RIPK1 inhibitors and methods of use

Abstract

Described herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) act as RIPK1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for RIPK1-related diseases.

Description

25866 RIPK1 INHIBITORS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 599,961, filed November 16, 2023, the contents of each of which are incorporated herein by reference in their entirety. FIELD

[0002] Disclosed herein are novel RIPK1 inhibitors. The RIPK1 inhibitors described herein can be useful in preventing, treating or acting as a remedial agent for RIPK1-related diseases. BACKGROUND

[0003] Receptor-interacting protein-1 kinase (RIPK1) belongs to the family serine / threonine protein kinase involved in innate immune signaling. RIPK1 has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This is supported by extensive studies which have demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways.

[0004] For example, RIPK1 inhibition has been found to be useful as a treatment of acute kidney injury (AKI), a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It has been found that RIPK1-mediated necroptosis plays an important role in AKI and a RIPK1 inhibitor may serve as a promising clinical candidate for AKI treatment. Wang JN, Liu MM, Wang F, Wei B, Yang Q, Cai YT, Chen X, Liu XQ, Jiang L, Li C, Hu XW, Yu JT, Ma TT, Jin J, Wu YG, Li J, Meng XM, RIPK1 Inhibitor Cpd-71 Attenuates Renal Dysfunction in Cisplatin-Treated Mice via Attenuating Necroptosis, Inflammation and Oxidative Stress. Clin Sci (Lond).2019 Jul 25;133(14):1609- 1627.

[0005] Additionally, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and multiple sclerosis as well as other inflammatory and neurodegenerative diseases. Alexei Degterev, Dimitry Ofengeim, and Junying Yuan, Targeting RIPK1 for the treatment of human diseases, PNAS, May 14, 2019, 116 (20), 9714-9722; Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al., RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS, Science, 2016, 353:603–8; Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, et al., Necroptosis activation in Alzheimer’s disease, Nat Neurosci, 2017, 20:1236–46;Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, et al., Activation of necroptosis in multiple sclerosis, Cell Rep., 2015, 10:1836–49.

[0006] It also has been demonstrated that necroptosis is a delayed component of ischemic neuronal injury, thus RIPK1 inhibition may also play a promising role as a treatment for stroke. Degterev A, et al., Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury, Nat Chem Biol 2005, 1(2):112-119.

[0007] Therefore, there is a need for inhibitors of RIPK1 that offer high selectivity, and which can penetrate the blood–brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer’s disease, ALS, and multiple sclerosis, as well as acute neurological diseases such as stroke and traumatic brain injuries. SUMMARY

[0008] Described herein are compounds of Formula I: acceptable sa1 2 3 4 5 6lts thereof, wherein A, B, D, E, J, G, R , R , R , R , R , R , R7, and R8are described below.

[0009] The compounds described herein are RIPK1 inhibitors, which can be useful in the prevention, treatment or amelioration of neurodegenerative, autoimmune, inflammatory diseases and other RIPK1-related diseases.

[0010] Also described herein are methods of treating neurodegenerative, autoimmune, and inflammatory diseases comprising administering to a patient in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof.

[0011] Also described herein are uses of a compound described herein, or a pharmaceutically acceptable salt thereof, to treat neurodegenerative, autoimmune, and inflammatory diseases in a patient in need thereof.

[0012] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] Also described herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier.

[0014] Also described herein are methods of treating neurodegenerative, autoimmune, and inflammatory diseases comprising administering to a patient in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0015] Also described herein are uses of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional agent, to treat neurodegenerative, autoimmune, and inflammatory diseases in a patient in need thereof.

[0016] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, at least one additional therapeutic agent and a pharmaceutically acceptable carrier.

[0017] Also described herein are pharmaceutical compositions comprising a compound described herein, at least one additional therapeutic agent and a pharmaceutically acceptable carrier.

[0018] The summary of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION

[0019] Described herein are compounds of Formula I: a pharmaceutically acceptable salt thereof, wherein:B is C or N; D is C or N; E is C or N; G is C or O; J is C, S, or O;25866 L is a (C3-C10)cycloalkyl; (C6-C10)aryl; heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O; or a heterocycle having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O; wherein L is not bicyclic or a bridged ring; R1is H; OH; (C1-C6)alkyl; or F R2is H, OH; (C1-C6)alkyl; or F and wherein R1and R2are absent if J is S or O; R3is H; Alternately, where n is 0, R1and R3together with the carbons to which they are attached can form a three membered cycloalkyl; R4is H; halogen; or (C1-C6) nitrile; R5is H or halogen; R6is H or halogen; R7is H or halogen; provided that where A, B, or D is N the respective R4, R6or R7is absent; R8is (C1-C6)alkyl optionally substituted with nitrile, up to 3 halo, (C3-C7)cycloalkyl, (C6- C10)aryl, (C3-C6)cycloalkyl-O-(C1-C6)m-(C6—C10)aryl, or heteroaryl having 5-10 ring atoms and containing up to 4 heteroatoms selected from N, S or O and further optionally substituted with up R10to 3 ; R9is H; C6)alkyl optionally substituted by a nitrile or up to 3 halogens;Q-(C3-C10)cycloalkyl optionally substituted by (C1-C6)alkyl, CF3, nitrile, or up to 3 halogens; (C1-C6)nitrile; -N-C(O)-(C6-C6)aryl optionally substituted by up to 3 halogens; (C1-C6) alkyl optionally substituted by up to 3 halogens; Q-(C6-C10) aryl optionally substituted by OH, (C1-C6) alkyl, up to 3 halogens, CN, a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O; Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and optionally substituted by up to 3 halogens, (C1-C6) alkyl, CF3, -CN, R18; S(O)2-R12; O-R13; (CH3)x-R14; or C(O)-R15; R10is H; halogen; (C1-C6)alkyl optionally substituted by up to 3 halogens; -O-(C1-C6)alkyl; or =O; R11is H; halogen; (C1-C6)alkyl optionally substituted by up to 3 halogens; -O-(C1-C6)alkyl; or =O; R12is (C1-C6)alkyl; (C3-C6)cycloalkyl; heterocycle having 4-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O optionally substituted by (C1-C6)alkyl; (C6-C8) aryl optionally substituted by up to 3 halogens or (C1-C6)alkyl optionally further substituted by up to 3 halogens; or -N(CH3)2;R13is (C1-C6)alkyl optionally substituted by (C3-C6)cycloalkyl, (C6-C6)aryl, or up to 3 halogens; (C3-C6)cycloalkyl optionally substituted by (C1-C6)alky further optionally substituted by up to 3 halogens; (C6-C10)aryl-(R16)y; heteroaryl-(R17)z said heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S and O; R14is (C3-C6)cycloalkyl; (C6)aryl; -O-(C1-C6)alkyl R15is -O-(C1-C6)alkyl or NH2R16is halogen; CF2; CF3; CN; (C1-C6)alkyl optionally substituted by a nitrile; -OCH3; or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and optionally substituted by a (C1-C6)alkyl; R17is halogen; CN; S-CH3; C(O)-NH2; -O-CF2; (C1-C6)alkyl optionally substituted by up to 3 halogens; or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and optionally substituted by a (C1-C6)alkyl or up to 3 halogens; R18is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O and optionally substituted by CN, (C1-C6)alkyl; Q is a bond, O, or (C1-C6)alkyl; n is 0 or 1; m is 0-6; x is 0-6; y is 0-3; and z is 0-3.

[0020] In regard to the compounds described herein, A is C or N. In some embodiments A is C. In other embodiments A is N.

[0021] In regard to the compounds described herein, B is C or N. In some embodiments B is C. In other embodiments B is N.

[0022] In regard to the compounds described herein, D is C or N. In some embodiments D is C. In other embodiments D is N.

[0023] In regard to the compounds described herein, E is C or N. In some embodiments E is C. In other embodiments e is N.

[0024] In regard to the compounds described herein, G is C or O. In some embodiments G is C. In other embodiments G is O.

[0025] In regard to the compounds described herein, J is C or O. In some embodiments J is C. In other embodiments J is O.

[0026] In regard to the compounds described herein, L is a (C3-C10)cycloalkyl; (C6-C10)aryl; heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O;or a heterocycle having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O. In some embodiments L is a (C3-C10)cycloalkyl. In other embodiments L is a (C6-C10)aryl. In further embodiments L is a heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O. In still further embodiments L is a heterocycle having 5- 10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O.

[0027] In regard to the compounds described herein, R1is H; OH; (C1-C6)alkyl; or F. In some embodiments R1is H. In other embodiments R1is OH. In further embodiments R1is (C1- C6)alkyl.

[0028] In regard to the compounds described herein, R2is H; OH; (C1-C6)alkyl; or F. In some embodiments R2is H. In other embodiments R2is OH. In further embodiments R2is (C1- C6)alkyl.

[0029] In embodiments where J is O, R1and R2are absent.

[0030] In particular embodiments where n is 0, R1and R3together with the carbons to which they are attached can form a three membered cycloalkyl.

[0031] In regard to the compounds described herein, R4is H; halogen; or (C1-C6) nitrile. In some embodiments R4is H. In other embodiments R4is halogen. In particular embodiments R4is F. In other embodiments R4is Cl. In certain embodiments R4is (C1-C6) nitrile.

[0032] In regard to the compounds described herein, R5is H or halogen. In some embodiments R5is H. In other embodiments R5is halogen. In particular embodiments R5is F. In other embodiments R5is Cl.

[0033] In regard to the compounds described herein, R6is H or halogen. In some embodiments R6is H. In other embodiments R6is halogen. In particular embodiments R6is F. In other embodiments R6is Cl.

[0034] In regard to the compounds described herein, R7is H or halogen. In some embodiments R7is H. In other embodiments R7is halogen. In particular embodiments R7is F. In other embodiments R7is Cl.

[0035] In embodiments where A, B, D or E is N the respective R4, R5, R6or R7is absent.

[0036] In regard to the compounds described herein, R8is (C1-C6)alkyl optionally substituted with nitrile, up to 3 halogens, (C3-C7)cycloalkyl, (C6-C10)aryl, (C3-C6)cycloalkyl-O-(C1-C6)m- (C6—C10)aryl, or heteroaryl having 5-10 ring atoms and containing up to 4 heteroatoms selected R10from N, S or O and further optionally substituted with up to 3 In some embodiments R8is (C1-C6)alkyl. In other embodiments R8iswithnitrile. In further embodiments R8is (C1-C6)alkyl substituted with 1, 2, or 3 halogens. In still further embodiments R8is (C1-C6)alkyl substituted with (C3-C7)cycloalkyl. In different embodiments R8is (C1-C6)alkyl substituted with (C6-C10)aryl. In particular embodiments R8is (C1-C6)alkyl substituted with (C3-C6)cycloalkyl-O-(C1-C6)m-(C6—C10)aryl. In other embodiments R8is (C1-C6)alkyl substituted with heteroaryl having 5-10 ring atoms and containing up to 4 heteroatoms selected from N, S or O. In still other embodiments R8is (C1-C6)alkyl substituted with a heteroaryl having 5-10 ring atoms and containing up to 4 heteroatoms selected from N, S or O which is further substituted with up to 3 halogens. In other embodiments R8is R10. to the compounds described herein, R9is H; halogen; -OH; =O; Q-(C1-substituted by a nitrile or up to 3 halogens; (C3-C10)cycloalkyl optionally substituted by (C1-C6)alkyl, CF3, nitrile, or up to 3 halogens; (C1-C6)nitrile; -N-C(O)-(C6)aryl optionally substituted by up to 3 halogens; (C1-C6) alkyl optionally substituted by up to 3 halogens; Q-(C6-C10) aryl optionally substituted by OH, (C1-C6)alkyl, up to 3 halogens, CN, or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O; Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and optionally substituted by up to 3 halogens, (C1-C6)alkyl, CF3, -CN, or R18; S(O)2-R12; O- R13; (CH3)x-R14; or C(O)-R15. In some embodiments R9is H. In other embodiments R9is halogen. In certain embodiments R9is F. In other embodiments R9is Cl. In further embodiments R9is -OH. In different embodiments R9is =O. In some embodiments R9is (C1-C6)alkyl. In other embodiments R9is (C1-C6)alkyl substituted by a nitrile. In further embodiments R9is (C1- C6)alkyl substituted by up to 3 halogens. In certain embodiments R9is (C1-C6)nitrile. In other embodiments R9is -N-C(O)-(C6)aryl. In further embodiments R9is -N-C(O)-(C6)aryl substituted by up to 3 halogens. In some embodiments R9is Q-(C6-C10) aryl. In certain embodiments R9is Q-(C6-C10) aryl substituted by OH. In further embodiments R9is Q-(C6-C10) aryl substituted by (C1-C6)alkyl. In still further embodiments R9is Q-(C6-C10) aryl substituted by up to 3 halogens. In additional embodiments R9is Q-(C6-C10) aryl substituted by CN. In other embodiments R9is Q-(C6-C10) aryl substituted by a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O. In further embodiments R9is Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O. In still further embodiments R9is Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and substituted by up to 3 halogens. In other embodiments R9is Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and substituted by -CN. In certain embodiments R9is Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and substituted by (C1-C6)alkyl. In further embodiments R9is Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and substituted by CF3. In stillfurther embodiments R9is Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and substituted by R18. In some embodiments R9is S(O)2-R12. In other embodiments R9is O- R13. In further embodiments R9is (CH3)x-R14. In still further embodiments R9is C(O)-R15.

[0038] In regard to the compounds described herein, R10is H; halogen; (C1-C6)alkyl optionally substituted by up to 3 halogens; -O-(C1-C6)alkyl; or =O. In some embodiments R10is H. In other embodiments R10is halogen. In further embodiments R10is F. In still further embodiments R10is Cl. In particular embodiments R10is (C1-C6)alkyl. In other embodiments R10is (C1-C6)alkyl substituted by up to 3 halogens. In some embodiments R10is -O-(C1-C6)alkyl. In certain embodiments R10is =O.

[0039] In regard to the compounds described herein, R11is H; halogen; (C1-C6)alkyl optionally substituted by up to 3 halogens; -O-(C1-C6)alkyl; or =O. In some embodiments R11is H. In other embodiments R11is halogen. In further embodiments R11is F. In still further embodiments R11is Cl. In particular embodiments R11is (C1-C6)alkyl. In other embodiments R11is (C1-C6)alkyl substituted by up to 3 halogens. In some embodiments R11is -O-(C1-C6)alkyl. In certain embodiments R11is =O.

[0040] In regard to the compounds described herein, R12is (C1-C6)alkyl; (C3-C6)cycloalkyl; heterocycle having 4-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O optionally substituted by (C1-C6)alkyl; (C6-C8) aryl optionally substituted by up to 3 halogens or (C1-C6)alkyl optionally further substituted by up to 3 halogens; or -N(CH3)2. In some embodiments R12is (C1-C6)alkyl. In other embodiments R12is (C3-C6)cycloalkyl. In certain embodiments R12is heterocycle having 4-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O. In particular embodiments R12is heterocycle having 4-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O substituted by (C1-C6)alkyl. In some embodiments R12is (C6-C8) aryl. In other embodiments R12is (C6-C8) aryl substituted by up to 3 halogens. In further other embodiments R12is (C6-C8) aryl substituted by (C1-C6)alkyl. In still further other embodiments R12is (C6-C8) aryl substituted by (C1-C6)alkyl further substituted by up to 3 halogens. In some embodiments R12is-N(CH3)2.

[0041] In regard to the compounds described herein, R13is (C1-C6)alkyl optionally substituted by (C3-C6)cycloalkyl, (C6)aryl, or up to 3 halogens; (C3-C6)cycloalkyl optionally substituted by(C1-C6)alky further optionally substituted by up to 3 halogens; (C6-C10)aryl-(R16)y; or heteroaryl- (R17)zsaid heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S and O. In some embodiments R13is (C1-C6)alkyl. In certain embodiments R13is (C1- C6)alkyl substituted by (C3-C6)cycloalkyl. In other embodiments R13is (C1-C6)alkyl substituted by (C6)aryl. In certain embodiments R13is (C1-C6)alkyl substituted by up to 3 halogens. In additional embodiments R13is (C3-C6)cycloalkyl. In further embodiments R13is (C3- C6)cycloalkyl substituted by (C1-C6)alky. In still further embodiments R13is (C3-C6)cycloalkyl substituted by (C1-C6)alky further substituted by up to 3 halogens. In certain embodiments R13is (C6-C10)aryl-(R16)y. In other embodiments R13is heteroaryl-(R17)z said heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S and O.

[0042] In regard to the compounds described herein, R14is (C3-C6)cycloalkyl; (C6)aryl; or - O- (C1-C6)alkyl. In some embodiments R14is (C3-C6)cycloalkyl. In other embodiments R14is (C6)aryl. In still other embodiments R14is O-(C1-C6)alkyl.

[0043] In regard to the compounds described herein, R15is -O-(C1-C6)alkyl or NH2. In certain embodiments R15is -O-(C1-C6)alkyl. In other embodiments R15is NH2.

[0044] In regard to the compounds described herein, R16is halogen; CF2; CF3; CN; (C1- C6)alkyl optionally substituted by a nitrile; -OCH3; or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and optionally substituted by a (C1- C6)alkyl. In some embodiments R16is halogen. In other embodiments R16is CF2. In particular embodiments R16is CF3. In certain embodiments R16is CN. In further embodiments R16is (C1- C6)alkyl. In still further embodiments R16is (C1-C6)alkyl substituted by a nitrile. In additional embodiments R16is -OCH3. In other embodiments R16is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O. In still other embodiments R16is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and substituted by a (C1-C6)alkyl.

[0045] In regard to the compounds described herein, R17is halogen; CN; S-CH3; C(O)-NH2; - O-CF2; (C1-C6)alkyl optionally substituted by up to 3 halogens; or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and optionally substituted by a (C1-C6)alkyl or up to 3 halogens. In some embodiments R17is halogen. In other embodiments R17is CN. In further embodiments R17is S-CH3. In still further embodiments R17is C(O)-NH2. In certain embodiments R17is -O-CF2. In additional embodiments R17is (C1-C6)alkyl. In other embodiments R17is (C1-C6)alkyl substituted by up to 3 halogens. In some embodiments R17is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O. In other embodiments R17is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms25866 selected from N and O substituted by a (C1-C6)alkyl. In still other embodiments R17is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O substituted by up to 3 halogens.

[0046] In regard to the compounds described herein R18is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O and optionally substituted by CN, or (C1-C6)alkyl. In some embodiments R18is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O. In further embodiments R18is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O and optionally substituted by CN. In other embodiments R18is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O and optionally substituted by (C1- C6)alkyl.

[0047] In regard to the compounds described herein Q is a bond, O or (C1-C6)alkyl. In some embodiments Q is a bond. In further embodiments Q is O. In still further embodiments Q is (C1- C6)alkyl.

[0048] In regard to the compounds described herein, n is 0-1. In some embodiments n is 0. In other embodiments n is 1.

[0049] In regard to the compounds described herein, m is 0-6. In some embodiments m is 0. In other embodiments m is 1. In certain embodiments m is 2. In further embodiments m is 3. In still further embodiments m is 4. In additional embodiments m is 5. In some embodiments m is 6.

[0050] In regard to the compounds described herein, x is 0-6. In some embodiments x is 0. In other embodiments x is 1. In certain embodiments x is 2. In further embodiments x is 3. In still further embodiments x is 4. In additional embodiments x is 5. In some embodiments x is 6.

[0051] In regard to the compounds described herein, y is 0-3. In some embodiments y is 0. In other embodiments y is 1. In certain embodiments y is 2. In further embodiments y is 3.

[0052] In regard to the compounds described herein, z is 0-3. In some embodiments z is 0. In other embodiments z is 1. In certain embodiments z is 2. In further embodiments z is 3. In particular embodiments of the present invention the compound of formula I is selected from the group consisting of: ,25866 F F F F ,Definitions

[0053] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature25866 used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0055] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0056] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0057] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0058] As used herein, the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of” and “consisting essentially of” the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0059] The term “halogen” includes fluorine, chlorine, bromine or iodine.

[0060] The term “nitrile” encompasses a carbon nitrogen triple bond.

[0061] The term “C1-C6alkyl” encompasses straight alkyl having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2- methylpropyl, 1-ethyl-1-methylpropyl, and the like.25866

[0062] The term "C3-C6cycloalkyl" encompasses bridged, saturated or unsaturated cycloalkyl groups having 3 to 6 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0063] The term "C3-C10cycloalkyl" encompasses bridged, saturated or unsaturated cycloalkyl groups having 3 to 10 carbons. "Cycloalkyl" also includes non-aromatic rings as well as monocyclic, non-aromatic rings fused to a saturated cycloalkyl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like. Examples described by structure include, ,heterocycloalkyl that contains at least one ring heteroatom selected from O, S and N. Examples of heteroaryl groups include pyridyl (pyridinyl), oxazolyl, azabenzothiazole, benzothiazole, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, and the like.

[0065] The term “heterocycloalkyl” means mono- or bicyclic or bridged partially unsaturated and saturated rings containing at least one heteroatom selected from N, S and O, each of said rings having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples include azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1- b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the25866 like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or n-substituted-(1H, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5- diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. Examples described by structure include, orpharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, n-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, n-ethylmorpholine, n-ethylpiperidinyl, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine,25866 morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0067] The term “patient” refers to a mammalian patient, preferably a human patient, receiving or about to receive medical treatment.

[0068] The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of these compounds.

[0069] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0070] Some of the compounds described herein contain substituted cycloalkanes having cis- and trans-isomers, and unless specified otherwise, are meant to include both cis- and trans- geometric isomers.

[0071] The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0072] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0073] It will be understood that the present invention is meant to include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable, of the compounds described herein, when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.25866

[0074] Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are included in the present invention as well.

[0075] Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.

[0076] In the compounds described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. A3H,11C,18F labeled compound may be used for PET or SPECT or other imaging studies. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents or Intermediates.

[0077] It should be noted that chemically unstable compounds are excluded from the embodiments contained herein. Methods of Treatment

[0078] The compounds described herein may be particularly useful for the prevention, treatment or amelioration of RIPK1-mediated diseases or disorders. Such RIPK1-mediated diseases or disorders are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary25866 diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non- alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, non- alcoholic fatty liver disease (NAFL-D), kidney damage / injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g., cisplatin, acute kidney injury (AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CV A, stroke), myocardial infarction (Ml), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet' s disease, interleukin- I converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke- induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, periodontitis, NEMO-mutations (mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency (also known as RBCKl) heme-oxidized IRP 2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GMl gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis, ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / mitigation, auditory disorders such as25866 noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to preserve vitality and function.

[0079] The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIPK1-mediated diseases or disorders: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH) autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage / injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g., cisplatin, acute kidney injury (AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (Ml), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-I converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis, ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, periodontitis, NEMO-mutations (mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency ((also known as RBCKl) heme-oxidized IRP 2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus,25866 and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GMl gangliosides, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), spinal cord injury, Stevens-Johnson syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and / or for the treatment of cells ex vivo to preserve vitality and function.

[0080] The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of glaucoma.

[0081] The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma.

[0082] The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIPK1-mediated disease or disorder: rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), and psoriasis.

[0083] The treatment of the above-noted diseases / disorders may concern, more specifically, the amelioration of organ injury or damage sustained as a result of the noted diseases / disorders. For example, the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or for amelioration of liver tissue injury or damage associated with non- alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen.

[0084] The compounds of this invention may be particularly useful for the amelioration of organ injury or damage sustained as a result of radiation therapy, or amelioration of spinal tissue injury or damage following spinal cord injury or amelioration of liver tissue injury or damage associated acute liver failure. The compounds of this invention may be particularly useful for25866 amelioration of auditory disorders, such as noise-induced hearing loss or auditory disorders following the administration of ototoxic drugs or substances e.g., cisplatin.

[0085] The compounds of this invention may be particularly useful for amelioration of solid organ tissue (particularly kidney, liver, and heart and / or lung) injury or damage following transplant or the administration of nephrotoxic drugs or substances e.g., cisplatin. It will be understood that amelioration of such tissue damage may be achieved where possible, by pre-treatment with a compound of the Formulae described herein, or a pharmaceutically acceptable salt thereof; for example, by pre-treatment of a patient prior to administration of cisplatin or pre-treatment of an organ or the organ recipient prior to transplant surgery. Amelioration of such tissue damage may be achieved by treatment with a compound of the Formulae described herein, or a pharmaceutically acceptable salt thereof, during transplant surgery.

[0086] Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with a compound of the Formulae described herein, or a pharmaceutically acceptable salt thereof, after transplant surgery.

[0087] In one embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.

[0088] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis.

[0089] In one embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of traumatic brain injury.

[0090] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Huntington's Disease or Niemann-Pick disease.

[0091] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer's disease.

[0092] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of age-related macular degeneration.

[0093] The treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease,25866 amyotrophic lateral sclerosis, and Niemann-Pick disease may concern, more specifically, the amelioration of organ injury or damage sustained as a result of these diseases / disorders. For example, the compounds described herein may be particularly useful for amelioration of brain tissue injury or damage following traumatic brain injury, or for amelioration of brain tissue injury or damage associated of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0094] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0095] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondylarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis.

[0096] In yet another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative and colitis.

[0097] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of lupus, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.

[0098] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.

[0099] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS).

[0100] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis.

[0101] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal25866 adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung carcinoma (NSCLC), and radiation induced necrosis.

[0102] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung carcinoma (NSCLC).

[0103] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC).

[0104] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.

[0105] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of type II diabetes and obesity.

[0106] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of atherosclerosis.

[0107] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of vasculitis.

[0108] In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of dependent inflammation and cell death that occurs in inherited and sporadic diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis as well as acute tissue injury caused by stroke, traumatic brain injury, encephalitis.

[0109] In another embodiment, the compounds of the Formulae described herein, or pharmaceutically acceptable salt thereof, may be useful for the treatment of ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0110] In another embodiment, the compounds of the Formulae described herein, or pharmaceutically acceptable salt thereof, may be useful for the treatment of non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non- alcoholic fatty liver disease (NAFLD).

[0111] The compounds of the invention, particularly the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment25866 of the RIPK1-mediated, cancer-related diseases or disorders. Gong et al., The role of necroptosis in cancer biology and therapy, Molecular Cancer (2019) 18:100. In one aspect the human has a solid tumor. In one aspect the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one aspect the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical, bladder, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another aspect, the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lyphomblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.

[0112] The present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of head and neck), kidney cancer, lung cancer (including lung squamous cell carcinoma, lung adenocarcinoma, lung small cell carcinoma, and non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, cancer of the uterus, renal cancer (including kidney clear cell cancer, kidney papillary cancer, renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.25866

[0113] Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and the like.

[0114] The cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia. These leukemias may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polcythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.

[0115] Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and the like. Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and / or extranodal sites. Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non-Hodgkin's lymphomas (B-NHLs). B-NHLs may be indolent (or low-grade), intermediate grade (or aggressive) or high-grade (very aggressive). Indolent B cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma(DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt's lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma. Other B- NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL may also include T-cell non-Hodgkin's lymphoma s(T-NHLs), which include, but are not limited to T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T- cell lymphoma, gamma / delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome.

[0116] Hematopoietic cancers also include Hodgkin's lymphoma (or disease) including classical Hodgkin's lymphoma, nodular sclerosing Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte predominant (LP) Hodgkin's lymphoma, nodular LP Hodgkin's lymphoma, and lymphocyte depleted Hodgkin's lymphoma. Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues" include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings. Pharmaceutical Compositions

[0117] Compounds described herein may be administered orally or parenterally. As formulated into a dosage form suitable for administration, the compounds described herein can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.

[0118] In clinical use of the compounds described herein, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

[0119] Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use.

[0120] Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.

[0121] The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds.

[0122] In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg / kg of body weight / day, and it may be administered at a time or in several times. In specific embodiments, the dose is from about 0.01 to about 25 mg / kg / day, in particular embodiments, from about 0.05 to about 10 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg. In specific embodiments, the dose is 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 or 1,000 milligrams of a compound25866 described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response. Combination Therapy

[0123] The compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.

[0124] The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered in an amount commonly used therefore, contemporaneously or sequentially with a compound described herein or a pharmaceutically acceptable salt thereof. When a compound described herein is used contemporaneously with one or more other drugs, the pharmaceutical composition may in specific embodiments contain such other drugs and the compound described herein or its pharmaceutically acceptable salt in unit dosage form. However, the combination therapy may also include therapies in which the compound described herein or its pharmaceutically acceptable salt and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound described herein or a pharmaceutically acceptable salt thereof. EXAMPLES

[0125] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. ABBREVIATIONS

[0126] The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.  ACN acetonitrile25866 CH2Cl2dichloromethane ClCH2CH2Cl 1,2-dichloroethane25866 MTBE methyl tert-butyl ether NaHCO3 sodium bicarbonateIntermediate I-1A ((S)-5-phenyl-2,5,6,7-[2,1-c][1,2,4]triazol-3-one). Scheme I-125866 Step 1.

[0127] Two reactions of identical scales were carried out in parallel: To a solution of pyrrolidine-2,5-dione (500 g, 5.05 mol, 1.0 equiv) in DCM (12.5 L) was added PhMgBr (3 M, 4.21 L, 2.5 eq) at -70 – -65 °C under N2, the reaction was stirred at 25-30 °C for 12 h. To the mixture was added NaBH3CN (1.28 kg, 6.06 mol, 1.2 eq) at 5-10 °C and stirred for 1 h. The reaction was acidified with TFA (2.31 kg, 20.3 mol, 1.50 L, 4.01 eq) to pH= 3-4. It was stirred at 25-30 °C for 2 h.

[0128] The two reactions were combined. The mixture was added into ice-H2O (25 L) and then extracted by DCM (5.0 L x 2). The organic layer was washed with saturated NaHCO3 (15 L) and separated. The organic layer was concentrated to afford the desired crude product. It was purified by flash silica gel chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1) to give 5- phenylpyrrolidin-2-one (495 g).1H NMR (400 MHz, CDCl3) δ 7.28-7.41 (m, 5H), 6.11 (br, s, 1H), 4.78 (t, J = 7.2 Hz, 1H), 2.44-2.61 (m, 3H), 1.99-2.03 (m, 1H). Step 2. Synthesis of 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole

[0129] Five reactions of identical scales were carried out in parallel: Trimethyloxonium tetrafluoroborate (109 g, 736 mmol, 1.2 equiv.) was added to a solution of 5-phenylpyrrolidin-2- one (99.0 g, 614 mmol, 1.0 equiv.) and K2CO3 (169 g, 1.23 mol, 2.0 eq) in DCM (990 mL) at 25- 30 °C. The mixture was stirred at 25-30 °C for 12 h. The mixture was added into saturated NaHCO3 (5.0 L) and extracted with DCM (1.0 L x 2). The organic layer was concentrated to afford the crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 1 / 1) to obtain 5-methoxy-2-phenyl-3,4-dihydro-2H- pyrrole (359 g).1H NMR (400 MHz, CDCl3) δ 7.20-7.34 (m, 5H), 4.97 (t, J = 7.2 Hz, 1H), 3.91 (s, 3H), 2.55-2.61 (m, 3H), 1.85-1.90 (m, 1H). Step 3. Synthesis of methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate

[0130] A solution of HCl / MeOH (4 M, 180 mL) was added to a mixture of 5-methoxy-2- phenyl-3,4-dihydro-2H-pyrrole (180 g, 1.03 mol, 1.0 equiv.) and compound methyl25866 hydrazinecarboxylate (97.1 g, 1.08 mol, 1.05 equiv.) in MeOH (1.8 L) at 25-30 °C. The reaction was stirred at 80 °C for 3 h. Upon completion, the mixture was concentrated. The crude product was washed with MTBE (300 mL) to afford methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (239 g).1H NMR(400 MHz, CD3OD) δ 7.33-7.40 (m, 5H), 5.07 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), 2.96-3.00 (m, 2H), 2.69-2.72 (m, 1H), 2.06-2.09 (m, 1H). Steps 4-5. Synthesis of 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one followed by SFC to afford I-1A

[0131] A solution of HCl / MeOH (4 M, 180 mL) was added to a mixture of 5-methoxy-2- phenyl-3,4-dihydro-2H-pyrrole (180 g, 1.03 mol, 1.0 equiv.) and compound methyl hydrazinecarboxylate (97.1 g, 1.08 mol, 1.05 equiv.) in MeOH (1.8 L) at 25-30 °C. The reaction was stirred at 80 °C for 3 h. Upon completion, the mixture was concentrated. The crude product was washed with MTBE (300 mL) to afford methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (239 g).1H NMR(400 MHz, CD3OD) δ 7.33-7.40 (m, 5H), 5.07 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), 2.96-3.00 (m, 2H), 2.69-2.72 (m, 1H), 2.06-2.09 (m, 1H). Steps 4-5. Synthesis of 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one followed by SFC to afford I-1A

[0132] Two reactions of identical scales were carried out in parallel: A solution of methyl 2-(2- phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (50.0 g, 214 mmol, 1.0 equiv.) in DMF (500 mL) was stirred at 145 °C for 1 h. Upon completion, the two reactions were combined and worked up together. The mixture was concentrated to remove the DMF. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1), then washed with MTBE (100 mL) to obtain 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (30.0 g).

[0133] The compound of 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (30.0 g, 149 mmol) was separated by preparative SFC (condition: AD_MeOH_IPAm_5_40_34_ 35_4min) to afford (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (10.0 g), the first eluting isomer and (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one (10.0 g), the second eluting isomer.

[0134] (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one:1H NMR (400 MHz, CD3OD) δ 7.21-7.39 (m, 5H), 5.23 (dd, J = 8.0, 4.4 Hz, 1H), 2.92-3.06 (m, 1H), 2.82-2.90 (m, 2H), 2.40-2.43 (m, 1H).

[0135] (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-1A):1H NMR (400 MHz, CD3OD) δ 7.22-7.39 (m, 5H), 5.23 (dd, J = 8.0, 4.4 Hz, 1H), 2.92-3.06 (m, 1H), 2.82-2.90 (m, 2H), 2.40-2.42 (m, 1H).25866 Intermediate I-2AStep 1.

[0136] To a solution of 1-bromo-3,5-difluorobenzene (906 g, 469 mmol) in THF (6.75 L) was added i-PrMgCl.LiCl (6 L) at 0 °C, the reaction was stirred at 50 °C for 1 h. The mixture was cooled to -78 °C then succinimide (310 g, 313 mmol) and DCM (300 mL) were added. The mixture was stirred at 25 °C for 16 h. To the mixture was added NaBH3CN (236 g, 3750 mmol) then the mixture was stirred at 25 °C for 1 h. The reaction was acidified to pH= 3-4 with HCl (6 M), it was stirred for 30 mins and neutralized with aq. NaOH (3 M). The mixture was quenched with water (5000 mL), extracted with DCM (5000 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude product, which was purified by flash silica gel chromatography (ISCO®, 80 g Agela Flash Colum, 0~100% EtOAc) to give 5-(3,5-difluorophenyl)pyrrolidin-2-one (180 g). Step 2. Synthesis of 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0137] To a solution of 5-(3,5-difluorophenyl)pyrrolidin-2-one (180 g, 913 mmol) in DCM (2000 mL) was added trimethyloxonium tetrafluoroborate (250 g, 1.69 mol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with sat. aq. NaHCO3 (3000 mL) then extracted with DCM (2000 mL x 3). The combined organic layers were dried over25866 Na2SO4, filtered and concentrated in vacuum to give crude of 2-(3,5-difluorocyclohexyl)-5- methoxy -3,4-dihydro-2H-pyrrole (185 g), which was used for next step directly. Step 3. Synthesis of N'-[5-(3,5-difluorophenyl) -4,5-dihydro-3H-pyrrol-2- yl]methoxycarbohydrazide

[0138] To a solution of 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (185 g, 876 mmol) in MeOH (2000 mL) was added hydrazine carboxylic acid, methyl ester (103 g, 1140 mmol) and HCl / MeOH (240 mL, 4.0 M). The mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature then purified by flash silica gel chromatography (ISCO®; 4 g Agela® Silica Flash Column, Eluent of 0~30% EtOAc / MeOH 30 mL / min) to give N'-[5-(3,5- difluorophenyl) -4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide (161 g). Steps 4-5. Synthesis of 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one followed by SFC to afford I-2A

[0139] A solution of N'-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2- yl]methoxycarbohydrazide (161 g) in DMF (1600 mL) was stirred at 145 °C for 16 h. The mixture was concentrated in vacuum to give crude product, which was slurried with CH3CN / PE (3:5) to give 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (75 g). The racemate was separated by preparative SFC (CHIRALPAK IC-3 Condition: EtOH 10% to 50% in 2.0 min, hold 1.0 min at 50%) to afford (5R)-5-(3,5-difluorophenyl) -2H,5H,6H,7H- pyrrolo[2,1-c][1,2,4]triazol-3-one (26.2 g), the first eluting isomer and (5S)-5-(3,5- difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (25.7 g), the second eluting isomer.

