71 (s, 3H), 3.46 (td, J = 11.8, 2.3 Hz, 2H), 3.18 (s, 3H), 2.91 (tt, J = 11.4, 3.8 Hz, 1H), 1.94–1.78 (m, 2H), 1.73–1.59 (m, 2H). LCMS R _{_T} = 0.70 min, m/z = 173.9 [M+H] ^⁺ . LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 minutes) was 0.70 min, and the measured ESI+ value [M+H] = 173.9.

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone

Method 2 was used to prepare N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% _NH₄OH in water, 10 min) to give ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran-4-yl) methyl ketone (167 mg, 85% yield). ^¹H NMR (400 MHz, DMSO- _d₆) )δ7.47-7.35 (m, 3H), 7.28-7.21 (m, 2H), 6.23 (ddd, J=56.4, 7.2, 1.9Hz, 1H), 5.73 (ddd, J=8.9, 6.5, 3.0Hz, 1H), 3.88 (ddt, J=11.0, 4.6, 2.4Hz, 2H), 3.74 (dddd, J=26.1, 15.5, 8.6, 7.2Hz, 1H) 3.60 (tt, J = 11.5, 3.8 Hz, 1H), 3.42 (tdd, J = 11.4, 3.6, 2.2 Hz, 2H), 2.70 (dddd, J = 26.7, 15.2, 3.1, 1.9 Hz, 1H), 1.76 (tdt, J = 10.8, 4.5, 2.2 Hz, 2H), 1.58 (dtdd, J = 13.3, 11.7, 8.8, 4.5 Hz, 2H). LCMS R _T = 4.22 min, m/z = 316.1 [M+H] ⁺ . LCMS (in water, 2 to 98% acetonitrile + 0.1% formic acid, within 7 minutes) retention time 4.22 min, ESI+ measured value [M+H] = 316.1.

Method 102

((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran-3-yl)methyl ketone

Step 1: N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide

Method 5 was used to prepare the mixture from tetrahydropyran-3-carboxylic acid. The crude reaction mixture was purified by rapid column chromatography (silica gel, 0-100% isopropyl acetate/heptane) to give N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide (697 mg, quantitative yield). ^¹H NMR (400 MHz, chloroform-d) δ 4.03-3.96 (m, 1H), 3.96-3.89 (m, 1H), 3.71 (s, 3H), 3.49 (t, J = 10.9 Hz, 1H), 3.45-3.37 (m, 1H), 3.16 (s, 3H), 3.07-2.94 (m, 1H), 1.94 (dtd, J = 11.1, 3.7, 1.9 Hz, 1H), 1.86-1.61 (m, 3H). LCMS R _T = 0.73 min, m/z = 173.9 [M+H] ⁺ . LCMS (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) retention time 0.73 min, ESI+ measured value [M+H] = 173.9.

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran-3-yl)methyl ketone

Method 2 was used to prepare N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% _NH₄OH in water, 10 min) to give ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydro-2H-pyran-3-yl) methyl ketone (169 mg, 86% yield). ^¹H NMR (400 MHz, DMSO- _d₆) )δ7.49-7.34 (m, 3H), 7.25 (dt, J=7.8, 1.4Hz, 2H), 6.23 (dddd, J=56.4, 7.2, 2.0, 0 .9Hz, 1H), 5.73 (ddd, J=8.8, 6.4, 3.0Hz, 1H), 4.01 (tdd, J=10.5, 3.9, 1.8Hz, 1H), 3 0.84-3.65 (m, 2H), 3.57 (tdd, J = 9.8, 3.8, 1.9 Hz, 1H), 3.45 (ddd, J = 10.9, 9.5, 2.6 Hz, 1H), 3.41-3.33 (m, 1H), 2.79-2.62 (m, 1H), 2.05-1.89 (m, 1H), 1.78-1.47 (m, 3H). LCMS R _T = 4.42 min, m/z = 316.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.42 min, ESI+ measured value [M+H] = 316.1.

Method 103

(5S,7S)-2-(D-prolyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Step 1: (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Prepared from N-Boc-D-proline using Method 1 (1.23 g, quantitative yield). The product was used without purification. ^¹H NMR (400 MHz, chloroform-d): δ 4.65 (ddd, J = 42.4, 8.5, 3.5 Hz, 1H), 3.74 (d, J = 25.4 Hz, 3H), 3.57 (dddd, J = 15.0, 10.5, 7.8, 5.0 Hz, 1H), 3.44 (ddt, J = 28.9, 10.3, 6.9 Hz, 1H), 3.19 (s, 3H), 2.27–2.08 (m, 1H), 2.08–1.74 (m, 3H), 1.43 (d, J = 17.9 Hz, 9H). LCMS R _T = 1.03 min, m/z = 158.9 [(M-Boc)+H] ⁺ . LCMS (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) retention time 1.03 min, ESI+ measured value [(M-Boc)+H] = 158.9.

Step 2: (R)-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl)pyrrolidin-1-tert-butyl carboxylate

Method 3 was used to prepare (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester. The product was used without purification. LCMS R _{_T} = 1.30 min, m/z = 300.9[(M-Boc)+H] ^⁺ .

LCMS (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 minutes) retention time 1.30 min, ESI+ measured value [(M-Boc)+H] = 300.9.

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

(R)-2-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at 0 °C. The reaction mixture was concentrated and purified by SFC (5-60% methanol/carbon dioxide, pyridylamide column, 12 min) to give (5S,7S)-2-(D-prolyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (3.7 mg, 3% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.48-7.29 (m, 3H), 7.23 (ddt, J=11.8, 6.1, 1.6Hz, 2H), 6.35-5.99 (m, 1H), 5.82-5.5 2 (m, 1H), 4.37-3.89 (m, 1H), 3.88-3.45 (m, 1H), 3.12-2.51 (m, 3H), 2.40-0.29 (m, 4H). LCMS _RT =0.88 min, m/z=300.9[M+H] ⁺ .

LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 minutes) was 0.88 min, and the measured ESI+ value [M+H] = 300.9.

Method 104

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

Step 1: N-methoxy-N,2-dimethyltetrahydrofuran-2-carboxamide

Method 2 was used to prepare the product from 2-methyltetrahydrofuran-2-carboxylic acid (76 mg, 38% yield). The product was used without purification. LCMS R _{_T} = 0.82 min, m/z = 174.0 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.82 min, ESI⁺ measured [M+H] = 174.0.

Step 2: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-methyltetrahydrofuran-2-yl)methyl ketone

Method 3 was used to prepare N-methoxy-N,2-dimethyltetrahydrofuran-2-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-methyltetrahydrofuran-2-yl) methyl ketone (24 mg, 17% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.48-7.35 (m, 3H), 7.28-7.19 (m, 2H), 6.23 (ddt, J=56.5, 7.2, 2.0Hz, 1H), 5.72 (ddt, J=8.9, 6.3, 2.8Hz, 1H), 3.93-3.82 (m, 1H), 3. 82-3.65 (m, 2H), 2.71 (dddd, J=26.6, 15.2, 3.1, 1.9Hz, 1H), 2.52 (m, 1H), 1.99-1.85 (m, 2H), 1.85-1.72 (m, 1H), 1.53 (d, J=3.6Hz, 3H). LCMS R _T = 4.66 min, m/z = 316.1 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.66 min, ESI+ measured value [M+H] = 316.1.

Method 105

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

Step 1: N-methoxy-N-methyltetrahydrofuran-3-carboxamide

Method 3 was used to prepare the product from tetrahydrofuran-3-carboxylic acid (97 mg, 47% yield). The product was used without purification. LCMS R _{_T} = 0.80 min, m/z = 160.0 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.80 min, ESI⁺ measured [M+H] = 160.0.

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

Method 3 was used to prepare N-methoxy-N-methyltetrahydrofuran-3-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give a diastereomeric mixture of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3-yl) methyl ketone (49 mg, 37% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.49-7.35 (m, 3H), 7.30-7.21 (m, 2H), 6.24 (ddd, J=56.2, 7.1, 1.9Hz, 1H), 5.74 (ddd, J=9.2, 6.6, 3.1Hz, 1H), 4.14-4.0 5 (m, 1H), 3.93 (dt, J=11.3, 8.4Hz, 1H), 3.87-3.65 (m, 4H), 2.72 (dddd, J=26.7, 15.3, 3.1, 1.9Hz, 1H), 2.19-2.00 (m, 2H). LCMS _RT =4.33 min, m/z=302.2[M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.33 min, ESI+ measured value [M+H] = 302.2.

Method 106

Examples 131 and 132

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

A mixture of diastereomers of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3-yl) ketone was purified by chiral SFC (retention time = 1.241 min) to give the specifically assigned ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((S)-tetrahydrofuran-3-yl) ketone (15 mg, 11% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.49-7.35 (m, 3H), 7.30-7.21 (m, 2H), 6.24 (ddd, J=56.2, 7.1, 1.9Hz, 1H), 5.74 (ddd, J=9.2, 6.6, 3.1Hz, 1H), 4.14-4.0 5 (m, 1H), 3.93 (dt, J=11.3, 8.4Hz, 1H), 3.87-3.65 (m, 4H), 2.72 (dddd, J=26.7, 15.3, 3.1, 1.9Hz, 1H), 2.19-2.00 (m, 2H). LCMS _RT =4.33 min, m/z=302.2[M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.33 min, ESI+ measured value [M+H] = 302.2.

((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-tetrahydrofuran-3-yl)methyl ketone

The diastereomeric mixture of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(tetrahydrofuran-3-yl) ketone was purified by chiral SFC (retention time = 1.627 min) to give the specifically assigned ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-tetrahydrofuran-3-yl) ketone (23 mg, 17% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.49-7.35 (m, 3H), 7.30-7.21 (m, 2H), 6.24 (ddd, J=56.2, 7.1, 1.9Hz, 1H), 5.74 (ddd, J=9.2, 6.6, 3.1Hz, 1H), 4.14-4.0 5 (m, 1H), 3.93 (dt, J=11.3, 8.4Hz, 1H), 3.87-3.65 (m, 4H), 2.72 (dddd, J=26.7, 15.3, 3.1, 1.9Hz, 1H), 2.19-2.00 (m, 2H). LCMSR _T , =4.33min, m/z=302.2[M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.33 min, ESI+ measured value [M+H] = 302.2.

SFC conditions: Column: Chiralpak IA (150mm*21.2mm, 5μm); Conditions: 0.1% _NH4OH MeOH; Start B10% End B10%; Flow rate (70mL/min); Column temperature 40℃.

SFC conditions: Column: Chiralpak IA (150mm*21.2mm, 5μm); Conditions: 0.1% _NH4OH MeOH; Start B10% End B10%; Flow rate (70mL/min); Column temperature 40℃.

