Bicyclic ketone compounds and methods of use thereof

Abstract

To provide inhibitors of RIP1 kinase useful for treating diseases and disorders associated with inflammation, cell death and others, and uses thereof.SOLUTION: There are provided novel compounds having general formula (I), and pharmaceutical compositions comprising the compounds. Specifically, for example, the following compounds are shown.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to organic compounds useful for therapy and / or prophylaxis in mammals, particularly inhibitors of RIP1 kinase, useful for treating diseases and disorders associated with inflammation, cell death and the like.

[0002] 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 most well-studied form of necroptotic cell death is initiated by TNFα (tumor necrosis factor-1), but necroptosis can also be induced by other members of the TNFα death ligand family (Fas and TRAIL / Apo2L), interferons, Toll-like receptor (TLR) signaling, and viral infection via the DNA sensor DAI (DNA-dependent activator of interferon regulatory factor) [1-3]. 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 domains present in both proteins [4]. Following initial recruitment to the TNFR1-associated signaling complex, RIP1 translocates to a secondary cytoplasmic complex, Complex-II [5-7]. Complex-II is formed by the death domain-containing 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, forming the necrosome, which leads to the initiation of necroptotic cell death [8-10]. Once the necrosome is formed, RIP1 and RIP3 participate in a series of auto- and cross-phosphorylation events that are essential for necroptotic cell death. Necroptosis can be completely blocked by kinase-inactivating mutations in either of the two kinases or chemically by RIP1 kinase inhibitors (necrostatins) or RIP3 kinase inhibitors [11-13]. Phosphorylation of RIP3 allows binding and phosphorylation of the pseudokinase MLKL (mixed lineage kinase domain-like), a key component of necroptotic cell death [ 14 , 15 ].

[0003] Necroptosis has important pathophysiological relevance in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel disease, retinal degeneration, and many other common clinical disorders.

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

[0004] Inhibitors of RIP1 kinase have been reported. The first publicly-described inhibitor of RIP1 kinase activity was necrostatin 1 (Nec-1)

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

[0005] The above cited references are each incorporated herein by reference in their entirety: [Table 1] TIFF0007734163000002.tif218165 Summary of the Invention

[0006] Formula I: [ka] (In the formula, R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl; R 1 is attached to the adjacent carbonyl by a carbon atom, and R 1is F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, hydroxyl, 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); each R N are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; or two R N may form a 4- to 6-membered ring together with the adjacent N; Ring A is a 5-membered heteroaryl having only one of the following heteroatoms: (i) 2 to 3 nitrogen atoms, (ii) 1 nitrogen atom and 1 oxygen atom, or (iii) 1 nitrogen atom and 1 sulfur atom; Ring A is bonded to the adjacent carbonyl by a carbon atom; and Ring B is a 4-8 membered cycloalkyl or a 4-8 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; Ring B is substituted according to (a), (b), or both (a) and (b): (a) Halogen, deuterium, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N ) 2, and 1 to 2 substituents selected from the group consisting of cyano; wherein the two C1-C6 alkyl substituents may be joined together to form a bridged or spirocyclic ring; and when the nitrogen atom in ring B is substituted, the substituent is not halogen, cyano, or C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom; (b) C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N )2, one substituent selected from the group consisting of phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclyl), CH2CH2-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl); wherein the phenyl ring or the 5- to 6-membered heteroaryl ring, when present, is optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, and cyclopropyl). or a pharmaceutically acceptable salt thereof.

[0007] Also provided herein are pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Certain embodiments include pharmaceutical compositions suitable for oral delivery.

[0008] Also provided herein are oral formulations of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

[0009] Also provided herein are methods for treating diseases and disorders associated with RIP1 kinase-associated inflammation, cell death, and the like, as further described below.

[0010] Also provided herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances.

[0011] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson-plus syndrome, taupathies, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0012] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any one of the embodiments provided herein, for the treatment of a disease or disorder selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson-plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0013] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson-plus syndrome, tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0014] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

[0015] [Detailed Description of the Invention] definition As provided herein, all chemical formulas and general chemical structures should be interpreted as providing appropriate valences and chemically stable bonds between atoms as understood by those skilled in the art. If necessary, a substituent may be bonded to more than one adjacent atom (e.g., alkyl includes methylene when two bonds are present).

[0016] In the chemical formulas provided herein, "halogen" or "halo" refers to fluorine, chlorine, or bromine (i.e., F, Cl, Br).

[0017] Unless otherwise defined, alkyl refers to an optionally substituted straight or branched chain C-C 12In some embodiments, alkyl refers to 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), NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl), S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SON2NH(C1-C4 alkyl), SON2N(C1-C4 alkyl), and NHSO2(C1-C4 alkyl). In some embodiments, the substituted alkyl group has 1 to 2 substituents. In some embodiments, the alkyl group is unsubstituted.

[0018] Unless otherwise defined, cycloalkyl includes optionally substituted C-C 12"Cycloalkyl" refers to a cycloalkyl group, including fused, spirocyclic, and bridged bicyclic groups, where 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), NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl), S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SON2NH(C1-C4 alkyl), SON2N(C1-C4 alkyl), and NHSO2(C1-C4 alkyl). In some embodiments, cycloalkyl refers to a C3-C6 cycloalkyl group. In some embodiments, the C3-C6 cycloalkyl group is optionally substituted with 1 to 3 halogen atoms. In some embodiments, the C3-C6 cycloalkyl group is optionally substituted with 1 to 3 fluorine atoms. Exemplary C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Exemplary C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 12 Cycloalkyl groups further include bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[4.1.0]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantanyl, decanylyl, and spiro[5.4]decanyl. Where appropriate, cycloalkyl groups may be fused to other groups such that there are two or more chemical bonds between the cycloalkyl group and another ring system (e.g., ring C of Formula I). ​​In some embodiments, the cycloalkyl group is unsubstituted.

[0019] Unless otherwise defined, haloalkyl refers to a straight or branched C-C alkyl group in which one or more hydrogen atoms are replaced by halogen. 12In some embodiments, haloalkyl refers to a C1-C6 haloalkyl group. In some embodiments, 1 to 3 hydrogen atoms of the haloalkyl group are replaced by halogen. In some embodiments, each hydrogen atom of the haloalkyl group is replaced by halogen (e.g., trifluoromethyl). In some embodiments, haloalkyl is as defined herein, and halogen in each instance is fluorine. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and pentafluoroethyl.

[0020] Unless otherwise defined, alkoxy refers to a straight or branched C-C alkyl group in which one or more oxygen atoms are present in each case between two carbon atoms. 12

[0023] In some embodiments, alkoxy refers to a C1-C6 alkoxy group. In some embodiments, the C1-C6 alkoxy groups provided herein have one oxygen atom. Exemplary alkoxy groups include methoxy, ethoxy, CHOCH3, CH2CHOCH3, CHOCH2CH3, CH2CHOCH2CH3, CH2CHOCH2CH3, CH2CHOCH2CH2CH3, CH2CHOCH(CH3), CH2OC(CH3), CH(CH3)OCH3, CH2CH(CH3)OCH3, CH(CH3)OCH2CH3, CHOCH2OCH3, CH2CHOCH2CH2OCH3, and CHOCH2OCH2OCH3.

[0021] Unless otherwise defined, cycloalkoxy is a C-C alkyl group as defined above. 10 or a C4-C6 alkoxy group, wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0022] Unless otherwise defined, haloalkoxy refers to a C1-C6 haloalkyl group, as defined above, in which there are 1 to 2 oxygen atoms between each pair of carbon atoms. In some embodiments, the C1-C6 haloalkoxy groups provided herein have one oxygen atom. Exemplary haloalkoxy groups include OCF3, OCHF2, and CH2OCF3.

[0023] Unless otherwise defined, thioalkyl is a C-C alkyl group as defined above. 12 or a C1-C6 alkoxy group in which an oxygen atom is replaced by a sulfur atom. In some embodiments, a thioalkyl group can contain a sulfur atom replaced by one to two oxygen atoms (i.e., alkylsulfone and alkylsulfoxide). Exemplary thioalkyl groups are those exemplified in the definition of alkoxy above (in each case, each oxygen atom is replaced by a sulfur atom).

[0024] Unless otherwise defined, thiocycloalkyl is a C-C alkyl group as defined above. 10 or a C4-C6 thioalkyl group, where the 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., a cyclic sulfone or sulfoxide). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiolanyl, and 1,1-dioxothianyl.

[0025] Unless otherwise defined, heterocyclyl refers to a single saturated or partially saturated 4- to 8-membered ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur; the term also includes multiple fused ring systems having at least one such saturated or partially unsaturated ring, the multiple fused ring systems having 7 to 12 atoms, as 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 about 1 to 7 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The ring may be C-branched (i.e., substituted with C-C alkyl). The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. Where valency requirements permit, rings of a fused ring system can be connected to each other via fused, spiro, and bridged bonds. It should be understood that the individual rings of a fused ring system can be connected to each other in any order. It should also be understood that the point of attachment of a fused ring system (as defined above for heterocycles) can be at any position on the fused ring system. It should also be understood that the point of attachment to a heterocycle or to a fused ring system of a heterocycle can be at any suitable atom of the heterocyclyl group, including carbon and nitrogen atoms.Exemplary heterocycles include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one. These include, but are not limited to, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidin-2-one.

[0026] In some embodiments, heterocyclyl is a C-C heterocyclic ring having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. 10 In some embodiments, the heterocyclyl group is not bicyclic or spirocyclic. In some embodiments, the heterocyclyl is a C5-C6 heterocyclyl having 1 to 3 heteroatoms, and if there are 3 heteroatoms, at least 2 of them are nitrogen.

[0027] Unless otherwise defined, aryl refers to a single all-carbon aromatic ring or an all-carbon fused ring system in which at least one of the rings is aromatic, with the aryl group having 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl radicals. Aryl also includes fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic, and the other rings may or may not be aromatic (i.e., carbocyclic). Such fused ring systems are optionally substituted by one or more (e.g., 1, 2, or 3) oxo groups on any portion of the carbocyclic ring of the fused ring system. Where valence requirements permit, the rings of the fused ring system may be connected to each other via fused, spiro, and bridged bonds. It should be understood that the point of attachment of the multiple fused ring systems defined above may be at any position on the ring system, including the aromatic or carbocyclic portions of the ring. Exemplary aryl groups include phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0028] Unless otherwise defined, heteroaryl refers to a 5-6-membered aromatic ring having at least one atom other than carbon within the ring, which atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple fused ring systems having 8-16 atoms and at least one such aromatic ring, which multiple fused ring systems are further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. When the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized form. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes multiple fused ring systems (e.g., ring systems containing two to three rings) in which a heteroaryl group, as defined above, is fused with one or more rings selected from heteroaryl (e.g., to form naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a multiple fused ring system. Thus, a heteroaryl (single aromatic ring or multiple fused ring system) has 1 to 15 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. Such multiple fused ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. Where valency requirements permit, rings of multiple fused ring systems can be connected to each other via fused, spiro, and bridged bonds. It should be understood that the individual rings of multiple fused ring systems can be connected to each other in any order. It should also be understood that the point of attachment of multiple fused ring systems (as defined above for heteroaryl) can be at any position of the multiple fused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portions of the multiple fused ring system.It should also be understood that the point of attachment for a heteroaryl or heteroaryl multiple fused ring system may be any suitable atom of the heteroaryl or heteroaryl multiple fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

[0029] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0030] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0031] As used herein, a wavy line crossing a bond in a chemical structure [ka] indicates the point of attachment of the bond that the wavy bond crosses in the chemical structure to the rest of the molecule.

[0032] As used herein, the term "C-linked" means that the group it describes is attached to the remainder of the molecule through a ring carbon atom.

[0033] As used herein, the term "N-linked" means that the group it describes is attached to the rest of the molecule through a ring nitrogen atom.

[0034] "Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0035] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0036] Stereochemical definitions and conventions used herein generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and, therefore, can exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, and mixtures thereof (such as racemic mixtures), are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to describe the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by a compound; (-) or l means the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may also be referred to as 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 may occur when there is neither stereoselection nor stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, lacking optical activity.

[0037] When a bond in a compound formula herein is drawn non-stereochemically (e.g., planar), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn stereochemically as defined (e.g., as a bold line, a bold-wedge, a dotted line, or a dotted-wedge), unless otherwise specified, the atom to which the stereochemical bond is attached is to be understood to be enriched in the absolute stereoisomer depicted. In one embodiment, the compound may be at least 51% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 97% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 98% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% of the absolute stereoisomer depicted.

[0038] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as protic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0039] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. In some embodiments, the hydrate of a compound provided herein is a ketone hydrate.

[0040] As used herein, the term "protecting group" refers to a substituent commonly used to block or protect a particular functional group in a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of the hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For an overview of protecting groups and their use, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4 th See, e.g., Wiley-Interscience, New York, 2006.

[0041] As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0042] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0043] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of the present invention.

[0044] In addition to salt forms, the present invention provides compounds in prodrug form. As used herein, the term "prodrug" refers to a compound that readily undergoes chemical changes under physiological conditions to provide a compound of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0045] Prodrugs of the present invention include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently bonded via an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of the present invention. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, commonly represented by their three-letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, gamma-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0046] Additional types of prodrugs are also encompassed. For example, free carboxyl groups of compounds of the invention can be derivatized as amides or alkyl esters. As another example, compounds of the invention containing free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group to groups such as, but not limited to, phosphate esters, hemisuccinate esters, dimethylaminoacetate esters, or phosphoryloxymethyloxycarbonyl groups, as reviewed 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 ester prodrugs of hydroxy and amino groups are also encompassed, as are carbonate ester, sulfonate ester, and sulfate ester prodrugs of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers (wherein the acyl group can be an alkyl ester (optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities) or the acyl group is an amino acid ester as described above) is also encompassed. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include prodrugs in which the hydrogen atom of the alcohol group is replaced with (C 1-6 ) alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, alpha-amino (C 1-4 ) alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl (each alpha-aminoacyl group is independently selected from naturally occurring L-amino acids), P(O)(OH), -P(O)(O(C1-6 ) alkyl) 2, or glycosyl (a group obtained by removing the hydroxyl group of the hemiacetal form of a carbohydrate).

[0047] 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 of Prodrugs," by 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), each of which is specifically incorporated herein by reference.

[0048] The present invention further provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced through metabolism in the body of a specified compound or a salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound.

[0049] The metabolites are typically radiolabeled compounds of the invention (e.g., 14 C or 3H) isotopes are prepared and identified by parenteral administration at a detectable dose (e.g., greater than about 0.5 mg / kg) to animals such as rats, mice, guinea pigs, monkeys, or humans, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding to epitopes surviving in the metabolites). The structures of the metabolites are determined by conventional methods, such as MS, LC / MS, or NMR analysis. In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, so long as they are not otherwise observed in vivo, are useful in diagnostic assays for therapeutic administration of the compounds of the invention.

[0050] Certain compounds of the present invention can exist in solvated forms, including hydrated forms, as well as unsolvated forms. In general, the solvated forms are equivalent to the unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0051] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.

[0052] The term "composition," as used herein, is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0053] The terms "treat" and "treatment" refer to both therapeutic and / or prophylactic treatment or preventative measures, the purpose of which is to prevent or slow down (lessen) an undesirable physiological change or disorder, such as the onset or metastasis of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, a decrease in the extent of the disease or disorder, a stabilized (i.e., not worsening) state of the disease or disorder, a delay or slowing of disease progression, an improvement or palliation of the disease state or disorder, and remission (whether partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder, as well as those prone to have the disease or disorder or those in whom the disease or disorder is to be prevented.

[0054] The phrase "therapeutically effective amount" or "effective amount" refers to an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. For cancer therapy, efficacy can be measured, for example, by assessing the time to progression (TTP) and / or determining the response rate (RR).

[0055] The term "bioavailability" refers to the systemic availability (i.e., blood / plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates a measure of both the time (rate) and total amount (extent) of drug that reaches the systemic circulation from an administered dosage form.

[0056] Inhibitors of RIP1 kinase The present invention relates to compounds of general formula I: [ka] (In the formula, R1 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl; R 1 is attached to the adjacent carbonyl by a carbon atom, and R 1 is F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, hydroxyl, 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); each R N are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; or two R N may form a 4- to 6-membered ring together with the adjacent N; Ring A is a 5-membered heteroaryl having only one of (i) 2 to 3 nitrogen atoms, (ii) 1 nitrogen atom and 1 oxygen atom, or (iii) 1 nitrogen atom and 1 sulfur atom as heteroatoms; Ring A is bonded to the adjacent carbonyl by a carbon atom; and Ring B is a 4-8 membered cycloalkyl or a 4-8 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; Ring B is substituted according to (a), (b), or both (a) and (b): (a) Halogen, deuterium, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N) 2, and 1 to 2 substituents selected from the group consisting of cyano; wherein the two C1-C6 alkyl substituents may be joined together to form a bridged or spirocyclic ring; and when the nitrogen atom in ring B is substituted, the substituent is not halogen, cyano, or C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom; (b) C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N )2, one substituent selected from the group consisting of phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclyl), CH2CH2-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl); wherein the phenyl ring or the 5- to 6-membered heteroaryl ring, when present, is optionally 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). or a pharmaceutically acceptable salt thereof.

[0057] In another embodiment, the compound of formula I: [ka] (In the formula, R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R N )2, phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; R 1 is attached to the adjacent carbonyl by a carbon atom, and R 1is optionally substituted with 1 to 2 substituents selected from the group consisting of F, Cl, methyl, ethyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy; Each R N are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; or two R N may form a 4- to 6-membered ring together with the adjacent N; Ring A is a 5-membered heteroaryl having only one of the following heteroatoms: (i) 2 to 3 nitrogen atoms, (ii) 1 nitrogen atom and 1 oxygen atom, or (iii) 1 nitrogen atom and 1 sulfur atom; Ring A is bonded to the adjacent carbonyl by a carbon atom; and Ring B is a 4-8 membered cycloalkyl or a 4-8 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; Ring B is substituted according to (a), (b), or both (a) and (b): (a) Halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N ) 2, and 1 to 2 substituents selected from the group consisting of cyano; wherein the two C1-C6 alkyl substituents may be joined to form a bridged or spirocyclic ring; and when the nitrogen atom in ring B is substituted, the substituent is not halogen, cyano, or C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom; (b) C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N)2, one substituent selected from the group consisting of phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclyl), CH2CH2-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl); wherein the phenyl ring, when present, is optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, and cyclopropyl). or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, R 1 is selected from the group consisting of C-C alkyl, C-C cycloalkyl, C-C haloalkyl, phenyl, benzyl, oxetanyl, oxabicyclo[3.1.0]hexan-6-yl, thienyl, and pyrazolyl; R 1 is optionally substituted with (i) one substituent selected from the group consisting of F, Cl, methyl, hydroxyl, hydroxymethyl, cyano, and trifluoromethyl, or (ii) two F substituents. In some of the above embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C4 alkyl. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is CF3CH2. In some embodiments, R 1 is 2-propyl. In some embodiments, R 1 is tert-butyl. In some embodiments, R 1 is (2-hydroxy)-2-propyl. In some embodiments, R1 is (2-cyano)-2-propyl. In some embodiments, R 1 is C1-C6 haloalkyl. In some embodiments, R 1 is C1-C4 haloalkyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is mono- or di-fluorocyclopropyl. In some embodiments, R 1 is 1-fluorocyclopropyl. In some embodiments, R 1 is 2-fluorocyclopropyl. In some embodiments, R 1 In some embodiments, R 1 is 1-(trifluoromethyl)cyclopropyl. In some embodiments, R 1 is 1-methylcyclopropyl. In some embodiments, R 1 is 1-(hydroxymethyl)cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is benzyl. In some embodiments, R 1 is oxetan-3-yl. In some embodiments, R 1 is 3-methyloxetan-3-yl. In some embodiments, R 1 is oxabicyclo[3.1.0]hexan-6-yl. In some embodiments, R 1 is 2-pyridyl. In some embodiments, R 1 is 1-methylpyrazol-4-yl. In some embodiments, R 1 is 2-thienyl.

[0059] In some embodiments, each R N is independently selected from the group consisting of H and C1-C6 alkyl. In some embodiments, each RN is C1-C4 alkyl. In some embodiments, each R N is methyl.