[0140] (5R)-5-(3,5-difluorophenyl) -2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.20 (tt, J = 9.4, 2.4 Hz, 1H), 7.10 – 6.96 (m, 2H), 5.20 (dd, J = 8.0, 4.8 Hz, 1H), 3.06 – 2.72 (m, 3H), 2.39 – 2.21 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -109.22. Calc’d C11H10F2N3O [M+H]+, 238; Found 238.

[0141] (5S)-5-(3,5-difluorophenyl) -2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-2A): 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.20 (tt, J = 9.3, 2.4 Hz, 1H), 7.10 – 6.96 (m, 2H), 5.20 (dd, J = 8.0, 4.8 Hz, 1H), 3.06 – 2.72 (m, 3H), 2.39 – 2.23 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -109.22. Calc’d C11H10F2N3O [M+H]+, 238; Found 238. Intermediate I-3A25866 ((S)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Scheme I-3 Step

[0142] To a stirred solution of 1-(2-fluorophenyl)ethan-1-one (10.0 g, 72.4 mmol) in THF (150 mL) and DMPU (50 mL, 72.4 mmol) was added LiHMDS (72.4 mL, 72.4 mmol) (1 M in THF) at ~ -60 °C (dry ice-acetone bath). After the addition was finished, the reaction was stirred at -60 °C for 30 minutes. Then ethyl 2-bromoacetate (12.69 g, 76 mmol) was added to the above mixture in one portion at - 60 °C. The resulting mixture was continuously stirred for another 30 min at -60 °C. The reaction was warmed to room temperature and stirred at room temperature for 2 h. The mixture was diluted with tert-butyl methyl ether (300 mL) and quenched with saturated aq. NH4Cl (250 mL). The mixture was extracted with tert-butyl methyl ether (300 mL x 2). The combined organic fractions were washed with brine (200 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica- CS (120 g), Eluent of 0 ~ 5% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give ethyl 4-(2-fluorophenyl)-4-oxobutanoate (5.0 g). Calc’d C12H14FO3 [M+H]+, 225; Found 225. Step 2. Synthesis of 5-(2-fluorophenyl)pyrrolidin-2-one

[0143] To a solution of methyl 4-(2-fluorophenyl)-4-oxobutanoate (5 g, 23.8 mmol) in MeOH (100 mL) was added ammonium acetate (5.50 g, 71.4 mmol) and sodium cyanotrihydroborate (3.74 g, 59.5 mmol) at room temperature. Then the mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, quenched with HCl (2M, ~ 5 mL), then concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent of 10% MeOH / DCM gradient @ 80 mL / min) to give 5- (2-fluorophenyl)pyrrolidin-2-one (2.5 g). Calc’d C10H11FNO [M+H]+, 180; Found 180.25866 Step 3. Synthesis of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0144] A mixture of 5-(2-fluorophenyl)pyrrolidin-2-one (2.0 g, 11.2 mmol) and trimethyloxonium tetrafluoroborate (2.15 g, 14.5 mmol) in DCM (50 ml) was stirred at 25 °C for 16 h. The reaction mixture was quenched with sat. NaHCO3(30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude 2-(4- fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.0 g). The crude was used in the next step without further purification. Calc’d C11H13FNO [M+H]+, 194; Found 194. Step 4. Synthesis of methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate

[0145] To a stirred solution of 2-(2-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.0 g, 10.4 mmol) in MeOH (20 mL) was added methyl hydrazinecarboxylate (1.21 g, 13.5 mmol) at 20 °C (room temperature) after the addition was finished, the reaction was stirred at 80 °C. The reaction was stirred at 80 °C for 2 h. The mixture was cooled to room temperature then concentrated in vacuo. The residue was purified by p-HPLC (Boston Green ODS 150x30mmx5um Condition water (0.1%TFA)-MeCN Begin B 3, End B 33 Gradient Time(min) 10, 100%B Hold Time(min) 2 flow rate(ml / min) 25, Injections 8) to give methyl 2-(2-(2- fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (300 mg). Calc’d C12H15FN3O2[M+H]+, 252; Found 252. Steps 5-6. Synthesis of 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one and chiral separation to isolate I-3A

[0146] A stirred solution of methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (450 mg, 1.80 mmol) in DMF (30 mL) was heated to 145 °C under N2 atmosphere. The reaction was stirred at 145 °C for 2 h, then allowed to cool to room temperature. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC Boston Green ODS 150 × 30mm × 5um , Condition water (0.1%TFA)-MeCN Begin B 12, End B 42 Gradient Time(min) 10, 100%B Hold Time(min) 2 flow rate(ml / min) 25 Injections 5) to give 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one.5-(2- fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (320 mg) was separated by SFC-21 (Method Column (s,s) WHELK-O1 (250mmx30mm,5um), Condition 0.1%NH3H2O EtOH Begin B 50% , End B 50% Gradient Time(min), 100%B Hold Time(min) flow rate(ml / min) 80, Injections 60) to give (R)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (140 mg) (SFC-P1) and (S)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (120 mg) (SFC-P2).25866 (R)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one:1H NMR (400MHz, CD3OD) δ 7.40 - 7.33 (m, 1H), 7.22 - 7.11 (m, 3H), 5.45 - 5.42 (m, 1H), 3.13 - 3.09 (m, 1H), 2.97 - 2.80 (m, 2H), 2.50 - 2.40 (m, 1H). (R)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-3A):1H NMR (400MHz, CD3OD) δ 7.37 - 7.36 (m, 1H), 7.22 - 7.11 (m, 3H), 5.45 - 5.42 (m, 1H), 3.13 - 3.09 (m, 1H), 2.98 - 2.85 (m, 2H), 2.46 - 2.44 (m, 1H). Intermediate I-4A ((S)-5-(5-fluoropyridin-3-yl)- pyrrolo[2,1-c][1,2,4]triazol-3-one)Scheme I-4 Step 1.

[0147] To a solution of 3-bromo-5-fluoropyridine (40 g, 227 mmol) in THF (250 mL) was added iPrMgCl^LiCl (1.3 M in THF) (192 mL, 250 mmol) at 0 ºC for 2 h. Then the mixture was added to a solution of dihydrofuran-2,5-dione (27.3 g, 273 mmol) in THF (450 mL) at -20 °C and the resulting mixture was stirred at -20 °C for 3 h. The reaction was warmed to room temperature then quenched with sat. NH4Cl (200 mL). Aqueous NaOH (2 M) was added until pH~11. After stirring for 30 min, the reaction was extracted with EtOAc (100 mL) and the aqueous phase was treated with HCl (2 M) until pH~5, then extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 4-(5-fluoropyridin-3- yl)-4-oxobutanoic acid (35 g), which was used to next step without further purification. Step 2. Preparation of methyl 4-(5-fluoropyridin-3-yl)-4-oxobutanoate25866

[0148] To a solution of 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid (34 g, 172 mmol) in MeOH (300 mL) was added H2SO4(12 mL, 225 mmol) and the resulting mixture was stirred at 70 °C for 12 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM (100 mL) and water (50 mL), then sat. NaHCO3 was added until the pH~8. The mixture was then extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent of 16 ~20% ethyl acetate / pet. ether gradient @ 120 mL / min) to give methyl 4-(5-fluoropyridin-3-yl)-4- oxobutanoate (5.3 g).1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 7.92- 7.99 (m, 1H), 3.72 (s, 3H), 3.33 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 6.4 Hz, 2H). Step 3. Preparation of 5-(5-fluoropyridin-3-yl)pyrrolidin-2-one

[0149] To a solution of methyl 4-(5-fluoropyridin-3-yl)-4-oxobutanoate (9 g, 42.6 mmol) in MeOH (150 mL) was added ammonium acetate (9.85 g, 128 mmol), NaBH3CN (8.03 g, 128 mmol) and the mixture was stirred at 80 °C for 12 h. The reaction solution was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column (EtOAc: EtOH=3:1) gradient @ 80 mL / min) to give 5-(5-fluoropyridin-3- yl)pyrrolidin-2-one (4.1 g).1H NMR (400 MHz, CD3OD) δ 8.35-8.46 (m, 2H), 7.66 (td, J = 2.0, 9.6 Hz, 1H), 4.90-4.94 (m, 1H), 2.60-2.74 (m, 1H), 2.43-2.50 (m, 2H), 1.91-2.03 (m, 1H). Step 4. Preparation of 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione

[0150] To a solution of 5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (4.1 g, 22.75 mmol) in toluene (40 mL) was added Lawesson’s reagent (4.60 g, 11.4 mmol) and the resulting mixture was stirred at 110 °C for 12 h. The reaction was allowed to cool to room temperature and then concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 50% ethyl acetate / pet. ether gradient @ 60 mL / min) to give 5-(5- fluoropyridin-3-yl)pyrrolidine-2-thione (4 g).1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 7.64 (td, J = 2.0, 9.2 Hz, 1H), 5.16 (t, J = 7.2 Hz, 1H), 2.88-3.09 (m, 2H), 2.72 (dtd, J = 5.6, 8.4, 13.25 Hz, 1H), 2.03-2.14 (m, 1H). Step 5. Preparation of 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine

[0151] To a solution of 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione (4.0 g, 20.4 mmol) in THF (70 mL) was added MeI (1.91 mL, 30.6 mmol) and the resulting mixture was stirred at 20 °C for 12 h. The reaction solution was concentrated. The residue was washed with sat. NaHCO3(40 mL) and the aqueous phase was extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 3-fluoro-5-(5-(methylthio)-3,4-25866 dihydro-2H-pyrrol-2-yl)pyridine (3.8 g), which was used in the next step without further purification. Step 6. Preparation of methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine- 1-carboxylate

[0152] To a solution of 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (3.8 g, 18.1 mmol) in MeOH (60 mL) was added methyl hydrazinecarboxylate (2.44 g, 27.1 mmol) and the resulting mixture was stirred at 80 °C for 5 h. The reaction was allowed to cool to room temperature and then concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 5~10% MeOH / DCM gradient @ 60 mL / min) to give methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate (3.7 g).1H NMR (400 MHz, CDCl3) δ 8.37-8.44 (m, 2H), 7.43-7.51 (m, 1H), 4.88 (t, J = 7.2 Hz, 1H), 3.66 (s, 3H), 2.65-2.79 (m, 2H), 2.53 (dt, J = 6.4, 12.8 Hz, 1H), 1.84-1.97 (m, 1H). Step 7. Preparation of 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0153] To a solution of methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (3.7 g, 14.7 mmol) in DMF (250 mL) was stirred at 145 °C for 12 h. The reaction was allowed to cool to room temperature and then concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column (EtOAc:EtOH=3:1) gradient @ 60 mL / min) to give 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1.8 g).1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 7.64 (td, J = 2.0, 9.2 Hz, 1H), 5.34 (dd, J = 5.6, 8.0 Hz, 1H), 3.06-3.18 (m, 1H), 2.93-3.03 (m, 1H), 2.83-2.93 (m, 1H), 2.53 – 2.47 (m, 1H). Step 8. Chiral separation to afford I-4A

[0154] The mixture of 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (1.8 g, 8.17 mmol) enantiomers were resolved by Chiral-SFC (Condition: SFC 5(Column: DAICEL CHIRALPAK AD(250 mm × 50 mm, 10 um)), Mobile phase: A: CO2B: 0.1%NH3H2O EtOH, Gradient:45 B, flow rate: 200 mL / min) to give (R)-5-(5-fluoropyridin-3- yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (806 mg) (Rt = 1.8 min) and (S)-5- (5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (778 mg) (Rt = 2.2 min). (R)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one:1H NMR (500 MHz, CD3OD) δ 8.45 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 7.63 (td, J = 2.0, 9.5 Hz, 1H), 5.34 (dd, J = 5.5, 8.0 Hz, 1H), 3.12 (dddd, J = 6.0, 8.0, 9.0, 13.47 Hz, 1H), 2.94-3.02 (m, 1H), 2.84-2.92 (m, 1H), 2.50 (tdd, J = 6.0, 9.0, 13.5 Hz, 1H).25866 (S)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-4A):1H NMR (500 MHz, CD3OD) δ 8.45 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 7.63 (td, J = 2.0, 9.5 Hz, 1H), 5.34 (dd, J = 5.5, 8.0 Hz, 1H), 3.12 (dddd, J = 5.5, 8.0, 9.0, 13.47 Hz, 1H), 2.94-3.02 (m,1H), 2.84-2.92 (m, 1H), 2.50 (tdd, J = 6.0, 9.0, 13.5 Hz, 1H). Intermediate I-5A ((S)-5-(3-fluorophenyl)-2,5,6,7- pyrrolo[2,1-c][1,2,4]triazol-3-one)Scheme I-5Step 1. Preparation of 5-(3-fluorophenyl) pyrrolidin-2-one

[0155] (3-fluorophenyl) magnesium bromide (323 mL, 323 mmol) was added to pyrrolidine- 2,5-dione (16 g, 161 mmol) at -78 °C under N2 by syringe dropwise. After the addition was completed, the reaction was allowed to warm up to 25 °C and stirred for another 16 h. Then NaBH3CN (10.15 g, 161 mmol) was added to the mixture and allowed to stir for another 3h.6M HCl was added to adjust the pH to 3. The mixture was stirred for another 1 h. Aqueous NaOH was added to adjust the pH to neutral. The reaction mixture extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent of 0-45% EA gradient @ 60 mL / min) to give 5-(3-fluorophenyl) pyrrolidin-2-one (17.5 g). Calc’d C10H11FNO [M+H]+, 180; Found 180. Step 2. Preparation of 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0156] A mixture of 5-(3-fluorophenyl) pyrrolidin-2-one (10 g, 55.8 mmol) and trimethyloxonium tetrafluoroborate (10.7 g, 72.5 mmol) in DCM (100 mL) was stirred at 25 °C25866 for 16 h to give brown mixture. Aqueous NaHCO3 was added to adjust the pH to neutral. The organic layer was separated and the aqueous was re-extracted with DCM (30 mL x 3) and the combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude 2-(3-fluorophenyl)-5-methoxy- 3,4-dihydro-2H-pyrrole (10.4 g) which was used directly. Calc’d C11H13FNO [M+H]+, 194; Found 194. Step 3. Preparation of methyl 2-(2-(3-fluorophenyl)-3, 4-dihydro-2H-pyrrol-5-yl) hydrazine-1- carboxylate

[0157] A mixture of 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (10 g, 51.8 mmol) and methyl hydrazinecarboxylate (6.06 g, 67.3 mmol) in MeOH (80 mL) and HCl^MeOH (2 mL) was stirred at 80 °C for 6.5 h to give pale yellow solution. The solvent was evaporated and the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent of 0-45% EtOAc / Pet.ether gradient @ 60 mL / min) to give methyl 2-(2-(3- fluorophenyl)-3, 4-dihydro-2H-pyrrol-5-yl) hydrazine-1-carboxylate (10 g). Calc’d C12H15FN3O2 [M+H]+, 252; Found 252. Step 4. Preparation of 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one

[0158] A mixture of methyl 2-(2-(3-fluorophenyl)-3, 4-dihydro-2H-pyrrol-5-yl) hydrazine-1- carboxylate (1.3 g, 5.17 mmol) in DMF (100 mL) was stirred at 145 °C for 3 h under N2. Then the reaction mixture was concentrated to give a brown solid. The solid was suspended in EtOAc and the turbid liquid was filtered and concentrated to give 5-(3-fluorophenyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (3.44 g). Calc’d C11H11FN3O [M+H]+, 220; Found 220. Step 5. Preparation of 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one

[0159] 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (3.7 g, 16.9 mmol) was separated by SFC (Instrument SFC 5; Method Column DAICEL CHIRALCEL OD (250 mm x 50 mm, 10 um); Condition 0.1% NH3H2O ETOH Begin B 25 End B 25 Gradient Time (min); 100% B Hold Time (min) flow rate(ml / min) 200; Injections 150) to give (R)-5-(3- fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1.6 g (t = 3.24 min) and (S)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1.6 g, (t = 3.59 min).

[0160] (R)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1H NMR (400MHz, CD3OD) δ 7.35-7.43 (m, 1H), 6.97-7.08 (m, 3H), 5.23 (dd, J = 4.4, 8.0 Hz, 1H), 3.00-3.11 (m, 1H), 2.85-2.95 (m, 1H), 2.76-2.85 (m, 1H), 2.34-2.46 (m, 1H).25866

[0161] (S)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-5A):

[0162] 1H NMR (400MHz, CD3OD) δ 7.32-7.43 (m, 1H), 6.96-7.07 (m, 3H), 5.23 (dd, J = 4.4, 8.0 Hz, 1H), 3.00-3.11 (m, 1H), 2.86-2.95 (m, 1H), 2.76-2.85 (m, 1H), 2.34-2.46 (m, 1H). Intermediate I-6A

[0163] Isopropylmagnesium chloride (48.0 mL, 52.0 mmol) was added to a solution of 3- bromo-5-chloropyridine (10 g, 52.0 mmol) in THF (100 mL) via syringe over 5 min in 0 °C. After stirring for 1h, this mixture was added to a solution of dihydrofuran-2,5-dione (6.76 g, 67.6 mmol) in THF (100 mL) at -20 °C via cannula over a period of 30 min. The resulting mixture was allowed to stir for 3 h. The pH was adjusted to around 9 by progressively adding aqueous NaHCO3. The aqueous phase was acidified with aqueous HCl and extracted with EtOAc (100 mL x 5). The combined organic layers were dried over NaSO4 and concentrated to give crude product 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid (9 g). Calc’d C9H9ClNO3[M+H]+, 214; Found 214. Step 2. Preparation of methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate

[0164] The crude 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid (8 g, 37.5 mmol) was dissolved in MeOH (80 mL) and H2SO4(3.2 mL). This mixture was stirred for 12 h. After stirring for 3 h, the pH was adjusted to around 9 by progressively adding solution NaHCO3. The combined aqueous layers were extracted with DCM (50 mL × 3). The combined organic layers were dried25866 over NaSO4 and concentrated. The solvent was evaporated and the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent of 0-45% EtOAc gradient @ 60 mL / min) to give methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate (1.8 g). Calc’d C10H11ClNO3[M+H]+, 228; Found 228. Step 3. Preparation of 5-(5-chloropyridin-3-yl)pyrrolidin-2-one

[0165] To a solution of methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate (3.4 g, 14.9 mmol) in MeOH (50 mL) was added ammonium acetate (3.45 g, 44.8 mmol), NaBH3CN (2.82 g, 44.8 mmol) and the mixture was stirred at 80 °C for 12 h. The combined aqueous layers were extracted with DCM (30 mL × 4). The combined organic layers were dried over Na2SO4 and concentrated. The organic phase was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column (EtOAc:EtOH=3:1) gradient @ 35 mL / min) to give 5-(5-chloropyridin-3-yl)pyrrolidin-2-one (700 mg). Calc’d C9H10ClN2O [M+H]+, 197; Found 197. Step 4. Preparation of 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione

[0166] To a solution of 5-(5-chloropyridin-3-yl)pyrrolidin-2-one (700 mg, 3.56 mmol) in Toluene (15 mL) was added Lawesson’s reagent (720 mg, 1.78 mmol) and the resulting mixture was stirred at 110 °C for 12 h. The reaction was allowed to cool to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 45% ethyl acetate / pet. ether gradient @ 35 mL / min) to give 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione (450 mg). Calc’d C9H10ClN2S [M+H]+, 213; Found 213. Step 5. Preparation of 3-chloro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine

[0167] To a solution of 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione (1.45 g, 6.82 mmol) in THF (20 mL) was added MeI (1.20 mL, 19.2 mmol) and the resulting mixture was stirred at 20 °C for 12 h. The reaction solution was concentrated to give crude product 3-chloro-5-(5- (methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (1.3 g), which was used in the next step without further purification. Calc’d C10H12ClN2S [M+H]+, 227; Found 227. Step 6. Preparation of methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine- 1-carboxylate

[0168] To a solution of 3-chloro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (1.3 g, 5.73 mmol) in MeOH (15 mL) was added methyl hydrazinecarboxylate (0.775 g, 8.60 mmol) and the resulting mixture was stirred at 80 °C for 5 h. The reaction was allowed to cool to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column (EtOAc:EtOH=3:1) gradient @ 35 mL / min) to25866 give methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.1 g). Calc’d C11H14ClN4O2[M+H]+, 269; Found 269. Step 7. Preparation of 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0169] A solution of methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine- 1-carboxylate (1.1 g, 4.09 mmol) in DMF (50 mL) was stirred at 145 °C for 12 h. The reaction was allowed to cool to room temperature then concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column (EtOAc:EtOH=3:1) gradient @ 35 mL / min) to give 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (0.75 g). Calc’d C10H10ClN4O [M+H]+, 237; Found 237. Step 8. Chiral separation to afford I-6A

[0170] The mixture of 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (700 mg, 2.96 mmol) enantiomers were resolved by Chiral-SFC (Condition: SFC 11, Method: Column DAICEL CHIRALPAK AD(250mmx30mm,10um), Condition: 0.1%NH3H2O EtOH Begin B 50% End B 50% Gradient Time(min) 100%B Hold Time(min) flow rate(ml / min) 80 Injections 80 to give (S)-5-(5-chloropyridin-3-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (220 mg) (Rt = 4.96 min) and (R)-5-(5- chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (250 mg) (Rt = 4.96 min).

[0171] (S)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I- 6A):

[0172] 1H NMR (400MHz, CD3OD) δ = 8.54 (d, J=2.3 Hz, 1H), 8.47 (d, J=1.9 Hz, 1H), 7.86 (t, J=2.1 Hz, 1H), 5.31 (dd, J=5.6, 8.1 Hz, 1H), 3.19 - 3.05 (m, 1H), 3.04 - 2.82 (m, 2H), 2.50 (tdd, J=6.1, 9.0, 13.2 Hz, 1H).

[0173] (R)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one:

[0174] 1H NMR (400MHz, CD3OD) δ = 8.54 (d, J=2.3 Hz, 1H), 8.47 (d, J=1.9 Hz, 1H), 7.86 (t, J=2.1 Hz, 1H), 5.31 (dd, J=5.7, 8.0 Hz, 1H), 3.19 - 3.05 (m, 1H), 3.04 - 2.82 (m, 2H), 2.57 - 2.44 (m, 1H). Intermediate I-7A ((S)-5-(4-fluorophenyl)-2,5,6,7-pyrrolo[2,1-c][1,2,4]triazol-3-one)25866 Scheme I-7 Stepswas pyrrolidine-2,5-dione (20 g, 202 mmol) at -78 °C under N2by syringe dropwise. After the addition was completed, the reaction was allowed to warm up to 25 °C and reacted for another 2.5 h. Then NaBH3CN (12.7 g, 202 mmol) was added to the mixture and reacted for another 16 h.6M HCl was added and the pH was adjusted to 3. The reaction was stirred for 1 h. Aqueous NaOH (25 mL EtOH+5 mL water) was added to adjust the mixture to pH~7. The reaction mixture was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% EtOAc gradient) to give 5-(4-fluorophenyl)pyrrolidin-2-one (13.0 g). Calc’d C10H11FNO [M+H]+, 180; Found 180.1H NMR (400MHz, CDCl3) δ 7.31 - 7.24 (m, 2H), 7.10 - 7.02 (m, 2H), 6.30 (br s, 1H), 4.75 (t, J = 7.1 Hz, 1H), 2.65 - 2.34 (m, 3H), 2.01 - 1.86 (m, 1H). Step 3. Preparation of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0176] A mixture of 5-(4-fluorophenyl)pyrrolidin-2-one (3.2 g, 17.9 mmol) and trimethyloxonium tetrafluoroborate (3.43 g, 23.2 mmol) in DCM (10 mL) was stirred at 25oC for 16 h to give brown mixture. The residue was dissolved in sat. NaHCO3 (10 mL) and DCM (10 mL). The organic layer was separated and the aqueous was re-extracted with DCM (10 mL x 3) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy- 3,4-dihydro-2H-pyrrole (2.90 g) which was used directly without further purification. Calc’d C11H13FNO [M+H]+, 194; Found 194. Step 4. Preparation of methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate25866

[0177] A mixture of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.90 g, 15.0 mmol, crude) and methyl hydrazinecarboxylate (1.76 g, 19.5 mmol) in MeOH (32 mL) and HCl in MeOH (0.5 mL) was stirred at 80oC for 4 h to give pale yellow solution. The reaction was cooled to room temperature, the solvent was evaporated, and the residue was purified by flash silica gel chromatography (eluent of 0-25% water / MeCN gradient) to give methyl 2-(2-(4- fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (2.7 g). Calc’d C12H15FN3O2[M+H]+, 252; Found 252.1H NMR (500MHz, DMSO-d6) δ 8.85 (br s, 1H), 7.45 - 7.28 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 7.02 (br s, 1H), 3.57 (s, 3H), 3.33 (br s, 1H), 2.48 - 2.39 (m, 2H), 2.37 - 2.28 (m, 1H), 2.37 - 2.28 (m, 1H), 1.76 - 1.58 (m, 1H). Step 5. Preparation of 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one

[0178] A mixture of methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate (2.2 g, 8.76 mmol) and methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (2.2 g, 8.76 mmol) in DMF (100 mL) was stirred at 145oC for 16 h to give pale yellow solution. The reaction was cooled to room temperature, the solvent was evaporated and the residue was purified by flash silica gel chromatography (eluent of 0-45% ethyl acetate / petroleum ether gradient) to give 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (1.0 g). Calc’d C11H11FN3O [M+H]+, 220; Found 220.1H NMR (500MHz, DMSO-d6) δ 11.26 (s, 1H), 7.35 - 7.26 (m, 2H), 7.24 - 7.14 (m, 2H), 5.17 (dd, J = 4.5, 8.2 Hz, 1H), 3.00 - 2.88 (m, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.68 (m, 1H), 2.31 - 2.21 (m, 1H). Step 6. Chiral SFC to afford (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (I-7A)

[0179] 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (2.5 g, 11.40 mmol) was purified by SFC(Method: Column DAICEL CHIRALCEL OD, Condition: 0.1%NH3H2O EtOH) to give (R)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (1.02 g) (peak 1) and (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (1.01 g) (peak 2).

[0180] (R)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one:1H NMR (500 MHz, DMSO-d6) δ 11.26 (s, 1 H) 7.26 - 7.33 (m, 2 H) 7.16 - 7.23 (m, 2 H) 5.17 (dd, J=8.01, 4.50 Hz, 1 H) 2.90 - 2.98 (m, 1 H) 2.79 - 2.86 (m, 1 H) 2.69 - 2.75 (m, 1 H) 2.22 - 2.30 (m, 1 H).

[0181] (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-7A):258661H NMR (500 MHz, DMSO-d6) δ 11.26 (s, 1 H) 7.26 - 7.32 (m, 2 H) 7.17 - 7.23 (m, 2 H) 5.17 (dd, J = 8.09, 4.58 Hz, 1 H) 2.90 - 2.99 (m, 1 H) 2.78 - 2.87 (m, 1 H) 2.69 - 2.77 (m, 1 H) 2.26 (qd, J = 8.90, 5.04 Hz, 1 H). Intermediate I-8A (5-(2,6-difluorophenyl)-2,5,6,7- pyrrolo[2,1-c][1,2,4]triazol-3-one)Scheme I-8Step 1. one

[0182] To a solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (15 mL) was added a solution of (3,4-difluorophenyl)magnesium bromide (60.6 mL, 30.3 mmol) at -78 °C under N2. The mixture was stirred at 25 °C for 16 h. Then to the mixture was added NaBH3CN (1.74 g, 27.8 mmol) at 25 °C and the mixture was stirred at 25 °C for 1 h. The reaction was acidified to pH = 3-4 with HCl (6 M), and stirred for 1 h. The mixture was then neutralized with aq. NaOH (4 M). The mixture was quenched with water (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude product. It was purified by flash silica gel chromatography (100% EtOAc) to give 5-(3,4- difluorophenyl)pyrrolidin-2-one (1 g). Calc’d C10H10F2NO [M+H]+, 198; Found 198.1H NMR (400 MHz, CD3OD) δ 7.20-7.32 (m, 2H), 7.14 (ddd, J = 4.0 Hz, 1H), 4.79 (t, J = 7.6 Hz, 1H), 2.53-2.66 (m, 1H), 2.38-2.47 (m, 2H), 1.85-1.97 (m, 1H). Step 2. Preparation of 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole25866

[0183] To a solution of 5-(3,4-difluorophenyl)pyrrolidin-2-one (1.00 g, 5.07 mmol) in DCM (10 mL) was added trimethyloxonium tetrafluoroborate (1.13 g, 7.61 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with sat. NaHCO3 (10 mL) until the bubbling stopped, extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude of 2-(3,4-difluorophenyl)- 5-methoxy-3,4-dihydro-2H-pyrrole (1.00 g), which was used to next step without further purification. Calc’d C11H12F2NO [M+H]+, 212; Found 212. Step 3. Preparation of methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate

[0184] To a solution of 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (1 g, 4.73 mmol) in MeOH (10 mL) was added methyl hydrazinecarboxylate (0.448 g, 4.97 mmol) and HCl / MeOH (2 ml) at 20 °C and the resulting mixture was stirred at 80 °C for 12 h. The reaction was cooled to room temperature, concentrated, and the residue was purified by recrystallization to give methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.10 g). Calc’d C12H14F2N3O2 [M+H]+, 270; Found 270.1H NMR (400 MHz, CD3OD) δ 7.28- 7.38 (m, 2H), 7.20 (br d, J = 8.8 Hz, 1H), 5.17 (t, J = 7.6 Hz, 1H), 3.78-3.81 (m, 3H), 3.07-3.15 (m, 2H), 2.73-2.84 (m, 1H), 2.10-2.21 (m, 1H). Step 4. Preparation of I-8A

[0185] To a solution of methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (1.1 g, 4.09 mmol) in MeOH (20 mL) was added sodium methylate (0.662 g, 12.3 mmol) and the resulting mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and adjusted to pH = 7 with HCl / MeOH (4 M). Then the mixture was filtered and the solid was dried by vacuum distillation to give 5-(3,4-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (800 mg). Calc’d C11H10F2N3O [M+H]+, 238; Found 238.1H NMR (500 MHz, CD3OD) δ 7.20-7.32 (m, 2H), 7.09 (ddd, J = 4.5 Hz, 1H), 5.22 (dd, J = 5.5 Hz, 1H), 3.02-3.13 (m, 1H), 2.90-2.98 (m, 1H), 2.79-2.88 (m, 1H), 2.43 (tdd, J = 13.5 Hz, 1H), 1.90-2.08 (m, 1H). Intermediate I-9A ((S)-5-phenyl-5,6,7,8-[4,3-a]pyridin-3(2H)-one)25866 Scheme I-9a g, (100 mL) was added phenylmagnesium bromide (30.9 mL, 93.0 mmol) by syringe dropwise at -78 °C under N2. After the addition was completed, the reaction was allowed to warm up to 25 °C and stirred for 16 h. NaBH3(CN) (3.06 g, 48.6 mmol) was then added and stirred at 25 °C for additional 2 h.4 M HCl was added and the pH was adjusted to 4. The resulting mixture was stirred for 1 h. Aqueous NaOH was added to adjust the neutral pH. The mixture was quenched with water (200 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude product. The crude mixture was purified by flash silica gel chromatography (100% EtOAc) to give 6-phenylpiperidin-2-one (2.00 g). Calc’d C11H14NO [M+H]+, 176; Found 176. Step 2. Preparation of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine

[0187] To a solution of 6-phenylpiperidin-2-one (2.50 g, 14.3 mmol) in DCM (100 mL) was added dimethyloxonium tetrafluoroborate (2.87 g, 21.4 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated NaHCO3 (50 mL), extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine (2.30 g), which was used to next step without further purification. Calc’d C12H16NO [M+H]+, 190; Found 190. Step 3. Preparation of methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1- carboxylate

[0188] To a solution of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine (2.30 g, 12.2 mmol) in MeOH (65 mL) was added methyl hydrazinecarboxylate (1.64 g, 18.2 mmol) at 20 °C and the resulting mixture was stirred at 80 °C for 12 h. The reaction was cooled to room temperature and concentrated. The residue was added to EtOAc (20 mL) and stirred for 0.5 h. Filtered the solid to25866 give methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate (2.8 g). Calc’d C13H18N3O2[M+H]+, 248; Found 248. Steps 4-5. Preparation of 5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one followed by SFC purification to afford (S)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-3(2H)-one

[0189] A solution of methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1- carboxylate (2.50 g, 10.1 mmol) in DMF (25 mL) was stirred at 145 °C for 12 h. The reaction was cooled to room temperature and concentrated to give (±)-5-phenyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2.00 g). The enantiomers were separated by SFC (Method: Column DAICEL CHIRALCEL OD, Condition: 0.1%NH3H2O EtOH) to give (R)-5- phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (600 mg) (peak 1) and (S)-5- phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (800 mg) (peak 2).

[0190] (R)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one:1H NMR (500 MHz, CD3OD) δ 7.31-7.38 (m, 2H), 7.24-7.30 (m, 1H), 7.04 (d, J = 7.5 Hz, 2H), 5.18 (dd, J = 3.5 Hz, 1H), 2.80-2.89 (m, 1H), 2.66-2.76 (m, 1H), 2.27 (dddd, J = 2.5 Hz, 1H), 1.98-2.08 (m, 1H), 1.62-1.82 (m, 2H).

[0191] (S)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (I-9A):1H NMR (500 MHz, CD3OD) δ 7.32-7.38 (m, 2H), 7.24-7.30 (m, 1H), 7.04 (d, J = 7.5 Hz, 2H), 5.18 (dd, J = 3.5 Hz, 1H), 2.80-2.87 (m, 1H), 2.66-2.77 (m, 1H), 2.27 (dddd, J = 3.5 Hz, 1H), 1.98-2.07 (m, 1H), 1.63-1.81 (m, 2H). Intermediate I-10A FF((S)-5-(3,5-difluorophenyl)-5,6,7,8-triazolo[4,3-a]pyridin-3(2H)-one)25866 Scheme I-10 Step 1.