Method 107

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

Step 1: N,3-Dimethoxy-N,2,2-Trimethylpropionamide

Method 2 was used to prepare the product from 3-methoxy-2,2-dimethylpropionic acid (184 mg, 46% yield). The product was used without purification. LCMS R _{_T} = 0.93 min, m/z = 176.0 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.93 min, ESI⁺ measured [M+H] = 176.0.

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

Method 3 was used to prepare N,3-dimethoxy-N,2,2-trimethylpropionamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-methoxy-2,2-dimethylprop-1-one (16 mg, 18% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.48-7.34 (m, 3H), 7.25-7.18 (m, 2H), 6.23 (ddd, J=56.5, 7.1, 1.9Hz, 1H), 5.74 (ddd, J=8.9, 6.5, 2.9Hz, 1H), 3. 84-3.71 (m, 2H), 3.79-3.66 (m, 1H), 3.07 (s, 3H), 2.71 (dddd, J=26.6, 15.2, 3.1, 1.9Hz, 1H), 1.25 (d, J=6.0Hz, 6H). LCMSR _T =5.44min, m/z=318.2[M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 5.44 min, ESI+ measured value [M+H] = 318.2.

Method 108

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

Step 1: (S)-3,3,3-trifluoro-2-hydroxy-N-methoxy-N-methylpropionamide

Method 2 was used to prepare (S)-3,3,3-trifluoro-2-hydroxypropionic acid (52 mg, 13% yield). The product was used without purification. LCMS R _{_T} = 0.72 min, m/z = 187.9 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.72 min, ESI⁺ measured [M+H] = 187.9.

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

Method 3 was used to prepare (S)-3,3,3-trifluoro-2-hydroxy-N-methoxy-N-methylpropionamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give (S)-3,3,3-trifluoro-1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxyprop-1-one (7.5 mg, 9% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.42 (dddd, J=9.2, 7.4, 6.3, 3.3Hz, 3H), 7.26 (td, J=8.3, 7.8, 1.6Hz, 2H), 6.27 (dddd, J=56.3, 7.3, 3.5, 2.0Hz, 1H), 5.7 7 (ddd, J=9.0, 6.3, 3.1Hz, 1H), 5.62 (dd, J=10.2, 4.0Hz, 1H), 3.77 (dddd, J=25.7, 15.5, 8.5, 7.2Hz, 1H), 2.80-2.65 (m, 1H). LCMS _RT =4.82 min, m/z=330.1[M+H] ⁺ . LCMS retention time (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) was 4.82 min, and the measured ESI+ value [M+H] was 330.1.

Method 109

1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethyl-1-one

Step 1: N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-2-yl)acetamide

Method 2 was used to prepare the product from 2-tetrahydropyran-2-ylacetic acid (200 mg, 77% yield). The product was used without purification. LCMS R _{_T} = 0.84 min, m/z = 188.0 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.84 min, ESI⁺ measured [M+H] = 188.0.

Step 2: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethyl-1-one

Method 3 was used to prepare N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-2-yl)acetamide. The crude reaction mixture was purified by RP-HPLC (5-85% acetonitrile/0.1% formic acid in water, 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethyl-1-one (2.5 mg, 3% yield). LCMS R- _T = 4.94 min, m/z = 330.2 [M+H] ⁺ . LCMS (2-98% acetonitrile in water + 0.1% formic acid, within 7 min) retention time 4.94 min, ESI+ measured [M+H] = 330.2.

Method 110

1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl-1-one

Step 1: N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide

Method 2 was used to prepare the product from 2-tetrahydropyran-4-ylacetic acid (154 mg, 59% yield). The product was used without purification. LCMS R _{_T} = 0.78 min, m/z = 188.0 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.78 min, ESI⁺ measured [M+H] = 188.0.

Step 2: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl-1-one

Method 3 was used to prepare the mixture from N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)acet-1-one (46 mg, 52% yield). ^¹H NMR (400 MHz, DMSO- _d6) was used. )δ7.46-7.34(m, 3H), 7.28-7.22(m, 2H), 6.22(ddd, J=56.4, 7.2, 1.9Hz, 1H), 5.71(dd d, J=8.5, 6.5, 3.1Hz, 1H), 3.84-3.63 (m, 3H), 3.28-3.21 (m, 1H), 2.94 (dd, J=6.8, 2.1H z, 2H), 2.71 (dddd, J=26.7, 15.2, 3.2, 2.0Hz, 1H), 2.10 (ttt, J=11.0, 7.1, 3.9Hz, 1H) , 1.55 (ddd, J=12.9, 4.2, 2.0Hz, 2H), 1.23 (qd, J=12.4, 4.4Hz, 2H), 0.87-0.65 (m, 1H). LCMS R _T =2.51 min, m/z =330.2[M+H] ⁺ .

LCMS retention time (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) was 2.51 min, and the measured ESI+ value [M+H] = 330.2.

Method 111

Examples 137 and 138

((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-3-methyltetrahydrofuran-3-yl) methyl ketone and ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((S)-3-methyltetrahydrofuran-3-yl) methyl ketone

Step 1: N-methoxy-N,3-dimethyltetrahydrofuran-3-carboxamide

Method 2 was used to prepare the product from 3-methyltetrahydrofuran-3-carboxylic acid (386 mg, 58% yield). The product was used without purification. LCMS R _{_T} = 0.89 min, m/z = 173.9 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.89 min, ESI⁺ measured [M+H] = 173.9.

((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-3-methyltetrahydrofuran-3-yl)methyl ketone

Method 3 was used to prepare N-methoxy-M3-dimethyltetrahydrofuran-3-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give a diastereomeric mixture of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyltetrahydrofuran-3-yl) methyl ketone (31 mg, 28% yield). A mixture of diastereomers of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-3-methyltetrahydrofuran-3-yl) ketone was purified by chiral SFC (retention time = 0.785 min) to give specifically assigned ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((R)-3-methyltetrahydrofuran-3-yl) ketone (11 mg, 10%). ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ7.46-7.35(m, 3H), 7.28-7.21(m, 2H), 6.24(ddd, J=56.4, 7.1, 2.0Hz, 1H) , 5.73 (ddd, J=8.9, 6.4, 3.1Hz, 1H), 4.18 (d, J=8.9Hz, 1H), 3.84-3.66 (m, 3H) , 3.64 (d, J=8.9Hz, 1H), 2.71 (dddd, J=26.6, 15.2, 3.1, 2.0Hz, 1H), 2.56 (dd d, J=12.6, 8.2, 6.8Hz, 1H), 1.85 (ddd, J=13.0, 7.6, 5.6Hz, 1H), 1.48 (s, 3H). LCMS R _T = 4.68 min, m/z = 316.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.68 min, ESI+ measured value [M+H] = 316.2.

SFC conditions: Column: Chiralpak IG (150mm*21.2mm, 5μm); Conditions: 0.1% _NH4OH MeOH; Start B20% End B20%; Flow rate (70mL/min); Column temperature 40℃.

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

A mixture of diastereomers of ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyltetrahydrofuran-3-yl) ketone was purified by chiral SFC (retention time = 0.966 min) to give the specifically assigned ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((S)-3-methyltetrahydrofuran-3-yl) ketone (12 mg, 11% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.47-7.34 (m, 3H), 7.28-7.21 (m, 2H), 6.24 (ddd, J=56.3, 7.1, 1.9Hz, 1H), 5.73 (ddd, J=8.9, 6.5, 3.1Hz, 1H), 4.21 (d, J=89.Hz, 1H), 3.83-3.6 4 (m, 3H), 3.67 (d, J=8.9Hz, 1H), 2.71 (dddd, J=26.6, 15.2, 3.1, 2.0Hz, 1H), 2.59-2.52 (m, 1H), 1.82 (dddd, J=12.6, 7.6, 5.7Hz, 1H), 1.47 (s, 3H). LCMS R _T = 4.68 min, m/z = 316.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.68 min, ESI+ measured value [M+H] = 316.2.

SFC conditions: Column: Chiralpak IG (150mm*21.2mm, 5μm); Conditions: 0.1% _NH4OH MeOH; Start B 25% End B 25%; Flow rate (70mL/min); Column temperature 40℃.

Method 112

Examples 139, 140 and 141

((1R,2R,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and ((1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7- Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and ((1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Step 1: N-methoxy-N-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Method 2 was used to prepare 7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (184 mg, 70% yield). The product was used without purification. LCMS R _{_T} = 0.76 min, m/z = 185.8 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.76 min, ESI⁺ measured [M+H] = 185.8.

Step 2: ((1R,2R,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Method 3 was used to prepare N-methoxy-N-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give a diastereomeric mixture of (7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (41 mg, 31% yield). A mixture of diastereomers of (7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone was purified by chiral SFC (retention time = 0.442 min) to give specifically assigned ((1R,2R,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (3 mg, 2% yield). ^¹H NMR (400 MHz, DMSO- _d6) )δ7.47-7.35 (m, 3H), 7.29-7.22 (m, 2H), 6.25 (ddd, J=56.4, 7.2, 2.0Hz, 1H), 5.74 (ddd, J=9.1, 6.4 , 3.1Hz, 1H), 4.91 (t, J=4.9Hz, 1H), 4.59 (t, J=5.2Hz, 1H), 3.96-3.87 (m, 1H), 3.75 (dddd, J=25.8, 15.5, 8.5, 7.2 Hz, 1H), 2.72 (dddd, J = 26.7, 15.1, 3.1, 2.0 Hz, 1H), 2.00 (dd, J = 11.9, 4.6 Hz, 1H), 1.75 (dddd, J = 12.0, 10.9, 5.3, 2.8 Hz, 1H), 1.66-1.52 (m, 1H), 1.50-1.36 (m, 2H), 1.29-1.17 (m, 1H). LCMSR _T = 4.61 min, m/z = 328.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.61 min, ESI+ measured value [M+H] = 328.2.

SFC conditions: Column: Chiralpak ID (250mm*21.2mm, 5μm); Conditions: 0.1% NH4OH MeOH; Start B 25% End B 25%; Flow rate (70mL/min); Column temperature 40℃.

((1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

A mixture of diastereomers of (7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone was purified by chiral SFC (retention time = 0.523 min) to give specifically assigned ((1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (3 mg, 2% yield). ^1H NMR (400MHz, chloroform-d) δ 7.43–7.34 (m, 3H), 7.25–7.19 (m, 2H), 6.03 (ddd, J = 55.8, 7.1, 1.7Hz, 1H), 5.50 (ddd, J = 8.8, 6.2, 2.8Hz, 1H), 4.83 (d, J = 4.7Hz, 1H), 4.70 (t, J = 4.8Hz, 1H), 3.77–3.51 (m, 2H), 2.95 (dddd, J = 25.0, 15.4, 2.8, 1.7Hz, 1H), 2.32 (dtd, J = 12.2, 5.0, 2.1Hz, 1H), 1.90–1.63 (m, 5H). LCMS R _T = 4.54 min, m/z = 328.2 [M+H] ⁺ . LCMS (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) retention time 4.54 min, ESI+ measured value [M+H] = 328.2.