[0060] In some embodiments of Formula (I), R 1 is as defined above, and the A and B rings together form the following: [ka] (In the formula, R 2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4- to 6-membered heterocyclyl), CH2CH2-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, and CH2-(5- to 6-membered heteroaryl); wherein the phenyl ring, when present, is optionally 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 R 3a and R 3b is selected as follows: (i)R 3a and R 3b one of which is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; (ii)R 3a and R 3b is selected from the group consisting of D, F, Cl, OH, CN, and methyl, with the proviso that R 3a and R 3b cannot both be OH or CN; or (iii)R 3a and R 3btogether form cyclopropyl) The compound is selected from the group consisting of:

[0061] In some embodiments of Formula (I), R 1 is as defined above, and the A and B rings together form: [ka] (In the formula, R 3a and R 3b is selected as follows: (i)R 3a and R 3b one of which is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; (ii)R 3a and R 3b is selected from the group consisting of D, F, Cl, OH, CN, and methyl, with the proviso that R 3a and R 3b cannot both be OH or CN; or (iii)R 3a and R 3b together to form cyclopropyl; Each R 5 is selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and m is 1, 2, or 3 The compound is selected from the group consisting of:

[0062] In some embodiments of Formula (I), R 1 is as defined above, and the A and B rings together form: [ka] (In the formula, Each R 5 is selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and m is 1, 2, or 3 It is of the type.

[0063] In some embodiments of formula (I), R 1 is as defined above, and the A and B rings together form: [ka] (In the formula, R 2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH2CH2-(C3-C6 cycloalkyl), CH2-(4-6 membered heterocyclyl), CH2CH2-(4-6 membered heterocyclyl), 5-6 membered heteroaryl, and CH2-(5-6 membered heteroaryl); wherein the phenyl ring, when present, is optionally 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; R 4a and R 4b is selected as follows: (i)R 4a and R 4b one of is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or (ii)R 4a and R 4b each is selected from the group consisting of D, F, Cl, and methyl; and Each R 5is selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy). The compound is selected from the group consisting of:

[0064] In some embodiments of Formula (I), R 1 is as defined above, and the A and B rings together form: [ka] (In the formula, R 4a and R 4b are selected as follows: (i)R 4a and R 4b one of is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or (ii)R 4a and R 4b each of which is selected from the group consisting of D, F, Cl, and methyl; Each R 5 is selected from the group consisting of H, F, Cl, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; and m is 1, 2, or 3 The compound is selected from the group consisting of:

[0065] In some of the above embodiments, R 2 is phenyl. In some embodiments, R 2 is mono- or difluorophenyl. In some embodiments, R 2 is mono- or dichlorophenyl. In some of the above embodiments, R 2 is pyridinyl. In some of the above embodiments, R 2 is a chloro-substituted pyridinyl. In some of the above embodiments, R 2is fluoro-substituted pyridinyl. In some of the above embodiments, R 2 is pyrazolyl. In some of the above embodiments, R 2 is 1-methyl-1H-pyrazol-4-yl. In some of the above embodiments, R 2 is 4-chloro-1-methyl-1H-pyrazol-3-yl.

[0066] In some of the above embodiments, R 3a and R 3b are each H. In some of the above embodiments, R 3a is H and R 3b is F. In some of the above embodiments, R 3a is H and R 3b is Cl. In some of the above embodiments, R 3a and R 3b are each F. In some of the above embodiments, R 3a and R 3b are each Cl. In some of the above embodiments, R 3a and R 3b are each methyl. In some of the above embodiments, R 3a is methyl and R 3b is F. In some of the above embodiments, R 3a is methyl and R 3b is Cl. In some of the above embodiments, R 3a is methyl and R 3b is OH. In some of the above embodiments, R 3a is methyl and R 3b is CN. In some of the above embodiments, R 3a and R 3b are each D. In some of the above embodiments, R 3a is H and R 3b is D. In some of the above embodiments, R 3a is D and R 3b is F. In some of the above embodiments, R 3a is D and R 3b is Cl. In some of the above embodiments, R 3a is D and R3b is methyl.

[0067] In some of the above embodiments, R 4a and R 4b are each H. In some of the above embodiments, R 4a One of them is H and R 4b is F. In some of the above embodiments, R 4a One of them is H and R 4b is methyl. In some of the above embodiments, R 4a One of them is H and R 4b is Cl. In some of the above embodiments, R 4a and R 4b are each F. In some of the above embodiments, R 4a and R 4b are each D. In some of the above embodiments, R 4a is H and R 4b is D. In some of the above embodiments, R 4a is D and R 4b is F. In some of the above embodiments, R 4a is D and R 4b is Cl.

[0068] In some of the above embodiments, R 5 is selected from the group consisting of H, F, Cl, CH3, CH2CH3, OCH3, CF3, OCF3, CF2H, and OCF2H.

[0069] In some of the above embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0070] In another embodiment, provided herein is a compound selected from the compounds in Table 1 below, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has a K of less than 100 nM in a biochemical or cell-based assay for RIP1K (including those described herein). iProvided herein are compounds of Table 1 having a K of less than 50 nM in biochemical or cell-based assays of RIP1K (including those described herein). i In yet another embodiment, the compounds of Table 1 have a K of less than 25 nM in biochemical or cell-based assays of RIP1K (including those described herein). i In yet another embodiment, the compounds of Table 1 have a K of less than 10 nM in biochemical or cell-based assays of RIP1K (including those described herein). i It has.

[0071] In another embodiment, provided herein is a compound selected from the compounds in Table 2 below, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has a K of less than 100 nM in a biochemical or cell-based assay for RIP1K (including those described herein). i Provided herein are compounds of Table 2 having a K of less than 50 nM in biochemical or cell-based assays of RIP1K (including those described herein). i In yet another embodiment, the compounds of Table 2 have a K of less than 25 nM in biochemical or cell-based assays of RIP1K (including those described herein). i In yet another embodiment, the compounds of Table 2 have a K of less than 10 nM in biochemical or cell-based assays of RIP1K (including those described herein). i It has.

[0072] In some embodiments, provided herein is a single stereoisomer of a compound of Table 1 or Table 2, characterized with reference to its chiral separation and isolation (e.g., by chiral SFC, as described in the Examples).

[0073] In some embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula I, as set forth in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Certain embodiments include pharmaceutical compositions suitable for oral delivery.

[0074] Also provided herein is an oral formulation of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described in any one of the above embodiments, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

[0075] In some embodiments, provided herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described in any one of the above embodiments, for treating neurodegenerative diseases and disorders. In some embodiments, the diseases and disorders treated are synucleopathies, such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Parkinson-plus syndrome. In some embodiments, the diseases and disorders treated are tauopathies, such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the diseases and disorders treated are demyelinating diseases, such as multiple sclerosis.

[0076] In some embodiments, the diseases and disorders treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Additional exemplary neurodegenerative diseases that may 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 neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0077] In some embodiments, the disease or disorder being treated is Alzheimer's disease. In some embodiments, the disease or disorder being treated is Parkinson's disease. In some embodiments, the disease or disorder being treated is Huntington's disease. In some embodiments, the disease or disorder being treated is multiple sclerosis. In some embodiments, the disease or disorder being treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder being treated is spinal muscular atrophy (SMA).

[0078] In some embodiments, provided herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as set forth in any one of the above embodiments, for treating inflammatory diseases and disorders. In some embodiments, the diseases and disorders treated include inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, liver injury / disease (non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune diseases, and inflammatory bowel disease). Hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen poisoning, hepatotoxicity), kidney damage / injury (nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, e.g., cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, muscle atrophy Atrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-kappa-B essential regulator gene (IKK gamma or IKKG)) deficiency syndrome), HOIL-1 deficiency (heme-oxidized IRP2 ubiquitin ligase-1 (also known as RBCKl) deficiency), linear ubiquitin assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases (particularly Gaucher disease, and also GM2, gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency,cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, childhood free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0079] In some embodiments, the disease or disorder being treated is inflammatory bowel disease. In some embodiments, the disease or disorder being treated is Crohn's disease. In some embodiments, the disease or disorder being treated is ulcerative colitis. In some embodiments, the disease or disorder being treated is glaucoma. In some embodiments, the disease or disorder being treated is psoriasis. In some embodiments, the disease or disorder being treated is rheumatoid arthritis. In some embodiments, the disease or disorder being treated is spondyloarthritis. In some embodiments, the disease or disorder being treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder being treated is osteoarthritis.

[0080] In some embodiments, provided herein are methods of treating or preventing a disease or disorder with a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and / or necroptosis. In some embodiments, the disease or disorder is selected from the specific diseases and disorders listed herein.

[0081] In some embodiments, provided herein are methods of inhibiting RIP1 kinase activity by contacting a cell with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0082] Pharmaceutical Compositions and Administration Provided herein are pharmaceutical compositions or medicaments containing a compound of the present invention (or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, isotope, pharmaceutically acceptable salt, or prodrug thereof) and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. For example, a compound of formula (I) may be formulated by mixing it at ambient temperature, at an appropriate pH, and at the desired purity level with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosages and concentrations employed in galenical dosage forms. The pH of the formulation will depend 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) 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 in aqueous solution.

[0083] Compositions are formulated, dispensed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to physicians. In some embodiments, the "effective amount" of the compound being administered is determined by such considerations and is the minimum amount necessary to inhibit RIP1 kinase activity to provide a therapeutic effect in the mammal being treated. Furthermore, such an effective amount may be below an amount that is toxic to normal cells or to the mammal as a whole.

[0084] In one example, a pharmaceutically effective amount of a compound of the invention administered intravenously or parenterally ranges from about 0.1 to 100 mg / kg (of patient body weight) per day, alternatively about 0.1 to 20 mg / kg, alternatively about 0.3 to 15 mg / kg / day, in a single dose range.

[0085] 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 a compound of the invention. The daily dosage, in certain embodiments, is given as a single daily dose, or in divided doses two to six times daily, or in sustained-release form. For a 70 kg adult, the total daily dose will generally be about 7 mg to about 1,400 mg. This dosing regimen may be adjusted to provide the optimal therapeutic response. The compound may be administered on a regimen of one to four times per day, preferably once or twice per day.

[0086] In some embodiments, low doses of the compounds of the invention are administered to provide therapeutic benefit while minimizing or preventing adverse effects.

[0087] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal, and, if local treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the compound of Formula I is administered orally. In other certain embodiments, the compound of Formula I is administered intravenously.

[0088] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0089] A typical formulation is prepared by mixing the compound 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 include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to enhance the presentation of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0090] Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The specific carrier, diluent, or excipient used will depend on the means and purpose for which the compounds of the present invention are being applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for mammalian administration. 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., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to enhance the presentation of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0091] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). The active pharmaceutical ingredients of the present invention (e.g., compounds of Formula I or embodiments thereof) may also be encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules, and poly-(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or interfacial polymerization. Such techniques are described in detail in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, PA.

[0092] Sustained-release preparations of the compounds of the invention (e.g., a compound of Formula I or an embodiment thereof) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula I or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)), and poly-D-(-)-3-hydroxybutyric acid (European Patent No. 133,988A). Sustained-release compositions also include compounds encapsulated in liposomes, 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. Patent Nos. 4,485,045 and 4,544,545; and European Patent No. 102,324A). Typically, liposomes are small (about 200-800 angstroms) unilamellar types with a lipid content of greater than about 30 mol% cholesterol, the ratio selected being adjusted to suit the optimal therapy.

[0093] In one example, a compound of Formula I or an embodiment thereof can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and at the desired purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosage amounts and concentrations used. The pH of the formulation will depend 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 an embodiment thereof) is formulated in acetate buffer at pH 5. In another embodiment, a 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.

[0094] An example of a suitable oral dosage form provided herein is a tablet containing about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg, and 500 mg) of a compound of the invention, combined with appropriate amounts of anhydrous lactose, croscarmellose sodium, polyvinylpyrrolidone (PVP) K30, and magnesium stearate. The powdered ingredients are first blended together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, blended with magnesium stearate, and compressed into tablet form using conventional equipment.

[0095] Formulations of compounds of the present invention (e.g., compounds of Formula I or embodiments thereof) may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. These suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution, among others. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any sterile, fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, can similarly be used in the preparation of injectables.

[0096] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 to 1,000 mg of the active agent, compounded with an appropriate and convenient amount of carrier, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution, allowing infusion of a suitable volume at a rate of about 30 mL / hour.

[0097] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0098] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier for injection, for example, water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0099] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or excipient.

[0100] When the binding target is located in the brain, certain embodiments of the present invention provide compounds of Formula I (or embodiments thereof) for crossing the blood-brain barrier. In these embodiments, the compounds provided herein exhibit sufficient brain penetrability as potential treatments for neurological disorders. In some embodiments, brain penetrability is measured by the free brain / plasma ratio (B ) as measured by in vivo pharmacokinetic studies in rodents or other methods known to those skilled in the art (see, e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008). u / P u ) is evaluated by evaluating the

[0101] Certain neurological disorders are associated with increased permeability of the blood-brain barrier, so that the compound of formula I (or an embodiment thereof) can be easily introduced into the brain. When the blood-brain barrier is intact, there are several approaches known in the art for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor- and channel-based methods. Physical methods for transporting the compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, bypassing the blood-brain barrier entirely or creating an opening in the blood-brain barrier.

[0102] Bypass methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial injection / convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of a delivery device into the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford).

[0103] Methods for creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002 / 0038086), osmotic pressure (e.g., by administering hypertonic mannitol (Neuwelt, E.A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, NY, 1989)), and permeabilization with, for example, bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0104] Lipid-based methods for transporting a compound of Formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating a compound of Formula I or II (or an embodiment thereof) in a liposome coupled to a binding fragment of an antibody (which binds to a receptor on the vascular endothelium of the blood-brain barrier) (see, e.g., U.S. Patent Publication No. 2002 / 0025313), and coating a compound of Formula I (or an embodiment thereof) with low-density lipoprotein particles (see, e.g., U.S. Patent Publication No. 2004 / 0204354) or apolipoprotein E (see, e.g., U.S. Patent Publication No. 2004 / 0131692).

[0105] Receptor- and channel-based methods for transporting a compound of Formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. Patent Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, e.g., U.S. Patent Publication No. 2005 / 0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Publication No. 2003 / 0073713); coating a compound of Formula I or II (or an embodiment thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. Patent Publication No. 2003 / 0129186), and cationizing antibodies (see, e.g., U.S. Patent No. 5,004,697).

[0106] When used intracerebrally, in certain embodiments, the compound can be administered continuously by infusion into CNS fluid reservoirs, although bolus injections are also acceptable. The inhibitor can be administered into the ventricles of the brain or introduced into the CNS or spinal fluid by other means. Administration can be achieved using continuous administration means, such as indwelling catheters and pumps, or by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitor can be infused through a chronically implanted cannula or can be infused chronically using an osmotic minipump. Subcutaneous pumps are available that deliver proteins to the ventricles through small tubing. Sophisticated pumps can be refilled through the skin, and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems (including continuous intraventricular infusion via a subcutaneous pump device or a completely implanted drug delivery system) are those used to administer dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models of Parkinson's disease, as described in Harbaugh, J. Neural Transm. Suppl. 24:271, 1987 and DeYebenes et al., Mov. Disord. 2: 143, 1987.

[0107] Indications and Treatment Methods The compounds of the present invention inhibit RIP1 kinase activity and are therefore useful for treating diseases and disorders mediated by this pathway and associated with inflammatory and / or necroptotic cell death.

[0108] In some embodiments, the diseases and disorders treated are neurodegenerative diseases and disorders. In some embodiments, the diseases and disorders treated are synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Parkinson-plus syndrome. In some embodiments, the diseases and disorders treated are tauopathies such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the diseases and disorders treated are demyelinating diseases such as multiple sclerosis.

[0109] In some embodiments, the diseases and disorders treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and stroke. Additional exemplary neurodegenerative diseases that may 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 neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0110] In some embodiments, the disease or disorder being treated is Alzheimer's disease. In some embodiments, the disease or disorder being treated is Parkinson's disease. In some embodiments, the disease or disorder being treated is Huntington's disease. In some embodiments, the disease or disorder being treated is multiple sclerosis. In some embodiments, the disease or disorder being treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder being treated is spinal muscular atrophy (SMA).

[0111] In some embodiments, the disease or disorder being treated is an inflammatory disease or disorder. In some embodiments, the disease or disorder being treated is inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, liver injury / disease (non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune liver disease), or other conditions. Biliary disorders, primary sclerosing cholangitis (PSC), acetaminophen poisoning, hepatotoxicity), renal damage / injury (nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, e.g., cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) A), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-kappa-B essential regulator gene (also known as IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency (also known as RBCKl) Heme-oxidizing IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza), and lysosomal storage diseases (particularly Gaucher disease, and GM2, gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis,GM1 gangliosidosis, mucolipidosis, childhood free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0112] In some embodiments, the disease or disorder being treated is inflammatory bowel disease. In some embodiments, the disease or disorder being treated is Crohn's disease. In some embodiments, the disease or disorder being treated is ulcerative colitis. In some embodiments, the disease or disorder being treated is glaucoma. In some embodiments, the disease or disorder being treated is psoriasis. In some embodiments, the disease or disorder being treated is rheumatoid arthritis. In some embodiments, the disease or disorder being treated is spondyloarthritis. In some embodiments, the disease or disorder being treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder being treated is osteoarthritis.

[0113] In some embodiments, the methods of treatment provided herein are treatment of one or more symptoms of the diseases or disorders listed above.

[0114] Also provided herein are uses of the compounds of the invention in therapy. In some embodiments, also provided herein are uses of the compounds of the invention for treating or preventing the above diseases and disorders. Also provided herein are uses of the compounds of the invention in the manufacture of a medicament for treating or preventing the above diseases and disorders.

[0115] Also provided herein are methods of treating a disease or disorder as provided above in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the mammal is a human.

[0116] Also provided herein is a method of treating a symptom of a disease or disorder in a mammal in need of such treatment, wherein the disease or disorder is selected from the group consisting of irritable bowel disorder (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of the kidney, liver, and lung, cisplatin-induced renal 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.

[0117] Also provided herein is a method of treating a disease or disorder in a human patient in need of such treatment, wherein the disease or disorder is selected from those provided above, and the method comprises orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in an orally acceptable pharmaceutical composition.

[0118] Combination therapy In treating the diseases and disorders provided herein, the compounds of the present invention may be used in combination with one or more other compounds of the present invention, or one or more other therapeutic agents, in 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 to be useful in treating the diseases or disorders selected from those listed above.

[0119] As used herein, "combination" refers to any mixture or permutation of one or more compounds of the present invention with one or more other compounds of the present invention or one or more additional therapeutic agents. Unless otherwise specified, "combination" may include simultaneous or sequential delivery of a compound of the present invention with one or more therapeutic agents. Unless otherwise specified, "combination" may include dosage forms of a compound of the present invention with another therapeutic agent. Unless otherwise specified, "combination" may include routes of administration of a compound of the present invention with another therapeutic agent. Unless otherwise specified, "combination" may include formulations of a compound 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.

[0120] In some embodiments, the compounds provided herein may be used in combination with another therapeutically active agent listed 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 listed in WO 2016 / 027253 is replaced with a compound of Formula I of the present disclosure.

[0121] In some embodiments, compounds provided herein may be used in combination with a DLK inhibitor to treat neurodegenerative diseases and disorders such as those listed elsewhere herein (including, but not limited to, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Parkinson-plus syndrome, Alzheimer's disease, frontotemporal dementia, demyelinating diseases such as multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophies, peripheral neuropathies, progressive supranuclear palsy, and corticobasal degeneration). DLK inhibitors are described, for example, in WO 2013 / 174780, WO 2014 / 177524, WO 2014 / 177060, WO 2014 / 111496, WO 2015 / 091889, and WO 2016 / 142310.

[0122] Example The present invention will be more fully understood by reference to the following examples, which should not be construed as limiting the scope of the invention.

[0123] These examples will serve to provide guidance to those of ordinary skill in the art for preparing and using the compounds, compositions, and methods of the present invention. While specific embodiments of the invention are described, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0124] The chemical reactions in the described examples can be readily adapted to prepare many other compounds of the invention, and other methods of preparing compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of compounds not exemplified according to the invention can be successfully carried out by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art, for example, by appropriately protecting interfering groups by utilizing other suitable reagents known in the art other than those described, and / or by routinely modifying reaction conditions.