[0192] a g, (50 mL) was added iPrMgCl^LiCl (1.3 M in THF) (34.0 mL, 44.2 mmol) at 0 °C and the mixture was stirred at 50 °C for 1 h. Then to the mixture was added piperidine-2,6-dione (2.00 g, 17.7 mmol) and DCM (2 mL) at -78 °C. The mixture was stirred at 20 °C for 12 h. To the mixture was added NaBH3CN (1.33 g, 21.2 mmol) at 20 °C, then the mixture was stirred at 25 °C for 1 h. The reaction was acidified to pH= 3~4 with HCl (6 M), then the mixture was stirred for 30 min and neutralized with aq. NaOH (3 M). The mixture was quenched with sat.NH4Cl (200 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was added to EtOAc (20 mL) and stirred for 0.5 h. Filtered the solid to give 6-(3,5-difluorophenyl)piperidin-2-one (1.80 g). Calc’d C11H12F2NO [M+H]+, 212; Found 212. Step 2. Preparation of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine

[0193] To a solution of 6-(3,5-difluorophenyl)piperidin-2-one (500 mg, 2.37 mmol) in DCM (10 mL) was added dimethyloxonium tetrafluoroborate (475 mg, 3.55 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with sat. aq. NaHCO3(20 mL), extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5- tetrahydropyridine (490 mg), which was used to next step without further purification. Calc’d C12H14F2NO [M+H]+, 226; Found 226. Step 3. Preparation of methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2- yl)hydrazine-1-carboxylate

[0194] To a solution of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine (490 mg, 2.18 mmol) in MeOH (10 mL) was added methyl hydrazinecarboxylate (294 mg, 3.26 mmol) at25866 20 °C and the resulting mixture was stirred at 80 °C for 12 h. The reaction was cooled to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (eluent of 5% MeOH / DCM gradient) to give methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6- tetrahydropyridin-2-yl)hydrazine-1-carboxylate (300 mg). Calc’d C13H16F2N3O2[M+H]+, 284; Found 284. Steps 4-5. Preparation of intermediate I-10A

[0195] A solution of methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2- yl)hydrazine-1-carboxylate (300 mg, 1.06 mmol) in DMF (15 mL) was stirred at 145 °C for 12 h. The reaction was cooled to room temperature and concentrated to give 5-(3,5-difluorophenyl)- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (220 mg).5-(3,5-difluorophenyl)- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (240 mg, 0.955 mmol) was resolved by Chiral-SFC (Method: Column DAICEL CHIRALCEL OD, Condition: 0.1%NH3H2O EtOH in CO2) to give (S)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)- one (85 mg) (peak 1) and (R)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-3(2H)-one (80 mg) (peak 2).

[0196] (S)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (I-10A):1H NMR (400 MHz, CD3OD) δ 6.87 (tt, J=2.35, 9.00 Hz, 1H), 6.67-6.77 (m, 2H), 5.13 (t, J=5.09 Hz, 1H), 2.79-2.91 (m, 1H), 2.65-2.78 (m, 1H), 2.29 (dddd, J=2.74, 6.06, 10.86, 13.99 Hz, 1H), 2.01 (tdd, J=3.42, 6.55, 13.99 Hz, 1H), 1.63-1.88 (m, 2H).

[0197] (R)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one:1H NMR (400 MHz, CD3OD) δ 6.87 (tt, J=2.20, 9.15 Hz, 1H), 6.68-6.76 (m, 2H), 5.13 (t, J=5.28 Hz, 1H), 2.79-2.89 (m, 1H), 2.65-2.77 (m, 1H), 2.29 (dddd, J=3.13, 5.87, 11.00, 14.04 Hz, 1H), 2.01 (tdd, J=3.33, 6.65, 14.09 Hz, 1H), 1.64-1.87 (m, 2H). Intermediate I-11A (5-(3,5-difluorophenyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one.25866- - 2- sulfinamide

[0198] To a stirred mixture of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (10.0 g, 57.4 mmol) in THF (250 mL) was added (S)-2-methylpropane-2-sulfinamide (9.04 g, 74.6 mmol), Ti(iPrO)4 (22.5 mL, 86.0 mmol) at 20 °C and the mixture was stirred at 20 °C for 12 h. The mixture was poured into brine (300 mL) and filtered. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0~20% EtOAc / petroleum ether) to give (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2- methylpropane-2-sulfinamide (11.5 g). Calc’d C12H28NO2SSi [M+H]+, 278; Found 278. Step 2. Preparation of (S)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2- methylpropane-2-sulfinamide

[0199] To a solution of 1-bromo-3,5-difluorobenzene (8.80 g, 45.6 mmol) in THF (100 mL) was added i-PrMgCl^LiCl (47.8 mL, 62.2 mmol) at 0 °C under N2 and the mixture was stirred at 40 °C for 1 h. Then the reaction mixture was added to a solution of (S,E)-N-(2-((tert- butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (11.5 g, 41.4 mmol) in THF (150 mL) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 5 h. The mixture was quenched with sat. NH4Cl (300 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (100% EtOAc) to give (S)-N-((R)-2-((tert- butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (7.00 g). Calc’d C18H32F2NO2SSi [M+H]+, 392; Found 392. Steps 3-4. Preparation of 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide25866

[0200] A solution of (S)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)- 2-methylpropane-2-sulfinamide (3.00 g, 7.66 mmol) in HCl / MeOH (50 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give product 2-amino- 2-(3,5-difluorophenyl)ethan-1-ol (1 g, 5.77 mmol). The crude product was used in the next step directly.

[0201] To a mixture of 2-amino-2-(3,5-difluorophenyl)ethan-1-ol (1 g, 5.77 mmol) and TEA (2.01 mL, 14.4 mmol) in THF (30 mL) was added 2-chloroacetyl chloride (0.459 mL, 5.77 mmol) at 0 °C and the resulting mixture was stirred at 20 °C for 2 h. Water (20 mL) was added then the solution was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (40% EtOAc / petroleum ether) to give 2-chloro-N-(1- (3,5-difluorophenyl)-2-hydroxyethyl)acetamide (560 mg). Calc’d C10H11ClF2NO2[M+H]+, 250; Found 250. Step 5. Preparation of 5-(3,5-difluorophenyl)morpholin-3-one

[0202] To a solution of 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide (560 mg, 2.243 mmol) in THF (44 mL) was added NaH (224 mg, 5.61 mmol) at 0 ºC and the mixture was stirred at 20 °C for 1 h. The mixture was added saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (100% ethyl acetate / petroleum ether) to give 5-(3,5-difluorophenyl)morpholin- 3-one (350 mg). Calc’d C10H10F2NO2[M+H]+, 214; Found 214. Step 6. Preparation of 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxazine

[0203] To a solution of 5-(3,5-difluorophenyl)morpholin-3-one (560 mg, 2.63 mmol) in DCM (10 mL) was added trimethyloxonium tetrafluoroborate (583 mg, 3.94 mmol) at 20 ºC. The mixture was stirred at 30 °C for 12 h. The mixture was quenched with saturated NaHCO3(20 mL) then extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum to give crude of 3-(3,5- difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxazine (580 mg), which was used in the next step without further purification. Calc’d C11H12F2NO2[M+H+H2O]+, 246; Found 246. Step 7. Preparation of methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxazin-3- yl)hydrazine-1-carboxylate

[0204] To a solution of 3-(3,5-difluorophenyl)-5-methoxymorpholine (580 mg, 2.53 mmol) in MeOH (10 mL) was added methyl hydrazinecarboxylate (342 mg, 3.80 mmol) at 20 °C and the resulting mixture was stirred at 80 °C for 5 h. The reaction was cooled to room temperature,25866 concentrated, and the residue was slurried with ethyl acetate (10 mL) to give methyl 2-(5-(3,5- difluorophenyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)hydrazine-1-carboxylate (480 mg). Calc’d C12H14F2N3O3 [M+H]+, 286; Found 286. Step 8. Preparation of intermediate I-11A (5-(3,5-difluorophenyl)-2,5,6,8-tetrahydro-3H- [1,2,4]triazolo[3,4-c][1,4]oxazin-3-one)

[0205] A solution of methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxazin-3- yl)hydrazine-1-carboxylate (480 mg, 1.68 mmol) in DMF (40 mL) was stirred at 145 °C for 12 h. The reaction was cooled to room temperature then concentrated. The residue was repurified by Prep-HPLC (Method Boston Green ODS, Condition water(0.01%TFA)-ACN) to give I-11A, 5- (3,5-difluorophenyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one (150 mg). Calc’d C11H10F2N3O2 [M+H]+, 286; Found 286.1H NMR (400 MHz, CD3OD) δ 6.82-6.98 (m, 3H), 5.05 (t, J = 3.6 Hz, 1H), 4.84 (s, 1H), 4.67 (d, J = 15.6 Hz, 1H), 4.17 (dd, J = 4.0, 12.4 Hz, 1H), 4.02 (dd, J = 3.2, 12.4 Hz, 1H). Intermediate I-12A ((R)-5-phenyl-2,5,6,8-triazolo[3,4-c][1,4]oxazin-3-one) Scheme I-12 O 1) F Cl Cl 3) FBF

[0206]

[0207] (R)-5-phenyl-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one (I-12A):1H NMR (400 MHz, CD3OD) δ 7.28-7.39 (m, 4H), 7.20-7.22 (m, 1H), 5.03 (t, J=3.52 Hz, 1H), 4.82 (s, 1H), 4.63-4.72 (m, 1H), 4.17 (dd, J=4.30, 12.13 Hz, 1H), 3.98 (dd, J=3.13, 12.13 Hz, 1H).25866 Intermediate I-13A (5-(3-oxo-2,5,6,7-tetrahydro- [1,2,4]triazol-5-yl)nicotinonitrile) Scheme I-13

[0208] To a solution of 3,5-dibromopyridine (23.7 g, 100 mmol) in THF (250 mL) was added iPrMgCl (92 mL, 120 mmol) at 0 °C for 1 h, then the mixture was added to dihydrofuran-2,5- dione (10.0 g, 100 mmol) in THF (250 mL) at 0 ºC. The mixture was stirred at -20 °C for 2 h. The mixture was quenched by aqueous ammonium chloride (50 mL). The pH was adjusted to pH>7 with 1 N NaOH. After 5 min, 1 N HCl was added until pH~ 7. Extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude product 4-(5-bromopyridin-2-yl)-4-oxobutanoic acid (20.0 g), which was used in the next step without further purification. Calc’d C9H9BrNO3[M+H]+, 258; Found 258. Step 2. Preparation of methyl 4-(5-bromopyridin-3-yl)-4-oxobutanoate

[0209] To a solution of 4-(5-bromopyridin-3-yl)-4-oxobutanoic acid (25.0 g, 97.0 mmol) crude in DCM (100 mL) and MeOH (100 mL) was added TMSCHN2 (100 mL, 200 mmol) and the resulting mixture was stirred at 20 °C for 3 h. The reaction solution was concentrated and the residue was purified by flash silica gel chromatography (Pet. ether / EtOAc) to give methyl 4-(5- bromopyridin-3-yl)-4-oxobutanoate (5.5 g). Calc’d C10H11BrNO3[M+H]+, 274; Found 274. Step 3. Preparation of 5-(5-bromopyridin-3-yl)pyrrolidin-2-one25866

[0210] To a solution of methyl 4-(5-bromopyridin-3-yl)-4-oxobutanoate (4.5 g, 16.5 mmol) in MeOH (100 mL) was added ammonium acetate (3.82 g, 49.6 mmol) and NaBH3CN (2.60 g, 41.3 mmol) and the mixture was stirred at 80 °C for 12 h. The reaction was cooled to room temperature, and the mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0~10% MeOH / DCM) to give 5-(5-bromopyridin-3-yl)pyrrolidin-2-one (2.10 g). Calc’d C9H10BrN2O [M+H]+, 241, 243; Found 241, 243. Step 4. Preparation of 5-(5-bromopyridin-3-yl)pyrrolidine-2-thione

[0211] A solution of 5-(5-bromopyridin-3-yl)pyrrolidin-2-one (2.10 g, 8.71 mmol) and Lawesson's reagent (1.76 g, 4.36 mmol) in toluene (40 mL) was stirred at 110 °C for 12 h. The reaction was cooled to room temperature, then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (100% EtOAc / petroleum ether) to give 5-(5-bromopyridin-3-yl)pyrrolidine-2-thione (1.67 g). Calc’d C9H10BrN2S [M+H]+, 257, 259; Found 259, 259. Step 5. Preparation of 3-bromo-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine

[0212] To a solution of 5-(5-bromopyridin-3-yl)pyrrolidine-2-thione (230 mg, 0.894 mmol) in THF (10 mL) was added MeI (0.2 mL, 3.20 mmol). The mixture was stirred for 12 h at 20 °C. The reaction mixture was concentrated and the resulting residue was partitioned between DCM (15 mL) and saturated NaHCO3 (15 mL) and the aqueous phase was extracted with DCM (15 mL x 3). The combined organic extract was dried over Na2SO4and concentrated to afford 3-bromo- 5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (110 mg). Calc’d C10H12BrN2S [M+H]+, 271, 273; Found 271, 273. Step 6. Preparation of methyl 2-(2-(5-bromopyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine- 1-carboxylate

[0213] To a solution of 3-bromo-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (1.60 g, 5.90 mmol) in MeOH (30 mL) was added methyl hydrazinecarboxylate (0.691 g, 7.67 mmol). The mixture was stirred at 80 °C for 3 h then the reaction was cooled to room temperature. The crude product was purified by flash silica gel chromatography (10% MeOH / DCM) to give methyl 2-(2-(5-bromopyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.40 g). Calc’d C11H14BrN4O2[M+H]+, 313, 315; Found 313, 315. Step 7. Preparation of 5-(5-bromopyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0214] A mixture of methyl 2-(2-(5-bromopyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine- 1-carboxylate (1.40 g, 4.47 mmol) in DMF (50 mL) was stirred at 140 °C for 16 h. The reaction was cooled to room temperature, then concentrated in vacuum to give crude product, which was25866 triturated with MeOH and EtOAc (1:5) to give 5-(5-bromopyridin-3-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (1.00 g). Calc’d C10H10BrN4O [M+H]+, 281, 283; Found 281, 283. Step 8. Preparation of 5-(3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5- yl)nicotinonitrile (I-13A)

[0215] To a solution of 5-(5-bromopyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (1.00 g, 3.56 mmol) in dioxane (10 mL) was added Zn(CN)2 (2.09 g, 17.8 mmol), [(tBu)3P]2Pd (0.727 g, 1.42 mmol) under N2atmosphere. The mixture was stirred at 120 °C for 12 h. The reaction was cooled to room temperature, then purified by HPLC (Method Boston Green ODS Condition water(0.1%TFA)-ACN) to give 5-(3-oxo-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-5-yl)nicotinonitrile (200 mg). Calc’d C11H10N5O [M+H]+, 228; Found 228. Intermediate I-14A (5-(pyrazin-2-yl)-2,5,6,7-[2,1-c][1,2,4]triazol-3-one) Scheme I-14 Step 1.

[0216] Two reactions of identical scale were carried out in parallel: To a solution of pyrazine-2-carbaldehyde (180 g, 1.67 mol) in MeOH (1.80 L) at 20 °C was added ethyl acrylate (205 g, 2.05 mol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide (83.9 g, 0.33 mol), and TEA (505 g, 5.00 mol). The mixture was a heated to 70 °C and stirred for 1 h. The reaction was cooled to room temperature. The two batches were combined and worked up together. The suspension was filtered and the filter cake was washed with EtOAc. The filtrate was washed with saturated NH4Cl (1.00 L) and the aqueous layer was extracted with EtOAc (1.00 L x 4). The organic layer was washed with sat. NaHCO3 (1.00 L), brine (0.50 L) and dried over Na2SO4. The organic layer was dried under reduced pressure and the crude residue was purified by flash column chromatography (petroleum ether / EtOAc). The fractions containing the desired product were pooled and concentrated to give ethyl 4-oxo-4-(pyrazin-2-yl)butanoate (320 g).1H (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.69 (d, J = 2.00 Hz, 1H), 8.58 (d, J = 0.80 Hz, 1H), 4.04-4.09 (m, 2H), 3.43 (t, J = 6.40 Hz, 2H), 2.68 (d, J = 6.80 Hz, 2H), 1.17 (t, J = 7.20 Hz, 2H). Steps 2-3. Preparation of 5-(pyrazin-2-yl)pyrrolidin-2-one

[0217] To a solution of ethyl 4-oxo-4-(pyrazin-2-yl)butanoate (160 g, 768 mmol) in EtOH (1.04 L) at 20 °C was added ammonium acetate (592 g, 7.68 mol) and molecular sieves (320 g, 1.32 mol). The resulting mixture was stirred at 20 °C for 12 h. The reaction was concentrated to dryness and the resulting brown liquid was used in the next step without further purification.

[0218] The subsequent step was carried out in two reactions of identical scale in parallel: To 4-oxo-4-(pyrazin-2-yl)butanamide (138 g, 768 mmol) in EtOH (960 mL) at 20 °C was added NaBH3CN (145 g, 2.31 mol) and the resulting mixture was stirred at 80 °C for 5 h. The reaction was cooled to room temperature. The two batches were combined and worked up together. The suspension was filtered and the filter cake was washed with EtOH (500 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH). The fractions containing the desired product mass were pooled and concentrated, the resulting residue was dissolved in DCM (1.00 L). The solution was filtered and the filter cake was washed with DCM (200 mL). The filtrate was concentrated to give 5-(pyrazin-2-yl)pyrrolidin-2-one (77.0 g).1H NMR (400MHz, CDCl3) δ 8.62-8.64 (m, 2H), 8.58 (d, J = 2.40 Hz, 1H), 8.14 (s, 1H), 4.79-4.82 (m, 1H), 2.49-2.50 (m, 1H), 2.23-2.30 (m, 2H), 1.98-2.21 (m, 1H). Step 4. Preparation of 5-(pyrazin-2-yl)pyrrolidine-2-thione

[0219] To a solution of 5-(pyrazin-2-yl)pyrrolidin-2-one (77.0 g, 472 mmol) in toluene (3.85 L) at 20 °C was added Lawesson’s reagent (95.4 g, 236 mmol). The resulting mixture was stirred at 80 °C for 0.5 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH). The fractions containing the desired product mass were pooled and concentrated to give 5-(pyrazin-2-yl)pyrrolidine-2-thione (84.0 g).1H NMR (400MHz, CDCl3) δ 8.61 (d, J = 1.20 Hz, 1H), 8.46 (t, J = 1.60 Hz, 1H), 8.40 (d, J = 2.40 Hz, 1H), 7.74-7.77 (m, 1H), 5.20 (t, J = 7.20 Hz, 1H), 4.17-4.21 (m, 1H), 2.70-2.79 (m, 2H), 2.52-2.55 (m, 1H), 2.46 (s, 3H), 2.06-2.10 (m, 2H). Step 5. Preparation of 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine

[0220] To a solution of 5-(pyrazin-2-yl)pyrrolidine-2-thione (84.0 g, 469 mmol) in acetone (494 mL) at 20 °C was added K2CO3(194 g, 1.41 mol). The mixture was stirred at 20 °C for 1 h. MeI (133 g, 937 mmol, 58.3 mL) was added dropwise and the reaction was stirred at 20 °C for 11 h. The reaction was filtered and the filter cake was washed with acetone (200 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography (petroleum ether / 30% EtOAc:EtOH). The fractions containing the desired product mass were pooled and concentrated to give 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2- yl)pyrazine (51.0 g).1H NMR (400MHz, CDCl3) δ 8.61 (d, J = 1.20 Hz, 1H), 8.46 (t, J = 0.8 Hz, 1H), 8.40 (d, J = 2.40 Hz, 1H), 7.74-7.77 (m, 1H), 5.20 (t, J = 7.20 Hz, 1H), 4.17-4.21 (m, 1H), 2.70-2.79 (m, 2H), 2.52-2.55 (m, 1H), 2.46 (s, 3H), 2.06-2.10 (m, 2H). Steps 6-7. Preparation of 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one

[0221] Two reactions of identical scale were carried out in parallel: To a solution of 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine (22.0 g, 114 mmol) in MeOH (440 mL) at 20 °C was added methyl hydrazinecarboxylate (15.4 g, 171 mmol). The reaction mixture was heated to 80 °C for 2 h. The reaction was cooled to room temperature, then concentrated to dryness and methyl 2-(2-(pyrazin-2-yl)-3,4-dihydro-2H-pyrrol-5- yl)hydrazine-1-carboxylate (53.6 g) was obtained and used into the next step without further purification.

[0222] The subsequent step was carried out in two reactions of identical scale in parallel: To a solution of methyl 2-(2-(pyrazin-2-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate (26.0 g, 111 mmol) in MeOH (485 mL) at 20 °C was added MeONa (25.6 g, 332 mmol). The resulting mixture was stirred at 80 °C for 12 h. The reaction was cooled to room temperature. The two batches were combined and poured into H2O (500 mL) at rt. The mixture was filtered and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated to give the desired crude residue which was purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH) to give 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one. After another cycle of purification by pre-HPLC (Method: Welch Xtimate C18; Condition water (TFA)-ACN) to give 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (I-14A) (25.0 g).1H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.69 (s, 1H),25866 8.57 (d, J = 2.40 Hz, 2H), 5.31-5.33 (m, 1H), 3.00-3.07 (m, 2H), 2.85-2.87 (m, 1H), 2.73-2.80 (m, 1H). Intermediate I-15A (Methyl 3-oxo-2,5,6,7- [2,1-c][1,2,4]triazole-5-carboxylate)Scheme I-15 Step 1.

[0223] a g, CH2Cl2(800 mL) was added dimethyloxonium tetrafluoroborate (70.1 g, 524 mmol) at 0 ºC. The mixture was stirred at 25 °C for 12 h then quenched with sat. aq. NaHCO3(400 mL) and extracted with DCM (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give crude methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (55 g), which was used in the next step without further purification. Calc’d C7H12NO3 [M+H]+, 158; Found 158. Step 2. Preparation of methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2- carboxylate

[0224] To a solution of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (55 g, 350 mmol) in MeOH (800 mL) was added methyl hydrazinecarboxylate (47.3 g, 525 mmol) and HCl / MeOH (4 M) (50 mL) at 20 °C. The resulting mixture was stirred at 80 °C for 4 h. The reaction was cooled to room temperature, concentrated, and the residue was slurried with ethyl acetate, MeOH to give methyl 5-(2-(methoxycarbonyl)hydrazineyl)-3,4-dihydro-2H-pyrrole-2- carboxylate (49 g). Calc’d C8H14N3O4 [M+H]+, 216; Found 216.1H NMR (400 MHz, CD3OD) δ 4.73 (dd, J = 4.8, 9.2 Hz, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 2.99-3.09 (m, 2H), 2.68 (qd, J = 8.8, 13.2 Hz, 1H), 2.35-2.43 (m, 1H). Step 3. Preparation of I-15A (methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole- 5-carboxylate)

[0225] To a solution of methyl 5-(2-(methoxycarbonyl)hydrazineyl)-3,4-dihydro-2H-pyrrole-2- carboxylate (20.0 g, 93.0 mmol) in MeOH (400 mL) was added sodium methanolate (15.1 g, 27925866 mmol) at ambient temperature. The resulting mixture was stirred at 80 °C for 8 h. To the reaction was added HCl (4.0 M in MeOH) until pH~5 and stirred at 80 °C for 2 h. The solid was filtered and the filtrate was purified by flash silica gel chromatography (MeOH / DCM) to give methyl 3- oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (I-15A). Calc’d C7H10N3O3 [M+H]+, 184; Found 184.1H NMR (400 MHz, CD3OD) δ 4.74 (dd, J = 3.2, 9.2 Hz, 1H), 3.80 (s, 3H), 2.93-3.05 (m, 1H), 2.75-2.88 (m, 2H), 2.57-2.67 (m, 1H). Intermediate I-16A (S)-5-(3,5-difluorophenyl)-2-( -2,5,6,7-tetrahydro-3H-pyrrolo[2,1-one Scheme I-16 F F I-2A O F OBn Step 1.

[0226] 4-methylbenzenesulfonyl chloride (471 mg, 2.469 mmol) and N,N-dimethylpyridin-4- amine (411 mg, 3.37 mmol) were added to a solution of cis-3-(benzyloxy)cyclobutan-1-ol (400 mg, 2.244 mmol) in DCM (10 mL). The resulting mixture was stirred at 20 °C for 12 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; Agela®Flash Column Silica-CS (1 g), Eluent of 0 ~ 5% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give cis-3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate. MS (EI) Calculated for C18H21O4S [M+H]+, 333; found, 333.25866 Step 2. Synthesis of (S)-2-((1R,3S)-3-(benzyloxy)cyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0227] To a mixture of cis-3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (200 mg, 0.602 mmol) in DMF (3 ml) was added Cs2CO3(392 mg, 1.203 mmol) and I-2A (171 mg, 0.722 mmol) at ambient temperature. The reaction was stirred at 90 °C for 16 h. The reaction was cooled to room temperature. The residue was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, eluent of 0-15% ethyl acetate / pet. ether gradient @ 60 mL / min) to give (S)-2-((1R,3S)-3-(benzyloxy)cyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C22H21F2N3O2 [M+H]+, 398; found, 398. Step 3. Synthesis of (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-hydroxycyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-16A)

[0228] To a solution of (S)-2-((1R,3S)-3-(benzyloxy)cyclobutyl)-5-(3,5-difluorophenyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (9 g, 22.65 mmol) in MeOH (150 mL) was added Pd(OH)2 / C (1.590 g, 2.265 mmol) and Pd / C (2.410 g, 2.265 mmol) at 20 ºC. The resulting mixture was stirred at 40 °C for 16 h under H2. The reaction solution was filtered and the filtrate was concentrated in vacuo to give (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3- hydroxycyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-16A).1H NMR (400 MHz, CD3OD) δ 6.86-6.96 (m, 3H), 5.23 (dd, J=4.95, 8.05 Hz, 1H), 4.80-4.85 (m, 1H), 4.54 (br dd, J=3.28, 3.99 Hz, 1H), 3.01-3.09 (m, 1H), 2.87-2.99 (m, 2H), 2.64-2.77 (m, 2H), 2.32-2.45 (m, 3H). MS (ESI) Calculated for C15H15F2N3O2[M+H]+, 308; found, 308. Intermediate I-17A (S)-5-(3,5-difluorophenyl)-2-(-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one25866 Scheme I-17 Step 1. [2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl 4-nitrobenzoate

[0229] DIAD (4.05 ml, 20.83 mmol) was added to a solution of (S)-5-(3,5-difluorophenyl)-2- ((1R,3S)-3-hydroxycyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (3.2 g, 10.4 mmol), 4-nitrobenzoic acid (1.91 g, 11.5 mmol) and Ph3P (5.46 g, 20.8 mmol) in THF (50 mL) under N2. The reaction mixture was stirred for 12 h at 25 °C. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 100% ethyl acetate / pet. ether gradient @ 35 mL / min) to give (1R,3S)-3-((S)-5-(3,5-difluorophenyl)-3-oxo- 6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl 4-nitrobenzoate (5 g). MS (EI) Calculated for C22H18F2N4O5 [M+H]+, 457; found, 457. Step 2. Synthesis of (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-hydroxycyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-17A)

[0230] To a solution of (1R,3S)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl 4-nitrobenzoate (5 g, 11.0 mmol) in MeOH (200 ml) was added K2CO3 (7.57 g, 54.8 mmol) and the reaction was stirred at 25 °C for 12 h. The mixture was filtered and concentrated in vacuo and the resulting residue was purified by prep- HPLC [Column Boston Prime C18150*30mm*5um eluting with water(NH3H2O+NH4HCO3)- ACN] to give (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-hydroxycyclobutyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-17A).1H NMR (500 MHz, CDCl3) δ 6.67-6.83 (m, 3H), 5.18 (dd, J=4.04, 8.16 Hz, 1H), 4.34 (quin, J=7.97 Hz, 1H), 4.12 (quin, J=6.94 Hz, 1H), 2.79- 3.06 (m, 5H), 2.37-2.51 (m, 3H). MS (EI) Calculated for C15H15F2N3O2 [M+H]+, 308; found, 308.25866 Intermediate I-18A 2-Bromo-2-(3,5- (tert-butyl)dimethylsilaneScheme I-18 Step 1. Preparation

[0231] To a stirred solution of 1-bromo-3,5-difluorobenzene (5 g, 25.9 mmol), potassium vinyltrifluoroborate (5.21 g, 38.9 mmol) and K2CO3 (10.74 g, 78 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added Pd(dppf)Cl2(1.90 g, 2.59 mmol) at 20 °C. The resulting mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction was cooled to room temperature. The reaction mixture was filtered and the solution was used directly in the next step without further purification. Step 2. Preparation of 1-(3,5-difluorophenyl)ethane-1,2-diol

[0232] To a solution of 1,3-difluoro-5-vinylbenzene (3.63 g, 25.9 mmol) in dioxane (50 mL) and H2O (50 mL) was added OsO4(0.5 g, 1.97 mmol) and NMO (6.07 g, 51.8 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with saturated Na2SO3 (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (0- 35% EtOAc / petroleum ether gradient) to give 1-(3,5-difluorophenyl)ethane-1,2-diol (4.00 g).1H NMR (500 MHz, CDCl3) δ 6.88-6.98 (m, 2H), 6.74 (tt, J = 2.5, 9.0 Hz, 1H), 4.82 (dd, J = 3.0, 8.0 Hz, 1H), 3.80 (dd, J = 3.5, 11.5 Hz, 1H), 3.62 (dd, J = 8.0, 11.5 Hz, 1H), 2.77 (br s, 1H), 2.07- 2.24 (m, 1H). Step 3. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-ol

[0233] To a solution of 1-(3,5-difluorophenyl)ethane-1,2-diol (2 g, 11.5 mmol) in DMF (40 mL) was added 1H-imidazole (0.938 g, 13.8 mmol) and TBSCl (2.08 g, 13.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (150 mL) and25866 extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give a residue which was purified by flash silica gel chromatography (3% EtOAc / petroleum ether gradient) to give 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-ol (2.50 g).1H NMR (400 MHz, CDCl3) δ 6.92 (br d, J = 6.4 Hz, 2H), 6.72 (tt, J = 2.0, 8.8 Hz, 1H), 4.73 (br d, J = 7.6 Hz, 1H), 3.78 (dd, J = 3.6, 10.4 Hz, 1H), 3.51 (dd, J = 8.0, 10.0 Hz, 1H), 2.98 (br s, 1H), 0.91 (s, 9H), 0.07 (d, J = 4.4 Hz, 6H). Step 4. Preparation of I-18A (2-bromo-2-(3,5-difluorophenyl)ethoxy)(tert-butyl)dimethylsilane)

[0234] To a solution of 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-ol (0.5 g, 1.73 mmol) in DCM (10 mL) was added triphenylphosphane (0.682 g, 2.60 mmol) and perbromomethane (0.862 g, 2.60 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give a residue which was purified by flash silica gel chromatography (10% EtOAc / petroleum ether gradient) to give 2-bromo-2-(3,5- difluorophenyl)ethoxy)(tert-butyl)dimethylsilane (I-18A).1H NMR (400 MHz, CDCl3) δ 6.85- 7.02 (m, 2H), 6.64-6.82 (m, 1H), 4.83 (t, J = 6.8 Hz, 1H), 4.01-4.12 (m, 1H), 3.92-4.01 (m, 1H), 0.84-0.91 (m, 9H), -0.03-0.08 (m, 3H). Intermediate I-19A (S)-2-((1R,3S)-3-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one Scheme I-193H- pyrrolo[2,1-c][1,2,4]triazol-3-one

[0235] To a solution of (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (3.2 g, 15.9 mmol) in DMF (100 mL) was added Cs2CO3(10.36 g, 31.8 mmol) and (1S,3S)-3- (benzyloxy)cyclobutyl 4-methylbenzenesulfonate (5.29 g, 15.9 mmol) at ambient temperature. The reaction was brought to 80 °C for 16 h then cooled to ambient temperature, diluted with water (200 mL) and extracted with EtOAc (3 x 70 mL). The combined organic extracts were concentrated, washed with brine (2 x50 mL), dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford (S)-2-((1R,3S)-3-(benzyloxy)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one. MS (EI) Calculated for C22H24N3O2 [M+H]+, 362; found, 362. Step 2. Preparation of ((S)-2-((1R,3S)-3-hydroxycyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one) (I-19A)

[0236] To a solution of (S)-2-((1R,3S)-3-(benzyloxy)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (3.8 g, 10.5 mmol) in MeOH (100 mL) was added Pd(OH)2 / C (0.369 g, 0.526 mmol) and Pd / C (0.280 g, 0.526 mmol) at ambient temperature. The resulting mixture was brought to 30 °C for 16 h under H2. The reaction mixture was filtered and concentrated under reduced pressure to afford (S)-2-((1R,3S)-3-hydroxycyclobutyl)-5-phenyl- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one which was taken on as is, without purification. MS (EI) Calculated for C15H18N3O2 [M+H]+, 272; found, 272. Intermediate I-20A (R)-5-phenyl-5,6-c][1,2,4]triazol-3(2H)-oneScheme I-20a - g, was added imidazole (24.81 g, 364 mmol) and TBS-Cl (41.2 g, 273 mmol) at ambient temperature. The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford (R)-2-((tert-butyldimethylsilyl)oxy)-1-phenylethan- 1-amine. MS (EI) Calculated for C14H26NOSi [M+H]+, 252; found, 252. Step 2. Preparation of methyl (R)-9,9,10,10-tetramethyl-4-oxo-6-phenyl-8-oxa-2,3,5-triaza-9- silaundecanoate

[0238] To a mixture of (R)-2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1-amine (42 g, 167 mmol) and CDI (40.6 g, 251 mmol) in DMF (500 mL) was added methyl hydrazinecarboxylate (37.6 g, 418 mmol) at ambient temperature. The mixture was brought to 50 °C for 12 h. The reaction was cooled to ambient temperature, diluted with water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified flash silica gel chromatography (EtOAc / hexanes) to afford (R)-9,9,10,10-tetramethyl-4-oxo-6-phenyl-8- oxa-2,3,5-triaza-9-silaundecanoate. MS (EI) Calculated for C17H30N3O4Si [M+H]+, 368; found, 368. Step 3. Preparation of (R)-4-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1,2,4-triazolidine- 3,5-dione

[0239] To a solution of (R)-9,9,10,10-tetramethyl-4-oxo-6-phenyl-8-oxa-2,3,5-triaza-9- silaundecanoate (33 g, 90 mmol) in MeOH (300 mL) was added sodium methanolate (14.55 g, 269 mmol) at ambient temperature. The mixture was brought to 80 °C for 5 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography25866 (isocratic gradient of EtOAc) to afford (R)-4-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)- 1,2,4-triazolidine-3,5-dione. MS (EI) Calculated for C16H26N3O3Si [M+H]+, 336; found, 336. Step 4. Preparation of (R)-4-(2-hydroxy-1-phenylethyl)-1,2,4-triazolidine-3,5-dione

[0240] To a solution of (R)-4-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1,2,4- triazolidine-3,5-dione (7.6 g, 22.6 mmol) in MeOH (80 mL) was added ammonium fluoride (8.39 g, 227 mmol) at ambient temperature. The mixture was brought to 80 °C for 12 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography (isocratic gradient of EtOAc) to afford (R)-4-(2-hydroxy-1-phenylethyl)-1,2,4-triazolidine-3,5- dione. MS (EI) Calculated for C10H12N3O3[M+H]+, 222; found, 222. Step 5. Preparation of ((R)-5-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one) (I-20A)

[0241] To a mixture of (R)-4-(2-hydroxy-1-phenylethyl)-1,2,4-triazolidine-3,5-dione (400 mg, 1.81 mmol) and triphenylphosphine (949 mg, 3.62 mmol) in THF (10 mL) was added DIAD (0.703 mL, 3.62 mmol) at ambient temperature under nitrogen. The mixture was brought to 50 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC elution conditions: water (0.1% TFA)-ACN to afford (R)-5-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one. MS (EI) Calculated for C10H10N3O2 [M+H]+, 204; found, 204. Intermediate I-21A methyl (S)-3-oxo-2,3,5,6,7,8-triazolo[4,3-a]pyridine-5-carboxylate Scheme I-21

[0242] To a solution of methyl (S)-6-oxopiperidine-2-carboxylate (15 g, 95 mmol) in DCM (500 mL) was added trimethyloxonium tetrafluoroborate (21.2 g, 143 mmol) at 0 ºC under nitrogen. The mixture was brought to 25 °C for 15 h then quenched with sat. aq. NaHCO3(50025866 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure afford crude methyl (S)-6-methoxy-2,3,4,5- tetrahydropyridine-2-carboxylate, which was used in the next step without further purification. Calc’d C8H14NO3[M+H]+, 172; Found 172. Step 2. Preparation of methyl (S)-6-(2-(methoxycarbonyl)hydrazineyl)-2,3,4,5- tetrahydropyridine-2-carboxylate

[0243] To a solution of methyl (S)-6-methoxy-2,3,4,5-tetrahydropyridine-2-carboxylate (16 g, 93 mmol) in MeOH (450 mL) was added methyl hydrazinecarboxylate (9.26 g, 103 mmol) and HCl / MeOH (4 M) (10 mL) at ambient temperature under nitrogen. The resulting mixture was brought to 80 °C for 2 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The resulting solid was thoroughly washed with EtOAc and hexanes to afford methyl (S)-6-(2-(methoxycarbonyl)hydrazineyl)-2,3,4,5-tetrahydropyridine-2-carboxylate, which was used in the next step without purification. Calc’d C9H16N3O4 [M+H]+, 230; Found 230. Step 3. Preparation of (methyl (S)-3-oxo-2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine-5- carboxylate) (I-21A)

[0244] A solution of (S)-6-(2-(methoxycarbonyl)hydrazineyl)-2,3,4,5-tetrahydropyridine-2- carboxylate (5 g, 21.8 mmol) in DMF (500 mL) was brought to 145 °C for 16 h under nitrogen. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford methyl (S)-3-oxo-2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate. Calc’d C8H12N3O3 [M+H]+, 198; Found 198. Intermediate I-22A 5-(5-fluoropyridin-2-yl)-pyrrolo[2,1-c][1,2,4]triazol-3-one25866 Scheme I-22 Step 3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate

[0245] To a solution of methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5- carboxylate (2g, 10.9 mmol) and Cs2CO3(5.34 g, 16.4 mmol) in DMF (50 mL) was added SEM- Cl (2.32 mL, 13.1 mmol) at 0 ºC. The resulting mixture was brought to 20 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford methyl 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazole-5-carboxylate, which was used in the next step without further purification. Calc’d C13H24N3O4Si [M+H]+, 314; Found 314. Step 2. Preparation of 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid

[0246] A mixture of methyl 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (3.5 g, 11.2 mmol) and LiOH^H2O (0.703 g, 16.7 mmol) in MeOH (80 mL) and Water (10 mL) was stirred at 25 °C for 12 h. The mixture was made acidic by addition of 0.5 N HCl to pH~4 and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5- carboxylic acid. Calc’d C12H22N3O4Si [M+H]+, 300; Found 300. Step 3. Preparation of 5-(5-fluoropyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0247] To a solution of 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid (1 g, 3.34 mmol) in DMF (20 mL) was added 2- bromo-5-fluoropyridine (1.176 g, 6.68 mmol), Cs2CO3 (1.632 g, 5.01 mmol), 2,2'-bipyridine (0.117 g, 0.751 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (0.110 g,25866 0.501 mmol) and 4CzIPN (0.132 g, 0.167 mmol) at ambient temperature under nitrogen. The resulting mixture was irradiated with a 450 nM blue LED for 12 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 5-(5- fluoropyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one. Calc’d C16H24FN4O2Si [M+H]+, 351; Found 351. Step 4. Preparation of (5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one) (I-22A)

[0248] To a solution of 5-(5-fluoropyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (300 mg, 0.856 mmol) in DCM (6 mL) was added TFA (2 mL, 0.856 mmol) at ambient temperature. The reaction mixture was held at 25 °C for 1 h then concentrated under reduced pressure. The resulting residue was dissolved in MeOH (6.00 mL) and aqueous ammonia (1 mL, 0.856 mmol) was added to the solution. The resulting solution was stirred for 15 minutes and the mixture was concentrated under reduced pressure. The resulting residue was taken up in water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to afford 5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one. Calc’d C10H10FN4O [M+H]+, 221; Found 221. Intermediate I-23A ethyl 4-(4-2-carboxylate25866 Scheme I-23 Step 1.

[0249] To a solution of ethyl 4-hydroxy-5-methylthiazole-2-carboxylate (1.4 g, 7.48 mmol) in DMA (35 mL) was added Cs2CO3 (4.87 g, 14.96 mmol) and 1,2-difluoro-4-nitrobenzene (1.785 g, 11.2 mmol) at ambient temperature under nitrogen. The reaction was brought to 60 °C for 2 h then the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 90 mL). The combined organic extracts were dried over Na2SO4, washed with brine (50 mL) and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford ethyl 4-(2-fluoro-4-nitrophenoxy)-5-methylthiazole- 2-carboxylate. Calc’d C13H12FN2O5S [M+H]+, 327; Found 327. Step 2. Preparation of ethyl 4-(4-amino-2-fluorophenoxy)-5-methylthiazole-2-carboxylate

[0250] A mixture of methyl ethyl 4-(2-fluoro-4-nitrophenoxy)-5-methylthiazole-2-carboxylate (2 g, 6.13 mmol), ammonium chloride-ammonium hydroxide buffer solution (5.48 mL, 61.3 mmol) and iron (3.42 g, 61.3 mmol) in water (40 mL) and ethanol (40 mL) was stirred at 90 °C for 4 h. The reaction mixture was cooled to ambient temperature and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with water (10 mL), washed with brine (10 mL), dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford ethyl 4-(4-amino-2- fluorophenoxy)-5-methylthiazole-2-carboxylate. Calc’d C13H14FN2O3S [M+H]+, 297; Found 297. Step 3. Preparation of (ethyl 4-(4-bromo-2-fluorophenoxy)-5-methylthiazole-2-carboxylate) (I- 23A)

[0251] To a solution of ethyl 4-(4-amino-2-fluorophenoxy)-5-methylthiazole-2-carboxylate (1 g, 3.37 mmol) in MeCN (15 mL) was added copper(II) bromide (0.678 g, 3.04 mmol) and tert- butyl nitrite (0.522 g, 5.06 mmol) at ambient temperature under nitrogen. The reaction mixture was brought to 30 °C for 1 h. The reaction mixture was extracted with EtOAc (3 x 20 mL). The25866 combined organic extracts were washed with H2O (10 mL), washed with brine (10 mL), dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford ethyl 4-(4-bromo-2-fluorophenoxy)- 5-methylthiazole-2-carboxylate. . Calc’d C13H12BrFNO3S [M+H]+, 360, 362; Found 360, 362. Intermediate I-24A olStep 1. Preparation of ((3-bromocyclobutoxy)methyl)benzene

[0252] To a solution of (1S,3S)-3-(benzyloxy)cyclobutan-1-ol (1 g, 5.61 mmol) in toluene (10 mL) was added CBr4 (2.79 g, 8.42 mmol) and Ph3P (2.207 g, 8.42 mmol) in portions at ambient temperature under nitrogen. The resulting mixture was brought to 80 °C for 4 h. The mixture was cooled to ambient temperature, diluted with water (15 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford ((3-bromocyclobutoxy)methyl)benzene.1H NMR (CDCl3, 400 MHz): δ 7.28-7.39 (m, 5H), 4.47-4.58 (m, 2H), 4.43 (s, 2H), 2.61-2.78 (m, 4H). Step 2. Preparation of 4-((1S,3S)-3-(benzyloxy)cyclobutoxy)pyrrolo[1,2-b]pyridazine

[0253] To a solution of pyrrolo[1,2-b]pyridazin-4-ol (110 mg, 0.820 mmol) in DMF (3 mL) was added ((3-bromocyclobutoxy)methyl)benzene (198 mg, 0.820 mmol) and Cs2CO3(534 mg, 1.640 mmol) at ambient temperature. The resulting mixture was brought to 70 °C for 12 h. The mixture was cooled to ambient temperature, diluted with water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over25866 Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by prep. TLC (hexanes : EtOAc=5:1) to give 4-((1S,3S)-3-(benzyloxy)cyclobutoxy) pyrrolo[1,2- b]pyridazine. Calc’d C18H19N2O2 [M+H]+, 295; Found 295. Step 3. Preparation of ((1S,3S)-3-(pyrrolo[1,2-b]cyclobutan-4-yloxy)cyclobutane-1-ol) (I-24A)

[0254] To a solution of 4-((1S,3S)-3-(benzyloxy)cyclobutoxy)pyrrolo[1,2-b]pyridazine (130 mg, 0.442 mmol) in MeOH (10 mL) was added Pd(OH)2 / C (31.0 mg, 0.044 mmol) and Pd / C (23.50 mg, 0.044 mmol) at ambient temperature. The resulting mixture was brought to 40 °C for 12 h under H2. The reaction solution was filtered and concentrated under reduced pressure to afford crude (1S,3S)-3-(pyrrolo[1,2-b]pyridazin-4-yloxy)cyclobutan-1-ol, which was taken on as is, without further purification. Calc’d C11H13N2O2[M+H]+, 205; Found 205. Intermediate I-25A methyl (5S,7R)-7-((tert- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate Scheme I-251,2-dicarboxylate.25866

[0255] A solution of 1-(tert-butyl) 2-methyl (2S)-4-hydroxypyrrolidine-1,2-dicarboxylate (30 g, 122 mmol), imidazole (16.7 g, 245 mmol) and tert-butylchlorodimethylsilane (27.7 g, 183 mmol) in DCM (400 ml) was stirred at 20 °C for 2 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (330 g Agela Silica Flash Column, Eluent of 5% EtOAc / Pet. ether gradient) to give 1-(tert-butyl) 2-methyl (2S)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (40 g, 89 mmol) as colorless oil. Step 2. Preparation of 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-5- oxopyrrolidine-1,2-dicarboxylate.

[0256] A solution of sodium periodate (29.7 g, 139 mmol) and RuO2-H2O (1.68 g, 11.1 mmol) in water (200 mL) was stirred at 25 °C for 5 min. To the mixture was added 1-(tert-butyl) 2- methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (20.0 g, 55.6 mmol) in EtOAc (100 ml) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was filtered and the filtrate was extracted with EtOAc (2 x 300 mL), the combined organic layers were washed with brine, dried over Na2SO4filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (220 g, SepaFlash Silica Flash Column, eluent of 30% EtOAc / Pet.ether gradient) to afford 1-(tert-butyl) 2-methyl (2S,4R)-4- ((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate (15.0 g, 36.1 mmol) as colorless oil. Step 3. Preparation of methyl (2S,4R)-4-hydroxy-5-oxopyrrolidine-2-carboxylate.

[0257] To a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-5- oxopyrrolidine-1,2-dicarboxylate (20 g, 53.5 mmol) in DCM (160 ml) was added dioxane / HCl (160 ml) and the resulting mixture was stirred at 25 °C for 1 h. The filtrate was concentrated to give methyl (2S,4R)-4-hydroxy-5-oxopyrrolidine-2-carboxylate (crude) as a colorless solid which was used in next step directly. Step 4. Preparation of methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5-oxopyrrolidine-2- carboxylate.

[0258] A solution of methyl (2S,4R)-4-hydroxy-5-oxopyrrolidine-2-carboxylate (8.52 g, 53.5 mmol), imidazole (7.29 g, 107 mmol) and TBDPSCl (19.13 g, 69.6 mmol) in DCM (200 ml) was stirred at 20 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-TLC (Pet. ether / EtOAc 1:1) to give methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5- oxopyrrolidine-2-carboxylate (6 g, 12.1 mmol) as colorless oil. Step 5. Preparation of methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5-methoxy-3,4-dihydro- 2H-pyrrole-2-carboxylate.25866

[0259] A mixture of methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5-oxopyrrolidine-2- carboxylate (12 g, 30.2 mmol) and trimethyloxonium tetrafluoroborate (6.70 g, 45.3 mmol) in DCM (150 ml) was stirred at 25oC for 12 h to give brown mixture. The reaction mixture was quenched with sat. NaHCO3(30 mL) and extracted with DCM (3 x 150 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude methyl (2S,4R)-4-((tert- butyldiphenylsilyl)oxy)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (crude) as yellow oil. The crude was used in the next step without further purification. Step 6. Preparation of methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5-(2- (methoxycarbonyl)hydrazineyl)-3,4-dihydro-2H-pyrrole-2-carboxylate.

[0260] To a solution of methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5-methoxy-3,4- dihydro-2H-pyrrole-2-carboxylate (12.0 g, 29.2 mmol) in MeOH (160 mL) was added methyl hydrazinecarboxylate (3.28 g, 36.4 mmol) and HCl / MeOH (10 ml) at 20 °C and the resultingmixture was stirred at 80 °C for 3 h under N2. The mixture was concentrated in vacuum to giveyellow solid which was purified by flash silica gel chromatography (120 g SepaFlash Silica Flash Column, eluent of 100% ethyl acetate gradient) to give methyl (2S,4R)-4-((tert- butyldiphenylsilyl)oxy)-5-(2-(methoxycarbonyl)hydrazineyl)-3,4-dihydro-2H-pyrrole-2- carboxylate (8 g, 13.63 mmol) as colorless oil. MS (EI) Calculated for C24H32N3O5Si [M+H]+, 470; found, 470. Step 7. Preparation of methyl (5S,7R)-7-((tert-butyldiphenylsilyl)oxy)-3-oxo-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (I-25A).

[0261] To a solution of methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-5-(2- (methoxycarbonyl)hydrazineyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (4.0 g, 8.52 mmol) in DMF (100 mL) was stirred at 145 °C for 12 h. The mixture was concentrated in vacuum to give yellow solid which was purified by flash silica gel chromatography (40 g SepaFlash Silica Flash Column, eluent of 22% ethyl acetate / pet. ether gradient) to give methyl (5S,7R)-7-((tert- butyldiphenylsilyl)oxy)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (2.0 g, 4.11 mmol) as yellow oil. MS (EI) Calculated for C23H28N3O4Si [M+H]+, 438; found, 438. Table A. Intermediate Structure25866 I-2A25866 I-14A25866 I-24Ample 1-1 (S)-5-(3,5-difluorophenyl)-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-onePreparation - - - pyrrolo[2,1- c][1,2,4]triazol-3-one

[0262] To a 250-mL RBF were added (S)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (4.5 g, 19.0 mmol), Cs2CO3(6.24 g, 19.2 mmol), copper(I) iodide (0.723 g, 3.79 mmol) and dioxane (150 mL). To the mixture was added 1-bromo-4- fluorobenzene (6.25 ml, 56.9 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (2.99 mL, 19.0 mmol). The reaction was stirred overnight at 100 °C. The reaction was filtered over a pad of celite and washed with EtOAc. The filtrated was concentrated to dryness and purified by flash column chromatography twice (60g silica gel, 5% EtOAc: Hex and then 35% EtOAc: Hex for desired product) to afford (S)-5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (7.14 g). Calc’d C17H13F3N3O [M+H]+, 332; Found 332.1H NMR (DMSO-d6) δ: 7.90 – 7.84 (m, 2H), 7.29 (t, J = 8.9 Hz, 2H), 7.25 – 7.15 (m, 3H), 5.33 (dd, J = 7.8, 5.4 Hz, 1H), 3.06 – 2.97 (m, 2H), 2.89 (tt, J = 10.6, 5.4 Hz, 1H), 2.40 – 2.32 (m, 1H).25866 General Scheme A

[0263] Themanner of that described for Example 1-1 and depicted in General Scheme A, using appropriate intermediates selected from Table A and commercial aryl or heteroaryl halides. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 1 Compound Exact Mass Structure Name Number [M+H]+ , 8 , 6 , , 6 , 2 , 8 , 625866 (S)-1-(4-(3-oxo-5-phenyl-6,7- dihydro-3H-pyrrolo[2,1- ' 3, 3 , 6 , 2 , 3 , 8 , 8 , 4 , 4 , 8 , 925866 yl)phenyl)cyclopropane-1- carbonitrile , 4 , 9 , 0 , 8 , 7 , 6 , 1 , 525866 (5S)-5-phenyl-2-{4-[(propan-2- Calc'd 336, 1-27 yl)oxy]phenyl}-2,5,6,7-tetrahydro- 6 , 4 , 4 , 8 , 8 , 6 , 7 , 1 0, 025866 (5S)-2-[4- (cyclopropanecarbonyl)phenyl]-5- Calc'd 346, 6 , 4 , 1 , 2 , 0 , 3 , 6 , 4 , 8 , 625866 tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one , 4 , 5 , 4 , 6 , 5 , 4 , 1 , 0 , 6tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one , 0 , 4 , 4 , 2 , 4 , 5 , 5 , 5 , 94-[(5S)-3-oxo-5-phenyl-6,7-dihydro- Calc'd 309, 1-64 3H-pyrrolo[2,1-c][1,2,4]triazol- 9 , 8 , 2 , 3 , 1 , 7 , 5 , 6 , 0 , 025866 5-[(5S)-5-(3,5-difluorophenyl)-3- oxo-6,7-dihydro-3H-pyrrolo[2,1- Calc'd 357, 7 , 3 , 3 , 5 , 4 , 4 , 4 , 1 , 625866 (5S)-2-[4-(difl r m th x ) h n l]-1-89 2-yl)-2,5,6,7-tetrahydro-3H- found 408 pyrrolo[2,1-c][1,2,4]triazol-3-one (S)-2-(3-fluoro-4-(1-methyl-1H- pyrazol-3-yl)phenyl)-5-phenyl- Calc'd 376, 1-90 2,5,6,7-tetrahydro-3H-pyrrolo[2,1- found 376 c][1,2,4]triazol-3-one (S)-2-(3-fluoro-4-(2-methylthiazol-4- yl)phenyl)-5-phenyl-2,5,6,7- Calc'd 393, 1-91 tetrahydro-3H-pyrrolo[2,1- found 393 c][1,2,4]triazol-3-one25866 ethyl (S)-4-(2-fluoro-4-(3-oxo-5- phenyl-6,7-dihydro-3H-pyrrolo[2,1- Calc'd 481, 1 , 3 , 4 , 2 , 2Example 2-1c][1,2,4]triazol-3-one25866

[0264] 4-Iodo-1,2-dimethylbenzene (31.1 mg, 0.134 mmol) was added to a stirred mixture of 5- phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (27 mg, 0.134 mmol), Pd2(dba)3 (12.3 mg, 0.013 mmol), XANTPHOS (9.32 mg, 0.016 mmol), Cs2CO3 (87 mg, 0.268 mmol) in dioxane (1340 µL) at 100 °C overnight. The reaction was cooled to room temperature, filtered with MeOH, and purified by reverse phase chromatography (15-70% MeCN / water with 0.1% NH4OH) to afford (S)-2-(3,4-dimethylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (4.2 mg). Calc’d C19H20N3O [M+H]+, 306; Found 306.1H NMR (500 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.56 (dd, J = 8.2, 2.0 Hz, 1H), 7.43 – 7.29 (m, 5H), 7.17 (d, J = 8.3 Hz, 1H), 5.30 (dd, J = 7.6, 4.7 Hz, 1H), 3.08 – 2.96 (m, 2H), 2.95 – 2.85 (m, 1H), 2.38 – 2.28 (m, 1H), 2.22 (d, J = 13.9 Hz, 6H). Example 3-1one

[0265] To a solution of (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (200 mg, 0.994 mmol) in DMF (9939 µL) was added cesium carbonate (648 mg, 1.99 mmol) tert-butyl 4-bromopiperidine-1-carboxylate (525 mg, 1.99 mmol). The reaction was heated to 80 °C overnight. The reaction was cooled to room temperature, diluted with MeOH, and then purified by reverse phase chromatography (2-95% MeCN / water with 0.1% NH4OH) to give the desired product which was taken on without further purification.

[0266] The product of the first step was taken up in DCM (5 mL) and TFA (2 mL) was added then aged at RT for 2 hours. The reaction was then diluted with DCM and quenched with 2M NaOH and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and dried to give (S)-5-phenyl-2-(piperidin-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (128.6 mg) which was used without further purification. Calc’d C16H20N4O [M+H]+, 285; Found 285.25866 Step 3. (5S)-5-phenyl-2-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0267] A vial containing (S)-5-phenyl-2-(piperidin-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (10 mg, 0.035 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (10.4 mg, 0.042 mmol), and triethylamine (4.3 mg, 0.042 mmol) in DCM (0.5 mL) was stirred at RT until complete. The reaction was then concentrated and purified via reverse phase chromatography (15-70% MeCN / water with 0.1% TFA) to afford (5S)-5-phenyl-2-(1-{[4- (trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (11.1 mg). Calc’d C23H23F3N4O3S [M+H]+, 493; Found 493.1H NMR (500 MHz, DMSO-d6) δ: 8.04 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 7.4 Hz, 2H), 5.18 (dd, J = 8.1, 4.4 Hz, 1H), 3.94 (s, 1H), 3.74 (d, J = 8.6 Hz, 2H), 2.93 (dt, J = 12.7, 7.9 Hz, 1H), 2.85 (dt, J = 16.0, 7.9 Hz, 1H), 2.80 – 2.70 (m, 1H), 2.57 (m, 2H), 2.24 (ddt, J = 12.9, 8.7, 4.7 Hz, 1H), 1.90 – 1.77 (m, 4H). General Scheme B

[0268] The following examples in Table 2 were prepared according to the route depicted in General Scheme B and in an analogous manner of that described for Example 3-1, using appropriate intermediates selected from Table A and commercial or known reagents and intermediates. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 2 Compound Exact Mass Structure Name , 725866 (5S)-2-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- Calc'd 459, 9 , 7 , 5 , 3a pe - (R)-5-(3,5-difluorophenyl)-2-[2,3-c][1,2,4]triazol-3(2H)-one) Step 1.3,5-dione25866

[0269] To a solution of 5-hydroxy-2-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (370 mg, 2.09 mmol), K2CO3(577 mg, 4.18 mmol) in DMF (6 mL) was added SEMCl (0.389 mL, 2.19 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction was transferred to a separatory funnel, water (15 mL) and EtOAc (10 mL) were added. The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give yellow oil which was purified by flash silica gel chromatography (eluent of 35% ethyl acetate / petroleum ether gradient) to give 1-phenyl-2-((2- (trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5-dione (220 mg). Calc’d C14H22N3O3Si [M+H]+, 250; Found 250. Step 2. Preparation of 4-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-1-phenyl- 2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5-dione

[0270] To a solution of 1-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5- dione (220 mg, 0.716 mmol), K2CO3 (247 mg, 1.79 mmol) in acetone (4 mL) was added I-18A (277 mg, 0.787 mmol) at 20 °C. The mixture heated to 80 °C and stirred for 12 h. The reaction was allowed to cool to ambient temperature and concentrated. The resulting residue was purified by flash silica gel chromatography (eluent of 10% ethyl acetate / petroleum ether gradient) to give 4-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-1-phenyl-2-((2- (trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5-dione (230 mg). Calc’d C28H42F2N3O4Si2 [M+H]+, 578; Found 578. Step 3. Preparation of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-1-phenyl-2-((2- (trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5-dione

[0271] To a solution of 4-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-1- phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5-dione (220 mg, 0.381 mmol) in THF (3 mL) was added TBAF (1.52 mL, 1.52 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was added water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL). The combined organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give 4-(1-(3,5- difluorophenyl)-2-hydroxyethyl)-1-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,4- triazolidine-3,5-dione (220 mg) which was used directly. Calc’d C22H28F2N3O4Si [M+H]+, 464; Found 464. Step 4. Preparation of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-1-phenyl-1,2,4-triazolidine-3,5- dione

[0272] To a solution of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-1-phenyl-2-((2- (trimethylsilyl)ethoxy)methyl)-1,2,4-triazolidine-3,5-dione (220 mg, 0.380 mmol) in DCM (625866 mL) was added TFA (2 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. Then the mixture was concentrated to give yellow oil. The oil was dissolved in MeOH (6mL), NH3^H2O (2 mL) was added at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction was concentrated and the residue was purified by flash column chromatography (50% petroleum ether / EtOAc) to give 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-1-phenyl-1,2,4-triazolidine-3,5-dione (90 mg). Calc’d C16H14F2N3O3[M+H]+, 334; Found 334. Steps 5 and 6. Preparation and isolation of (R)- 5-(3,5-difluorophenyl)-2-phenyl-5,6- dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one

[0273] To a solution of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-5-hydroxy-2-phenyl-2,4- dihydro-3H-1,2,4-triazol-3-one (80 mg, 0.240 mmol), triphenylphosphine (94 mg, 0.360 mmol) in DCM (4.5 mL) was added DIAD (0.070 mL, 0.360 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h under N2. The mixture was concentrated to give a residue which was purified by prep-HPLC (Method Column Boston Green ODS, Condition water (0.1%TFA)-ACN) to give (±)-5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one (14 mg). The enantiomers were separated by SFC (Method Column DAICEL CHIRALPAK AD, Condition 0.1%NH3H2O / ETOH) to give (S)-5-(3,5-difluorophenyl)-2-phenyl-5,6- dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one (7.41 mg) (SFC-P1) and 4-1, (R)-5-(3,5- difluorophenyl)-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one (6.73 mg) (SFC- P2). (S)-5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one:1H NMR (400 MHz, CD3OD) δ 7.79 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.16-7.24 (m, 1H), 7.09-7.15 (m, 2H), 7.03 (tt, J = 2.4, 9.2 Hz, 1H), 5.65 (dd, J = 6.0, 8.0 Hz, 1H), 5.45 (t, J = 8.8 Hz, 1H), 4.90 (dd, J = 6.0, 8.8 Hz, 1H). (R)-5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one (4-1):1H NMR (400 MHz, CD3OD) δ 7.73-7.86 (m, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.15-7.24 (m, 1H), 7.09-7.15 (m, 2H), 7.03 (tt, J = 2.4, 9.2 Hz, 1H), 5.65 (dd, J = 6.0, 8.0 Hz, 1H), 5.45 (t, J = 8.8 Hz, 1H), 4.89 (dd, J = 6.0, 8.8 Hz, 1H). Example 5-1 (R)-5-(3,5-difluorophenyl)-2-[2,3-c][1,2,4]triazol-3(2H)-one)25866 OF F F F2) N F F HN N O Step(0.512 mL, 9.61 mmol) in HOAc (60 mL) was added NBS (3.42 g, 19.2 mmol) in three portions at 1 h intervals while maintaining the internal temperature at 10 °C. The mixture was stirred at 10 °C for 1 h. Then the mixture was warmed to 25 °C and stirred at 25 °C for 16 h. To the reaction mixture was added water (60 mL) and toluene (100 mL). The content was transferred to a separatory funnel and the layers were separated. The organic layer was washed with additional water (1 x 80 mL), saturated NaHCO3(2 x 80 mL) and water (1 x 80 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to give 2-bromo-1-(3,5- difluorophenyl)ethan-1-one (4.28 g) which was used directly without further purification.1H NMR (400 MHz, CDCl3) δ 7.46-7.55 (m, 2H), 7.08 (tt, J = 2.4, 8.4 Hz, 1H), 4.39 (s, 2H). Step 2. Preparation of 5-((2-(3,5-difluorophenyl)-2-oxoethyl)thio)-2-phenyl-2,4-dihydro-3H- 1,2,4-triazol-3-one

[0275] To a stirred solution of 5-mercapto-2-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 1.55 mmol) in EtOH (8 mL) was added 2-bromo-1-(3,5-difluorophenyl)ethan-1-one (405 mg, 1.553 mmol) at 20 °C. The mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, concentrated, then purified by flash column chromatography (20% EtOAc / petroleum) to give 5-((2-(3,5-difluorophenyl)-2-oxoethyl)thio)-2-phenyl-2,4-dihydro-3H- 1,2,4-triazol-3-one (360 mg). Calc’d C16H12F2N3O2S [M+H]+, 348; Found 348. Step 3. Preparation of 5-((2-(3,5-difluorophenyl)-2-hydroxyethyl)thio)-2-phenyl-2,4-dihydro-3H- 1,2,4-triazol-3-one

[0276] To a stirred solution of 5-((2-(3,5-difluorophenyl)-2-oxoethyl)thio)-2-phenyl-2,4- dihydro-3H-1,2,4-triazol-3-one (360 mg, 1.04 mmol) in MeOH (6 mL) was added NaBH4(118 mg, 3.11 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h then concentrated. The residue was redissolved in EtOAc (15 mL) and added water (15 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and then washed with brine (20 mL). The combined organic layers were25866 dried over Na2SO4, filtered and concentrated to give 5-((2-(3,5-difluorophenyl)-2- hydroxyethyl)thio)-2-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg) which was used directly. Calc’d C16H14F2N3O2S [M+H]+, 350; Found 350. Step 4. Preparation of 5-((2-bromo-2-(3,5-difluorophenyl)ethyl)thio)-2-phenyl-2,4-dihydro-3H- 1,2,4-triazol-3-one

[0277] To a stirred solution of 5-((2-(3,5-difluorophenyl)-2-hydroxyethyl)thio)-2-phenyl-2,4- dihydro-3H-1,2,4-triazol-3-one (140 mg, 0.401 mmol) in DCM (3 mL) was added PPh3 (158 mg, 0.601 mmol) and CBr4(199 mg, 0.601 mmol). The mixture was stirred at 20 °C for 16 h under N2. The mixture was concentrated to give yellow oil which was purified by flash column chromatography (1:1 petroleum ether / EtOAc) to give 5-((2-bromo-2-(3,5- difluorophenyl)ethyl)thio)-2-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (110 mg). Calc’d C16H13BrF2N3OS [M+H]+, 412, 414; Found 412, 414. Steps 5 and 6. Preparation and isolation of 5-1 (R)- 5-(3,5-difluorophenyl)-2-phenyl-5,6- dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one)

[0278] To a solution of 5-((2-bromo-2-(3,5-difluorophenyl)ethyl)thio)-2-phenyl-2,4-dihydro- 3H-1,2,4-triazol-3-one (200 mg, 0.485 mmol) in acetone (5 mL) was added K2CO3 (168 mg, 1.21 mmol). The mixture was heated to 80 °C and stirred for 2 h. The reaction was cooled to room temperature, concentrated, and the residue was purified by flash column chromatography (18% ethyl acetate / petroleum ether) to give 5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrothiazolo[2,3- c][1,2,4]triazol-3(2H)-one (130 mg). The enantiomers were separated by SFC (Method Column Phenomenex-Cellulose-2, Condition 0.1%NH3H2O / MEOH) to give (S)-5-(3,5-difluorophenyl)-2- phenyl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one (52.2 mg) (SFC-P1) and 5-1, (R)-5- (3,5-difluorophenyl)-2-phenyl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one (53 mg) (SFC- P2). (S)-5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one:1H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 8.8 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.17-7.26 (m, 1H), 6.94-7.11 (m, 3H), 5.60 (dd, J = 4.4, 7.6 Hz, 1H), 4.37-4.47 (m, 1H), 3.73-3.81 (m, 1H). (R)-5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one (5-1):1H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 8.8 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.18-7.27 (m, 1H), 6.95-7.11 (m, 3H), 5.60 (dd, J = 4.4, 7.6 Hz, 1H), 4.43 (dd, J = 7.6, 11.6 Hz, 1H), 3.78 (dd, J = 4.4, 11.6 Hz, 1H).25866 Example 6-1 ((5S,7R)-2-(4-fluorophenyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-

[0279] A 901 (30 mg) in0.1 M potassium phosphate buffer (14.4 mL, pH ~8.0) was prepared, 290 uL of this stock was added to each well of a 24-well plate. MCYP0141 (116 mg) was weighed out and dissolved in 0.1 M potassium phosphate buffer (7.2 mL, pH ~8.0), 300 uL of this enzyme stock solution was pipetted into each well. Finally, compound 1-24 (55 mg, 0.186 mmol) in DMSO (300 µL) was prepared. To each well was added 12 uL of the DMSO stock solution. The plate was incubated at 28 °C, shaking at ~700 rpm (high shake rate is necessary to achieve aeration of the reaction) for 16 hours. To analyze the reactions, each well was quenched with an equal volume of MeCN and allowed to sit with occasional agitation to ppt the protein. Each well was analyzed using LC / MS filter vials (taking 100 microliters of solution from each well). The reactions were combined into a separatory funnel and extracted with 1:3 IPA / EtOAc (5x). Washed with brine and dried over sodium sulfate. The organic layer was concentrated and purified by flash column chromatography (5% EtOAc: Hex then 30% EtOAc Hex) to give exclusively compound (5S,7R)- 2-(4-fluorophenyl)-7-hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 6-1 (14.6 mg) as a single diastereomer.1H NMR (499 MHz, DMSO-d6) δ 7.87 (dd, J = 9.0, 4.9 Hz, 2H), 7.43 – 7.36 (m, 2H), 7.35 – 7.25 (m, 5H), 6.17 (d, J = 5.9 Hz, 1H), 5.47 – 5.36 (m, 1H), 5.19 (q, J = 6.0 Hz, 1H), 2.84 – 2.72 (m, 1H), 2.68 – 2.57 (m, 1H).25866 Example 6-2 ((5S,7S)-2-(4-fluorophenyl)- tetrahydro-3H-pyrrolo[2,1-

[0280] To atetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (15.0 mg, 0.048 mmol) and 4-(diphenylphosphino)benzoic acid (25.1 mg, 0.082 mmol) in THF (482 µL) was added DMEAD (16.9 mg, 0.072 mmol) in THF (482 µL). After 15 min, 0.5 mL of 2 M NaOH was added and stirred at rt for 1 hour. The reaction was quenched with H2O and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. Purified by flash column chromatography (0-5% EtOAc: Hex then 40% EtOAc: Hex for desired product). The diastereomers were separated by SFC (Method IB-N, Condition 25% MeOH with 0.1% NH4OH). The first eluting diastereomer was recovered (5S,7R)-2-(4-fluorophenyl)-7-hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one, 6-1, and the second diastereomer was (5S,7S)-2-(4- fluorophenyl)-7-hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 6-2 (20.3 mg).1H NMR (500 MHz, DMSO-d6) δ 7.86 (dd, J = 8.9, 4.9 Hz, 2H), 7.46 – 7.22 (m, 7H), 6.21 (d, J = 5.4 Hz, 1H), 5.20 (dd, J = 8.0, 5.3 Hz, 1H), 5.13 – 5.03 (m, 1H), 3.30 – 3.25 (m, 1H), 2.17 (dt, J = 13.6, 4.8 Hz, 1H). General Scheme Cthe route depicted in General Scheme C and in an analogous manner of that described for Example 6-1 and 6-2, using appropriate starting material and commercial or known reagents and intermediates. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed.25866 Table 3. Compound Exact Mass Structure Name Number [M+H]+ 8, 8 8, 8((5S,7R)-2-(4-fluorophenyl)-7- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Step 1. Preparation[2,1- c][1,2,4]triazole-3,7(2H)-dione

[0282] To the stirred solution of (5S,7R)-2-(4-fluorophenyl)-7-hydroxy-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 6-1 (24.3 mg, 0.078 mmol) in CH2Cl2 (781 µL) was added Dess-Martin periodinane (66.2 mg, 0.156 mmol) in one portion at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. The reaction was concentrated to dryness and purified by flash column chromatography (5~100% EtOAc in hexanes) to yield (S)- 2-(4-fluorophenyl)-5-phenyl-5,6-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3,7(2H)-dione (23 mg).1H NMR (500 MHz, CDCl3) δ 8.05 – 7.93 (m, 2H), 7.42 (dt, J = 15.1, 7.0 Hz, 3H), 7.29 (d,25866 J = 7.1 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 5.59 (dd, J = 8.2, 3.2 Hz, 1H), 3.69 (dd, J = 19.5, 8.2 Hz, 1H), 3.14 (dd, J = 19.5, 3.3 Hz, 1H). Step 2. Preparation of compound 7-1 ((5S,7R)-2-(4-fluorophenyl)-7-hydroxy-7-methyl-5-phenyl- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one)

[0283] To a 25 mL RBF containing (S)-2-(4-fluorophenyl)-5-phenyl-5,6-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazole-3,7(2H)-dione (18 mg, 0.058 mmol) was added lanthanum trichloride lithium chloride complex (485 µL, 0.291 mmol) dropwise at room temperature. The reaction mixture was immediately cooled to -20 °C and stirred for 15 min at the same temp, followed by dropwise addition of methylmagnesium chloride (97 µL, 0.291 mmol) at -20 °C. The reaction mixture was stirred for 30 min at -20 °C and then allowed to warm to rt and stirred overnight, before being quenched with cold (0 ~ 5 °C) saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (5~100% EtOAc in hexanes) to yield 7-1, (5S,7R)-2-(4-fluorophenyl)-7-hydroxy-7-methyl-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (2.8 mg) with >95:5 d.r. by 1H NMR.1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J = 9.1, 4.9 Hz, 2H), 7.48 – 7.22 (m, 7H), 6.11 (s, 1H), 5.39 (t, J = 7.2 Hz, 1H), 2.91 (dd, J = 13.5, 7.1 Hz, 1H), 2.38 (dd, J = 13.4, 7.3 Hz, 1H), 1.58 (s, 3H). Example 8-1 (5S,7S or 7R)-2-(4-fluorophenyl)-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one25866 Step

[0284] To a solution of 5-fluoronicotinaldehyde (5.00 g, 40.0 mmol) in ethanol (70.0 mL) was added hydroxylamine hydrochloride (3.33 g, 48.0 mmol), Na2CO3(10.6 g, 100 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give (E)-5-fluoronicotinaldehyde oxime (5.6 g), which was used in next step without further purification. Calc’d C6H6FN2O [M+H]+, 141; Found 141.1H NMR (500 MHz, CD3OD) δ 8.57 (t, J = 1.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 7.81-7.88 (m, 1H). Step 2. Preparation of methyl 3-(5-fluoropyridin-3-yl)-4,5-dihydroisoxazole-5-carboxylate

[0285] To a solution of (E)-5-fluoronicotinaldehyde oxime (5.60 g, 40.0 mmol), methyl acrylate (3.62 mL, 40.0 mmol) in THF (170 mL) was added sodium hypochlorite (60 mL, 40.0 mmol) at 0 ºC and the resulting mixture was stirred at 25 °C for 12 h. The mixture was added to water (300 mL) and extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (35% EtOAc / petroleum ether gradient) to give methyl 3-(5-fluoropyridin-3-yl)-4,5-dihydroisoxazole-5-carboxylate (4.5 g).1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.55 (d, J = 2.8 Hz, 1H), 7.76-7.87 (m, 1H), 5.27 (dd, J = 7.2, 11.2 Hz, 1H), 3.85 (s, 3H), 3.59-3.76 (m, 2H). Step 3. Preparation of 5-(5-fluoropyridin-3-yl)-3-hydroxypyrrolidin-2-one

[0286] A mixture of methyl 3-(5-fluoropyridin-3-yl)-4,5-dihydroisoxazole-5-carboxylate (4.5 g, 20.1 mmol) and Pd-C (10% in activated carbon) (1.00 g, 0.940 mmol) in EtOH (150 mL) was stirred at 50 °C with H2 gas atmosphere (50 psi) for 12 h. The mixture was filtered and the filtrate25866 was concentrated in vacuo to afford crude 5-(5-fluoropyridin-3-yl)-3-hydroxypyrrolidin-2-one (4.00 g), which was used directly in next step without further purification. Calc’d C9H10FN2O2[M+H]+, 197; Found 197. Step 4. Preparation of 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (Peak 1) and 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (Peak 2)

[0287] To a solution of 5-(5-fluoropyridin-3-yl)-3-hydroxypyrrolidin-2-one (4.00 g, 20.4 mmol) in DCM (100 mL) was added imidazole (2.78 g, 40.8 mmol) and TBSCl (4.61 g, 30.6 mmol). The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography (40 ~ 90% EtOAc / petroleum ether) to give 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3- yl)pyrrolidin-2-one (Peak 1, 1.2 g) and 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3- yl)pyrrolidin-2-one (Peak 2, 840 mg). 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (Peak 1):1H NMR (500 MHz, CDCl3) δ 8.35-8.52 (m, 2H), 7.37 (td, J = 2.0, 9.0 Hz, 1H), 6.40 (br s, 1H), 4.94 (dd, J = 5.5, 7.5 Hz, 1H), 4.37 (dd, J = 4.5, 7.0 Hz, 1H), 2.53 (ddd, J = 4.5, 7.5, 13.0 Hz, 1H), 2.20 (ddd, J = 5.0, 7.0, 13.5 Hz, 1H), 0.92 (s, 9H), 0.16 (d, J = 4.5 Hz, 6H). 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (Peak 2):1H NMR (500 MHz, CDCl3) δ 8.37-8.50 (m, 2H), 7.57 (td, J = 2.0, 9.0 Hz, 1H), 6.39 (br s, 1H), 4.70 (t, J = 7.0 Hz, 1H), 4.39 (t, J = 7.5 Hz, 1H), 2.86 (td, J = 7.5, 13.0 Hz, 1H), 1.93 (td, J = 7.5, 13.0 Hz, 1H), 0.90 (s, 9H), 0.12-0.21 (m, 6H). Step 5. Preparation of 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidine-2- thione (Isomer 1) and 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidine-2- thione (Isomer 2)

[0288] To a solution of 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidin-2- one (Peak 1, 1.2 g, 3.87 mmol) in toluene (15 mL) was added Lawesson’s reagent (0.782 g, 1.93 mmol). The resulting mixture was stirred at 110 °C for 3 h. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by flash column chromatography (25% EtOAc / petroleum ether) to give 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3- yl)pyrrolidine-2-thione (Isomer 1, 840 mg).1H NMR (500 MHz, CDCl3) δ 8.35-8.54 (m, 2H), 7.31-7.39 (m, 1H), 5.15 (br t, J = 6.0 Hz, 1H), 4.65 (dd, J = 4.0, 6.5 Hz, 1H), 2.54-2.64 (m, 1H), 2.30 (td, J = 6.0, 13.0 Hz, 1H), 0.93 (s, 9H), 0.21 (d, J = 4.5 Hz, 6H).

[0289] To a solution of 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidin-2- one (Peak 2, 840 mg, 2.71 mmol) in toluene (15 mL) was added Lawesson’s reagent (547 mg, 1.35 mmol) and the resulting mixture was stirred at 110 °C for 3 h. The reaction solution was25866 cooled to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (25% EtOAc / petroleum ether) to give 3-((tert-butyldimethylsilyl)oxy)-5-(5- fluoropyridin-3-yl)pyrrolidine-2-thione (Isomer 2, 540 mg).1H NMR (500 MHz, CDCl3) δ 8.33- 8.53 (m, 2H), 7.51-7.61 (m, 1H), 4.91 (br s, 1H), 4.62 (t, J = 6.5 Hz, 1H), 2.96 (td, J = 7.0, 13.5 Hz, 1H), 2.05 (quin, J = 6.5 Hz, 1H), 0.91 (s, 9H), 0.18-0.27 (m, 6H) Step 6. Preparation of 3-(4-((tert-butyldimethylsilyl)oxy)-5-(methylthio)-3,4-dihydro-2H-pyrrol- 2-yl)-5-fluoropyridine (Isomer 1a) and 3-(4-((tert-butyldimethylsilyl)oxy)-5-(methylthio)-3,4- dihydro-2H-pyrrol-2-yl)-5-fluoropyridine (Isomer 2a)

[0290] To a solution of 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidine-2- thione (Isomer 1, 830 mg, 2.54 mmol) in THF (20 mL) was added iodomethane (0.636 mL, 10.2 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo to afford crude 3-(4-((tert-butyldimethylsilyl)oxy)-5-(methylthio)-3,4-dihydro-2H-pyrrol- 2-yl)-5-fluoropyridine (Isomer 1a, 860 mg), which was used directly in next step without further purification. Calc’d C16H26FN2OSSi [M+H]+, 341; Found 341.

[0291] To a solution of 3-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)pyrrolidine-2- thione (Isomer 2, 54 mg, 1.65 mmol) in THF (15 mL) was added iodomethane (0.414 mL, 6.62 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo to afford crude 3-(4-((tert-butyldimethylsilyl)oxy)-5-(methylthio)-3,4-dihydro-2H-pyrrol- 2-yl)-5-fluoropyridine (Isomer 2a, 560 mg), which was used directly in next step without further purification. Calc’d C16H26FN2OSSi [M+H]+, 341; Found 341. Step 7. Preparation of methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-3-yl)-3,4- dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (Isomer 1b) and methyl 2-(4-((tert- butyldimethylsilyl)oxy)-2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1- carboxylate (Isomer 2b)

[0292] To a solution of 3-(4-((tert-butyldimethylsilyl)oxy)-5-(methylthio)-3,4-dihydro-2H- pyrrol-2-yl)-5-fluoropyridine (Isomer 1a, 860 mg, 2.53 mmol) in MeOH (25 mL) was added methyl hydrazinecarboxylate (296 mg, 3.28 mmol) and the reaction was stirred at 80 °C for 3 h. The mixture was concentrated and the residue was repurified by Prep-HPLC (NH4HCO3 modifier in MeCN) to give methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-3-yl)-3,4- dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (Isomer 1b, 240 mg). Calc’d C17H28FN4O3Si [M+H]+, 383; Found 383.

[0293] To a solution of 3-(4-((tert-butyldimethylsilyl)oxy)-5-(methylthio)-3,4-dihydro-2H- pyrrol-2-yl)-5-fluoropyridine (Isomer 2a, 560 mg, 1.644 mmol) in MeOH (20 mL) was added methyl hydrazinecarboxylate (193 mg, 2.14 mmol) and the reaction was stirred at 80 °C for 3 h.25866 The mixture was concentrated and the residue was repurified by Prep-HPLC (NH4HCO3 modifier in MeCN) to give methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-3-yl)-3,4- dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (Isomer 2b, 180 mg). Calc’d C17H28FN4O3Si [M+H]+, 383; Found 383. Step 8. Preparation of 7-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1c) and 7-((tert- butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (Isomer 2c)

[0294] A mixture of methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-3-yl)-3,4- dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (Isomer 1b, 240 mg, 0.627 mmol) in DMF (100 mL) was stirred at 145 °C for 12 h. The reaction mixture was concentrated and the residue was purified by Prep-HPLC (NH4HCO3modifier in MeCN) to give 7-((tert-butyldimethylsilyl)oxy)- 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1c, 100 mg).1H NMR (400 MHz, CD3OD) δ 8.40-8.50 (m, 2H), 7.65 (td, J = 2.4, 9.2 Hz, 1H), 5.48 (t, J = 7.2 Hz, 1H), 5.25 (dd, J = 2.8, 6.4 Hz, 1H), 2.87-3.00 (m, 1H), 2.76 (td, J = 6.8, 13.6 Hz, 1H), 0.94 (s, 9H), 0.20 (d, J = 12.4 Hz, 6H).

[0295] A mixture of methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-3-yl)-3,4- dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (Isomer 2b, 180 mg, 0.471 mmol) in DMF (50 mL) was stirred at 145 °C for 12 h. The reaction mixture was concentrated and the residue was purified by Prep-HPLC (NH4HCO3 modifier in MeCN) to give 7-((tert-butyldimethylsilyl)oxy)- 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 2c, 90 mg).1H NMR (500 MHz, CD3OD) δ 8.40-8.53 (m, 2H), 7.68-7.73 (m, 1H), 5.35 (dd, J = 2.0, 8.5 Hz, 1H), 5.13 (dd, J = 1.5, 6.5 Hz, 1H), 3.34-3.40 (m, 1H), 2.41 (td, J = 2.0, 14.0 Hz, 1H), 0.85- 0.86 (m, 9H), 0.17 (d, J = 7.48 Hz, 6H). Step 9. Preparation of 7-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-5-(5-fluoropyridin-3- yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1d) and 7-((tert- butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 2d)

[0296] To a solution of 7-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1c, 100 mg, 0.285 mmol) in dioxane (5 mL) was added 1-bromo-4-fluorobenzene (59.9 mg, 0.342 mmol), DMEDA (25.2 mg, 0.285 mmol), Cs2CO3 (279 mg, 0.856 mmol), CuI (43.5 mg, 0.228 mmol) under N2 and the resulting mixture was stirred at 100 °C for 12 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography25866 (15% EtOAc / petroleum ether) to give 7-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-5-(5- fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1d, 120 mg). Calc’d C22H27F2N4O2Si [M+H]+, 445; Found 445.

[0297] To a solution of 7-((tert-butyldimethylsilyl)oxy)-5-(5-fluoropyridin-3-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 2c, 90 mg, 0.257 mmol) in dioxane (5 mL) was added 1-bromo-4-fluorobenzene (53.9 mg, 0.308 mmol), DMEDA (22.6 mg, 0.257 mmol), Cs2CO3 (251 mg, 0.770 mmol), CuI (39.1 mg, 0.205 mmol) under N2 and the resulting mixture was stirred at 100 °C for 12 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether) to give 7-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-5-(5- fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 2d, 100 mg). Calc’d C22H27F2N4O2Si [M+H]+, 445; Found 445. Step 10. Preparation of 2-(4-fluorophenyl)-5-(5-fluoropyridin-3-yl)-7-hydroxy-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1e) and 2-(4-fluorophenyl)-5-(5- fluoropyridin-3-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 2e)

[0298] To a solution of 7-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-5-(5-fluoropyridin- 3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1d, 120 mg, 0.270 mmol) in THF (3 mL) was added TBAF (0.540 mL, 0.540 mmol, 1 M in THF) and the resulting mixture was stirred at 25 °C for 12 h. The mixture was added to water (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether) to give 2- (4-fluorophenyl)-5-(5-fluoropyridin-3-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (Isomer 1e, 80 mg). Calc’d C16H13F2N4O2 [M+H]+, 331; Found 331.

[0299] To a solution of 7-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-5-(5-fluoropyridin- 3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 2d, 100 mg, 0.225 mmol) in THF (3 mL) was added TBAF (0.450 mL, 0.450 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The mixture was added to water (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether) to give 2-(4- fluorophenyl)-5-(5-fluoropyridin-3-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (Isomer 2e, 70 mg). Calc’d C16H13F2N4O2 [M+H]+, 331; Found 331. Step 11. Resolution by SFC to obtain compound 8-1 ((5S,7S or 7R)-2-(4-fluorophenyl)-5-(5- fluoropyridin-3-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one)25866

[0300] The two isomers were combined (30 mg, 0.091 mmol) and resolved under chiral SFC (Method DAICEL CHIRALPAK IG, Condition 0.1%NH3H2O / EtOH modifier in CO2) to give 8- 1 as the fourth eluting isomer.

[0301] 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.79-7.92 (m, 3H), 7.17 (t, J = 8.8 Hz, 2H), 5.38 (dd, J = 4.4, 8.4 Hz, 1H), 5.17 (dd, J = 3.6, 7.2 Hz, 1H), 3.36- 3.49 (m, 1H), 2.41 (td, J = 4.0, 14.0 Hz, 1H). Example 9-1 and 9-2 (5S,7S or 7R)-7-fluoro- tetrahydro-3H-pyrrolo[2,1-one

[0302] To atetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (25 mg, 0.080 mmol) in DCM (1.61 mL) at 25 °C was added DAST (21.1 µL, 0.161 mmol). After 60 min, the reaction was diluted with DCM and quenched with saturated sodium bicarbonate and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (5% EtOAc: Hexanes, then 25% EtOAc: Hexanes for peak 1 and lastly 45% EtOAc: Hexanes for peak 2). The desired fractions were concentrated and lyophilized to give the desired products. Peak 1 (5S,7S)-7-fluoro-2-(4-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one (9-1): 1H NMR (500 MHz, CDCl3) δ 7.92 (dd, J = 9.0, 4.8 Hz, 2H), 7.45 – 7.34 (m, 3H), 7.28 (d, J = 7.2 Hz, 2H), 7.09 (t, J = 8.7 Hz, 2H), 5.91 (dd, J = 55.3, 6.0 Hz, 1H), 5.45 (t, J = 6.9 Hz, 1H), 3.33 – 3.10 (m, 1H), 2.86 – 2.71 (m, 1H). Peak 2 (5S,7R)-7-fluoro-2-(4-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one (9-2):258661H NMR (500 MHz, CDCl3) δ 7.91 (dd, J = 9.1, 4.8 Hz, 2H), 7.46 – 7.28 (m, 5H), 7.10 (t, J = 8.7 Hz, 2H), 5.83 (dd, J = 55.5, 6.5 Hz, 1H), 5.33 (d, J = 8.7 Hz, 1H), 3.51 – 3.24 (m, 1H), 2.83 (dd, J = 23.3, 15.6 Hz, 1H). General Scheme D

[0303] Theroute depicted in General Scheme D and in an analogous manner of that described for Example 9-1 and 9-2, using appropriate starting material and commercial or known reagents. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 4. Compound Exact Mass Structure Name N b M+H + 0, 0 0, 0 3, 0Example 10-1 and 10-2 5-(3,5-difluorophenyl)-2-(4-- [3,4]pyrrolo [2,1- c][1,2,4]triazol-3(2H)-one (Isomer 1 and Isomer 2)25866 Step 1.

[0304] a g, mL) was added i-PrMgBr^LiCl (17.3 mL, 22.5 mmol) at 0 °C. The reaction was then heated to 50 °C for 1 h. The reaction was then cooled to -78 °C where 3-azabicyclo[3.1.0]hexane-2,4-dione (1 g, 9.00 mmol) in DCM (5 mL) was added. The mixture was allowed to warm to 25 °C and stirred for 16 h. The mixture was then treated with NaBH3CN (0.679 g, 10.8 mmol) at 25 °C. After stirring for 1 hour at 25 °C the reaction was acidified to pH= 3-4 with HCl (6 M), and then was stirred for 30 mins before being neutralized with aq. NaOH (3 M). The mixture was diluted with water (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuum to give crude product which was purified by flash column chromatography (0~100% EtOAc: Hexanes) to give 4-(3,5-difluorophenyl)-3-azabicyclo [3.1.0]hexan-2-one (600 mg). Calc’d C11H10F2NO [M+H]+, 210; Found 210. Steps 2 and 3. Preparation of methyl 2-(4-(3, 5-difluorophenyl)-3-azabicyclo [3.1.0] hex-2-en-2- yl) hydrazine-1-carboxylate

[0305] A mixture of 4-(3, 5-difluorophenyl)-3-azabicyclo [3.1.0] hexan-2-one (300 mg, 1.43 mmol) and trimethyloxonium tetrafluoroborate (300 mg, 2.03 mmol) in DCM (6 mL) was stirred at 30 °C for 16 h. The reaction mixture was quenched with saturated NaHCO3 (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude 4-(3,5-difluorophenyl)-2-methoxy-3-azabicyclo[3.1.0]hex-2-ene (300 mg). The crude was used in the next step without further purification.

[0306] A mixture of 4-(3,5-difluorophenyl)-2-methoxy-3-azabicyclo[3.1.0]hex-2-ene (crude, 300 mg, 1.34 mmol) and methyl hydrazinecarboxylate (157 mg, 1.75 mmol) in MeOH (10 mL) and HCl in MeOH (0.2 mL, 4 M) was stirred at 80 °C for 16 h. The reaction was cooled to room temperature, the solvent was evaporated, and the residue was purified by flash column25866 chromatography (0-8% MeOH / DCM) to give methyl 2-(4-(3,5-difluorophenyl)-3-azabicyclo [3.1.0] hex-2-en-2-yl) hydrazine-1-carboxylate (180 mg). Calc’d C13H14F2N3O2[M+H]+, 282; Found 282. Step 4. Preparation of 5-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[2,1- c][1,2,4]triazol-3(2H)-one

[0307] A mixture of methyl 2-(4-(3, 5-difluorophenyl)-3-azabicyclo [3.1.0] hex-2-en-2-yl) hydrazine-1-carboxylate (180 mg, 0.640 mmol) in DMF (10 mL) was stirred at 145 °C for 16 h under nitrogen. The mixture was cooled to room temperature, concentrated, and purified by prep- HPLC (TFA modified ACN / water) to give 5-(3,5-difluorophenyl)-5,5a,6,6a- tetrahydrocyclopropa[3,4]pyrrolo[2,1-c][1,2,4]triazol-3(2H)-one (90 mg). Calc’d C12H10F2N3O [M+H]+, 250; Found 250. Steps 5 and 6. Preparation of 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-5,5a,6,6a- tetrahydrocyclopropa[3,4]pyrrolo[2,1-c][1,2,4]triazol-3(2H)-one followed by SFC purification to obtain compounds 10-1 and 10-2

[0308] To a mixture of 5-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[2,1- c][1,2,4] triazol-3(2H)-one (80 mg, 0.321 mmol), 1-bromo-4-fluorobenzene (67.4 mg, 0.385 mmol), DMEDA (28.3 mg, 0.321 mmol) and Cs2CO3 (314 mg, 0.963 mmol) in dioxane (3 mL) was added CuI (48.9 mg, 0.257 mmol) at 20 °C. The mixture was stirred at 130 °C for 30 h under nitrogen, then allowed to cool to room temperature. The mixture was purified by pre-HPLC (TFA modified ACN / water) to afford 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-5,5a,6,6a- tetrahydrocyclopropa[3,4]pyrrolo[2,1-c][1,2,4]triazol-3(2H)-one. The mixture of isomers were separated SFC (Method DAICEL CHIRALCEL OD-H Condition 0.1% NH3H2O / EtOH) to afford 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[2,1- c][1,2,4]triazol-3(2H)-one (8.52 mg) (SFC-P1), 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)- 5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[2,1-c] [1,2,4]triazol-3(2H)-one (8.36 mg) 10-1, SFC- P2), 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo [2,1- c][1,2,4]triazol-3(2H)-one (13.6 mg) (SFC-P3), and 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)- 5,5a,6,6a-tetrahydrocyclopropa[3,4] pyrrolo[2,1-c][1,2,4]triazol-3(2H)-one (14.9 mg) 10-2, SFC- P4). Compound 10-1:1H NMR (500 MHz, CDCl3) δ 7.83-7.91 (m, 2H), 7.10 (t, J = 9.0 Hz, 2H), 6.91 (br d, J = 6.0 Hz, 2H), 6.76-6.85 (m, 1H), 5.53 (d, J = 6.0 Hz, 1H), 2.69-2.81 (m, 1H), 2.47-2.54 (m, 1H), 1.24- 1.29 (m, 1H), 0.95-1.03 (m, 1H). Compound 10-2:258661H NMR (500 MHz, CDCl3) δ 7.81-7.90 (m, 2H), 7.04-7.14 (m, 2H), 6.79-6.89 (m, 3H), 5.09 (s, 1H), 2.54-2.61 (m, 1H), 2.36-2.40 (m, 1H), 1.55 (td, J = 8.0, 6.0 Hz, 1H), 1.02-1.09 (m, 1H). Example 11-1 2-Isobutyl-5-phenyl-2,5,6,7- [2,1-c][1,2,4]triazol-3-one

[0309] A vial was, (324 mg, 0.994 mmol) and DMF (3.31 mL).1-Iodo-2-methylpropane (68.6 µL, 0.596 mmol) was added and the reaction was heated to 80 °C and stirred overnight. The reaction was cooled to room temperature then concentrated. The crude residue was purified by reverse phase chromatography (15-70% MeCN / water with 0.1% TFA) giving 2-isobutyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one.1H NMR (500 MHz, DMSO-d6) δ 7.37 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 5.21 (dd, J = 8.2, 4.2 Hz, 1H), 3.41 (d, J = 7.1 Hz, 2H), 2.96 (m, 1H), 2.92 – 2.83 (m, 1H), 2.77 (ddd, J = 16.6, 9.4, 4.9 Hz, 1H), 2.25 (ddt, J = 13.0, 8.8, 4.6 Hz, 1H), 2.01 (dp, J = 13.6, 6.8 Hz, 1H), 0.86 (d, J = 6.7 Hz, 6H). MS (EI) Calculated for C15H20N3O [M+H]+, 258; found, 258. Example 12-1

[0310] A vial was charged with 1A (19 mg, 0.094 mmol), Cs2CO3 (61.5 mg, 0.189 mmol) and DMF (944 µL). Iodocyclohexane (18.3 µL, 0.142 mmol) was added and the reaction was heated to 70 °C and stirred overnight. The reaction was cooled to room temperature then loaded directly25866 onto silica and purified by chromatography on silica gel (12 g silica gel, 5-100% EtOAc / Hexanes) giving (S)-2-cyclohexyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one.1H NMR (500 MHz, DMSO-d6) δ 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 7.4 Hz, 2H), 5.21 (dd, J = 8.1, 4.2 Hz, 1H), 3.91 – 3.73 (m, 1H), 3.04 – 2.92 (m, 1H), 2.85 (m, 1H), 2.81 – 2.71 (m, 1H), 2.26 (ddt, J = 13.0, 8.8, 4.5 Hz, 1H), 1.76 (m, 4H), 1.72 – 1.56 (m, 3H), 1.44 – 1.28 (m, 2H), 1.14 (m, 1H). MS (EI) Calculated for C17H22N3O [M+H]+, 284; found, 284. Example 13-1 3-((S)-5-(3,5-Difluorophenyl)-3- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-

[0311] A vial0.245 mmol) and DMF (1.22 mL).3-Bromobutanenitrile (36.2 mg, 0.245 mmol) was added and the reaction was heated to 80 °C and stirred overnight. The reaction was cooled to room temperature, filtered, and then concentrated. The crude residue was purified by chromatography on silica gel (4 g silica gel, 5-35% EtOAc / Hexanes) giving 3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)butanenitrile as a mixture of diastereomers. The diastereomers were then separated by SFC using a Sepiatec Prep 100. A Chiral Technologies IC column (5 µm, 250 mm * 21 mm) was used as the chiral stationary phase. Injection and collection were carried out using the following isocratic SFC conditions: 75% carbon dioxide and 25% methanol with 0.1% ammonium hydroxide as the mobile phase, 215 nm UV wavelength, 100 bar outlet pressure, 40 ºC column compartment temperature, 70 mL / min total flow rate. Retention times for peak collection were as follows: first eluting peak, 2.15 min; second eluting peak, 2.65 min. Peak 2 isolated as desired isomer 13-1.1H NMR (500 MHz, DMSO-d6) δ 7.19 (t, J = 9.3 Hz, 1H), 6.99 (d, J = 6.7 Hz, 2H), 5.27 (dd, J = 8.1, 4.7 Hz, 1H), 4.51 – 4.37 (m, 1H), 3.04 – 2.84 (m, 4H), 2.79 (m, 1H), 2.30 (ddt, J = 13.0, 9.2, 4.9 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H). MS (EI) Calculated for C15H15F2N4O [M+H]+, 305; found, 305.25866 General Scheme E

[0312] The followingTable 5 wereto the route depicted in General Scheme E and in an analogous manner of that described for either Example 12-1 or 13- 1, using appropriate intermediate in Table A and commercial or known alkyl halides. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 5. Compound Exact Mass Structure Name Number [M+H]+ 6, 6 6, 6 0, 0 8, 8 6, 6 0, 025866 (S)-2-(cyclopentylmethyl)-5-phenyl- Calc'd 284, 13-8 2,5,6,7-tetrahydro-3H-pyrrolo[2,1- 4 2, 2 2, 2 6, 6 8, 8 2, 2 8, 8Example 14-1 (S)-2-(Bicyclo[1.1.1]pentan-1--2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one Step 1.25866

[0313] A round-bottom flask containing bicyclo[1.1.1]pentan-1-ylmethanol (40 mg, 0.408 mmol), 4-methylbenzene-1-sulfonyl chloride (311 mg, 1.630 mmol), DCM (5 ml) and triethylamine (0.170 ml, 1.223 mmol) was stirred for 18 hrs at 30 °C. The mixture was concentrated in vacuo and the residue was purified by prep-TLC (SiO2, PE:EA=30:1) to give bicyclo[1.1.1]pentan-1-ylmethyl 4-methylbenzenesulfonate (100 mg).1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 3.91 (s, 2H), 2.47 (s, 1H), 2.43 (s, 3H), 1.70 (s, 6H). Step 2. Preparation of (S)-2-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0314] A vial was charged with I-2A (23.7 mg, 0.10 mmol), K2CO3(27.6 mg, 0.20 mmol) and DMF (1.0 mL). Bicyclo[1.1.1]pentan-1-ylmethyl 4-methylbenzenesulfonate (30.3 mg, 0.12 mmol) was added and the reaction was heated to 80 °C and stirred overnight. The reaction was cooled to room temperature then purified by reverse phase chromatography (MeCN / water with 0.1% TFA) to afford (S)-2-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (14-1).1H NMR (500 MHz, DMSO-d6) δ 7.20 (t, J = 9.2 Hz, 1H), 6.97 (d, J = 7.1 Hz, 2H), 5.25 (dd, J = 8.0, 4.7 Hz, 1H), 3.64 (s, 2H), 3.01 – 2.93 (m, 1H), 2.93 – 2.82 (m, 1H), 2.76 (ddd, J = 16.2, 9.3, 5.4 Hz, 1H), 2.47 (s, 1H), 2.30 (ddt, J = 13.5, 9.3, 4.8 Hz, 1H), 1.69 (s, 6H). MS (EI) Calculated for C17H18 F2N3O [M+H]+, 318; found, 318. Example 15-1 (S)-5-Phenyl-2-((1R,3S)-3-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-oneStep 1. Preparation of (1S,3S)-3-phenylcyclobutyl methanesulfonate25866

[0315] A solution of (1S,3S)-3-phenylcyclobutan-1-ol (233 mg, 1.57 mmol) and triethylamine (0.285 ml, 2.04 mmol) in DCM (20.2 mL) was cooled to 0 °C and then Ms-Cl (0.141 mL, 1.81 mmol) was added dropwise. After 15 minutes at 0 °C the reaction was allowed to warm to RT. After 30 min at RT the reaction mixture was partitioned between DCM and sat. sodium bicarbonate solution. The organic layer was washed with water, followed by brine, dried over sodium sulfate, filtered and concentrated to obtain desired mesylate (358 mg) which was used without further purification.1H NMR (CDCl3) δ: 7.40 – 7.32 (m, 2H), 7.26 (td, J = 6.4, 1.6 Hz, 3H), 5.05 (tt, J = 8.1, 7.0 Hz, 1H), 3.20 – 3.11 (m, 1H), 3.05 (s, 3H), 2.97 – 2.89 (m, 2H), 2.46 (dddd, J = 10.5, 9.3, 8.1, 2.9 Hz, 2H). Step 2. Preparation of (S)-5-phenyl-2-((1R,3S)-3-phenylcyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one

[0316] A vial was charged with I-1A (20.5 mg, 0.10 mmol), Cs2CO3(66.4 mg, 0.20 mmol) and DMF (1.0 mL). (1S,3S)-3-phenylcyclobutyl methanesulfonate (34.6 mg, 0.15 mmol) was added and the reaction was heated to 70 °C and stirred overnight. The reaction was cooled to room temperature, diluted with dichloromethane then purified by chromatography on silica gel (12 g silica gel, 5-100% EtOAc / Hexanes) to afford (S)-5-phenyl-2-((1R,3S)-3-phenylcyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (15-1).1H NMR (500 MHz, DMSO-d6) δ 7.42 – 7.28 (m, 7H), 7.27 – 7.17 (m, 3H), 5.25 – 5.17 (m, 1H), 4.72 (p, J = 7.5 Hz, 1H), 3.68 (tt, J = 9.7, 5.1 Hz, 1H), 3.06 – 2.75 (m, 5H), 2.57 – 2.43 (m, 2H), 2.34 – 2.24 (m, 1H). MS (EI) Calculated for C21H22N3O [M+H]+, 332; found, 332. Example 16-125866

[0317] To a solution of TEA (0.645 ml, 4.63 mmol) and 3,3-difluorocyclobutan-1-ol (0.25 g, 2.31 mmol) in DCM (5 mL) was cooled to 0 °C under N2atmosphere. Then 4- (trifluoromethyl)benzenesulfonyl chloride (0.849 g, 3.47 mmol) in DCM (5.00 mL) was added to the solution. The mixture was added to water (20 mL). The organic phase was separated. The aqueous phase was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by flash silica gel chromatography (ISCO; 12 g Agela Silica Flash Column, Eluent of 0~5% EtOAc / Pet. ether gradient @ 30 mL / min) to give 3,3- difluorocyclobutyl 4-(trifluoromethyl)benzenesulfonate (0.7 g).1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.23 Hz, 2 H), 7.87 (d, J=8.34 Hz, 2 H), 4.77 - 4.89 (m, 1 H), 2.92 - 3.09 (m, 2 H), 2.75 - 2.91 (m, 2 H). Step 2. Preparation of give 2-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0318] To a solution of I-2A (20 mg, 0.084 mmol) in DMF (2 mL) was added K2CO3(23.3 mg, 0.169 mmol) and 3,3-difluorocyclobutyl 4-(trifluoromethyl)benzenesulfonate (40.0 mg, 0.126 mmol) at 20°C. The reaction was stirred at 65 °C for 2.5 d. The mixture was purified by HPLC (Instrument EB Method Column Phenomenex Synergi C18150 mm * 30 mm * 4 um Condition water (0.1%TFA)-ACN Begin B 44 End B 64 Gradient Time (min) 10100%B Hold Time (min) 2 flow rate (mL / min) 25 Injections 1 HPLC 6) to give 2-(3,3-difluorocyclobutyl)-5-(3,5- difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (16-1).1H NMR (400 MHz, CD3OD) δ 6.84-6.92 (m, 3H), 5.22 (dd, J = 5.2, 8.0 Hz, 1H), 4.50-4.66 (m, 1H), 2.83-3.12 (m, 7H), 2.33-2.48 (m, 1H). MS (EI) Calculated for C15H14F4N3O [M+H]+, 328; found, 328. Example 17-1, 17-2, 17-3 (5S)-5-Phenyl-2-(3-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (Isomer 1, 2 and 3)25866 Step 1. Preparation

[0319] 4- g, dimethylpyridin-4- amine (1.13 g, 9.25 mmol) were added to a solution of 3-phenylcyclopentan-1-ol (1.00 g, 6.16 mmol) in DCM (20 mL). The resulting mixture was stirred at 20 °C for 12 h. The mixture was quenched with water (20 mL). The mixture was extracted with DCM (20 mL x 3). The combined organic fractions were washed with NaSO4 (20 mL) and brine (20 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (1 g), Eluent of 0 ~ 10% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give two product peaks: Peak 1: 3-phenylcyclopentyl 4-methylbenzenesulfonate (300 mg) and Peak 2: 3-phenylcyclopentyl 4-methylbenzenesulfonate (500 mg). Peak 1:1H NMR (400 MHz, CD3OD) δ 7.81 (dd, J=2.21, 8.40 Hz, 2H), 7.39-7.49 (m, 1H), 7.39- 7.49 (m, 1H), 7.37-7.49 (m, 1H), 7.11-7.28 (m, 5H), 5.01-5.16 (m, 1H), 2.97-3.29 (m, 1H), 2.45 (s, 3H), 2.35-2.42 (m, 1H), 2.08-2.27 (m, 2H), 1.71-2.06 (m, 3H), 1.53-1.66 (m, 1H) Peak 2:1H NMR (400 MHz, CD3OD) δ 7.79-7.81 (m, 2H), 7.43-7.48 (m, 2H), 7.16-7.24 (m, 5H), 5.03-5.12 (m, 1H), 2.96-3.28 (m, 1H), 2.44 (s, 3H), 2.24-2.42 (m, 1H), 2.07-2.23 (m, 1H), 1.69-2.05 (m, 4H). Step 2. Preparation of (5S)-5-phenyl-2-(3-phenylcyclopentyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0320] To a mixture of 3-phenylcyclopentyl 4-methylbenzenesulfonate (Peak 2 from Step 1) (94.0 mg, 0.298 mmol) in DMF (1 mL) was added Cs2CO3(162 mg, 0.497 mmol) and I-1A (50.0 mg, 0.248 mmol). The reaction was stirred at 90 °C for 16 h. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC (EJ Method Column Boston Green ODS 150*30mm*5um Condition water(0.01%TFA)-ACN Begin B 45 End B 85 Gradient Time(min) 10100%B Hold Time 2 Flow Rate(ml / min) 25 Injections 3) to give (5S)-5-phenyl-2-(3-phenylcyclopentyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one as a mixture of isomers. The isomers were separated by SFC using a Waters UPCC. A25866 Chiralcel C2 column was used as the chiral stationary phase. Injection and collection were carried out using the following isocratic SFC conditions: 60% carbon dioxide and 40% ethanol with 0.1% ammonium hydroxide as the mobile phase, 80 mL / min total flow rate. Retention times for peak collection were as follows: first eluting peak, 2.90 min; second eluting peak, 3.26 min; third eluting peak, 3.85 min. (5S)-5-phenyl-2-(3-phenylcyclopentyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (17-1): First eluting peak.1H NMR (400 MHz, CD3OD) δ 7.30-7.41 (m, 3H), 7.25-7.30 (m, 4H), 7.23 (d, J = 7.6 Hz, 2H), 7.17 (qd, J = 6.4 Hz, 1H), 5.26 (dd, J = 8.0 Hz, 1H), 4.74-4.82 (m, 1H), 3.43-3.54 (m, 1H), 2.83-3.12 (m, 3H), 2.38-2.47 (m, 1H), 2.21-2.36 (m, 3H), 2.00-2.15 (m, 2H), 1.67-1.80 (m, 1H). MS (EI) Calculated for C22H24N3O [M+H]+, 346; found, 346. (5S)-5-phenyl-2-(3-phenylcyclopentyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (17-2): Second eluting peak.1H NMR (400 MHz, CD3OD) δ 7.30-7.42 (m, 3H), 7.24-7.30 (m, 4H), 7.22 (d, J = 7.6 Hz, 2H), 7.12-7.19 (m, 1H), 5.24 (dd, J = 8.0 Hz, 1H), 4.78 (dq, J = 8.0 Hz, 1H), 3.41-3.53 (m, 1H), 2.81-3.12 (m, 3H), 2.40 (tdd, J = 8.8 Hz, 1H), 2.21-2.35 (m, 3H), 2.01- 2.17 (m, 2H), 1.66-1.80 (m, 1H). MS (EI) Calculated for C22H24N3O [M+H]+, 346; found, 346. (5S)-5-phenyl-2-(3-phenylcyclopentyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (17-3): Third eluting peak.1H NMR (400 MHz, CD3OD) δ 7.35-7.41 (m, 2H), 7.25-7.35 (m, 5H), 7.20-7.25 (m, 2H), 7.14-7.20 (m, 1H), 5.26 (dd, J = 8.0 Hz, 1H), 4.65-4.76 (m, 1H), 2.83-3.17 (m, 4H), 2.36-2.48 (m, 2H), 2.04-2.22 (m, 4H), 1.90-2.04 (m, 1H). MS (EI) Calculated for C22H24N3O [M+H]+, 346; found, 346. Example 18-1 (S)-2-((1R,3S)-3-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0321] Atriazol-3-one I-14A (100 mg, 0.492 mmol), (1S,3S)-3-phenylcyclobutyl methanesulfonate (3690 µL, 0.738 mmol) and 18-crown-6 (130 mg, 0.492 mmol) in DMSO (3281 µL) was heated to 70 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc and water, the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over25866 sodium sulfate, filtered and concentrated. The residue purified by chromatography on silica gel (12 g silica gel, 20-100% 3:1 EtOAc:EtOH / Hexanes) to afford 2-((1r,3S)-3-phenylcyclobutyl)-5- (pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as a mixture of enantiomers. The enantiomers were separated by SFC using a Waters UPCC. An AD-H column was used as the chiral stationary phase. Injection and collection were carried out using the following isocratic SFC conditions: 60% carbon dioxide and 40% 1:1 MeOH / MeCN with 0.1% DIPA as the mobile phase. Retention times for peak collection were as follows: first eluting peak, 4.30 min; second eluting peak, 5.11 min. (S)-2-((1R,3S)-3-phenylcyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (18-1): Second eluting peak.1H NMR (500 MHz, CD3CN) δ 8.65 (s, 1H), 8.54 (s, 2H), 7.35 (s, 4H), 7.21 (s, 1H), 5.26 (m, 1H), 4.73 (q, J = 7.7 Hz, 1H), 3.70 (m, 1H), 3.08 – 2.75 (m, 5H), 2.67 – 2.41 (m, 3H). MS (EI) Calculated for C19H20N5O [M+H]+, 334; found, 334. General Scheme F

[0322] The following examples in Table 6 were prepared according to the route depicted in General Scheme F and in an analogous manner of that described for Examples 14-1, 15-1, 16-1, 17-1,2,3 or 18-1 using appropriate intermediates in Table A and commercial or known sulfonyl chlorides. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 6. Compound Exact Mass Structure Name 2, 225866 (S)-2-((1r,3S)-3-(benzyloxy)cyclobutyl)- 5-(3,5-difluorophenyl)-2,5,6,7- Calc'd 398, 8 0, 0 0, 0 8, 8 2, 2 2, 2 2, 2 7, 725866 Example 19-1 and 19-2 (S)-5-(3,5- 7-yl)cyclobutyl)-2,5,6,7- - (3,5-difluorophenyl)- 2-((1S,3R)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (19-2). F F F N

[0323] To a stirred mixture of ((3-iodocyclobutoxy)methyl)benzene (2.01 g, 2.91 mmol), 7- chloro-3-fluoropyrazolo[1,5-a]pyrimidine (250 mg, 1.46 mmol),tetrabutylammonium iodide (269 mg, 0.729 mmol), zinc (381 mg, 5.83 mmol), pyridine-2,6-bis(carboximidamide) hydrochloride (145 mg, 0.729 mmol) in DMA (20 mL) was added NiBr2^DME (180 mg, 0.583 mmol) at 20 °C and the mixture was stirred at 40 °C for 16 h under N2atmosphere. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic fraction were washed with brine (20 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 17% EtOAc / Pet.ether gradient @ 30 mL / min) to give 7-(3-(benzyloxy)cyclobutyl)-3-fluoropyrazolo[1,5-a]pyrimidine (400 mg). MS (EI) Calculated for C17H17FN3O [M+H]+: 298.1; found 298. Step 2. Preparation of 3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutan-1-ol

[0324] To a solution of 7-(3-(benzyloxy)cyclobutyl)-3-fluoropyrazolo[1,5-a]pyrimidine (380 mg, 1.28 mmol) in DCM (10 mL) was added trichloroborane (3.83 mL, 3.83 mmol) at -78 ºC. The resulting mixture was stirred at 20 °C for 2 h. The mixture was diluted with NaHCO3 (20 m25866 L) and extracted with DCM (3 x 20 mL). The combined organic fraction were washed with brine (20 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®;4 g SepaFlash® Silica Flash Column, eluent of 17% EtOAc / Pet.ether gradient @ 30 mL / min) to give 3-(3-fluoropyrazolo[1,5- a]pyrimidin-7-yl)cyclobutan-1-ol (200 mg). MS (EI) Calculated for C10H11FN3O [M+H]+: 208; found 208. Step 3. Preparation of 3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl 4- methylbenzenesulfonate

[0325] To a solution of 3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutan-1-ol (200 mg, 0.965 mmol) in DCM (5 mL) was added N,N-dimethylpyridin-4-amine (59.0 mg, 0.483 mmol), 4-methylbenzenesulfonyl chloride (368 mg, 1.93 mmol) and the resulting mixture was stirred at 40 °C for 12 h. The mixture was concentrated and purified by flash silica gel chromatography (ISCO; 4 g Agela Silica Flash Column, Eluent of 0~40% EtOAc / Pet. ether gradient @ 30 mL / min) to give 3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl 4-methylbenzenesulfonate (250 mg). MS (EI) Calculated for C17H17FN3O3S [M+H]+: 362; found 362. Step 4. Preparation of (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(3-fluoropyrazolo[1,5- a]pyrimidin-7-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (19-2) and (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (19-1).

[0326] To a mixture of 3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl 4- methylbenzenesulfonate (50.0 mg, 0.125 mmol) in DMF (1 mL) was added Cs2CO3(82.0 mg, 0.253 mmol) and I-2A (30.0 mg, 0.126 mmol), the reaction was stirred at 90 °C for 16 h. The reaction was cooled to room temperature then diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous was re-extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC(EtOAc) to afford (S)-5-(3,5- difluorophenyl)-2-(3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one as a mixture of cis and trans isomers. The isomers were separated by SFC using a Waters UPCC. A Chiralcel AS column (3 µm, 150 mm * 6 mm) was used as the chiral stationary phase. Injection and collection were carried out using the following gradient SFC conditions: solvent A – carbon dioxide, solvent B - ethanol with 0.05% diethyl amine; gradient: from 5% to 40% solvent B in 4 min and from 40% to 5% of B in 0.2 min, then hold 5% for 1.8 min.215 nm UV wavelength, 1500 psi outlet pressure, 35 ºC column25866 compartment temperature, 2.5 mL / min total flow rate. Retention times for peak collection were as follows: first eluting peak, 3.81 min; second eluting peak, 4.20 min. (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (19-1): First eluting peak.1H NMR (400MHz, CDCl3): δ 8.46 (d, J = 4.0 Hz, 1H), 8.03 (d, J = 4.0 Hz, 1H), 6.63-6.96 (m, 4H), 5.17 (dd, J = 8.0, 4.0 Hz, 1H), 4.83-5.03 (m, 1H), 3.77-4.08 (m, 1H), 2.77-3.09 (m, 7H), 2.38-2.48 (m, 1H). MS (EI) Calculated for C21H18F3N6O [M+H]+, 427; found, 427. (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (19-2): Second eluting peak.1H NMR (400MHz, CDCl3): 8.48 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 3.6 Hz, 1H), 6.88 (d, J = 4.0 Hz, 1H), 6.68-6.83 (m, 3H), 5.18 (dd, J = 8.0, 4.0 Hz, 1H), 4.95 (q, J = 7.6 Hz, 1H), 4.33 (tt, J = 9.6, 4.4 Hz, 1H), 2.91-3.24 (m, 5H), 2.64-2.82 (m, 2H), 2.40-2.50 (m, 1H). MS (EI) Calculated for C21H18F3N6O [M+H]+, 427; found, 427.

[0327] The following examples in Table 7 were prepared according to the methods described for Example 19-1 and 19-2, using appropriate intermediates and commercial or known reagents and starting materials. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 7: Compound Exact Mass Structure Name 1, 1 1, 1 8, 825866 tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one 8, 8N-((1S,3R)-3-((S)-5-(3,5- 3H-pyrrolo[2,1-c][1,2,4]triazol-2 - - Step 1.

[0328] To a 20 mL red cap vial containing benzyl ((1S,3S)-3-hydroxycyclobutyl)carbamate (739 mg, 3.34 mmol) in DCM (16.7 mL) was added Hunig's Base (2916 µL, 16.7 mmol) at rt, the mixture was cooled to -15 °C, followed by addition of methanesulfonyl chloride (520 µL, 6.68 mmol) at -15 °C. The reaction mixture was allowed to warm and stirred at rt. After 2 h the reaction mixture was directly purified on a 40g SiO2gold column by Isco (5~100% EtOAc in hexanes) to yield (1S,3S)-3-(((benzyloxy)carbonyl)amino)cyclobutyl methanesulfonate (610 mg). MS (EI) Calculated for C13H17NNaO5S [M+Na]+, 322; found, 322. Step 2. Preparation of benzyl ((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)carbamate25866

[0329] A solution of I-2A (320 mg, 1.35 mmol), Cs2CO3 (879 mg, 2.70 mmol), and (1S,3S)-3- (((benzyloxy)carbonyl)amino)cyclobutyl methanesulfonate (606 mg, 2.02 mmol) in DMF (13.5 mL) was heated to 70 °C and stirred for 48 h. The reaction was cooled to room temperature, diluted with DCM, filtered, and purified by chromatography on silica gel (40 g silica gel, 5-100% EtOAc / Hexanes) giving benzyl ((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)carbamate. MS (EI) Calculated for C23H23F2N4O3 [M+H]+, 441; found, 441. Step 3. Preparation of (S)-2-((1R,3S)-3-aminocyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0330] A round bottom flask under nitrogen atmosphere was charged with benzyl ((1S,3R)-3- ((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)carbamate (70 mg, 0.16 mmol) and EtOAc (1.59 mL) followed by addition of Pd / C (16.9 mg, 0.016 mmol). The reaction mixture was sparged with hydrogen while stirring for 15 minutes, then sealed and stirred under hydrogen at room temperature overnight. The reaction mixture was then filtered through Celite and concentrated to give (S)-2-((1R,3S)-3- aminocyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one. MS (EI) Calculated for C15H17F2N4O [M+H]+, 307; found, 307. Step 4. Preparation of N-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)-2-fluorobenzamide.

[0331] A vial was charged with (S)-2-((1R,3S)-3-aminocyclobutyl)-5-(3,5-difluorophenyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (16.7 mg, 0.055 mmol), DCM (545 µL), and Hunig’s Base (47.6 µL, 0.273 mmol).2-Fluorobenzoyl chloride (13.0 µL, 0.109 mmol) was added and the reaction was allowed to stir at room temperature overnight. The crude reaction mixture was purified directly by chromatography on silica gel (40 g silica gel, 5-100% EtOAc / Hexanes) giving N-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)-2-fluorobenzamide.1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 7.0 Hz, 1H), 7.59 (td, J = 7.5, 1.5 Hz, 1H), 7.56 – 7.48 (m, 1H), 7.33 – 7.24 (m, 2H), 7.19 (m, 1H), 7.05 (d, J = 6.4 Hz, 2H), 5.22 (dd, J = 7.7, 5.1 Hz, 1H), 4.78 (p, J = 7.3 Hz, 1H), 4.61 – 4.45 (m, 1H), 3.04 – 2.88 (m, 2H), 2.81 (ddd, J = 16.1, 10.1, 5.7 Hz, 1H), 2.69 (m, 2H), 2.48 – 2.38 (m, 2H), 2.37 – 2.26 (m, 1H). MS (EI) Calculated for C22H20F3N4O2 [M+H]+, 429; found, 429.25866 Example 21-1 (S)-5-(3,5-Difluorophenyl)-2- 3-yl)-2,5,6,7-tetrahydro-3H-3-one Step 1. 3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)azetidine-1-carboxylate.

[0332] A solution of (S)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one I-2A (39.0 mg, 0.164 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (58.2 mg, 0.247 mmol) and Cs2CO3(107 mg, 0.329 mmol) in DMA (600 µL) was heated to 100 °C for 30 minutes. The reaction was cooled, partitioned between EtOAc and water. The organic layer was washed with water three times, followed by a brine wash, then dried over sodium sulfate, filtered and concentrated to provide crude material which was taken forward without purification. MS (EI) Calculated for C19H23F2N4O2[M+H]+, 393; found, 393. Step 2. Preparation of (S)-2-(azetidin-3-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one hydrochloride.

[0333] A 4M solution of HCl in 1,4-dioxane (440 µL, 1.76 mmol) was added to a solution of tert-butyl (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)azetidine-1-carboxylate (69.0 mg, 0.176 mmol) in EtOAc (1758 µL). The reaction stirred at RT overnight. The volatiles were then removed and the crude material was used in the next step without further purification. MS (EI) Calculated for C14H15F2N4O [M+H]+, 293; found, 293. Step 3. Preparation of (S)-5-(3,5-difluorophenyl)-2-(1-(2-fluoropyridin-4-yl)azetidin-3-yl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one25866

[0334] A solution of (S)-2-(azetidin-3-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one hydrochloride (20.0 mg, 0.061 mmol) and 2,4-difluoropyridine (14.0 mg, 0.122 mmol) was treated with Cs2CO3 (59.5 mg, 0.183 mmol) at 65 °C in DMA (304 µl). After 40 minutes the reaction was complete. The reaction was cooled, partitioned between MTBE and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification via silica gel chromatography (ISCO 4g cartridge, eluting with 10-100% EtOAcHexanes) gave desired product (S)-5-(3,5-difluorophenyl)-2-(1-(2- fluoropyridin-4-yl)azetidin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one.1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 5.8 Hz, 1H), 6.79 (ddd, J = 10.8, 6.5, 2.1 Hz, 1H), 6.76 – 6.73 (m, 2H), 6.23 – 6.18 (m, 1H), 5.86 (d, J = 1.9 Hz, 1H), 5.31 – 5.22 (m, 1H), 5.17 (dd, J = 8.3, 4.2 Hz, 1H), 4.43 – 4.30 (m, 3H), 4.26 (dd, J = 8.1, 5.4 Hz, 1H), 3.07 – 3.02 (m, 1H), 2.95 – 2.92 (m, 1H), 2.89 – 2.82 (m, 1H), 2.45 (ddt, J = 13.1, 8.7, 4.5 Hz, 1H). MS (EI) Calculated for C19H17F3N5O [M+H]+, 388; found, 388. Example 22-1 and 22-26-((1R,3S)-3-((S)-5-(3,5-Difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile (22-1) and 6-((1S,3R)-3-((S)-5-(3,5- difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrimidine-4-carbonitrile (22-2)25866 Step 1. Preparation of (S)-5-(3,5-difluorophenyl)-2-(3-iodocyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one

[0335] Ph3P (68.3 mg, 0.260 mmol), 1H-imidazole (26.6 mg, 0.390 mmol) and I2 (49.6 mg, 0.195 mmol) were added to a solution of I-16 (S)-5-(3,5-difluorophenyl)-2-(3- hydroxycyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (40.0 mg, 0.130 mmol) in PhMe (2 mL). The resulting mixture was stirred at 120 °C for 2 h. The mixture was cooled to room temperature, concentrated in vacuo, and purified by prep. TLC (Pet.ether / EtOAc = 1 : 1) to give product (S)-5-(3,5-difluorophenyl)-2-(3-iodocyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C15H15F2IN3O [M+H]+, 418; found, 418. Step 2. Preparation of (S)-6-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile

[0336] To a stirred mixture of (S)-5-(3,5-difluorophenyl)-2-(3-iodocyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (50.0 mg, 0.120 mmol), 6-chloropyrimidine-4- carbonitrile (50.2 mg, 0.360 mmol), tetrabutylammonium iodide (22.1 mg, 0.060 mmol), manganese (26.3 mg, 0.479 mmol), picolinimidamide hydrochloride (9.44 mg, 0.060 mmol) in DMA (2 mL) was added nickel(II) chloride ethylene glycol dimethyl ether complex (10.5 mg, 0.048 mmol) at 20 °C and the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was cooled to room temperature, filtered, and purified by prep. HPLC (Instrument EJ Method Column Boston Green ODS 150*30mm*5um Condition water(TFA)-ACN Begin B 35 End B 55 Gradient Time(min) 10100%B Hold Time(min) 2 flow rate(ml / min) 25 Injections 5) to give (S)-6-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile as a mixture of isomers. The isomers were separated by SFC using a Agilent 1260. A Chiralcel OD-3 column was used as the chiral stationary phase. Injection and collection were carried out using the following gradient SFC conditions: solvent A – carbon dioxide, solvent B - ethanol with 0.05% diethyl amine; gradient: from 5% to 40% solvent B in 4.5 min, then hold 5% of B for 1.5 min.220 nm UV wavelength, 100 bar outlet pressure, 40 ºC column compartment temperature, 2.5 mL / min total flow rate. Retention times for peak collection were as follows: first eluting peak, 3.85 min; second eluting peak, 4.10 min; third eluting peak, 4.49 min. Peak 2 (22-1): 6-((1R,3S)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile1H NMR (500 MHz, CDCl3) δ 9.30 (d, J = 1.22 Hz, 1H), 7.67 (d, J = 1.22 Hz, 1H), 6.73-6.83 (m, 3H), 5.16 (dd, J = 3.97, 8.2425866 Hz, 1H), 4.80-4.91 (m, 1H), 3.39-3.48 (m, 1H), 2.84-3.06 (m, 7H), 2.44 (tdd, J = 4.39, 8.62, 12.97 Hz, 1H). MS (EI) Calculated for C20H17F2N6O [M+H]+, 395; found, 395. Peak 3 (22-2): 6-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile.1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 7.52 (d, J = 1.0 Hz, 1H), 6.71-6.85 (m, 3H), 5.09-5.23 (m, 2H), 3.76 (br s, 1H), 2.84-3.08 (m, 5H), 2.71-2.81 (m, 2H), 2.40-2.50 (m, 1H). MS (EI) Calculated for C20H17F2N6O [M+H]+, 395; found, 395. Example 22-3 and 22-4 4-2(5H)- yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile (22-3) and 4-((1R,3S)-3-((S)-3-oxo-5- phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrazolo[1,5-a]pyridine- 7-carbonitrile (22-4) Step 1.pyrrolo[2,1- c][1,2,4]triazol-3-one

[0337] Ph3P (3.63 g, 13.8 mmol), 1H-imidazole (1.88 g, 27.6 mmol) and I2(3.51 g, 13.8 mmol) were added to a solution of I-19A (S)-2-((1R,3S)-3-hydroxycyclobutyl)-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (2.5 g, 9.21 mmol) in PhMe (100 mL). The resulting mixture was stirred at 110 °C for 2 h. The mixture was cooled to room temperature,25866 diluted with saturated aqueous Na2CO3 (60 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were dried over Na2SO4, concentrated in vacuo, and purified by flash silica gel chromatography (EtOAc / hexanes) to give (S)-2-(3-iodocyclobutyl)-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C15H17IN3O [M+H]+, 382; found, 382. Step 2. Preparation of (S)-4-(3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[0338] To a stirred mixture of (S)-2-(3-iodocyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (100 mg, 0.262 mmol), 4-chloropyrazolo[1,5-a]pyridine-7- carbonitrile (69.9 mg, 0.393 mmol), tetrabutylammonium iodide (48.4 mg, 0.131 mmol), zinc (51.5 mg, 0.787 mmol), pyridine-2,6-bis(carboximidamide) (21.4 mg, 0.131 mmol) in DMA (1.5 mL) was added nickel(II) bromide ethylene glycol dimethyl ether complex (37 mg, 0.105 mmol) at 20 °C and the mixture was stirred at 50 °C for 3 h under N2 atmosphere. The mixture was cooled to room temperature, diluted with water (8 mL) and extracted with EtOAc (3 x 10 mL). The combined organic fractions were dried over Na2SO4, concentrated in vacuo, and purified by prep. TLC (Pet.ether / EtOAc = 1 : 1) to give (S)-4-(3-(3-oxo-5-phenyl-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile as a mixture of isomers. The isomers were separated by SFC using an Agilent 1260. A Chiralcel OJ- H column was used as the chiral stationary phase. Injection and collection were carried out using the following SFC conditions: solvent A – carbon dioxide, solvent B - ethanol with 0.05% diethyl amine; isocratic: 40% solvent B.220 nm UV wavelength, 100 bar outlet pressure, 40 ºC column compartment temperature, 2.5 mL / min total flow rate. Retention times for peak collection were as follows: first eluting peak, 3.33 min; second eluting peak, 4.39 min. Peak 1 (22-3): 4-((1S,3R)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile.1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 2.4 Hz, 1H), 7.36-7.42 (m, 3H), 7.30-7.36 (m, 1H), 7.19-7.24 (m, 2H), 7.14 (dd, J = 7.3, 1.1 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 5.21-5.28 (m, 1H), 4.86-4.96 (m, 1H), 4.01-4.05 (m, 1H), 2.84-3.18 (m, 5H), 2.65-2.77 (m, 2H), 2.46-2.55 (m, 1H). MS (EI) Calculated for C23H21N6O [M+H]+, 397; found, 397. Peak 2 (22-4): 4-((1R,3S)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile.1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 2.3 Hz, 1H), 7.30-7.43 (m, 4H), 7.18-7.25 (m, 2H), 7.10 (dd, J = 7.3, 1.0 Hz, 1H), 6.79- 6.82 (m, 1H), 5.22 (dd, J = 8.0, 3.9 Hz, 1H), 4.83-4.92 (m, 1H), 3.47-3.60 (m, 1H), 2.75-3.10 (m,25866 7H), 2.96 (s, 6H), 2.42-2.53 (m, 1H). MS (EI) Calculated for C23H21N6O [M+H]+, 397; found, 397. Example 22-5 1-(2-((1S,3R)-3-((S)-5- 3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl) - 4-carbonitrile

[0339] To a mixture of 1H-pyrazole-4-carbonitrile (400 mg, 4.30 mmol) in MeCN (20 mL) was added 2,4-dichloropyrimidine (704 mg, 4.73 mmol) and K2CO3(1188 mg, 8.59 mmol) at ambient temperature. The mixture was brought to 80 °C for 12 hours then cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 1-(2-chloropyrimidin-4-yl)-1H- pyrazole-4-carbonitrile. MS (EI) Calculated for C8H5ClN5[M+H]+, 206; found, 206. Step 2. Preparation of 1-(2-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile

[0340] To a mixture of (S)-5-(3,5-difluorophenyl)-2-(3-iodocyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (60 mg, 0.144 mmol), 1-(2-chloropyrimidin-4-yl)-1H- pyrazole-4-carbonitrile (35.5 mg, 0.173 mmol), TBAI (26.6 mg, 0.072 mmol), zinc (37.6 mg, 0.575 mmol) and pyridine-2,6-bis(carboximidamide) hydrochloride (5.74 mg, 0.029 mmol) in DMA (1 mL) was added NiBr2^DME (8.88 mg, 0.029 mmol) at ambient temperature under nitrogen. The reaction mixture was brought to 60 °C for 2.5 hours then cooled to ambient temperature and filtered. The filtrate was directly purified by prep. RP-HPLC elution conditions: water (NH4HCO3)-ACN to afford 1-(2-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile as a mixture of isomers. The isomers were separated by SFC using a Diacel CHIRALCEL OJ 30 x 250 mm, 10 ^m column; 40% EtOH with 0.1% NH4OH; flow rate = 80 mL / min. Retention25866 times for peak collection were as follows: first eluting peak, 1.648 min, second eluting peak, 1.765 min, third eluting peak, 2.284 min and fourth eluting peak at 2.611 min. The third eluting peak gave 1-(2-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutyl)pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile. MS (EI) Calculated for C23H19F2N8O [M+H]+, 461; found, 461.1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.78 (d, J = 5.6 Hz, 1H), 7.97 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 6.55-6.78 (m, 3H), 4.98- 5.23 (m, 2H), 3.58-3.92 (m, 1H), 2.67-3.10 (m, 7H), 2.38 (tdd, J = 4.4, 8.4, 12.4 Hz, 1H). General Scheme G inan manner 2, 22-3, 22-4 and 22-5 using appropriate intermediates and commercial aryl halides or aryl halides prepared in an analogous manner of that described for Example 22-5. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 8. Compound Exact Mass Structure Name + 9, 9 9, 9 2, 225866 3H-pyrrolo[2,1-c][1,2,4]triazol-3- one 2, 2 3, 3 4, 4 4, 4 4, 4 4, 4 4, 425866 (S)-2-((1R,3S)-3-(3-(5-methyl- 1,3,4-oxadiazol-2- ' 4, 4 4, 4 1, 1 1, 1 1, 1Example 23-1 and 23-2 (5S)-5-(3,5-Difluorophenyl)-2--2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one25866mesityl- I3-iodanediyl diacetate (450 mg, 1.24 mmol) in Toluene (20 mL) was concentrated in vacuo at 55 °C. Then the residue was dissolved in Toluene (20 mL) and concentrated in vacuo at 55 °C Repeat the process three times to afford crude mesityl-l3-iodanediyl bis(2-phenylcyclopropane-1- carboxylate). The material was carried forward as is. Step 2. Preparation of (5S)-5-(3,5-difluorophenyl)-2-(2-phenylcyclopropyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0343] A mixture of I-2A (S)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (100 mg, 0.422 mmol), copper(I) thiophene-2-carboxylate (16.1 mg, 0.084 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (144 mg, 0.843 mmol), 4,4'- bis(trifluoromethyl)-2,2'-bipyridinebis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl)phenyl] iridium(III) hexafluorophosphate (4.83 mg, 4.22 µmol) and mesityl-l3-iodanediyl bis(2- phenylcyclopropane-1-carboxylate) (479 mg, 0.843 mmol) in MeCN (12 mL) was stirred at 25 °C under N2 with photoreactor (450 nm blue LED lamps) for 1 h. The mixture was concentrated in vacuo and purified by pre-HPLC (Instrument EJ Column Boston Green ODS 150*30 mm*5 um Condition water (TFA)-ACN Begin B 50 End B 80 Gradient Time (min) 10100%B Hold Time (min) 2 flow rate (mL / min) 25 Injections 2) to give (5S)-5-(3,5-difluorophenyl)-2-(2- phenylcyclopropyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as a mixture of isomers. The isomers were separated by SFC (Instrument SFC 17 Column DAICEL CHIRALPAK IC (250 mm*50 mm, 10 um) Condition 0.1% NH3^H2O EtOH Begin B 60 End B 60 flow rate (mL / min) 200 Injections 30). Retention times for peak collection were as follows: first eluting peak, 2.13 min; second eluting peak, 4.50 min. First eluting peak: (5S)-5-(3,5-difluorophenyl)-2-(2-phenylcyclopropyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (23-1):1H NMR (CD3OD, 500 MHz): δ 7.25-7.30 (m, 2H), 7.16-7.22 (m, 3H), 6.87-6.96 (m, 3H), 5.24 (dd, J = 8.0, 5.0 Hz, 1H), 3.27-3.30 (m, 1H), 3.01- 3.10 (m, 1H), 2.91-2.99 (m, 1H), 2.80-2.88 (m, 1H), 2.53 (ddd, J = 10.0, 6.5, 3.5 Hz, 1H), 2.37- 2.45 (m, 1H), 1.67 (ddd, J = 10.0, 6.0, 4.5 Hz, 1H), 1.41-1.46 (m, 1H). MS (EI) Calculated for C20H18F2N3O [M+H]+, 354; found, 354.25866 Second eluting peak: (5S)-5-(3,5-difluorophenyl)-2-(2-phenylcyclopropyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (23-2):1H NMR (CD3OD, 500 MHz): δ 7.25-7.30 (m, 2H), 7.16-7.22 (m, 3H), 6.89-6.96 (m, 3H), 5.24 (dd, J = 8.0, 5.0 Hz, 1H), 3.28-3.30 (m, 1H), 3.01- 3.10 (m, 1H), 2.92-2.99 (m, 1H), 2.80-2.89 (m, 1H), 2.51 (ddd, J = 10.0, 6.5, 3.5 Hz, 1H), 2.41 (br dd, J = 13.5, 8.5 Hz, 1H), 1.69 (ddd, J = 10.0, 6.0, 4.5 Hz, 1H), 1.42-1.47 (m, 1H). MS (EI) Calculated for C20H18F2N3O [M+H]+, 354; found, 354.

[0344] The following example in Table 9 were prepared according to the methods described for Example 23-1 and 23-2, using the appropriate commercially available or known carboxylic acid for the sequence. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 9. Compound Exact Mass Structure Name Number [M+H]+ , 8 , 6 , 6xamp e -25866 (S)-2-((1R,3S)-3-(4-(Oxazol-4-yl)phenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one  Step 1. Preparation of (((1R,3R)-3-iodocyclobutoxy)methyl)benzene

[0345] Ph3P (58.9 g, 224 mmol), 1H-imidazole (15.3 g, 224 mmol) and I2(42.7 g, 168 mmol) were added to a solution of cis-3-(benzyloxy)cyclobutan-1-ol (20.0 g, 112 mmol) in PhMe (500 mL). The resulting mixture was stirred at 120 °C for 2 h under N2. The mixture was cooled to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent of 5% ethyl acetate / pet. ether gradient @ 60 mL / min) to give (((1R,3R)-3-iodocyclobutoxy)methyl)benzene (40 g).1H NMR (400 MHz, CDCl3) δ 7.34-7.39 (m, 5H), 4.43 (s, 2H), 3.90-4.09 (m, 2H), 2.97-3.07 (m, 2H), 2.72-2.76 (m, 1H), 2.63-2.67 (m, 1H). Step 2. Preparation of 4-(4-((1S,3S)-3-(benzyloxy)cyclobutoxy)phenyl)oxazole

[0346] To a solution of (((1R,3R)-3-iodocyclobutoxy)methyl)benzene (983 mg, 3.41 mmol) in DMF (15 mL) was added 4-(oxazol-4-yl)phenol (500 mg, 3.10 mmol), and Cs2CO3(2.02 g, 6.21 mmol) at 20 ºC. The resulting mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature then added to water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 3% ethyl acetate / pet. ether gradient @ 35 mL / min) to 4-(4-((1S,3S)-3-(benzyloxy)cyclobutoxy)phenyl)oxazole (600 mg) MS (EI) Calculated for C20H19NO3[M+H]+, 322; found, 322. Step 3. (1S,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutan-1-ol25866

[0347] To a solution of 4-(4-((1S,3S)-3-(benzyloxy)cyclobutoxy)phenyl)oxazole (550 mg, 1.71 mmol) in DCM (8 mL) was added trichloroborane (5.13 mL, 5.13 mmol) at -78 ºC under N2. The resulting mixture was stirred at 20 °C for 2 h. Then the mixture was diluted with NaHCO3 (50 mL) and extracted with DCM (3 x 50 mL). The combined organic fraction were concentrated washed with brine (50 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give crude product which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 17% EtOAc / Pet.ether gradient @ 60 mL / min) to give (1S,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutan-1-ol (316 mg). MS (EI) Calculated for C13H13NO3 [M+H]+, 232; found, 232. Step 4. (1S,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutyl 4-methylbenzenesulfonate

[0348] To a solution of (1S,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutan-1-ol (266 mg, 1.15 mmol) in DCM (5 mL) was added 4-methylbenzenesulfonyl chloride (241 mg, 1.27 mmol) , DMAP (211 mg, 1.73 mmol) at 20 ºC. The resulting mixture was stirred at 25 °C for 12 h. The mixture was added water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 3% ethyl acetate / pet. ether gradient @ 35 mL / min) to obtain (1S,3S)-3-(4- (oxazol-4-yl)phenoxy)cyclobutyl 4-methylbenzenesulfonate (441 mg). MS (EI) Calculated for C20H19NO5S [M+H]+, 386; found, 386. Step 5. (S)-2-((1R,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0349] To a solution of (1S,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutyl 4- methylbenzenesulfonate (40.0 mg, 0.104 mmol) in DMF (1.5 mL) was added (S)-5-(pyrazin-2- yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (23.2 mg, 0.114 mmol), K2CO3 (43.0 mg, 0.311 mmol) and 18-Crown-6 (27.4 mg, 0.104 mmol). Then the reaction was stirred at 50 °C for 16 h. The mixture was purified by pre-HPLC (Welch Xtimate C18150*25mm*5um Condition water(10mM-NH4HCO3)-ACN Begin B 26 End B 56 Gradient Time(min) 11100%B Hold Time 2 Flow Rate(ml / min) 25 Injections 1 HPLC) to give (S)-2-((1r,3S)-3-(4-(oxazol-4- yl)phenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (10 mg). MS (EI) Calculated for C22H20N6O3 [M+H]+, 417; found, 417.

[0350] The chirality was upgraded with SFC chiral resolution: 8.0 mg, (0.019 mmol) was injected on DAICEL CHIRALCEL OJ(250mm*30mm,10um) eluting with isocratic 40% of EtOH w / 0.1%NH3H2O to give chiral (S)-2-((1r,3S)-3-(4-(oxazol-4-yl)phenoxy)cyclobutyl)-5- (pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as the major peak (6.2425866 mg). MS (EI) Calculated for C22H20N6O3 [M+H]+, 417; found, 417.1H NMR (400 MHz, CDCl3) ^ 8.69 (s, 1H), 8.57 (s, 2H), 7.92 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 8.58 Hz, 2H), 6.86 (d, J = 8.70 Hz, 2H), 5.32 (dd, J = 3.28, 8.18 Hz, 1H), 4.92-5.06 (m, 2H), 2.99-3.14 (m, 2H), 2.86-2.96 (m, 3H), 2.62-2.80 (m, 3H). Example 25-1 (S)-5-(3,5-Difluorophenyl)-2-( cyclobutyl)-2,5,6,7-tetrahydro-3H-3-one Step 1.