SFC conditions: Column: Chiralpak ID (250mm*21.2mm, 5μm); Conditions: 0.1% _NH4OH MeOH; Start B 25% End B 25%; Flow rate (70mL/min); Column temperature 40℃.

((1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

A mixture of diastereomers of (7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone was purified by chiral SFC (retention time = 1.220 min) to give specifically assigned ((1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (21 mg, 16% yield). ^¹H NMR (400 MHz, DMSO- _d6) )δ7.47-7.35 (m, 3H), 7.31-7.24 (m, 2H), 6.23 (ddd, J=56.3, 7.2, 1.9Hz, 1H), 5.74 (ddd, J=8.9, 6.5, 3. 1Hz, 1H), 4.94 (t, J=4.9Hz, 1H), 4.59 (t, J=5.2Hz, 1H), 3.93-3.83 (m, 1H), 3.75 (dddd, J=26.1, 15.5, 8. 5, 7.2Hz, 1H), 2.72 (dddd, J=26.6, 15.2, 3.1, 1.9Hz, 1H), 1.99 (dd, J=12.0, 4.6Hz, 1H), 1.73 (dddd, J= 11.9, 10.8, 5.3, 2.8Hz, 1H), 1.59 (ddt, J=12.8, 8.5, 4.8Hz, 1H), 1.51-1.37 (m, 2H), 1.28-1.17 (m, 1H). LCMS _RT =4.61 min, m/z=328.2[M+H] ⁺ .

LCMS retention time (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) was 4.61 min, and the measured ESI+ value [M+H] was 328.2.

SFC conditions: Column: Chiralpak ID (250mm*21.2mm, 5μm); Conditions: 0.1% _NH4OH MeOH; Start B 25% End B 25%; Flow rate (70mL/min); Column temperature 40℃.

Method 113

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

Step 1: N-methoxy-N-methyl-2-(trifluoromethoxy)acetamide

Method 2 was used to prepare the product from 2-(trifluoromethoxy)acetic acid (129 mg, 20% yield). The product was used without purification. LCMS R _{_T} = 0.88 min, m/z = 187.8 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.88 min, ESI⁺ measured [M+H] = 187.8.

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

Method 3 was used to prepare N-methoxy-N-methyl-2-(trifluoromethoxy)acetamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(trifluoromethoxy)ethyl-1-one (2 mg, 2% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.47-7.36 (m, 3H), 7.30-7.24 (m, 2H), 6.26 (ddd, J=56.2, 7.2, 1.9Hz, 1H), 5.75 (ddd, J=8.8, 6.5 , 3.1Hz, 1H), 5.50 (d, J=1.2Hz, 2H), 3.84-3.63 (m, 1H), 2.74 (dddd, J=26.8, 15.3, 3.2, 1.9Hz, 1H). LCMS _RT =5.39 min, m/z=330.1[M+H] ⁺ . LCMS retention time (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) was 5.39 min, and the measured ESI+ value [M+H] = 330.1.

Method 114

((1R,5R)-3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and ((1S,5S)-3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

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

Method 3 was used to prepare the product from 3-oxabicyclo[3.1.0]hexane-1-carboxylic acid (150 mg, 56% yield). The product was used without purification. LCMS R _{_T} = 0.72 min, m/z = 171.9 [M+H]^⁺. LCMS retention time (5 to 100% acetonitrile + 0.1% formic acid in water, within 1.6 min) was 0.72 min, ESI⁺ measured [M+H] = 171.9.

Step 2: ((1R,5R)-3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Method 3 was used to prepare N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-1-carboxamide. The crude reaction mixture was purified by RP-HPLC (20-60% acetonitrile/0.1% formic acid in water, 10 min) to give a diastereomeric mixture of (3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (30 mg, 27% yield). A mixture of diastereomers of (3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone was purified by chiral SFC (retention time = 0.736 min) to give specifically assigned ((1R,5R)-3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (28 mg, 25% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.48-7.33 (m, 3H), 7.24 (dt, J=7.8, 1.5Hz, 2H), 6.22 (dddd, J=56.4, 7.2, 3.5, 1.9Hz, 1H), 5.76-5.65 (m, 1H), 4.11-4.04 (m, 1 H), 4.00 (dd, J=8.7, 1.7Hz, 1H), 3.81-3.64 (m, 3H), 2.83-2.61 (m, 2H), 1.84 (td, J=8.3, 3.9Hz, 1H), 1.13 (dd, J=5.7, 4.0Hz, 1H). LCMS _RT =4.58 min, m/z=314.1[M+H] ⁺ .

LCMS retention time (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) was 4.58 min, and the measured ESI+ value [M+H] was 314.1.

SFC conditions: Column: Chiralcel OX (50mm*4.6mm, 3μm); Conditions: 0.1% _NH4OH MeOH; Start B 25% End B 25%; Flow rate (4mL/min); Column temperature 40℃.

((1S,5S)-3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

A mixture of diastereomers of (3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone was purified by chiral SFC (retention time = 0.914 min) to give specifically assigned ((1S,5S)-3-oxabicyclo[3.1.0]hex-1-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone (0.5 mg, 0.05% yield). LCMS R _{_T} = 4.58 min, m/z = 314.2 [M+H] ^⁺ . LCMS retention time (2 to 98% acetonitrile + 0.1% formic acid in water, within 7 minutes) was 4.58 min, and the measured ESI+ value [M+H] was 314.2.

SFC conditions: Column: Chiralcel OX (50mm*4.6mm, 3μm); Conditions: 0.1% _NH4OH MeOH; Start B 25% End B 25%; Flow rate (4mL/min); Column temperature 40℃.

Method 115

Cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl) methyl ketone, and

(S)-Cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl ketone

Step 1: 2-Bromo-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Hydrogen gas was bubbled through a solution of 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (0.90 g, 4.28 mmol) and platinum oxide (IV) (97.2 mg, 0.428 mmol) in acetic acid (43 mL). After 5 minutes, the needle-like substance was removed from the solution, and the reaction was stirred under a hydrogen atmosphere for 48 hours (~50% conversion). The reaction was filtered through a diatomaceous earth stopper using methanol. The filtrate was concentrated under reduced pressure, and the crude residue was passed to the next step without further purification.

Crude 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (0.80 g, 3.81 mmol) was added to a solution of copper(II) bromide (1.72 g, 7.61 mmol) and tert-butyl nitrite (0.750 mL, 5.71 mmol) in acetonitrile (7.6 mL) at 60 °C. The reaction was then heated at 75 °C for 1 hour. After cooling to room temperature, 1 M HCl was added. The aqueous layer was extracted with isopropyl acetate. The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 50% isopropyl acetate-heptane) to give 2-bromo-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (0.354 g, 1.27 mmol, 33% yield). LCMS _RT =1.15 min, m/z=277.8[M=H] ⁺ .

Step 2: Cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl) methyl ketone

(S)-Cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl ketone

Isopropyl magnesium chloride (2.0 M, in THF, 0.27 mL, 0.540 mmol) was added dropwise over 15 minutes at 0 °C to a solution of 2-bromo-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (50 mg, 0.180 mmol) and N-methoxy-N-methylcyclopropaneformamide (71 mg, 0.54 mmol) in THF (1.8 mL). After 1 hour, a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative TLC (100% isopropyl acetate) to give cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-a]pyridin-2-yl) ketone (20.9 mg, 0.078 mmol, 44% yield). The crude material was further purified by preparative SFC to provide specifically attributed (S)-cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-a]pyridin-2-yl) ketone.

Cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl) methyl ketone:

¹ H NMR (400MHz, DMSO-d ₆ )δ7.41-7.27(m, 3H), 7.12-7.04(m, 2H), 5.62(t, J=5.9Hz, 1H), 3.12-2.83(m, 3 H), 2.46-2.35 (m, 1H), 2.13-2.01 (m, 1H), 1.93-1, 81 (m, 2H), 1.04-0.92 (m, 4H). LCMS R _T =4.37 min, m/z =268.1 [M+H] ⁺ .

(S)-Cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl) methyl ketone:

¹ H NMR (400MHz, DMSO-d ₆ )δ7.42-7.23(m, 3H), 7.12-7.04(m, 2H), 5.62(t, J=6.0Hz, 1H), 3.12-2.85(m, 3 H), 2.45-2.35(m, 1H), 2.13-2.00(m, 1H), 1.96-1.82(m, 2H), 1.05-0.93(m, 4H). LCMS _RT =4.39 min, m/z=268.1[M+H] ⁺ .

Preparative SFC information: Column: Chiralcel OJ 5μm (250x21.2mm), Mobile phase: Carbon dioxide (A)/0.1% ammonium hydroxide in methanol (B), Isocratic elution program: 15% B

Flow rate: 70 mL/min, column temperature: 30℃, wavelength: 220 nm

Method 116

Examples 147, 148 and 149

Cyclopropyl((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and cyclopropyl-[racemic-(5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[racemic-(5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

Step 1: 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(o-tolyl)propane-1,3-dione

Bis(trimethylsilyl)aminolithium (1.0 M, in THF, 26 mL, 26 mmol) was added to a solution of 1-(o-tolyl)acetone (1.9 mL, 15 mmol) and methyl 3-bromo-1H-1,2,4-triazol-5-carboxylate (2.0 g, 9.7 mmol) in THF (32 mL) at -78 °C. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and isopropyl acetate. A 5% citric acid solution (100 mL) was added, and the aqueous layer was extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 80% isopropyl acetate-heptane) to give 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(o-tolyl)propane-1,3-dione (2.03 g, 6.59 mmol, 68% yield). LCMS R _{_T} = 1.28 min, m/z = 307.8 [M+H] ^⁺ .

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

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

Sodium borohydride (3.84 g, 97.4 mmol) was added to a solution of 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(o-tolyl)propane-1,3-dione (2.00 g, 6.49 mmol) in ethanol (130 mL) at room temperature. After 1 hour, a saturated aqueous solution of ammonium chloride was added, and the reaction was concentrated under reduced pressure. The crude residue was dissolved in isopropyl acetate and water. The aqueous layer was extracted with isopropyl acetate (6 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next step without further purification. LCMS R _{_T} = 0.96 min, m/z = 311.8 [M+H]^⁺ . Trifluoroacetic acid (65 mL) was added to a solution of the crude residue in dichloromethane (65 mL) at room temperature. After 30 minutes, the reaction was concentrated under reduced pressure. The crude residue was dissolved in dichloromethane. Water and a saturated aqueous solution of sodium bicarbonate were added. The aqueous layer was extracted with dichloromethane (4 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next step without further purification. LCMS R _{_T} = 1.08 min, m/z = 293.8 [M+H] ^⁺ , and LCMS R _{_T} = 0.98 min, m/z = 293.8 [M+H]^⁺ . Diethylaminosulfur trifluoride (3.60 mL, 26.0 mmol) was added to the solution of the crude residue in dichloromethane (65 mL) at room temperature. After 30 minutes, a saturated aqueous solution of sodium bicarbonate was carefully added. The aqueous layer was extracted with dichloromethane (4 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 10% to 100% isopropyl acetate-heptane, then 10% methanol-dichloromethane) to give (5S,7R)-2-bromo-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol and (5S,7R)-2- A 2:1 mixture (0.470 g) of bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (5S,7S)-2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.350 g, 1.18 mmol, 18% yield).