[0125] In the following examples, all temperatures are given in degrees Celsius unless otherwise specified. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI, or Maybridge and were used without further purification unless otherwise specified. Reactions described below were generally carried out under a positive pressure of nitrogen or argon, or in anhydrous solvents (unless otherwise specified), using drying tubes; reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried. 1H NMR spectra were obtained in solutions of deuterated CDCl3, d6-DMSO, CH3OD, or d6-acetone solvents using trimethylsilane (TMS) or residual non-deuterated solvent peaks as reference standards (reported in ppm). When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, when given, are reported in Hz (Hertz).

[0126] All abbreviations used to describe reagents, reaction conditions, or equipment are intended to correspond to the definitions set forth in the following list of abbreviations: Chemical names for individual compounds of the invention were typically obtained using the structural nomenclature of the ChemDraw naming program.

[0127] Abbreviation ACN Acetonitrile Boc tert-butoxycarbonyl DAST Diethylaminosulfur trifluoride DCE 1,2-dichloroethane DCM dichloromethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPPH 2,2-diphenyl-1-picrylhydrazyl HPLC High-Performance Liquid Chromatography LCMS Liquid Chromatography-Mass Spectrometry PCC Pyridinium Chlorochromate RP reverse phase RT or R T retention time SEM 2-(trimethylsilyl)ethoxymethyl SFC Supercritical Fluid Chromatography TFA trifluoroacetic acid THF tetrahydrofuran

[0128] Synthesis scheme In addition to the specific synthetic methods of the Examples below, further compounds of the invention can be prepared, for example, according to the following synthetic schemes.

[0129] The gem-difluoro moiety is prepared according to Scheme 1 after following steps 1-5 of Method 9 below: [ka]

[0130] According to Scheme 2, a variety of nucleophiles (including, but not limited to, halide and cyanide sources) are used to prepare further diverse B rings of compounds of Formula I. [ka]

[0131] Compounds of formula I with gem-dimethyl substitution on the B ring are prepared according to Scheme 3. [ka]

[0132] The following intermediates used in the examples below were prepared according to the procedures described in WO2017 / 004500, which is incorporated herein by reference in its entirety: [ka]

[0133] Unless stated in a specific method, any utilized N-methoxy-N-methyl-alkyl, aryl, heteroaryl, or heterocyclic carboxamide was prepared in the same manner as cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide in Method 5 below.

[0134] Method 1: Compound Examples 1 and 2 [ka] [(1S,2S)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and [(1R,2R)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and cis-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (157 mg, 1.06 mmol) in tetrahydrofuran (12 mL) was added n-butyllithium (2.5 M in hexanes, 0.64 mL, 1.60 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 h and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (20–45% acetonitrile / 0.225% HCl in water). The racemic material was further separated by chiral SFC with the arbitrary assignment: To give [(1S,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 3.635 min) (4.0 mg, 2.5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 3H), 7.30 - 7.28 (m, 2H), 6.20 - 6.18 (m, 0.5H), 6.06 - 6.04 (m, 0.5H), 5.65 - 5.64 (m, 1H), 5.04 - 5.02 (m, 0.5H), 4.90 - 4.87 (m, 0.5H), 3.80 - 3.74 (m, 1H), 3.25 - 3.21 (m, 1H), 2.88 - 2.81 (m, 1H), 2.03 - 1.96 (m, 1H), 1.34 - 1.28 (m, 1H). LCMS retention time=1.662 min, m / z=290.1 ​​[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 1.662 min, ESI+ found [M+H] = 290.1. To give [(1R,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 3.995 min) (15.9 mg, 10%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.30 - 7.28 (m, 2H), 6.21 - 6.18 (m, 0.5H), 6.06 - 6.05 (m, 0.5H), 5.66 - 5.65 (m, 1H), 5.05 - 5.04 (m, 0.5H), 4.90 - 4.87 (m, 0.5H), 3.82 - 3.74 (m, 1H), 3.23 - 3.20 (m, 1H), 2.88 - 2.82 (m, 1H), 2.02 - 1.96 (m, 1H), 1.34 - 1.30 (m, 1H). LCMS retention time=1.654 min, m / z=290.1 ​​[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 1.654 min, ESI+ found [M+H] = 290.1. SFC conditions: Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A:CO2 B:iso-propanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min Flow rate: 2.5 mL / min Column temperature 35°C.

[0135] Method 2: Compounds Examples 3 and 4 [ka] [(1S,2S)-2-Fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and [(1R,2R)-2-Fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70°C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and cis-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (156.5 mg, 1.06 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 0.64 mL, 1.60 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -70°C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (35-65% acetonitrile / 0.05% ammonia hydroxide in water) to give [cis-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (35 mg, 22.5%) as a pink solid. The racemic material was separated by chiral SFC to give the following arbitrary assignment: To give [(1S,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 4.787 min) (5.9 mg, 17%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.39 (m, 3H), 7.28 - 7.27 (m, 2H), 6.13 - 6.11 (m, 1H), 5.99 - 5.97 (m, 1H), 5.53 - 5.49 (m, 1H), 3.69 - 3.61 (m, 1H), 3.27 - 3.24 (m, 1H), 3.03 - 2.96 (m, 1H), 2.23 - 2.15 (m, 1H), 1.29 - 1.24 (m, 1H). LC-MS retention time=0.846 min, m / z=289.9 (M+H) + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.846 min, ESI+ found [M+H] = 289.9. To give [(1R,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 5.711 min) (11.7 mg, 33%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.37 (m, 3H), 7.28 - 7.27 (m, 2H), 6.13 - 6.11 (m, 1H), 5.99 - 5.97 (m, 1H), 5.53 - 5.50 (m, 1H), 3.69 - 3.63 (m, 1H), 3.27 - 3.23 (m, 1H), 3.03 - 2.96 (m, 1H), 2.23 - 2.16 (m, 1H), 1.29 - 1.24 (m, 1H). LC-MS retention time=0.849 min, m / z=289.9 (M+H) +LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.849 min, ESI+ found [M+H] = 289.9. SFC conditions: Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Isopropanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min Flow rate: 2.5 mL / min Column temperature: 35°C.

[0136] Chiral SFC purification and analysis conditions: In the method shown in the table below, solvent A is carbon dioxide and solvent B is 0.1% NH4 in CH3OH (aq). [Table 2] TIFF0007734163000019.tif171165

[0137] Method SP 5 [ka] 2-Hydroxy-2-methyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one Arbitrarily assigned 2-hydroxy-2-methyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (10.94 mg, 43% yield). 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 retention time=4.029 min, m / z=290.1 ​​(M+H) + .

[0138] Method SP 6 [ka] 2-Hydroxy-2-methyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one Arbitrarily assigned 2-hydroxy-2-methyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (11.1 mg, 43% yield). 1 H NMR (400 MHz, DMSO-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 retention time=4.029 min, m / z=290.1 ​​(M+H) + .

[0139] Method SP 37 [ka] 2,2-Dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one Arbitrarily assigned 2,2-dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (2.84 mg, 48% yield). LC-MS retention time = 5.26 min, m / z = 288.1 (M+H). + .

[0140] Method SP 38 [ka] 2,2-Dimethyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one Arbitrarily assigned 2,2-dimethyl-1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (4.2 mg, 77% yield). LC-MS retention time = 5.26 min, m / z = 288.1 (M+H). + .

[0141] Method SP 39 [ka] (1-Methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone Arbitrarily assigned (1-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (19.23 mg, 77% yield). 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 retention time=3.99 min, m / z=312.1 (M+H) + .

[0142] Method SP 40 [ka] (1-Methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone Arbitrarily assigned (1-methylpyrazol-4-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (20.4 mg, 82% yield). 1 H NMR (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 retention time=3.99 min, m / z=312.1 (M+H) + .

[0143] Method 3 [ka] 2-Phenyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone To a solution of ethyl [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.363 mmol) in tetrahydrofuran (2 mL) was added benzylmagnesium chloride (2 M in tetrahydrofuran, 0.20 mL, 0.400 mmol) at −78° C. under nitrogen. After the addition, the reaction mixture was stirred at −78° C. for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (1 mL). The mixture was extracted with isopropyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% isopropyl acetate in heptane) to give 2-phenyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone as a white solid (80 mg, 69% yield). LCMS retention time = 5.24 min, m / z = 322.1 [M+H] + LCMS (5-95% acetonitrile in water + 0.1% formic acid in 10 min) retention time 5.24 min, ESI+ observed value [M+H] = 322.1

[0144] Method 4 [ka] [(1S,2R)-2-Fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and [(1R,2S)-2-Fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70°C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and trans-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (156 mg, 1.06 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 0.64 mL, 1.60 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -70°C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (35-65% acetonitrile / 0.05% ammonia hydroxide in water) to give [trans-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (35 mg, 23%) as a pink solid. This racemic material was further separated by chiral SFC to give the arbitrary assignment: To give [(1S,2R)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.836 min) (14.3 mg, 40%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.866 min, m / z=289.9 (M+H) + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.866 min, ESI+ found [M+H] = 289.9. To give [(1R,2S)-2-fluorocyclopropyl]-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 3.725 min) (11.3 mg, 32%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.865 min, m / z=289.9 (M+H) + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.865 min, ESI+ found [M+H] = 289.9. SFC conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min Flow rate: 2.5 mL / min.

[0145] Method 5 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2S)-2-fluorocyclopropyl]methanone

[0146] [ka] Step 1: cis-2-fluoro-N-methoxy-N-methylcyclopropanecarboxamide 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 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give cis-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (420 mg, 59%) as a colorless oil. 1 H NMR (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).

[0147] [ka] Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2S)-2-fluorocyclopropyl]methanone To a 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-methylcyclopropanecarboxamide (52 mg, 0.35 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (2.5 M in hexanes, 0.21 mL, 0.53 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2S)-2-fluorocyclopropyl]methanone (2.0 mg, 4%) as a pale yellow oil. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.37 (m, 3H), 7.29 - 7.27 (m, 2H), 6.19 - 6.18 (m, 0.5H), 6.04 - 6.03 (m, 0.5H), 5.67 - 5.61 (m, 1H), 5.08 - 4.89 (m, 1H), 3.81 - 3.70 (m, 1H), 3.26 - 3.16 (m, 1H), 2.91 - 2.75 (m, 1H), 2.07 - 1.90 (m, 1H), 1.36 - 1.29 (m, 1H). LCMS retention time=1.038 min, m / z=290.1 ​​[M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 1.038 min, ESI+ found [M+H] = 290.1.

[0148] Method 6 [ka] (2,2-Difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0149] [ka] Step 1: 2,2-Difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide 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 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (200 mg, 49%) as a colorless oil. LCMS retention time = 0.427 min, m / z = 166.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.427 min, ESI+ found [M+H] = 166.1.

[0150] [ka] Step 2: (2,2-Difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (59 mg, 0.35 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in hexanes, 0.25 mL, 0.62 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 35–65% / 0.05% ammonia hydroxide in water) to give (2,2-difluorocyclopropyl)-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (10.6 mg, 19%) as a colorless oil. 1 H NMR (400 MHz, 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 retention time=0.875 min, m / z=307.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.875 min, ESI+ found [M+H] = 307.9.

[0151] Method 7 [ka] Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone Phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone was prepared from ethyl [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate and phenylmagnesium according to Method 3. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% isopropyl acetate in heptane) to give the final product (17 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.12 (m, 2H), 7.74 - 7.65 (m, 1H), 7.61 - 7.52 (m, 2H), 7.48 - 7.33 (m, 3H), 7.32 - 7.24 (m, 2H), 6.28 (ddd, J = 56.4, 7.2, 1.9 Hz, 1H), 5.78 (ddd, J = 8.5, 6.5, 3.1 Hz, 1H), 3.78 (dddd, J = 25.8, 15.4, 8.5, 7.1 Hz, 1H), 2.74 (dddd, J = 26.7, 15.2, 3.2, 2.0Hz, 1H). LC-MS retention time=5.04 min, m / z=308.1 (M+H) + . LCMS (5 to 95% acetonitrile in water + 0.1% formic acid in 10 min) retention time 5.04 min, ESI+ observed [M+H] = 308.1.

[0152] Method 8 [ka]

[0153] [ka] Step 1: (E)-Benzaldehyde oxime To a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL) was added sodium carbonate (112.3 g, 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g, 508.9 mmol). The reaction mixture was stirred at 25 °C for 3 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 × 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 (£)-benzaldehyde oxime as a colorless oil (51.0 g, 99%), which was used in the next step without further purification.

[0154] [ka] 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) was added methyl acrylate (14.2 g, 165.1 mmol), sodium iodide (24.7 g, 165.1 mmol), 2,6-lutidine (17.6 g, 165.1 mmol), and tert-butyl hypochlorite (17.9 g, 165.1 mmol). The reaction mixture was stirred at 25 °C for 24 h and then 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-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g, 74%). LCMS retention time=0.871 min, m / z=206.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.871 min, ESI+ found [M+H] = 206.2.

[0155] [ka] Step 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one A mixture of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (25.0 g, 121.8 mmol) and palladium (10% on carbon, 2.5 g) in ethanol (800 mL) was hydrogenated (50 psi) at 25 °C for 2 h, then filtered, and the filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%), which was used in the next step without further purification. LCMS retention time = 0.270 min, m / z = 177.8 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.270 min, ESI+ found [M+H] = 177.8.

[0156] [ka] Step 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one and trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol) in dichloromethane (300 mL) was added tert-butyldimethylchlorosilane (19.1 g, 126.9 mmol) and imidazole (11.5 g, 169.3 mmol). The reaction mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-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) Also afforded trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g, 38%). 1 H 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).

[0157] [ka] Step 5: cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one To a solution of cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 42.8 mmol) in N,N-dimethylformamide (400 mL) was slowly added sodium hydride (60%, 2.6 g, 64.1 mmol) at 0 °C. After the addition, the mixture was stirred at 0 °C for 20 minutes, followed by the addition of O-(diphenylphosphoryl)hydroxylamine (14.9 g, 64.1 mmol). The reaction mixture was stirred at 25 °C for 16 hours and then filtered. The filtrate was concentrated under reduced pressure to give crude cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a yellow oil (9.5 g, 73%), which was used in the next step without further purification. LCMS retention time = 0.877 min, m / z = 307.0 [M+H]+ LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.877 min, ESI+ found [M+H] = 307.0.

[0158] [ka] Step 6: Ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate To a solution of cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (9.5 g, 31.0 mmol) in ethanol (250 mL) was added ethyl 2-ethoxy-2-imino-acetate (6.7 g, 46.5 mmol). The reaction mixture was stirred at 60 °C for 6 hours and then concentrated under reduced pressure to give crude ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate as a yellow oil (10.6 g, 84%), which was used in the next step without further purification. LCMS retention time = 2.106 min, m / z = 406.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 2.106 min, ESI+ observed [M+H] = 406.2.

[0159] [ka] 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 ethyl 2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate (10.6 g, 26.1 mmol) in toluene (200 mL) was added p-toluenesulfonic acid (4.5 g, 26.1 mmol). The reaction mixture was heated at 120 °C for 24 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-80% ethyl acetate in petroleum ether) to give ethyl cis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate as a white solid (6.5 g, 64%), which was used directly in the next step.

[0160] [ka] 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-pyrrolidin-1-yl]amino]-2-imino-acetate (3.1 g, 7.6 mmol) and tert-butylammonium fluoride (1.0 M in THF, 7.6 mL, 7.6 mmol) in tetrahydrofuran (60 mL) was heated at 60 °C for 18 h and then 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 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%). 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.32 (m, 5H), 5.73 (d, J = 3.5 Hz, 1H), 5.50 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.73 - 3.65 (m, 1H), 2.76 (td, J = 4.5 Hz, 13.9 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H).

[0161] [ka] Step 1: trans-ethyl 7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate To a solution of cis-ethyl-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.37 mmol) in dichloromethane (8 mL) was added diethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then quenched by the addition of water (20 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R f =0.5) to give trans-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 30%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.40 - 7.37 (m, 3H), 7.14 - 7.12 (m, 2H), 6.14 (d, J = 5.2 Hz, 0.5H), 6.00 (d, J = 5.2 Hz, 0.5H), 5.74 - 5.71 (m, 1H), 4.51 - 4.45 (m, 2H), 3.42 - 3.35 (m, 1H), 3.07 - 2.96 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H).

[0162] [ka] Step 2: trans-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid To a solution of trans-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 0.11 mol) in tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide monohydrate (14 mg, 0.33 mmol). The reaction mixture was stirred at 25 °C for 2 hours and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by the addition of hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid as a white solid (13 mg, 48%), which was used in the next step without further purification.

[0163] 1-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one To a cooled (-78°C) solution of trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (15 mg, 0.05 mmol) in tetrahydrofuran (10 mL) was added ethylmagnesium bromide (3 M in THF, 0.03 mL, 0.10 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 1 hour and quenched by the addition of saturated aqueous ammonium chloride solution (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 (34–64% acetonitrile / 0.05% hydrochloride in water) to give 1-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (7.4 mg, 50%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.30 - 7.26 (m, 2H), 6.27 - 6.26 (m, 0.5H), 6.14 - 6.12 (m, 0.5H), 5.87 - 5.84 (m, 1H), 3.44 - 3.41 (m, 1H), 3.12 -3.02 (m, 3H), 1.16 (t, J = 7.2 Hz, 3H). LCMS retention time=0.840 min, m / z=260.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.840 min, ESI+ found [M+H] = 260.1.

[0164] Method 9 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(trifluoromethyl)cyclopropyl]methanone [ka] Step 1: 3,5-Dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole To a solution of 3,5-dibromo-1h-1,2,4-triazole (150.0 g, 661.2 mmol) in tetrahydrofuran (1500 mL) at 0 °C, p-toluenesulfonic acid (17.1 g, 99.2 mmol) was slowly added, followed by 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 adjusted to pH = 9 by the addition of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was washed with methanol (2×50 mL) 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 (400 MHz, CDCl3) δ 5.49 - 5.46 (m, 1H), 4.12 - 3.99 (m, 1H), 3.72 - 3.61 (m, 1H), 2.38 - 2.26 (m, 1H), 2.18 - 2.07 (m, 1H), 1.98 - 1.90 (m, 1H), 1.78 - 1.60 (m, 3H).

[0165] [ka] Step 2: 1-phenylbut-3-en-1-ol To a cooled (0 °C) solution of benzaldehyde (130 g, 1.23 mol) in tetrahydrofuran (1000 mL) was added allylmagnesium chloride (2 M in THF, 858 mL, 1.72 mol) over 30 min. After the addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was then quenched by the addition of saturated aqueous ammonium chloride (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–5% ethyl acetate in petroleum ether) to give 1-phenylbut-3-en-1-ol (140 g, 77%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.37 - 7.34 (m, 4H), 7.29 - 7.26 (m, 1H), 5.83 - 5.75 (m, 1H), 5.21 - 5.08 (m, 2H), 4.76 - 4.69 (m, 1H), 2.55 - 2.45 (m, 2H), 2.12 (d, J = 2.8 Hz, 1H).

[0166] [ka] 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) was added imidazole (27.0 g, 391.6 mmol) and tert-butyldimethylchlorosilane (39.0 g, 254.4 mmol). After the addition, the reaction mixture was stirred at 25 °C for 16 h and then quenched by the addition of water (200 mL). The mixture was extracted with dichloromethane (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to give tert-butyl-dimethyl-(1-phenylbut-3-enoxy)silane (43.0 g, 84%) as a colorless oil, which was used directly in the next step.

[0167] [ka] Step 4: 3-((tert-butyldimethylsilyl)oxy)-3-phenylpropanal 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) was added osmium tetroxide (968 mg, 3.8 mmol). After stirring at 15° C. for 30 minutes, sodium periodate (163 g, 762.0 mmol) was added in small portions over 2 hours. The resulting mixture was stirred at 30° C. for an additional 2 hours and then quenched by the addition of cold saturated aqueous sodium thiosulfate (500 mL). The mixture was stirred for 30 minutes and then extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% 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).

[0168] [ka] Step 5: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-phenylpropan-1-ol To a cooled (-78 °C) solution of 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (39.0 g, 125.4 mmol) in tetrahydrofuran (400 mL) under a N atmosphere was added n-butyllithium (2.5 M in hexanes, 55.0 mL, 137.5 mmol) dropwise. The mixture was stirred at -78 °C for 30 minutes, 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 hours and then quenched by the addition of saturated aqueous ammonium chloride (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under 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-phenylpropan-1-ol (50.0 g, 80%) as a pale yellow oil.

[0169] [ka] 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-phenylpropan-1-ol (50.0 g, 100.7 mmol) in dichloromethane (150 mL) was slowly added trifluoroacetic acid (150 mL). The resulting mixture was heated at 50° C. for 2 hours and then concentrated under reduced pressure. The residue was adjusted to pH=9 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–32% ethyl acetate in petroleum ether) to give trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (5.5 g, 20%) as a yellow solid (also a second fraction (8.5 g, 30%) was obtained as a 4:3 mixture of trans / cis products). 1 H NMR (400 MHz, 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 retention time=0.682 min, m / z=279.8 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.682 min, ESI+ found [M+H] = 279.8.

[0170] [ka] Step 7: (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole To a stirred solution of trans-2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (3.0 g, 10.71 mmol) in dichloromethane (60 mL) was added diethylaminosulfur trifluoride (7.8 g, 48.19 mmol) slowly at 0° C. The reaction mixture was stirred at 0° C. for 2.5 hours and then slowly added to a stirred saturated aqueous sodium bicarbonate solution (100 mL) at 0° C. The mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–20% 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: 1 H 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 retention time=0.632 min, m / z=281.9 [M+H]+ LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.632 min, ESI+ found [M+H] = 281.9. trans-2-Bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole: 1 H NMR (400 MHz, 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).

[0171] The racemic cis material was further separated by chiral SFC to give the arbitrary assignment: (5R,7R)-2-Bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 1, retention time = 2.963 min) (350 mg, 44%) as a white solid. (5S,7S)-2-Bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 3.174 min) (350 mg, 44%) as a white solid. SFC conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min Flow rate: 2.5 mL / min.

[0172] [ka] Step 8: N-Methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide 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 (3×30 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)cyclopropanecarboxamide (330 mg, 64%) as a light oil. 1 H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.29 (s, 3H), 1.37 - 1.17 (m, 4H).

[0173] [ka] Step 9: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(trifluoromethyl)cyclopropyl]methanone To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (70 mg, 0.35 mmol) in tetrahydrofuran (4 mL) was added n-butyllithium (2.5 M in hexanes, 0.1 mL, 0.25 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (5 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC ((acetonitrile 45–75% / 0.05% ammonia hydroxide in water)) to give arbitrarily assigned (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[1-(trifluoromethyl)cyclopropyl]methanone (14.1 mg, 23%) as a red solid. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.35 (m, 3H), 7.24 - 7.22 (m, 2H), 6.15 - 5.99 (m, 1H), 5.61 - 5.60 (m, 1H), 3.77 - 3.68 (m, 1H), 2.84 - 2.77 (m, 1H), 2.27 - 2.17 (m, 2H), 1.60 - 1.55 (m, 2H). LC-MS retention time=0.933 min, m / z=339.9 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 3.0 min) retention time 0.933 min, ESI+observed [M+H] = 339.9.

[0174] Method 10 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3-methyloxetan-3-yl)methanone

[0175] [ka] 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 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (120 mg, 29.2%) as a colorless oil. 1 H 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).

[0176] [ka] Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3-methyloxetan-3-yl)methanone To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (40 mg, 0.14 mmol) and N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (45 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in hexanes, 0.17 mL, 0.43 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(3-methyloxetan-3-yl)methanone (11.5 mg, 27%) as a yellow oil. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.26 - 7.23 (m, 2H), 6.17 - 6.01 (m, 1H), 5.65 - 5.63 (m, 1H), 5.08 - 5.03 (m, 2H), 4.52 - 4.48 (m, 2H), 3.78 - 3.70 (m, 1H), 2.86 - 2.76 (m, 1H), 1.75 (s, 3H). LCMS retention time=0.816 min, m / z=302.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.816 min, ESI+ found [M+H] = 302.0.

[0177] Method 11 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2R)-2-fluorocyclopropyl]methanone

[0178] [ka] Step 1: trans-2-Fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide 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 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (70 mg, 50%) as a colorless oil. 1 H NMR (400 MHz, 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 retention time=0.292 min, m / z=148.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.292 min, ESI+ found [M+H] = 148.1.

[0179] [ka] Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2R)-2-fluorocyclopropyl]methanone To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (40 mg, 0.14 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (42 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in hexanes, 0.07 mL, 0.18 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 35-65% / 0.05% ammonia hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-[rac-(1S,2R)-2-fluorocyclopropyl]methanone (3.3 mg, 7.6%) as a colorless oil. 1 H NMR (400 MHz, 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 retention time=0.862 min, m / z=289.9 [M+H] +LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.862 min, ESI+ found [M+H] = 289.9.

[0180] Method 12 [ka] 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one

[0181] [ka] Step 1: 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol To a solution of imidazole (40.0 g, 587.5 mmol), acetic acid (1.8 mL), and 1,4-dioxane (600 mL) was added acrolein (58.8 mL, 881.3 mmol). The resulting mixture was stirred at 110 °C for 24 h and cooled to 0 °C. The resulting solid was collected by filtration 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, which was used directly in the next step.

[0182] [ka] 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) was added N-chlorosuccinimide (10.8 g, 80.6 mmol). The mixture was stirred at 50 °C for 2 h and then 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-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.

[0183] [ka] 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) was added N-iodosuccinimide (8.3 g, 37.1 mmol). The mixture was heated at 60 °C for 3 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% 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.

[0184] [ka] Step 4: 3-chloro-2-iodo-5H-pyrrolo[1,2-a]imidazol-7(6H)-one To a solution of 3-chloro-2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (5.3 g, 18.6 mmol) in dichloromethane (20 mL) was added manganese dioxide (8.1 g, 93.2 mmol). The mixture was heated at 40° C. for 5 hours and filtered. The filtrate was concentrated to dryness under reduced pressure to give crude 3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-one (3.2 g, 61%) as a brown solid, which was used directly in the next step.

[0185] [ka] Step 5: N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methyl-benzenesulfonamide A mixture of 4-methylbenzenesulfonohydrazide (2.1 g, 11.3 mmol) and 3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-one (3.2 g, 11.3 mmol) in ethanol (70 mL) was heated at 90° C. for 7 h and cooled to 15° C. The resulting solid was collected by filtration and dried under reduced pressure to give crude N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methyl-benzenesulfonamide (2.8 g, 54%) as a pale green solid, which was used as such in the next step.

[0186] [ka] Step 6: 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole A mixture of N-[(Z)-(3-chloro-2-iodo-5,6-dihydropyrrolo[1,2-a]imidazol-7-ylidene)amino]-4-methyl-benzenesulfonamide (1.8 g, 3.88 mmol), phenylboronic acid (710 mg, 5.82 mmol), and potassium carbonate (1.6 g, 11.65 mmol) in 1,4-dioxane (40 mL) was heated at 110 °C for 18 h under a N atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200 mg, 15%) as a light brown solid. LCMS retention time=0.879 min, m / z=334.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time: 0.879 min, ESI+ found [M+H] = 334.9.

[0187] [ka] Step 7: methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate A mixture of 3-chloro-2-iodo-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200 mg, 0.58 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (24 mg, 0.03 mmol), and triethylamine (0.4 mL, 2.9 mmol) in N,N-dimethylformamide (24 mL) / methanol (8 mL) was heated at 90°C under CO (50 Psi) for 18 hours. The mixture was filtered through a short pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R f=0.4) to give methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (140 mg, 87%) as a light brown solid. LCMS retention time = 0.676 min, m / z = 277.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) Retention time: 0.676 min, ESI+ Found [M+H] = 277.0

[0188] [ka] Step 8: Methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate A mixture of methyl 3-chloro-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (120 mg, 0.43 mmol) and palladium (10% on carbon, 103 mg, 0.10 mmol, 50% wet) in methanol (50 mL) was hydrogenated (40 psi) at 50° C. for 24 h and then filtered. The filtrate was concentrated under reduced pressure to give crude methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (100 mg, 95%) as a brown oil, which was used directly in the next step. 1 H NMR (400MHz, 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 retention time=0.513 min, m / z=243.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time: 0.513 min, ESI+ found [M+H] = 243.1.

[0189] [ka] Step 9: 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid A mixture of methyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (100 mg, 0.41 mmol) and lithium hydroxide monohydrate (118 mg, 2.89 mmol) in tetrahydrofuran (2 mL), water (1 mL), and methanol (2 mL) was heated at 25° C. for 18 hours. Sodium hydroxide (100 mg) was added, and the mixture was heated at 40° C. for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and adjusted to pH 3 by the addition of 2 M HCl. The resulting mixture was lyophilized to give crude 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (94 mg, 99%) as a white solid, which was used directly in the next step.

[0190] [ka] Step 10: N-Methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide A mixture of 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (60 mg, 0.26 mmol), N,O-dimethylhydroxylamine hydrochloride (77 mg, 0.79 mmol), triethylamine (0.11 mL, 0.79 mmol), 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 for 2 hours at 15° C. The mixture was 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]imidazole-2-carboxamide (70 mg, 98%) as a white solid. LCMS retention time=0.506 min, m / z=272.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time: 0.506 min, ESI+ found [M+H] = 272.1.

[0191] [ka] Step 11: 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one To a cooled (-70 °C) solution of N-methoxy-N-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL) under a N atmosphere was added ethylmagnesium bromide (3.0 M in THF, 0.61 mL, 1.83 mmol). After the addition, the mixture was stirred at -70 °C for 2 h and then quenched by the addition of saturated aqueous ammonium chloride (3 mL). The mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (25-55% acetonitrile / 0.05% ammonia hydroxide in water) to give 1-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-1-one (4.6 mg, 9%) as a light brown solid. 1 H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.35 - 7.31 (m, 2H), 7.30 - 7.21 (m, 3H), 4.42 - 4.38 (m, 1H), 4.25 - 4.23 (m, 1H), 4.20 - 4.11 (m, 1H), 3.12 - 3.10 (m, 1H), 2.89 - 2.83 (m, 2H), 2.58 - 2.50 (m, 1H), 1.14 - 1.10 (m, 3H). LCMS retention time=0.634 min, m / z=241.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.634 min, ESI+ found [M+H] = 241.1.

[0192] Method 13 [ka] Cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0193] [ka] 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 analyzed by preparative TLC (50% ethyl acetate in petroleum ether, R f =0.7) to give trans-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (30 mg, 51%) as a white solid.

[0194] [ka] Step 2: Cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone 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) under a nitrogen atmosphere was added cyclopropylmagnesium bromide (0.5 M in THF, 0.2 mL, 0.10 mmol). After the addition, the mixture was stirred at -78°C for 1 hour and quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35–65% / 0.05% hydrochloride in water) to give cyclopropyl-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (7.6 mg, 50%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.40 (m, 3H), 7.30 - 7.26 (m, 2H), 6.29 - 6.26 (m, 0.5H), 6.14 - 6.12 (m, 0.5H), 5.92 - 5.87 (m, 1H), 3.44 - 3.41 (m, 1H), 3.01 - 3.02 (m, 2H), 1.19 - 1.16 (m, 2H), 1.12 - 1.09 (m, 2H). LCMS retention time=0.849 min, m / z=272.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.849 min, ESI+ found [M+H] = 272.0.

[0195] Method 14 [ka] 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one

[0196] [ka] Step 1: Ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate To a solution of prop-2-yn-1-ol (30.0 g, 535.14 mmol) in toluene (300 mL) was added ethyl 2-diazoacetate (67.2 g, 588.66 mmol). The reaction mixture was stirred at 110 °C for 5 h and cooled to room temperature. The crude product was collected by filtration and washed with 10% ethyl acetate in petroleum ether (50 mL) to give a mixture of ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (15.8 g, 17%) and ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (inseparable, 1:3, 63.1 g, 69%) as a pale yellow solid, which was used as a mixture in the next step. Ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (major isomer): 1 H NMR (DMSO-d6) 12.60 (1H, s, broad); 6.70 (1H, s); 4.70 (1H, s); 4.35 (2H, q, J=7.0 Hz); 4.45 (1H, s, broad); 1.25 (3H, t, J=7.0 Hz). Ethyl 4-(hydroxymethyl)-1H-pyrazole-5-carboxylate (minor isomer): 1 H NMR (DMSO-d6) 12.60 (1H, s, broad); 7.65 (1H, s); 4.75 (1H, s); 4.35 (2H, q, J=7.0 Hz); 4.13 (1H, s, broad); 1.25 (3H, t, J=7.0 Hz).

[0197] [ka] Step 2: Ethyl 3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate and ethyl 4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate 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 (inseparable, 3.7 g, 52%), which were used as a mixture in the next step. LC-MS retention time = 0.855 min, m / z = 322.9 (M+H). + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.855 min, ESI+observed [M+Na] = 322.9.

[0198] [ka] 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) was added manganese dioxide (7.0 g, 80.52 mmol). The mixture was stirred at 25 °C for 15 h and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% 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, CDCl3) δ 10.02 (s, 1H), 7.38 (s, 1H), 5.94 (s, 2H), 4.40 (q, J=8.0 Hz, 2H), 3.69 - 3.60 (m, 2H), 1.40 (t, J=8.0 Hz, 3H), 0.98 - 0.89 (m, 2H), 0.02 - 0.07 (m, 9H).

[0199] [ka] Step 4: (E)-ethyl 3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylate To a solution of ethyl 5-formyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (700 mg, 2.35 mmol) in dichloromethane (100 mL) was added trimethyl((1-phenylvinyl)oxy)silane (499 mg, 2.59 mmol) and titanium tetrachloride (875 mg, 4.61 mmol). The mixture was stirred at 40 °C for 48 h and then quenched by the addition of water (50 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100–200 mesh, 0–30% ethyl acetate in petroleum ether) to give (E)-ethyl 3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylate (310 mg, 49%) as a yellow solid. LC-MS retention time=0.853 min, m / z=270.9 (M+H) + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.853 min, ESI+ found [M+H] = 270.9.

[0200] [ka] Step 5: Ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate A mixture of (E)-ethyl 3-(3-oxo-3-phenylprop-1-en-1-yl)-1H-pyrazole-5-carboxylate (310 mg, 1.15 mmol) and palladium (10% on carbon, 122 mg) in methanol (20 mL) was hydrogenated (15 psi) at 25° C. for 15 hours and then filtered. The filtrate was concentrated under reduced pressure to give crude ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate (314 mg, 99%) as a pale yellow oil. This crude product was used directly in the next step without further purification.

[0201] [ka] Step 6: Ethyl 3-(3-chloro-3-phenylpropyl)-1H-pyrazole-5-carboxylate To a solution of ethyl 3-(3-hydroxy-3-phenylpropyl)-1H-pyrazole-5-carboxylate (314 mg, 1.14 mmol) in acetonitrile (5 mL) was added sulfurous dichloride (681 mg, 5.72 mmol). The mixture was heated at 65° C. for 15 h and then concentrated under reduced pressure to give crude ethyl 3-(3-chloro-3-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 retention time = 0.861 min, m / z = 314.9 (M+H). + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.861 min, ESI+observed [M+H] = 314.9.

[0202] [ka] 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 retention time = 0.824 min, m / z = 279.0 (M+H). +LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.824 min, ESI+ found [M+H] = 279.0.

[0203] [ka] Step 8: 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid A mixture of ethyl 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (60 mg, 0.23 mmol) and lithium hydroxide monohydrate (50 mg, 1.2 mmol) in tetrahydrofuran (5 mL), methanol (5 mL), and water (2 mL) was stirred at 25 °C for 3 hours and then concentrated under reduced pressure. The residue was adjusted to pH = 5 by the addition of hydrochloric acid (2 N). The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (30 mg, 56%) as a yellow solid, which was used directly in the next step.

[0204] [ka] 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 (3×15 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 retention time = 0.952 min, m / z = 272.1 (M+H). + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.952 min, ESI+ found [M+H] = 272.1.

[0205] [ka] Step 10: 1-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one 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) was added dropwise ethylmagnesium chloride (3.0 M in THF, 0.07 mL, 0.21 mmol) under a nitrogen atmosphere. The mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under 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]pyrazol-2-yl)propan-1-one (13.0 mg, 61%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.39 - 7.30 (m, 3H), 7.11 - 7.09 (m, 2H), 6.60 (s, 1H), 5.54 - 5.50 (m, 1H), 3.11 - 3.01 (m, 3H), 2.95 - 2.89 (m, 2H), 2.52 - 2.48 (m, 1H), 1.11 (t, J=7.2 Hz, 3H). LC-MS retention time=1.858 min, m / z=241.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 3.0 min) retention time 1.858 min, ESI+ found [M+H] = 214.2.

[0206] Method 15 [ka] 1-[(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one and 1-[(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one To a cooled (-78°C) solution of 4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (200 mg, 0.63 mmol) in tetrahydrofuran (13 mL) was added dropwise ethylmagnesium chloride (2 M in THF, 0.63 mL, 1.26 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under 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]propan-1-one (120 mg, 70%) as a white solid. This racemic material was further separated by chiral SFC to give the following compound with the arbitrary assignment: To give 1-[(4S)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 1, retention time = 2.979 min) (45.0 mg, 37%) as a white solid. 1 H NMR (400 MHz, 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 retention time=1.761 min, m / z=275.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 3.0 min) retention time 1.761 min, ESI+ found [M+H] = 275.2. To give 1-[(4R)-4-(2-fluorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 2, retention time = 3.234 min) (52 mg, 43%) as a white solid. 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-MS retention time=1.755 min, m / z=275.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 3.0 min) retention time 1.752 min, ESI+ found [M+H] = 275.2. SFC conditions: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: 5% to 40% B in 5.5 min, then hold at 40% for 3 min, and hold at 5% B for 1.5 min Flow rate: 2.5 mL / min, Column temperature: 40°C.

[0207] Method 16 [ka] 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-3-oxo-propanenitrile

[0208] [ka] Step 1: cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-oxopropanenitrile To a cooled (-78°C) solution of acetonitrile (298 mg, 7.27 mmol) in tetrahydrofuran (15 mL) was added potassium t-butoxide (611.4 mg, 5.45 mmol). After stirring for 30 minutes, ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (500 mg, 1.82 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the slow addition of cold saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure to give crude cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-oxo-propanenitrile (150 mg, 31%) as a white solid, which was used directly in the next step.

[0209] [ka] Step 2: 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-3-oxo-propanenitrile To a cooled (0 °C) solution of cis-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-3-oxo-propanenitrile (140 mg, 0.52 mmol) in N,N-dimethylformamide (6 mL) was added cesium carbonate (422 mg, 1.30 mmol). After stirring for 30 minutes, iodomethane (2800 mg, 19.7 mmol) was added, and the reaction mixture was stirred at 0 °C for 4 hours. The mixture was then quenched by the addition of cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hyfroxide in water) to give 3-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-3-oxo-propanenitrile (28.0 mg, 17%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.38 (m, 3H), 7.27 - 7.25 (m, 2H), 6.15 - 6.13 (m, 0.5H), 6.01 - 5.99 (m, 0.5H), 5.57 - 5.56 (m, 1H), 3.74 - 3.63 (m, 1H), 3.06 - 2.95 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H). LC-MS retention time=1.734 min, m / z=299.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 3.0 min) retention time 1.734 min, ESI+ found [M+H] = 299.2.

[0210] Method 17 [ka] 1-[(4S)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one and 1-[(4R)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one

[0211] [ka] 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 analyzed by preparative TLC (10% methanol in dichloromethane, R f =0.7) to give N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (100 mg, 91%) as a colorless oil. LCMS retention time = 0.593 min, m / z = 272.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.593 min, ESI+ found [M+H] = 272.1.

[0212] [ka] Step 2: 1-[(4S)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one and 1-[(4R)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]propan-1-one To a cooled (-78°C) solution of N-methoxy-N-methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (100 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added dropwise ethylmagnesium chloride (2.7 M in THF, 0.54 mL, 1.47 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were concentrated under reduced pressure to give crude 1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one (80 mg, 90%) as a light brown solid, which was further separated by chiral SFC to give the following arbitrary assignment: To give (R)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one (peak 1, retention time = 2.581 min) (25.4 mg, 32%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.843 min, m / z=240.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.843 min, ESI+ found [M+H] = 240.9. To give (S)-1-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)propan-1-one (peak 2, retention time = 2.968 min) (22.7 mg, 28%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.838 min, m / z=241.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.838 min, ESI+ found [M+H] = 241.0. SFC conditions: Column: Chiralpak AD (250mm*30mm, 5μm); Conditions: 0.1% NH3H2O ​​iPrOH; Start B 15% End B 15%; Flow rate (60mL / min), column temperature 40℃.

[0213] Method 18 [ka] 1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxy-2-methyl-propan-1-one To a solution of 1-[cis-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-methyl-propan-1-one (50 mg, 0.18 mmol) in dimethyl sulfoxide (4 mL) was added 1-bromo-2,5-pyrrolidinedione (33 mg, 0.18 mmol). The mixture was heated at 100 °C in air for 15 h. The solvent was evaporated under reduced pressure, and the residue was analyzed by RP-HPLC (25-55% acetonitrile / 0.05% ammonia hydroxide in water) and preparative TLC (ethyl acetate, R f =0.6) to give 1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-hydroxy-2-methyl-propan-1-one (48.6 mg, 91%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.27 - 7.25 (m, 2H), 6.20 - 6.03 (m, 1H), 5.66 - 5.57 (m, 1H), 3.79 - 3.71 (m, 1H), 2.87 - 2.77 (m, 1H), 1.60 (s, 3H), 1.56 (s, 3H). LC-MS retention time=0.771 min, m / z=290.1 ​​(M+H) + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.771 min, ESI+ found [M+H] = 290.1.

[0214] Method 19 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone

[0215] [ka] 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 A mixture of cis-1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)propan-1-one (120 mg, 0.46 mmol), dibromomethane (1931 mg, 11.11 mmol) and diethylamine (1625 mg, 22.22 mmol) in acetonitrile (10 mL) was heated at 100° C. for 30 min under microwave conditions. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% 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 retention time = 1.020 min, m / z = 272.1 [M+H] + LCMS (0-60% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.020 min, ESI+ found [M+H] = 272.1.

[0216] [ka] Step 2: (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone To a mixture of diethylzinc (123 mg, 1.00 mmol) and nickel chloride (8 mg, 0.07 mmol) in dichloromethane (5 mL) was added diiodomethane (355 mg, 1.33 mmol) at 0° C. After stirring for 30 minutes, 1-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-prop-2-en-1-one (90 mg, 0.33 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 hours. The mixture was quenched by the addition of cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×15 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 (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone (3.0 mg, 3%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.41 - 7.37 (m, 3H), 7.24 - 7.23 (m, 2H), 6.15 - 6.13 (m, 0.5H), 6.01 - 5.99 (m, 0.5H), 5.60 - 5.59 (m, 1H), 3.76 - 3.68 (m, 1H), 2.84 - 2.74 (m, 1H), 1.82 - 1.76 (m, 2H), 1.41 (s, 3H), 0.97 - 0.92 (m, 2H). LC-MS retention time=1.068 min, m / z=286.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.068 min, ESI+ found [M+H] = 286.1.

[0217] method 20 [ka] 1-[(4S)-4-Phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one and 1-[(4R)-4-Phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one

[0218] [ka] Step 1: N-Methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide A mixture of 4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid (156 mg, 0.64 mmol), N,O-dimethylhydroxylamine hydrochloride (125 mg, 1.28 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (291.42 mg, 0.77 mmol), and triethylamine (258 mg, 2.55 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (10% methanol in dichloromethane, R f =0.7) to give N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide (80 mg, 43.6%) as a colorless oil.

[0219] [ka] Step 2: 1-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one and 1-[(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one To a cooled (-78°C) solution of N-methoxy-N-methyl-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide (60 mg, 0.21 mmol) in tetrahydrofuran (6 mL) was added dropwise ethylmagnesium chloride (2.7 M in THF, 0.39 mL, 1.04 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure to give the crude racemic product, which was further separated by chiral SFC to give the following arbitrary assignments: To give 1-[(4S)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 1, retention time = 3.254 min) (11.5 mg, 21%) as a white solid. 1 H NMR (400 MHz, 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 retention time=1.026 min, m / z=257.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.026 min, ESI+ found [M+H] = 257.1. To give 1-[(4R)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl]propan-1-one (peak 2, retention time = 4.381 min) (13.6 mg, 25%) as a white solid. 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 retention time=1.023 min, m / z=257.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.023 min, ESI+observed [M+H] = 257.1. SFC conditions: Column: OD (250mm*30mm, 5μm); Conditions: 0.1% NH3H2O ​​EtOH; Start B: 30%; End B: 30%; flow rate (60mL / min), column temperature 40℃.

[0220] Method 21 [ka] 3,3,3-Trifluoro-1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)propan-1-one

[0221] [ka] Step 1: 1-cis-7-fluoro-5-phenyl-2-(1-((trimethylsilyl)oxy)vinyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole To a solution of 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)ethanone (200 mg, 0.82 mmol) in 1,4-dioxane (6 mL) was added triethylamine (165 mg, 1.63 mmol) and trimethylsilyl trifluoromethanesulfonate (254 mg, 1.14 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours and quenched by the addition of cold saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were concentrated under reduced pressure to give crude 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 (400 MHz,CDCl3) δ 7.17 - 7.10 (m, 3 H), 6.98 - 6.96 (m, 2 H), 5.79 - 5.78 (m, 0.5 H), 5.65 - 5.64 (m, 0.5 H), 5.21 - 5.17 (m, 2 H), 4.40 (s, 1 H), 4.49 (s, 1 H), 3.37 - 3.27 (m, 1 H), 2.66 - 2.56 (m, 1 H), 0.03 (s, 9 H).

[0222] [ka] Step 2: 3,3,3-trifluoro-1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)propan-1-one A mixture of 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (418 mg, 1.32 mmol), 1-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)vinyloxy-trimethyl-silane (210 mg, 0.66 mmol) and cuprous thiocyanate (16 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 15° C. for 15 hours and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25–55% / 0.05% HCl in acetonitrile) to give 3,3,3-trifluoro-1-(rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)propan-1-one (31 mg, 15%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.40 - 7.37 (m, 3H), 7.28 - 7.26 (m, 2H), 6.19 - 6.17 (m, 0.5H), 6.05 - 6.03 (m, 0.5H), 5.65 - 5.63 (m, 1H), 4.09 - 4.01 (m, 2H), 3.78 - 3.29 (m, 1H), 2.89 - 2.77 (m, 1H). LC-MS retention time=1.072 min, m / z=314.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 2.0 min) retention time 1.072 min, ESI+observed [M+H] = 314.1.

[0223] Method 22 [ka] 1-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one To a cooled (-78°C) solution of ethyl (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (200 mg, 0.78 mmol) in tetrahydrofuran (20 mL) was added dropwise ethylmagnesium chloride (3.0 M in THF, 0.58 mL, 1.74 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–50% ethyl acetate in petroleum ether) to give 1-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (60 mg, 32%) as a white solid. 1 H NMR (400 MHz, 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 retention time=1.523 min, m / z=242.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 1.523 min, ESI+ observed value [M+H] = 242.2.

[0224] Method 23 [ka] 1-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one 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) was added dropwise ethylmagnesium chloride (2.7 M in THF, 1.33 mL, 3.6 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 h and then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude racemic product, which was further purified by chiral SFC and RP-HPLC (25-55% acetonitrile / 0.05% ammonia hydroxide in water) to give the following product with arbitrary assignment: To give 1-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (peak 2, retention time = 3.038 min) (17 mg, 8%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.977 min, m / z=260.1 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.977 min, ESI+ found [M+H] = 260.1. SFC conditions: Column: OJ (250mm*30mm, 5μm); Conditions: 0.1% NH3H2O ​​EtOH; Start B: 20%; End B: 20%; flow rate (60mL / min), column temperature 40℃.

[0225] Method 24 [ka] 1-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0226] [ka] Step 1: (E)-methyl 4-phenylbut-3-enoate To a solution of (E)-4-phenylbut-3-enoic acid (15.0 g, 92.48 mmol) in methanol (60 mL) was added sulfuric acid (2.3 g, 23.12 mmol). The mixture was heated at 90° C. for 18 hours and cooled. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (30 mL), saturated aqueous sodium bicarbonate (30 mL), brine (30 mL), dried, and concentrated under reduced pressure to give crude methyl (E)-4-phenylbut-3-enoate (14.8 g, 91%) as a light oil, which was used directly in the next step. 1 H NMR (400MHz, CDCl3) 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).

[0227] [ka] Step 2: Methyl 2-(3-phenyloxiran-2-yl)acetate To a mixture of methyl (E)-4-phenylbut-3-enoate (14.8 g, 84.0 mmol) and sodium bicarbonate (34.4 g, 409.0 mmol) in acetone (300 mL) was added dropwise a solution of potassium monopersulfate triple salt (67.1 g, 109.2 mmol) in water (80 mL) at 0 °C. After the addition, the resulting mixture was allowed to warm to 25 °C, stirred for 4 h, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give methyl 2-(3-phenyloxiran-2-yl)acetate (15.0 g, 93%) as a colorless oil. LC-MS retention time = 0.799 min, m / z = 233.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.799 min, ESI+ found [M+H] = 233.9.

[0228] [ka] Step 3: methyl (rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate To a solution of methyl 2-(3-phenyloxiran-2-yl)acetate (15.0 g, 78.0 mmol) in acetonitrile (400 mL) was added lithium bromide (6.8 g, 78.0 mmol) and magnesium perchlorate (1.7 g, 78.0 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hours and diluted with dichloromethane (100 mL). The resulting mixture was washed with hydrochloric acid (1 N, 100 mL). The separated aqueous layer was washed with dichloromethane (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude methyl (rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate (20.0 g, 94%) as a colorless oil. The crude product was used in the next step without further purification. LC-MS retention time=0.610 min, m / z=256.9 [M+H]+ LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.610 min, ESI+ found [M+H] = 256.9.

[0229] [ka] Step 4: Methyl (rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate A mixture of methyl (rac-3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate (20.0 g, 73.2 mmol) and sodium azide (14.3 g, 219.7 mmol) in N,N-dimethylformamide (500 mL) was stirred at 20 °C for 16 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude methyl (rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate (17.0 g, 99%) as a yellow oil. LC-MS retention time = 0.978 min, m / z = 208.3 [M+H] + . LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.978 min, ESI+observed [M+H] = 208.3.

[0230] [ka] Step 5: methyl (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate A mixture of methyl (rac-3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate (17.0 g, 72.3 mmol) and palladium (10% on carbon, 7.7 g) in ethyl acetate (800 mL) was hydrogenated (15 psi) at 25 °C for 24 hours and then filtered. The filtrate was concentrated under reduced pressure to give crude methyl (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate (15.0 g, 99%) as a colorless oil. The crude product was used in the next step without further purification. LC-MS retention time = 0.315 min, m / z = 210.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.315 min, ESI+ found [M+H] = 210.2.

[0231] [ka] Step 6: cis-4-hydroxy-5-phenylpyrrolidin-2-one A solution of methyl (rac-3R,4R)-4-amino-3-hydroxy-4-phenylbutanoate (15.0 g, 71.7 mmol) in methanol (200 mL) was heated at 50° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol in dichloromethane) to give cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g, 76%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.678 min, m / z=178.2 [M+H] + . LCMS (0-60% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.678 min, ESI+observed [M+H] = 178.2.

[0232] [ka] Step 7: cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one To a solution of cis-4-hydroxy-5-phenylpyrrolidin-2-one (9.6 g, 54.2 mmol) in dichloromethane (300 mL) was added imidazole (11.1 g, 162.5 mmol) and tert-butyldimethylsilyl chloride (16.3 g, 108.4 mmol). The resulting mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (10.0 g, 63%) as a white solid. LC-MS retention time = 1.257 min, m / z = 292.3 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.257 min, ESI+ found [M+H] = 292.3.

[0233] [ka] Step 8: cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one To a solution of cis-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (10.0 g, 34.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60%, 2.1 g, 51.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, (aminooxy)diphenylphosphine oxide (12.0 g, 51.47 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 12 hours and filtered. The filtrate was concentrated under reduced pressure to give crude cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (9.0 g, 86%) as a brown solid. This crude product was used in the next step without further purification. LC-MS retention time = 1.225 min, m / z = 307.4 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.225 min, ESI+ found [M+H] = 307.4.

[0234] [ka] Step 9: Ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate A mixture of cis-1-amino-4-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (9.0 g, 29.4 mmol) and ethyl 2-ethoxy-2-imino-acetate (21.3 g, 146.8 mmol) in toluene (500 mL) was heated at 90° C. for 18 hours and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were concentrated under reduced pressure to give crude ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate (10.0 g, 84%) as a brown oil. LC-MS retention time = 1.128 min, m / z = 406.4 [M+H] +LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.128 min, ESI+ found [M+H] = 406.4.

[0235] [ka] Step 10: Ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate A mixture of ethyl cis-2-((3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-phenylpyrrolidin-1-yl)amino)-2-iminoacetate (10.0 g, 24.7 mmol) and 4-methylbenzenesulfonic acid hydrate (4.7 g, 24.7 mmol) in toluene (300 mL) was heated at 120° C. for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (5.5 g, 58%) as a brown oil. LC-MS retention time = 1.345 min, m / z = 388.4 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.345 min, ESI+ found [M+H] = 388.4.

[0236] [ka] Step 11: Ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate To a solution of tetrabutylammonium fluoride (18.5 g, 70.9 mmol) in tetrahydrofuran (200 mL) was added ethyl cis-6-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (5.5 g, 14.2 mmol). The resulting mixture was stirred at 25° C. for 16 hours and diluted with ethyl acetate (300 mL). The mixture was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.8 g, 46%) as a yellow solid. LC-MS retention time = 1.036 min, m / z = 274.3 [M+H] + LCMS (0-60% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.036 min, ESI+ found [M+H] = 274.3.

[0237] [ka] Step 12: Ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate To a solution of ethyl cis-6-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (1.0 g, 3.66 mmol) in dichloromethane (50 mL) was added diethylaminosulfur trifluoride (10.0 g, 62.0 mmol) dropwise at 25° C. The resulting mixture was stirred at 25° C. for 1 hour and then quenched by the slow addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–40% ethyl acetate in petroleum ether) to give ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (400 mg, 40%) as a white solid. 1 H NMR (400MHz, 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 retention time=0.958 min, m / z=276.2 [M+H] + LCMS (10 to 80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.958 min, ESI+observed [M+H] = 276.2.

[0238] [ka] Step 13: 1-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one To a cooled (-78°C) solution of ethyl trans-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) in tetrahydrofuran (5 mL) was added dropwise ethylmagnesium chloride (3.0 M in THF, 0.25 mL, 0.75 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–50% ethyl acetate in petroleum ether) to give, with arbitrary assignment, 1-[rac-(5R,6S)-6-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (13.6 mg, 45%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.31 (m, 3H), 6.90 - 6.87 (m, 2H), 5.63 - 5.61 (m, 0.5H), 5.59 - 5.57 (m, 1H), 5.46 - 5.44 (m, 0.5H), 3.42 - 3.28 (m, 1H), 3.26 - 3.21 (m, 1H), 3.03 - 3.01 (m, 2H), 1.16 (t, J=7.2 Hz, 3H). LCMS retention time=0.977 min, m / z=260.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.977 min, ESI+ found [M+H] = 260.1.

[0239] Method 25 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl)methanone To a solution of 2-bromopyridine (435 mg, 2.76 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexane, 1.10 mL, 2.76 mmol) at −78° C. After the addition, the mixture was allowed to warm to 30° C. and stirred for 2 hours. The mixture was cooled to −78° C., and cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (200 mg, 0.69 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at −78° C. for 6 hours and quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25–55% / 0.05% ammonia hydroxide in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-pyridyl)methanone (32.0 mg, 15%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.65 (m, 1H), 8.00 - 7.90 (m, 2H), 7.62 - 7.59 (m, 1H), 7.42 - 7.30 (m, 3H), 7.25 - 7.20 (m, 2H), 6.30 - 6.22 (m, 0.5H), 6.18 - 6.14 (m, 0.5H), 5.75 - 5.55 (m, 1H), 3.77 - 3.67 (m, 1H), 2.74 - 2.45 (m, 1H). LCMS: Retention time=1.510 min, m / z=309.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 1.510 min, ESI+observed [M+H] = 309.1.

[0240] Method 26 [ka] Cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0241] [ka] Step 1: Cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a cooled (-78°C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (4 mL) was added dropwise cyclopropylmagnesium bromide (0.5 M in THF, 1.45 mL, 0.73 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (30–60% acetonitrile / 0.05% ammonia hydroxide in water) to give cis racemic cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (15 mg, 10%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.45 - 7.35 (m, 3H), 7.27 - 7.25 (m, 2H), 6.18 - 6.15 (m, 0.5H), 6.05 - 6.00 (m, 0.5H), 5.65 - 5.60 (m, 1H), 3.77 - 3.65 (m, 1H), 3.05 - 2.95 (m, 1H), 2.90 - 2.70 (m, 1H), 1.17 - 1.13 (m, 2H), 1.10 - 1.05 (m, 2H). LCMS retention time=1.031 min, m / z=272.3 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.031 min, ESI+ found [M+H] = 272.3.

[0242] [ka] Step 2: Cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone Racemic cyclopropyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (100 mg, 0.37 mmol) was separated by chiral SFC to give the compound with the arbitrary assignment: to give cyclopropyl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 3.575 min) (25.5 mg, 24%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.29 - 7.27 (m, 2H), 6.19 (d, J=5.6 Hz, 0.5H), 6.05 (d, J=5.2 Hz, 0.5H), 5.66 - 5.62 (m, 1H), 3.79 - 3.71 (m, 1H), 3.05 - 3.02 (m, 1H), 3.01 - 2.81 (m, 1H), 1.29 - 1.09 (m, 4H). LCMS retention time=0.816 min, m / z=271.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.816 min, ESI+ found [M+H] = 271.9. to give cyclopropyl-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 3.849 min) (18.5 mg, 17%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.817 min, m / z=271.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.817 min, ESI+ found [M+H] = 271.9. SFC conditions: Column: Chiralpak AD (250mm*30mm, 10μm); Conditions: 0.1% NH3H2O ​​iPrOH; Start B 25% End B 25%; Flow rate (60mL / min), column temperature 40℃.

[0243] Method 27 [ka] Cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0244] [ka] 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 stirred, cooled (−78° C.) solution of cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (10 mL). After the addition, the mixture was stirred at 25° C. for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 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 retention time=0.611 min, m / z=302.1[M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.611 min, ESI+observed [M+H] = 302.1.

[0245] [ka] Step 2: Cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a solution of cis-cyclopentyl(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol (100 mg, 0.33 mmol) in dichloromethane (15 mL) was added manganese dioxide (288 mg, 3.32 mmol). The reaction mixture was stirred at 35° C. for 2 hours and then filtered through a short pad of Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to give cyclopentyl-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (18.2 mg, 18%) as a white solid. 1 H NMR (400 MHz, 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 retention time=2.070 min, m / z=300.2 [M+H] + LCMS (0-60% acetonitrile in water + 0.03% trifluoroacetic acid in 3.0 min) retention time 2.070 min, ESI+ found [M+H] = 300.2.

[0246] Method 28 [ka] (rac-(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-thienyl)methanone To a cooled (-78 °C) solution of 2-iodothiophene (289 mg, 1.38 mmol) in tetrahydrofuran (10 mL) under a N atmosphere was added n-butyllithium (2.5 M in hexanes, 0.55 mL, 1.38 mmol) dropwise. The mixture was stirred at -78 °C for 1 h, followed by the addition of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.34 mmol) in tetrahydrofuran (2 mL). The mixture was stirred at -78 °C for an additional 2 h and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40–70% / 0.05% hydrochloride in water) to give (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(2-thienyl)methanone (15.6 mg, 14%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.50 - 8.49 (m, 1H), 7.96 - 7.94 (m, 1H), 7.49 - 7.35 (m, 3H), 7.35 - 7.27 (m, 2H), 7.26 - 7.20 (m, 1H), 6.24 - 6.22 (m, 0.5H), 6.10 - 6.08 (m, 0.5H), 5.74 - 5.68 (m, 1H), 3.86 - 3.72 (m, 1H), 2.91 - 2.79 (m, 1H). LCMS retention time=0.891 min, m / z=314.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.891 min, ESI+ found [M+H] = 314.1.

[0247] Method 29 [ka] Cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (0 °C) mixture of magnesium (234 mg, 9.65 mmol), iodine (12 mg, 0.05 mmol), and 1,2-dibromoethane (0.1 mL, 0.10 mmol) in tetrahydrofuran (15 mL) under a N atmosphere, bromocyclobutane (0.5 mL, 5.85 mmol) was added dropwise. The mixture was stirred at 35 °C for approximately 1 h. The above freshly prepared cyclobutylmagnesium bromide solution (1.0 mL, 0.39 mmol) was added dropwise to a stirred, cooled (-78 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (28 mg, 0.10 mmol) in tetrahydrofuran (2 mL). After the addition, the mixture was stirred at −78° C. for 1 h and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (42–62% acetonitrile / 0.05% hydrochloride in water) to give cyclobutyl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (2 mg, 7%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.40 - 7.30 (m, 3H), 7.25 - 7.21 (m, 2H), 6.15 - 6.10 (m, 0.5H), 6.01 - 5.95 (m, 0.5H), 5.60 - 5.55 (m, 1H), 4.15 - 4.07 (m, 1H), 3.74 - 3.65 (m, 1H), 2.80 - 2.70 (m, 1H), 2.35 - 2.20 (m, 3H), 2.20 - 2.15 (m, 1H), 2.12 - 2.00 (m, 1H), 1.90 - 1.85 (m, 1H). LCMS retention time=0.883 min, m / z=286.0 [M+H]+ LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.883 min, ESI+ found [M+H] = 286.0.

[0248] method 30 [ka] 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-propan-1-one To a cooled (-78°C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) in tetrahydrofuran (3 mL) was added dropwise tert-butyllithium (1.3 M in pentane, 0.17 mL, 0.22 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 45–75% / 0.05% hydrochloride in water) to give 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2,2-dimethyl-propan-1-one (12.7 mg, 40%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.907 min, m / z=288.0 [M+H] +LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.907 min, ESI+ found [M+H] = 288.0.

[0249] Method 31 [ka] 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-propan-1-one To a cooled (-78°C) solution of ethyl cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (200 mg, 0.73 mmol) in tetrahydrofuran (10 mL) was added dropwise isopropylmagnesium chloride (2.0 mL in THF, 1.1 mL, 2.20 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30–60% / 0.05% ammonia hydroxide in water) to give racemic 1-(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methyl-propan-1-one (6.9 mg, 3.4%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.36 (m, 3H), 7.28 - 7.26 (m, 2H), 6.18 - 6.16 (m, 0.5H), 6.05 - 6.02 (m, 0.5H), 5.65 - 5.61 (m, 1H), 3.78 - 3.72 (m, 1H), 3.64 - 3.61 (m, 1H), 2.87 - 2.76 (m, 1H), 1.19 (d, J=7.2 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H). LCMS retention time=1.971 min, m / z=274.2[M+H] + LCMS (0-60% acetonitrile in water + 0.03% trifluoroacetic acid in 3.0 min) retention time 1.971 min, ESI+ found [M+H] = 274.2.

[0250] Method 32 [ka] 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one and 1-[(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0251] [ka] Step 1: 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one To a cooled (-70°C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (30 mg, 0.10 mmol) in tetrahydrofuran (3 mL) was added ethylmagnesium bromide (3.0 M in THF, 0.1 mL, 0.30 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at 30°C for approximately 3 hours and then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25–55% / 0.05% ammonia hydroxide in water) to give 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (6.3 mg, 23%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.38 - 7.35 (m, 3H), 7.25 - 7.23 (m, 2H), 6.15 - 6.13 (m, 0.5H), 6.01 - 5.99 (m, 0.5H), 5.59 - 5.53 (m, 1H), 3.77 - 3.67 (m, 1H), 3.05 - 2.99 (m, 2H), 2.84 - 2.73 (m, 1H), 1.13(t, J=7.2 Hz, 3H). LCMS retention time=1.038 min, m / z=260.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.038 min, ESI+ found [M+H] = 260.2.

[0252] [ka] Step 2: 1-[(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one and 1-[(5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one Racemic 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (220 mg) was separated by chiral SFC to give the compound with the arbitrary assignment: to give 1-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (peak 1, retention time = 2.265 min) (78 mg, 35%, 88% ee) as a pale yellow oil. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.32 (m, 3H), 7.27 - 7.23 (m, 2H), 6.17 - 6.14 (m, 0.5H), 6.02 - 6.00 (m, 0.5H), 5.65 - 5.58 (m, 1H), 3.84 - 3.64 (m, 1H), 3.06 - 3.00 (m, 2H), 2.88 - 2.69 (m, 1H), 1.13 (t, J=7.2 Hz, 3H). LCMS retention time=0.822 min, m / z=260.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.822 min, ESI+ found [M+H] = 260.0. to give 1-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (peak 2, retention time = 2.382 min) (80 mg, 35%, 91% ee) as a pale yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.43 - 7.32 (m, 3H), 7.27 - 7.23 (m, 2H), 6.17 - 6.14 (m, 0.5H), 6.02 - 6.00 (m, 0.5H), 5.65 - 5.58 (m, 1H), 3.84 - 3.64 (m, 1H), 3.06 - 3.00 (m, 2H), 2.88 - 2.69 (m, 1H), 1.13 (t, J=7.2 Hz, 3H). LCMS retention time=0.817 min, m / z=260.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.817 min, ESI+ found [M+H] = 260.0. SFC conditions: Column: AS (250mm*30mm, 5μm); Conditions: 0.1% NH3H2O ​​EtOH; Start B 20% End B 20%; Flow rate (60mL / min), column temperature 40℃.

[0253] Method 33 [ka] (1-Methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70 °C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (137 mg, 0.47 mmol) and 1-methyl-4-iodo-1h-pyrazole (393 mg, 1.89 mmol) in tetrahydrofuran (10 mL) was added dropwise tert-butyllithium (1.3 M in hexanes, 1.45 mL, 1.89 mmol) under a nitrogen atmosphere. The mixture was stirred at -70 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 27–57% / 0.05% hydrochloride in water) to give cis racemic (1-methylpyrazol-4-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (53.4 mg, 36%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.24 (s, 1H), 7.46 - 7.34 (m, 3H), 7.32 - 7.25 (m, 2H), 6.22 - 6.19 (m, 0.5H), 6.08 - 6.05 (m, 0.5H), 5.72 - 5.65 (m, 1H), 3.93 (s, 3H), 3.85 - 3.70 (m, 1H), 2.90 - 2.75 (m, 1H). LCMS retention time=0.791 min, m / z=311.9[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.791 min, ESI+ found [M+H] = 311.9.

[0254] Method 34 [ka] 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone

[0255] [ka] Step 1: (E)-Benzaldehyde oxime To a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL) was added sodium carbonate (112.3 g, 1060.1 mmol) and hydroxylamine hydrochloride (35.3 g, 508.9 mmol). The reaction mixture was stirred at 25 °C for 3 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 × 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 (£)-benzaldehyde oxime as a colorless oil (51.0 g, 99%), which was used in the next step without further purification.

[0256] [ka] 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) was added methyl acrylate (14.2 g, 165.1 mmol), sodium iodide (24.7 g, 165.1 mmol), 2,6-lutidine (17.6 g, 165.1 mmol), and hypochlorous acid tert-butyl ester (17.9 g, 165.1 mmol). The reaction mixture was stirred at 25 °C for 24 h and then 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-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g, 74%). LCMS retention time=0.871 min, m / z=206.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.871 min, ESI+ found [M+H] = 206.2.

[0257] [ka] Step 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one A mixture of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (25.0 g, 121.8 mmol) and palladium (10% on carbon, 2.5 g) in ethanol (800 mL) was hydrogenated (50 psi) at 25 °C for 2 h, then filtered, and the filtrate was concentrated under reduced pressure to give crude 3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%), which was used in the next step without further purification. LCMS retention time = 0.270 min, m / z = 177.8 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.270 min, ESI+ found [M+H] = 177.8.

[0258] [ka] Step 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one and trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol) in dichloromethane (300 mL) was added tert-butyldimethylchlorosilane (19.1 g, 126.9 mmol) and imidazole (11.5 g, 169.3 mmol). The reaction mixture was stirred at 25 °C for 16 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 the following arbitrary assignment: To give cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 51%). 1 H 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 To give trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a colorless oil (9.3 g, 38%). 1 H 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).

[0259] [ka] Step 5: trans-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one To a solution of trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g, 24.0 mmol) in N,N-dimethylformamide (200 mL), sodium hydride (1.44 g, 36.0 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 20 minutes. o-(Diphenylphosphoryl)hydroxylamine (8.40 g, 36.03 mmol) was then added. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give trans-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g, 95.1%) as a yellow oil, which was used in the next step without further purification. LCMS retention time = 0.775 min, m / z = 307.0 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.775 min, ESI+ found [M+H] = 307.0.

[0260] [ka] Step 6: trans-ethyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetate To a solution of trans-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g, 22.8 mmol) in ethanol (150 mL) was added ethyl 2-ethoxy-2-imino-acetate (6.63 g, 45.7 mmol). The reaction mixture was stirred at 60° C. for 16 hours and then concentrated under reduced pressure to give crude trans-ethyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetate (8.50 g, 92%) as a yellow oil, which was used in the next step without further purification. LCMS retention time = 2.154 min, m / z = 406.3 [M+H] + LCMS (0-60% acetonitrile in water + 0.03% trifluoroacetic acid in 3.0 min) retention time 2.143 min, ESI+ found [M+H] = 406.3.

[0261] [ka] Step 7: trans-ethyl 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate To a solution of ethyl 2-[[trans-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate (8.5 g, 21.0 mmol) in toluene (100 mL) was added p-toluenesulfonic acid (4.4 g, 25.2 mmol). The reaction mixture was stirred at 120 °C for 16 h and then concentrated under reduced pressure to give crude trans-ethyl 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (7.5 g, 92.3%) as a yellow oil, which was used in the next step without further purification. LCMS retention time = 1.022 min, m / z = 374.2 [M+H] + . LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.022 min, ESI+observed [M+H] = 374.2.

[0262] [ka] Step 8: trans-Ethyl 7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate To a solution of ethyl trans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (7.0 g, 18.06 mmol) in tetrahydrofuran (120 mL) was added tetrabutylammonium fluoride (1N in THF, 18.06 mL, 18.06 mmol). The reaction mixture was stirred at 40 °C for 3 h and then concentrated under reduced pressure to give crude trans-ethyl 7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (3.5 g, 57%) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.39 - 7.35 (m, 3H), 7.14 - 7.12 (m, 2H), 5.73 - 5.70 (m, 1H), 5.54 - 5.51 (m, 1H), 4.47 - 4.40 (m, 2H), 3.24 - 3.21 (m, 1H), 3.05 - 3.00 (m, 1H), 1.41 - 1.36 (m, 3H).

[0263] [ka] Step 9: cis-ethyl 7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate To a solution of trans-ethyl 7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.37 mmol) in dichloromethane (8 mL) was added diethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then quenched by the addition of water (20 mL). The resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R f =0.5) to give cis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (54 mg, 54%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.44 - 7.31 (m, 3H), 7.25 - 7.17 (m, 2H), 6.09 (dd, J=1.4 Hz, 7.2 Hz, 1H), 5.95 (dd, J=1.4 Hz, 7.2 Hz, 1H), 5.52 - 5.47(m, 1H), 4.53 - 4.37 (m, 2H), 3.74 - 3.54 (m, 1H), 3.05 - 2.82 (m, 1H), 1.48 - 1.33 (m, 3H).

[0264] [ka] Step 10: cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid To a solution of cis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (54 mg, 0.20 mol) in tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide monohydrate (25 mg, 0.59 mmol). The reaction mixture was stirred at 25° C. for 2 hours and then concentrated under reduced pressure. The residue was adjusted to pH 5 by the addition of hydrochloric acid (2 N). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (45 mg, 93%) as a white solid, which was used in the next step without further purification.

[0265] [ka] 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone

[0266] [ka] 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 analyzed by preparative TLC (50% ethyl acetate in petroleum ether, R f =0.7) to give cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (225 mg, 54.7%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.41 - 7.35 (m, 3H), 7.26 - 7.22 (m, 2H), 6.09 - 6.07 (m, 0.5H), 5.96 - 5.93 (m, 0.5H), 5.49 - 5.46 (m, 1H), 3.78 (s, 3H), 3.66 - 3.59 (m, 1H), 3.55 - 3.35 (brs, 3H), 2.99 - 2.88 (m, 1H). LCMS retention time=0.564 min, m / z=291.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.564 min, ESI+observed [M+H] = 291.1.

[0267] [ka] Step 12: 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone To a cooled (-70°C) solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (30 mg, 0.10 mmol) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (3.0 M in THF, 0.1 mL, 0.30 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at 30°C for approximately 3 hours and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25–55% / 0.05% ammonia hydroxide in water) to give 1-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]ethanone (4 mg, 15%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.954 min, m / z=246.2 [M+H] + LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.954 min, ESI+ found [M+H] = 246.2.

[0268] Method 35 [ka] [(1S,2R)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and [(1R,2S)-2-Fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (157 mg, 1.06 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 0.64 mL, 1.60 mmol) under a nitrogen atmosphere. After the addition, the mixture was stirred at -70°C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (37-67% acetonitrile / 0.05% ammonia hydroxide in water) to give [trans-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (25 mg, 16%) as a dark red solid. This material was further separated by chiral SFC to give the following arbitrary assignment: To give [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 3.130 min) (11.2 mg, 44%) as a white solid. 1H NMR (400MHz, CD3OD) δ 7.51 - 7.33 (m, 3H), 7.30 - 7.28 (m, 2H), 6.21 - 6.03 (m, 1H), 5.68 - 5.64 (m, 1H), 5.02 - 4.94 (m, 1H), 4.84 - 4.80 (m, 1H), 3.84 - 3.70 (m, 1H), 3.47 - 3.44 (m, 1H), 2.90 - 2.78 (m, 1H), 1.73 - 1.62 (m, 1H), 1.60 - 1.52 (m, 1H). LCMS retention time=1.765 min, m / z=290.1 ​​[M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 2.0 min) retention time 1.765 min, ESI+ found [M+H] = 290.1. To give [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 3.464 min) (10.2 mg, 40%) as a white solid. 1 H NMR (400MHz, CD3OD) δ 7.51 - 7.33 (m, 3H), 7.32 - 7.20 (m, 2H), 6.21 - 6.04 (m, 1H), 5.70 - 5.62 (m, 1H), 5.00 - 4.82 (m, 1H), 3.83 - 3.70 (m, 1H), 3.47 - 3.42 (m, 1H), 2.90 - 2.77 (m, 1H), 1.74 - 1.63 (m, 1H), 1.60 - 1.52 (m, 1H). LCMS retention time=1.756 min, m / z=290.1 ​​[M+H] + LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 2.0 min) retention time 1.756 min, ESI+observed [M+H] = 290.1. SFC conditions: Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min Flow rate: 2.5 mL / min.

[0269] method 36 [ka] (1-Fluorocyclopropyl)(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0270] [ka] Step 1: 1-Fluoro-N-methoxy-N-methylcyclopropanecarboxamide A mixture of 1-fluorocyclopropanecarboxylic acid (150 mg, 1.44 mmol), N,N-diisopropylethylamine (465 mg, 3.60 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (712 mg, 1.87 mmol), and N,O-dimethylhydroxylamine hydrochloride (183 mg, 1.87 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 1-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (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).

[0271] [ka] Step 2: (1-Fluorocyclopropyl)(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone 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-cyclopropanecarboxamide (52 mg, 0.35 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (2.5 M in hexanes, 0.21 mL, 0.53 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 h and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (20-45% acetonitrile / 0.05% HCl in water) to give the crude product (20 mg). The crude product was purified by preparative TLC (30% ethyl acetate in petroleum ether, R f =0.3) to give (1-fluorocyclopropyl)(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (10.2 mg, 19%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.37 (m, 3H), 7.23 - 7.21 (m, 2H), 6.09 - 6.07 (m, 0.5H), 5.96 - 5.93 (m, 0.5H), 5.51 - 5.50 (m, 1H), 3.67 - 3.58 (m, 1H), 3.00 - 2.90 (m, 1H), 1.92 - 1.88 (m, 2H), 1.62 - 1.58 (m, 2H). LCMS retention time=1.726 min, m / z=290.1[M+H] + . LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time: 1.726 min, ESI+observed [M+H] = 290.1.

[0272] Method 37 [ka] ((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyloxetan-3-yl)methanone To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (80 mg, 0.28 mmol) and N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (90 mg, 0.57 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexanes, 0.34 mL, 0.85 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30–60% / 0.05% ammonia hydroxide in water) to give [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(3-methyloxetan-3-yl)methanone (16.3 mg, 19%) as a pink solid. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.25 - 7.23 (m, 2H), 6.17 - 6.15 (m, 0.5H), 6.03 - 6.01 (m, 0.5H), 5.65 - 5.62 (m, 1H), 5.09 - 5.02 (m, 2H), 4.52 - 4.26 (m, 2H), 3.78 - 3.70 (m, 1H), 2.86 - 2.76 (m, 1H), 1.74 (s, 3H). LCMS retention time=0.675 min, m / z=302.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time: 0.675 min, ESI+ found [M+H] = 302.1.

[0273] Method 38 [ka] ((5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyloxetan-3-yl)methanone

[0274] [ka] 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 × 15 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), dried, and concentrated under reduced pressure to give crude N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (270 mg, 98%) as a colorless oil. The crude product was used in the next step without further purification. 1 H 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).

[0275] [ka] Step 2: ((5R,7R)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3-methyloxetan-3-yl)methanone To a cooled (-78 °C) solution of (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) and N-methoxy-N,3-dimethyl-oxetane-3-carboxamide (113 mg, 0.71 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexanes, 0.43 mL, 1.06 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30–60% / 0.05% ammonia hydroxide in water) to give [(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(3-methyloxetan-3-yl)methanone (13.6 mg, 13%) as a pink solid. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.25 - 7.23 (m, 2H), 6.17 - 6.15 (m, 0.5H), 6.03 - 6.01 (m, 0.5H), 5.65 - 5.62 (m, 1H), 5.09 - 5.02 (m, 2H), 4.52 - 4.26 (m, 2H), 3.78 - 3.70 (m, 1H), 2.86 - 2.76 (m, 1H), 1.74 (s, 3H). LCMS retention time=0.678 min, m / z=302.1[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time: 0.678 min, ESI+ found [M+H] = 302.1.

[0276] Method 39 [ka] 3-Oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0277] [ka] 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 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), 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. 1 H 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).

[0278] [ka] Step 2: 3-oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and N-methoxy-N-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxamide (61 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexane, 0.21 mL, 0.53 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 h and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 30–60% / 0.05% ammonia hydroxide in water) to give 3-oxabicyclo[3.1.0]hexan-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (2.2 mg, 3.9%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.39 (m, 3H), 7.27 - 7.26 (m, 2H), 6.12 - 5.96 (m, 1H), 5.53 - 5.49 (m, 1H), 4.02 - 3.99 (m, 2H), 3.82 - 3.80 (m, 2H), 3.70 - 3.61 (m, 1H), 3.07 - 3.05 (m, 1H), 3.02 - 2.95 (m, 1H), 2.45 - 2.43 (m, 2H). LCMS retention time=0.821 min, m / z=313.9 [M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.821 min, ESI+observed [M+H] = 313.9.

[0279] method 40 [ka] Oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0280] [ka] 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), brine (20 mL), and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate in petroleum ether, R f =0.3) to give N-methoxy-N-methyl-oxetane-3-carboxamide (60 mg, 14%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) 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).

[0281] [ka] Step 2: Oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-70 °C) solution of cis-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (38 mg, 0.13 mmol) and N-methoxy-N-methyl-oxetane-3-carboxamide (39 mg, 0.27 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexanes, 0.16 mL, 0.40 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 1 h and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 25–55% / 0.05% ammonia hydroxide in water) to give oxetan-3-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (6.3 mg, 15.5%) as a white solid. 1 H NMR (400 MHz, 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 retention time=0.782 min, m / z=287.9 ​​[M+H] + LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.782 min, ESI+ found [M+H] = 287.9.

[0282] Method 41 [ka] [1-(Hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0283] [ka] 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) was added tert-butyldimethylchlorosilane (532 mg, 3.53 mmol) and imidazole (240 mg, 3.53 mmol). The mixture was stirred at 25° C. for 5 hours and then quenched by the addition of water (10 mL). The mixture was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (6 mL) / water (6 mL) and sodium hydroxide (138 mg, 3.44 mmol) was added. The resulting mixture was stirred at 25° C. for 10 hours and then adjusted to pH=4 by the addition of citric acid. The solution was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried and concentrated under reduced pressure to give crude 1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropanecarboxylic acid (400 mg, 100%) as a colorless oil.

[0284] [ka] Step 2: 1-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methyl cyclopropanecarboxamide 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-cyclopropanecarboxamide (200 mg, 42%) as a colorless oil. LCMS (5-95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time: 0.848 min, ESI+ found [M+H] = 274.1.

[0285] [ka] Step 3: (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a 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-cyclopropanecarboxamide (116 mg, 0.43 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexanes, 0.26 mL, 0.64 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78°C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R f =0.4) to give [1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (34 mg, 38%) as a light brown oil.

[0286] [ka] Step 4: [1-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone A mixture of [1-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (34 mg, 0.08 mmol) and 2,2,2-trifluoroacetic acid (0.50 mL) in dichloromethane (3 mL) was stirred at 20° C. for 2 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30–60% / 0.05% ammonia hydroxide in water) to give [1-(hydroxymethyl)cyclopropyl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (4.1 mg, 16%) as a light brown oil. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.37 (m, 3H), 7.27 - 7.25 (m, 2H), 6.17 - 6.15 (m, 0.5H), 6.03 - 6.01 (m, 0.5H), 5.63 - 5.61 (m, 1H), 3.96 - 3.85 (m, 2H), 3.77 - 3.71 (m, 1H), 2.86 - 2.75 (m, 1H), 1.71 - 1.67 (m, 2H), 1.10 - 1.07 (m, 2H). LCMS retention time=0.648 min, m / z=302.1[M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.648 min, ESI+observed [M+H] = 302.1.

[0287] method 42 [ka] ((1S)-2,2-Difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone and ((1R)-2,2-Difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0288] [ka] Step 1: 2,2-Difluoro-N-methoxy-N-methylcyclopropanecarboxamide A mixture of 2,2-difluorocyclopropanecarboxylic acid (1.00 g, 8.19 mmol), N,N-diisopropylethylamine (2646 mg, 20.5 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (4.05 g, 10.6 mmol), and N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), brine (30 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 2,2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide (700 mg, 52%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 3.77 (s, 3 H), 3.26 (s, 3 H), 2.96 - 2.91 (m, 1 H), 2.16-2.12 (m, 1 H), 1.69-1.65 (m, 1 H).

[0289] [ka] Step 2: ((1S)-2,2-Difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone and ((1R)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (300 mg, 1.06 mmol) and 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (351 mg, 2.13 mmol) in tetrahydrofuran (15 mL) was added n-butyllithium (2.5 M in hexanes, 1.28 mL, 3.19 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (x 15 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by RP-HPLC (20-45% acetonitrile / 0.225% HCl in water) to give (2,2-difluorocyclopropyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (120 mg, 37%) as a white solid. This material was further separated by chiral SFC to give the following compound with the arbitrary assignment: To give ((1S)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (peak 1, retention time = 2.069 min) (35.0 mg, 29%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.42 - 7.38 (m, 3H), 7.31 - 7.29 (m, 2H), 6.21 - 6.19 (m, 0.5H), 6.07 - 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 retention time=1.834 min, m / z=308.1 [M+H] + LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time: 1.834 min, ESI+observed [M+H] = 308.1. To give ((1R)-2,2-difluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (peak 2, retention time = 3.055 min) (35.0 mg, 29%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.45 - 7.41 (m, 3H), 7.30 - 7.28 (m, 2H), 6.21 - 6.19 (m, 0.5H), 6.07 - 6.05 (m, 0.5H), 5.66 - 5.65 (m, 1H), 3.87 - 3.74 (m, 2H), 2.89 - 2.79 (m, 1H), 2.33 - 2.28 (m, 1H), 1.98 - 1.97 (m, 1H). LCMS R T =1.822 min, m / z=308.1 [M+H] + LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time: 1.822 min, ESI+observed [M+H] = 308.1. SFC conditions: Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A:CO2 B:iso-propanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35°C.

[0290] method 43 [ka] (1-Fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a cooled (-78 °C) solution of 1-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (313 mg, 2.13 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (300 mg, 1.06 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (2.5 M in hexanes, 1.28 mL, 3.19 mmol) dropwise under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-45% / 0.05% HCl in water) and then by preparative TLC (30% ethyl acetate in petroleum ether, R f =0.3) to give (1-fluorocyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (80 mg, 25%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.40 - 7.37 (m, 3H), 7.23 - 7.21 (m, 2H), 6.09 - 6.07 (m, 0.5H), 5.96 - 5.94 (m, 0.5H), 5.51 - 5.49 (m, 1H), 3.67 - 3.58 (m, 1H), 3.00 - 2.90 (m, 1H), 1.92 - 1.88 (m, 2H), 1.62 - 1.60 (m, 2H). LCMS retention time=1.736 min, m / z=290.1[M+H]+ LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time: 1.736 min, ESI+observed [M+H] = 290.1.

[0291] method 44 [ka] Cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0292] [ka] Step 1: 1-(2-fluorophenyl)but-3-en-1-ol To a solution of 2-fluorobenzaldehyde (15.0 g, 120.86 mmol) in tetrahydrofuran (250 mL) was added allylmagnesium bromide (1.0 M in tetrahydrofuran, 150.0 mL, 150.0 mmol) at 0 °C under a nitrogen atmosphere. After the addition, the mixture was allowed to warm to 25 °C and stirred for 2 h before being quenched by the addition of saturated aqueous ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–5% 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, CDCl3) δ 7.49 - 7.27 (m, 1H), 7.29 - 7.12 (m, 2H), 7.05 - 7.00 (m, 1H), 5.89 - 5.80 (m, 1H), 5.20 - 5.13 (m, 2H), 5.15 - 5.07 (m, 1H), 2.66 - 2.55 (m, 1H), 2.57 - 5.48 (m, 1H).

[0293] [ka] Step 2: tert-butyl((1-(2-fluorophenyl)but-3-en-1-yl)oxy)dimethylsilane To a solution of 1-(2-fluorophenyl)but-3-en-1-ol (6.0 g, 36.1 mmol) in dichloromethane (50 mL) was added imidazole (4.9 g, 72.2 mmol) and tert-butyldimethylchlorosilane (7.1 g, 146.9 mmol). The reaction mixture was stirred at 25 °C for 16 h and quenched by the addition of water (100 mL). The mixture was extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to give tert-butyl-[1-(2-fluorophenyl)but-3-enoxy]-dimethyl-silane (8.5 g, 84%) as a light oil. 1 H NMR (400MHz, CDCl3) δ 7.60 - 7.36 (m, 1H), 7.34 - 7.18 (m, 2H), 7.13 - 7.02 (m, 1H), 5.97 - 5.85 (m, 1H), 5.21 - 5.07 (m, 3H), 2.60 - 2.48 (m, 2H), 0.99 (s, 9H), 0.15 (s, 3H), 0.00 (s, 3H).

[0294] [ka] Step 3: 3-((tert-butyldimethylsilyl)oxy)-3-(2-fluorophenyl)propanal 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) was added osmium tetroxide (0.15 g, 0.6 mmol). After stirring at 25° C. for 30 minutes, sodium periodate (25.90 g, 121.2 mmol) was added in portions over 2 hours. The resulting mixture was stirred at 25° C. for 2 hours and quenched by the addition of cold saturated aqueous sodium thiosulfate solution (100 mL). The mixture was stirred for 30 minutes and then extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–5% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g, 64%) as a black oil. 1 H NMR (400MHz, CDCl3) δ 9.84 - 9.77 (m, 1H), 7.53 - 7.51 (m, 1H), 7.31 - 7.24 (m, 1H), 7.21 - 7.13 (m, 1H), 7.09 - 6.98 (m, 1H), 5.58 - 5.55 (m, 1H), 2.85 - 2.80 (m, 1H), 2.74 - 2.64 (m, 1H), 0.92 - 0.85 (m, 9H), 0.09 (s, 3H), -0.09 (s, 3H).

[0295] [ka] Step 4: 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(2-fluorophenyl)propan-1-ol 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) under a nitrogen atmosphere was added n-butyllithium (2.5 M in hexanes, 8.6 mL, 21.4 mmol). The mixture was stirred at -78°C for 30 minutes, and then a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(2-fluorophenyl)propanal (5.5 g, 19.5 mmol) in tetrahydrofuran (25 mL) was added dropwise. After the addition, the mixture was stirred at -78°C for 1.5 hours and then quenched by the addition of saturated aqueous ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under 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)propan-1-ol (8.0 g, 80%) as a yellow oil, which was used as is in the next step.

[0296] [ka] 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)propan-1-ol (8.0 g, 15.55 mmol) and trifluoroacetic acid (30.0 mL) in dichloromethane (3.0 mL) was stirred at 50° C. for 5 hours and concentrated under reduced pressure. The residue was adjusted to pH=9 by the addition of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% 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 retention time = 0.505 min, m / z = 298.1 [M+H] + . LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 0.505 min, ESI+observed [M+H] = 298.1.

[0297] [ka] Step 6: (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole To a solution of 2-bromo-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (750 mg, 2.52 mmol) in toluene (20 mL) was added diethylaminosulfur trifluoride (1.62 g, 10.06 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then slowly added to ice water (20 mL) at 0° C. The mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–15% ethyl acetate in petroleum ether) to give rac-(5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (250 mg, 33%) as a pale yellow solid. 1 H NMR (400MHz, 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 retention time=1.112 minutes, m / z=300.0[M+H] + . LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2.0 min) retention time 1.112 min, ESI+observed [M+H] = 300.0.

[0298] This cis mixture was further separated by chiral SFC to give the arbitrary assignment: (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%) was obtained as a white solid. (The 5R,7R-isomer was also collected (peak 1, retention time = 3.139 min) (100 mg, 40%). SFC conditions: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, then hold at 40% for 2.5 min, and hold at 5% B for 2.5 min Flow rate: 2.5 mL / min Column temperature: 35°C.

[0299] [ka] Step 7: Cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a solution of (5S,7S)-2-bromo-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.33 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (86 mg, 0.67 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 0.27 mL, 0.67 mmol) under a nitrogen atmosphere at −78° C. The mixture was stirred at −78° C. for 2 hours and quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (35–65% acetonitrile / 0.05% ammonium hydroxide in water) to give arbitrarily assigned cyclopropyl-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (7.2 mg, 7%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.47 - 7.41 (m, 1H), 7.25 - 7.18 (m, 2H), 7.16 -7.13 (m, 1H), 6.22 - 6.06 (m, 1H), 5.92 - 5.88 (m, 1H), 3.85 - 3.78 (m, 1H), 3.08 - 3.02 (m, 1H), 2.93 - 2.78 (m, 1H), 1.22 - 1.17 (m, 2H), 1.15 - 1.09 (m, 2H). LCMS retention time=1.043 min, m / z=290.2 [M+H] + . LCMS (10-80% acetonitrile in water + 0.03% ammonium bicarbonate in 3.0 min) retention time 1.043 min, ESI+observed [M+H] = 290.2.

[0300] method 45 [ka] (S)-Cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a solution of ethyl (5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.36 mmol) in tetrahydrofuran (3 mL) was added cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 0.72 mL, 0.36 mmol) dropwise at −78° C. under a nitrogen atmosphere. After the addition, the mixture was stirred at −78° C. for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (40-50% acetonitrile / 0.05% ammonia hydroxide in water) to give cyclopropyl-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (50 mg, 51%) as a white solid (80% ee). The product was further purified by chiral SFC to give (S)-cyclopropyl(5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (17.5 mg, 34%) as a brown oil with arbitrary assignment. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.35 (m, 1H), 7.23 - 7.16 (m, 3H), 5.81 - 5.77 (m, 1H), 3.37 - 3.29 (m, 1H), 3.21 - 3.03 (m, 2H), 2.99 - 2.93 (m, 1H), 2.77 - 2.65 (m, 1H), 1.16 - 1.09 (m, 2H), 1.09 - 1.00 (m, 2H). LC-MS retention time=0.699 min, m / z=272.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.699 min, ESI+observed [M+H] = 272.1. SFC conditions: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: 5% to 40% B in 5.5 min, then hold at 40% for 3 min, and hold at 5% B for 1.5 min Flow rate: 2.5 mL / min Column temperature: 40°C.

[0301] method 46 [ka] (3,3-Difluorocyclobutyl)((5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a solution of 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (76 mg, 0.43 mmol) and (5R,7R)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg, 0.21 mmol) in tetrahydrofuran (13 mL) was added n-butyllithium (2.5 M in hexanes, 0.26 mL, 0.64 mmol) dropwise at −78° C. After the addition, the mixture was stirred at −78° C. for 2 hours and quenched by the addition of saturated aqueous ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (20–45% acetonitrile / 0.225% hydrochloric acid in water) to give arbitrarily assigned (3,3-difluorocyclobutyl)-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (11.0 mg, 16%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.43 - 7.38 (m, 3H), 7.29 - 7.27 (m, 2H), 6.19 - 6.17 (m, 0.5H), 6.05 - 6.03 (m, 0.5H), 5.64 - 5.63 (m, 1H), 3.94 - 3.93 (m, 1H), 3.79 - 3.75 (m, 1H), 2.90 - 2.82 (m, 5H). LCMS retention time=1.904 min, m / z=322.1 [M+H] + . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 1.904 min, ESI+observed [M+H] = 322.1.

[0302] method 47 [ka] [(5S)-7,7-Difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2-fluorocyclopropyl]methanone and [(5S)-7,7-Difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone

[0303] [ka] Step 1: 2-bromo-5-phenyl-5H-pyrrolo[1,2-b][1,2,4]triazol-7(6H)-one To a solution of 2-bromo-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (2.0 g, 7.14 mmol) in dichloromethane (100 mL) was added pyridinium chlorochromate (1.7 g, 7.85 mmol). The mixture was stirred at 20 °C for 18 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% 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, which was used directly in the next step.

[0304] [ka] Step 2: (S)-2-Bromo-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole To a cooled solution of 2-bromo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-one (1.7 g, 6.11 mmol) in dichloromethane (80 mL) was added diethylaminosulfur trifluoride (7.88 mL, 61.13 mmol) at 0 °C. After stirring at 25 °C for 2 h, the mixture was poured into ice water (10 mL) and extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–30% 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 retention time=0.774 min, m / z=303.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.774 min, ESI+observed [M+H] = 303.1.

[0305] The racemic material (950 mg, 3.17 mmol) was further separated by chiral SFC to give the following arbitrary assignments: to give (5R)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (peak 1, retention time = 2.308 min) (410 mg, 43%) as a light brown solid. to give (5S)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (peak 2, retention time = 2.614 min) (440 mg, 46%) as a light brown solid. SFC conditions: Column: OJ (250mm*50mm, 10um); Mobile phase: A:CO2 B:0.1% NH3H2O ​​EtOH Gradient: B from 20% to 20%; Flow rate: 180mL / min, Column temperature: 40℃.

[0306] [ka] Step 3: [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2-fluorocyclopropyl]methanone and [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone To a mixture of (5S)-2-bromo-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole (200 mg, 0.67 mmol) and trans-2-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (196 mg, 1.33 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexane, 0.8 mL, 2.0 mmol) dropwise at −78° C. under a nitrogen atmosphere. After the addition, the mixture was stirred at −78° C. for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were concentrated to dryness under reduced pressure to give the crude product, which was purified by RP-HPLC (45-75% acetonitrile / 0.05% ammonia hydroxide in water) to give [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[trans-2-fluorocyclopropyl]methanone (50 mg, 24%) as a brown oil. This racemic material was separated by chiral SFC to give the arbitrary assignment: To give [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1S,2R)-2-fluorocyclopropyl]methanone (peak 1, retention time = 2.365 min) (15.1 mg, 30%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.49 - 7.44 (m, 3H), 7.33 - 7.30 (m, 2H), 5.99 - 5.92 (m, 1H), 5.02 - 5.00 (m, 0.5H), 4.86 - 4.82 (m, 0.5H), 3.89 - 3.86 (m, 1H), 3.51 - 3.47 (m, 1H), 3.34 - 3.33 (m, 0.5H), 3.32 - 3.22 (m, 0.5H), 1.78 - 1.70 (m, 1H), 1.63 - 1.57 (m, 1H). LC-MS retention time=0.822 min, m / z=308.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.822 min, ESI+observed [M+H] = 308.0. To give [(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone (peak 2, retention time = 3.163 min) (13.6 mg, 27%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.47 - 7.43 (m, 3H), 7.31 - 7.29 (m, 2H), 5.98 - 5.94 (m, 1H), 5.05 - 4.99 (m, 0.5H), 4.86 - 4.83 (m, 0.5H), 3.91 - 3.86 (m, 1H), 3.47 - 3.45 (m, 1H), 3.34 - 3.26 (m, 1H), 1.74 - 1.68 (m, 1H), 1.62 - 1.56 (m, 1H). LC-MS retention time=0.818 min, m / z=308.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.818 min, ESI+observed [M+H] = 308.1. SFC conditions: Column: AD (250mm*30mm, 5μm); Mobile phase: A:CO2 B:0.1% NH3H2O ​​EtOH; Gradient: B from 20% to 20%; Flow rate: 50mL / min Column temperature: 40℃.

[0307] method 48 [ka] Cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone and cyclopropyl-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a solution of 7,7-difluoro-N-methoxy-N-methyl-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 2.6 mL, 1.3 mmol) at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 2 hours and quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–30% ethyl acetate in petroleum ether) to give cyclopropyl-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (60 mg, 64%) as a white solid. 1 H NMR (400MHz, 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).

[0308] This racemate was further separated by chiral SFC to give the arbitrary assignment: to give cyclopropyl-[(5S)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 2, retention time = 2.971 min) (22.4 mg, 37%) as a white solid. 1H NMR (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 retention time=1.238 min, m / z=290.2 [M+H] + . LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 1.238 min, ESI + Measured value [M+H]=290.2. to give cyclopropyl-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (peak 1, retention time = 2.677 min) (24.7 mg, 41%) as a white solid. 1 H NMR (400MHz, CDCl3) 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 retention time=1.239 min, m / z=290.2[M+H] + . LCMS (10-80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 1.239 min, ESI + Measured value [M+H]=290.2. SFC conditions: Column: Chiralcel OJ (250 mm * 30 mm, 5 μm) Mobile phase: A: CO2 B: Ethanol (0.1% NH3H2O) Gradient: B 25% to 25% in 5 min: 2.5 mL / min Column temperature: 35 °C

[0309] method 49 [ka] (2,2-Difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0310] [ka] 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 × 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. 1 H NMR (400MHz, 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).

[0311] [ka] Step 2: (2,2-Difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-78 °C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) and 2,2-difluoro-N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (73 mg, 0.35 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in n-hexane, 0.28 mL, 0.71 mmol) under a nitrogen atmosphere. The mixture was stirred at -78 °C for 2 hours and quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 47–77% / 0.2% formic acid in water) to give (2,2-difluorospiro[2.3]hexan-5-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (10.8 mg, 17%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.38 (m, 3H), 7.28 - 7.26 (m, 2H), 6.18 - 6.02 (m, 1H), 5.64 - 5.62 (m, 1H), 4.24 - 4.08 (m, 1H), 3.87 - 3.64 (m, 1H), 2.91 - 2.74 (m, 1H), 2.68 - 2.28 (m, 4H), 1.32 - 1.23 (m, 2H). LCMS retention time=1.281 and 1.298 min, m / z=348.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention times 1.281 and 1.298 min, ESI+ observed [M+H] = 348.1

[0312] method 50 [ka] 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one

[0313] [ka] Step 1: Ethyl 4-(2-chlorophenyl)-4-oxobutanoate To a solution of 2-chloroacetophenone (100.0 g, 646.87 mmol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1h)-pyrimidinone (156.4 mL, 1293.70 mmol) in tetrahydrofuran (500 mL) was added [bis(trimethylsilyl)amino]lithium (1.0 M in tetrahydrofuran, 711.6 mL, 711.56 mmol) at −60° C. The mixture was stirred at −60° C. for 100 minutes, and ethyl bromoacetate (143.5 mL, 1293.7 mmol) was added rapidly. The resulting mixture was allowed to warm to 25° C. and stirred for 15 hours. The reaction was quenched by the addition of water (400 mL) and extracted with ethyl acetate (3×1000 mL). The combined organic layers were washed with water (2 × 500 mL), brine (1500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 4-(2-chlorophenyl)-4-oxo-butanoate (50.0 g, 32%) as a colorless oil, which was used directly in the next step.

[0314] [ka] Step 2: tert-butyl (2-(2-chlorophenyl)-5-oxopyrrolidin-1-yl)carbamate To a solution of ethyl 4-(2-chlorophenyl)-4-oxobutanoate (10.0 g, 41.55 mmol) in acetic acid (33 mL) and tetrahydrofuran (100 mL) was added tert-butyl hydrazinecarboxylate (11.0 g, 83.10 mmol). The mixture was stirred 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 an additional 12 hours and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with saturated sodium carbonate (80 mL), hydrochloric acid (2 M, 80 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20-50% ethyl acetate in petroleum ether) to give tert-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (5.0 g, 39%) as a pale yellow oil. LCMS retention time = 0.840 min, m / z = 255.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.840 min, ESI + observed [M-55] = 255.0.

[0315] [ka] Step 3: 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one A solution of tert-butyl N-[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (5.0 g, 16.09 mmol) in hydrochloric acid (4.0 M in 1,4-dioxane, 40.2 mL, 160.89 mmol) was stirred at 25° C. for 12 hours and filtered. The filter cake was washed with ethyl acetate (20 mL) and dissolved in water (20 mL). The solution was adjusted to pH=9 by the addition of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (4×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one (3.3 g, 97%) as a white solid. LCMS retention time=0.615 min, m / z=211.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.615 min, ESI+observed [M+H] = 211.0.

[0316] [ka] Step 4: 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one A mixture of 1-amino-5-(2-chlorophenyl)pyrrolidin-2-one (3.3 g, 15.67 mmol) and ethyl 2-ethoxy-2-imino-acetate (4.6 g, 31.33 mmol) in ethanol (50 mL) was stirred at 70° C. for 18 hours and concentrated under reduced pressure to give crude ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate (4.8 g, 99%) as a brown oil. LCMS retention time = 0.675 min, m / z = 310.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.675 min, ESI+observed [M+H] = 310.0.

[0317] [ka] Step 5: (S)-ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate A mixture of ethyl 2-[[2-(2-chlorophenyl)-5-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate (4.8 g, 15.5 mmol) and phosphorus oxychloride (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 × 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 retention time=0.741 min, m / z=292.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.741 min, ESI+observed [M+H] = 292.1.

[0318] The above racemic material (1.0 g, 3.43 mmol) was further separated by SFC to give, with arbitrary assignment: (S)-ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (peak 2, retention time = 4.111 min) (400 mg, 40%) and (R)-ethyl 5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (peak 1, retention time = 3.762 min) (400 mg, 40%), both as yellow solids. SFC conditions: Column: AD-3 (250mm*30mm, 5μm); Conditions: 0.1% NH3H2O ​​EtOH; Start B 30% End B 30%; Flow rate (60mL / min), column temperature 40℃.

[0319] [ka] 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-carboxylate (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 the addition of 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]triazole-2-carboxylic acid (350 mg, 97%) as a white solid. LCMS retention time=0.642 min, m / z=264.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.642 min, ESI+observed [M+H] = 264.0.

[0320] [ka] 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 was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×25 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-35% 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 retention time = 0.700 min, m / z = 307.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.700 min, ESI+observed [M+H] = 307.0.

[0321] [ka] Step 8: 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-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) was added ethylmagnesium bromide (1.0 M in hexanes, 0.42 mL, 0.42 mmol). The mixture was stirred at 0–5 °C for 1 h and quenched by the addition of saturated aqueous ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by RP-HPLC (32–62% acetonitrile / 0.2% formic acid in water) to give 1-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one (5.7 mg, 31%) as a white solid. 1 H NMR (400MHz, CD3OD) δ 7.52 - 7.50 (m, 1H), 7.38 - 7.33 (m, 2H), 6.96 - 6.94 (m, 1H), 5.99 - 5.96 (m, 1H), 3.40 - 3.33 (m, 1H), 3.14 - 3.11 (m, 2H), 3.07 - 3.03 (m, 2H), 2.68 - 2.65 (m, 1H), 1.18 (d, J=7.2 Hz, 3H). LCMS retention time=1.185 min, m / z=276.1 [M+H] + . LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.185 min, ESI+ observed [M+H] = 276.1

[0322] Method 51 [ka] [1-(Hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[0323] [ka] Step 1: 1-(ethoxycarbonyl)cyclopropanecarboxylic acid To a mixture of diethyl 1,1-cyclopropanedicarboxylate (10.0 g, 53.7 mmol) in ethanol (70 mL) and water (35 mL) was added sodium hydroxide (2.1 g, 53.7 mmol). The reaction 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 the addition of aqueous hydrochloric acid (4 M). The mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-ethoxycarbonylcyclopropanecarboxylic acid (6.6 g, 78%) as a colorless oil. 1 H NMR (400MHz, CDCl3) 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).

[0324] [ka] Step 2: Ethyl 1-(hydroxymethyl)cyclopropanecarboxylate To a mixture of 1-ethoxycarbonylcyclopropanecarboxylic acid (6.6 g, 41.7 mmol) and triethylamine (6.98 mL, 50.1 mmol) in tetrahydrofuran (60 mL) was added isobutyl chloroformate (8.12 mL, 62.6 mmol) dropwise at 0°C. After the 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. 1 H NMR (400MHz, CDCl3) δ 4.17 - 4.08 (m, 2H), 3.62 (s, 2H), 1.29 - 1.21 (m, 5H), 0.87 - 0.84 (m, 2H).

[0325] [ka] Step 3: Ethyl 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylate To a stirred solution of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (1.0 g, 6.94 mmol) in N,N-dimethylformamide (20 mL) was added imidazole (1.4 g, 20.81 mmol) and tert-butyldiphenylchlorosilane (3.8 g, 13.87 mmol) at 0 °C. The mixture was stirred at 25 °C for 18 h and poured into water (30 mL). The solution was extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–20% ethyl acetate in petroleum ether) to give ethyl 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylate (2.3 g, 87%) as a colorless oil. 1 H NMR (400MHz, CD3OD) δ 7.70 - 7.61 (m, 4H), 7.46 - 7.35 (m, 6H), 4.15 - 4.06 (m, 2H), 3.85 (s, 2H), 1.23 (t, J=7.0 Hz, 3H), 1.17 - 1.11 (m, 2H), 1.04 (s, 9H), 0.93 - 0.87 (m, 2H).

[0326] [ka] Step 4: 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarboxylic acid A mixture of ethyl 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylate (1.0 g, 2.61 mmol) and lithium hydroxide monohydrate (438 mg, 10.46 mmol) in tetrahydrofuran (16 mL), methyl alcohol (16 mL), and water (8 mL) was 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 by the addition of aqueous hydrochloric acid (4 M) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg, 100%) as a light stick white solid. This crude product was used in the next step without further purification.

[0327] [ka] Step 5: 1-(((tert-butyldiphenylsilyl)oxy)methyl)-N-methoxy-N-methylcyclopropanecarboxamide A mixture of 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanecarboxylic acid (950 mg, 2.68 mmol), N,O-dimethylhydroxylamine hydrochloride (523 mg, 5.36 mmol), N,N-diisopropylethylamine (1.43 mL, 8.04 mmol), 1-hydroxybenzotriazole (217 mg, 1.61 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (771 mg, 4.02 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 18 h. The resulting mixture was poured into water (20 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (15% ethyl acetate in petroleum ether, R f=0.4) to give 1-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropanecarboxamide (700 mg, 66%) as a colorless oil. 1 H NMR (400MHz, 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).

[0328] [ka] Step 6: (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (100 mg, 0.35 mmol) and 1-[[tert-butyl(diphenyl)silyl]oxymethyl]-N-methoxy-N-methyl-cyclopropanecarboxamide (282 mg, 0.71 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M in hexanes, 0.43 mL, 1.06 mmol) dropwise under a nitrogen atmosphere at −78° C. After the addition, the mixture was stirred at −78° C. for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R f=0.4) to give [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (60 mg, 31%) as a light brown oil.

[0329] [ka] Step 7: [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a solution of [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (60 mg, 0.11 mmol) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.17 mL, 0.17 mmol). The mixture was stirred at 25° C. for 3 hours and poured into water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 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 (25–55% acetonitrile / 0.05% ammonia hydroxide in water) to give arbitrarily assigned [1-(hydroxymethyl)cyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (7.8 mg, 18%) as a light brown oil. 1H NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 3H), 7.30 - 7.26 (m, 2H), 6.19 - 6.16 (m, 0.5H), 6.05 - 6.02 (m, 0.5H), 5.65 - 5.61 (m, 1H), 3.97 - 3.85 (m, 2H), 3.84 - 3.68 (m, 1H), 2.87 - 2.80 (m, 1H), 1.72 - 1.67 (m, 2H), 1.11 - 1.08 (m, 2H). LC-MS retention time=0.695 min, m / z=302.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.695 min, ESI+observed [M+H] = 302.1.

[0330] method 52 [ka] (3,3-Difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

[0331] [ka] Step 1: 3,3-Difluoro-N-methoxy-N-methylcyclobutanecarboxamide A mixture of 1-hydroxybenzotriazole (297 mg, 2.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (845 mg, 4.41 mmol), 3,3-difluorocyclobutanecarboxylic acid (500 mg, 3.67 mmol), N,O-dimethylhydroxylamine hydrochloride (537 mg, 5.51 mmol), and N,N-diisopropylethylamine (1187 mg, 9.18 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 5 hours and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (430 mg, 65%) as a colorless oil. 1 H NMR (400MHz, CDCl3) 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).

[0332] [ka] Step 2: (3,3-Difluorocyclobutyl)((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone To a solution of 3,3-difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (76 mg, 0.43 mmol) and (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (60 mg, 0.21 mmol) in tetrahydrofuran (13 mL) was added n-butyllithium (2.5 M in hexanes, 0.26 mL, 0.64 mmol) dropwise at −78° C. After the addition, the mixture was stirred at −78° C. for 2 hours and quenched by the addition of saturated aqueous ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (20–45% acetonitrile / 0.225% hydrochloric acid in water) to give arbitrarily assigned (3,3-difluorocyclobutyl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (12.4 mg, 18%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 3H), 7.30 - 7.28 (m, 2H), 6.20 - 6.17 (m, 0.5H), 6.06 - 6.03 (m, 0.5H), 5.66 - 5.64 (m, 1H), 3.97 - 3.80 (m, 1H), 3.78 - 3.74 (m, 1H), 2.91 - 2.83 (m, 5H). LCMS retention time=1.241 min, m / z=322.2 [M+H] + . LCMS (10-80% acetonitrile in water + 0.03% trifluoroacetic acid in 2 min) retention time 1.241 min, ESI+ observed [M+H] = 322.2.

[0333] method 53 [ka] ((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-(pyridin-2-yl)cyclopropyl)methanone

[0334] [ka] Step 1: N-Methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide A mixture of 1-hydroxybenzotriazole (149 mg, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (423 mg, 2.21 mmol), 2-(pyridin-2-yl)cyclopropanecarboxylic acid (300 mg, 1.84 mmol), N,O-dimethylhydroxylamine hydrochloride (269 mg, 2.76 mmol), and N,N-diisopropylethylamine (594 mg, 4.60 mmol) in dichloromethane (10 mL) was stirred at 25° C. for 16 hours and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-2-(pyridin-2-yl)cyclopropanecarboxamide (300 mg, 79%) as a colorless oil. 1 H NMR (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).

[0335] [ka] Step 2: ((5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(2-(pyridin-2-yl)cyclopropyl)methanone To a cooled (-78°C) solution of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (150 mg, 0.53 mmol) and N-methoxy-N-methyl-2-(2-pyridyl)cyclopropanecarboxamide (219 mg, 1.06 mmol) in 2-methyltetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in n-hexane, 0.64 mL, 1.6 mmol) under a nitrogen atmosphere. The mixture was stirred at -78°C for approximately 30 minutes and quenched by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (32–62% acetonitrile / 0.05% ammonia hydroxide in water) to give arbitrarily 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]methanone (11.0 mg, 6%) as a faint pink solid. 1 H NMR (400 MHz, CD3OD) δ 8.39 - 8.37 (m, 1H), 7.69 - 7.65 (m, 1H), 7.42 - 7.31 (m, 4H), 7.27 - 7.17 (m, 3H), 6.18 - 6.02 (m, 1H), 5.65 - 5.61 (m, 1H), 3.83 - 3.67 (m, 1H), 3.56 - 3.51 (m, 1H), 2.88 - 2.73 (m, 2H), 1.86 - 1.79 (m, 2H). LCMS retention time=0.745 min, m / z=348.9 [M+H] + . LCMS (10 to 80% acetonitrile in water + 0.1% aqueous ammonia in 3.0 min) retention time 0.745 min, ESI+observed [M+H] = 348.9.

[0336] method 54 [ka] [(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(1S,2S)-2-methylcyclopropyl]methanone To a solution of trans-N-methoxy-N,2-dimethyl-cyclopropanecarboxamide (137 mg, 0.96 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (180 mg, 0.64 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium bromide (3.0 M in tetrahydrofuran, 0.85 mL, 2.55 mmol) dropwise at 0°C under a nitrogen atmosphere. After the addition, the mixture was stirred at 0°C for 1 hour and quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting solution was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether, R f =0.2) to give [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(1S,2S)-2-methylcyclopropyl]methanone (mixture of trans and methylcyclopropyl) (80 mg, 44%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.42 - 7.37 (m, 3H), 7.28 - 7.26 (m, 2H), 6.20 - 6.16 (m, 0.5H), 6.05 - 6.02 (m, 0.5H), 5.65 - 5.63 (m, 1H), 3.78 - 3.68 (m, 1H), 2.83 - 2.75 (m, 2H), 1.59 - 1.52 (m, 1H), 1.45 - 1.37 (m, 1H), 1.19 - 1.14 (m, 3H), 1.01 - 0.91 (m, 1H). LC-MS retention time=0.793 min, m / z=286.1 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.793 min, ESI+observed [M+H] = 286.1.

[0337] method 55 [ka] [(5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexan-5-yl-methanone

[0338] [ka] 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 h and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water (2 × 10 mL), brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–20% 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 (400 MHz, CDCl3) 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).

[0339] [ka] 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]hexan-5-yl-methanone To a solution of N-methoxy-N-methyl-spiro[2.3]hexane-5-carboxamide (43 mg, 0.25 mmol), (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.21 mL, 0.42 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour and quenched by the addition of saturated aqueous ammonium chloride (5 mL). The solution was then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (water (0.05% ammonia hydroxide v / v)-acetonitrile 45–70%) to give arbitrarily assigned [(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-spiro[2.3]hexan-5-yl-methanone (42 mg, 75%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.42 - 7.37 (m, 3H), 7.27 - 7.23 (m, 2H), 6.10 - 5.94 (m, 1H), 5.50 - 5.47 (m, 1H), 4.32 - 4.26 (m, 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 retention time=0.904 min, m / z=312.0 [M+H] + . LCMS (5 to 95% acetonitrile in water + 0.03% trifluoroacetic acid in 1.5 min) retention time 0.904 min, ESI + Measured value [M+H]=312.0.

[0340] method 56 [ka] Cyclopropyl-[(5S)-5-(2-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone To a cooled (-78°C) solution of (5S)-5-(2-chlorophenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (100 mg, 0.33 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 4.24 mL, 2.12 mmol) under a nitrogen atmosphere. The mixture was stirred at -78°C for 1 hour and quenched by the addition of saturated aqueous ammonium chloride...

Claims

1. Formula (I): 【Chemical 1】 (In the formula, R １ is C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C １ -C ６ Alkyl-N(R Ｎ ) ２ , phenyl, benzyl, 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl; R １ is attached to the adjacent carbonyl by a carbon atom, and R １ are F, Cl, Br, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C １ -C ６ Alkyl-N(R Ｎ ) ２ , hydroxyl, hydroxymethyl, methoxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C １ -C ６ Alkyl, phenyl, benzyl, CH ２ -(C ３ -C ６ cycloalkyl), 5-6 membered heteroaryl, and CH ２ -(5-6 membered heteroaryl); Each R Ｎ is H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, and C １ -C ６ haloalkyl; or two R Ｎ may form a 4- to 6-membered ring together with the adjacent N; and The A and B rings together form the following: 【Chemistry 2】 (In the formula, R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, phenyl, benzyl, CH 2 —(C 3 -C 6 cycloalkyl), CH 2 CH 2 —(C 3 -C 6 cycloalkyl), CH 2 —(4- to 6-membered heterocyclyl), CH 2 CH 2 —(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, and CH 2 —(5- to 6-membered heteroaryl); wherein the phenyl ring, when present, is selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy and cyano; and R 3a and R 3b are selected 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, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy; (ii) each of R 3a and R 3b is selected from the group consisting of D, F, Cl, OH, CN, and methyl, with the proviso that R 3a and R 3b cannot both be OH or CN; or (iii) R 3a and R 3b together form a cyclopropyl group. selected from the group consisting of Compound.

2. Formula (I): 【Chemistry 3】 (In the formula, R １ is C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C １ -C ６ Alkyl-N(R Ｎ ) ２ , phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; R １ is attached to the adjacent carbonyl by a carbon atom, and R １ is optionally substituted by 1 to 2 substituents selected from the group consisting of F, Cl, Br, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl-N(RN) 2 , hydroxyl, hydroxymethyl, methoxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C 1 -C 6 alkyl, phenyl, benzyl, CH 2 -(C 3 -C 6 cycloalkyl), 5-6 membered heteroaryl, and CH 2 -(5-6 membered heteroaryl); Each R Ｎ is H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, and C １ -C ６ haloalkyl; or two R Ｎ may form a 4- to 6-membered ring together with the adjacent N; and The A and B rings together form the following: 【Chemistry 4】 (In the formula, R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, phenyl, benzyl, CH 2 —(C 3 -C 6 cycloalkyl), CH 2 CH 2 —(C 3 -C 6 cycloalkyl), CH 2 —(4- to 6-membered heterocyclyl), CH 2 CH 2 —(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, and CH 2 —(5- to 6-membered heteroaryl); wherein the phenyl ring, when present, is selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy and cyano; and R 4a and R 4b are selected as follows: (i) one of R 4a and R 4b is H and the other is selected from the group consisting of D, F, Cl, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy; or (ii) each of R 4a and R 4b is selected from the group consisting of D, F, Cl, and methyl; selected from the group consisting of Compound.

3. R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl-N(RN) 2 , phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; R 1 is bonded to the adjacent carbonyl by a carbon atom, and R 1 is optionally substituted by 1 to 2 substituents selected from the group consisting of F, Cl, methyl, ethyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy; The compound of claim 1 or 2, wherein each R N is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl; or two R N may together with the adjacent N form a 4- to 6-membered ring.

4. R ２ 2. The compound of claim 1, wherein is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl, and dichlorophenyl.

5. The A and B rings together form the following: 【Chemistry 5】 (In the formula, R ３ａ and R ３ｂ are selected as follows: (i) R ３ａ and R ３ｂ One of the groups is H and the other is D, F, Cl, OH, CN, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, cyclopropyl, C １ -C ４ Alkoxy, and C １ -C ４ haloalkoxy; (ii) R ３ａ and R ３ｂ each is selected from the group consisting of D, F, Cl, OH, CN, and methyl, with the proviso that R ３ａ and R ３ｂ cannot both be OH or CN; or (iii) R ３ａ and R ３ｂ together to form cyclopropyl; Each R ５ are H, F, Cl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, and C １ -C ６ haloalkoxy; and m is 1, 2, or 3.

2. The compound of claim 1 selected from the group consisting of:

6. A and B rings together, 【Chemistry 6】 (In the formula, Each R ５ are H, F, Cl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, and C １ -C ６ haloalkoxy; and m is 1, 2, or 3.

2. The compound of claim 1, wherein:

7. R ２ The compound of claim 2, wherein is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl, and dichlorophenyl.

8. The A and B rings together form the following: 【Chemistry 7】 (In the formula, R ４ａ and R ４ｂ is selected as follows: (i) R ４ａ and R ４ｂ One of the groups is H, and the other is F, Cl, OH, CN, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, cyclopropyl, C １ -C ４ Alkoxy, and C １ -C ４ haloalkoxy; Or, (ii) R ４ａ and R ４ｂ each is selected from the group consisting of F, Cl, and methyl; Each R ５ are H, F, Cl, C １ -C ６ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, and C １ -C ４ haloalkoxy; and, m is 1, 2, or 3.

3. The compound of claim 2 selected from the group consisting of:

9. cyclopropyl-[(5R,7S)-5-ethyl-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone, cyclopropyl-[(5R,7S)-7-fluoro-5-propyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone, cyclopropyl-[(5S,7S)-7-fluoro-5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone, 1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-tetrahydropyran-2-yl-ethanone, and 1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-2-tetrahydropyran-4-yl-ethanone A compound selected from:

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