[0351] To a solution of (1S,3S)-3-(benzyloxy)cyclobutan-1-ol (300 mg, 1.68 mmol) in THF (6 mL) was added PPh3 (662 mg, 2.52 mmol), 4-fluorophenol (377 mg, 3.37 mmol) and DEAD (0.266 ml, 1.68 mmol) at 0 ºC. The reaction was stirred at 80 °C for 15 h, then cooled to room temperature. The residue was purified by flash silica gel chromatography (15% EtOAc / petroleum ether) to give 1-((1R,3R)-3-(benzyloxy)cyclobutoxy)-4-fluorobenzene (400 mg).1H NMR (400 MHz, CD3OD) δ 7.19-7.47 (m, 5H), 6.88-7.07 (m, 2H), 6.70-6.85 (m, 2H), 4.73-4.85 (m, 1H), 4.45 (s, 2H), 4.25-4.37 (m, 1H), 2.27-2.59 (m, 4H). Step 2. Preparation of (1R,3R)-3-(4-fluorophenoxy)cyclobutan-1-ol

[0352] To a solution of 1-((1R,3R)-3-(benzyloxy)cyclobutoxy)-4-fluorobenzene (500 mg, 1.836 mmol) in MeOH (5 mL) was added dihydroxypalladium (129 mg, 0.184 mmol) and Pd-C (195 mg, 0.184 mmol) at 20 ºC. The resulting mixture was stirred at 20 ºC for 12 h under H2. The reaction solution was filtered and the filtrate was concentrated in vacuo to give (1R,3R)-3-(4- fluorophenoxy)cyclobutan-1-ol (300 mg).1H NMR (400 MHz, CD3OD) δ 6.93-7.02 (m, 2H), 6.73-6.81 (m, 2H), 4.73-4.83 (m, 1H), 4.48 (tt, J=5.32, 6.90 Hz, 1H), 2.28-2.48 (m, 4H). Step 3. Preparation of (1R,3R)-3-(4-fluorophenoxy)cyclobutyl 4-methylbenzenesulfonate25866

[0353] 4-methylbenzenesulfonyl chloride (403 mg, 2.11 mmol) and N,N-dimethylpyridin-4- amine (352 mg, 2.88 mmol) were added to a solution of (1R,3R)-3-(4-fluorophenoxy)cyclobutan- 1-ol (350 mg, 1.921 mmol) in DCM (10 ml). The resulting mixture was stirred at 20 °C for 12 h. The mixture was quenched with water (20 mL). The mixture was extracted with DCM (20 ml x 3). The combined organic fractions were washed with NaHSO4 (20 mL) and brine (20 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (1 g), Eluent of 0 ~ 10% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give (1R,3R)-3-(4-fluorophenoxy)cyclobutyl 4-methylbenzenesulfonate (300 mg).1H NMR (400 MHz, CD3OD) δ 7.74-7.85 (m, 2H), 7.45 (d, J=8.58 Hz, 2H), 6.91-7.03 (m, 2H), 6.65-6.78 (m, 2H), 4.97-5.10 (m, 1H), 4.73-4.83 (m, 1H), 2.52-2.62 (m, 2H), 2.34-2.45 (m, 2H). Step 4. Preparation of (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-(4-fluorophenoxy)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0354] To a mixture of (1R,3R)-3-(4-fluorophenoxy)cyclobutyl 4-methylbenzenesulfonate (71.5 mg, 0.212 mmol) in DMF (1 ml) was added Cs2CO3 (115 mg, 0.354 mmol) and (S)-5-(3,5- difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one I-2A (42 mg, 0.177 mmol), the reaction was stirred at 90 °C for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give a residue which was purified by preparative HPLC (Boston Green ODS Column 150*30mm*5um Condition water(0.01%TFA)-ACN Begin: B 57 End: B 77. Gradient Time (min) 10100%B Hold Time 2 Flow Rate(ml / min) 25 Injections 3) to give (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-(4-fluorophenoxy)cyclobutyl-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (37.5 mg). MS (EI) Calculated for C21H18F3N3O2[M+H]+, 402; found, 402. Example 26-1 (S)-5-(3,5--2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one25866- (15 mL) was added (4-fluorophenyl)boronic acid (942 mg, 6.73 mmol), N,N-dimethylpyridin-4- amine (41.1 mg, 0.337 mmol), pyridine (399 mg, 5.05 mmol) and molecular sieves (4Å). The reaction was stirred at 20 °C for 10 min, then diacetoxycopper (306 mg, 1.68 mmol) was added. The resulting mixture was stirred at 90 °C for 48 h under O2. The reaction was allowed to cool to room temperature then the mixture was filtered and the filter cake was washed with DCM (2 x 100 mL). Water (100 mL) was added to the eluant and the resulting mixture was extracted with DCM (3 x 100 mL), washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash silica gel chromatography (ISCO®; 25g Agela® Silica Flash Column, Eluent of 0~15% EtOAc / Pet. ether gradient @ 40 mL / min) to give 1- ((1S,3S)-3-(benzyloxy)cyclobutoxy)-4-fluorobenzene (300 mg).1H NMR (500 MHz, CD3OD) δ 7.23-7.37 (m, 5H), 7.06-7.13 (m, 2H), 6.92-7.00 (m, 2H), 4.41-4.47 (m, 2H), 4.23-4.32 (m, 1H), 3.84 (quin, J=7.02 Hz, 1H), 2.81-2.89 (m, 2H), 2.01-2.08 (m, 2H). Step 2. Preparation of (1S,3S)-3-(4-fluorophenoxy)cyclobutan-1-ol

[0356] To a solution of 1-((1S,3S)-3-(benzyloxy)cyclobutoxy)-4-fluorobenzene (300 mg, 1.102 mmol) in MeOH (5 mL) was added dihydroxypalladium (77 mg, 0.110 mmol) and Pd-C (117 mg, 0.110 mmol) at 20 ºC. The resulting mixture was stirred at 20 ºC for 12 h under H2. The reaction solution was filtered and the filtrate was concentrated in vacuo to give (1S,3S)-3-(4- fluorophenoxy)cyclobutan-1-ol (100 mg).1H NMR (400 MHz, CD3OD) δ 6.90-7.03 (m, 2H), 6.73-6.86 (m, 2H), 4.17-4.27 (m, 1H), 3.90-4.03 (m, 1H), 2.82-2.92 (m, 2H), 1.95-2.01 (m, 2H) Step 3. Preparation of (1S,3S)-3-(4-fluorophenoxy)cyclobutyl 4-methylbenzenesulfonate

[0357] 4-Methylbenzenesulfonyl chloride (115 mg, 0.604 mmol) and N,N-dimethylpyridin-4- amine (101 mg, 0.823 mmol) were added to a solution of (1S,3S)-3-(4- fluorophenoxy)cyclobutan-1-ol (100 mg, 0.549 mmol) in DCM (5 mL). The resulting mixture was stirred at 20 °C for 12 h. The mixture was quenched with water (20 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organic fractions were washed with NaHSO4(20 mL) and brine (20 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under25866 reduced pressure. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (1 g), Eluent of 0 ~ 15% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give (1S,3S)-3-(4- fluorophenoxy)cyclobutyl 4-methylbenzenesulfonate (150 mg).1H NMR (400 MHz, CD3OD) δ 7.73-7.84 (m, 2H), 7.45 (d, J=7.99 Hz, 2H), 6.89-7.00 (m, 2H), 6.68-6.81 (m, 2H), 4.62 (quin, J=7.12 Hz, 1H), 4.10 (q, J=7.15 Hz, 1H), 2.76-2.90 (m, 2H), 2.10-2.23 (m, 2H). Step 4. Preparation of (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(4-fluorophenoxy)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0358] To a mixture of (1S,3S)-3-(4-fluorophenoxy)cyclobutyl 4-methylbenzenesulfonate (51.1 mg, 0.152 mmol) in DMF (1 mL) was added Cs2CO3(82 mg, 0.253 mmol) and (S)-5-(3,5- difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one I-2A (30 mg, 0.126 mmol),the reaction was stirred at 90 °C for 16 h. The mixture was cooled wo room temperature, filtered, and the filtrate was concentrated to give a residue which was purified by preparative HPLC (EJ Method Column Boston Green ODS 150*30mm*5um Condition water(0.01%TFA)-ACN Begin B 52 End B 72 Gradient Time(min) 10100%B Hold Time 2 Flow Rate(ml / min) 25 Injections 2 ) to give (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(4- fluorophenoxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (29.9 mg).1H NMR (500 MHz, CD3OD) δ 6.96-7.02 (m, 2H), 6.80-6.94 (m, 5H), 5.24 (dd, J=4.96, 8.16 Hz, 1H), 4.40-4.54 (m, 2H), 3.00-3.10 (m, 1H), 2.83-2.99 (m, 4H), 2.57-2.68 (m, 2H), 2.37-2.46 (m, 1H). MS (EI) Calculated for C21H18F3N3O2 [M+H]+, 402; found, 402. General Scheme G

[0359] The following examples in Table 10 were prepared according to General Scheme G using the methods described for Example 26-1, using the appropriate Intermediates in Table A and commercially available or known boronates for the sequence. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed.25866 Table 10. Compound Exact Mass Structure Name Number [M+H]+ , 8 , 8 , 8 , 8Example 27-1 6-((1S,3R)-3-((S)-5-(3,5-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutoxy)pyrimidine-4-carbonitrile

[0360] A-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one I-16A (100 mg, 0.325 mmol) and 6- chloropyrimidine-4-carbonitrile (54.5 mg, 0.390 mmol) in DMF (3 mL) was purged with nitrogen for 1 min followed by addition of Cs2CO3(159 mg, 0.488 mmol). The resulting mixture25866 was stirred at room temperature in a sealed reaction vessel overnight. The crude reaction was purified by reverse phase chromatography (C1826 g cartridge) eluting with acetonitrile / water + 0.05% TFA mixture. Related fractions were pooled and evaporated in vacuo to afford a brown solid which was further purified by preparative TLC (silica gel) developed with EtOAc / hexanes (20 v / v % ethyl acetate) to give 6-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutoxy)pyrimidine-4-carbonitrile.1H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 1.0 Hz, 1H), 7.10 (d, J = 1.1 Hz, 1H), 6.82 – 6.70 (m, 3H), 5.61 (tt, J= 7.3, 4.0 Hz, 1H), 5.16 (dd, J = 8.2, 4.0 Hz, 1H), 5.00 (tt, J = 8.7, 6.1 Hz, , 3.09 – 2.90 (m, 4H), 2.86 (ddd, J = 16.8, 9.4, 4.7 Hz, 1H), 2.74 – 2.62 (m, 2H), 2.44 (ddt, J = 12.9, 8.5, 4.4 Hz, 1H). MS (EI) Calculated for C20H17F2N6O2[M+H]+, 411; found, 411. Example 28-1tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one I-16A (50 mg, 0.163 mmol) in DMF (2 ml) wasadded sodium hydride (13 mg, 0.325 mmol) under N2, the mixture was stirred at 20 °C for 0.5 h,then 4-chloropyridine-2-carbonitrile (33.8 mg, 0.244 mmol) was added. The mixture was stirred at 20 °C for 12 h. The mixture was dissolved in water and EtOAc. The organic layer was separated and the aqueous was re-extracted twice with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-HPLC (Instrument ed Method Column Boston Prime C18150*30mm*5um Condition Water(0.05%NH3H2O+10mM NH4HCO3)-ACN Begin B 41 End B 71 Gradient Time(min) 10100%B Hold Time 2 Flow Rate (ml / min) 25 Injections 3) to give methyl 4-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutoxy)picolinonitrile.1H NMR (500 MHz, CDCl3) δ ppm 2.44 (ddt, J = 13.0, 8.5, 4.0, 4.0 Hz, 1H) 2.64 - 2.72 (m, 2H) 2.86 - 2.95 (m, 3H) 2.99 - 3.09 (m, 2H)25866 4.96 - 5.04 (m, 1H) 5.16 (dd, J = 8.0, 4.0 Hz, 1H) 5.58 - 5.63 (m, 1H) 6.72 - 6.80 (m, 3H) 7.11 (d, J = 1.0 Hz, 1H) 8.83 (d, J = 1.0 Hz, 1H). MS (EI) Calculated for C21H17F2N5O2[M+H]+, 410; found, 410. General Scheme I

[0362] TheScheme I using the methods described for Example 28-1, using the appropriate Intermediates and commercially available or known aryl halides for the sequence. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 11 Compound Exact Mass Structure Name N b M+H + nd nd nd25866 6-({trans-3-[(5S)-5-(3,5- difluorophenyl)-3-oxo-6,7- ' nd nd nd nd nd nd25866 tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one nd nd nd nd nd nd25866 tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one nd nd nd nd nd nd25866 yl]cyclobutyl}oxy)pyridine-3- carbonitrile nd nd nd nd nd nd25866 Example 29-1- oxo- - yl)cyclobutoxy)pyrimidine-4-carbonitrile 27-1 (7.5 mg, 0.018 mmol) and ghaffar-parkins catalyst (1.569 mg, 3.66 µmol) in Ethanol (0.5 mL) / Water (0.5 ml) was heated to 100 °C for 1 h. The resulting mixture was purified by reverse phase chromatography to afford 6-((1S,3R)-3-((S)-5- (3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutoxy)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate (8.5 mg).1H NMR (500 MHz, CD3OD) δ: 8.81 (d, J = 0.9 Hz, 1H), 7.47 (d, J = 1.0 Hz, 1H), 6.97 – 6.89 (m, 3H), 5.63 (tt, J = 7.4, 4.2 Hz, 1H), 5.27 (dd, J = 8.1, 5.0 Hz, 1H), 4.93 (tt, J = 8.7, 5.9 Hz, 1H), 3.14 – 3.06 (m, 1H), 3.06 – 2.90 (m, 4H), 2.79 – 2.67 (m, 2H), 2.51 – 2.40 (m, 1H) C20H18F2N6O3[M+H]+, 429; found, 429. Example 30-1 and 30-2 2-((1S,3R)-3-((S)-5-[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutoxy)pyrimidine-4-carbonitrile (30-1) and (S)-2-((1R,3S)-3-((2-chloropyrimidin- 4-yl)oxy)cyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one (30-2)25866was added NaH (15.62 mg, 0.390 mmol) at 0 ºC and stirred for 20 min. Then 2-chloropyrimidine-4- carbonitrile (43.6 mg, 0.312 mmol) was added and the resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by the addition of water (2 mL) and extracted with EtOAc (3 × 1 mL). The organic layer was concentrated in vacuo and purified by prep. RP-HPLC elution conditions: water(10 mM-NH4HCO3)-ACN to give 2 products: First eluting peak: 2-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutoxy)pyrimidine-4-carbonitrile (30-1) (38.05 mg).1H NMR (400 MHz, CDCl3) δ: 2.45 (ddt, J=12.76, 8.43, 4.25, 4.25 Hz, 1 H) 2.67 - 2.81 (m, 2 H) 2.84 - 3.09 (m, 5 H) 5.02 (tt, J=8.63, 5.86 Hz, 1 H) 5.17 (dd, J=8.11, 3.93 Hz, 1 H) 5.45 - 5.63 (m, 1 H) 6.64 - 6.86 (m, 3 H) 7.29 (d, J=4.77 Hz, 1 H) 8.75 (d, J=4.77 Hz, 1 H). MS (EI) Calculated for C20H16F2N6O2 [M+H]+, 411; found, 411. Second Eluting peak: (S)-2-((1R,3S)-3-((2-chloropyrimidin-4-yl)oxy)cyclobutyl)-5-(3,5- difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (30-2) (29.81 mg).1H NMR (400 MHz, CDCl3) δ: 2.45 (ddd, J=12.84, 8.67, 4.23 Hz, 1 H) 2.59 - 2.74 (m, 2 H) 2.86 - 3.09 (m, 5 H) 4.94 - 5.09 (m, 1 H) 5.17 (dd, J=8.23, 3.93 Hz, 1 H) 5.56 (tt, J=7.08, 3.65 Hz, 1 H) 6.62 - 6.85 (m, 4 H) 8.32 (d, J=5.72 Hz, 1 H). MS (EI) Calculated for C19H16ClF2N5O2[M+H]+, 420; found, 420. Example 31-125866 Step 1. Preparation 3H-pyrrolo[2,1-c][1,2,4]triazol-2 -

[0365] (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-hydroxycyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one I-17A (167mg, 0.543 mmol) and triethylamine (114 µL, 0.815 mmol) in DCM (3623 µL) was cooled to 0 °C where Ms-Cl (55.0 µL, 0.706 mmol) was added. The reaction was allowed to warm to RT and after 30 minutes the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phase was washed with water followed by brine and then dried over sodium sulfate, filtered and concentrated. Purification via silica gel chromatography (ISCO 12g Gold cartridge, eluting with 15-100% gradient of EtOAc / Hexanes) to afford product as a glassy oil. MS (EI) Calculated for C16H17F2N3O4S [M+H]+, 386; found, 386. Step 2. Preparation (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4- yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1R,3S)-3-((S)-5- (3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl methanesulfonate (35 mg, 0.091 mmol), pyrrolo[1,2-b]pyridazin-4-ol (21.32 mg, 0.159 mmol) and cesium carbonate (74.0 mg, 0.227 mmol) in DMA (605 µL) was heated to 90 °C overnight with stirring.

[0366] The reaction was cooled to room temperature then partitioned between EtOAc and water, washing the organic phase with water (2 x 20 mL) and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified via Silica gel chromatography (12g ISCO gold cartridge eluting with a gradient of 15-100% [(3:1)EtOAc:EtOH / Hexanes]. Fractions containing desired mass were pooled, concentrated and further purified RP-HPLC ISCO 13g column eluting with TFA modified conditions. The eluted product was neutralized with sat. sodium bicarbonate solution and extracted with EtOAc, dried over magnesium sulfate, filtered and concentrated to give product which was lyophilized to obtain the desired product.1H NMR (CDCl3) δ: 7.88 (d, J = 5.3 Hz, 1H), 7.70 (s, 1H), 6.86 – 6.74 (m, 3H), 6.66 (d, J = 3.1 Hz, 1H), 5.73 (d, J = 5.3 Hz, 1H), 5.19 (td, J = 7.9, 7.4, 3.7 Hz,25866 2H), 5.07 (ddd, J = 14.9, 8.8, 6.2 Hz, 1H), 3.15 – 2.75 (m, 6H), 2.47 (ddt, J = 12.9, 8.6, 4.4 Hz, 1H), 0.95 – 0.79 (m, 2H). MS (EI) Calculated for C22H19F2N5O2[M+H]+, 424; found, 424. General Scheme JJ using the methods described for Example 31-1, using the appropriate Intermediates and commercially available or known aromatic phenols for the sequence. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 12 Compound Exact Mass Structure Name Number [M+H]+ 2, 2 9, 9 0, 0 4, 4 7, 725866 c][1,2,4]triazol-2(5H)-yl]cyclobutyl}oxy)- 2-fluorobenzonitrile 2, 2 7, 7 5, 5 9, 9 8, 8 2, 2 1, 1 1, 125866 (5S)-2-{trans-3-[(1,2-benzoxazol-7- yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)- Calc'd 425, 5 5, 5 0, 0 3, 3 7, 7 1, 1 3, 3 4, 4 1, 125866 2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one 3, 3 2, 2 9, 9 3, 3 3, 3 5, 5 1, 1 9, 925866 2-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3- oxo-6,7-dihydro-3H-pyrrolo[2,1- Calc'd 427, 7 6, 6 1, 1 2, 2 1, 1 6, 6 2, 2 3, 3 5, 525866 2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one 5, 5 5, 5 7, 7 3, 3 6, 6 9, 9 7, 7Example 32-125866 (S)-2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-oneone

[0368] To a solution of (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (200 mg, 0.994 mmol) in 1,4-Dioxane (3 mL) was added N,N'-dimethylethylenediamine (88 mg, 0.994 mmol), 4-bromo-2-fluorophenol (190 mg, 0.994 mmol), Cs2CO3 (971 mg, 2.98 mmol) and copper(I) iodide (151 mg, 0.795 mmol) at ambient temperature under nitrogen. The resulting mixture was brought to 115 °C for 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, EtOAc / hexanes : 1 / 1) to afford (S)-2-(3-fluoro-4-hydroxyphenyl)-5- phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C17H15FN3O2 [M+H]+, 312; found, 312. Step 2. Preparation of (S)-2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0369] To a mixture of (S)-2-(3-fluoro-4-hydroxyphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (70 mg, 0.225 mmol) in DMF (1 mL) was added 5-bromo-4- methylthiazole (60.1 mg, 0.337 mmol) and K2CO3(62.2 mg, 0.450 mmol) at ambient temperature under nitrogen. The resulting mixture was stirred at 60 °C for 12 h. The reaction was cooled to ambient temperature and filtered. The filtrate was directly purified by RP-HPLC elution conditions: water (10 mM NH4HCO2)-ACN to afford (S)-2-(3-fluoro-4-((4-methylthiazol- 5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C21H18FN4O2S [M+H]+, 409; found, 409.1H NMR (400 MHz, CDCl3) δ = 8.32 (s, 1H), 7.78 - 7.82 (m, 1H), 7.59 - 7.64 (m, 1H), 7.23 - 7.37 (m, 3H), 7.15 - 7.19 (m, 2H), 6.85 - 6.94 (m, 1H), 5.17 - 5.29(m, 1H), 2.78-3.05 (m, 3H), 2.41 - 2.513 (m, 1H), 2.27 (s, 3H).25866 Example 33-1 3-((1S,3R)-3-((S)-3-oxo-5- [1,2,4]triazolo[4,3-a]pyridin-2(3H)-

[0370] To a solution of (1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-ol (400 mg, 1.98 mmol) in toluene (10 mL) was added 3-bromobenzonitrile (504 mg, 2.77 mmol), Cs2CO3(1288 mg, 3.95 mmol), RockPhos (93 mg, 0.198 mmol) and [PdCl(C3H5)]2 (72.3 mg, 0.198 mmol) at ambient temperature under nitrogen. The resulting mixture was brought to 80 °C for 3 h. The reaction was cooled to ambient temperature and filtered. The filtrate was concentrated and the resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 3- ((1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)benzonitrile. MS (EI) Calculated for C17H26NO2Si [M+H]+, 304; found, 304. Step 2. Preparation of 3-((1S,3S)-3-hydroxycyclobutoxy)benzonitrile

[0371] To a mixture of 3-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)benzonitrile (60 mg, 0.198 mmol) in MeOH (2 mL) was added ammonium fluoride (73.2 mg, 1.98 mmol) at ambient temperature. The reaction was brought to 40 °C for 16 h then cooled to ambient25866 temperature and concentrated under reduced pressure. The resulting residue was taken up in DCM then filtered. The filtrate was concentrated under reduced pressure to afford 3-((1S,3S)-3- hydroxycyclobutoxy)benzonitrile which was used in next step directly. MS (EI) Calculated for C11H12NO2[M+H]+, 190; found, 190. Step 3. Preparation of (1S,3S)-3-(3-cyanophenoxy)cyclobutyl 4-methylbenzenesulfonate

[0372] To a mixture of 3-((1S,3S)-3-hydroxycyclobutoxy)benzonitrile (190 mg, 1.00 mmol) in DCM (10 mL) was added 4-methylbenzenesulfonyl chloride (211 mg, 1.10 mmol) and DMAP (184 mg, 1.506 mmol) at ambient temperature. The reaction was stirred for 12 h then concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford (1S,3S)-3-(3-cyanophenoxy)cyclobutyl 4- methylbenzenesulfonate. Step 4. Preparation of methyl (S)-2-((1R,3S)-3-(3-cyanophenoxy)cyclobutyl)-3-oxo-2,3,5,6,7,8- hexahydro-[1,2,4]triazolo[4,3-a] carboxylate

[0373] To a solution of methyl2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine- 5-carboxylate (160 mg, 0.811 mmol) in DMF (4 mL) was added Cs2CO3 (793 mg, 2.43 mmol) and (1S,3S)-3-(3-cyanophenoxy)cyclobutyl 4-methylbenzenesulfonate (306 mg, 0.893 mmol) at ambient temperature. The reaction mixture was brought to 80 ºC for 2 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC elution conditions: water (0.1% NH4HCO3)-ACN to afford methyl (S)-2-((1R,3S)-3-(3-cyanophenoxy)cyclobutyl)-3-oxo-2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3- a]pyridine-5-carboxylate. MS (EI) Calculated for C19H21N4O4[M+H]+, 369; found, 369. Step 5. Preparation of (S)-2-((1R,3S)-3-(3-cyanophenoxy)cyclobutyl)-3-oxo-2,3,5,6,7,8- hexahydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid

[0374] To a mixture of methyl (S)-2-((1R,3S)-3-(3-cyanophenoxy)cyclobutyl)-3-oxo- 2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (200 mg, 0.543 mmol) in THF (6 mL) and water (2 mL) was added lithium hydroxide hydrate (68.3 mg, 1.63 mmol) at ambient temperature. The reaction mixture was held at 25 °C for 3 h then purified directly by RP-HPLC elution conditions: water (0.1% NH4HCO3)-ACN to afford (S)-2-((1R,3S)-3-(3- cyanophenoxy)cyclobutyl)-3-oxo-2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine-5- carboxylic acid. MS (EI) Calculated for C18H19N4O4[M+H]+, 355; found, 355. Step 6. Preparation of 3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)cyclobutoxy)benzonitrile

[0375] To a solution of (S) -3-(3-cyanophenoxy)cyclobutyl)-3-oxo-2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid (50 mg, 0.141 mmol) in DMF (1.525866 ml) was added 2-chloropyrazine (48.5 mg, 0.423 mmol), Cs2CO3 (92 mg, 0.282 mmol), 2,2'- bipyridine (4.41 mg, 0.028 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (3.10 mg, 0.014 mmol) and 4CzIPN (2.78 mg, 3.53 µmol) at ambient temperature under nitrogen. The resulting mixture was irradiated with a 450 nM blue LED for 12 hours. The mixture was filtered and the filtrate was purified directly by RP-HPLC elution conditions: water (0.1% NH4HCO3)-ACN to afford 3-((1R,3R)-3-(3-oxo-5-(pyrazin-2-yl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)cyclobutoxy)benzonitrile as a mixture of isomers. The isomers were separated by SFC using a Diacel CHIRALCEL OJ 30 x 250 mm, 10 ^m column; 40% EtOH with 0.1% NH4OH; flow rate = 80 mL / min. Retention times for peak collection were as follows: first eluting peak, 1.447 min and second eluting peak, 1.793 min. The first eluting peak gave 3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-2(3H)-yl)cyclobutoxy)benzonitrile. MS (EI) Calculated for C21H21N6O2[M+H]+, 389; found, 389.1H NMR (400 MHz, CDCl3) δ 8.43-8.60 (m, 3H), 7.33-7.41 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H) 7.09 (m, 2H), 5.23 (t, J = 5.2 Hz, 1H), 4.92-5.06 (m, 2H), 2.86-2.98 (m, 3H),2.73-2.82 (m, 1H), 2.63 (ddd, J = 3.6, 8.8, 12.0 Hz, 2H), 2.18-2.36 (m, 2H), 1.83-1.92 (m, 2H). Example 34-1 -25866 Step 1. Preparation of 3-(3-(benzyloxy)cyclobutyl)benzonitrile

[0376] To a solution of (1S,3S)-3-(benzyloxy)cyclobutan-1-ol (200 mg, 1.12 mmol) and 5,7-di- tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (444 mg, 1.12 mmol) in MTBE (9 mL) was added a solution of pyridine (0.091 mL, 1.12 mmol) in MTBE (2.2 mL) at ambient temperature under nitrogen. The resulting solution was stirred for 1 hour then added to a solution of Quinuclidine (218 mg, 1.96 mmol), 3-bromobenzonitrile (306 mg, 1.68 mmol), Ir(ppy)2(dtbbpy)PF6 (15 mg, 0.017 mmol) and NiBr2^dtbbpy (27 mg, 0.056 mmol) in DMA (11.2 mL) under nitrogen. The final solution was irradiated with blue LEDs (450 nM) for 18 h. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic extracts were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 3-(3- (benzyloxy)cyclobutyl)benzonitrile. MS (EI) Calculated for C18H18NO [M+H]+, 264; found, 264. Step 2. Preparation of 3-(3-hydroxycyclobutyl)benzonitrile

[0377] To a solution of 3-(3-(benzyloxy)cyclobutyl)benzonitrile (163 mg, 0.619 mmol) in EtOAc (6.2 mL) was added Pd(OH)2 / C (43 mg, 0.062 mmol). The reaction headspace was evacuated and refilled with hydrogen (3x) and the reaction stirred at ambient temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 3-(3-hydroxycyclobutyl)benzonitrile. MS (EI) Calculated for C18H18NO [M+H]+, 174; found, 174. Step 3. Preparation of 3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutyl)benzonitrile

[0378] To a of 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one (47 mg,and 3-(3-hydroxycyclobutyl)benzonitrile (44 mg, 0.25 mmol) in toluene (1 mL) was added CMBP (76 ^L, 0.29 mmol) at ambient temperature. The resulting mixture was brought to 90 °C for 18 hours then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep. RP-HPLC elution conditions: water (0.01% TFA)-ACN to give (S)-3-(3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutyl)benzonitrile as a mixture of isomers. The isomers were separated by SFC resolution using a CCA 21 x 250 mm , 5 ^m column; 20% MeOH with 0.1% NH4OH; flow rate = 70 mL / min to give 3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)benzonitrile as the fourth of four eluting peaks with a retention time of 10.68 min. MS (EI) Calculated for C20H19N6O [M+H]+, 359;25866 found, 359.1H NMR (499 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.65 (s, 2H), 7.87 (s, 1H), 7.74 – 7.67 (m, 2H), 7.59 – 7.52 (m, 1H), 5.44 – 5.37 (m, 1H), 4.76 – 4.66 (m, 1H), 3.80 – 3.71 (m, 1H), 3.05 – 2.745H), 2.60 – 2.50 (m, 3H). Example 35-1 2-chloro-3-((1S,3R)-3-((S)-3- 3H-pyrrolo[2,1-c][1,2,4]triazol-- Cl CN

[0379] A mixture of Ir[dF(CF3)ppy]2(dtbpy)PF6 (33.7 mg, 0.03 mmol), Ni(4,4'-dtbbpy)Cl2 (5.97 mg, 0.015 mmol), 2,6-lutidine (0.699 ml, 6.0 mmol), 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (0.926 mL, 3.0 mmol), 3-bromo-2-chlorobenzonitrile (649 mg, 3.0 mmol) and 2-bromo-5,8-dioxaspiro[3.4]octane (1737 mg, 9.0 mmol) was taken up in DME (26 ml). The resulting solution was degassed with nitrogen for 10 minutes then irradiated with blue LEDs (450 nM) for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 2-chloro-3-(5,8-dioxaspiro[3.4]octan-2-yl)benzonitrile. MS (EI) Calculated for C13H13ClNO2 [M+H]+, 250; found, 250. Step 2. Preparation of 2-chloro-3-(3-oxocyclobutyl)benzonitrile

[0380] To a solution of 2-chloro-3-(5,8-dioxaspiro[3.4]octan-2-yl)benzonitrile (556 mg, 2.23 mmol) in acetone (11.1 mL) was added PTSA monohydrate (466 mg, 2.45 mmol) and water (401 uL) at ambient temperature. The mixture was brought to 70 °C for 4 h then cooled to ambient25866 temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 2-chloro-3-(3- oxocyclobutyl)benzonitrile. Calculated for C11H9ClNO [M+H]+, 206; found, 206. Step 3. Preparation of 2-chloro-3-(3-hydroxycyclobutyl)benzonitrile

[0381] To a solution of 2-chloro-3-(3-oxocyclobutyl)benzonitrile (278 mg, 1.35 mmol) in MeOH (3.4 mL) was added sodium borohydride (61.4 mg, 1.62 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 18 hours then concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 2-chloro-3-(3-hydroxycyclobutyl)benzonitrile. Calculated for C11H11ClNO [M+H]+, 208; found, 208. Step 4. Preparation of 2-chloro-3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)benzonitrile

[0382] To a mixture of 5- 2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one (30 mg, 0.148 mmol)chloro-3-(3-hydroxycyclobutyl)benzonitrile (33.7 mg, 0.162 mmol) in toluene (0.5 mL) was added CMBP (49 ^L, 0.185 mmol) at ambient temperature. The resulting mixture was brought to 80 °C for 18 hours then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep. RP-HPLC elution conditions: water (0.01% TFA)-ACN to afford (S)-2-chloro-3-(3-(3-oxo-5-(pyrazin-2-yl)- 6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutyl)benzonitrile as a mixture of isomers. The isomers were separated by SFC resolution using an IH 21 x 250 mm , 5 ^m column; 30% MeOH with 0.1% NH4OH; flow rate = 70 mL / min to give 2-chloro-3-((1S,3R)-3- ((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)benzonitrile as the second of two eluting peaks with a retention time of 4.4 min. MS (EI) Calculated for C20H18ClN6O [M+H]+, 393; found, 393.1H NMR (499 MHz, DMSO-d6) δ 8.76 (d, J = 1.3 Hz, 1H), 8.67 – 8.63 (m, 2H), 7.98 (d, J = 7.8 Hz, 1H), 7.87 (dd, J = 7.7, 1.2 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 5.43 – 5.39 (m, 1H), 4.67 – 4.58 (m, 1H), 4.03 – 3.94 (m, 1H), 3.04 – 2.78 (m, 5H), 2.66 – 2.46 (m, 3H). The following examples in Table 13 were prepared in an analogous manner of that described for Example 35-1, using appropriate intermediates and commercial aryl bromides or known ketones. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed.25866 Table 13. Compound Exact Mass Structure IUPAC Name Number [M+H]+ nd nd nd nd nd nd nd25866 (S)-5-phenyl-2-((1R,3S)-3-(pyridin- Calc'd 2-yl)cyclobutyl)-2,5,6,7-tetrahydro- nd nd nd nd nd ndExample 36-1 (S)-2-((1R,3S)-3-(4-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one25866 2)NI-14AN O N Step 1.

[0383] To a mixture of 3-(4-methoxyphenyl)cyclobutan-1-one (2 g, 11.4 mmol) in MeOH (30 mL) was added NaBH4(0.344 g, 9.08 mmol) at 0 °C. The reaction was brought to 25 °C and held for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was brought up in water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford (1S,3S)-3-(4- methoxyphenyl)cyclobutan-1-ol. Crude material was taken on as is.1H NMR (400 MHz, CDCl3) δ = 7.21 - 7.14 (m, 2H), 6.93 - 6.81 (m, 2H), 4.34 - 4.22 (m, 1H), 3.80 (s, 3H), 2.99 - 2.85 (m, 1H), 2.83 - 2.69 (m, 2H), 2.05 - 1.91 (m, 2H). Step 2. Preparation of (S)-2-((1R,3S)-3-(4-methoxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7- tetrahydro-3H- c][1,2,4]triazol-3-one

[0384] To a(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one (300 mg, 1.48 mmol) and (1S,3S)-3-(4-methoxyphenyl)cyclobutan-1-ol (289 mg, 1.62 mmol) in toluene was added CMBP (1069 mg, 4.43 mg) at ambient temperature. The mixture was purged with nitrogen for 1 minute then brought to 100 °C for 24 hours. The reaction mixture was cooled to ambient temperature then concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (MeOH / DCM). The resulting material was further purified by RP-HPLC elution conditions: water (0.1% TFA)-ACN to afford to afford 2- ((1R,3R)-3-(4-methoxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one as a mixture of isomers. The isomers were separated by SFC using a Daicel CHIRALPAK AD 30 x 250 mm, 10 ^m column; 55% EtOH with 0.1% NH4OH; flow rate = 80 mL / min. Retention times for peak collection were as follows: first eluting peak, 2.435 min; second eluting peak, 2.764 min. The second eluting peak was (S)-2-((1R,3S)-3-(4- methoxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-25866 3-one and was taken on to next step. MS (EI) Calculated for C20H22N5O2 [M+H]+, 364; found, 364. Step 3. Preparation of (S)-2-((1R,3S)-3-(4-hydroxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0385] To a mixture of (S)-2-((1R,3S)-3-(4-methoxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (100 mg, 0.275 mmol) in DCM (1 mL) was added BBr3 (0.053 mL, 0.55 mmol) at -70 °C under nitrogen. The resulting mixture was held at -70 °C for 2 hours then added to saturated aqueous NaHCO3(10 mL). The aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic extracts were concentrated under reduced pressure and the resulting residue was purified by SFC using a Daicel CHIRALPAK AD 30 x 250 mm, 10 ^m column; 45% EtOH with 0.1% NH4OH; flow rate = 80 mL / min to afford (S)-2-((1R,3S)-3-(4-hydroxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one as the first eluting peak. MS (EI) Calculated for C19H20N5O2 [M+H]+, 350; found, 350.1H NMR (400 MHz, METHANOL-d4) δ = 8.62 - 8.58 (m, 1H), 8.53 - 8.45 (m, 2H), 7.08 - 7.01 (m, 2H), 6.69 - 6.59 (m, 2H), 5.35 - 5.29 (m, 1H), 4.71 - 4.65 (m, 1H), 3.54 - 3.47 (m, 1H), 3.02 - 2.90 (m, 2H), 2.87 - 2.74 (m, 3H), 2.59 - 2.50 (m, 1H), 2.43 - 2.33 (m, 2H). Example 37-1 and 37-2 (R or S)-5--2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (37-1) and (S or R)-5-(pyrazin-2-yl)-2- ((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4-yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one (37-2)25866 Step 1. Preparation of 2-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-(pyrazin-2-yl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one

[0386] To a solution of (1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl 4- methylbenzenesulfonate (421 mg, 1.18 mmol) in DMF (5 mL) was added Cs2CO3(962 mg, 2.95 mmol), (S)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (200 mg, 0.984 mmol) and 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (200 mg, 0.984 mmol) at ambient temperature. The reaction mixture was brought to 80 °C for 16 h then cooled to ambient temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford 2-((1R,3R)-3-((tert- butyldimethylsilyl)oxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one. MS (EI) Calculated for C19H30N5O2Si [M+H]+, 388; found, 388. Step 2. Preparation of 2-((1R,3R)-3-hydroxycyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]

[0387] To a solution-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-(pyrazin-2- yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (150 mg, 0.387 mmol) in MeOH (2 mL) was added HCl / MeOH (2 mL) at ambient temperature. The reaction was brought to 40 °C for 16 h. The solvent was evaporated under reduced pressure. The crude material was suspended in DCM and the mixture was filtered. The filtrate was concentrated under reduced pressure to afford 2-((1R,3R)-3-hydroxycyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one, which used in next step directly. MS (EI) Calculated for C13H16N5O2 [M+H]+, 274; found, 274. Step 3. Preparation of 2-(3-iodocyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0388] Ph3P (72.0 mg, 0.274 mmol), 1H-imidazole (62.3 mg, 0.915 mmol) and I2 (69.7 mg, 0.274 mmol) were added to a solution of 2-((1R,3R)-3-hydroxycyclobutyl)-5-(pyrazin-2-yl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (50.0 mg, 0.183 mmol) in DMF (1 mL). The resulting mixture was stirred at 110 °C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep. TLC (EtOAc) to give 2-(3-iodocyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one. MS (EI) Calculated for C13H15IN5O [M+H]+, 384; found, 384. Step 4. Preparation of 5-(pyrazin-2-yl)-2-((1R,3R)-3-(pyrrolo[1,2-b]pyridazin-4- yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one25866

[0389] To a solution of 2-(3-iodocyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (35.0 mg, 0.091 mmol) and pyrrolo[1,2-b]pyridazin-4-ol (14.7 mg, 0.110 mmol) in DMF (2 mL) was added cesium carbonate (89.0 mg, 0.274 mmol). The reaction was heated to 80 °C for 16 hours then directly purified by prep. RP-HPLC elution conditions: water (0.01% TFA)-ACN to give 5-(pyrazin-2-yl)-2-((1R,3R)-3-(pyrrolo[1,2- b]pyridazin-4-yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as a mixture of isomers. The isomers were separated by SFC using a Daicel CHIRALPAK AD 30 x 250 mm, 10 ^m column; 55% EtOH with 0.1% NH4OH; flow rate = 80 mL / min. Retention times for peak collection were as follows: first eluting peak, 1.024 min; second eluting peak, 2.024 min. Peak 1 (37-1): (R or S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4- yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one.1H NMR (400 MHz, CDCl3) δ 8.60 (br s, 3H), 7.87 (d, J=5.25 Hz, 1H), 7.66-7.70 (m, 1H), 6.74 (dd, J=2.68, 4.23 Hz, 1H), 6.64 (dd, J=1.61, 4.23 Hz, 1H), 5.71 (d, J=5.36 Hz, 1H), 5.34 (dd, J=3.40, 8.17 Hz, 1H), 5.13-5.2 (m, 1H), 4.97-5.06 (m, 1H), 2.88-3.08 (m, 5H), 2.74-2.83 (m, 3H). MS (EI) Calculated for C20H20N7O2[M+H]+, 390; found, 390. Peak 2 (37-2): (S or R)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4- yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one.1H NMR (400 MHz, CDCl3) δ 8.61 (br s, 3H), 7.87 (d, J=5.36 Hz, 1H), 7.65-7.70 (m, 1H), 6.75 (dd, J=2.74, 4.17 Hz, 1H), 6.64 (dd, J=1.61, 4.35 Hz, 1H), 5.72 (d, J=5.36 Hz, 1H), 5.35 (dd, J=3.34, 8.23 Hz, 1H), 5.13-5.2 (m, 1H), 4.97-5.06 (m, 1H), 2.87-3.09 (m, 5H), 2.74-2.83 (m, 3H). MS (EI) Calculated for C20H20N7O2[M+H]+, 390; found, 390. Example 38-1 (S)-5-(pyrazin-2-yl)-2-(tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one25866 Step 1. 3H-pyrrolo

[0390] To a mixture of 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one (500 mg, 2.46 mmol) and 3-(benzyloxy)cyclobutan-1-ol (482 mg, 2.71 mmol) in toluene (11 mL) was added CMBP (807 ^L, 3.08 mmol) at ambient temperature. The resulting mixture was brought to 80 °C for 18 hours then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting with 0-100% gradient of (3:1 EtOAc / EtOH) / Hexanes) to afford 2-(3-(benzyloxy)cyclobutyl)-5-(pyrazin-2-yl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C20H22N5O2 [M+H]+, 364; found, 364. Step 2. Preparation of 2-(3-oxocyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one

[0391] To a mixture of 2-(3-(benzyloxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (0.573 g, 1.58 mmol) in acetonitrile (7.9 mL) and water (0.79 mL) was added 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (1.656 g, 5.52 mmol) at ambient temperature. The resulting mixture was brought to 30 °C for 18 hours then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting with 0-100% gradient of (3:1 EtOAc / EtOH) / Hexanes) to afford 2-(3-oxocyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C13H14N5O2 [M+H]+, 272; found, 272. Step 3. Preparation of 5-(pyrazin-2-yl)-2-((1R,3R)-3-(o-tolyl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one

[0392] To a mixture of 2-(3-oxocyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (54.3 mg, 0.2 mmol) in acetonitrile (1 mL) was added 4-25866 methylbenzenesulfonohydrazide (37.2 mg, 0.2 mmol) at ambient temperature. The resulting mixture was brought to 50 °C for 2 hours then cooled to room temperature and concentrated under reduced pressure. Potassium carbonate (41.5 mg, 0.3 mmol) and o-tolylboronic acid (40.8 mg, 0.3 mmol) were added to the resulting residue and the mixture was taken up in dioxane (1 mL). The mixture was heated to 110 °C for 18 hours then concentrated under reduced pressure. The resulting residue was purified by prep. RP-HPLC elution conditions: water (0.01% TFA)- ACN to give 5-(pyrazin-2-yl)-2-(3-(o-tolyl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one as a mixture of isomers. The isomers were separated by SFC using a Lux- 2 21 x 250 mm, 5 ^m column; 45% MeOH with 0.1% NH4OH; flow rate = 70 mL / min. Retention times for peak collection were as follows: first eluting peak, 3.45 min; second eluting peak, 3.90 min and third eluting peak, 4.60 min. The second eluting peak was further resolved by SFC using an OJ-H 21 x 250 mm, 5 ^m column; 15% MeOH with 0.1% NH4OH; flow rate = 70 mL / min. Retention times for peak collection were as follows: first eluting peak, 2.40 min; second eluting peak, 2.90 min. The first eluting peak of this resolution gave 5-(pyrazin-2-yl)-2- ((1R,3R)-3-(o-tolyl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. MS (EI) Calculated for C20H22N5O [M+H]+, 348; found, 348.1H NMR (499 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.65 (s, 2H), 7.46 – 7.41 (m, 1H), 7.24 – 7.10 (m, 3H), 5.44 – 5.38 (m, 1H), 4.65 – 4.59 (m, 1H), 3.79 – 3.73 (m, 1H), 3.07 – 2.74 (m, 6H), 2.49 – 2.39 (m, 2H), 2.19 (s, 3H).

[0393] The following examples in Table 14 were prepared in an analogous manner of that described for either Example 38-1, using appropriate intermediate and commercial or known boronic acids. The compounds were generally purified via reverse phased HPLC with chiral SFC resolution when needed. Table 14. Compound Exact Mass Structure IUPAC Name + nd25866 Example 39-1 and 39-2 -5-

[0394] To a mixture of tert-butyl 3-hydroxycyclobutane-1-carboxylate (700 mg, 4.06 mmol), DMAP (50 mg, 0.406 mmol) and imidazole (830 mg, 12.2 mmol) in DCM (15 mL) was added TBSCl (919 mg, 6.1 mmol) at ambient temperature under nitrogen. The resulting mixture was stirred for 18 hours then diluted with water and extracted with DCM. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford tert-butyl 3-((tert- butyldimethylsilyl)oxy)cyclobutane-1-carboxylate. MS (EI) Calculated for C15H30NaO3Si [M+Na]+, 309; found, 309. Step 2. Preparation of tert-butyl 3-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)cyclobutane- 1-carboxylate

[0395] To a mixture of 2,2,6,6-tetramethylpiperidine lithium salt (1:1) (219 mg, 1.48 mmol) in toluene (1.5 mL) was added tert-butyl 3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carboxylate (368 mg, 1.28 mmol) at ambient temperature under a nitrogen. The resulting mixture was stirred for 20 minutes then ZnCl2(1.9 M in 2-MeTHF) (0.782 mL, 1.48 mmol). The reaction was25866 allowed to stir an additional 30 minutes at ambient temperature. Finally, a solution of CPhos Pd G4 (36.1 mg, 0.044 mmol) and 1-bromo-3-chlorobenzene (211 mg, 1.1 mmol) in toluene (1.5 mL) was added to the mixture which was brought to 40 °C for 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford tert-butyl 3-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)cyclobutane-1-carboxylate. MS (EI) Calculated for C17H26ClO3Si [M+H-tBu]+, 341; found, 341. Step 3. Preparation of tert-butyl 1-(3-chlorophenyl)-3-hydroxycyclobutane-1-carboxylate

[0396] To a mixture of tert-butyl 3-((tert-butyldimethylsilyl)oxy)-1-(3- chlorophenyl)cyclobutane-1-carboxylate (425 mg, 1.07 mmol) in THF (5 mL) was added TBAF (1 M in THF) (1.3 mL, 1.3 mmol) at ambient temperature. After 3 hours CaCO3 (500 mg, 5 mmol), Dowex ® resin (1.5 g) and MeOH (4 mL) was added to the reaction mixture. The resulting slurry was stirred for 2 hours then filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography [(3:1 EtOAc:EtOH) / hexanes] to afford tert-butyl 1-(3-chlorophenyl)-3- hydroxycyclobutane-1-carboxylate. MS (EI) Calculated for C15H19ClNaO3 [M+Na]+, 305; found, 305. Step 4. Preparation of tert-butyl 1-(3-chlorophenyl)-3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutane-1-carboxylate

[0397] To a mixture of 5- 2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one (198 mg, 0.973 mmol)butyl 1-(3-chlorophenyl)-3-hydroxycyclobutane-1- carboxylate (250 mg, 0.884 mmol) in toluene (4 mL) was added CMBP (290 ^L, 1.10 mmol) at ambient temperature. The resulting mixture was brought to 80 °C for 18 hours, cooled to room temperature and diluted with water. Aqueous layer was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford tert-butyl 1-(3-chlorophenyl)-3-(3- oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutane-1- carboxylate. MS (EI) Calculated for C24H27ClN5O3 [M+H]+, 468; found, 468. Step 5. Preparation of 1-(3-chlorophenyl)-3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1- c][1,2,4]triazol-2(5H)-yl)cyclobutane-1-carboxylic acid

[0398] To a mixture of 2-(3-(benzyloxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one (300 mg, 0.641 mmol) in DCM (1.5 mL) was added HCl (4 M in 1,4-dioxane) (1.5 mL, 6 mmol) at ambient temperature. The reaction mixture was stirred for 18 hours then concentrated under reduced pressure. The resulting residue was taken up in25866 water / DCM and made basic by addition of aqueous NaOH (2N). The aqueous mixture was washed with DCM then made acidic by addition of concentrated HCl. The resulting aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 1-(3-chlorophenyl)-3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutane-1-carboxylic acid which was taken on without purification. MS (EI) Calculated for C20H19ClN5O3[M+H]+, 412; found, 412. Step 6. Preparation of (S)-2-((1S,3R)-3-(3-chlorophenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and (S)-2-((1R,3S)-3-(3- chlorophenyl)cyclobutyl)-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one

[0399] To a mixture of 1-(3-chlorophenyl)-3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H- pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)cyclobutane-1-carboxylic acid (263 mg, 0.639 mmol), diphenyl disulfide (13.9 mg, 0.064 mmol) and Mes-Acr (14.7 mg, 0.032 mmol) was added a degassed solution of DIPEA (22 uL, 0.128 mmol) in 2,2,2-trifluoroethanol (2 mL) under nitrogen. The reaction vessel was sealed, and the reaction mixture was irradiated with a 450 nM light source for 24 hours. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was filtered through a phase separator and concentrated under reduced pressure. The resulting residue was purified by prep. RP-HPLC elution conditions: water (0.01% TFA)-ACN to give 2-(3-(3-chlorophenyl)cyclobutyl)-5-(pyrazin-2-yl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as a mixture of isomers. The isomers were separated by SFC using an IA 21 x 250 mm, 5 ^m column; 40% MeOH with 0.1% NH4OH; flow rate = 70 mL / min. Retention times for peak collection were as follows: first eluting peak, 2.65 min; second eluting peak, 3.15 min; third eluting peak, 3.58 min and fourth eluting peak, 4.5 min. The second eluting peak gave (39-1) (S)-2-((1S,3R)...

Claims

25866 WHAT IS CLAIMED IS:

1. A compound of formula I: a pharmaceutically acceptable salt thereof, wherein:D is C or N; E is C or N; G is C or O; J is C, S or O; L is a (C3-C10)cycloalkyl; (C6-C10)aryl; heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O; or a heterocycle having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O; and wherein L is not bicyclic or a bridged ring; R1is H; OH; (C1-C6)alkyl; or F R2is H, OH; (C1-C6)alkyl; or F and wherein R1and R2are absent if J is S or O; R3is H; Alternately, where n is 0, R1and R3together with the carbons to which they are attached, can form a three membered cycloalkyl; R4is H; halogen; or (C1-C6) nitrile; R5is H or halogen; R6is H or halogen; R7is H or halogen; provided that where A, B, or D is N the respective R4, R6or R7is absent; R8is (C1-C6)alkyl optionally substituted with nitrile, up to 3 halo, (C3-C7)cycloalkyl, (C6- C10)aryl, (C3-C6)cycloalkyl-O-(C1-C6)m-(C6—C10)aryl, or heteroaryl having 5-10 ring atoms and containing up to 4 heteroatoms selected from N, S or O and further optionally substituted with upto 3 ;R9is H;C6)alkyl optionally substituted by a nitrile or up to 3 halogens; -25866 Q-(C3-C10)cycloalkyl optionally substituted by (C1-C6)alkyl, CF3, nitrile, or up to 3 halogens; (C1-C6)nitrile; -N-C(O)-(C6)aryl optionally substituted by up to 3 halogens; (C1-C6) alkyl optionally substituted by up to 3 halogens; -Q-(C6-C10) aryl optionally substituted by OH, (C1- C6)alkyl, up to 3 halogens, CN, or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O; -Q-heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S, and O and optionally substituted by up to 3 halogens, (C1- C6)alkyl, CF3, -CN, or R18; S(O)2-R12; O-R13; (CH3)x-R14; or C(O)-R15; R10is H; halogen; (C1-C6)alkyl optionally substituted by up to 3 halogens; -O-(C1-C6)alkyl; or =O; R11is H; halogen; (C1-C6)alkyl optionally substituted by up to 3 halogens; -O-(C1-C6)alkyl; or =O; R12is (C1-C6)alkyl; (C3-C6)cycloalkyl; heterocycle having 4-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O optionally substituted by (C1-C6)alkyl; (C6-C8) aryl optionally substituted by up to 3 halogens or (C1-C6)alkyl optionally further substituted by up to 3 halogens; or -N(CH3)2; R13is (C1-C6)alkyl optionally substituted by (C3-C6)cycloalkyl, (C6)aryl, or up to 3 halogens; (C3-C6)cycloalkyl optionally substituted by (C1-C6)alky further optionally substituted by up to 3 halogens; (C6-C10)aryl-(R16)y; heteroaryl-(R17)z said heteroaryl having 5-10 ring atoms and containing up to 3 heteroatoms selected from N, S and O; R14is (C3-C6)cycloalkyl; (C6)aryl; -O-(C1-C6)alkyl R15is -O-(C1-C6)alkyl or NH2R16is halogen; CF2; CF3; CN; (C1-C6)alkyl optionally substituted by a nitrile; -OCH3; or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and optionally substituted by a (C1-C6)alkyl; R17is halogen; CN; S-CH3; C(O)-NH2; -O-CF2; (C1-C6)alkyl optionally substituted by up to 3 halogens; or a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N and O and optionally substituted by a (C1-C6)alkyl or up to 3 halogens; R18is a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O and optionally substituted by CN or (C1-C6)alkyl; Q is a bond, O, or (C1-C3)alkyl; n is 0 or 1; m is 0-6; x is 0-6; y is 0-3; and25866 z is 0-3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8is .of any of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a (C3-C10)cycloalkyl or (C6-C10)aryl.

4. The compound of any of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R9is a (C6-C10) aryl optionally substituted by a heteroaryl having 5-6 ring atoms and containing up to 3 heteroatoms selected from N, S and O.

5. The compound of any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R9is a (C6-C10) aryl.

6. The compound of any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A, B, D, E, and J are C.

7. The compound of any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A and D are N.

8. The compound of any of claims 1 and 7, or a pharmaceutically acceptable salt thereof, wherein B is N.

9. The compound of any of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R4and R6are H.

10. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4is CN.

11. The compound of any of claims 1 to 6 and 7 to 10, or a pharmaceutically acceptable salt thereof, wherein J is O.25866 12. The compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R1is H.

13. The compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R1is F or OH.

14. The compound of any of claims 1 and 7 to 10, or a pharmaceutically acceptable salt thereof, wherein R8is a (C1-C6)alkyl substituted by a (C6)aryl.

15. The compound of any of claims 1 and 7 to 10, or a pharmaceutically acceptable salt thereof, wherein R8is a (C1-C6)alkyl substituted by up to 3 halogens.

16. The compound of any of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein n is 1.

17. The compound of any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R10is H.

18. The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R11is H.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from: (S)-5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (S)-2,5-diphenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(3,5-dimethylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(4-ethylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(3-ethylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(4-(1-methylcyclopropyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(4-cyclopropylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 (S)-2-(4-(1-ethylcyclopropyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-1-(4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)phenyl)cyclopropane-1-carbonitrile; (S)-5-phenyl-2-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (S)-2-(4-(1,1-difluoroethyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (S)-2-(6-methylpyridin-3-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(1-benzyl-1H-pyrazol-4-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (S)-2-(4-methylthiophen-3-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (S)-2-(benzo[b]thiophen-3-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(benzo[b]thiophen-6-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(naphthalen-2-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-1-(4-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)phenyl)cyclopropane-1-carbonitrile; (S)-5-(3,5-difluorophenyl)-2-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-1-(4-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)phenyl)cyclopropane-1-carbonitrile; (5S)-2-[4-(ethylsulfonyl)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (5S)-2-[4-(3,3-difluorocyclobutyl)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 1-{4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]phenyl}cyclobutane-1-carbonitrile; (5S)-2-(4-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (5S)-5-phenyl-2-{4-[(pyrrolidin-1-yl)sulfonyl]phenyl}-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; N,N-dimethyl-4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]benzene-1-sulfonamide; (5S)-5-phenyl-2-{4-[(propan-2-yl)oxy]phenyl}-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one;25866 (5S)-2-[4-(cyclopropyloxy)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-2-[4-(difluoromethoxy)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-2-[4-(1,1-difluoroethoxy)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{4-[(pyrrolidin-1-yl)sulfonyl]phenyl}-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; 4-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]- N,N-dimethylbenzene-1-sulfonamide; (5S)-2-[4-(difluoromethoxy)phenyl]-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-2-[4-(cyclopropanecarbonyl)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-2-[4-(2-methylpropyl)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-2-{4-[(3-methylazetidin-1-yl)sulfonyl]phenyl}-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-[4-(trifluoromethoxy)phenyl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-2-[3-fluoro-4-(trifluoromethoxy)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]benzonitrile (5S)-2-(4-fluoro-3-methoxyphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-5-phenyl-2-(thiophen-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (5S)-2-(5-methylthiophen-3-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (5S)-5-phenyl-2-[4-(trifluoromethyl)phenyl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one;25866 (5S)-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-2-(4-{[(2R)-2-methylpyrrolidin-1-yl]sulfonyl}phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-[5-(difluoromethyl)thiophen-3-yl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-2-[4-(methylsulfonyl)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; 2-[(2R)-butan-2-yl]-5-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]-2,3-dihydro-1H-1lambda~6~,2-benzothiazole-1,1-dione; (5S)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 2-fluoro-5-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]benzonitrile; (5S)-2-(4-fluoro-3-methylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (5S)-2-[3-(difluoromethyl)-4-fluorophenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-2-(3-chloro-4-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (5S)-2-(4-fluoro-3,5-dimethylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-2-(3,4-difluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-(4-fluoro-3-hydroxyphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-2-(3,4-difluoro-5-methoxyphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; {2-fluoro-5-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]phenyl}acetonitrile; (S)-2-(4-fluorophenyl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-(1,2-thiazol-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-(3-methyl-1,2-thiazol-4-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one;25866 4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]thiophene-2- carbonitrile; (5S)-2-(furan-3-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(2-(4-fluorophenyl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5- yl)nicotinonitrile; 3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]benzonitrile; 3-fluoro-5-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]benzonitrile; 3-chloro-5-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]benzonitrile; 3-chloro-2-fluoro-5-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]benzonitrile; (5S)-2-[3-chloro-4-(trifluoromethoxy)phenyl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (R)-2-(3,4-difluorophenyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(3,4-difluorophenyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 5-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]-2- fluorobenzonitrile; (R)-2-(3,4-difluorophenyl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(3,4-difluorophenyl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 4-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]thiophene-2-carbonitrile; (S)-5-(2-fluorophenyl)-2-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (S)-2,5-bis(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3-fluorophenyl)-2-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (S)-5-(5-chloropyridin-3-yl)-2-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one;25866 (5S)-2-(3,4-difluorophenyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (5S)-2-[4-(difluoromethoxy)phenyl]-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 2-fluoro-5-[(5S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl]benzonitrile; (5S)-2-(4-fluorophenyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3- one; (S)-2-(3,4-dichlorophenyl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; (S)-5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin- 3(2H)-one; (R)-2-(4-fluorophenyl)-5-phenyl-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one; (S)-2-(3,4-dimethylphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{1-[(4-chloro-2,5-dimethylphenyl)sulfonyl]piperidin-4-yl}-5-phenyl-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{1-[(4-chloro-2-fluorophenyl)sulfonyl]piperidin-4-yl}-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-[1-(phenylsulfonyl)piperidin-4-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-phenyl-2-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (R)-5-(3,5-difluorophenyl)-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one; (5S,7R)-2-(4-fluorophenyl)-7-hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S,7S)-2-(4-fluorophenyl)-7-hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S,7R)-5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S,7S)-5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one;25866 (5S,7R)-2-(4-fluorophenyl)-7-hydroxy-7-methyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S,7S or 7R)-2-(4-fluorophenyl)-5-(5-fluoropyridin-3-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S,7S or 7R)-7-fluoro-2-(4-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one(5S)-5-(3,5-difluorophenyl)-7-fluoro-2-(4-fluorophenyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-7-fluoro-2-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 7-fluoro-2-(4-fluorophenyl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 5-(3,5-difluorophenyl)-2-(4-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo [2,1- c][1,2,4]triazol-3(2H)-one; 2-Isobutyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-Cyclohexyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 3-((S)-5-(3,5-Difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)butanenitrile; 2-(cyclopropylmethyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(2,2-difluoroethyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-cyclopentyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-(sec-butyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; S)-2-cyclobutyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(cyclobutylmethyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(cyclopentylmethyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-benzyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(2-cyclohexylethyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-phenethyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-cycloheptyl-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((3-phenoxycyclobutyl)methyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(2,3-dihydro-1H-inden-2-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (S)-2-(Bicyclo[1.1.1]pentan-1-ylmethyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 (S)-5-Phenyl-2-((1R,3S)-3-phenylcyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; 2-(3,3-Difluorocyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-Phenyl-2-(3-phenylcyclopentyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-Phenylcyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-(3,5-difluorophenyl)-2-(spiro[3.3]heptan-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-((1r,3S)-3-(benzyloxy)cyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-difluorophenyl)-2-(3-fluorocyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; Methyl (1S,3r)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutane-1-carboxylate; (S)-2-((1s,3R)-3-(benzyloxy)cyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1s,3R)-3-phenylcyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 3-one; (S)-2-((1r,3S)-3-(benzyloxy)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 2-(3,3-difluorocyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-Difluorophenyl)-2-((1R,3S)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-difluorophenyl)-2-((1S,3R)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1s,3R)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1r,3S)-3-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; N-((1S,3R)-3-((S)-5-(3,5-Difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)-2-fluorobenzamide; (S)-5-(3,5-Difluorophenyl)-2-(1-(2-fluoropyridin-4-yl)azetidin-3-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 6-((1R,3S)-3-((S)-5-(3,5-Difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile; 6-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrimidine-4-carbonitrile; 6-((1S,3r)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrimidine-4-carbonitrile; 6-((1R,3s)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrimidine-4-carbonitrile; (5S)-5-(3,5-Difluorophenyl)-2-(2-phenylcyclopropyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(spiro[2.3]hexan-5-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-yl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-yl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(4-(Oxazol-4-yl)phenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-Difluorophenyl)-2-((1S,3R)-3-(4-fluorophenoxy)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(4-fluorophenoxy)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(3-(trifluoromethyl)phenoxy)cyclobutyl)-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(3-(1,3,4-oxadiazol-2-yl)phenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(4-(1,3,4-oxadiazol-2-yl)phenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 6-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutoxy)pyrimidine-4-carbonitrile; 4-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyrimidine-2-carbonitrile;25866 3-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyridine-2-carbonitrile; 5-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyridine-3-carbonitrile; 6-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyrazine-2-carbonitrile; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[6-(1H-imidazol-1-yl)pyrimidin-4-yl]oxy}cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 6-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyridine-2-carbonitrile; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]oxy}cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-(trans-3-{[4-(difluoromethyl)pyridin-2-yl]oxy}cyclobutyl)-5-(3,5-difluorophenyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4- yl]oxy}cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-(trans-3-{[5-(difluoromethyl)pyridin-2-yl]oxy}cyclobutyl)-5-(3,5-difluorophenyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[6-(2-methyl-1H-imidazol-1-yl)pyrimidin-4- yl]oxy}cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]cyclobutyl}-5-(3,5- difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(imidazo[1,2-c]pyrimidin-5-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]cyclobutyl}- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(5-fluoropyrimidin-4-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(pyrazin-2-yl)oxy]cyclobutyl}-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(pyrazolo[1,5-a]pyrimidin-7-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 2-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyridine-4-carbonitrile;25866 5-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyrazine-2-carbonitrile; 5-(5-fluoropyridin-3-yl)-2-{trans-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 6-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyridine-3-carbonitrile; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[2-(methylsulfanyl)pyrimidin-4-yl]oxy}cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(5-fluoropyridin-3-yl)-2-((1R,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3- (pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 6-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutoxy)pyrimidine-4-carboxamide; 2-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutoxy)pyrimidine-4-carbonitrile; (S)-2-((1R,3S)-3-((2-chloropyrimidin-4-yl)oxy)cyclobutyl)-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4-yloxy)cyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[3-(trifluoromethyl)phenoxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 4-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)benzonitrile; (5S)-2-[trans-3-(3,4-difluorophenoxy)cyclobutyl]-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-[trans-3-(4-methoxyphenoxy)cyclobutyl]-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; 4-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)-2-fluorobenzonitrile; (5S)-5-(3,5-difluorophenyl)-2-[trans-3-(3-fluorophenoxy)cyclobutyl]-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3- yl]oxy}cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(4-methyl-1,3-thiazol-2-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(5-chloropyridin-3-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(1-methyl-1H-pyrazol-5-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[4-(trifluoromethyl)phenoxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[4-(1,3-oxazol-4-yl)phenoxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(4,6-difluoropyridin-3-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(1,2-benzoxazol-7-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(1,3-benzoxazol-2-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 5-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)pyridine-2-carbonitrile; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(3-fluoropyridin-4-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 3-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)-4-fluorobenzonitrile; (5S)-2-{trans-3-[(1,2-benzothiazol-4-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; [3-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)phenyl]acetonitrile; (5S)-5-(3,5-difluorophenyl)-2-[trans-3-(3-methoxyphenoxy)cyclobutyl]-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(1,2-benzothiazol-7-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[2-(trifluoromethyl)pyridin-4-yl]oxy}cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-[trans-3-(2-fluorophenoxy)cyclobutyl]-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 3-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)benzonitrile; [4-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)phenyl]acetonitrile; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[5-(trifluoromethyl)pyridin-3-yl]oxy}cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(1,3-benzoxazol-4-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-(trans-3-{[6-(difluoromethoxy)pyridin-3-yl]oxy}cyclobutyl)-5-(3,5-difluorophenyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(2-chloropyridin-4-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 2-({trans-3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)-4-fluorobenzonitrile; (5S)-5-(3,5-difluorophenyl)-2-[trans-3-(4-fluoro-3-methylphenoxy)cyclobutyl]-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(1,2-benzothiazol-5-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[3-(1,3,4-oxadiazol-2-yl)phenoxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[4-(4H-1,2,4-triazol-4-yl)phenoxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-(trans-3-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]oxy}cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(1,2,5-thiadiazol-3-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(6-fluoro-1,2-benzoxazol-3-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-2-{trans-3-[(1,2-benzoxazol-3-yl)oxy]cyclobutyl}-5-(3,5-difluorophenyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(imidazo[1,2-c]pyrimidin-5-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(pyrrolo[1,2-d][1,2,4]triazin-4-yl)oxy]cyclobutyl}- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 5-(4-fluorophenyl)-2-{trans-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]cyclobutyl}-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 4-fluoro-3-({trans-3-[(5S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl]cyclobutyl}oxy)benzonitrile; (S)-2-((1R,3S)-3-(3,4-difluorophenoxy)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; 2-(4-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutoxy)phenyl)acetonitrile; (5S)-5-(3,5-difluorophenyl)-2-{trans-3-[(2-sulfanylidene-2,3-dihydro-1,3-benzoxazol-4- yl)oxy]cyclobutyl}-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(4-(2,4-difluorophenoxy)phenyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(3-fluoro-4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-(3-fluoro-4-(2-methylthiazol-4-yl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; ethyl (S)-4-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)phenoxy)-5-methylthiazole-2-carboxylate; (S)-4-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)phenoxy)-5-methylthiazole-2-carboxylic acid; (S)-2-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-(2-hydroxy-5-(trifluoromethyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 5-(5-fluoropyridin-2-yl)-2-((1R,3R)-3-(pyrrolo[1,2-b]pyridazin-4-yloxy)cyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 4-((1S,3R)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-((1R,3S)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile; (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 (S)-5-(pyrazin-2-yl)-2-((1S,3R)-3-(3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)cyclobutyl)- 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 4-((1S,3R)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-((1R,3S)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)pyrazolo[1,5-a]pyridine-7-carbonitrile; 1-(2-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile; (S)-5-phenyl-2-((1R,3S)-3-(pyrazolo[1,5-a]pyridin-7-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1S,3R)-3-(pyrazolo[1,5-a]pyridin-7-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyrazin-2-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyridazin-4-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyrimidin-4-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyrimidin-5-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyrimidin-2-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)cyclobutyl)-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1S,3R)-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)cyclobutyl)-5-phenyl-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(4-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidin-2- yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; 1-(4-((1S,3R)-3-((S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile; (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidin-4- yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one;25866 7-((1S,3R)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutoxy)pyrazolo[1,5-a]pyridine-4-carbonitrile; 4-((1S,3R)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutoxy)pyrazolo[1,5-a]pyridine-7-carbonitrile; 4-((1R,3S)-3-((S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutoxy)pyrazolo[1,5-a]pyridine-7-carbonitrile; (S)-2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; 3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-2(3H)- yl)cyclobutoxy)benzonitrile; 3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)cyclobutyl)benzonitrile; 2-chloro-3-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)benzonitrile; (S)-5-(3,5-difluorophenyl)-2-((1R,3S)-3-(pyridin-3-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(2-fluorophenyl)-2-((1R,3S)-3-(pyridin-3-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyridin-3-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-(4-fluorophenyl)-2-((1R,3S)-3-(pyridin-3-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(pyridin-3-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-(5-fluoropyridin-3-yl)-2-((1R,3S)-3-(pyridin-3-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-(2-fluorophenyl)-2-((1R,3S)-3-(pyridin-2-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(pyridin-2-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-5-(4-fluorophenyl)-2-((1R,3S)-3-(pyridin-2-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; 2-fluoro-5-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)benzonitrile;25866 (S)-2-((1S,3S)-3-benzylcyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 3-fluoro-4-((1S,3R)-3-((S)-3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol- 2(5H)-yl)cyclobutyl)benzonitrile; (S)-2-((1R,3S)-3-(5-fluoropyridin-3-yl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(4-hydroxyphenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (R)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4-yloxy)cyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (37-1); (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(pyrrolo[1,2-b]pyridazin-4-yloxy)cyclobutyl)-2,5,6,7- tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (37-2); (S)-5-(pyrazin-2-yl)-2-((1R,3S)-3-(o-tolyl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; 5-(pyrazin-2-yl)-2-((1R,3R)-3-(p-tolyl)cyclobutyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1- c][1,2,4]triazol-3-one; (S)-2-((1S,3R)-3-(3-chlorophenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(3-chlorophenyl)cyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(4-(isothiazol-5-yl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-2-((1R,3S)-3-(4-(isoxazol-4-yl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenyl-2,5,6,7-tetrahydro- 3H-pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(4-(pyridin-3-yl)-1H-pyrazol-1-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(4-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-5-phenyl-2-((1R,3S)-3-(4-(pyrazin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (S)-4-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)- yl)phenoxy)-5-methylthiazole-2-carboxamide; (R)-5-phenyl-2-((1R,3R)-3-phenylcyclobutyl)-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one25866 (R)-5-phenyl-2-((1R,3R)-3-phenylcyclobutyl)-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-3(2H)-one (43-2); (5R,7S)-7-hydroxy-2-((1r,3S)-3-phenylcyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; (5S,7R)-7-hydroxy-2-((1r,3R)-3-phenylcyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one; and (5S,7S)-7-fluoro-2-((1r,3S)-3-phenylcyclobutyl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H- pyrrolo[2,1-c][1,2,4]triazol-3-one.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is selected from: ,25866 ,occurs in inherited and sporadic diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis as well as acute tissue injury caused by stroke, traumatic brain injury, encephalitis comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 20.

22. A method of treating amyotrophic lateral sclerosis comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 20.

23. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 20 to treat amyotrophic lateral sclerosis in a patient in need thereof.

24. A pharmaceutical composition comprising a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound of any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

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