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

¹ H NMR (400MHz, DMSO-d ₆ )δ7.30-7.18 (m, 3H), 6.88 (d, J=7.6Hz, 1H), 6.30 (ddd, J=56.2, 6.8, 1.6Hz, 1H), 6.11 (td , J=6.8, 3.8Hz, 1H), 3.44-3.27 (m, 1H), 2.92 (ddt, J=27.9, 15.2, 6.5Hz, 1H), 2.36 (s, 3H). LCMS R _T =1.26 min, m/z =295.8[M+H] ⁺ .

(5S,7S)-2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.38–7.09 (m, 3H), 6.78–6.69 (m, 1H), 6.20 (ddd, J = 56.4, 7.2, 1.9 Hz, 1H), 5.95–5.80 (m, 1H), 3.69 (dddd, J = 25.4, 15.4, 8.5, 7.2 Hz, 1H), 2.66–2.51 (m, 1H), 2.39 (s, 3H). LCMS R _{_T} = 1.25 min, m/z = 295.7 [M+H] ^⁺ .

Step 3: Cyclopropyl((5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and cyclopropyl((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At 0 °C, over 15 minutes, isopropyl magnesium chloride (2.0 M, 2.4 mL, 4.76 mmol) was added dropwise to a 2:1 mixture (0.470 g) of (5S,7R)-2-bromo-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (5S,7R)-2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole in THF (15.9 mL). After 1 hour, a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (2 x 20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative HPLC/SFC to obtain cyclopropyl((5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (137 mg, 0.480 mmol) and cyclopropyl((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (33.8 mg, 0.119 mmol).

Cyclopropyl((5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.33–7.14 (m, 3H), 6.89 (d, J = 7.5 Hz, 1H), 6.35 (ddd, J = 56.2, 6.8, 1.6 Hz, 1H), 6.19 (td, J = 6.9, 3.2 Hz, 1H), 3.59–3.27 (m, 1H), 3.11–2.91 (m, 2H), 2.38 (s, 3H), 1.14–1.01 (m, 4H). LCMS R _T =4.81 min, m/z =286.1[M+H] ⁺ .

Preparative SFC information: Column: Torus Diol 5 μm (150 x 30 mm), Mobile phase: Carbon dioxide (A) / 0.1% ammonium hydroxide in methanol (B), Isocratic elution program: 5% B

Flow rate: 150 mL/min, column temperature: 25℃, wavelength: 220 nm

Cyclopropyl((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.30–7.13 (m, 3H), 7.01–6.94 (m, 1H), 6.25 (bs, 1H), 5.75 (dd, J = 8.1, 5.8 Hz, 1H), 5.23 (dd, J = 7.9, 4.6 Hz, 1H), 3.63–3.52 (m, 1H), 3.03–2.92 (m, 1H), 2.38 (s, 3H), 2.31–2.14 (m, 1H), 1.09–0.96 (m, 4H). LCMS R _T =4.08 min, m/z =284.1 [M+H] ⁺ .

Preparative HPLC information: Column: Gemini-NX C18, 5 μm (50 x 30 mm); Mobile phase: 0.1% ammonium hydroxide (A)/acetonitrile (B) in water; Elution program gradient: 10% to 60% B; Flow rate: 60 mL/min; Column temperature: 25 °C; Wavelength: 254 nm

Step 4: Cyclopropyl((5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in THF, 1.80 mL, 3.55 mmol) was added dropwise over 15 minutes to a solution of (5S,7S)-2-bromo-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.350 g, 1.18 mmol) and N-methoxy-N-methylcyclopropaneformamide (0.472 g, 3.55 mmol) in 11.8 mL of THF. After 1 hour, a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (2 x 20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give cyclopropyl((5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (0.179 g, 0.627 mmol, 53% yield) specifically assigned.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.35-7.14 (m, 3H), 6.76-6.66 (m, 1H), 6.26 (ddd, J=56.3, 7.2, 1.9Hz, 1H), 5.94 (ddd, J=8.5, 6.6, 3.2Hz, 1H), 3.94-3. 48 (m, 1H), 3.01 (ddt, J=7.6, 6.1, 5.2Hz, 1H), 2.66 (dddd, J=26.8, 15.1, 3.2, 2.0Hz, 1H), 2.42 (s, 3H), 1.18-0.99 (m, 4H). LCMS R _T =4.80 min, m/z =286.1[M+H] ⁺ .

Preparative SFC information: Column: Torus Diol 5 μm (150 x 30 mm), Mobile phase: Carbon dioxide (A) / 0.1% ammonium hydroxide in methanol (B), Isocratic elution program: 5% B

Flow rate: 150 mL/min, column temperature: 25℃, wavelength: 220 nm.

Method 117

Examples 150 and 151

Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Step 1: Methyl 3-(3-fluoropyridin-2-yl)-4,5-dihydroisoxazole-5-carboxylate

At 0 °C, triethylamine (9.8 mL, 70 mmol) was added to a solution of (2Z)-3-fluoro-N-hydroxypyridine-2-carboximidoyl chloride (12.0 g, 68.7 mmol) and methyl acrylate (6.3 mL, 70 mmol) in dichloromethane (460 mL). The reaction was warmed to room temperature and stirred for another 4 hours. Water was added, and the aqueous layer was extracted with dichloromethane (3 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give methyl 3-(3-fluoro-2-pyridyl)-4,5-dihydroisoxazole-5-carboxylate (10.6 g, 47.3 mmol, 68% yield).

For the preparation of (2Z)-3-fluoro-N-hydroxy-pyridine-2-carboxyiminoyl chloride, please refer to: WO2006/114706, 2006, A1. LCMS R _T = 0.89 min, m/z = 224.8 [M+H] ⁺ .

Step 2: 3-((tert-butyldimethylsilyl)oxy)-5-(3-fluoropyridin-2-yl)pyrrolidine-2-one

Under nitrogen atmosphere, nickel(II) hexahydrate (21.6 g, 89.2 mmol) and methyl 3-(3-fluoro-2-pyridyl)-4,5-dihydroisoxazole-5-carboxylate (10.0 g, 44.6 mmol) were dissolved in methanol (372 mL) and cooled to -30 °C. Sodium borohydride (8.79 g, 223 mmol) was added in portions over 10 minutes. The reaction was then warmed to room temperature and stirred for another hour. Ammonium hydroxide (100 mL) was added, and the reaction was stirred overnight at room temperature. The precipitate was filtered off. The filtrate was concentrated, and the crude residue was submitted to the next step without further purification. LCMS R _{_T} = 0.75 min, m/z = 196.8 [M = H] ^⁺ . To a solution of crude material and imidazole (9.11 g, 134 mmol) and tert-butyldimethylchlorosilane (13.9 g, 89.2 mmol) in dimethyl sulfoxide (89 mL), 4-dimethylaminopyridine (0.545 g, 4.46 mmol) was added. After 24 hours, the reaction mixture was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 3-[tert-butyl(dimethyl)silyl]oxy-5-(3-fluoro-2-pyridyl)pyrrolidine-2-one (9.6 g, 31 mmol, 69% yield).

^¹H NMR (400 MHz, chloroform-d) δ 8.41–8.36 (m, ¹H), 7.45–7.35 (m, ¹H), 7.31–7.22 (m, ¹H), 6.21 (s, 0.5H), 5.87 (s, 0.5H), 5.18–5.10 (m, 0.5H), 4.90 (ddd, J = 9.5, 6.3, 1.3 Hz, 0.5H), 4.59–4 .47 (m, 1H), 3.01-2.90 (m, 0.5H), 2.61 (ddd, J＝13.0, 7.5, 3.7Hz, 0.5H), 2.48 (ddd, J＝13.2, 8.1, 6.5Hz, 0.5H), 2.21 (dt, J=12.3, 9.5Hz, 0.5H), 0.93 (s, 4.5H), 0.91 (s, 4.5H), 0.22-0.13 (m, 6H). LCMS _RT =1.38 min, m/z=311.0[M+H] ⁺ .

Step 3: Ethyl 5-(3-fluoropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

At 0 °C, sodium hydride (60%, in oil, 0.390 g, 9.7 mmol) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-5-(3-fluoro-2-pyridyl)pyrrolidine-2-one (2.0 g, 6.4 mmol) in N,N-dimethylformamide (64 mL). After 30 minutes, O-diphenylphosphohydroxylamine (2.3 g, 9.7 mmol) was added. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was filtered, and the filtrate was evaporated under reduced pressure. The crude residue was submitted to the next reaction without further purification. LCMS R_{_T} = 1.34 min, m/z = 326.0 [M+H] ^⁺ , and LCMS R _{_T} = 1.30 min, m/z = 326.0 [M+H] ^⁺ . Ethyl 2-ethoxy-2-iminoacetate (2.50 g, 16 mmol) and the crude residue were dissolved in ethanol (23 mL), and the reaction was heated at 90 °C for 16 h. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was submitted to the next reaction without further purification. _{LCMSR T} = 1.38 min, m/z = 425.0 [M+H] ⁺ , and LCMS R _T = 1.34 min, m/z = 425.0 [M+H] ⁺ . p-Toluenesulfonic acid monohydrate (1.5 g, 7.7 mmol) was added to the solution of the crude residue in toluene (25 mL). The reaction was heated at 120 °C for 16 h. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was submitted to the next reaction without further purification. LCMS R_{_T} = 1.55 min, m/z = 407.0 [M+H] ^⁺ , and LCMS R _{_T} = 1.50 min, m/z = 407.1 [M+H]^⁺. Tetrabutylammonium fluoride (1.0 M, in THF, 6.4 mL, 6.4 mmol) was added to a solution of the crude residue in THF (21 mL), and the reaction was heated at 40 °C for 1 hour. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (4 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 10% methanol/dichloromethane) to give ethyl 5-(3-fluoro-2-pyridyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.800 g, 2.74 mmol, 42% yield). ¹ H NMR (400 MHz, chloroform-d) δ 8.41–8.29 (m, 1H), 7.63–7.26 (m, 2H), 6.12 (dd, J = 8.1, 4.4 Hz, 0.5H), 6.07 (d, J = 8.2 Hz, 0.5H), 5.64 (dd, J = 7.6, 4.0 Hz, 0.5H), 5.21 (d, J = 6.5 Hz, 0.5H) for a 1:1 mixture of diastereomers. ), 4.51-4.38 (m, 2H), 3.45 (ddd, J=14.7, 8.3, 6.6Hz, 0.5H), 3.29 (ddd, J=13.8, 7.5, 4.3Hz, 0 .5H), 3.10 (ddd, J=13.8, 8.1, 4.0Hz, 0.5H), 2.74 (d, J=14.4Hz, 0.5H), 1.40 (t, J=7.1Hz, 3H). LCMS R _T =0.89 min, m/z =292.9[M+H] ⁺ .

Step 4: 7-Fluoro-5-(3-Fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester

At room temperature, diethylaminosulfonate trifluoride (1.53 mL, 10.9 mmol) was added to a solution of ethyl 5-(3-fluoro-2-pyridyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.800 g, 2.74 mmol) in dichloromethane (27.4 mL). After 20 minutes, a saturated aqueous solution of sodium bicarbonate was added. The aqueous layer was extracted with dichloromethane (4 x 30 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 10% DCM-methanol) to give ethyl 7-fluoro-5-(3-fluoro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.800 g, 2.72 mmol, 99% yield). LCMS R _{_T} = 1.01 min, m/z = 294.8 [M+H] ^⁺ .

Step 5: 7-Fluoro-5-(3-Fluoropyridin-2-yl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

At room temperature, lithium hydroxide monohydrate (1.20 g, 27 mmol) was added to a solution of ethyl 7-fluoro-5-(3-fluoro-2-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.80 g, 2.7 mmol) in THF (9.1 mL), water (4.5 mL), and methanol (9.1 mL). After 1 hour, the reaction was neutralized with 1 M HCl (27 mL). The reaction was extracted with isopropyl acetate (10 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next reaction without further purification. LCMS R _{_T} = 0.83 min, m/z = 266.8 [M+H] ^⁺ . Triethylamine (1.5 mL, 11 mmol) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.790 g, 4.1 mmol), 1-hydroxybenzotriazole (0.370 g, 2.7 mmol), N,O-dimethylhydroxylamine hydrochloride (0.540 g, 5.4 mmol), and the crude residue in N,N-dimethylformamide (9.1 mL) at room temperature. After 2 hours, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by rapid column chromatography (0% to 10% methanol-dichloromethane) to give 7-fluoro-5-(3-fluoro-2-pyridinyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.224 g, 0.724 mmol, 27% yield). LCMS _RT =0.85 min, m/z=309.9[M+H] ⁺ .

Step 6: Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone and cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At -50°C, cyclopropylmagnesium bromide (0.5 M, in THF, 5.7 mL, 2.85 mmol) was added to a solution of 7-fluoro-5-(3-fluoro-2-pyridyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.220 g, 0.711 mmol) in THF (2.4 mL). After 20 minutes, the reaction was placed in a room temperature bath and stirred for 3 minutes. Water was added, and the reaction mixture was diluted with isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4 x 20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give specifically attributed cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (16.59 mg, 0.057 mmol, 8% yield) and cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (23.7 mg, 0.082 mmol, 12% yield).

Cyclopropyl ((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone: ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ8.45 (dt, J=4.6, 1.5Hz, 1H), 7.89 (ddd, J=10.0, 8.4, 1.3Hz, 1H), 7.57 (dt, J=8.6, 4.4Hz, 1H), 6.26 (ddd, J=56.6, 7 .7, 2.7Hz, 1H), 6.10-5.99 (m, 1H), 3.74 (dddd, J=19.7, 14.7, 8.5, 7.7Hz, 1H), 3.16-2.84 (m, 2H), 1.18-0.93 (m, 4H). LCMS R _T =3.64 min, m/z =291.1 [M+H] ⁺ .

Preparative SFC information: Column: Chiralcel OJ 5μm (250x21.2mm), Mobile phase: Carbon dioxide (A)/Methanol (B), Isocratic elution program: 15% B; Flow rate: 70mL/min, Column temperature: 35℃, Wavelength: 261nm

Cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.42 (dt, J = 4.6, 1.5Hz, 1H), 7.89 (ddd, J = 10.0, 8.5, 1.3Hz, 1H), 7.56 (dt, J = 8.6, 4.4Hz, 1H), 6.58–6.32 (m, 2H), 3.55–3.19 (m, 2H), 2.95 (tt, J = 7.5, 4.9Hz, 1H), 1.13–0.98 (m, 4H). LCMS R _T =3.82 min, m/z =291.1[M+H] ⁺ .

Preparative SFC information: Column: Chiralcel OJ 5μm (250x21.2mm), mobile phase: carbon dioxide (A)/methanol (B), isocratic elution program: 15% B; flow rate: 70mL/min, column temperature: 35℃, wavelength: 261nm.

Method 118

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

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)propane-1,3-dione

To a solution of methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-carboxylate (2.0 g, 5.9 mmol) and 1-(1-methylpyrazol-4-yl)acetone (1.20 g, 9.5 mmol) in THF (40 mL), lithium bis(trimethylsilyl)amino (1.0 M, in THF, 9.5 mL, 9.5 mmol) was added. The reaction mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and isopropyl acetate. A 5% citric acid solution was added, and the aqueous layer was extracted with isopropyl acetate (4 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(1-methylpyrazol-4-yl)propane-1,3-dione (2.40 g, 5.60 mmol, 94% yield). LCMS R _{_T} = 1.57 min, m/z = 427.9 [M+H] ^⁺ .

Step 2: 2-Bromo-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

At room temperature, sodium borohydride (3.30 g, 84 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(1-methylpyrazol-4-yl)propane-1,3-dione (2.4 g, 5.6 mmol) in ethanol (110 mL). After 30 min, the reaction was quenched with a saturated aqueous solution of ammonium chloride, and the volatiles were removed under reduced pressure. The crude residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next step without further purification. LCMS R _{_T} = 1.17 min, m/z = 431.9 [M+H] ^⁺ . Trifluoroacetic acid (56 mL) and dichloromethane (56 mL) were added to the crude residue, and the reaction was heated at 50 °C for 16 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The crude residue was dissolved in dichloromethane, and a saturated aqueous solution of sodium bicarbonate was added. The aqueous layer was extracted with dichloromethane (4 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next step without further purification. LCMS R _T = 0.82 min, m/z = 283.8 [M+H] ⁺ . Diethylaminosulfur trifluoride (3.1 mL, 22 mmol) was added to the solution of the crude residue in dichloromethane (56 mL) at room temperature. After 20 min, sodium bicarbonate (5.0 g) was added to the reaction. The reaction was diluted with water and isopropyl acetate. Brine was added, and the aqueous layer was extracted with isopropyl acetate (4 x 100 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (50% to 100% isopropyl acetate-heptane) to give 2-bromo-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.379 g, 1.32 mmol, 24% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.84 (s, 0.5 H), 7.78 (s, 0.5 H), 7.52 (d, J = 0.8 Hz, 0.5 H), 7.45 (d, J = 0.8 Hz, 0.5 H), 6.33–6.03 (m, 1 H), 5.88–5.74 (m, 0.5 H), 5.63–5.51 (m, 0.5 H), 3.83 (s, 1.5 H), 3.82 (s, 1.5 H), 3.65–3.47 (m, 0.5 H), 3.25–3.00 (m, 1 H), 2.81–2.64 (m, 0.5 H). LCMS R _T =0.92 min, m/z =285.8[M+H] ⁺ .

Step 3: Cyclopropyl((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At 0 °C, isopropyl magnesium chloride (2.0 M, in THF, 2.0 mL, 3.97 mmol) was added to a solution of 2-bromo-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.379 g, 1.32 mmol) and N-methoxy-N-methylcyclopropaneformamide (0.529 g, 3.97 mmol) in 13.2 mL of THF. After 5 minutes, the reaction was warmed to room temperature and stirred for another 1 hour. Water was added, and the reaction mixture was diluted with isopropyl acetate. Brine was added, and the aqueous layer was extracted with isopropyl acetate (4 x 50 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give cyclopropyl((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone (44.23 mg, 0.161 mmol, 12% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.80 (d, J=0.8Hz, 1H), 7.48 (d, J=0.8Hz, 1H), 6.21 (ddd, J=56.4, 7.0, 2.4Hz, 1H), 5.66 (ddd, J=8.2, 6.0, 3.6Hz, 1H), 3. 81 (s, 3H), 3.73-3.55 (m, 1H), 2.99 (tt, J=7.5, 4.9Hz, 1H), 2.80 (dddd, J=26.4, 14.9, 3.7, 2.4Hz, 1H), 1.14-0.95 (m, 4H). LCMS R _T =3.10 min, m/z =276.1[M+H] ⁺ .

Preparative SFC information: Column: Whelko-01 5 μm (150 x 21.2 mm), Mobile phase: Carbon dioxide (A) / 0.1% ammonium hydroxide in methanol (B), Isocratic elution program: 35% B

Flow rate: 70 mL/min, column temperature: 40℃, wavelength: 220 nm.

Method 119

Cyclopropyl (7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(5-methylisoxazol-4-yl)propane-1,3-dione

At 0 °C, bis(trimethylsilyl)aminolithium (1.0 M, in THF, 7.1 mL, 7.1 mmol) was added to a solution of methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-carboxylate (1.5 g, 4.5 mmol) and 1-(5-methylisoxazol-4-yl)acetone (0.890 g, 7.1 mmol) in THF (30 mL). After 5 minutes, the reaction was warmed to room temperature and stirred for another 30 minutes. Water was added, and the reaction was diluted with isopropyl acetate. A 10% aqueous citric acid solution was added to adjust the pH to 2. The aqueous layer was extracted with isopropyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(5-methylisoxazol-4-yl)propane-1,3-dione (1.6 g, 3.7 mmol, 84% yield). LCMS R _{_T} = 1.35 min, m/z = 428.9 [M+H] ^⁺ .

Step 2: Cyclopropyl(7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Sodium borohydride (3.30 g, 84 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(5-methylisoxazol-4-yl)propane-1,3-dione (2.4 g, 5.6 mmol) in ethanol (110 mL) at room temperature. After 30 min, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The volatiles were removed under reduced pressure. The crude residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next step without further purification. LCMS R _{_T} = 1.27 min, m/z = 432.9 [M+H]^⁺ . Sulfuric acid (10 mL) was added to the crude residue, and the reaction was heated at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water. Sodium hydroxide (3M, in water) was added until the aqueous layer became alkaline. The aqueous layer was extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was submitted to the next step without further purification. Diethylaminosulfur trifluoride (0.470 mL, 3.37 mmol) was added to a solution of the crude residue in dichloromethane (8.4 mL) at room temperature. After 20 minutes, sodium bicarbonate (2.0 g) was added. The reaction mixture was diluted with water and isopropyl acetate. Brine was added, and the aqueous layer was extracted with isopropyl acetate (4 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue (0.110 g, 0.383 mmol) was submitted to the next reaction without further purification. LCMS R _T = 1.02 min, m/z = 286.8 [M+H] ⁺ . To a solution of crude residue and N-methoxy-N-methylcyclopropaneformamide (0.153 g, 1.15 mmol) in THF (3.8 mL), isopropyl magnesium chloride (2.0 M, in THF, 0.38 mL, 0.766 mmol) was added. After 5 minutes, the reaction was warmed to room temperature and stirred for another 20 minutes. Water was added, and the reaction was diluted with isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give a diastereomeric mixture (1.26 mg, 0.0046 mmol) of cyclopropyl (7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) ketone. LCMS R _T =3.63 min, m/z =277.1 [M+H] ⁺ .

Preparative SFC information: Column: Chiracel OX 5 μm (150 x 21.2 mm), Mobile phase: Carbon dioxide (A)/Methanol (B), Isocratic elution program: 20% B; Flow rate: 70 mL/min, Column temperature: 40 °C, Wavelength: 220 nm

Method 120

Examples 154 and 155

((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone and ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-chloro-1-methyl-1H-pyrazol-3-yl)propane-1,3-dione

To a solution of methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-carboxylate (2.0 g, 5.9 mmol) and 1-(4-chloro-1-methylpyrazol-3-yl)acetone (0.940 g, 5.9 mmol) in THF (40 mL), lithium bis(trimethylsilyl)amino (1.0 M, in THF, 5.9 mL, 5.9 mmol) was added. After 5 minutes, the reaction was warmed to room temperature and stirred for another 30 minutes. Water was added, and the reaction was diluted with isopropyl acetate. A 10% aqueous citric acid solution was added to adjust the pH to 2. The aqueous layer was extracted with isopropyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(4-chloro-1-methyl-pyrazol-3-yl)propane-1,3-dione (2.40 g, 5.19 mmol, 87% yield). LCMS R _{_T} = 1.68 min, m/z = 461.9 [M+H] ^⁺ .

Step 2: ((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone and ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone

Sodium borohydride (3.10 g, 78 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(4-chloro-1-methylpyrazol-3-yl)propane-1,3-dione (2.4 g, 5.2 mmol) in ethanol (100 mL) at room temperature. After 30 minutes, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The volatiles were removed under reduced pressure. The solution was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was proceeded to the next step without further purification. Sulfuric acid (10 mL) was added to the crude residue, and the reaction was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction was diluted with water. Sodium hydroxide (3 M, in water) was added until the aqueous layer became alkaline. The aqueous layer was extracted with isopropyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was proceeded to the next step without further purification.

To a solution of the crude residue in dichloromethane (26 mL) at room temperature, add 1.5 mL of diethylaminosulfonium trifluoride (10 mmol). After 20 minutes, add sodium bicarbonate (2.0 g). Dilute the reaction mixture with water and isopropyl acetate. Add brine and extract the aqueous layer with isopropyl acetate (4 x 50 mL). Dry the combined organic layers with sodium sulfate, concentrate, and proceed to the next reaction with the crude residue (0.40 g, 1.25 mmol) without further purification. To a solution of the crude residue and N-methoxy-N-methylcyclopropaneformamide (0.498 g, 3.74 mmol) in THF (12.5 mL) at 0 °C, add isopropyl magnesium chloride (2.0 M, 1.2 mL, 2.50 mmol in THF). After 5 minutes, warm the reaction mixture to room temperature and stir for another 20 minutes. Add water and dilute the reaction mixture with isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (4 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give specifically attributed ((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone (8.4 mg, 0.027 mmol) and ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone (38.8 mg, 0.125 mmol).

((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.03 (s, 1H), 6.23 (ddd, J = 56.8, 7.8, 3.3 Hz, 1H), 5.70 (ddd, J = 8.4, 6.5, 5.0 Hz, 1H), 3.82 (s, 3H), 3.72 (ddt, J = 16.3, 14.6, 8.1 Hz, 1H), 3.02–2.82 (m, 2H), 1.14–0.99 (m, 4H). LCMS _RT =3.86 min, m/z=310.0[M+H] ⁺ .

Preparative SFC information: Column: Chiralpak IB-N 5 μm (150 x 21.2 mm), Mobile phase: Carbon dioxide (A) / 0.1% ammonium hydroxide (B) in methanol, Isocratic elution program: 20% B

Flow rate: 70 mL/min, column temperature: 40℃, wavelength: 225 nm

((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.03 (s, 1H), 6.58–6.22 (m, 1H), 6.04 (ddd, J = 7.4, 6.1, 3.1 Hz, 1H), 3.81 (s, 3H), 3.46–3.21 (m, 2H), 2.97 (tt, J = 7.6, 4.8 Hz, 1H), 1.14–1.00 (m, 4H). LCMS R _{_T} = 4.01 min, m/z = 310.0 [M+H] ^⁺ .

Preparative SFC information: Column: Chiralpak IB-N 5 μm (150 x 21.2 mm), Mobile phase: Carbon dioxide (A) / 0.1% ammonium hydroxide (B) in methanol, Isocratic elution program: 20% B

Flow rate: 70 mL/min, column temperature: 40℃, wavelength: 225 nm.

Method 121

Cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Step 1: 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(3-methoxyphenyl)propane-1,3-dione

To a solution of methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-carboxylate (3.00 g, 8.9 mmol) and 1-(3-methoxyphenyl)ethyl ketone (2.0 mL, 14 mmol) in THF (59 mL), lithium bis(trimethylsilyl)amino (1.0 M, in THF, 14 mL, 14 mmol) was added. After 5 minutes, the reaction was warmed to room temperature and stirred for another 30 minutes. Water was added, and the reaction mixture was diluted with isopropyl acetate. A 10% aqueous citric acid solution was added to adjust the pH to 2. The aqueous layer was extracted with isopropyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane)1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(3-methoxyphenyl)propane-1,3-dione (4.10 g, 9.02 mmol, 100% yield - product contaminated with 1-(3-methoxyphenyl)ethenone). LCMS R _{_T} = 1.80 min, m/z = 453.9 [M+H] ^⁺ .

Step 2: 2-Bromo-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Sodium borohydride (5.30 g, 140 mmol) was added to a solution of 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-3-(3-methoxyphenyl)propane-1,3-dione (4.1 g, 9.0 mmol) in ethanol (180 mL) at room temperature. After 30 minutes, a saturated aqueous solution of ammonium chloride was added. The volatiles were removed under reduced pressure. The crude residue was dissolved in isopropyl acetate and diluted with water. The aqueous layer was extracted with isopropyl acetate (4 x 100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was proceeded to the next step without further purification. LCMS R _{_T} = 1.40 min, m/z = 357.9 [M+H] ^⁺ . Sulfuric acid (10 mL) was added to the solution of the crude residue, and the reaction was heated at 100 °C for 2 hours. After cooling to room temperature, dilute the reaction mixture with water. Add sodium hydroxide (3M, in water) until the aqueous layer becomes alkaline. Extract the aqueous layer with isopropyl acetate (3 x 100 mL). Dry the combined organic layers with sodium sulfate, concentrate, and proceed to the next step with the crude residue without further purification. LCMS R _{_T} = 1.02 min, m/z = 309.8 [M+H] ^⁺ . Add diethylaminosulfur trifluoride (2.50 mL, 17.9 mmol) to a solution of the crude residue in dichloromethane (89 mL) at room temperature. After 20 minutes, add sodium bicarbonate (5.0 g). Dilute the reaction mixture with water and isopropyl acetate. Add brine, and extract the aqueous layer with isopropyl acetate (4 x 100 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 2-bromo-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.160 mmol, 1.79% yield). ¹ H NMR (400MHz, chloroform-d) δ7.35-7.26 (m, 1H), 6.90 (ddd, J=8.3, 2.5, 0.9Hz, 1H), 6.83 (dd, J=7.6, 1.6Hz, 1H), 6.76 (t, J=2.1 Hz, 1H), 5.97 (ddd, J=56.0, 7.1, 1.8Hz, 1H), 5.39 (t, J=9.1Hz, 1H), 3.79 (s, 3H), 3.64-3.46 (m, 1H), 2.96-2.80 (m, 1H). LCMS R _T =1.16 min, m/z =311.8[M+H] ⁺ .

Step 3: Cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At 0 °C, over 15 minutes, isopropyl magnesium chloride (2.0 M, in THF, 0.24 mL, 0.481 mmol) was added dropwise to a solution of (5S,7S)-2-bromo-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.160 mmol) and N-methoxy-N-methylcyclopropaneformamide (64 mg, 0.481 mmol) in 1.6 mL of THF. The reaction was then stirred at this temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give specifically assigned cyclopropyl-[(5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (2.35 mg, 0.0078 mmol, 5% yield). LCMS R _{_T} = 4.92 min, m/z = 302.1 [M+H] ^⁺ .

Preparative SFC information: Column: Cellulose-1 5μm (150x21.2mm), Mobile phase: Carbon dioxide (A)/Methanol (B), Elution program: Isocratic rate: 15% B; Flow rate: 70mL/min, Column temperature: 40℃, Wavelength: 220nm

Method 122

Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

Step 1: Methyl 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-oxo-propionate

To a solution of methyl 3-bromo-1H-1,2,4-triazol-5-carboxylate (20.0 g, 97.1 mmol) and methyl acetate (15.5 mL, 194 mmol) in THF (324 mL), lithium bis(trimethylsilyl)amino (1.0 M, in THF, 194 mL, 194 mmol) was added at -20 °C. After addition, the reaction mixture was warmed to room temperature and stirred overnight. The pH of the reaction was adjusted to pH 1 by adding 10% aqueous citric acid. The aqueous layer was extracted with isopropyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give methyl 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-oxo-propionate (15.4 g, 62.1 mmol, 64.0% yield). LCMS R _{_T} = 0.91 min, m/z = 247.7 [M+H] ^⁺ .

Step 2: 2-Bromo-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

Methyl 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-oxo-propionate (2.00 g, 8.1 mmol) and 3-fluoro-5-(trifluoromethyl)benzaldehyde (1.2 mL, 8.1 mmol) in benzene (8.1 mL) were added to a solution of piperidinium acetate (0.250 g, 1.6 mmol). The reaction mixture was fitted with a Dean-Stark trap and a reflux condenser and heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give methyl 2-bromo-5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-hydroxy-5H-pyrrolo[1,2-b][1,2,4]triazole-6-carboxylate (0.60 g, 1.4 mmol, 18% yield), which was immediately used for the next reaction. LCMS R _{_T} = 1.28 min, m/z = 421.8 [M+H]^⁺ .

Sodium chloride (0.830 g, 14 mmol) was added to a solution of the crude residue in dimethyl sulfoxide (4.7 mL) and water (0.47 mL). The reaction was then heated at 120 °C for 15 min, during which time the reaction was placed in a water bath at room temperature, and sodium borohydride (0.270 g, 7.1 mmol) was added. After 10 min, a saturated aqueous solution of ammonium chloride was added, and the reaction was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 2-bromo-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (0.320 g, 0.874 mmol, 61% yield). ^¹H NMR (400 MHz, chloroform-d) for a 3:1 mixture of diastereomers: δ 7.45 (s, ¹H), 7.39–7.25 (m, 2H), 5.46–5.35 (m, 2H), 3.63–3.49 (m, 0.75H), 3.18 (ddd, J = 14.3, 7.5, 2.5 Hz, 0.25H), 2.90 (ddd, J = 14.2, 7.1, 6.1 Hz, 0.25H), 2.66 (ddd, J = 14.5, 3.9, 3.0 Hz, 0.75H). LCMS R _{_T} = 1.19 min, m/z = 365.8 [M+H] ^⁺ .

Step 3: 2-Bromo-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

To a solution of 2-bromo-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (0.320 g, 0.874 mmol) in dichloromethane (17.5 mL), diethylaminosulfur trifluoride (0.230 mL, 1.75 mmol) was added. After 10 minutes, a saturated aqueous solution of sodium bicarbonate was added. The reaction mixture was diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by rapid column chromatography (silica gel, 0% to 100% isopropyl acetate-heptane) to give 2-bromo-7-fluoro-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.250 g, 0.679 mmol, 78% yield). ^¹H NMR (400 MHz, chloroform-d) for a 3:1 mixture of diastereomers: δ 7.42–7.33 (m, ¹H), 7.27 (d, J = 12.2 Hz, ¹H), 7.15–7.04 (m, ¹H), 6.14–5.88 (m, ¹H), 5.72 (td, J = 6.8, 3.6 Hz, 0.75 H), 5.60–5.44 (m, 0.25 H), 3.70–3.52 (m, 0.25 H), 3.41 (dddd, J = 22.4, 15.3, 7.0, 1.3 Hz, 0.75 H), 3.01–2.80 (m, ¹H). LCMS: R _{_T} = 1.35 min, m/z = 367.7 [M+H] ^⁺ .

Step 4: Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone

At 0 °C, over 15 minutes, isopropyl magnesium chloride (2.0 M, in THF, 1.0 mL, 2.04 mmol) was added dropwise to a solution of N-methoxy-N-methylcyclopropaneformamide (0.271 g, 2.04 mmol) and 2-bromo-7-fluoro-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (0.250 g, 0.679 mmol) in THF (6.8 mL). After 1 hour, a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (2 x 20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the crude residue was purified by preparative SFC to give cyclopropyl-[7-fluoro-5-[3-fluoro-5-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (3.47 mg, 0.0097 mmol, 1.4% yield). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.76 (dt, J=8.8, 2.1Hz, 1H), 7.61 (s, 1H), 7.47 (dt, J=9.4, 1.9Hz, 1H), 6.26 (ddd, J=56.2, 7.0, 2.1Hz, 1H), 5.89 (ddd, J=8.9, 6.2, 3.4H z, 1H), 3.86-3.66 (dddd, J=25.2, 15.4, 8.5, 7.1Hz, 1H), 3.09-2.93 (m, 1H), 2.83 (dddd, J=26.1, 15.2, 3.4, 2.2Hz, 1H), 1.16-0.99 (m, 4H). LCMS _RT =5.51 min, m/z=358.1[M+H] ⁺ .

Preparative SFC information: Column: Whelko-01 5μm (150x21.2mm), mobile phase: carbon dioxide (A)/methanol (B), isocratic elution program: 20% B; flow rate: 70mL/min, column temperature: 40℃, wavelength: 220nm.

Method 123

(1-((1H-pyrazol-1-yl)methyl)cyclopropyl)(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl ketone

According to methods 2 and 3, (1-((1H-pyrazol-1-yl)methyl)cyclopropyl)(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl ketone was prepared from (1R,2R)-2-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid. The crude residue was further purified by preparative HPLC (Gemini-NX C18 50x30 mm, 5 μm, 20-60% formic acid/acetonitrile in water) to give the final product (20.2 mg, 32%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.57 (d, J=2.2Hz, 1H), 7.44-7.30 (m, 4H), 7.26-7.18 (m, 2H), 6.16 (d, J=2.2Hz, 1H), 5.60 (dd, J=8.3, 5.8H z, 1H), 4.63 (q, J=14.4Hz, 2H), 3.22-2.81 (m, 2H), 2.61-2.28 (m, 1H), 1.70-1.53 (m, 2H), 1.35-1.13 (m, 3H). LCMS _RT =4.31 min, m/z=334.2(M+H) ⁺ . LCMS retention time (5-95% acetonitrile + 0.1% formic acid in water, within 10 minutes) was 4.31 min, and the measured ESI+ value [M+H] = 334.2.

Other chiral SFC purification and analysis conditions:

SFC 1

Cyclopropyl ((4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) methyl ketone

Specifically assigned cyclopropyl((4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) methyl ketone (7.9 mg, 55% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.46–7.28 (m, 3H), 7.28–7.07 (m, 2H), 6.94 (d, J = 2.6 Hz, 1H), 6.34–5.96 (m, 1H), 5.88–5.51 (m, 1H), 2.94–2.75 (m, 1H), 2.76–2.55 (m, 1H), 2.07 (s, 1H), 1.04–0.74 (m, 4H). LC-MS R _T =5.11 min, m/z =271.1(M+H) ⁺ .

SFC 2

[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-(trifluoromethyl)cyclopropyl] methyl ketone

The specifically assigned [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-(trifluoromethyl)cyclopropyl] methyl ketone (4.2 mg, 31% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.59–7.08 (m, 5H), 6.50–6.06 (m, 1H), 5.93–5.55 (m, 1H), 3.76–3.25 (m, 1H), 2.58 (d, J = 2.5 Hz, 1H), 1.88–1.15 (m, 2H). LC-MS R _{_T} = 5.36 min, m/z = 340.1 (M+H) ^.

SFC 3

[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1R,2R)-2-(trifluoromethyl)cyclopropyl] methyl ketone

The specifically assigned [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1R,2R)-2-(trifluoromethyl)cyclopropyl] methyl ketone (12.2 mg, 89% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.50–7.13 (m, 5H), 6.51–6.05 (m, 1H), 5.93–5.49 (m, 1H), 3.90–3.54 (m, 1H), 2.84–2.59 (m, 1H), 2.62–2.53 (m, 1H), 2.07 (s, 1H), 1.64–1.26 (m, 2H). LC-MS _RT =5.40min, m/z=340.1(M+H) ⁺ .

SFC 4

[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2S)-spiro[2,2]pentan-2-yl] ketone.

The methyl methacrylate [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2S)-spiro[2,2]pentan-2-yl] ketone (3.2 mg, 39% yield) was determined by specific classification. LC-MS R _{_T} = 4.95 min, m/z = 298.1 (M+H) ^⁺ .

SFC 5

[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2R)-spiro[2,2]pentan-2-yl]methyl ketone

The methyl [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2R)-spiro[2,2]pentan-2-yl] methyl ketone (x mg, x% yield) was determined by specific classification. LC-MS R _{_T} = 4.94 min, m/z = 298.1 (M+H).

*All column temperatures were 40°C, except for the SFC 1 preparation (which was 30°C).

RIP1 kinase inhibition assay (biochemical assay)

The ability of the compounds of the present invention to inhibit RIP1K activity was tested as described below.

Enzyme Assay: The ability of receptor-interacting protein kinase 1 (RIPK1) to catalyze the hydrolysis of adenosine-5′-triphosphate (ATP) was monitored using a Transcreener ADP (adenosine-5′-bisphosphate) assay (BellBrook Labs). The purified human RIP1 kinase domain (2-375) (50 nM) from a baculovirus-infected insect cell expression system was incubated with the test compound for 2 h in 50 mM Hepes buffer (pH 7.5) containing ₃₀ mM MgCl2, 1 mM dithiothreitol, 50 μM ATP, 0.002% Brij-35, and 0.5% dimethyl sulfoxide (DMSO). The reaction was quenched by adding 1X Bell Brooks stop buffer B (20 mM Hepes (pH 7.5), 40 mM EDTA, 55 μg/mL ADP2 antibody, and 4 nM 633 tracer). The tracer bound to the antibody was replaced by ADP generated during the RIP1K reaction, resulting in reduced fluorescence polarization as measured using a FP microplate reader M1000 via laser excitation at 633 nm. Fractional activity was plotted against sample concentration. The data were fitted to the tight-binding epigenetic inhibition constant ( _Kiapp ) Morrison equation using Genedata Screener software (Genedata; Basel, Switzerland) [Williams, JW and Morrison, JF (1979) The kinetics of reversible tight-binding inhibition ^{. Methods} Enzymol 63: 437-67]. The following equation was used to calculate fractional activity and _Kiapp :

[E] _T and [I] _T are the total concentrations of the active enzyme and the test sample, respectively.

Exemplary compounds of the present invention are provided in Tables 1 and 2, along with their physicochemical characterization and in vitro RIP1 kinase inhibitory activity data. The “Method” in the first column of each table refers to one or more synthetic methods for preparing each compound as shown in the examples above. In some embodiments, chiral column retention times (min) are provided for certain stereoisomers. Unless otherwise stated, the stereochemistry shown in each structure represents the relative configuration of a single stereoisomer, and the absolute configuration (i.e., “R” and/or “S”) is arbitrarily assigned. In some embodiments, when the method is described as including the isolation of stereoisomers, a single stereoisomer of the compounds in Table 1 or Table 2 is provided.

Table 1

Table 2

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety.

Although the foregoing invention has been described in considerable detail for ease of understanding, it will be apparent that certain variations and modifications may be made within the scope of the appended claims. Therefore, the described embodiments should be considered exemplary rather than restrictive, and the invention is not limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

Claims (27)

1. A compound of formula (I): Or its medicinal salt, in which ^R1 is selected from the group consisting of: _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 -C6 haloalkoxy, phenyl, benzyl, 4- to ₈ -membered heterocyclic and 5- to 6-membered heteroaryl; wherein ^R1 is linked to an adjacent carbonyl group via a carbon atom, and wherein ^R1 is optionally substituted by one or two substituents selected from the group consisting of: F, Cl, Br, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, C1- _C6 alkoxy, _C1 - _C6 haloalkyl, _{C1 - C6} haloalkoxy, hydroxy, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O) _C1 - _C6 alkyl, phenyl, benzyl, _CH2- ( _C3 - _C6 cycloalkyl), 5- to 6-membered heteroaryl and _CH2 -(5 to 6-membered heteroaryl groups); Together, select the following groups from both ring A and ring B: in ^R2 is selected from the group consisting of: _C1 - _C6 haloalkyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, C1- _C6 haloalkoxy, _C1 - _C6 alkylthio, phenyl, benzyl, _CH2- ( _C3 - _C6 cycloalkyl), _{CH2CH2-(C3-C6 cycloalkyl), CH2- ( 4-} to 6 _- membered heterocyclic), _CH2CH2- ( _4- to 6-membered heterocyclic), 5- to ₆ -membered heteroaryl, and _CH2- ( _5- to 6-membered heteroaryl); wherein, when a benzene ring or a 5- to 6-membered heteroaryl ring is present, it may be substituted by 1 to 3 substituents selected from the group consisting of: halogen, _C1 - _C4 alkyl, _C1 - _{C4 haloalkyl, C1-C4 alkoxy , C1} - _C4 haloalkoxy, and cyano; and The choices for ^R3a and ^R3b are as follows: (i) One of ^R3a and ^R3b is H, and the other is selected from the group consisting of: D, halogen, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; or (ii) Each of ^R3a and ^R3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, provided that ^R3a and ^R3b cannot both be OH or CN. 2. The compound according to claim 1, or a pharmaceutical salt thereof, wherein ring A and ring B together are selected from the group consisting of: 3. The compound according to claim 1, or a pharmaceutical salt thereof, wherein ring A and ring B together are: 4. The compound according to claim 1, or a pharmaceutical salt thereof, wherein ^R2 is selected from the group consisting of: phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl, dichlorophenyl, pyridyl, monochloropyridyl, monofluoropyridyl, pyrazolyl, 1-methyl-1H-pyrazol-4-yl and 4-chloro-1-methyl-1H-pyrazol-3-yl. 5. The compound according to claim 1, or a pharmaceutical salt thereof, wherein ring A and ring B together are selected from the group consisting of: in The choices for ^R3a and ^R3b are as follows: (i) One of ^R3a and ^R3b is H, and the other is selected from the group consisting of: D, F, Cl, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; or (ii) Each of ^R3a and ^R3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, provided that ^R3a and ^R3b cannot both be OH or CN; ^R5 are each selected from the group consisting of: H, F, Cl, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; and m can be 1, 2, or 3. 6. The compound according to claim 1, or a pharmaceutical salt thereof, wherein ring A and ring B together are: in ^R5 are each selected from the group consisting of: H, F, Cl, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, _C1 - _C4 alkoxy, and _C1 - _C4 haloalkoxy; and m can be 1, 2, or 3. 7. A compound, or a pharmaceutical salt thereof, wherein said compound is selected from the group consisting of: ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2R)-2-fluorocyclopropyl) methyl ketone; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; 2-Hydroxy-2-methyl-1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 2-Hydroxy-2-methyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 2-Phenyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]acetone; (7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[racemic-(1S,2S)-2-fluorocyclopropyl] ketone; (2,2-Difluorocyclopropyl)-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Phenyl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 1-[racemic-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(trifluoromethyl)cyclopropyl] ketone; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3-methyloxetane-3-yl) ketone; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[racemic-(1S,2R)-2-fluorocyclopropyl] ketone; 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-1-one; Cyclopropyl-[racemic-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)prop-1-one; 1-[racemic-(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propyl-1-one; 3-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-3-oxo-propionitrile; (S)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)prop-1-one; 1-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxy-2-methyl-prop-1-one; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl) ketone; 1-[racemic-(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]prop-1-one; 3,3,3-Trifluoro-1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 1-[racemic-(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 1-[racemic-(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 1-[racemic-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl)methyl ketone; Cyclopropyl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopentyl-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; 2,2-Dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 2,2-Dimethyl-1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; (1-Methylpyrazol-4-yl)-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-thienyl)methyl ketone; Cyclopropyl-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Cyclobutyl-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-prop-1-one; 1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-prop-1-one; 1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; (1-Methylpyrazol-4-yl)-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 1-[racemic-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]acetone; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2S)-2-fluorocyclopropyl) methyl ketone; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1S,2R)-2-fluorocyclopropyl) methyl ketone; (1-Fluorocyclopropyl)-(racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; (3-Methyloxetane-3-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 3-Oxabicyclo[3.1.0]hex-6-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Oxycyclobut-3-yl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [1-(hydroxymethyl)cyclopropyl]-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; [(1R)-2,2-difluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(1S)-2,2-difluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (1-Fluorocyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone; Cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[racemic-(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (3,3-Difluorocyclobutyl)-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone; [(1S,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2-fluorocyclopropyl] methyl ketone; [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S)-2-fluorocyclopropyl] methyl ketone; Cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(1R,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (2,2-Difluorospiro[2.3]hex-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone; 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; (3,3-Difluorocyclobutyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone; [2-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-methylcyclopropyl] ketone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hex-5-yl methyl ketone; Cyclopropyl-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[racemic-(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] ketone; [1-(fluoromethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (3,3-Difluoro-6-bicyclo[3.1.0]hexyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(trifluoromethyl)cyclopropyl] ketone; (6,6-Difluoro-3-bicyclo[3.1.0]hexyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 2-[1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]cyclopropyl]acetonitrile; Cyclopropyl-[(5S,7S)-7-methoxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-7-fluoro-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 2-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl]-cyclopropanecarboxylonitrile; Cyclopropyl-[(5S,7S)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2S)-2-methylcyclopropyl] ketone; [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2R)-2-methylcyclopropyl] ketone; Cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxylon; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,2]pent-2-yl-methyl ketone; [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2,3]hex-2-yl-methyl ketone; [1-(2-pyridyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (1-Cyclopropylcyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methyl ketone; Cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7S)-5-(2,5-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-7-deuterated-7-fluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Racemic-(1R,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl]cyclopropanecarboxylon; Cyclopropyl-[(5S,7S)-5-(2,3-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-7-fluoro-5-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-5-cyclopropyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-7-deuterated-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5R,7S)-5-(cyclopropylmethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S)-7,7-dideuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5R,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7R)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[racemic-(5S,7S)-5-(3-chloro-2-pyridyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[racemic-(5S,7S)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[racemic-(5S,7R)-7-chloro-7-deuterated-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-5-(1,1-difluoropropyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[racemic-(5S,7S)-5-(1,1-difluoroethyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-5-(3-chloro-2-pyridinyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 2-[(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile; (1-Ethylcyclopropyl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]tetrahydropyran-4-yl-methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]tetrahydropyran-3-yl-methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2R)-pyrrolidin-2-yl] methyl ketone; (2-Methyltetrahydrofuran-2-yl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]tetrahydrofuran-3-yl-methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(3S)-tetrahydrofuran-3-yl] methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(3R)-tetrahydrofuran-3-yl] methyl ketone; 3-Methoxy-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; Racemic-(2S)-3,3,3-trifluoro-2-hydroxy-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]prop-1-one; 1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-tetrahydropyran-2-yl-acetone; 1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-tetrahydropyran-4-yl-acetone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(3R)-3-methyltetrahydrofuran-3-yl] ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(3S)-3-methyltetrahydrofuran-3-yl] ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1R,2R,4S)-7-oxabicyclo[2.2.1]hept-2-yl]methyl ketone; ((1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; ((1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-yl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; 1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-(trifluoromethoxy)ethyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1R,5R)-3-oxabicyclo[3.1.0]hex-1-yl] methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,5S)-3-oxabicyclo[3.1.0]hex-1-yl] methyl ketone; Cyclopropyl-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl) ketone; (S)-Cyclopropyl(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl) methyl ketone; Cyclopropyl((5S,7R)-7-hydroxy-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Cyclopropyl-[racemic-(5S,7R)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[racemic-(5S,7S)-7-fluoro-5-(o-tolyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Cyclopropyl((5S,7R)-7-fluoro-5-(3-fluoropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Cyclopropyl((5S,7S)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Cyclopropyl(7-fluoro-5-(5-methylisoxazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; ((5S,7S)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone; ((5S,7R)-5-(4-chloro-1-methyl-1H-pyrazol-3-yl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(cyclopropyl) methyl ketone; Cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; Cyclopropyl((5S,7S)-7-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; (5-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(pyrazol-1-ylmethyl)cyclopropyl] ketone; Cyclopropyl((4S,6S)-4-fluoro-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) methyl ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1S,2S)-2-(trifluoromethyl)cyclopropyl] ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(1R,2R)-2-(trifluoromethyl)cyclopropyl] ketone; [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2S)-spiro[2,2]pentan-2-yl] ketone; and [racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[racemic-(2R)-spiro[2,2]pentan-2-yl] ketone. 8. A compound, or a pharmaceutical salt thereof, wherein said compound is selected from the group consisting of: 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl-1-one; ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2R)-2-fluorocyclopropyl) methyl ketone; Phenyl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl) ketone; Cyclopropyl((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; and Cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone. 9. A compound, or a pharmaceutical salt thereof, wherein the compound is 1-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl-1-one. 10. A compound, or a pharmaceutical salt thereof, wherein the compound is ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2R)-2-fluorocyclopropyl) methyl ketone. 11. A compound, or a pharmaceutical salt thereof, wherein the compound is phenyl-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone. 12. A compound, or a pharmaceutical salt thereof, wherein the compound is (racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl) ketone. 13. A compound, or a pharmaceutical salt thereof, wherein the compound is cyclopropyl((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone. 14. A compound, or a pharmaceutical salt thereof, wherein the compound is [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone. 15. A compound, or a pharmaceutical salt thereof, wherein the compound is cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone. 16. A compound, or a pharmaceutical salt thereof, wherein the compound is cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone. 17. A compound, or a pharmaceutical salt thereof, wherein the compound is cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone. 18. A compound, or a pharmaceutical salt thereof, wherein the compound is cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone. 19. A pharmaceutical composition comprising a compound according to any one of claims 1-18 or a pharmaceutical salt thereof, and a therapeutically inert carrier. 20. The compound or its pharmaceutical salt according to any one of claims 1-18, which is used as a therapeutically active substance. 21. The compound or its pharmaceutical salt according to any one of claims 1-18, for the treatment of diseases or conditions selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, tau proteinosis, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases. 22. The compound or its pharmaceutical salt according to any one of claims 1-18, for the treatment of diseases or conditions selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis. 23. The compound or its pharmaceutical salt according to any one of claims 1-18, for the treatment of Crohn's disease or ulcerative colitis. 24. The compound or pharmaceutical salt thereof according to any one of claims 1-18, for the treatment of diseases or conditions selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, ischemia-reperfusion injury of parenchymal organs, cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS). 25. Use of the compound or pharmaceutical salt thereof according to any one of claims 1-18 for the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis. 26. Use of the compound or a pharmaceutical salt thereof according to any one of claims 1-18 for the preparation of a medicament for the treatment of Crohn's disease or ulcerative colitis. 27. Use of the compound or pharmaceutical salt thereof according to any one of claims 1-18 for the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, ischemia-reperfusion injury of parenchymal organs, cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS).