RIPK1 inhibitors and methods of use

Abstract

To provide compounds that act as RIPK1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for RIPK1-related diseases.SOLUTION: Described herein is a compound of Formula I having a specific substituent or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Disclosed herein are RIPK1 inhibitors. The RIPK1 inhibitors described herein may be useful for preventing, treating, or as therapeutic agents for RIPK1-associated diseases. [Background technology]

[0002] Receptor-interacting protein 1 kinase (RIPK1) belongs to a family of serine / threonine protein kinases 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 demonstrating that RIPK1 is a key mediator of apoptotic and necrotic cell death, as well as inflammatory pathways.

[0003] For example, RIPK1 inhibition has been shown to be an effective therapeutic agent for acute kidney injury (AKI), a devastating clinical condition induced by multiple insults, including ischemia-reperfusion, nephrotoxic drugs, and sepsis. RIPK1-mediated necroptosis has been shown to play a critical role in AKI, and RIPK1 inhibitors may be promising clinical candidates for the treatment of AKI. 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.

[0004] Furthermore, human genetic evidence has implicated RIPK1 dysregulation in the development 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.

[0005] Furthermore, because necroptosis has been demonstrated to be a delayed component of ischemic neuronal damage, RIPK1 inhibition may also play a promising role in the treatment of 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. [Prior art documents]

Non-Patent Literature

[0006]

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[0007] Therefore, there is a need for RIPK1 inhibitors that offer high selectivity to cross the blood-brain barrier and the potential to target the neuroinflammation and cell death that cause various neurological conditions such as Alzheimer's disease, ALS, and multiple sclerosis, as well as acute neurological diseases such as stroke and traumatic brain injury. [Means for solving the problem]

[0008] Described herein are compounds of Formula I and pharmaceutically acceptable salts thereof: [ka] In the formula, R 1 , R 2 , R 3 and R 4is described below.

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

[0010] Also described herein are methods for 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 is the use of the compounds described herein, or pharmaceutically acceptable salts 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 that include a compound described herein and a pharmaceutically acceptable carrier.

[0014] Also described herein are methods for 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 is the treatment of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional agent, for treating neurodegenerative, autoimmune, and inflammatory diseases in a patient in need thereof.

[0016] Also described herein are pharmaceutical compositions that include 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 that include a compound described herein, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION

[0018] Described herein are compounds of Formula I: [ka] During the ceremony, R 1 is selected from C3-C6 cycloalkyl, aryl, and heteroaryl, each of said C3-C6 cycloalkyl, aryl, and heteroaryl independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (4)-C2-C6 alkynyl; (5)-C3-C6 cycloalkyl; (6) —O—C1-C6 alkyl; and (7)-OH may be substituted with 1 to 4 substituents selected from: R 2 is C3-C 10 selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 10 Each of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, —CN, —OH, —O—C1-C6 alkyl, and heteroaryl; (4) —O—C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R ais -OH, -C1-C6 alkyl, -O-C1-C6 alkyl and -NR b R c Selected from R b and R c are independently selected from hydrogen and —C1-C6 alkyl optionally substituted with heteroaryl; and (6) Aryl optionally substituted with 1 to 3 halogens may be substituted with 1 to 4 substituents selected from: R 3 and R 4 together with the atoms to which they are attached form a 5- or 6-membered ring fused to the triazole ring, said 5- or 6-membered ring optionally containing a heteroatom selected from N, O, or S, and optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, and —C1-C6 alkyl.

[0019] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from -C4-C6 cycloalkyl, phenyl, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; The -C4-C6 cycloalkyl, phenyl, and heteroaryl are (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) -CH2CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and -CN; (5) ethynyl; (6) cyclopropyl; (7) —O—CH3; and (8)-O-CH2CH3 It may be substituted with 1 to 3 substituents selected from the following.

[0020] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl, wherein the cyclobutyl, cyclopentyl, phenyl, pyridyl, and pyrazinyl are selected from (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) ethynyl; (5) cyclopropyl; and (6)-O-CH3 It may be substituted with 1 to 3 substituents selected from the following.

[0021] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 teeth, (1) halogen; (2)-CN; and (3) —CH3, which may be substituted with 1 to 3 substituents independently selected from halogen and —CN and phenyl which may be substituted with 1 to 3 substituents selected from the group consisting of:

[0022] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 2 is a bridge C5-C 10 selected from cycloalkyl, and bridged heterocyclic alkyl, phenyl, and heteroaryl; The crosslinking C5-C 10 The cycloalkyl or bridged heterocycloalkyl is unsubstituted or independently (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—C1-C4 alkyl; (4) —O—C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl and -NHR c Selected from R c is selected from hydrogen and —C1-C4 alkyl optionally substituted with heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It is substituted with 1 to 3 substituents selected from:

[0023] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 2 is C3-C 10 selected from cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; Said C3-C 10 Cycloalkyl is [ka] Selected from; The heterocyclic alkyl is [ka] Selected from; said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl and isoquinolyl; Said C3-C 10 Each of cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl independently represents (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—C1-C4 alkyl; (4) —O—C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl and -NHR c Selected from R c is selected from hydrogen and —C1-C4 alkyl optionally substituted with heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from the following.

[0024] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 2 teeth, [ka] and phenyl; [ka] and phenyl are each independently (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—CH3; (4) —O—CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a are -OH, -CH3, -O-CH3, and -NHR c Selected from; R c is selected from hydrogen and —CH3 optionally substituted with thienyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from the following.

[0025] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 2 teeth [ka] and independently, (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—CH3; (4)-C(O)-OCH3; (5) —C(O)CH2-thiemyl; and (6) Phenyl It may be substituted with 1 to 3 substituents selected from the following.

[0026] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 3 and R 4together with the atoms to which they are attached form a 5-membered aliphatic ring fused to the triazole ring, and the 5-membered aliphatic ring is optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CH, —CHCH, and —CHCHCH.

[0027] In one embodiment of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is of Formula Ia: [ka] During the ceremony, n is 1 or 2; R 1 is selected from C3-C6 cycloalkyl, aryl, and heteroaryl, each of said C3-C6 cycloalkyl, aryl, and heteroaryl independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (4)-C2-C6 alkynyl; (5) -C3-C6 cycloalkyl; and (6) -O-C1-C6 alkyl may be substituted with 1 to 3 substituents selected from: R 2 is C3-C 10 selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 10 Each of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently: (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, —CN, —OH, —O—C1-C6 alkyl, and heteroaryl; (4) —O—C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (5)-C(O)-Ra [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NR b R c Selected from R b and R c are each independently selected from hydrogen and —C1-C6 alkyl optionally substituted with heteroaryl; and (6) Aryl optionally substituted with 1 to 3 halogens may be substituted with 1 to 4 substituents selected from: R 5 Each occurrence of is independently selected from hydrogen, halogen, —C1-C6 alkyl, and —OH.

[0028] In one embodiment of the compounds of Formula Ia, or a pharmaceutically acceptable salt thereof, n is 1.

[0029] In one embodiment of the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 1 is selected from -C4-C6 cycloalkyl, phenyl, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; The -C4-C6 cycloalkyl, phenyl, and heteroaryl are (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) -CH2CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and -CN; (5) ethynyl; (6) cyclopropyl; (7) —O—CH3; and (8)-O-CH2CH3 It may be substituted with 1 to 3 substituents selected from the following.

[0030] In one embodiment of the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 1 is selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl, wherein said cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl are (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) ethynyl; (5) cyclopropyl; and (6)-O-CH3 It may be substituted with 1 to 3 substituents selected from the following.

[0031] In one embodiment of the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 2 is C3-C 10 selected from cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; Said C3-C 10 Cycloalkyl is [ka] Selected from; The heterocyclic alkyl is [ka] Selected from; said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl and isoquinolyl; Said C3-C 10Each of cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl independently (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—C1-C4 alkyl; (4) —O—C1-C4 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NHR c Selected from R c is selected from hydrogen and —C1-C4 alkyl optionally substituted with heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from the following.

[0032] In one embodiment of the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 2 teeth, [ka] and phenyl, [ka] and phenyl are each independently (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—CH3; (4) —O—CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a are -OH, -CH3, -O-CH3, and -NHR c Selected from; R c is selected from hydrogen and —CH3 optionally substituted with thienyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from the following.

[0033] In one embodiment of the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 1 is selected from -C4-C6 cycloalkyl, phenyl, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; The -C4-C6 cycloalkyl, phenyl, and heteroaryl are (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) -CH2CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and -CN; (5) ethynyl; (6) cyclopropyl; (7) —O—CH3; and (8)-O-CH2CH3 may be substituted with 1 to 3 substituents selected from: R 2 teeth, [ka] and phenyl, [ka] and phenyl are each independently (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—CH3; (4) —O—CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a are -OH, -CH3, -O-CH3, and -NHR c Selected from; R c is selected from hydrogen and —CH3 optionally substituted with thienyl; and (6) Phenyl optionally substituted with 1 to 3 halogens may be substituted with 1 to 3 substituents selected from: R 5 is selected from hydrogen, halogen, —C1-C4 alkyl, and —OH.

[0034] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 teeth, (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) cyclopropyl; and (5)-O-CH3 phenyl optionally substituted by 1 to 3 substituents selected from: R 2 teeth [ka] and it is independent (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—CH3; (4)-C(O)O-CH3; (5) —C(O)CH2-thienyl; and (6) Phenyl may be substituted with 1 to 3 substituents selected from: R 5 is selected from hydrogen, halogen, —CH 3 , and —OH.

[0035] In one embodiment of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is of Formula Ib: [ka] During the ceremony, R 1 is selected from C3-C6 cycloalkyl, phenyl, and heteroaryl, each of said C3-C6 cycloalkyl, phenyl, and heteroaryl independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4)-C2-C6 alkynyl; (5) -C3-C6 cycloalkyl; and (6) -O-C1-C6 alkyl may be substituted with 1 to 3 substituents selected from: R 2 is C3-C 10 cycloalkyl and heterocyclic alkyl, wherein the C3-C 10 Each of cycloalkyl and heterocycloalkyl independently represents (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—C1-C6 alkyl; (4) —O—C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NR b R c Selected from R b and R c are independently selected from hydrogen and —C1-C6 alkyl optionally substituted with heteroaryl; and (6) Aryl optionally substituted with 1 to 3 halogens may be substituted with 1 to 3 substituents selected from: R 5 is selected from hydrogen, halogen, —C1-C6 alkyl, and —OH.

[0036] In one embodiment of the compound of formula Ib or a pharmaceutically acceptable salt thereof, R 1 teeth, (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) cyclopropyl; and (5)-O-CH3 phenyl substituted with 1 to 3 substituents selected from: R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3) —CH3 optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, and —O—CH3; (4)-C(O)O-CH3; (5) —C(O)CH2-thienyl; and (6) Phenyl substituted with 1 to 3 substituents selected from: R 5 is hydrogen.

[0037] In one embodiment of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is (5S)-2-(bicyclo[2.2.1]heptan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-5-(3,5-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(bicyclo[2.1.1]hexan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (5S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-5-(5-fluoropyridin-3-yl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (5S)-5-(3,5-difluorophenyl)-2-(3-phenylbicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-5-(5-fluoropyridin-3-yl)-2-(3-phenylbicyclo[1.1.1]pentan-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-methyl-2-oxobicyclo[2.1.1]hexan-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, methyl 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carboxylate, methyl 3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carboxylate, (5S)-5-(3,5-difluorophenyl)-2-(4-fluoropentacyclo[4.2.0.0~2,5~.0~3,8~.0~4,7~]octan-1-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]pentacyclo[4.2.0.0~2,5~.0~3,8~.0~4,7~]octane-1-carbonitrile, (S)-3-(5-(5-chloropyridin-3-yl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, 3-[(5S)-5-(2-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(5-(3-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (5S)-2-(bicyclo[2.2.2]octan-1-yl)-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-(4-methoxybicyclo[2.2.1]heptan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-[4-(difluoromethyl)bicyclo[2.2.1]heptan-1-yl]-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-5-(3,5-difluorophenyl)-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]bicyclo[2.2.1]heptane-1-carbonitrile, 4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[2.2.1]heptane-1-carbonitrile, (5S)-2-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1-yl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1-yl]-5-(3-fluorophenyl)-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]bicyclo[2.1.1]hexane-1-carbonitrile, methyl 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate, (5S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-5-(4-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, 4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[2.1.1]hexane-1-carbonitrile, (S)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-3-(5-(2,6-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(5-(3,4-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-5-(4-chlorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-3-(5-(4-chlorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(5-(2,4-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-5-(2,4-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-3-(3-oxo-5-(3-(trifluoromethyl)phenyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(3-oxo-5-(4-(trifluoromethyl)phenyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(5-(3,5-difluoro-4-methylphenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, 3-[5-(S or R)-(3,5-difluorophenyl)-6-(S or R)-methyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, 3-(5-(S or R)-cyclopentyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, 3-(5-(S or R)-cyclohexyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (5S)-5-(3,5-difluorophenyl)-2-[3-(methoxymethyl)bicyclo[1.1.1]pentan-1-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]-N-[(thiophen-2-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]-N-[(thiophen-3-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide, (S)-2-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)acetonitrile, (5S)-2-(3-acetylbicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]-2,2-difluorobicyclo[1.1.1]pentane-1-carbonitrile, 2,2-difluoro-3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (±)-3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (±)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluoro-5-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (±)-3-[2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-yl]benzonitrile, (±)-5-(3-ethynylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (±)-5-(2,3-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (±)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluoro-5-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-3-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-5-(3-fluoro-5-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(4-(difluoromethyl)phenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(4-cyclopropylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(6-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S,7R)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-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-(3-fluorobicyclo[1.1.1]pentan-1-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, 3-[(5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-5-(2-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-5-(2-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (S)-5-(3,5-difluoro-4-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one, (S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-4-(3-oxo-5-(pyrazin-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[2.1.1]hexane-1-carbonitrile, (S)-2-(bicyclo[2.1.1]hexan-1-yl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-3-(5-(3-chlorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-5-(3-chlorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-2(3H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (R)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-2(3H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-4-(2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-yl)benzonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(6-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, 3-((5S,7R)-5-(3,5-difluorophenyl)-7-methyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, 3-((5S,7S)-5-(3,5-difluorophenyl)-7-methyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(3-chloro-5-fluoro-4-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(3,5-difluoro-4-hydroxyphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(2,6-difluoro-4-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(4-chloro-3-fluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-5-(4-chloro-3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (R)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one, (R)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6-dihydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-2(8H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]-2,2-difluorobicyclo[1.1.1]pentane-1-carbonitrile, methyl (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylate, 2,2-difluoro-3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl]bicyclo[1.1.1]pentane-1-carbonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(o-tolyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-(trifluoromethyl)pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, (5S,7S)-7-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, and (S)-3-(5-(4-(difluoromethyl)phenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile is selected from.

[0038] In one embodiment, disclosed herein is a method of treating RIPK1-dependent inflammation and cell death that occurs in genetic 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, and acute tissue damage caused by stroke, traumatic brain injury, and encephalitis, comprising administering to a patient in need of treatment a compound described herein or a pharmaceutically acceptable salt thereof.

[0039] In one embodiment, disclosed herein is a method for treating amyotrophic lateral sclerosis, comprising administering to a patient in need thereof a compound described herein or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0041] In one embodiment, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0042] In one embodiment of Formula Ia, n is 1.

[0043] In one embodiment of Formula Ia, n is 2.

[0044] In one embodiment of Formula I, Ia, or Ib, R 1 is C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 4 substituents selected from: (1) halogen; (2) —CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) —C2-C6 alkynyl; (5) —C3-C6 cycloalkyl; and (6) —O—C1-C6 alkyl.

[0045] In one embodiment, R 1 teeth, [ka] and C3-C6 cycloalkyl selected from:

[0046] In one embodiment, R 1 teeth, [ka] is a C3-C6 cycloalkyl selected from: The C3-C6 cycloalkyl is substituted with 1 to 4 substituents selected from: (1) halogen; (2) —CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) —C2-C6 alkynyl; (5) —C3-C6 cycloalkyl; and (6) —O—C1-C6 alkyl.

[0047] In one embodiment, R 1 teeth, [ka] is a C3-C6 cycloalkyl selected from: The C3-C6 cycloalkyl is substituted with 1 to 3 halogens.

[0048] In one embodiment, R 1 teeth, [ka] is a C3-C6 cycloalkyl selected from: The C3-C6 cycloalkyl is substituted with -CN.

[0049] In one embodiment, R 1 teeth, [ka] is a C3-C6 cycloalkyl selected from: The C3-C6 cycloalkyl is substituted with -C1-C6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -CN. In one embodiment, the C3-C6 cycloalkyl is substituted with 1 to 3 substituents independently selected from methyl, ethyl, propyl, butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, and -CH2CN.

[0050] In one embodiment, R1 teeth, [ka] is a C3-C6 cycloalkyl selected from: The C3-C6 cycloalkyl is substituted with -C2-C6 alkynyl. In one embodiment, the C3-C6 cycloalkyl is substituted with ethynyl or propynyl. In one embodiment, the C3-C6 cycloalkyl is substituted with ethynyl.

[0051] In one embodiment, R 1 teeth, [ka] is a C3-C6 cycloalkyl selected from: In one embodiment, the C3-C6 cycloalkyl is substituted with -C3-C6 cycloalkyl. In one embodiment, the C3-C6 cycloalkyl is substituted with cyclopropyl. In one embodiment, the C3-C6 cycloalkyl is substituted with cyclobutyl.

[0052] In one embodiment, R 1 teeth, [ka] is a C3-C6 cycloalkyl selected from: In one embodiment, the C3-C6 cycloalkyl is substituted with -O-C1-C6 alkyl. In one embodiment, the C3-C6 cycloalkyl is substituted with -OCH3. In one embodiment, the C3-C6 cycloalkyl is substituted with -OCH2CH3. In one embodiment, the C3-C6 cycloalkyl is substituted with -OCH2CH2CH3. In one embodiment, the C3-C6 cycloalkyl is substituted with -OCH2CH2CH2CH3. In one embodiment, the C3-C6 cycloalkyl is substituted with -OCH2CH2CH2CH3.

[0053] In one embodiment, R 1is aryl, which is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen; (2) —CN; (3) —C1-C6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) —C2-C6 alkynyl; (5) —C3-C6 cycloalkyl; and (6) —O—C1-C6 alkyl.

[0054] In one embodiment, R 1 is unsubstituted phenyl.

[0055] In one embodiment, R 1 is phenyl, which is independently substituted with 1 to 3 substituents selected from: (1) halogen; (2) —CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (4) —C2-C6 alkynyl; (5) —C3-C6 cycloalkyl; and (6) —O—C1-C6 alkyl.

[0056] In one embodiment, R 1 is phenyl, which is substituted with 1 to 3 halogens. 1 is phenyl, which is substituted with 1 to 3 fluoro. 1 is phenyl, which is substituted with 1 to 3 chloro groups.

[0057] In one embodiment, R 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from halogen and —CN.

[0058] In one embodiment, R 1 is phenyl, which is substituted with —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN.

[0059] In one embodiment, R 1is phenyl, which is substituted with 1 to 3 substituents independently selected from methyl, ethyl, propyl, butyl, pentyl, —CHF, —CHF, —CF, —CHCHF, —CHCF, and —CHCN. 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from methyl, ethyl, propyl, butyl, and pentyl. 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from -CHF, -CHF, -CF, -CHCHF, -CHCF, and -CHCN. 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from methyl and —CF 3 .

[0060] In one embodiment, R 1 is phenyl, which is independently substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, —CH 2 F, —CHF 2 , and —CF 3 .

[0061] In one embodiment, R 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from halogen, —O-methyl, —O-ethyl, and —O-propyl.

[0062] In one embodiment, R 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from halogen and —C3-C6 cycloalkyl. 1 is phenyl, which is substituted with cyclopropyl. 1 is phenyl, which is substituted with cyclobutyl. 1 is phenyl, which is substituted with cyclopentyl. 1is phenyl, which is substituted with cyclohexyl.

[0063] In one embodiment, R 1 is heteroaryl, which is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen; (2) —CN; (3) —C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (4) —C2-C6 alkynyl; (5) —C3-C6 cycloalkyl; and (6) —O—C1-C6 alkyl.

[0064] In one embodiment, R 1 is an unsubstituted heteroaryl selected from pyridyl (pyridinyl), oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl.

[0065] In one embodiment, R 1 is an unsubstituted heteroaryl selected from pyridyl and pyrazinyl. 1 is unsubstituted pyridyl. In one embodiment, R 1 is an unsubstituted pyrazinyl.

[0066] In one embodiment, R 1is heteroaryl selected from pyridyl (pyridinyl), oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is independently substituted with 1 to 3 substituents selected from (1) halogen; (2) —CN; (3) —C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and —CN; (4) —C2-C6 alkynyl; (5) —C3-C6 cycloalkyl; and (6) —O—C1-C6 alkyl.

[0067] In one embodiment, R 1 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is substituted with 1 to 3 halogens.

[0068] In one embodiment, R 1 is a heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with 1 to 3 halogens.

[0069] In one embodiment, R 1 is fluoro-substituted pyridyl. 1 is pyridyl substituted with two fluoro. 1 is pyridyl substituted with chloro. In one embodiment, R 1 is a pyridyl substituted with two chloros.

[0070] In one embodiment, R 1 is pyrazinyl substituted with fluoro. 1is pyrazinyl substituted with two fluoro. 1 is pyrazinyl substituted with chloro. 1 is pyrazinyl substituted with two chloros.

[0071] In one embodiment, R 1 is heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is substituted with -CN. 1 is a heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with -CN.

[0072] In one embodiment, R 1 is heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is substituted with 1 to 2 substituents independently selected from C1-C6 alkyl. 1 is heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with 1 to 2 substituents independently selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0073] In one embodiment, R 1 is pyridyl substituted with methyl, ethyl, propyl, butyl, pentyl, or hexyl. 1 is a methyl-substituted pyridyl.

[0074] In one embodiment, R 1 is pyrazinyl substituted with methyl, ethyl, propyl, butyl, pentyl, or hexyl. 1 is pyrazinyl substituted with methyl.

[0075] In one embodiment, R 1 is heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is substituted with -C2-C6 alkynyl. 1 is a heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with -C=CH3.

[0076] In one embodiment, R 1 is heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is substituted with —C3-C6 cycloalkyl. 1 is heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is pyridyl substituted with cyclopropyl or cyclobutyl. 1 is pyrazinyl substituted with cyclopropyl or cyclobutyl.

[0077] In one embodiment, R 1is heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is substituted with —O—C1-C6 alkyl. 1 is heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -O-pentyl, or -O-hexyl. 1 is pyridyl substituted with -O-methyl, -O-ethyl, or -O-propyl. 1 is pyridyl substituted with -O-methyl. 1 is pyrazinyl substituted with -O-methyl, -O-ethyl, or -O-propyl. 1 is pyrazinyl substituted with -O-methyl.

[0078] In one embodiment, R 2 is C3-C 10 cycloalkyl, which are independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—C1-C6 alkyl, and heteroaryl; (4) —O—C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NR b R c Selected from R b and R care independently selected from hydrogen and —C1-C6 alkyl optionally substituted with heteroaryl; and (6) Aryl optionally substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from the following.

[0079] In one embodiment, R 2 teeth, [ka] unsubstituted C3-C 10 It is cycloalkyl.

[0080] In one embodiment, R 2 teeth, [ka] unsubstituted C3-C 10 It is cycloalkyl.

[0081] In one embodiment, R 2 is not replaced [ka] is.

[0082] In one embodiment, R 2 is not replaced [ka] is.

[0083] In one embodiment, R 2 is not replaced [ka] is.

[0084] In one embodiment, R 2 is not replaced [ka] is.

[0085] In one embodiment, R 2 is not replaced [ka] is.

[0086] In one embodiment, R 2 is not replaced [ka] is.

[0087] In one embodiment, R 2 is not replaced [ka] is.

[0088] In one embodiment, R 2 teeth, [ka] C3-C to be selected 10 is cycloalkyl, Said C3-C 10 Cycloalkyl is independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—C1-C6 alkyl, and heteroaryl; (4) —O—C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R ais -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NR b R c Selected from R b and R c are independently selected from hydrogen and —C1-C6 alkyl optionally substituted with heteroaryl; and (6) Aryl optionally substituted with 1 to 3 halogens It is substituted with 1 to 3 substituents selected from:

[0089] In one embodiment, R 2 teeth, [ka] C3-C to be selected 10 is cycloalkyl, Said C3-C 10 Cycloalkyl is independently (1) halogen; (2)-CN; (3) —C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—C1-C6 alkyl, and heteroaryl; (4) —O—C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NR b R c Selected from R b and R c are independently selected from hydrogen and —C1-C6 alkyl optionally substituted with heteroaryl; and (6) Aryl optionally substituted with 1 to 3 halogens It is substituted with 1 to 3 substituents selected from:

[0090] In one embodiment, R 2 teeth, [ka] C3-C to be selected 10 is cycloalkyl, Said C3-C 10 Cycloalkyl is independently (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-C1-C4 alkyl, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; (4) —O—C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —CN; (5)-C(O)-R a [R a is -OH, -C1-C4 alkyl, -O-C1-C4 alkyl, and -NR b R c Selected from R b and R c each is independently selected from hydrogen and —C1-C4 alkyl optionally substituted with heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It is substituted with 1 to 3 substituents selected from:

[0091] In one embodiment, R 2 teeth, [ka] C3-C to be selected 10 is cycloalkyl, Said C3-C 10 Cycloalkyl is independently (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [R a is selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It is substituted with 1 to 3 substituents selected from:

[0092] In one embodiment, R 2 teeth, [ka] C3-C to be selected 10 is cycloalkyl, Said C3-C 10 Cycloalkyl is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3; (5)-CH2OH; (6)-CH2-O-CH3; (7)-CH2CN; (8)-CHF2; (9)-CF3; (10) —CH2-heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrazinyl, and pyrimidyl; (11)-O-CH3; (12)-C(O)-CH3; (13)-C(O)-O-CH3; (14) —C(O)—NH—CH-heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrazinyl, and pyrimidyl; and (15) Phenyl It is substituted with 1 to 3 substituents selected from:

[0093] In one embodiment, R 2 teeth, [ka] and it is independent (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [R ais selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It is substituted with 1 to 3 substituents selected from:

[0094] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3; (5)-CH2OH; (6)-CH2-O-CH3; (7)-CH2CN; (8)-CHF2; (9)-CF3; (10) —CH2-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; (11)-O-CH3; (12)-C(O)-CH3; (13)-C(O)-O-CH3; (14) —C(O)—NH—CH-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; and (15) Phenyl It is substituted with 1 to 3 substituents selected from:

[0095] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3) —C1-C4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—CH3, —OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [R a is selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It is substituted with 1 to 3 substituents selected from:

[0096] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3; (5)-CH2OH; (6)-CH2-O-CH3; (7)-CH2CN; (8)-CHF2; (9)-CF3; (10) —CH2-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; (11)-O-CH3; (12)-C(O)-CH3; (13)-C(O)-O-CH3; (14) —C(O)—NH—CH-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; and (15) Phenyl It is substituted with 1 to 3 substituents selected from:

[0097] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3) -CH3; and (4)-CHF2 It is substituted with 1 to 3 substituents selected from:

[0098] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [R a is selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It is substituted with 1 to 3 substituents selected from:

[0099] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3; (5)-CH2OH; (6)-CH2-O-CH3; (7)-CH2CN; (8)-CHF2; (9)-CF3; (10) —CH2-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; (11)-O-CH3; (12)-C(O)-CH3; (13)-C(O)-O-CH3; (14) —C(O)—NH—CH-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; and (15) Phenyl It is substituted with 1 to 3 substituents selected from:

[0100] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CHF2; and (5)-O-CH3 It is substituted with 1 to 3 substituents selected from:

[0101] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [R a is selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It is substituted with 1 to 3 substituents selected from:

[0102] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3; (5)-CH2OH; (6)-CH2-O-CH3; (7)-CH2CN; (8)-CHF2; (9)-CF3; (10) —CH2-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; (11)-O-CH3; (12)-C(O)-CH3; (13)-C(O)-O-CH3; (14) —C(O)—NH—CH-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; and (15) Phenyl It is substituted with 1 to 3 substituents selected from:

[0103] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CHF2; (5)-O-CH3 It is substituted with 1 to 3 substituents selected from:

[0104] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [Ra is selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It is substituted with 1 to 3 substituents selected from:

[0105] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3; (5)-CH2OH; (6)-CH2-O-CH3; (7)-CH2CN; (8)-CHF2; (9)-CF3; (10) —CH2-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; (11)-O-CH3; (12)-C(O)-CH3; (13)-C(O)-O-CH3; (14) —C(O)—NH—CH-heteroaryl, wherein the heteroaryl is selected from furyl, triazinyl, and thienyl; and (15) Phenyl It is substituted with 1 to 3 substituents selected from:

[0106] In one embodiment, R 2 teeth, [ka] and it is independently (1) halogen; (2)-CN; and (3)-CH3 It is substituted with 1 to 3 substituents selected from:

[0107] In one embodiment, R 2 teeth, [ka] is a heterocycloalkyl selected from The heterocyclic alkyl is (1) halogen; (2)-CN; (3) -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl, wherein the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; (4) -O-C1-C4 alkyl; (5)-C(O)-R a [R a is selected from -OH, -CH, -CHCH, -O-CH, -CHCH, and -NH-CH-heteroaryl, wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl; and (6) Phenyl It may be substituted with 1 to 3 substituents selected from the following.

[0108] In one embodiment, R 2 teeth, [ka] and an unsubstituted heterocycloalkyl selected from:

[0109] In one embodiment, R2 is not replaced [ka] is.

[0110] In one embodiment, R 2 teeth [ka] and that is, (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—CH3, and —OCH2CH3. It is substituted with 1 to 3 substituents selected from:

[0111] In one embodiment, R 2 teeth, [ka] and it is, (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3 It is substituted with 1 to 3 substituents selected from:

[0112] In one embodiment, R 2 teeth, [ka] which is substituted with -CH3.

[0113] In one embodiment, R 2 is unsubstituted phenyl.

[0114] In one embodiment, R 2 is phenyl, which is (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—CH3, and —OCH2CH3. It is substituted with 1 to 3 substituents selected from:

[0115] In one embodiment, R 2 is phenyl, which is (1) halogen; (2)-CN; (3)-CH3; (4)-CH2CH3 It is substituted with 1 to 3 substituents selected from:

[0116] In one embodiment, R 2 is an unsubstituted heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl.

[0117] In one embodiment, R 2 is heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl and isoquinolyl, which is (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—CH3, and —OCH2CH3. It is substituted with 1 to 3 substituents selected from:

[0118] In one embodiment, R 2 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, and pyridazinyl, which is (1) halogen; (2)-CN; (3) —C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —OH, —O—CH3, and —OCH2CH3. It is substituted with 1 to 3 substituents selected from:

[0119] In one embodiment of Formula Ia, R 5 is independently selected from hydrogen, halogen, —C1-C6 alkyl, and —OH. In one embodiment, n is 1.

[0120] In one embodiment of Formula Ia, R 5 is independently selected from hydrogen, halogen, -CH3, -CH2CH3, and -OH. In one embodiment, n is 1.

[0121] In one embodiment of Formula Ia, n is 1 and R 5 is hydrogen.

[0122] In one embodiment of Formula Ia, R 5 is a halogen. In one embodiment, n is 1 and R 5 is -F. In one embodiment, n is 1 and R 5 is -Cl.

[0123] In one embodiment of Formula Ia, R 5 Each occurrence of is -OH.

[0124] definition The term "halogen" includes fluorine, chlorine, bromine or iodine.

[0125] The term "C1-C6 alkyl" includes linear alkyl having 1 to 6 carbon atoms and branched alkyl having 3 to 6 carbon atoms. 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.

[0126] The term "C3-C6 cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having from 3 to 6 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0127] "C3-C 10 The term "cycloalkyl" includes 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 saturated cycloalkyl groups. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. Examples illustrated by structure include: [ka]

[0128] The term "heteroaryl" refers to a monocyclic or polycyclic, including bicyclic, aromatic heterocycloalkyl containing 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.

[0129] The term "heterocycloalkyl" means monocyclic, bicyclic, or bridged, partially unsaturated, and saturated rings containing at least one heteroatom selected from N, S, and O, each of which has 3 to 10 atoms, and the point of attachment can 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 the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones or n-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through the nitrogen. 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, 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. Examples illustrated by structure include: [ka]

[0130] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, lauric acid, and the like.

[0023] Examples of suitable pharmaceutically acceptable salts include, but are not limited to, methyl nitrate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate. Furthermore, when the compounds of the present invention contain 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, manganese, manganous, potassium, sodium, and zinc. Particularly preferred are 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, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0131] The term "patient" refers to a mammalian patient, preferably a human patient, undergoing or about to undergo medical treatment.

[0132] The compounds of the present invention may contain one or more asymmetric centers and may therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers, and the present invention is intended to encompass all such isomeric forms of these compounds.

[0133] Some of the compounds described herein contain double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0134] Some of the compounds described herein include substituted cycloalkanes having cis and trans isomers, and unless otherwise specified, are meant to include both cis and trans geometric isomers.

[0135] The independent syntheses of these diastereomers or their chromatographic separations can be carried out according to methods known in the art, with appropriate modification of the methods disclosed herein. Their absolute stereochemistry can be determined, if necessary, by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. This separation can be carried out by methods well known in the art, for example, by coupling a racemic mixture of the compound with 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 often involves the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives can 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 using chiral stationary phases, which methods are well known in the art.

[0136] 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.

[0137] It will be understood that the present invention is intended to include pharmaceutically acceptable salts of the compounds described herein, as well as non-pharmaceutically acceptable salts, when used as precursors to the free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[0138] Solvates, particularly hydrates, of the compounds of the structural formulae described herein are also included in the present invention.

[0139] Some of the compounds described herein may exist as tautomers, which differ in the point of attachment of hydrogen with one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The compounds of the present invention include individual tautomers as well as mixtures thereof.

[0140] In the compounds described herein, atoms may exhibit their natural isotopic abundance, 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 disclosure is intended to encompass all suitable isotopic variations of compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 These include protium (H). Protium is the predominant hydrogen isotope found in nature. Enriching deuterium may offer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. 3 H, 11 C. 18 F-labeled compounds can be used in PET or SPECT and 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 preparation methods similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0141] It should be noted that chemically unstable compounds are excluded from the embodiments contained herein.

[0142] Treatment method The compounds described herein may be particularly useful for preventing, treating, or ameliorating RIPK1-mediated diseases or disorders, which may be controlled, at least in part, by programmed necrosis, apoptosis, or the production of inflammatory cytokines, and include, among others, 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)), and psoriatic arthritis), lupus, systemic lupus erythematosus (SLEP), and other conditions. E), Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / disease (non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage / failure (nephritis, kidney 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 transplanted organs, tissues, and cells), ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), arteriosclerosis, 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 (asthma) and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-I converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO mutations (mutations in the NF-κB essential regulatory gene (also known as IKK gamma or IKKG)), particularly NEMO deficiency syndrome,HOIL-1 deficiency (also known as RBCKI, heme-oxidizing IRP2 ubiquitin ligase 1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematopoietic and solid organ malignancies, bacterial and viral infections (influenza, staphylococcus, tuberculosis, etc.), and lysosomal storage diseases (especially Gaucher disease, GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pigmented dysplasia, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, 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 cancer (NSCLC), radiation-induced necrosis, ischemic kidney injury, ophthalmic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure, and hearing disorders such as radioprotection / mitigation, noise-induced hearing loss, and drugs associated with ototoxicity such as cisplatin, or ex vivo cell therapy to maintain vitality and function.

[0143] The compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be used to treat 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, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / disease (non-alcoholic), liver damage / disease (non-alcoholic), liver diseases (including liver damage / disease (non-alcoholic), liver diseases (including liver diseases ... Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage / failure (nephritis, kidney 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 transplanted organs, tissues and cells) encephalopathy), solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), arteriosclerosis, 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, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-I converting enzyme Inflammatory cell death syndrome (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, melanoma, metastasis, breast cancer, non-small cell lung cancer (NSCLC), radiation-induced necrosis, ischemic kidney injury, ophthalmic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, periodontitis, NEMO mutations (mutations in the NF-κB essential regulator gene (also known as IKK gamma or IKKG)), especially NEMO deficiency syndrome, HOIL-1 deficiency (also known as RBCKI heme-oxidizing IRP2 ubiquitin ligase 1 deficiency),Linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematopoietic and solid organ malignancies, bacterial and viral infections (influenza, staphylococcus, tuberculosis, etc.), and lysosomal storage diseases (especially Gaucher disease, GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acidosis, etc.) It may be particularly useful in the treatment of conditions such as sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pigmented osseous dysplasia, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease), spinal cord injury, Stevens-Johnson syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and / or ex vivo cell therapy to maintain vitality and function.

[0144] Compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of glaucoma.

[0145] The compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be particularly useful in the treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma.

[0146] The compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be particularly useful in the treatment of the following RIPK1-mediated diseases or disorders: rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), and psoriasis.

[0147] The treatment of the above-mentioned disease / disorder may more particularly be related to the improvement of the organ injury or damage sustained as a result of the above-mentioned disease / disorder.For example, the compound of the present invention may be particularly useful for improving the brain tissue injury or damage after ischemic brain injury or traumatic brain injury, or improving the heart tissue injury or damage after myocardial infarction, or improving the brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or improving the liver tissue injury or damage associated with non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, or primary sclerosing cholangitis, or acetaminophen overdose.

[0148] The compounds of the invention may be particularly useful in ameliorating organ injury or damage sustained as a result of radiation therapy, or spinal cord tissue injury or damage following spinal cord injury, or liver tissue injury or damage associated with acute liver failure. The compounds of the invention may be particularly useful in ameliorating hearing loss, such as noise-induced hearing loss, or hearing loss following the administration of ototoxic drugs or substances such as cisplatin.

[0149] The compounds of the present invention may be particularly useful in ameliorating injury or damage to solid organ tissues (particularly the kidney, liver, heart, and / or lung) following transplantation or administration of nephrotoxic drugs or substances such as cisplatin. It is understood that amelioration of such tissue damage can be achieved, if 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 organ recipient prior to transplant surgery. Amelioration of such tissue damage can be achieved by treatment with a compound of the formulae described herein or a pharmaceutically acceptable salt thereof at the time of transplant surgery.

[0150] Amelioration of such tissue damage may also be achieved by short-term treatment of the patient with a compound of the formulae described herein, or a pharmaceutically acceptable salt thereof, following transplant surgery.

[0151] In one embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.

[0152] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of multiple sclerosis.

[0153] In one embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of traumatic brain injury.

[0154] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of Huntington's disease or Niemann-Pick disease.

[0155] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer's disease.

[0156] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of age-related macular degeneration.

[0157] Treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may more specifically involve ameliorating organ damage or injury sustained as a result of these diseases / disorders. For example, the compounds described herein may be particularly useful in ameliorating brain tissue injury or injury following traumatic brain injury or ameliorating brain tissue injury or injury associated with Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0158] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and in the amelioration of brain tissue injury or damage resulting from multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0159] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic-onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis.

[0160] In yet another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of psoriasis, rheumatoid arthritis, and ulcerative colitis.

[0161] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of lupus, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.

[0162] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in 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.

[0163] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of amyotrophic lateral sclerosis (ALS).

[0164] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of multiple sclerosis.

[0165] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung cancer (NSCLC), and radiation-induced necrosis.

[0166] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung cancer (NSCLC).

[0167] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of pancreatic ductal adenocarcinoma (PDAC).

[0168] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.

[0169] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of type II diabetes and obesity.

[0170] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of atherosclerosis.

[0171] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of vasculitis.

[0172] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of dependent inflammation and cell death that occurs in genetic and sporadic diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis, and acute tissue injury caused by stroke, traumatic brain injury, encephalitis.

[0173] In another embodiment, the compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be useful in the treatment of ischemic renal injury, ocular ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0174] In another embodiment, the compounds of the formulae described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).

[0175] The compounds of the formulae described herein, or pharmaceutically acceptable salts thereof, may be particularly useful for treating 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 embodiment, the human has a solid tumor. In one embodiment, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung cancer (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one embodiment, the human has one or more of colorectal cancer (CRC), esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung cancer, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another embodiment, the human has a liquid tumor such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myeloid leukemia.

[0176] The present disclosure also relates to a variety of cancers, including brain (glioma), glioblastoma, astrocytoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple-negative breast cancer, inflammatory breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including head and neck squamous cell carcinoma), kidney cancer, lung cancer (squamous cell carcinoma of the lung, adenocarcinoma of the lung, small cell carcinoma of the lung, non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous cell pancreatic carcinoma), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, leukemia, and lymphoma. Myeloid leukemia, acute myeloid 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 carcinoma, lung cancer, vulvar cancer, cervical cancer, endometrial cancer, uterine cancer, kidney cancer (including renal clear cell carcinoma, papillary renal carcinoma, and renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, oral cancer (buccal The present invention also relates to a method for treating or lessening the severity of cancer selected from the group consisting of breast cancer, oral cancer, GIST (gastrointestinal stromal tumor), and testicular cancer.

[0177] Specific examples of clinical conditions based on hematological malignancies include leukemias such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; and lymphomas such as non-Hodgkin's lymphoma and Hodgkin's lymphoma.

[0178] The cancer may be any cancer in which there is an abnormal number of blast cells or unwanted cell proliferation, or which is diagnosed as a blood cancer, and includes both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic, myeloid, or myeloblastic) leukemia (undifferentiated or differentiated), acute promyelocytic (or promyelocytic, promyelocytic, or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia, and megakaryocytic (or megakaryoblastic) leukemia. These leukemias are sometimes collectively referred to as acute myeloid (or myelocytic or myeloid) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), such as, but not limited to, chronic myeloid (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may also be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); and myelofibrosis (MFS) with or without myelodysplasia of unknown cause.

[0179] Specific examples of clinical conditions based on hematological malignancies include leukemias such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; and lymphomas such as non-Hodgkin's lymphoma and Hodgkin's lymphoma. Hematopoietic cancers also include lymphoid malignancies that can affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extra-lymphatic sites. Lymphoid cancers include B-cell malignancies, including, but not limited to, B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL can be low-grade (or low-grade), intermediate-grade (or high-grade), or high-grade (highly aggressive). Low-grade 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 leukemia 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 lymphoma (BL), Burkitt-like lymphoma, small noncleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, 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 lymphocytic (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease.NHL can also include T-cell non-Hodgkin's lymphoma (T-NHL), which includes, but is not limited to, T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphopathy (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0180] Hematopoietic cancers also include Hodgkin lymphomas (or diseases) such as classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte-predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocytopenic Hodgkin lymphoma. Hematopoietic cancers also include multiple myeloma (MM), such as 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 can also include other cancers of additional hematopoietic cells, such as polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues such as the spleen, lymph nodes, mucosa-associated lymphoid tissues (such as gut-associated lymphoid tissue), tonsils, Peyer's patches and appendix, and other mucosa-associated lymphoid tissues such as the bronchial lining.

[0181] Pharmaceutical Composition The compounds described herein can be administered orally or parenterally. When formulated into a dosage form suitable for administration, the compounds described herein can be used as pharmaceutical compositions for the prevention, treatment, or amelioration of the above-mentioned diseases.

[0182] In clinical use of the compounds described herein, the compounds are usually formulated into various formulations with pharmaceutically acceptable additives depending on the dosage form, and then administered. "Pharmaceutically acceptable" means that the additive, carrier, diluent, or excipient must be compatible with other ingredients of the formulation and not harmful to the recipient. Therefore, various additives commonly used in the field of pharmaceutical formulations can be used. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminometasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid esters, polysorbates, sucrose fatty acid esters, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, and hydroxypropylcyclodextrin.

[0183] The preparations formed using these additives include, for example, solid preparations such as tablets, capsules, granules, powders, and suppositories; and liquid preparations such as syrups, elixirs, and injections. These can be prepared according to conventional methods known in the field of pharmaceutical preparations. Liquid preparations can also be in a form that can be dissolved or suspended in water or other suitable medium when used.

[0184] In particular, in the case of injections, the preparation may be dissolved or suspended in physiological saline or glucose solution, and a buffer or preservative may be optionally added thereto, as desired.

[0185] The pharmaceutical composition may contain the compound of the present invention in an amount of 1 to 99.9% by weight, preferably 1 to 60% by weight, of the composition. The composition may further contain other therapeutically effective compounds.

[0186] When the compounds of the present invention are used for the prevention or treatment of the above-mentioned diseases, the dosage and frequency of administration can be varied depending on the patient's sex, age, weight, and condition, as well as the type and extent of the intended therapeutic effect. Generally, when administered orally, the dosage can be 0.001 to 50 mg / kg / day, which can be administered once or several times. In a specific embodiment, the dosage is about 0.01 to about 25 mg / kg / day, and in a particular embodiment, about 0.05 to about 10 mg / kg / day. For oral administration, the composition is preferably provided in the form of a tablet or capsule containing 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 compound described herein. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0187] Combination therapy The compounds of the invention are also useful in a method for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.

[0188] The compounds of the present invention can be used in combination with one or more other drugs in the treatment, prevention, suppression, or amelioration of diseases or conditions for which the compounds described herein or other drugs may be useful, where the combination of drugs is safer or more effective than either drug alone. Accordingly, such other drugs can be administered simultaneously or sequentially with the compounds described herein or pharmaceutically acceptable salts thereof, in amounts commonly used in the treatment of such diseases or conditions. When the compounds described herein are used simultaneously with one or more other drugs, in specific embodiments, a pharmaceutical composition can contain such other drugs and the compounds described herein or pharmaceutically acceptable salts thereof in a unit dosage form. However, combination therapy can also include therapy in which the compounds described herein or pharmaceutically acceptable salts thereof 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 alone. Accordingly, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds described herein or pharmaceutically acceptable salts thereof. [Example]

[0189] Abbreviation Abbreviations used herein have the meanings tabulated below. Abbreviations not listed below have the meaning of their commonly used abbreviation unless specifically stated otherwise.

[0190] [Table 1] TIFF2025061677000063.tif116161

[0191] Synthesis of common intermediates (Table A) Preparation of Intermediate I-1A ((S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-1A was prepared from pyrrolidine-2,5-dione according to the method described below. [ka]

[0192] Step 1. Synthesis of 5-phenylpyrrolidin-2-one Two identical-scale reactions were carried out in parallel. To a solution of pyrrolidine-2,5-dione (500 g, 5.05 mol) in DCM (12.5 L) was added PhMgBr (3 M, 4.21 L) under N at -70 to -65 °C, and the reaction was stirred at 25-30 °C for 12 h. To the mixture was added NaBHCN (1.28 kg, 6.06 mol) at 5-10 °C and stirred for 1 h. The reaction was acidified to pH 3-4 with TFA (2.31 kg, 20.3 mol). It was then stirred at 25-30 °C for 2 h.

[0193] The two reactions were combined and worked up together. The mixture was added to ice-H2O (25 L) and extracted with DCM (2 x 5.0 L) to give the organic layer. The organic layer was washed with saturated NaHCO3 (15 L) and separated. The organic layer was then purified by flash silica gel chromatography (petroleum ether / ethyl acetate) to give 5-phenylpyrrolidin-2-one. 1 H 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).

[0194] Step 2. Synthesis of 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole Five identical-scale reactions were performed in parallel. Trimethyloxonium tetrafluoroborate (109 g, 736 mmol) was added to a solution of 5-phenylpyrrolidin-2-one (99.0 g, 614 mmol) and K2CO3 (169 g, 1.23 mol) in DCM (990 mL) at 25-30 °C. The mixture was stirred at 25-30 °C for 12 h. The mixture was added to saturated NaHCO3 (5.0 L) and extracted with DCM (2 x 1.0 L) to obtain an organic layer. The organic layer was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole. 1 H 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).

[0195] Step 3. Synthesis of methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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) and compound methyl hydrazine carboxylate (97.1 g, 1.08 mol) in MeOH (1.8 L) at 25-30°C. The reaction was stirred at 80°C for 3 hours. Upon completion, the mixture was concentrated. The crude product was washed with MTBE (300 mL) to give methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 1 H 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).

[0196] Step 4 - Synthesis of 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and subsequent SFC to obtain I-1A Two identical reactions were run in parallel. A solution of methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (50.0 g, 214 mmol) in DMF (500 mL) was stirred at 145 °C for 1 hour. Upon completion, the two reactions were combined and worked up together. The mixture was concentrated to remove the DMF to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) and washed with MTBE (100 mL) to give 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (30.0 g).

[0197] The compound 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 (method column DAICEL AD; conditions MeOH / IPA) to give (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, the first eluting isomer, and I-1A ((S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one), the second eluting isomer.

[0198] (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 HNMR (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). (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-1A): 1 H 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).

[0199] Preparation of Intermediate I-2A ((5S)-5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-2A was prepared from 1-bromo-3,5-difluorobenzene according to the method described below. [ka]

[0200] Step 1. Synthesis of 5-(3,5-difluorophenyl)pyrrolidin-2-one 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, and the reaction mixture was stirred at 50 °C for 1 hour. Succinimide (310 g, 313 mmol) and DCM (300 mL) were then added to the mixture at −78 °C. The mixture was stirred at 25 °C for 16 hours. NaBH3CN (236 g, 3750 mmol) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was acidified to pH 3–4 with 6 M HCl, stirred for 30 minutes, and neutralized with 3 M aqueous NaOH. The mixture was quenched with water (5000 mL) and extracted with DCM (3 x 5000 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (hexanes / ethyl acetate) to give 5-(3,5-difluorophenyl)pyrrolidin-2-one. 10 H 10 F2NO[M+H] + Calculated value: 198; Measured value: 198.

[0201] Step 2. Synthesis of 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 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 saturated aqueous NaHCO (3000 mL) and extracted with DCM (3 x 2000 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3,5-difluorocyclohexyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly in the next step. 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0202] Step 3. Synthesis of N'-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide 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 hydrazinecarboxylic 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 purified by flash silica gel chromatography (EtOAc / MeOH) to give N′-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide. 12 H 14 F2N3O2[M+H] + Calculated value: 270; Measured value: 270.

[0203] Steps 4-5. Synthesis of 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one and subsequent SFC to obtain I-2A 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 under reduced pressure to give the crude product, which was slurried in CHCN / 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 compound 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (75 g, 316 mmol, 1.00 equiv.) was separated by preparative SFC (CHIRALPAK IC-3 column; 10% EtOH) to give (5R)-5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one, the first eluting isomer, and I-2A, ((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.

[0204] (5R)-5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H 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). 19 F NMR (282 MHz, DMSO-d6) δ -109.22.C 11 H 10 F2N3O[M+H] + Calculated value: 238; Measured value: 238.

[0205] (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). 19 F NMR (282 MHz, DMSO-d6) δ -109.22.C 11 H 10 F2N3O[M+H] + Calculated value: 238; Measured value: 238.

[0206] Preparation of Intermediate I-3A ((S)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-3A was prepared from 1-(2-fluorophenyl)ethan-1-one according to the method described below. [ka]

[0207] Step 1. Synthesis of ethyl 4-(2-fluorophenyl)-4-oxobutanoate 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), LiHMDS (72.4 mL, 72.4 mmol) (1 M solution in THF) was added at approximately −60°C (dry ice-acetone bath). After the addition was complete, the reaction was stirred at −60°C for 30 min. Next, ethyl 2-bromoacetate (12.7 g, 76 mmol) was added in one portion to the mixture at −60°C. The resulting mixture was continuously stirred at −60°C for an additional 30 min. The reaction was allowed to warm 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 aqueous NH4Cl (250 mL). The mixture was extracted with tert-butyl methyl ether (2×300 mL). The combined organic portions were washed with brine (200 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give ethyl 4-(2-fluorophenyl)-4-oxobutanoate. 12 H 14 FO3 [M+H] + Calculated value: 225; Measured value: 225.

[0208] Step 2. Synthesis of 5-(2-fluorophenyl)pyrrolidin-2-one 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. The mixture was then stirred at 80° C. for 12 hours. The reaction mixture was quenched with HCl (2 M, approximately 5 mL) and concentrated. The residue was purified by flash silica gel chromatography (DCM / MeOH) to give 5-(2-fluorophenyl)pyrrolidin-2-one. 10 H 11 FNO[M+H] + Calculated value: 180; Measured value: 180.

[0209] Step 3. Synthesis of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 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 hours. The reaction mixture was quenched with saturated NaHCO (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole. The crude material was used in the next step without further purification. 11 H 13 FNO[M+H] + Calculated value: 194; Measured value: 194.

[0210] Step 4. Synthesis of methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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 hydrazine carboxylate (1.21 g, 13.5 mmol) at 20° C. until the addition was complete. The reaction was stirred at 80° C. for 2 hours and concentrated under reduced pressure. The residue was purified by p-HPLC (Boston Green ODS 150×30 mm×5 μm; conditions: water (0.1% TFA)-MeCN) to give methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 15 FN3O2[M+H] + Calculated value: 252; Measured value: 252.

[0211] Step 5-6. Synthesis of 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and isolation of I-3A by chiral separation 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 a N atmosphere and stirred at 145 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method: Column Boston Green ODS 150 × 30 mm × 5 μm; Conditions: water (0.1% TFA)-MeCN) to give 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. The racemic mixture of 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (320 mg, 1.46 mmol) was separated by SFC (Method: Column (S,S) WHELK-O1 (250 mm × 30 mm, 5 μm); Conditions: 0.1% NH3H2O / EtOH) to give (R)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. I-3A ((S)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (SFC-P2, ee=100%) and I-3B ((S)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (SFC-P3, ee=100%) were obtained.

[0212] (R)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H 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). (S)-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).

[0213] Preparation of Intermediate I-4A ((S)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-4A was prepared from 3-bromo-5-fluoropyridine according to the method described below. [ka]

[0214] Step 1. Preparation of 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid 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 °C for 2 h. The mixture was then 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. Saturated NH₄Cl (200 mL) and aqueous NaOH (2 M) were added to the reaction mixture until the pH reached approximately 11. After stirring for 30 min, the reaction mixture was extracted with EtOAc (100 mL). 2 M HCl was added to the aqueous layer until the pH reached approximately 5, followed by extraction with EtOAc (3 x 100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid, which was used in the next step without further purification.

[0215] Step 2. Preparation of methyl 4-(5-fluoropyridin-3-yl)-4-oxobutanoate To a solution of 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid (34 g, 172 mmol) in MeOH (300 mL) was added HSO (12 mL, 225 mmol), and the resulting mixture was stirred at 70 °C for 12 h. The mixture was directly concentrated. The residue was dissolved in DCM (100 mL) and water (50 mL), and saturated NaHCO was added until pH 8, followed by extraction with DCM (3 x 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give methyl 4-(5-fluoropyridin-3-yl)-4-oxobutanoate. 1 H 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 = 6.4Hz, 2H).

[0216] Step 3. Preparation of 5-(5-fluoropyridin-3-yl)pyrrolidin-2-one To a solution of methyl 4-(5-fluoropyridin-3-yl)-4-oxobutanoate (9 g, 42.6 mmol) in MeOH (150 mL) were added ammonium acetate (9.85 g, 128 mmol) and NaBHCN (8.03 g, 128 mmol), and the mixture was stirred at 80° C. for 12 hours. The reaction solution was concentrated, and the residue was purified by flash silica gel chromatography (ethyl acetate / ethanol) to give 5-(5-fluoropyridin-3-yl)pyrrolidin-2-one. 1 H 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).

[0217] Step 4. Preparation of 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione 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 for 12 hours at 110° C. The reaction solution was directly concentrated, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione. 1 H 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).

[0218] Step 5. Preparation of 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine 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 hours. The reaction solution was concentrated. The residue was washed with saturated NaHCO (40 mL), and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine, which was used in the next step without further purification.

[0219] Step 6. Preparation of methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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 hydrazine carboxylate (2.44 g, 27.1 mmol), and the resulting mixture was stirred at 80° C. for 5 hours. The reaction solution was directly concentrated, and the residue was purified by flash silica gel chromatography (MeOH / DCM) to give methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 11 H 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).

[0220] 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 A solution of methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (3.7 g, 14.67 mmol) in DMF (250 mL) was stirred at 145° C. for 12 hours. The reaction solution was concentrated. The residue was purified by flash silica gel chromatography (EtOAc / EtOH) to give 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 1 H 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).

[0221] Step 8. Obtaining I-4A by chiral separation 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) A mixture of enantiomers was purified by chiral SFC (method: column DAICEL CHIRALPAK) Conditions: 0.1% NH3HO / EtOH) to afford (R)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (806 mg) (ee=99%) and I-4A ((S)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (ee=100%).

[0222] (R)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H 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). (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).

[0223] Preparation of Intermediate I-5A ((S)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-5A was prepared from pyrrolidine-2,5-dione according to the method described below. [ka]

[0224] Step 1. Preparation of 5-(3-fluorophenyl)pyrrolidin-2-one (3-Fluorophenyl)magnesium bromide (323 mL, 323 mmol) was added dropwise to pyrrolidine-2,5-dione (16 g, 161 mmol) via syringe at −78 °C under N2. After the addition was complete, the reaction was warmed to 25 °C and allowed to react for an additional 16 h. NaBH3CN (10.2 g, 161 mmol) was then added to the mixture, which was allowed to react for an additional 3 h. 6 M HCl was added, and the pH was adjusted to 3. It was allowed to react for an additional 1 h. Aqueous NaOH was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers 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 (hexane / ethyl acetate) to give 5-(3-fluorophenyl)pyrrolidin-2-one. C 10 H 11 FNO[M+H] + Calculated value: 180; Measured value: 180.

[0225] Step 2. Preparation of 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 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 °C for 16 hours to give a brown mixture. Aqueous NaHCO was added to adjust the pH to neutral. The organic layer was separated, the aqueous solution 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 NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly. 11 H 13 FNO[M+H] + Calculated value: 194; Measured value: 194.

[0226] Step 3. Preparation of methyl 2-(2-(3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate A mixture of 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (10 g, 51.8 mmol) and methyl hydrazine carboxylate (6.06 g, 67.3 mmol) in MeOH (80 mL) and HCl (2 mL, 4 M solution in MeOH) was stirred at 80° C. for 6.5 hours to give a solution. The solvent was evaporated and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give methyl 2-(2-(3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 15 FN3O2[M+H] + Calculated value: 252; Measured value: 252.

[0227] Step 4. Preparation of 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 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. under N for 3 hours. The reaction mixture was then concentrated to give a solid. The solid was suspended in EtOAc, and the cloudy 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. 11 H 11 FN3O[M+H] + Calculated value: 220; Measured value: 220.

[0228] Step 5. Preparation of 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 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 (method: column DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 μm); conditions: 0.1% NH₃HO / EtOH) to give (R)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (ee=99.6%) and I-5A ((S)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (ee=98.9%).

[0229] (R)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 1 H 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). (S)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-5A) 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).

[0230] Preparation of Intermediate I-6A ((S)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-6A was prepared from pyrrolidine-2,5-dione and 3-bromo-5-chloropyridine according to the method described below. [ka]

[0231] Step 1. Preparation of 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid Isopropylmagnesium chloride (48.0 mL, 52.0 mmol) was added via syringe over 5 minutes at 0°C to a solution of 3-bromo-5-chloropyridine (10 g, 52.0 mmol) in 100 mL of THF. After stirring for 1 hour, the mixture was added via cannula over a 30-minute period at -20°C to a solution of dihydrofuran-2,5-dione (6.76 g, 67.6 mmol) in 100 mL of THF, followed by stirring at -20°C for 3 hours. The pH was adjusted to approximately 9 by the slow addition of NaHCO3 solution. The aqueous layer was acidified with aqueous HCl and extracted with EtOAc (5 x 100 mL). The combined organic layers were dried over NaSO4 and concentrated to give the crude product, 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid. C9H9ClNO3 [M+H] + Calculated value: 214; Measured value: 214.

[0232] Step 2. Preparation of methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate Crude 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid (8 g, 37.5 mmol) was added to MeOH (80 mL). The mixture was stirred for 12 hours. After stirring for 3 hours, the pH was adjusted to approximately 9 by slow addition of NaHCO3 solution. The combined aqueous layers were extracted with DCM (3 x 50 mL) to remove neutral impurities. The combined organic layers were dried over NaSO4 and concentrated. The solvent was evaporated, and the residue was purified by flash silica gel chromatography (hexane / ethyl acetate) to give methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate. C 10 H 11 ClNO3[M+H] + Calculated value: 228; Measured value: 228.

[0233] Step 3. Preparation of 5-(5-chloropyridin-3-yl)pyrrolidin-2-one 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) and NaBHCN (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 (4 x 30 mL) to remove neutral impurities. The combined organic layers were dried over NaSO and concentrated. The organic layer was concentrated, and the residue was purified by flash silica gel chromatography (EtOAc / EtOH) to give 5-(5-chloropyridin-3-yl)pyrrolidin-2-one. C9H 10 ClNO[M+H] + Calculated value: 197; Measured value: 197.

[0234] Step 4. Preparation of 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione 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 hours. The reaction solution was directly concentrated, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione. 10ClNS[M+H] + Calculated value: 213; Measured value: 213.

[0235] Step 5. Preparation of 3-chloro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine To a solution of 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione (1.45 g, 6.82 mmol) in THF (20 mL) was added iodomethane (1.20 mL, 19.2 mmol), and the resulting mixture was stirred at 20° C. for 12 hours. The reaction solution was concentrated to give the crude product, 3-chloro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine, which was used in the next step without further purification. 10 H 12 ClNS[M+H] + Calculated value: 227; Measured value: 227.

[0236] Step 6. Preparation of methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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 hydrazine carboxylate (0.775 g, 8.60 mmol), and the resulting mixture was stirred at 80° C. for 5 hours. The reaction solution was directly concentrated, and the residue was purified by flash silica gel chromatography (EtOAc / EtOH) to give methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 11 H 14 ClN4O2[M+H] + Calculated value: 269; Measured value: 269.

[0237] 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 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 hours. The reaction solution was directly concentrated. The residue was purified by flash silica gel chromatography (EtOAc / EtOH) to give 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 10 H 10 ClNO[M+H] + Calculated value: 237; Measured value: 237.

[0238] Step 8. Obtaining I-6A by chiral separation 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) enantiomer mixture was purified by chiral-SFC (method: column DAICEL CHIRALPAK) Resolution by AD (250 mm × 30 mm, 10 μm; conditions: 0.1% NH 3 HO / EtOH) gave I-6A ((S)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (retention time = 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 (retention time = 4.96 min).

[0239] (S)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-6A): 1 H 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). (R)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H 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).

[0240] Preparation of Intermediate I-7A (Methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate) Intermediate I-7A was prepared from methyl 5-oxopyrrolidine-2-carboxylate according to the method described below. [ka]

[0241] Step 1. Preparation of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate To a solution of methyl 5-oxopyrrolidine-2-carboxylate (50 g, 349 mmol) in CHCl (800 mL) was added dimethyloxonium tetrafluoroborate (70.1 g, 524 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h. The mixture was quenched with saturated aqueous NaHCO (400 mL) and extracted with DCM (2×200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate, which was used in the next step without further purification. C 12 NO3[M+H] + Calculated value: 158; Measured value: 158.

[0242] Step 2. Preparation of methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate 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 hydrazine carboxylate (47.3 g, 525 mmol) and HCl / MeOH (4 M) (50 mL) at 20° C., and the resulting mixture was stirred at 80° C. for 4 hours. The reaction mixture was directly concentrated, and the residue was slurried with ethyl acetate and MeOH to give methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. 14 N3O4[M+H] + Calculated value: 216; Measured value: 216. 1 H 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).

[0243] Step 3. Preparation of I-7A (methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate) To a solution of methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (20.0 g, 93.0 mmol) in MeOH (400 mL) was added sodium methanolate (15.1 g, 279 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. HCl (4.0 M in MeOH) was added to the reaction mixture until the pH reached approximately 5, and the mixture was stirred at 80° C. for 2 hours. 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. C7H 10 N3O3[M+H] + Calculated value: 184; Measured value: 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).

[0244] Preparation of Intermediate I-8A ((S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-8A was prepared from pyrrolidine-2,5-dione according to the method described below. [ka]

[0245] Step 1—Preparation of 2.5-(4-fluorophenyl)pyrrolidin-2-one (4-Fluorophenyl)magnesium bromide in THF (404 mL, 404 mmol) was added dropwise to pyrrolidine-2,5-dione (20 g, 202 mmol) via syringe at -78 °C under N2. After the addition was complete, the reaction was warmed to 25 °C and allowed to react for an additional 2.5 h. NaBH3CN (12.68 g, 202 mmol) was then added to the mixture, and the reaction was allowed to continue for an additional 16 h. HCl (6 M aqueous solution) was added to adjust the pH to 3. The reaction was stirred for an additional 1 h. NaOH (25 mL EtOH + 5 mL water) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers 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 (EtOAc / hexanes) to give 5-(4-fluorophenyl)pyrrolidin-2-one. 10 H 11 FNO[M+H] + Calculated value: 180; Measured value: 180. 1 H 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).

[0246] Step 3. Preparation of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 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 25 °C for 16 hours. The residue was diluted with a mixture of saturated aqueous NaHCO (10 mL) and DCM (10 mL). The organic layer was separated, the aqueous layer was re-extracted with DCM (3 x 10 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly in the next step without further purification. 11 H 13 FNO[M+H] + Calculated value: 194; Measured value: 194.

[0247] Step 4. Preparation of methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate A mixture of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.9 g, crude) and methyl hydrazine carboxylate (1.76 g, 19.51 mmol) in MeOH (32 mL) and HCl (4 M solution in MeOH, 0.5 mL) was stirred at 80° C. for 4 hours. The solvent was evaporated and the residue was purified by flash silica gel chromatography (aqueous MeCN) to give methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 15 FN3O2[M+H] + Calculated value: 252; Measured value: 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).

[0248] Step 5. Preparation of 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one A mixture of 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 145° C. for 16 hours. The solvent was evaporated, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 11 FN3O[M+H] + Calculated value: 220; Measured value: 220. 1 H 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).

[0249] Step 6. Chiral SFC to obtain (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-8A) 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 (250 mm × 50 mm, 10 μm); conditions: 0.1% NH₃HO / EtOH) to give (R)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as the first eluting peak (t = 0.991 min) and (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as the second eluting peak (t = 1.100 min).

[0250] (R)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H 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). (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-8A): 1 H 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).

[0251] Preparation of Intermediate I-9A (5-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-9A was prepared from 1-(2,6-difluorophenyl)ethan-1-one according to the method described below. [ka]

[0252] Step 1. Preparation of ethyl 4-(2,6-difluorophenyl)-4-oxobutanoate To a stirred solution of 1-(2,6-difluorophenyl)ethan-1-one (5 g, 32.0 mmol) in THF (150 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (8.21 g, 64.0 mmol) at −78° C. was added lithium bis(trimethylsilyl)amide (32.0 mL, 32.0 mmol) (1 M solution in THF). After the addition was complete, the reaction was stirred at −78° C. for 30 minutes. Then, 2-bromoethyl acetate (3.73 mL, 33.6 mmol) was added in one portion to the above mixture at −78° C. After the addition was complete, the reaction was stirred at 20° C. for 2 hours. LCMS indicated the reaction was complete. The mixture was diluted with tert-butyl methyl ether (200 mL) and quenched with saturated aqueous NH4Cl (200 mL). The mixture was extracted with tert-butyl methyl ether (2 x 200 mL). The combined organic portions were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give ethyl 4-(2,6-difluorophenyl)-4-oxobutanoate. 12 H 13 F2O3[M+H] + Calculated value: 243; Measured value: 243.

[0253] Step 2. Preparation of 5-(2,6-difluorophenyl)pyrrolidin-2-one To a solution of ethyl 4-(2,6-difluorophenyl)-4-oxobutanoate (2.8 g, 11.6 mmol) in EtOH (20 mL) were added ammonium acetate (13.4 g, 173 mmol) and sodium cyanoborohydride (1.45 g, 23.1 mmol), and the reaction was stirred at 90 °C for 12 hours. Water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(2,6-difluorophenyl)pyrrolidin-2-one. C 10 H 10 F2NO[M+H] + Calculated value: 198; Measured value: 198.

[0254] Step 3. Preparation of 2-(2,6-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(2,6-difluorophenyl)pyrrolidin-2-one (1.8 g, 9.13 mmol) in DCM (50 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (2.03 g, 13.7 mmol). The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(2,6-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0255] Step 4. Preparation of methyl 2-(2-(2,6-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (1.7 g, 8.05 mmol) in MeOH (34 mL) was added methyl hydrazine carboxylate (0.761 g, 8.45 mmol) and HCl (1 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was stirred at 80° C. under N for 2 hours. The mixture was concentrated under reduced pressure, and the crude residue was washed with EtOAc and hexanes and filtered to give crude methyl 2-(2-(2,6-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without further purification. 12 H 14 F2N3O2[M+H] + Calculated value: 270; Measured value: 270.

[0256] Step 5. Preparation of I-9A (5-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) To a solution of methyl 2-(2-(2,6-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.1 g, 4.09 mmol) in MeOH (25 mL) was added sodium methoxide (0.662 g, 12.3 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified to pH=7 with HCl (4 M in MeOH). The mixture was then filtered, and the solid was dried by vacuum distillation to give 5-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 10 F2N3O[M+H] + Calculated value: 238; Measured value: 238. 1 H NMR (400 MHz, CD3OD) δ 7.36-7.49 (m, 1H), 6.94-7.12 (m, 2H), 5.60 (dd, J = 5.2, 8.8 Hz, 1H), 3.08-3.21 (m, 1H), 2.87-3.06 (m, 2H), 2.54-2.66 (m, 1H).

[0257] Preparation of Intermediate I-10A (5-(3,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-10A was prepared from pyrrolidine-2,5-dione and (3,4-difluorophenyl)magnesium bromide according to the method described below. [ka]

[0258] Step 1. Preparation of 5-(3,4-difluorophenyl)pyrrolidin-2-one To a solution of (3,4-difluorophenyl)magnesium bromide (60.6 mL, 30.3 mmol) in THF (15 mL) was added isopropylmagnesium chloride lithium chloride complex solution (17.47 mL, 22.71 mmol) at -78 °C under N2. The reaction mixture was then stirred at -78 °C for 1 h. To a solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (50 mL) was added the above at -78 °C under N2. The mixture was stirred at 25 °C for 16 h. To the mixture was then added NaBH3CN (1.74 g, 27.8 mmol) at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified to pH = 3-4 with HCl (6 M aqueous solution), and the resulting mixture was stirred for 1 h and neutralized with NaOH (4 M aqueous solution). The mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to give 5-(3,4-difluorophenyl)pyrrolidin-2-one. 10 H 10 F2NO[M+H] + Calculated value: 198; Measured value: 198. 1 H 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).

[0259] Step 2. Preparation of 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(3,4-difluorophenyl)pyrrolidin-2-one (1 g, 5.07 mmol) in DCM (10 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (1.13 g, 7.61 mmol). The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0260] Step 3. Preparation of methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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 hydrazine carboxylate (0.448 g, 4.97 mmol) and HCl (2 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was directly 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. 12 H 14 F2N3O2[M+H] + Calculated value: 270; Measured value: 270. 1 H 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)

[0261] Stage 4. Manufacturing of I-10A 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 methoxide (0.662 g, 12.3 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified to pH=7 with HCl (4 M in MeOH). The mixture was then 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. 11 H 10 F2N3O[M+H] + Calculated value: 238; Measured value: 238. 11 H 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).

[0262] Preparation of Intermediate I-11A (5-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-11A was prepared from pyrrolidine-2,5-dione according to the method described below. [ka]

[0263] Step 1. Preparation of 5-(4-chlorophenyl)pyrrolidin-2-one To a solution of (4-chlorophenyl)magnesium bromide (60.6 mL, 60.6 mmol) in THF (200 mL) was added isopropylmagnesium chloride-lithium chloride complex solution (34.9 mL, 45.4 mmol) at 0 °C under N2. The reaction mixture was then stirred at 0 °C for 1 h. To a separate solution of pyrrolidine-2,5-dione (5 g, 50.5 mmol) in THF (100 mL) was added the above solution at -78 °C under N2. The mixture was stirred at 25 °C for 16 h. Next, to the mixture was added NaBH3CN (3.49 g, 55.5 mmol) at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified to pH = 3-4 with HCl (6 M aqueous solution), and the resulting mixture was stirred for 1 h and neutralized with NaOH (4 M aqueous solution). The mixture was quenched with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to give 5-(4-chlorophenyl)pyrrolidin-2-one. 1 H NMR (CDCl3, 400MHz) δ 7.31-7.37 (m, 2H), 7.20-7.26 (m, 2H), 4.73 (t, J = 7.2 Hz, 1H), 2.49-2.62 (m, 1H), 2.30-2.46 (m, 2H), 1.83-1.98 ppm (m, 1H).

[0264] Step 2. Preparation of 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(4-chlorophenyl)pyrrolidin-2-one (12 g, 61.3 mmol) in DCM (300 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (13.6 g, 92 mmol). The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 13 ClNO[M+H] +Calculated value: 210; Measured value: 210.

[0265] Step 3. Preparation of methyl 2-(2-(4-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (6 g, 28.6 mmol) in MeOH (200 mL) was added methyl hydrazine carboxylate (3.35 g, 37.2 mmol) and HCl (15 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was stirred at 80° C. for 6 hours under N2. The mixture was concentrated under reduced pressure, and the residue was then washed with EtOAc / PE (1:1) to give methyl 2-(2-(4-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 15 ClN3O2[M+H] + Calculated value: 268; Measured value: 268.

[0266] Stage 4. Construction of I-11A To a solution of methyl 2-(2-(4-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (5.9 g, 22.0 mmol) in MeOH (150 mL) was added sodium methoxide (3.57 g, 66.1 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified to pH=7 with HCl (4 M in MeOH). The mixture was then filtered, and the solid was dried by vacuum distillation to give 5-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 11 ClNO[M+H] + Calculated value: 236; Measured value: 236.

[0267] Preparation of Intermediate I-12A (5-(2,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-12A was prepared from 1-(2,4-difluorophenyl)ethan-1-one according to the method described below. [ka]

[0268] Step 1. Preparation of ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate To a stirred solution of 1-(2,4-difluorophenyl)ethan-1-one (10 g, 64.0 mmol) in THF (300 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (16.4 g, 128 mmol) at −78 °C was added lithium bis(trimethylsilyl)amide (64.0 mL, 64.0 mmol, 1 M solution in THF). After the addition was complete, the reaction was stirred at −78 °C for 30 min. Then, 2-bromoethyl acetate (7.46 mL, 67.3 mmol) was added in one portion at −78 °C. After the addition was complete, the reaction was stirred at 20 °C for 2 h. The mixture was diluted with tert-butyl methyl ether (200 mL) and quenched with saturated aqueous NH4Cl (200 mL). The mixture was extracted with tert-butyl methyl ether (2×200 mL). The combined organic portions were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to afford ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate. 12 H 13 F2O3[M+H] + Calculated value: 243; Measured value: 243.

[0269] Step 2. Preparation of 5-(2,4-difluorophenyl)pyrrolidin-2-one To a solution of ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate (2.5 g, 10.3 mmol) in EtOH (100 mL) were added ammonium acetate (11.9 g, 155 mmol) and sodium cyanoborohydride (1.30 g, 20.6 mmol), and the reaction mixture was stirred at 90° C. for 12 hours. Water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL). The organic layer was separated, and the aqueous solution was re-extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(2,4-difluorophenyl)pyrrolidin-2-one. C10 H 10 F2NO[M+H] + Calculated value: 198; Measured value: 198.

[0270] Step 3. Preparation of 2-(2,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(2,4-difluorophenyl)pyrrolidin-2-one (2 g, 10.1 mmol) in DCM (50 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (2.25 g, 15.21 mmol). The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(2,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0271] Step 4. Preparation of methyl 2-(2-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(2,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2 g, 9.47 mmol) in MeOH (50 mL) at 20° C., methyl hydrazine carboxylate (0.896 g, 9.94 mmol) and HCl (1 mL, 4 M solution in MeOH) were added, and the resulting mixture was stirred at 80° C. for 3 hours under N2. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give methyl 2-(2-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 14 F2N3O2[M+H] + Calculated value: 270; Measured value: 270.

[0272] Step 5. Preparation of 5-(2,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-12A) To a solution of methyl 2-(2-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (900 mg, 3.34 mmol) in MeOH (20 mL) was added sodium methoxide (542 mg, 10.0 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The residue was purified by RP-HPLC (column Boston Green ODS 150×30 mm×5 μm; condition: water (TFA)-ACN) to give 5-(2,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 10 F2N3O[M+H] + Calculated value: 238; Measured value: 238.

[0273] Preparation of Intermediate I-13A ((S)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-13A was prepared from 1-bromo-3-(trifluoromethyl)benzene and pyrrolidine-2,5-dione according to the method described below. [ka]

[0274] Step 1. Preparation of 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one To a solution of the first 1-bromo-3-(trifluoromethyl)benzene (4.54 g, 20.2 mmol) in THF (40 mL) was added i-PrMgCl·LiCl (21.7 mL, 28.3 mmol) at 0 °C under N2. The reaction mixture was then stirred at 25 °C for 1 h. To a solution of the second pyrrolidine-2,5-dione (2 g, 20.2 mmol) in THF (60 mL) was added i-PrMgCl·LiCl (14.0 mL, 18.2 mmol) at 0 °C under N2. The reaction mixture was then stirred at 0 °C for 1 h. The first solution was added to the second mixture at -78 °C. The resulting mixture was then stirred at 25 °C for 16 h. To the mixture was then added NaBH3CN (1.40 g, 22.2 mmol) at 25 °C, and the mixture was then stirred at 25 °C for 1 h. The reaction was acidified to pH = 3-4 with HCl (6 M aqueous solution), stirred for 1 h, and then made basic with NaOH (4 M aqueous solution). The mixture was quenched with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one. 11 H 11 F3NO[M+H] + Calculated value: 230; Measured value: 230. 1 H NMR (500 MHz, CDCl3) δ 7.43-7.63 (m, 4H), 4.83 (t, J=7.17 Hz, 1H), 2.56-2.68 (m, 1H), 2.38-2.50 (m, 2H), 1.90-2.00 (m, 1H).

[0275] Step 2. Preparation of 5-methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole To a solution of 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one (2.1 g, 9.16 mmol) in DCM (40 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (2.03 g, 13.7 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NaHCO (80 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 5-methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 13 F3NO[M+H] + Calculated value: 244; Measured value: 244.

[0276] Step 3. Preparation of methyl 2-(2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole (2 g, 8.22 mmol) in MeOH (40 mL) was added methyl hydrazine carboxylate (0.815 g, 9.04 mmol) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give methyl 2-(2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 15 F3N3O2[M+H] + Calculated value: 302; Measured value: 302.

[0277] Step 4. Preparation of 5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.3 g, 4.32 mmol) in MeOH (15 mL) was added sodium methoxide (0.70 g, 13.0 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified with HCl (4 M in MeOH) to pH=7. The mixture was then filtered, washed with water (80 mL), and the solid was dried by vacuum distillation to give 5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 12 H 11 F3N3O[M+H] + Calculated value: 270; Measured value: 270. 1 H NMR (400 MHz, DMSO-d6) δ 7.67-7.72 (m, 1H), 7.59-7.66 (m, 2H), 7.51-7.59 (m, 1H), 5.29 (dd, J=5.01, 8.11 Hz, 1H), 2.99 (dtd, J=6.32, 8.67, 13.05 Hz, 1H), 2.71-2.91 (m, 2H), 2.27-2.38 (m, 1H).

[0278] Step 5. Chiral separation for the isolation of (S)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-13A) The racemic mixture of 5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (900 mg, 3.34 mmol) was purified by chiral SFC (method: column DAICEL CHIRALCEL Separation by OD-H (250 mm × 30 mm, 5 μm; conditions: 0.1% NH₃H₂O / IPA) gave (R)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as the first eluting peak (t = 2.878 min) and (S)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as the second eluting peak (t = 3.317 min).

[0279] (R)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: C 12 H 11 F3N3O[M+H] + Calculated value: 270; Measured value: 270. (S)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-13A): C 12 H 11 F3N3O[M+H] + Calculated value: 270; Measured value: 270.

[0280] Preparation of Intermediate I-14A (5-(4-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-14A was prepared from 1-bromo-4-(trifluoromethyl)benzene and pyrrolidine-2,5-dione according to the method described below. [ka]

[0281] Step 1. Preparation of 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one To a solution of the first 1-bromo-4-(trifluoromethyl)benzene (9.08 g, 40.4 mmol) in THF (70 mL) was added i-PrMgCl·LiCl (43.5 mL, 56.5 mmol) at 0 °C under N2. The reaction mixture was then stirred at 25 °C for 1 h. To a solution of the second pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (70 mL) was added i-PrMgCl·LiCl (27.9 mL, 36.3 mmol) at 0 °C under N2. The reaction mixture was then stirred at 0 °C for 1 h. To the second mixture was added the first solution at -78 °C. The mixture was then stirred at 25 °C for 16 h. To the mixture was then added NaBH3CN (3.04 g, 48.4 mmol) at 25 °C, and the mixture was then stirred at 25 °C for 1 h. The reaction was acidified to pH 3-4 with HCl (6M aqueous solution), stirred for 1 h, and neutralized with NaOH (4M aqueous solution). The mixture was quenched with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to give 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one. 11 H 11 F3NO[M+H] + Calculated value: 230; Measured value: 230. 1 H NMR (400 MHz, CD3OD) δ ppm 1.21 ( dd, J=4.53, 2.28 Hz, 2 H) 1.98 ( d, J=2.15 Hz, 2 H) 4.06 (d, J=6.92 Hz, 1 H) 7.28 - 7.91 (m, 4 H) 8.51 - 8.54 (m, 1 H).

[0282] Step 2. Preparation of 5-methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole To a solution of 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (900 mg, 3.93 mmol) in DCM (20 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (1450 mg, 9.82 mmol). The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO (80 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 5-methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 13 F3NO[M+H] + Calculated value: 244; Measured value: 244.

[0283] Step 3. Preparation of methyl 2-(2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole (3.18 g, 13.1 mmol) in MeOH (50 mL) at 20° C., methyl hydrazine carboxylate (1.24 g, 13.7 mmol) and HCl (2 mL, 4 M solution in MeOH) were added, and the resulting mixture was stirred at 80° C. under N for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give methyl 2-(2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 15 F3N3O2[M+H] + Calculated value: 302; Measured value: 302.

[0284] Step 4. Preparation of 5-(4-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (715 mg, 2.37 mmol) in MeOH (10 mL) was added sodium methanolate (385 mg, 7.12 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified with HCl (4 M in MeOH) to pH=7. The resulting mixture was filtered, and the filtrate was purified by RP-HPLC (column: Boston Green ODS 150×30 mm×5 μm, mobile phase AB: water (0.01% TFA)-ACN) to give I-14A, 5-(4-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 12 H 11 F3N3O[M+H] + Calculated value: 270; Measured value: 270.

[0285] Preparation of Intermediate I-15A (5-(3,5-difluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-15A was prepared from 5-bromo-1,3-difluoro-2-methylbenzene and pyrrolidine-2,5-dione according to the method described below. [ka]

[0286] Step 1. Preparation of 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one To a solution of the first 5-bromo-1,3-difluoro-2-methylbenzene (1250 mg, 6.06 mmol) in THF (10 mL) at 0 °C under N2, i-PrMgCl·LiCl (6.52 mL, 8.48 mmol) was added. The reaction was then stirred at 25 °C for 1 h. To a solution of the second pyrrolidine-2,5-dione (600 mg, 6.06 mmol) in THF (15 mL) at 0 °C under N2, i-PrMgCl·LiCl (4.19 mL, 5.45 mmol) was added. The reaction was then stirred at 0 °C for 1 h. The first solution was then added to the second mixture at -78 °C. The reaction was warmed to 25 °C and stirred at 25 °C for 12 h. NaBH3CN (419 mg, 6.66 mmol) was then added, and the resulting mixture was stirred for 1 h. The reaction mixture was acidified with HCl (6M aqueous solution) to pH 3 and stirred for 1 hour. Then, NaOH (4M aqueous solution) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one. 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212. 1 H NMR (400 MHz, CD3OD) δ 6.82-6.95 (m, 2H), 4.77 (t, J=7.09 Hz, 1H), 2.54-2.66 (m, 1H), 2.36-2.44 (m, 2H), 2.16 (t, J=1.55 Hz, 3H), 1.82-1.96 (m, 1H).

[0287] Step 2. Preparation of 2-(3,5-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one (150 mg, 0.710 mmol) in DCM (3 mL) was added dimethyloxonium tetrafluoroborate (143 mg, 1.07 mmol) at 0° C. The mixture was stirred at 30° C. for 12 hours. The mixture was quenched with saturated aqueous NaHCO (10 mL) and extracted with DCM (2×5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3,5-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 F2NO[M+H] + Calculated value: 226; Measured value: 226.

[0288] Step 3. Preparation of methyl 2-(2-(3,5-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(3,5-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (160 mg, 0.710 mmol) in MeOH (3 mL) was added methyl hydrazine carboxylate (96 mg, 1.07 mmol) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated, and the residue was added to EtOAc (10 mL). The resulting mixture was stirred for 10 minutes and filtered to give methyl 2-(2-(3,5-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 16 F2N3O2[M+H] + Calculated value: 284; Measured value: 284. 1 H NMR (400 MHz, CD3OD) δ 6.93-7.04 (m, 2H), 5.15 (t, J=7.27 Hz, 1H), 3.76-3.86 (m, 3H), 3.06-3.15 (m, 2H), 2.73-2.85 (m, 1H), 2.18 (s, 3H), 2.09-2.17 (m, 1H).

[0289] Phase 4. Construction of I-15A To a solution of methyl 2-(2-(3,5-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (110 mg, 0.388 mmol) in MeOH (3 mL) was added sodium methanolate (62.9 mg, 1.16 mmol) at 20 ° C., and the resulting mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was adjusted to pH 6 by adding HCl (0.3 mL, 4 M solution in MeOH), then filtered, and the filtrate was purified by RP-HPLC (Method: Column: Boston Green ODS (150 × 30 mm × 5 μm); Conditions: Mobile phase AB: water (0.01% TFA)-ACN) to give 5-(3,5-difluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 12 H 12 F2N3O[M+H] + Calculated value: 252; Measured value: 252.

[0290] Preparation of Intermediate I-16A (5-(3,5-difluorophenyl)-6-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-16A was prepared from 1-(3,5-difluorophenyl)propan-1-one according to the method described below. [ka]

[0291] Step 1. Preparation of ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate To a stirred solution of 1-(3,5-difluorophenyl)propan-1-one (5 g, 29.4 mmol) in THF (30 mL) was added 1,3-dimethyltetrahydropyrimidin-2(1H)-one (7.53 g, 58.8 mmol) and LHMDS (29.4 mL, 29.4 mmol) at −78 °C under N. After the addition was complete, the reaction was stirred at −78 °C for 30 min. Ethyl 2-bromoacetate (3.44 mL, 30.9 mmol) was then added to the above mixture in one portion at −78 °C. After the addition was complete, the reaction was stirred at 20 °C for 2 h. The mixture was diluted with tert-butyl methyl ether (10 mL) and quenched with saturated aqueous NH4Cl (20 mL). The mixture was extracted with tert-butyl methyl ether (2×30 mL). The combined organic portions were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate. 13 H 15 F2O3[M+H] + Calculated value: 257; Measured value: 257.

[0292] Step 2. Preparation of 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one To a solution of ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate (5.4 g, 21.07 mmol) in EtOH (30 mL), ammonium acetate (8.12 g, 105 mmol) and sodium cyanoborohydride (2.65 g, 42.1 mmol) were added, and the reaction was stirred at 80 °C for 12 hours. Water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic layer was separated, and the aqueous solution was re-extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one. C 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0293] Step 3. Preparation of 2-(3,5-difluorophenyl)-5-methoxy-3-methyl-3,4-dihydro-2H-pyrrole To a solution of 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one (2.1 g, 9.94 mmol) in DCM (30 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (2.21 g, 14.9 mmol). The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3,5-difluorophenyl)-5-methoxy-3-methyl-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 F2NO[M+H] + Calculated value: 226; Measured value: 226.

[0294] Step 4. Preparation of methyl 2-(2-(3,5-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(3,5-difluorophenyl)-5-methoxy-3-methyl-3,4-dihydro-2H-pyrrole (2 g, 8.88 mmol) in MeOH (10 mL) was added methyl hydrazine carboxylate (0.840 g, 9.32 mmol) and HCl (2 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was directly concentrated, and the residue was purified by recrystallization to give methyl 2-(2-(3,5-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 16 F2N3O2[M+H] + Calculated value: 284; Measured value: 284.

[0295] Step 5. Preparation of I-16A (5-(3,5-difluorophenyl)-6-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) To a solution of methyl 2-(2-(3,5-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.5 g, 5.30 mmol) in MeOH (2 mL) was added sodium methoxide (0.858 g, 15.89 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified to pH=7 with HCl (4 M in MeOH). The mixture was concentrated, and the residue was purified by recrystallization to give I-16A. 12 H 12 F2N3O[M+H] + Calculated value: 252; Measured value: 252.

[0296] Preparation of Intermediate I-17A ((S)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one) Intermediate I-17A was prepared from 1-bromo-3,5-difluorobenzene and piperidine-2,6-dione according to the method described below. [ka]

[0297] Step 1. Preparation of 6-(3,5-difluorophenyl)piperidin-2-one To a solution of 1-bromo-3,5-difluorobenzene (5.12 g, 26.5 mmol) in THF (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. Next, piperidine-2,6-dione (2 g, 17.7 mmol) in DCM (2 mL) was added at -78 °C. The mixture was stirred at 20 °C for 12 h. NaBH3CN (1.33 g, 21.2 mmol) was added to the mixture at 20 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified to pH = 3-4 with HCl (6 M), and the mixture was stirred for 30 min and neutralized with aqueous NaOH (3 M). The mixture was quenched with saturated NH4Cl (200 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was added to ethyl acetate (20 mL) and stirred for 0.5 h. The solid was filtered to give 6-(3,5-difluorophenyl)piperidin-2-one. C 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0298] Step 2. Preparation of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine 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 hours. The mixture was quenched with saturated aqueous NaHCO (20 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine, which was used in the next step without further purification. 12 H 14 F2NO[M+H] + Calculated value: 226; Measured value: 226.

[0299] Step 3. Preparation of methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate To a solution of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine (490 mg, 2.175 mmol) in MeOH (10 mL) was added methyl hydrazine carboxylate (294 mg, 3.26 mmol) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction was directly concentrated, and the residue was purified by flash silica gel chromatography (MeOH / DCM) to give methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate. 13 H 16 F2N3O2[M+H] + Calculated value: 284; Measured value: 284.

[0300] Steps 4-5. Preparation of Intermediate I-17A 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 hours. The reaction solution was directly 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, 0.841 mmol). 5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was resolved by chiral SFC (method: column DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); conditions: 0.1% NH₃HO / EtOH) to give 5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (ee%=97.6%) and 5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (ee%=97.3%).

[0301] ( S)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (I-17A): 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). (R)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: 1 H 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).

[0302] Preparation of Intermediate I-18A (5-Cyclopentyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-18A was prepared from cyclopentylmagnesium bromide and pyrrolidine-2,5-dione according to the method described below. [ka]

[0303] Step 1. Preparation of 5-cyclopentylpyrrolidin-2-one To a solution of pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (150 mL) at -78 °C under N2, cyclopentylmagnesium bromide (121 mL, 121 mmol) was added dropwise via syringe. After the addition was complete, the reaction was warmed to 25 °C and allowed to react for an additional 16 h. NaBH3CN (3.04 g, 48.4 mmol) was then added to the mixture, which was allowed to react for an additional 2 h. 6 M HCl was added to adjust the pH to 4. It was then stirred for an additional 1 h. Aqueous NaOH was added to neutralize the pH. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (hexane / ethyl acetate) to give 5-cyclopentylpyrrolidin-2-one. CH 16 NO[M+H] + Calculated value: 154; Measured value: 154.

[0304] Step 2. Preparation of 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-cyclopentylpyrrolidin-2-one (520 mg, 3.39 mmol) in DCM (20 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (753 mg, 5.09 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated NaHCO (800 mL) until all effervescence ceased and extracted with DCM (2 x 300 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 10 H 18 NO[M+H] + Calculated value: 168; Measured value: 168.

[0305] Step 3. Preparation of methyl 2-(2-cyclopentyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole (520 mg, 3.11 mmol) in MeOH (20 mL) was added methyl hydrazine carboxylate (308 mg, 3.42 mmol) and HCl / MeOH (0.06 mL) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction was directly concentrated, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give methyl 2-(2-cyclopentyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 11 H 20 N3O2[M+H] + Calculated value: 226; Measured value: 226.

[0306] Phase 4. Construction of I-18A To a solution of methyl 2-(2-cyclopentyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (200 mg, 0.888 mmol) in MeOH (6 mL) was added sodium methoxide (144 mg, 2.66 mmol), and the resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature and acidified with HCl / MeOH (4 M) to pH=7. The mixture was then filtered and purified by preparative HPLC (method: Boston Green ODS column 150×30 mm×5 μm; condition: water (0.01% TFA)-CAN) to give 5-cyclopentyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 10 H 16 NO[M+H] + Calculated value: 194; Measured value: 194. 1 H NMR (400 MHz, CD3OD) δ 4.12-4.19 (m, 1H), 2.81 (d, J = 8.1 Hz, 1H), 2.59-2.75 (m, 2H), 2.27-2.46 (m, 2H), 1.79-1.88 (m, 1H), 1.65-1.77 (m, 3H), 1.60 (ddd, J = 10.4, 5.4, 2.4 Hz, 2H), 1.42 (br d, J = 9.2 Hz, 2H).

[0307] Preparation of Intermediate I-19A (5-Cyclohexyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-19A was prepared from cyclohexylmagnesium bromide and pyrrolidine-2,5-dione according to the method described below. [ka]

[0308] Step 1. Preparation of 5-cyclohexylpyrrolidin-2-one To a solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (100 mL) at -78 °C under N2, cyclohexylmagnesium bromide (76 mL, 76 mmol) was added dropwise via syringe. After the addition was complete, the reaction was warmed to 25 °C and stirred for 16 h. NaBH3CN (2.378 g, 37.8 mmol) was then added to the mixture, which was allowed to stir for an additional 2 h. 6 M HCl was added to adjust the pH to 4. It was then stirred for an additional 1 h. Aqueous NaOH was added to adjust the pH to 7. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give 5-cyclohexylpyrrolidin-2-one. C 10 H 18 NO[M+H] + Calculated value: 168; Measured value: 168.

[0309] Step 2. Preparation of 2-cyclohexyl-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-cyclohexylpyrrolidin-2-one (1.3 g, 7.77 mmol) in DCM (30 mL) was added trimethyloxonium tetrafluoroborate (1.72 g, 11.7 mmol) at 0 °C under N2. The mixture was stirred at 35 °C for 12 h. The mixture was quenched with saturated NaHCO3 (40 mL) until all effervescence ceased and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-cyclohexyl-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 20 NO[M+H] + Calculated value: 182; Measured value: 182.

[0310] Step 3. Preparation of methyl 2-(2-cyclohexyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-cyclohexyl-5-methoxy-3,4-dihydro-2H-pyrrole (1.3 g, 5.74 mmol) in MeOH (20 mL) was added methyl hydrazine carboxylate (0.620 g, 6.88 mmol) and HCl / MeOH (0.06 mL) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction was directly concentrated, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give methyl 2-(2-cyclohexyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 22 N3O2[M+H] + Calculated value: 240; Measured value: 240.

[0311] Phase 4. Construction of I-19A To a solution of methyl 2-(2-cyclohexyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (700 mg, 2.92 mmol) in MeOH (20 mL) was added sodium methoxide (474 ​​mg, 8.77 mmol), and the resulting mixture was stirred at 80° C. for 24 hours. The mixture was cooled to room temperature and acidified to pH=7 with HCl / MeOH (4 M). The mixture was then filtered and purified by preparative HPLC (method: column Boston Uni C18 150×40 mm×5 μm; conditions: water (0.01% TFA)-CAN) to give 5-cyclohexyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 18 NO[M+H] + Calculated value: 208; Measured value: 208. 1 H NMR (500 MHz, CD3OD) δ 4.06 (dt, J = 8.4, 4.1 Hz, 1H), 2.66-2.80 (m, 2H), 2.51-2.60 (m, 1H), 2.41 (dt, J = 8.9, 4.4 Hz, 1H), 1.98 (br d, J = 4.4 Hz, 1H), 1.76-1.84 (m, 2H), 1.67-1.75 (m, 2H), 1.46-1.52 (m, 1H), 1.25-1.37 (m, 2H), 1.17-1.24 (m, 2H), 1.09 (dd, J = 12.6, 3.6 Hz, 1H).

[0312] Preparation of Intermediate I-20A ((S and R)-5-(3-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-20A was prepared from pyrrolidine-2,5-dione and 3-bromo-5-chloropyridine according to the method described below. [ka]

[0313] Step 1. Preparation of 5-(3-chlorophenyl)pyrrolidin-2-one To a solution 1 of 1-bromo-3-chlorobenzene (10.1 g, 52.5 mmol) in THF (100 mL) at 0 °C under N2, i-PrMgCl·LiCl (56.5 mL, 73.5 mmol) was added. The reaction mixture was then stirred at 25 °C for 1 h. To a solution 2 of pyrrolidine-2,5-dione (5.2 g, 52.5 mmol) in THF (200 mL) at 0 °C under N2, isopropylmagnesium(II) lithium chloride (36.3 mL, 47.2 mmol) was added. The reaction mixture was then stirred at 25 °C for 1 h. The first solution was added to the second solution at -78 °C under N2 and stirred at 25 °C for 12 h. NaBH3CN (3.63 g, 57.7 mmol) was then added, and the reaction mixture was stirred for 1 h. HCl (6 M) was added to the reaction mixture until the pH reached approximately 3, and the mixture was stirred for 1 h. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (250 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g silica gel, eluent: 100% ethyl acetate / petroleum ether gradient) to give 5-(3-chlorophenyl)pyrrolidin-2-one. 10 H 11 ClNO[M+H] + Calculated value: 196; Measured value: 196.

[0314] Step 2. Preparation of 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(3-chlorophenyl)pyrrolidin-2-one (7.0 g, 35.8 mmol) in DCM (180 mL) was added trimethyloxonium tetrafluoroborate (7.94 g, 53.7 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated NaHCO3 (150 mL) until all effervescence ceased and extracted with DCM (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 13 ClNO[M+H] + Calculated value: 210; Measured value: 210.

[0315] Step 3. Preparation of methyl 2-(2-(3-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate A mixture of 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (7.5 g, 35.8 mmol) and methyl hydrazine carboxylate (3.22 g, 35.8 mmol) in MeOH (180 mL) and HCl·MeOH (2 mL) was stirred at 80 °C for 12 h to give a yellow solution. The solvent was evaporated, and the residue was purified by recrystallization to give methyl 2-(2-(3-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 15 ClN3O2[M+H] + Calculated value: 268; Measured value: 268.

[0316] Step 4. Preparation of I-20A, (S and R)-5-(3-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(3-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (5.0 g, 18.7 mmol) in MeOH (100 mL) was added sodium methylate (3.03 g, 56.0 mmol), and the resulting mixture was stirred at 80° C. for 8 hours. The mixture was cooled to room temperature and acidified to pH=7 with HCl / MeOH (4 M). The mixture was then filtered, and the solid was dried by vacuum distillation to give I-20A, (S and R)-5-(3-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 11 ClNO[M+H] + Calculated value: 236; Measured value: 236.

[0317] Preparation of I-21A (5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-21A was prepared from pyrazine-2-carbaldehyde according to the method described below: [ka]

[0318] Step 1. Preparation of ethyl 4-oxo-4-(pyrazin-2-yl)butanoate Two reactions of the same scale were carried out in parallel.

[0319] To a solution of pyrazine-2-carbaldehyde (180 g, 1.67 mol) in MeOH (1.80 L) at 20 °C, ethyl acrylate (205 g, 2.05 mol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (83.9 g, 0.33 mol), and TEA (505 g, 5.00 mol) were added. The mixture was heated to 70 °C and stirred for 1 h. 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 (4 x 1.00 L). The organic layer was washed with saturated NaHCO3 (1.00 L), brine (0.50 L), and dried over Na2SO4. The organic layer was dried under vacuum, and the crude residue was purified by flash column chromatography (petroleum ether / EtOAc). Fractions containing the desired product were pooled and concentrated to give ethyl 4-oxo-4-(pyrazin-2-yl)butanoate. 1 H (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).

[0320] Step 2-3. Preparation of 5-(pyrazin-2-yl)pyrrolidin-2-one 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 hours. The reaction was concentrated to dryness, and the resulting brown liquid was used in the next step without further purification.

[0321] Subsequent steps were carried out in parallel in two identically scaled reactions.

[0322] To 4-oxo-4-(pyrazin-2-yl)butanamide (138 g, 768 mmol) in EtOH (960 mL) was added NaBHCN (145 g, 2.31 mol) at 20 °C, and the resulting mixture was stirred at 80 °C for 5 h. 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). Fractions containing the desired product portion were pooled and concentrated, and 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. 1 H 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).

[0323] Step 4. Preparation of 5-(pyrazin-2-yl)pyrrolidine-2-thione 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 hours. The reaction was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH). Fractions containing the desired product portion were pooled and concentrated to give 5-(pyrazin-2-yl)pyrrolidine-2-thione. 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).

[0324] Step 5. Preparation of 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine 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). Fractions containing the desired product portion were pooled and concentrated to give 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine. 1 H 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).

[0325] Stage 6-7. Manufacturing of I-21A Two reactions of the same scale were carried out in parallel.

[0326] 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 hydrazine carboxylate (15.4 g, 171 mmol). The reaction mixture was heated to 80° C. for 2 h. The reaction was concentrated to dryness to give methyl 2-(2-(pyrazin-2-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without further purification.

[0327] The next step was carried out in parallel in two reactions of the same scale.

[0328] 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) was added MeONa (25.6 g, 332 mmol) at 20 °C. The resulting mixture was stirred at 80 °C for 12 h. The two batches were combined and poured into HO (500 mL) at room temperature. The mixture was filtered, and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated to give the crude desired 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 purification cycle by preparative HPLC (method: Welch Xtimate C18; conditions: water (TFA)-ACN), I-21A, 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, was obtained. 1 H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.69 (s, 1H), 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).

[0329] Preparation of Intermediate I-22A ((S and R)-5-(3,5-difluorophenyl)-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one) Intermediate I-22A was prepared from 2-amino-2-(3,5-difluorophenyl)ethan-1-ol according to the method described below. [ka]

[0330] Step 1. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine To a mixture of 2-amino-2-(3,5-difluorophenyl)ethan-1-ol (800 mg, 4.62 mmol) in DCM (20 mL) was added imidazole (472 mg, 6.93 mmol) and TBSCl (836 mg, 5.54 mmol) at 0 °C under N 2 . The mixture was stirred at 20 °C for 12 h. Distilled water (40 mL) was added, and after stirring for 10 min, the mixture was extracted with DCM (2 x 30 mL), washed with brine (40 mL), and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica gel, eluent: 4% EtOAc / petroleum ether gradient) to give 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine. C 14 H 24 F2NOSi[M+H] + Calculated value: 288; Measured value: 288.

[0331] Step 2. Preparation of tert-butyl(2-(3,5-difluorophenyl)-2-isothiocyanatoethoxy)dimethylsilane A solution of 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine (700 mg, 2.435 mmol) in DCM (5 mL) and aqueous NaHCO (5 mL) was stirred at 25 °C for 15 min. To the lower layer of the mixture, thiophosgene (0.355 mL, 4.87 mmol) was added via syringe at 25 °C, and the mixture was stirred at 25 °C for 1.5 h. The mixture was quenched with brine and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na SO and filtered. The filtrate was concentrated under reduced pressure to give crude tert-butyl(2-(3,5-difluorophenyl)-2-isothiocyanatoethoxy)dimethylsilane, which was used directly in the next step without further purification. 15 H 22 F2NOSSi[M+H] + Calculated value: 330; Measured value: 330.

[0332] Step 3. Preparation of methyl 6-(3,5-difluorophenyl)-9,9,10,10-tetramethyl-4-thioxo-8-oxo-2,3,5-triaza-9-silaundecanoate A mixture of tert-butyl(2-(3,5-difluorophenyl)-2-isothiocyanatoethoxy)dimethylsilane (680 mg, 2.06 mmol), EtN (0.863 mL, 6.19 mmol), and methyl hydrazine carboxylate (223 mg, 2.477 mmol) in THF (10 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (8 g silica gel, eluent: 55% ethyl acetate / petroleum ether gradient) to give methyl 6-(3,5-difluorophenyl)-9,9,10,10-tetramethyl-4-thioxo-8-oxo-2,3,5-triaza-9-silaundecanoate. 17 H 28 F2N3O3SSi[M+H] + Calculated value: 420; Measured value: 420.

[0333] Step 4. Preparation of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-5-mercapto-2,4-dihydro-3H-1,2,4-triazol-3-one A mixture of methyl 6-(3,5-difluorophenyl)-9,9,10,10-tetramethyl-4-thioxo-8-oxo-2,3,5-triaza-9-silaundecanoate (630 mg, 1.50 mmol) in sodium hydroxide (10 mL, 1.000 mmol) was stirred at 25° C. for 3 hours. The mixture was purified by preparative HPLC (column: Boston Green ODS, conditions: water (0.01% TFA)-CAN) to give 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-5-mercapto-2,4-dihydro-3H-1,2,4-triazol-3-one. C 10 H 10 F2N3O2S[M+H] + Calculated value: 274; Measured value: 274.

[0334] Step 5. Preparation of I-22A, (S and R)-5-(3,5-difluorophenyl)-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one To a solution of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-5-mercapto-2,4-dihydro-3H-1,2,4-triazol-3-one (200 mg, 0.183 mmol) and triphenylphosphane (96 mg, 0.366 mmol) in THF (4 mL) was added DIAD (0.071 mL, 0.366 mmol) at 25 °C, and the mixture was stirred at 40 °C under N2 (g) for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Green ODS, conditions: water (0.01% TFA)-CAN) to give I-22A, (S and R)-5-(3,5-difluorophenyl)-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one. 10 H8F2N3OS[M+H] + Calculated value: 274; Measured value: 274.

[0335] Intermediate I-23A ((S and R) - Preparation of 5-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediate I-23A was prepared from pyrrolidine-2,5-dione according to the method described below. [ka]

[0336] Step 1. Preparation of 5-(4-methoxyphenyl)pyrrolidin-2-one To a solution of pyrrolidine-2,5-dione (2 g, 20.2 mmol) in THF (100 mL) at 78 °C under N2, 4-methoxyphenylmagnesium bromide (89 mL, 44.4 mmol) was added dropwise via syringe. After the addition was complete, the reaction was warmed to 25 °C and stirred for an additional 16 h. NaBH3CN (1.52 g, 24.2 mmol) was then added to the mixture, which was stirred for an additional 2 h. Aqueous HCl (4 M) was added to adjust the pH to 4. The mixture was stirred for an additional 1 h at room temperature. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (40 g silica gel, eluent 80% to 100% EtOAc gradient) to give 5-(4-methoxyphenyl)pyrrolidin-2-one. 11 H 14 NO2[M+H] + Calculated value: 192; Measured value: 192.

[0337] Step 2. Preparation of 5-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole To a solution of 5-(4-methoxyphenyl)pyrrolidin-2-one (600 mg, 3.14 mmol) in DCM (20 mL) at 0 °C under N was added trimethyloxonium tetrafluoroborate (696 mg, 4.71 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated NaHCO (20 mL) until all effervescence ceased and extracted with DCM (2 x 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 5-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 16 NO2[M+H] + Calculated value: 206; Measured value: 206.

[0338] Step 3. Preparation of methyl 2-(2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole (600 mg, 2.92 mmol) in MeOH (20 mL) was added methyl hydrazine carboxylate (290 mg, 3.22 mmol) and HCl / MeOH (0.06 mL) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was directly concentrated, and the residue was washed with petroleum ether / EtOAc (1:1) to give methyl 2-(2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 18 N3O3[M+H] + Calculated value: 264; Measured value: 264.

[0339] Step 3. Preparation of I-23A, (S and R)-5-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (400 mg, 1.52 mmol) in MeOH (10 mL) was added NaOMe (410 mg, 7.60 mmol), and the resulting mixture was stirred at 80° C. for 24 hours. The mixture was cooled to room temperature and acidified with HCl / MeOH (4 M) to pH=7. The mixture was then filtered and purified by preparative HPLC (column: Boston Uni C18, conditions: water (0.01% TFA)-ACN) to give I-23A (S and R)-5-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 12 H 14 N3O2[M+H] + Calculated value: 232; Measured value: 232.

[0340] Preparation of Intermediate I-24A ((S and R)-4-(3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-yl)benzonitrile) Intermediate I-24A was prepared from I-11A according to the method described below. [ka]

[0341] To a stirred solution of 5-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (200 mg, 0.849 mmol) in dioxane (5 mL) and water (5 mL) at 20 °C was added potassium ferrocyanide trihydrate (358 mg, 0.849 mmol), potassium acetate (250 mg, 2.55 mmol), and Brettphos Pd G3 (115 mg, 0.127 mmol). After the addition was complete, the reaction was stirred at 100 °C under a N2 atmosphere for 12 h. The reaction was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX, conditions: water (7 mM HCOONH4)-ACN) to give I-24A, (S and R)-4-(3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-yl)benzonitrile. 12 H 11 NO[M+H] + Calculated value: 227; Measured value: 227.

[0342] Preparation of Intermediate I-25A ((S and R)-5-(6-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-25A was prepared according to the method described below. [ka]

[0343] Step 1. Preparation 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 To a solution of methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (5.0 g, 27.3 mmol) and CsCO (13.3 g, 40.9 mmol) in DMF (136 mL) was added SEM-Cl (5.81 mL, 32.8 mmol) at 0 °C, and the resulting mixture was stirred at 20 °C for 12 hours. The reaction was filtered, and the filtrate was concentrated to give 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. 12 H22 N3O4Si[M+H] + Calculated value: 300; Measured value: 300.

[0344] Step 2. 5-(6-Methylpyrazin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 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 (500 mg, 1.670 mmol) in DMF (10 mL) under N was added 2-chloro-6-methylpyrazine (429 mg, 3.34 mmol), CsCO (816 mg, 2.505 mmol), 2,2′-bipyridine (58.7 mg, 0.376 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (55.0 mg, 0.250 mmol), and 4CzIPN (65.9 mg, 0.083 mmol). The mixture was stirred under 450 nm blue light for 12 h. Water (50 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (100% ethyl acetate / petroleum ether gradient eluent) to give 5-(6-methylpyrazin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 16 H 26 N5O2Si[M+H] + Calculated value: 348; Measured value: 348.

[0345] Step 3. Preparation of I-25A, (S and R)-5-(6-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a mixture of 5-(6-methylpyrazin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (320 mg, 0.921 mmol) in DCM (4.5 mL) was added TFA (1.5 mL), and the resulting mixture was stirred at 20 °C for 2 h. The reaction solution was directly concentrated. The residue was dissolved in MeOH (5 mL), and NH3·H2O (0.5 mL) was added to adjust the pH to approximately 8, followed by stirring for 1 h. The solution was then concentrated, and the residue was purified by preparative HPLC (column: Boston Uni C18, conditions: water (0.01% TFA)-ACN) to give I-25A, (S and R)-5-(6-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 10 H 12 NO[M+H] + Calculated value: 218; Measured value: 218.

[0346] Preparation of Intermediate I-26A (5S,7R)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and I-27A (5S,7S)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediates I-26A and I-27A were prepared from 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoic acid according to the method described below. [ka]

[0347] Step 1. Synthesis of methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate To a solution of 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoic acid (21 g, 92 mmol) in MeOH (20 mL) was added HCl / MeOH (200 mL). The resulting mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with saturated aqueous NaHCO (150 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give impure methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate. The material was further purified by preparative SFC (Method: Column DAICEL CHIRALPAK AD; Conditions: MeOH (0.1% NH3H2O)) to give methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate as a combination of the first and second eluting peaks. 1 H NMR (400 MHz, MeOD) δ 7.54-7.62 (m, 2H), 7.20-7.29 (m, 1H), 3.67 (s, 3H), 3.44 (dd, J = 18.24, 8.70 Hz, 1H), 3.09-3.17 (m, 1H), 2.99-3.09 (m, 1H), 1.27 (d, J = 7.27 Hz, 3H).

[0348] Step 2. Synthesis of 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one To a solution of methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate (2.5 g, 10.3 mmol) in MeOH (25 mL) at 0 °C under a nitrogen atmosphere, ammonium acetate (0.796 g, 10.3 mmol) and sodium cyanoborohydride (0.649 g, 10.3 mmol) were added. The resulting mixture was heated to 70 °C for 12 hours. The mixture was cooled to ambient temperature, poured into ice water (100 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one. 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0349] Step 3. Synthesis of 2-(3,5-difluorophenyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole To a solution of 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one (1.5 g, 7.1 mmol) in DCM (15 mL) at 0 °C under nitrogen was added trimethyloxonium tetrafluoroborate (1.58 g, 10.6 mmol). The resulting mixture was stirred at 45 °C for 16 h. The mixture was quenched by dropwise addition to saturated aqueous NaHCO (100 mL) at 5-10 °C and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-(3,5-difluorophenyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole, which was used in the next step without purification. 12 H 14 F2NO[M+H] + Calculated value: 226; Measured value: 226.

[0350] Step 4. Synthesis of methyl 2-(2-(3,5-difluorophenyl)-4-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(3,5-difluorophenyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole (1.6 g, 7.1 mmol) in MeOH (20 mL) at 25° C. under nitrogen was added methyl hydrazine carboxylate (0.672 g, 7.46 mmol). The resulting mixture was stirred at 80° C. for 3 hours. The reaction was concentrated under reduced pressure to give methyl 2-(2-(3,5-difluorophenyl)-4-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without purification. 13 H 16 F2N3O2[M+H] + Calculated value: 284; Measured value: 284.

[0351] Step 5 - Synthesis of 6.5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and subsequent SFC to obtain I-26A and I-27A To a solution of methyl 2-(2-(3,5-difluorophenyl)-4-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (2 g, 7.06 mmol) in MeOH (20 mL) at 0° C. under nitrogen was added sodium methylate (3.58 g, 21.2 mmol). The resulting mixture was heated to 80° C. for 12 h. The mixture was cooled to 0° C. and acidified to pH=7 with HCl / MeOH (4 M). The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Welch Xtimate C18 250*70mm*10μm column; conditions: water (NH4HCO3)-MeCN) to give 5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as a racemic mixture. The mixture was separated by preparative SFC (DAICEL CHIRALCEL OD (250mm x 30mm, 10μm column; conditions: 0.1% NH3H2O / IPA) to give I-27A, (5S,7S)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, as the fourth eluting peak. The second and third elution peaks were poorly soluble and were combined and concentrated under reduced pressure. The resulting residue was repurified by preparative SFC (column: (s,s) WHELK-O1 (250 mm × 30 mm, 5 μm) with 0.1% NH₃H₂O / EtOH) to give I-26A, (5S,7R)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, as the second elution peak.

[0352] (5S,7R)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-26A): 1 H NMR (400 MHz, MeOD) δ 6.83-6.97 (m, 3H), 5.29 (dd, J = 3.2, 8.2, Hz, 1H) 3.32-3.38 (m, 1H), 2.58-2.79 (m, 2H), 1.34 (d, J = 6.9 Hz, 3H).C 12 H12 F2N3O[M+H] + Calculated value: 252; Measured value: 252.

[0353] (5S,7S)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-27A): 1 H NMR (400 MHz, MeOD) δ 6.85-7.01 (m, 3H), 5.09-5.24 (m, 1H), 3.15-3.28 (m, 2H), 1.97-2.12 (m, 1H), 1.34 (d, J=6.5 Hz, 3H).C 12 H 12 F2N3O[M+H] + Calculated value: 252; Measured value: 252.

[0354] Preparation of Intermediate I-28A 5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediate I-28A was prepared from 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid according to the method described below. [ka]

[0355] Step 1. Synthesis 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 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 (700 mg, 2.34 mmol) in DMF (14 mL) under N was added 2-bromo-5-fluoropyridine (411 mg, 2.34 mmol), CsCO (1143 mg, 3.51 mmol), 2,2′-bipyridine (82 mg, 0.53 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (77 mg, 0.35 mmol), and 4CzIPN (92 mg, 0.12 mmol). The resulting mixture was stirred for 12 h under 450 nm blue light. The mixture was purified by preparative HPLC (column: Boston Green ODS150*30mm*5μm; condition: water (0.1% TFA)-MeCN) to obtain 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. 16 H 24 FN4O2Si[M+H] + Calculated value: 351; Measured value: 351.

[0356] Step 2. Synthesis of I-28A 5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a mixture 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 (220 mg, 0.628 mmol) in DCM (6 mL) was added TFA (2 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The reaction was concentrated, and the resulting residue was dissolved in MeOH (10 mL). Ammonium hydroxide was added until the pH was approximately 8, and the resulting solution was stirred for 1 hour. The solution was concentrated, and the resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; condition: water (10mM-NH4HCO3)-MeCN) to give I-28A, 5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one.10 H 10 FN4O[M+H] + Calculated value: 221; Measured value: 221.

[0357] Preparation of Intermediate I-29A 5-(3-chloro-5-fluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediate I-29A was prepared from 5-bromo-1-chloro-3-fluoro-2-methylbenzene according to the method described below. [ka]

[0358] Step 1. Synthesis of 5-(3-chloro-5-fluoro-4-methylphenyl)pyrrolidin-2-one To a solution of 5-bromo-1-chloro-3-fluoro-2-methylbenzene (4.96 g, 22.2 mmol) in THF (100 mL) at 0 °C under nitrogen, was added iPrMgCl·LiCl (1.3 M solution in THF) (18.63 mL, 24.22 mmol). The resulting solution was stirred at 20 °C for 1 h. To a separate solution of pyrrolidine-2,5-dione (2.00 g, 20.2 mmol) in THF (100 mL) at 0 °C under nitrogen, was added iPrMgCl·LiCl (1.3 M solution in THF) (13.97 mL, 18.17 mmol). The resulting solution was stirred at 0 °C for 1 h. The first solution was added to the second solution at −78 °C. The resulting mixture was allowed to warm to ambient temperature and stirred for 16 h. NaBH3CN (1.78 g, 28.3 mmol) was added to the reaction mixture at ambient temperature, and the reaction was stirred for 1 hour. The reaction was acidified to pH = 3-4 with HCl (6 M), stirred for 1 hour, and neutralized with aqueous NaOH (4 M). The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate) to give 5-(3-chloro-5-fluoro-4-methylphenyl)pyrrolidin-2-one. C 11 H 12 ClFNO[M+H] + Calculated value: 228; Measured value: 228.

[0359] Step 2. Synthesis of 2-(3-chloro-5-fluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(3-chloro-5-fluoro-4-methylphenyl)pyrrolidin-2-one (1.6 g, 7.0 mmol) in DCM (20 mL) at 0 °C under nitrogen was added trimethyloxonium tetrafluoroborate (1.559 g, 10.54 mmol). The mixture was stirred at 40 °C under nitrogen for 24 hours. The mixture was cooled to ambient temperature, quenched with saturated aqueous NaHCO (50 mL), and extracted with DCM (2 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2-(3-chloro-5-fluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 ClFNO[M+H] + Calculated value: 242; Measured value: 242.

[0360] Step 3. Synthesis of methyl 2-(2-(3-chloro-5-fluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(3-chloro-5-fluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (1.1 g, 4.5 mmol) in MeOH (30 mL) at ambient temperature was added methyl hydrazine carboxylate (0.451 g, 5.01 mmol) and HCl / MeOH (3 mL). The resulting mixture was brought to 80° C. and stirred under nitrogen for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was slurried with ethyl acetate for 15 minutes and filtered to give methyl 2-(2-(3-chloro-5-fluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without further purification. 13 H 15 ClFN3O2[M+H] + Calculated value: 300; Measured value: 300.

[0361] Step 4. Synthesis of I-29A 5-(3-chloro-5-fluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one A mixture of methyl 2-(2-(3-chloro-5-fluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (700 mg, 2.33 mmol) in DMF (100 mL) was stirred under nitrogen at 145° C. for 4 hours. The mixture was cooled to ambient temperature, washed with ethyl acetate (10 mL), filtered, and purified by preparative HPLC (column Boston Prime C18 150*40 mm*5 μm; condition: water (0.1% TFA)-MeCN) to give I-29A, 5-(3-chloro-5-fluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one.

[0362] 5-(3-chloro-5-fluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H NMR (400 MHz, MeOD): δ 7.16 (s, 1H), 6.98 (dd, J = 10.0, 1.6 Hz, 1H), 5.20 (dd, J = 8.0, 4.8 Hz, 1H), 3.00-3.13 (m, 1H), 2.89-2.98 (m, 1H), 2.74-2.87 (m, 1H), 2.40-2.48 (m, 1H), 2.30 (d, J = 2.4 Hz, 3H).C 12 H 12 ClFNO[M+H] + Calculated value: 268; Measured value: 268.

[0363] Preparation of Intermediate I-30A Intermediate I-30A was prepared from 4-bromo-2,6-difluorophenol according to the method described below. [ka]

[0364] Step 1. Preparation of 2-(benzyloxy)-5-bromo-1,3-difluorobenzene To a solution of 4-bromo-2,6-difluorophenol (5 g, 23.92 mmol) in DMF (100 mL) was added K2CO3 (4.96 g, 35.9 mmol) and (bromomethyl)benzene (3.41 mL, 28.7 mmol), and the resulting mixture was stirred at 25 °C for 12 h. Water (500 mL) was added to the mixture, and the solution was then extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with a 2% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 2-(benzyloxy)-5-bromo-1,3-difluorobenzene. 1 H NMR (400 MHz, CD3OD) δ 7.28-7.44 (m, 5H), 7.15-7.25 (m, 2H), 5.14 (s, 2H).

[0365] Step 2. Preparation of 5-(4-(benzyloxy)-3,5-difluorophenyl)pyrrolidin-2-one To a solution of 2-(benzyloxy)-5-bromo-1,3-difluorobenzene (5.5 g, 18.39 mmol) in THF (40 mL) (referred to as Solution-1) was added iPrMgCl·LiCl (1.3 M solution in THF) (21.74 mL, 28.3 mmol) at 0 °C under N2. The reaction mixture was stirred at 45 °C for 1 h. Separately, iPrMgCl·LiCl (1.3 M solution in THF) (13.97 mL, 18.17 mmol) was added to a solution of pyrrolidine-2,5-dione (2 g, 20.18 mmol) in THF (40 mL) at 0 °C under N2 and stirred at 0 °C for 1 h. The mixture was cooled to -78 °C, and Solution-1 was added. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 12 h. NaBH3CN (1.395 g, 22.20 mmol) was added and the reaction was stirred for 1 hour. HCl (6 M) was added until the pH was approximately 4 and stirred for 1 hour. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 100% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 5-(4-(benzyloxy)-3,5-difluorophenyl)pyrrolidin-2-one. C 17 H 16 F2NO2[M+H] + Calculated value: 304; Measured value: 304.

[0366] Step 3. Preparation of 2,6-difluoro-4-(5-methoxy-3,4-dihydro-2H-pyrrol-2-yl)phenol To a solution of 5-(4-(benzyloxy)-3,5-difluorophenyl)pyrrolidin-2-one (2.9 g, 9.56 mmol) in DCM (45 mL) was added trimethyloxonium tetrafluoroborate (2.121 g, 14.34 mmol) at 0° C. The mixture was stirred at 30° C. for 48 hours. The mixture was quenched with saturated aqueous NaHCO (50 mL) and then extracted with DCM (3×15 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give 2,6-difluoro-4-(5-methoxy-3,4-dihydro-2H-pyrrol-2-yl)phenol, which was used in the next step without further purification. 11 H 12 F2NO2[M+H] + Calculated value: 228; Measured value: 228.

[0367] Step 4. Preparation of methyl 2-(2-(3,5-difluoro-4-hydroxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2,6-difluoro-4-(5-methoxy-3,4-dihydro-2H-pyrrol-2-yl)phenol (2.1 g, 9.24 mmol) in MeOH (35 mL) at 20° C. was added methyl hydrazine carboxylate (1.249 g, 13.86 mmol), and the resulting mixture was stirred at 80° C. for 5 hours. The reaction was cooled to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 5% MeOH / ethyl acetate gradient at 35 mL / min) to give methyl 2-(2-(3,5-difluoro-4-hydroxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 14 F2N3O3[M+H] + Calculated value: 286; Measured value: 286.

[0368] Step 5. Preparation of Intermediate I-30A To a solution of methyl 2-(2-(3,5-difluoro-4-hydroxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.6 g, 5.61 mmol) in MeOH (30 mL) was added sodium methanolate (1.515 g, 28.0 mmol) and the resulting mixture was stirred at 80° C. for 12 h. The reaction was allowed to cool to room temperature and HCl / MeOH (4 M) was added until the pH was approximately 5 and stirred for 10 min. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluting with a 5% MeOH / DCM gradient at 35 mL / min) to afford I-30A, 5-(3,5-difluoro-4-hydroxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 10 F2N3O2[M+H] + Calculated value: 254; Measured value: 254. 1 H NMR (400 MHz, CD3OD) δ 6.85 (d, J = 7.6 Hz, 2H), 5.13 (dd, J = 4.8, 7.6 Hz, 1H), 2.99-3.09 (m, 1H), 2.74-2.98 (m, 2H), 2.41 (tdd, J = 5.2, 8.4, 13.2 Hz, 1H).

[0369] Preparation of Intermediate I-31A 5-(2,6-difluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediate I-31A was prepared from 1-(4-bromo-2,6-difluorophenyl)ethan-1-one according to the method described below. [ka]

[0370] Step 1. Synthesis of 1-(2,6-difluoro-4-methylphenyl)ethan-1-one To a solution of 1-(4-bromo-2,6-difluorophenyl)ethan-1-one (6.0 g, 25 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (10.94 mL, 38.3 mmol), and K2CO3 (10.58 g, 77 mmol) in dioxane (10 mL) and water (1 mL) under nitrogen was added Pd(dppf)Cl2 (1.868 g, 2.55 mmol). The resulting mixture was heated to 100 °C for 12 h. The mixture was cooled to ambient temperature, diluted with water (40 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 1-(2,6-difluoro-4-methylphenyl)ethan-1-one. 1 H NMR (400 MHz, CDCl3) δ 6.74 (d, J = 8.8 Hz, 2H), 2.55 (t, J = 2.0 Hz, 3H), 2.35 (s, 3H).C9H9F2O[M+H] + Calculated value: 171; Measured value: 171.

[0371] Step 2. Synthesis of ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate To a stirred solution of 1-(2,6-difluoro-4-methylphenyl)ethan-1-one (3.19 g, 18.7 mmol) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (4.81 g, 37.5 mmol) in THF (20 mL) at −78 °C was added lithium bis(trimethylsilyl)amide (1 M solution in THF) (18.75 mL, 18.75 mmol). The mixture was stirred at −78 °C for 30 minutes, and then ethyl 2-bromoacetate (2.183 mL, 19.68 mmol) was added. The reaction was allowed to warm to ambient temperature and maintained for 2 hours. The mixture was diluted with tert-butyl methyl ether (100 mL) and quenched with saturated aqueous NH₄Cl (100 mL). The mixture was extracted with tert-butyl methyl ether (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate. 1 H NMR (400 MHz, CDCl3) δ 6.62 (d, J = 9.2 Hz, 2H), 3.95-4.04 (m, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 2.22 (s, 3H), 1.10-1.13 (m, 3H).C 13 H 15 F2O3[M+H] + Calculated value: 257; Measured value: 257.

[0372] Step 3. Synthesis of 5-(2,6-difluoro-4-methylphenyl)pyrrolidin-2-one To a solution of ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate (2.2 g, 8.6 mmol) and AcONH (1.985 g, 25.8 mmol) in EtOH (40 mL) at ambient temperature was added NaBH(CN) (1.349 g, 21.46 mmol). The mixture was heated to 90 °C for 12 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was taken up in water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(2,6-difluoro-4-methylphenyl)pyrrolidin-2-one. 1 H NMR (400 MHz, CDCl3) δ 6.54-6.71 (m, 2H), 5.09 (dd, J = 5.2, 8.76 Hz, 1H), 2.48-2.60 (m, 2H), 2.34-2.46 (m, 1H), 2.25 (s, 3H), 2.08-2.19 (m, 1H).C 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0373] Step 4. Synthesis of 2-(2,6-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(2,6-difluoro-4-methylphenyl)pyrrolidin-2-one (700 mg, 3.31 mmol) in DCM at 0° C. under nitrogen was added trimethyloxonium tetrafluoroborate (637 mg, 4.31 mmol). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched with saturated NaHCO (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-(2,6-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 F2NO[M+H] + Calculated value: 226; Measured value: 226.

[0374] Step 5. Synthesis of methyl 2-(2-(2,6-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(2,6-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (380 mg, 1.69 mmol) in MeOH (20 mL) at 20° C. under nitrogen was added methyl hydrazine carboxylate (167 mg, 1.86 mmol) and HCl / MeOH (1 mL). The resulting mixture was heated to 80° C. for 2 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate / methanol) to give methyl 2-(2-(2,6-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 1 H NMR (400 MHz, CD3OD) δ 6.92 (d, J = 9.6 Hz, 2H), 5.50-5.60 (m, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.11-3.24 (m, 2H), 2.76-2.88 (m, 1H), 2.38 (s, 3H).C 13 H 16 F2N3O2[M+H] + Calculated value: 284; Measured value: 284.

[0375] Step 6. Synthesis of I-31A 5-(2,6-difluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(2,6-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (250 mg, 0.883 mmol) in MeOH (10 mL) was added sodium methanolate (143 mg, 2.65 mmol). The resulting mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to ambient temperature, and HCl / MeOH (4 M) was added until the pH was approximately 6, and the solution was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (50 mL) and filtered. The filtrate was concentrated to give I-31A 5-(2,6-difluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 12 H12 F2N3O[M+H] + Calculated value: 252; Measured value: 252.

[0376] Preparation of Intermediate I-32A 5-(4-chloro-3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediate I-32A was prepared from 4-bromo-1-chloro-2-fluorobenzene according to the method described below. [ka]

[0377] Step 1. Synthesis of 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one To a solution of 4-bromo-1-chloro-2-fluorobenzene (5.28 g, 25.2 mmol) in THF (100 mL) at 0 °C under nitrogen, was added iPrMgCl·LiCl (1.3 M in THF) (27.2 mL, 35.3 mmol). The resulting solution was stirred at ambient temperature for 1 h. To a separate solution of pyrrolidine-2,5-dione (2.5 g, 25 mmol) in THF (100 mL) at 0 °C under nitrogen, was added iPrMgCl·LiCl (1.3 M in THF) (17.47 mL, 22.71 mmol). The resulting solution was stirred at 0 °C for 1 h. The first solution was added to the second solution at −78 °C. The resulting solution was allowed to warm to ambient temperature and stirred for 12 h. NaBH3(CN) (1.744 g, 27.8 mmol) was added to the reaction mixture at ambient temperature and stirred for 1 hour. The reaction was acidified to pH 3 with HCl (6 M), stirred for 1 hour, and neutralized with aqueous NaOH (4 M). The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one. C 10 H 10 ClFNO[M+H] + Calculated value: 214; Measured value: 214.

[0378] Step 2. Synthesis of 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one (1.00 g, 4.68 mmol) in DCM (23.4 mL) at 0 °C under nitrogen was added trimethyloxonium tetrafluoroborate (1.039 g, 7.02 mmol). The mixture was stirred at ambient temperature for 15 hours. The mixture was quenched with saturated aqueous NaHCO (150 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 ClFNO[M+H] + Calculated value: 228; Measured value: 228.

[0379] Step 3. Synthesis of methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (1.00 g, 3.51 mmol) in MeOH (20 mL) at ambient temperature was added methyl hydrazine carboxylate (0.422 g, 4.68 mmol) and HCl / MeOH (1 mL). The resulting mixture was brought to 80° C. and stirred for 12 hours. The mixture was concentrated under reduced pressure. The resulting residue was slurried with ethyl acetate for 15 minutes and filtered to give methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without further purification. 12 H 14 ClFN3O2[M+H] + Calculated value: 286; Measured value: 286.

[0380] Step 4. I-32A Synthesis of 5-(4-chloro-3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.00 g, 3.50 mmol) in MeOH (20 mL) was added sodium methanolate (0.945 g, 17.5 mmol). The resulting mixture was stirred at 80° C. for 5 hours. The reaction mixture was cooled to ambient temperature, and HCl / MeOH (4 M) was added until the pH was approximately 6, and the solution was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (50 mL) and filtered. The filtrate was concentrated to give I-32A, 5-(4-chloro-3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 10 ClFNO[M+H] + Calculated value: 254; Measured value: 254.

[0381] Preparation of Intermediate I-33A 5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Intermediate I-33A was prepared from 5-bromo-1,2,3-trifluorobenzene according to the method described below. [ka]

[0382] Step 1. Synthesis of 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one To a solution of 5-bromo-1,2,3-trifluorobenzene (4.90 g, 23.2 mmol) in THF (60 mL) (referred to as Solution-1) was added iPrMgCl·LiCl (1.3 M solution in THF) (25 mL, 32.5 mmol) at 0 °C under nitrogen. The resulting solution was stirred at ambient temperature for 1 h. To another solution of pyrrolidine-2,5-dione (2.3 g, 23 mmol) in THF (100 mL) was added iPrMgCl·LiCl (1.3 M solution in THF) (16.07 mL, 20.89 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 1 h. The first solution was added to the second solution at −78 °C. The resulting solution was warmed to ambient temperature and stirred for 12 h. NaBH3(CN) (1.605 g, 25.5 mmol) was added to the reaction mixture at ambient temperature and stirred for 1 hour. The reaction was acidified to pH 3 with HCl (6 M), stirred for 1 hour, and neutralized with aqueous NaOH (4 M). The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one. C 10 H9F3NO[M+H] + Calculated value: 216; Measured value: 216.

[0383] Step 2. Synthesis of 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole To a solution of 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one (1.00 g, 4.65 mmol) in DCM (20 mL) at 0 °C under nitrogen was added trimethyloxonium tetrafluoroborate (1.031 g, 6.97 mmol). The mixture was stirred at ambient temperature for 15 h. The mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 11 F3NO[M+H]+ Calculated value: 230; Measured value: 230.

[0384] Step 3. Synthesis of methyl 2-(2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole (1.00 g, 4.36 mmol) in MeOH (30 mL) at ambient temperature was added methyl hydrazine carboxylate (0.413 g, 4.58 mmol) and HCl / MeOH (1 mL). The resulting mixture was brought to 80° C. and stirred under nitrogen for 3 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give methyl 2-(2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 13 F3N3O2[M+H] + Calculated value: 288; Measured value: 288.

[0385] Step 4. Synthesis of I-33A 5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.00 g, 3.48 mmol) in MeOH (16 mL) was added sodium methanolate (0.940 g, 17.4 mmol). The resulting mixture was stirred at 80° C. for 5 hours. The reaction mixture was cooled to ambient temperature, and HCl / MeOH (4 M) was added until the pH was approximately 6, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to afford I-33A, 5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H9F3N3O[M+H] + Calculated value: 256; Measured value: 256.

[0386] Preparation of Intermediate I-34A Intermediate I-34A was prepared from 5-bromo-2-chloro-1,3-difluorobenzene according to the method described below. [ka]

[0387] Step 1. Preparation of 5-(4-chloro-3,5-difluorophenyl)pyrrolidin-2-one To a solution of 5-bromo-2-chloro-1,3-difluorobenzene (10.10 g, 44.4 mmol) in THF (40 mL) was added iPrMgCl·LiCl (1.3 M in THF) (37.3 mL, 48.4 mmol) at 0 °C under N2. The reaction was stirred at 20 °C for 1 h to give mixture #1. Separately, iPrMgCl·LiCl (1.3 M in THF) (27.9 mL, 36.3 mmol) was added to another solution of pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (40 mL) at 0 °C under N2, and the reaction was stirred at 0 °C for 1 h to give mixture #2. Mixture #2 was added to mixture #1 at -78 °C. The reaction was stirred at 25 °C for 16 h. The reaction was warmed to 25°C and NaBH3(CN) (3.81 g, 60.6 mmol) was added, followed by stirring at 25°C for 1 h. The reaction was acidified to pH = 3-4 with 6 M HCl, stirred for 1 h, and neutralized with 4 M aqueous NaOH. The mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®, 40 g Agela flash column, 100% EtOAc) to give 5-(4-chloro-3,5-difluorophenyl)pyrrolidin-2-one. 10 H9ClF2NO[M+H] + Calculated value: 232; Measured value: 232.

[0388] Step 2. Preparation of 2-(4-chloro-3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A mixture of 5-(4-chloro-3,5-difluorophenyl)pyrrolidin-2-one (4.4 g, 19.00 mmol) and trimethyloxonium tetrafluoroborate (3.65 g, 24.69 mmol) in DCM (50 mL) was stirred at 40 °C for 16 hours to give a brown mixture. The reaction mixture was quenched with saturated NaHCO (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-(4-chloro-3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole. The crude product was used in the next step without further purification. 11 H 11 ClF2NO[M+18+H] + Calculated value: 264; Measured value: 264.

[0389] Step 3. Preparation of methyl 2-(2-(4-chloro-3,5-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(4-chloro-3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (4 g, 16.28 mmol) in MeOH (60 mL) at 20 °C, methyl hydrazine carboxylate (1.613 g, 17.91 mmol) and HCl / MeOH (4 mL) were added, and the resulting mixture was stirred at 80 °C under N for 2 h. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a DCM / EtOAc gradient at 60 mL / min) to give methyl 2-(2-(4-chloro-3,5-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 13 ClF2N3O2[M+H] + Calculated value: 304; Measured value: 304.

[0390] Phase 4. Construction of the I-34A To a solution of methyl 2-(2-(4-chloro-3,5-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (100 mg, 0.329 mmol) in MeOH (5 mL) was added sodium methanolate (89 mg, 1.646 mmol), and the resulting mixture was stirred at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, and then HCl / MeOH (4 M) was added until the pH reached approximately 6. The solution was concentrated, and the residue was dissolved in MeOH (50 mL), filtered, and the filtrate was concentrated to give I-34A, 5-(4-chloro-3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H9ClF2N3O[M+H] + Calculated for: 272; found: 272. 1H NMR (400 MHz, CD3OD) δ 6.71-7.15 (m, 2H), 5.20-5.26 (m, 1H), 3.02-3.13 (m, 1H), 2.89-2.99 (m, 1H), 2.78-2.88 (m, 1H), 2.78-2.88 (m, 1H), 2.38-2.50 (m, 1H).

[0391] Preparation of Intermediate I-35A Intermediate I-35A was prepared from (R)-2-amino-2-phenylethan-1-ol according to the method described below. [ka]

[0392] Step 1. Preparation of (R)-5-phenylmorpholin-3-one To a mixture of (R)-2-amino-2-phenylethan-1-ol (5 g, 36.4 mmol) and TEA (12.70 mL, 91 mmol) in THF (100 mL) was added 2-chloroacetyl chloride (2.90 mL, 36.4 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in THF (70 mL), NaH (1.749 g, 43.7 mmol) was added, and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (2 x 20 mL). 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®; 80 g SepaFlash® silica flash column, elution with a 5% MeOH / DCM gradient at 35 mL / min) to give (R)-5-phenylmorpholin-3-one. 10 H 12 NO2[M+H] + Calculated value: 178; Measured value: 178.

[0393] Step 2. Preparation of (R)-5-methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxodine To a solution of (R)-5-phenylmorpholin-3-one (1 g, 5.64 mmol) in DCM (20 mL) was added dimethyloxonium tetrafluoroborate (1.133 g, 8.46 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NaHCO (30 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude (R)-5-methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxidine, which was used in the next step without further purification.

[0394] Step 3. Preparation of methyl (R)-2-(5-phenyl-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate To a solution of (R)-5-methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxozin-3-yl (1 g crude) in MeOH (20 mL) was added methyl hydrazine carboxylate (0.699 g, 7.76 mmol) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction was allowed to cool to room temperature, concentrated, and the residue purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 3% MeOH / DCM gradient at 35 mL / min) to give methyl (R)-2-(5-phenyl-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate. 12 H 16 N3O3[M+H] + Calculated value: 250; Measured value: 250.

[0395] Phase 4. Construction of I-35A A solution of (R)-2-(5-phenyl-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate (1.2 g, 4.81 mmol) in DMF (40 mL) was stirred at 145° C. for 12 hours. The reaction was allowed to cool to room temperature and concentrated. Petroleum ether (10 mL) and ethyl acetate (3 mL) were added to the residue, and the resulting slurry was stirred for 10 minutes. The mixture was filtered, and the filtrate was purified by preparative HPLC (Method: Boston Green ODS, Conditions: water (0.01% TFA)-ACN) to give I-35A, (R)-5-phenyl-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one. 11 H 12 N3O2[M+H] + Calculated value: 218; Measured value: 218. 1 H NMR (400 MHz, CD3OD) δ 7.28-7.39 (m, 4H), 7.20-7.22 (m, 1H), 5.03 (t, J = 3.6 Hz, 1H), 4.82 (s, 1H), 4.63-4.72 (m, 1H), 4.15-4.19 (m, 1H), 3.96-4.00 (m, 1H).

[0396] Preparation of Intermediate I-36A (5-(3,5-difluorophenyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one) Intermediate I-36A was prepared from 2-((tert-butyldimethylsilyl)oxy)acetaldehyde according to the method described below. [ka]

[0397] Step 1. Preparation of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide To a stirred mixture of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (10 g, 57.4 mmol) in THF (250 mL) at 20 °C, (S)-2-methylpropane-2-sulfinamide (9.04 g, 74.6 mmol) and Ti(iPrO) (22.5 mL, 86 mmol) were added, 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 (3 x 100 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% to 20% EtOAc / petroleum ether) to give (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide. 12 H 28 NO2SSi[M+H] + Calculated value: 278; Measured value: 278.

[0398] Step 2. Preparation of (S)—N-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of 1-bromo-3,5-difluorobenzene (8.80 g, 45.6 mmol) in THF (100 mL) at 0 °C under N2, i-PrMgCl·LiCl (47.8 mL, 62.2 mmol) was added, and the mixture was stirred at 40 °C for 1 h. Next, 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 saturated NH4Cl (300 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 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. 18 H 32 F2NO2SSi[M+H] + Calculated value: 392; Measured value: 392.

[0399] Steps 3-4. Preparation of 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide A solution of (S)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3 g, 7.66 mmol) in HCl / MeOH (50 mL) was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give the product, 2-amino-2-(3,5-difluorophenyl)ethan-1-ol (1 g, 5.77 mmol) as a yellow oil. The crude product was used directly in the next step. 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 hours. The mixture was added to water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO, 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. 10 H 11 ClF2NO2[M+H] + Calculated value: 250; Measured value: 250.

[0400] Step 5. Preparation of 5-(3,5-difluorophenyl)morpholin-3-one 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° C., and the mixture was stirred at 20° C. for 1 hour. The mixture was added to saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (2×10 mL). 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. C 10 H 10 F2NO2[M+H] +Calculated value: 214; Measured value: 214.

[0401] Step 6. Preparation of 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxodine 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° C. The mixture was stirred at 30° C. for 12 hours. The mixture was quenched with saturated NaHCO (20 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxidine, which was used in the next step without further purification. 11 H 12 F2NO2[M+H+H2O] + Calculated value: 246; Measured value: 246.

[0402] Step 7. Preparation of methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate To a solution of 3-(3,5-difluorophenyl)-5-methoxymorpholine (580 mg, 2.53 mmol) in MeOH (10 mL) was added methyl hydrazine carboxylate (342 mg, 3.80 mmol) at 20° C., and the resulting mixture was stirred at 80° C. for 5 hours. The reaction mixture was directly concentrated, and the residue was slurried in ethyl acetate (10 mL) to give methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate. 12 H 14 F2N3O3[M+H] + Calculated value: 286; Measured value: 286.

[0403] Stage 8. Construction of I-36A A solution of methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate (480 mg, 1.68 mmol) in DMF (40 mL) was stirred at 145° C. for 12 hours. The reaction solution was directly concentrated. The residue was repurified by preparative HPLC (method: Boston Green ODS, conditions: water (0.01% TFA)-ACN) to give I-36A, 5-(3,5-difluorophenyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one. C 11 H 10 F2N3O2[M+H] + Calculated value: 286; Measured value: 286. 1 H 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).

[0404] Preparation of Intermediate I-37A ((S)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one) Intermediate I-37A was prepared from piperidine-2,6-dione according to the method described below. [ka]

[0405] Step 1. Preparation of 6-phenylpiperidin-2-one To a solution of piperidine-2,6-dione (5 g, 44.2 mmol) in THF (100 mL) at −78 °C under N was added phenylmagnesium bromide (30.9 mL, 93 mmol) dropwise via syringe. After the addition was complete, the reaction was warmed to 25 °C and stirred for 16 h. NaBH(CN) (3.06 g, 48.6 mmol) was added to the mixture, which was stirred at 25 °C for an additional 2 h. 4 M HCl was added to adjust the pH to 4. The resulting mixture was stirred for 1 h. Aqueous NaOH was added to adjust the pH to neutral. The mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil. It was purified by flash silica gel chromatography (100% EtOAc) to give 6-phenylpiperidin-2-one. C 11 H 14 NO[M+H] + Calculated value: 176; Measured value: 176.

[0406] Step 2. Preparation of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine To a solution of 6-phenylpiperidin-2-one (2.5 g, 14.3 mmol) in CHCl (100 mL) at 25° C. was added dimethyloxonium tetrafluoroborate (2.87 g, 21.4 mmol). The mixture was stirred at 25° C. for 12 hours. The mixture was quenched with saturated NaHCO (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give crude 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine, which was used in the next step without further purification. 12 H 16 NO[M+H] + Calculated value: 190; Measured value: 190.

[0407] Step 3. Preparation of methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate To a solution of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine (2.3 g, 12.2 mmol) in MeOH (65 mL) was added methyl hydrazine carboxylate (1.64 g, 18.2 mmol) at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The reaction solution was directly concentrated. The residue was added to EtOAc (20 mL) and stirred for 0.5 hours. The solid was filtered to give methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate. C 13 H 18 N3O2[M+H] + Calculated value: 248; Measured value: 248.

[0408] Steps 4 and 5. Preparation of Intermediate I-37A A solution of methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate (2.5 g, 10.1 mmol) in DMF (25 mL) was stirred for 12 hours at 145° C. The reaction solution was directly concentrated to give (±)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2 g, 7.43 mmol). The enantiomers were separated by SFC (method: column DAICEL CHIRALCEL OD, conditions: 0.1% NH3HO EtOH) to give (R)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (peak 1, ee=100%) and I-37A, (S)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (peak 2, ee=100%).

[0409] (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). (S)-5-Phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (I-37A): 1 H 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).

[0410] Preparation of Intermediate I-38A Methyl (5S,7S)-7-fluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate Intermediate I-38A was prepared from (2S,4S)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid according to the method described below. [ka]

[0411] Step 1. Preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate To a solution of 1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (10 g, 42.9 mmol) in DMF (100 mL) was added KCO (11.85 g, 86 mmol) and then iodomethane (8.01 mL, 129 mmol) at 0 °C. The mixture was stirred at 30 °C under a N atmosphere for 2 hours. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NHCl and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 3:1) to give 1-(tert-butyl) 2-methyl-4-fluoropyrrolidine-1,2-dicarboxylate. 11 H 19 FNO4[M+H] + Calculated value: 248; Measured value: 248.

[0412] Step 2. Preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate A solution of sodium periodate (55.0 g, 257 mmol) and ruthenium(iii) chloride hydrate (9.66 g, 42.9 mmol) in water (450 mL) was stirred at 25° C. for 5 minutes. To this mixture was added 1-(tert-butyl)-2-methyl-4-fluoropyrrolidine-1,2-dicarboxylate (10.6 g, 42.9 mmol) in EtOAc (180 mL), and the reaction was stirred at 25° C. for 12 hours. To the mixture was added IPA (100 mL), and the reaction was stirred at 25° C. for 3 hours. The mixture was filtered, and the filtrate was extracted with EtOAc (2×500 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, elution with a 50% EtOAc / petroleum ether gradient at 60 mL / min) to give 1-(tert-butyl)-2-methyl-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate. C6H8FNO3[M-Boc+H] + Calculated value: 162; Measured value: 162.

[0413] Step 3. Preparation of methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-2-carboxylate A mixture of 1-(tert-butyl)-2-methyl-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate (5 g, 19.14 mmol) in DCM (45 mL) and TFA (15 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give crude methyl-(2S,4S)-4-fluoro-5-oxopyrrolidine-2-carboxylate, which was used directly in the next step without further purification. C6H8FNO3 [M+H] + Calculated value: 162; Measured value: 162.

[0414] Step 4. Preparation of methyl (2S,4S)-4-fluoro-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate A mixture of methyl-4-fluoro-5-oxopyrrolidine-2-carboxylate (3 g, 18.62 mmol) and trimethyloxonium tetrafluoroborate (3.58 g, 24.20 mmol) in DCM (30 mL) was stirred at 25 °C for 16 h to give a brown mixture. The reaction mixture was quenched with saturated NaHCO (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude methyl-4-fluoro-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate. The crude material was used in the next step without further purification. C7H 11 FNO3[M+H] + Calculated value: 176; Measured value: 176.

[0415] Step 5. Preparation of methyl (2S,4S)-4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate To a solution of methyl-4-fluoro-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (1.8 g, 10.28 mmol) in MeOH (6 mL) at 20 °C was added methyl hydrazine carboxylate (1.018 g, 11.30 mmol) and HCl / MeOH (0.5 mL). The resulting mixture was stirred at 80 °C under N for 2 h. The reaction was cooled to room temperature, and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 10% MeOH / EtOAc gradient at 60 mL / min) to give methyl 4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. CH 13 FN3O4[M+H] + Calculated value: 234; Measured value: 234.

[0416] Step 6. Preparation of Intermediate I-38A A mixture of methyl (2S,4S)-4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (600 mg, 2.57 mmol) in DMF (20 mL) was stirred at 145° C. under N for 12 hours. The reaction was cooled to room temperature, and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 10% MeOH / EtOAc gradient at 60 mL / min) to give I-38A, methyl (5S,7S)-7-fluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate. C7H9FN3O3 [M+H] + Calculated value: 202; Measured value: 202. 1 H NMR (400 MHz, CD3OD) δ 5.62-5.84 (m, 1H), 4.81-4.88 (m, 1H), 3.81-3.87 (m, 3H), 3.20-3.33 (m, 1H), 2.76-2.93 (m, 1H).

[0417] Table A. Chemical structures of intermediates I-1A to I-38A [Table 2] TIFF2025061677000102.tif255153

[0418] Synthesis of common intermediates (Table B) Preparation of Intermediate I-2B (Mesityl-13-iodanediylbis(3-fluorobicyclo[1.1.1]pentane-1-carboxylate)) Intermediate I-2B was prepared from 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid according to the method described below. [ka]

[0419] A mixture of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (143 mg, 1.098 mmol) and mesityl-13-iodanediyl diacetate (200 mg, 0.549 mmol) in toluene (15 mL) was concentrated under reduced pressure at 55° C., the residue was redissolved in toluene (15 mL) and then concentrated under vacuum at 55° C. The residue was redissolved in toluene (15 mL) and then concentrated under vacuum at 55° C. The residue was redissolved in toluene (15 mL) and then concentrated under vacuum at 55° C. to give crude mesityl-13-iodanediyl bis(3-fluorobicyclo[1.1.1]pentane-1-carboxylate). 1 H NMR (400 MHz, CDCl3) δ 6.99-7.24 (m, 3H), 2.61-2.69 (m, 4H), 2.28-2.35 (m, 3H), 2.11-2.21 (m, 8H).

[0420] Preparation of Intermediate I-5B (Mesityl-13-iodanediylbis(3-cyanobicyclo[1.1.1]pentane-1-carboxylate)) Intermediate I-5B was prepared from methyl 3-cyanobicyclo[1.1.1]pentane-1-carboxylate according to the method described below. [ka]

[0421] Step 1. Preparation of 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid To a solution of methyl 3-cyanobicyclo[1.1.1]pentane-1-carboxylate (170 mg, 1.13 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (81 mg, 3.37 mmol). The reaction was stirred at 20 °C for 12 hours. TLC showed the starting material was consumed, and a new spot was observed. Water (4 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (1 x 2 mL). The aqueous layer was acidified to pH 4 with 2 M HCl and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid, which was used in the next step without further purification.

[0422] Stage 2. Manufacturing I-5B To a solution of 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 0.730 mmol) in toluene (20 mL) was added mesityl-13-iodanediyl diacetate (133 mg, 0.365 mmol), and the resulting mixture was concentrated four times on a rotary evaporator at 55 °C, using fresh toluene (20 mL) each time. The crude product was concentrated under reduced pressure to give mesityl-13-iodanediyl bis(3-cyanobicyclo[1.1.1]pentane-1-carboxylate). The crude product was used directly in the next step. 1 H NMR (400 MHz, CD3OD) δ 7.18 (s, 2H), 2.71 (s, 9H), 2.37-2.41 (m, 6H), 2.16 (br s, 6H).

[0423] Intermediates I-1B, I-3B, I-4B, and I-6B through I-19B were prepared using the corresponding commercially available acids and mesityl-13-iodanediyl diacetate reagent in a manner similar to the procedure used to prepare I-2B.

[0424] Table B. Chemical structures of intermediates I-1B to I-19B [Table 3] TIFF2025061677000106.tif164168

[0425] General diagram 1 [ka]

[0426] In General Scheme 1, the intermediates of Tables A and B were coupled under photoredox conditions in the presence of copper and iridium catalysts to give the desired products listed in Table 1.

[0427] Example 1.1. Preparation of Compound 1-2 ((5S)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Compound 1-2 was prepared from intermediates I-2A and I-2B according to the method described below. [ka]

[0428] Into four individual 40 mL vials, intermediate I-2A ((S)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (600 mg, 2.53 mmol), intermediate I-2B (mesityl-13-iodanediylbis(3-fluorobicyclo[1.1.1]pentane-1-carboxylate) (2550 mg, 5.06 mmol), Ir(ppy)3 Tris(2-phenylpyridine)iridium (33.1 mg, 0.051 mmol), Cu(OAc)2 (331 mg, 1.27 mmol), and MeCN (25.3 mL) were added. Each mixture was purged with nitrogen gas and placed in a photoreactor (fan rpm 4700, agitator rpm 1000, 450 nm, 100% light intensity) for 5 h. The reactions were diluted with CAN, filtered through a pad of Celite, combined, and purified by flash column chromatography (60 g silica gel, ELSD, 35% EtOAc:hexane and then 70% EtOAc:hexane for the desired product). Fractions containing the desired product were pooled and concentrated to dryness to give compound 1-2. The desired product can be recrystallized by dissolving in a minimal amount of EtOAc over 24-48 hours. After filtration and hexane washing, the product can be isolated in >99.9% purity. 16 H 15 F3N3O[M+H] + Calculated value: 322; Measured value: 322. 1 H NMR (499 MHz, DMSO-d6) δ 7.19 (t, J = 9.3 Hz, 1H), 7.05 (d, J = 6.6 Hz, 2H), 5.19 (m, 1H), 2.99 - 2.82 (m, 2H), 2.81 - 2.70 (m, 1H), 2.52 (d, J = 1.8 Hz, 6H), 2.35 - 2.24 (m, 1H).

[0429] Preparation of Example 1.2.1-40 Compound 1-40 was prepared from intermediates I-9A and I-2B according to the method described below. [ka]

[0430] A mixture of intermediate I-9A (20 mg, 0.084 mmol), Cu(OAc) (11.04 mg, 0.042 mmol), Ir(ppy) (1.104 mg, 1.69 μmol), and intermediate I-2B (85 mg, 0.169 mmol) in MeCN (2 mL) was stirred under 450 nm blue LED light irradiation at 25 °C under N for 2 h. LCMS showed that the product had formed. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (method: column Boston Prime C18 (150 × 30 mm × 5 μm); conditions: water (NH3H2O ​​+ NH4HCO3) -ACN) to give 5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. The enantiomers were separated by SFC (method: column DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); conditions: 0.1% NH 3 HO / EtOH) to give (R)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (SFC-P1, ee = 100%) and compound 1-40 ((S)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (SFC-P2, ee = 100%).

[0431] (R)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H NMR (400 MHz, CDCl3) δ 7.27-7.35 (m, 1H), 6.92 (t, J = 8.4 Hz, 2H), 5.52 (dd, J = 4.8, 8.8 Hz, 1H), 2.97-3.14 (m, 2H), 2.82-2.94 (m, 1H), 2.59 (d, J = 2.0 Hz, 6H). (S)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1-40): 1 H NMR (400 MHz, CDCl3) δ 7.28-7.35 (m, 1H), 6.93 (t, J = 8.4 Hz, 2H), 5.52 (dd, J = 4.8, 8.8 Hz, 1H), 2.99-3.14 (m, 2H), 2.82-2.93 (m, 1H), 2.59 (d, J = 2.0 Hz, 6H).

[0432] Table 1. [Table 4] TIFF2025061677000111.tif255161TIFF2025061677000112.tif255167TIFF2025061677000113.tif255167 TIFF2025061677000114.tif255160TIFF2025061677000115.tif255163TIFF2025061677000116.tif255164 TIFF2025061677000117.tif253169TIFF2025061677000118.tif255166TIFF2025061677000119.tif255160 TIFF2025061677000120.tif250169TIFF2025061677000121.tif254170TIFF2025061677000122.tif154168

[0433] Synthesis of common intermediates (TABLEC) Preparation of Intermediate I-1C ((S)-5-(3,5-difluorophenyl)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Intermediate I-1C was prepared from compound 1-18 according to the method described below. [ka]

[0434] To a solution of compound 1-18 (240 mg, 0.664 mmol) in THF (5 mL) at 25 °C under N2, lithium borohydride (0.664 mL, 1.33 mmol) was added dropwise, and the reaction was stirred at 25 °C for 1 hour. LCMS indicated the reaction was complete. The mixture was added to H2O (20 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give intermediate I-3A (S)-5-(3,5-difluorophenyl)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, which was used directly. C 17 H 18 F2N3O2[M+H] + Calculated value: 334; Measured value: 334.

[0435] Preparation of Intermediate I-2C ((S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid) Intermediate I-2C was prepared from compound 1-18 according to the method described below. [ka]

[0436] To a solution of compound 1-18 (300 mg, 0.830 mmol) in MeOH / THF / HO (3 / 3 / 1, volume ratio) (10 mL) was added lithium hydroxide (23.86 mg, 0.996 mmol) at 25 °C, and the resulting mixture was stirred for 16 h at 25 °C. Water (30 mL) and EtOAc (10 mL) were added, and the mixture was extracted with EtOAc (2 x 8 mL). The organic layer was discarded. The pH of the aqueous layer was adjusted to approximately 4.0 by adding aqueous HCl (3 M) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure to give intermediate I-2C(S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid. 17H 16 F2N3O3[M+H] + Calculated value: 348; Measured value: 348.

[0437] Preparation of Intermediate I-3C ((S)-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate) Intermediate I-3C was prepared from compound I-1C by mesylation according to the method described below. [ka]

[0438] To a solution of intermediate I-1C (35 mg, 0.100 mmol) in DCM (2 mL) was added DIEA (0.035 mL, 0.199 mmol) and Ms-Cl (0.014 mL, 0.175 mmol) at 0° C., and the mixture was stirred at 25° C. for 1 h. LCMS showed the reaction was complete. Water (10 mL) and DCM (10 mL) were added, and the mixture was extracted with DCM (3 x 6 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC (SiO2, petroleum ether / EtOAc) to give I-3C(S)-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate. 18 H 20 F2N3O4S[M+H] + Calculated value: 412; Measured value: 412.

[0439] Table C. Chemical structures of intermediates I-1C to I-3C [Table 5]

[0440] Example 2.1. Preparation of Compound 2-1 ((5S)-5-(3,5-difluorophenyl)-2-[3-(methoxymethyl)bicyclo[1.1.1]pentan-1-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Compound 2-1 was prepared from intermediate I-1C according to the method described below. [ka]

[0441] To a solution of I-1C (50 mg, 0.150 mmol) in CH2Cl2 (2 mL) was added dimethyloxonium tetrafluoroborate (26.1 mg, 0.195 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 x 6 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude oil, which was purified by preparative HPLC (method: Boston Green ODS column 150 mm × 30 mm × 5 μm; conditions: water (TFA)-ACN) to give compound 2-1 ((5S)-5-(3,5-difluorophenyl)-2-[3-(methoxymethyl)bicyclo[1.1.1]pentan-1-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one). 18 H 20 F2N3O2[M+H] + Calculated value: 348; Measured value: 348. 1 H NMR (400 MHz, CD3OD) δ 6.87-6.97 (m, 3H), 5.21 (dd, J = 4.8, 8.0 Hz, 1H), 3.53 (s, 2H), 3.36 (s, 3H), 2.78-3.10 (m, 3H), 2.35-2.45 (m, 1H), 2.19 (s, 6H).

[0442] Example 2.2. Preparation of Compound 2-2 ((S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-(thiophen-2-ylmethyl)bicyclo[1.1.1]pentane-1-carboxamide) Compound 2-2 was prepared from intermediate I-2C according to the method described below. [ka]

[0443] A 0.3M stock solution of I-2C in DMSO (10 μL, 3 μmol) was added to a 384-well plate, followed by a 0.5M solution of thiophen-2-ylmethanamine in DMSO (24 μL, 12 μmol). Next, a 0.8M solution of n-propylphosphonic anhydride in DMF (7.5 μL, 6 μmol) was added, and the reaction plate was sealed and stirred overnight at room temperature. After 16 hours, the reaction was diluted to 100 μL with DMSO, filtered, and purified by RP-HPLC (Method: Column: XBridge BEH C18 OBD Prep Column, 130A, 5 μm, 10 mm x 50 mm; Conditions: 0.16% TFA, 20% to 55% ACN / H2O) to give compound 2-2. 22 H 21 F2N4O2S[M+H] + Calculated value: 443; Measured value: 443.

[0444] Example 2.3. Preparation of Compound 2-4 ((S)-2-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)acetonitrile) Compound 2-4 was prepared from intermediate I-3C according to the method described below. [ka]

[0445] To a solution of intermediate I-2C (23 mg, 0.056 mmol) in DMF (1 mL) was added sodium cyano (20 mg, 0.408 mmol) at 20 °C. The resulting mixture was stirred at 60 °C for 16 h. LCMS showed the reaction was complete. H2O (10 mL) and EtOAc (10 mL) were added. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (Instrument Eh; Method: Column Welch Xtimate C18 150 mm x 25 mm x 5 μm; Conditions: Water (NH4HCO3)-ACN) to give compound 2-4. C 18 H 17 F2N4O[M+H] + Calculated value: 343; Measured value: 343. 1H NMR (400 MHz, CD3OD) δ 6.84-7.00 (m, 3H), 5.21 (dd, J = 4.8, 8.0 Hz, 1H), 2.90-3.10 (m, 2H), 2.87 (s, 2H), 2.78-2.86 (m, 1H), 2.35-2.49 (m, 1H), 2.24-2.32 (m, 6H).

[0446] Example 2.4. Preparation of Compound 2-5 ((S)-2-(3-acetylbicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one)

[0447] Compound 2-5 was prepared from intermediate I-2C according to the method described below. [ka]

[0448] Step 1. Preparation of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide To a solution of I-2C (220 mg, 0.633 mmol) in DCM (6 mL) was added TEA (0.309 mL, 2.217 mmol) and N,O-dimethylhydroxylamine hydrochloride (93 mg, 0.950 mmol) at 25 °C. The mixture was cooled to 0 °C, and 1-propanephosphonic anhydride solution (685 mg, 1.08 mmol) was added slowly under N. The resulting mixture was stirred at 25 °C for 16 h. Water (30 mL) and EtOAc (10 mL) were added. The mixture was extracted with EtOAc (2 x 10 mL), washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide. 19 H 21 F2N4O3[M+H] + Calculated value: 391; Measured value: 391.

[0449] Step 2. Preparation of Compounds 2-5 To a solution of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (230 mg, 0.589 mmol) in THF (8 mL) was added methylmagnesium bromide (0.236 mL, 0.707 mmol) at −5° C., and the resulting mixture was stirred at −5° C. for 2 hours. The mixture was slowly warmed to 25° C., and the reaction was stirred at 25° C. for 16 hours. Saturated NH4Cl (20 mL) and EtOAc (10 mL) were added, and the mixture was extracted with EtOAc (2 x 8 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give an oil, which was purified by preparative TLC (SiO2, petroleum ether / EtOAc = 1 / 2) to give compound 2-5. 18 H 18 F2N3O2[M+H] + Calculated value: 346; Measured value: 346. 1 H NMR (400 MHz, CDCl3) δ 6.71-6.81 (m, 3H), 5.12 (dd, J = 4.4, 8.0 Hz, 1H), 2.76-3.07 (m, 3H), 2.55 (s, 6H), 2.42 (tdd, J = 4.8, 8.4a, 13.2 Hz, 1H), 2.20 (s, 3H).

[0450] Table 2 [Table 6]

[0451] Example 3.1. Preparation of Compound 3-1 [ka]

[0452] Step 1. Preparation of methyl (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate In a glovebox, two 20 mL red-capped vials containing intermediate I-2A (80 mg, 0.337 mmol) were charged with I-19B (568 mg, 0.675 mmol), Ir(ppy)3 (2.21 mg, 3.37 μmol), and Cu(OAc)2 (22.1 mg, 0.084 mmol). The vials were then placed in a glovebox, and DMF (5620 μL) and MeCN (5620 μL) were added to form a homogeneous solution, which was then sealed and removed from the glovebox. The reaction mixture was irradiated at 450 nm (100% intensity) for 23 h. The reaction mixture was directly purified using silica gel flash column chromatography (ethyl acetate / EtOH / hexanes) to give a crude mixture containing the product, which was then subjected to EKB purification (TFA as a modifier). The sample was lyophilized to give (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate. 18 H 16 F4N3O3[M+H] + Calculated value: 398; Measured value: 398.

[0453] Step 2. Preparation of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylic acid To a 20 mL red-capped vial containing (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate (61 mg, 0.154 mmol) was added MeOH (658 μL), MeOH (658 μL), and LiOH (219 μL, 0.219 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was carefully quenched with 2 N HCl (110 μL) to adjust the pH to approximately 3 and extracted three times with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated to give crude (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylic acid, which was used directly without further purification. 17 H 14 F4N3O3[M+H] + Calculated value: 384; Measured value: 384.

[0454] Step 3. Preparation of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxamide To a stirred solution of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylic acid (58 mg, 0.151 mmol) in DCM (408 μL) was added isobutyl chloroformate (21.7 μL, 0.166 mmol) at 0° C., followed by the addition of TEA (42.2 μL, 0.303 mmol) in one portion. The reaction mixture was stirred at 0° C. for 30 min, then ammonia solution in dioxane (3030 μL, 1.51 mmol) was added at 0° C., and the resulting mixture was stirred for an additional 1 h. The reaction mixture was directly purified by silica gel flash column chromatography (ethyl acetate / EtOH / hexanes) to give (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxamide. 17 H 15 F4N4O2[M+H] + Calculated value: 383; Measured value: 383.

[0455] Step 4. Preparation of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carbonitrile To a 20 mL red-capped vial containing (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxamide (55 mg, 0.144 mmol) was added ClCHCHCl (2800 μL), followed by POCl (500 μL, 5.36 mmol) in one portion, and the reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was directly purified by silica gel flash column chromatography (ethyl acetate / EtOH / hexanes) to give (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carbonitrile after lyophilization. 17H 13 F4N4O[M+H] + Calculated value: 365; Measured value: 365.

[0456] Example 3.2. Preparation of Compound 3-3 [ka]

[0457] Step 1. Preparation of methyl (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylate 3-2 A mixture of intermediate I-1A (60 mg, 0.298 mmol), Cu(OAc) (39.0 mg, 0.149 mmol), Ir(ppy) (3.90 mg, 5.96 μmol), and I-19B (391 mg, 0.596 mmol) in MeCN (5960 μL) was stirred under N with 450 nm blue LED illumination at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was then purified by preparative HPLC (method: Boston Green ODS 150 × 30 mm × 5 μm column; conditions: water (0.01% TFA)-CAN) to give methyl (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylate (3-2). 18 H 18 F2N3O3[M+H] + Calculated value: 362; Measured value: 362. 1 H NMR (400 MHz, CDCl3): δ 7.31-7.43 (m, 3H), 7.22 (d, J = 6.9 Hz, 2H), 5.20 (dd, J = 7.7, 4.4 Hz, 1H), 3.80 (s, 3H), 2.93-3.05 (m, 2H), 2.81-2.91 (m, 3H), 2.47-2.53 (m, 1H), 2.37-2.44 (m, 2H).

[0458] Step 2. Preparation of (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxamide A solution of methyl (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylate (45 mg, 0.125 mmol) in NH₃·MeOH (7 M) (2 mL) was stirred at 60°C for 12 hours. The mixture was concentrated under reduced pressure to give crude (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxamide. 17 H 17 F2N4O2[M+H] + Calculated value: 347; Measured value: 347.

[0459] Step 3. Preparation of Compound 3-3 To a solution of (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxamide (45 mg, 0.130 mmol) in pyridine (2 mL), 2,2,2-trifluoroacetic anhydride (109 mg, 0.520 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by preparative HPLC (method: Boston Prime C18 column 150 × 30 mm × 5 μm; conditions: water (10 mM NH4HCO3)-ACN) to give compound 3-3. 17 H 15 F2N4O[M+H] + Calculated value: 329; Measured value: 329. 1 H NMR (400 MHz, CDCl3): δ 7.32-7.43 (m, 3H), 7.20-7.25 (m, 2H), 5.17 (dd, J = 7.6, 4.4 Hz, 1H), 2.99-3.06 (m, 1H), 2.98 (s, 2H), 2.91-2.97 (m, 1H), 2.80-2.90 (m, 1H), 2.53-2.60 (m, 2H), 2.51 (dd, J = 9.2, 4.4 Hz, 1H).

[0460] Table 3 [Table 7]

[0461] Preparation of Intermediate I-1D ((S)-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate) Intermediate I-1D was prepared from intermediate I-7A according to the method described below. [ka]

[0462] Step 1. Preparation of methyl 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate A vial was charged with intermediate I-7A (325 mg, 1.77 mmol), I-5B (1840 mg, 3.55 mmol), Ir(ppy) (23.2 mg, 0.035 mmol), Cu(OAc) (232 mg, 0.887 mmol), and MeCN (17 mL). The mixture was purged with nitrogen gas and placed in a photoreactor (fan rpm 4700, stir rpm 1000, 450 nm, 100% light intensity) for 3 h. The reaction was diluted with MeCN and filtered through a pad of Celite. The resulting mixture was purified by flash column chromatography (12 g silica gel, ELSD, 35% EtOAc:hexane, then 70% EtOAc:hexane, then 100% EtOAc:hexane, for the desired product). Fractions containing the desired product were pooled and concentrated to dryness to give methyl 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate. 13 H 15 N4O3[M+H] + Calculated value: 275; Measured value: 275.

[0463] Step 2. Preparation of 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid To a mixture of methyl 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (195 mg, 0.711 mmol) in 3:1 THF / water, LiOH (51.1 mg, 2.133 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was dissolved in water (20 mL) and DCM (20 mL). The organic layer was separated, and HCl was added to the aqueous layer until the pH was <7. The aqueous layer was re-extracted with DCM (2 x 20 mL), and the combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid. 12 H 13 N4O3[M+H] + Calculated value: 261; Measured value: 261.

[0464] Intermediate I-2D was prepared from I-7A and I-2B by a procedure similar to that used to prepare I-1D. Intermediate I-3D was prepared from I-38A and I-2B by a procedure similar to that used to prepare I-1D.

[0465] Table D [Table 8]

[0466] General diagram 2a [ka]

[0467] In general scheme 2a, intermediate I-7A and the intermediates in Table B were coupled under photoreduction-oxidation conditions in the presence of copper and iridium catalysts. Subsequent hydrolysis of the products afforded the corresponding acids. Treatment with the desired aryl halides under Ni catalysis afforded the desired products listed in Table 4.

[0468] General diagram 2b [ka]

[0469] In general scheme 2b, treatment of an intermediate from Table D with the desired aryl halide under Ni catalyzed conditions affords the products listed in Table 4.

[0470] Example 4.1. Preparation of Compound 4-2 [ka]

[0471] To a 2-dram vial containing I-2D (12.7 mg, 0.05 mmol), 1-bromo-3-fluoro-5-methoxybenzene (15.4 mg, 0.075 mmol), isoindoline-1,3-dione (7.4 mg, 0.05 mmol), DTBPYNiCl 4HO (4.7 mg, 0.01 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (17.1 mg, 0.1 mmol), and (Ir[DF(CF)PPY](DTBPY))PF (1.1 mg, 1.0 μmol) was added DMSO (1.25 mL). The reaction mixture was degassed by bubbling nitrogen through the solution with stirring for 15 min. The reaction mixture was then irradiated for 18 hours under 450 nm LED light in a PennOC / Merck photoreactor at 100% LED power, 2500 rpm fan, and 630 rpm agitation. The reaction mixture was filtered and purified by reverse-phase chromatography (MeCN / water + 0.1% TFA) to give 4-2(±)-5-(3-fluoro-5-methoxyphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 17 H 18 F2N3O2[M+H] + Calculated value: 334; Measured value: 334.

[0472] Example 4.2. Preparation of Compound 4-7 ((S)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile)

change

[0473] Step 1-2. Preparation of 3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile followed by SFC to obtain 4-7 To a 2-dram vial containing I-1D (30 mg, 0.115 mmol), 1-bromo-4-methylbenzene (29.6 mg, 0.173 mmol), isoindoline-1,3-dione (17.0 mg, 0.115 mmol), DTBPYNiCl 4HO (9.18 mg, 0.023 mmol), 1-bromo-4-methylbenzene (29.6 mg, 0.173 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (39.5 mg, 0.231 mmol), and (Ir[DF(CF)PPY](DTBPY))PF (2.59 mg, 2.31 μmol) was added DMSO (2880 μL). The reaction mixture was degassed by bubbling nitrogen through the solution with stirring for 15 min. The reaction mixture was then irradiated for 14 hours under 450 nm LED illumination in a PennOC / Merck photoreactor at 100% LED power, 1000 rpm fan, and 4700 rpm agitation. The reaction was diluted with DCM and HO, transferred to a separatory funnel, and shaken. The resulting mixture was extracted three times with DCM, dried over NaSO, and then concentrated to dryness. The product was purified by flash column chromatography (24 g silica gel, ELSD, 5% EtOAc:hexane, then 45% EtOAc:hexane, then 75% EtOAc:hexane for the desired product). Fractions containing the desired product portion were pooled and concentrated. The product, 3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, was isolated as a racemic mixture.The enantiomers were separated by SFC purification (column & dimensions: OJ-H, 21 x 250 mm, 5 µm, conditions: 10% MeOH + 0.1% NH4OH) to give (R)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile (retention time = 2.95 min) and 4-7(S)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile (retention time = 4.26 min).

[0474] (R)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile: 1 H NMR (499 MHz, DMSO-d6) δ 7.17 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 5.11 (m, 1H), 2.87 (m, 2H), 2.79 - 2.69 (m, 1H), 2.65 (s, 6H), 2.28 (s, 3H), 2.23 (m, 1H). (S)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carbonitrile, (4-7): 1 H NMR (499 MHz, DMSO-d6) δ 7.17 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 5.17 - 5.06 (m, 1H), 2.97 - 2.79 (m, 2H), 2.80 - 2.68 (m, 1H), 2.65 (s, 6H), 2.28 (s, 3H), 2.23 (m, 1H).

[0475] Example 4.3. Preparation of Compound 4-16 (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-(trifluoromethyl)pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one [ka]

[0476] Step 1-2. Preparation of 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-(trifluoromethyl)pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one followed by SFC to obtain 4-16 To a solution of I-2D (30 mg, 0.118 mmol) in DMF (1 mL) under N was added 2-chloro-5-(trifluoromethyl)pyrazine (40 mg, 0.219 mmol), CsCO (107 mg, 0.329 mmol), 2,2′-bipyridine (5.13 mg, 0.033 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (4.81 mg, 0.022 mmol), and 4CZIPN (4.32 mg, 5.48 μmol). The resulting mixture was irradiated with 450 nm blue light for 12 h with stirring. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (preparative HPLC conditions: preparative HPLC on an EB system equipped with a Boston Green ODS150*30 mm*5 μm using mobile phase AB: water (0.01% TFA)-ACN, gradient: 35-55% B, 0-10 min; 100% B, 10-12 min, 10% B, 12-14 min. Flow rate: 25 mL / min) to give 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-(trifluoromethyl)pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one as a racemic mixture. The enantiomers were separated by chiral SFC (apparatus: SFC-21 method: REGIS(s,s)WHELK-O1 (250 mm*30 mm, 5 μm) condition: 25% EtOH + 0.1% NH4OH) to obtain (R)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-(trifluoromethyl)pyrazin-2-yl)-2,5,6,7-tetrahydro-3H -pyrr...

Claims

1. A compound of formula I below, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, R １ C ３ -C ６ Selected from cycloalkyl, aryl, and heteroaryl, where C ３ -C ６ Each of the cycloalkyl, aryl, and heteroaryl groups is independent of (1) Halogen; (2) - CN; (3) -C which may be independently substituted with 1 to 4 substituents selected from halogens and -CN １ -C ６ Alkyl; (4)-C ２ -C ６ alkynyl; (5)-C ３ -C ６ Cycloalkyl; (6)-O-C １ -C ６ alkyl; and (7)-OH It may also be substituted with 1 to 4 substituents selected from; R ２ C ３ -C １０ Selected from cycloalkyl, heterocyclic alkyl, aryl and heteroaryl, where C ３ -C １０ Each of the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups can be independently... (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH, -O-C １ -C ６ It may be substituted with 1 to 4 substituents selected from alkyl and heteroaryl groups -C １ -C ６ Alkyl; (4) -O-C which may be independently substituted with 1 to 4 substituents selected from halogens and -CN １ -C ６ Alkyl; (5)-C(O)-R ａ [R ａ is -OH, -C １ -C ６ Alkyl, -O-C １ -C ６ Alkyl and -NR ｂ R ｃ Selected from, R ｂ and R ｃ Each of these may be independently substituted with hydrogen and / or heteroaryl atoms -C １ -C ６ Selected from alkyl groups; and (6) Aryl compounds which may be substituted with 1 to 3 halogens. It may also be substituted with 1 to 4 substituents selected from; R ３ and R ４ These, together with the atoms to which they are bonded, form a five-membered or six-membered ring condensed on a triazole ring, where the five-membered or six-membered ring may contain a heteroatom selected from N, O, or S, and independently, a halogen, -OH, and -C １ -C ６ It may be substituted with 1 to 4 substituents selected from alkyl groups.

2. R １ However, -C ４ -C ６ Selected from cycloalkyl, phenyl, and heteroaryl, where the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; Here, -C ４ -C ６ Cycloalkyl, phenyl, and heteroaryl are (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ２ CH ３ ; (5) Ethynyl; (6) Cyclopropyl; (7)-O-CH ３ and (8)-O-CH ２ CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

3. R １ However, it is selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl, where the cyclobutyl, cyclopentyl, phenyl, pyridyl, and pyrazinyl are, (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) Ethynyl; (5) Cyclopropyl; and (6)-O-CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

4. R １ but, (1) Halogen; (2)-CN; and (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a phenyl which may be substituted with one to three substituents selected from the above.

5. R ２ However, C ３ -C １０ Selected from cycloalkyl, heterocyclic alkyl, phenyl, and heteroaryl, Here, C ３ -C １０ Cycloalkyls are 【Chemistry 2】 Selected from; Here, the heterocyclic alkyl is 【Transformation 3】 Selected from; and, The heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; Here, C ３ -C １０ Each of the cycloalkyl, heterocyclic alkyl, phenyl, and heteroaryl groups is independently: (1) Halogen; (2) - CN; (3) Independently, halogen, -CN, -OH and -O-C １ -C ４ It may be substituted with 1 to 3 substituents selected from alkyl groups -C １ -C ４ Alkyl; (4) -O-C which may be independently substituted with 1 to 3 substituents selected from halogens and -CN １ -C ４ Alkyl; (5)-C(O)-R ａ [R ａ is -OH, -C １ -C ６ Alkyl, -O-C １ -C ６ Alkyl and -NHR ｃ Selected from, and, R ｃ C may be substituted with hydrogen and a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, sinnolinyl, phthalazinyl, quinazolinyl, naphthylidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl. １ -C ４ Selected from alkyl; and (6) Phenyl which may be substituted with 1 to 3 halogens The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

6. R ２ but, 【Chemistry 4】 and selected from phenyl, where, 【Transformation 5】 And each of phenyl independently (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH and -O-CH ３ It may be substituted with 1 to 3 substituents selected from -CH ３ ; (4) -O-CH which may be substituted with 1 to 3 substituents independently selected from halogens and -CN ３ ; (5)-C(O)-R ａ [R ａ is selected from -OH, -CH ３ , -O-CH ３ , and -NHR ｃ ; and R ｃ is selected from hydrogen and -CH ３ which may be substituted with thienyl.]; and (6) Phenyl which may be substituted with 1 to 3 halogens The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

7. R ２ but 【Transformation 6】 And independently, (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH and -O-CH ３ It may be substituted with 1 to 3 substituents selected from -CH ３ ; (4)-C(O)OMe; (5)-C(O)CH ２ - Thienil; and (6) Phenyl The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

8. R ３ and R ４ form a 5-membered aliphatic ring fused to a triazole ring together with the atoms to which they are attached, wherein the 5-membered aliphatic ring is independently halogen, -OH, -CH ３ , -CH ２ CH ３ , and -CH ２ CH ２ CH ３ and may be substituted with 1 to 4 substituents selected from, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 of the following formula Ia, or a pharmaceutically acceptable salt thereof. 【Transformation 7】 [In the formula, n is either 1 or 2; R １ C ３ -C ６ Selected from cycloalkyl, aryl, and heteroaryl, where C ３ -C ６ Each of the cycloalkyl, aryl, and heteroaryl groups is independent of (1) Halogen; (2) - CN; (3) -C which may be independently substituted with 1 to 4 substituents selected from halogens and -CN １ -C ６ Alkyl; (4)-C ２ -C ６ Alkinyl; (5)-C ３ -C ６ Cycloalkyl; and (6)-O-C １ -C ６ Alkyl It may also be substituted with 1 to 3 substituents selected from; R ２ C ３ -C １０ Selected from cycloalkyl, heterocyclic alkyl, aryl and heteroaryl, where C ３ -C １０ Each of the following is independently: cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl: (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH, -O-C １ -C ６ It may be substituted with 1 to 4 substituents selected from alkyl and heteroaryl groups -C １ -C ６ Alkyl; (4) -O-C which may be independently substituted with 1 to 4 substituents selected from halogens and -CN １ -C ６ Alkyl; (5)-C(O)-R ａ [R ａ is -OH, -C １ -C ６ Alkyl, -O-C １ -C ６ Alkyl and -NR ｂ R ｃ Selected from, R ｂ and R ｃ Each of these may be independently substituted with hydrogen and / or heteroaryl atoms -C １ -C ６ Selected from alkyl; and (6) Aryl compounds which may be substituted with 1 to 3 halogens. It may be substituted with 1 to 4 substituents selected from; and, R ５ Each occurrence is independently of hydrogen, halogen, and -C. １ -C ６ Selected from alkyl and -OH groups.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein n is 1.

11. R １ However, -C ４ -C ６ Selected from cycloalkyl, phenyl, and heteroaryl, where the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; Here, -C ４ -C ６ Cycloalkyl, phenyl, and heteroaryl are (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ２ CH ３ ; (5) Ethynyl; (6) Cyclopropyl; (7)-O-CH ３ and (8)-O-CH ２ CH ３ The compound according to claim 10 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

12. R １ However, it is selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl, where the cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl are, (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) Ethynyl; (5) Cyclopropyl; and (6)-O-CH ３ The compound according to claim 10 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

13. R ２ However, C ３ -C １０ Selected from cycloalkyl, heterocyclic alkyl, phenyl, and heteroaryl, Here, C ３ -C １０ Cycloalkyls are 【Transformation 8】 Selected from; The aforementioned heterocyclic alkyl is 【Chemistry 9】 Selected from; The heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; Here, C ３ -C １０ Each of the cycloalkyl, heterocyclic alkyl, phenyl, and heteroaryl groups is independently (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH, and -O-C １ -C ４ It may be substituted with 1 to 3 substituents selected from alkyl groups -C １ -C ４ Alkyl; (4) -O-C which may be independently substituted with 1 to 4 substituents selected from halogens and -CN １ -C ４ Alkyl; (5)-C(O)-R ａ [R ａ is -OH, -C １ -C ６ Alkyl, -O-C １ -C ６ alkyl, and -NHR ｃ Selected from, and, R ｃ C may be substituted with hydrogen and a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, sinnolinyl, phthalazinyl, quinazolinyl, naphthylidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl. １ -C ４ Selected from alkyl; and (6) Phenyl which may be substituted with 1 to 3 halogens The compound according to claim 10 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

14. R ２ but, 【Chemistry 10】 and selected from phenyl, where the above 【Chemistry 11】 And each of phenyl independently (1) Halogen; (2) - CN; (3) Independently, halogen, -CN, -OH and -O-CH ３ It may be substituted with 1 to 3 substituents selected from -CH ３ ; (4) -O-CH which may be substituted with 1 to 3 substituents independently selected from halogens and -CN ３ ; (5)-C(O)-R ａ [R ａ is -OH, -CH ３ , -O-CH ３ , and -NHR ｃ Selected from; and, R ｃ -CH ３ Selected from: ]; and (6) Phenyl which may be substituted with 1 to 3 halogens The compound according to claim 10 or a pharmaceutically acceptable salt thereof, which may be substituted with one to three substituents selected from the above.

15. R １ However, -C ４ -C ６ Selected from cycloalkyl, phenyl, and heteroaryl, where the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridadinyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; Here, -C ４ -C ６ Cycloalkyl, phenyl, and heteroaryl are (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ２ CH ３ ; (5) Ethynyl; (6) Cyclopropyl; (7)-O-CH ３ and (8)-O-CH ２ CH ３ It may also be substituted with 1 to 3 substituents selected from; R ２ but, 【Chemistry 12】 and selected from phenyl, where the above 【Chemistry 13】 And each of phenyl independently (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH and -O-CH ３ It may be substituted with 1 to 3 substituents selected from -CH ３ ; (4) -O-CH which may be substituted with 1 to 3 substituents independently selected from halogens and -CN ３ ; (5)-C(O)-R ａ [R ａ is -OH, -CH ３ , -O-CH ３ , and -NHR ｃ Selected from; and, R ｃ -CH ３ Selected from: ]; and (6) Phenyl which may be substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from; and, R ５ However, hydrogen, halogen, -C １ -C ４ A compound according to claim 10 or a pharmaceutically acceptable salt thereof, selected from alkyl and -OH.

16. R １ but, (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) Cyclopropyl; and (5)-O-CH ３ A phenyl compound which may be substituted with one to three substituents selected from: R ２ but 【Chemistry 14】 And that is independently (1) Halogen; (2) - CN; (3) Independently, halogen, -CN, -OH and -O-CH ３ It may be substituted with 1 to 3 substituents selected from -CH ３ It may be substituted with 1 to 3 substituents selected from; and, R ５ However, hydrogen, halogens, -CH ３ A compound according to claim 10 or a pharmaceutically acceptable salt thereof, selected from , and -OH.

17. The compound according to claim 1 of the following formula Ib, or a pharmaceutically acceptable salt thereof. 【Chemistry 15】 [In the formula, R １ C ３ -C ６ Selected from cycloalkyl, phenyl and heteroaryl, where C ３ -C ６ Each of the cycloalkyl, phenyl, and heteroaryl compounds is independently (1) Halogen; (2) - CN; (3) -C may be substituted with 1 to 3 substituents independently selected from halogens and -CN. １ -C ６ Alkyl; (4)-C ２ -C ６ Alkinyl; (5)-C ３ -C ６ Cycloalkyl; and (6)-O-C １ -C ６ Alkyl It may also be substituted with 1 to 3 substituents selected from; R ２ C ３ -C １０ Selected from cycloalkyl and heterocyclic alkyl, where the C ３ -C １０ Each of the cycloalkyl and heterocyclic alkyl groups can be independently... (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH, and -O-C １ -C ６ It may be substituted with 1 to 3 substituents selected from alkyl groups -C １ -C ６ Alkyl; (4) -O-C which may be independently substituted with 1 to 3 substituents selected from halogens and -CN １ -C ６ Alkyl; (5)-C(O)-R ａ [R ａ is -OH, -C １ -C ６ Alkyl, -O-C １ -C ６ Alkyl and -NR ｂ R ｃ Selected from, R ｂ and R ｃ Each of these may be independently substituted with hydrogen and / or heteroaryl atoms -C １ -C ６ Selected from alkyl groups; and (6) Aryl compounds which may be substituted with 1 to 3 halogens. It may be substituted with 1 to 3 substituents selected from; and, R ５ is hydrogen, halogen, -C １ -C ６ Selected from alkyl and -OH groups.

18. R １ but, (1) Halogen; (2) - CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogens and -CN ３ ; (4) Cyclopropyl; and (5)-O-CH ３ Phenyl compounds that are substituted with one to three substituents selected from: R ２ but, 【Chemistry 16】 And that is independent, (1) Halogen; (2) - CN; (3) Independently halogen, -CN, -OH and -O-CH ３ It may be substituted with 1 to 3 substituents selected from -CH ３ ; (4)-C(O)O-CH ３ ; (5)-C(O)CH ２ - Thienil; and (6) Phenyl It is substituted with one to three substituents selected from; and, R ５ The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

19. (5S)-2-(bicyclo[2.2.1]heptan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-5-(3,5-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(bicyclo[2.1.1]hexane-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, (5S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(bicyclo[1,1,1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(3-fluorobicyclo[1,1,1]pentan-1-yl)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-5-(5-fluoropyridine-3-yl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, (5S)-5-(3,5-difluorophenyl)-2-(3-phenylbicyclo[1,1,1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-5-(5-fluoropyridine-3-yl)-2-(3-phenylbicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-5-(3,5-difluorophenyl)-2-(1-methyl-2-oxobicyclo[2.1.1]hexane-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, Methyl 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentane-1-carboxylate, Methyl 3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentane-1-carboxylate, (5S)-5-(3,5-difluorophenyl)-2-(4-fluoropentacyclo[4.2.0.0-2,5-.0-3,8-.0-4,7-]octan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 4-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]pentacyclo[4.2.0.0-2,5-.0-3,8-.0-4,7-]octane-1-carbonitrile, (S)-3-(5-(5-chloropyridine-3-yl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, 3-[(5S)-5-(2-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, (S)-3-(5-(3-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitride, (5S)-2-(bicyclo[2.2.2]octan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-5-(3,5-difluorophenyl)-2-(4-methoxybicyclo[2.2.1]heptan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-[4-(difluoromethyl)bicyclo[2.2.1]heptan-1-yl]-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 4-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[2.2.1]heptan-1-carbonitrile, 4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[2.2.1]heptan-1-carbonitrile, (5S)-2-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1-yl]-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1-yl]-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 4-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[2.1.1]hexane-1-carbonitrile, Methyl 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate, (5S)-2-(3-fluorobicyclo[1,1,1]pentan-1-yl)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-5-(4-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, 4-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[2.1.1]hexane-1-carbonitrile, (S)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1,1,1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-3-(5-(2,6-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-3-(5-(3,4-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-5-(4-chlorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-3-(5-(4-chlorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitride, (S)-3-(5-(2,4-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitride, (S)-5-(2,4-difluorophenyl)-2-(3-fluorobicyclo[1,1,1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-3-(3-oxo-5-(3-(trifluoromethyl)phenyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-3-(3-oxo-5-(4-(trifluoromethyl)phenyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-3-(5-(3,5-difluoro-4-methylphenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, 3-[5-(S or R)-(3,5-difluorophenyl)-6-(S or R)-methyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitride, (S)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-2(3H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, 3-(5-(S or R)-cyclopentyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, 3-(5-(S or R)-cyclohexyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (5S)-5-(3,5-difluorophenyl)-2-[3-(methoxymethyl)bicyclo[1.1.1]pentan-1-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]-N-[(thiophen-2-yl)methyl]bicyclo[1.1.1]pentan-1-carboxamide, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]-N-[(thiophen-3-yl)methyl]bicyclo[1.1.1]pentan-1-carboxamide, (S)-2-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)acetonitrile, (5S)-2-(3-acetylbicyclo[1,1,1]pentan-1-yl)-5-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]-2,2-difluorobicyclo[1.1.1]pentan-1-carbonitride, 2,2-difluoro-3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, (±)-3-(3-oxo-5-(pyrazine-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (±)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluoro-5-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (±)-3-[2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-yl]benzonitrile, (±)-5-(3-ethynylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (±)-5-(2,3-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (±)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3-fluoro-5-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-3-(3-oxo-5-(p-tolyl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-3-(3-oxo-5-(pyrazine-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-5-(3-fluoro-5-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(4-(difluoromethyl)phenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(4-cyclopropylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(pyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(6-methylpyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-methylpyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S,7R)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S,7S)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-7-hydroxy-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S)-7-(S or R)-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-[(5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitride, 3-[(5S)-5-(3,5-difluorophenyl)-7-(S or R)-fluoro-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitride, 3-[(5S)-7-(S or R)-fluoro-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-5-(2-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, 3-[(5S)-7-(S or R)-fluoro-5-(2-fluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, (S)-5-(3,5-difluoro-4-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one, (S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(pyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-4-(3-oxo-5-(pyrazine-2-yl)-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[2.1.1]hexane-1-carbonitrile, (S)-2-(bicyclo[2.1.1]hexane-1-yl)-5-(pyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-3-(5-(3-chlorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-5-(3-chlorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6-dihydrothiazolo[2,3-c][1,2,4]triazole-2(3H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (R)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6-dihydrothiazolo[2,3-c][1,2,4]triazole-2(3H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-4-(2-(3-fluorobicyclo[1,1,1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-yl)benzonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(6-methylpyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, 3-((5S,7R)-5-(3,5-difluorophenyl)-7-methyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitride, 3-((5S,7S)-5-(3,5-difluorophenyl)-7-methyl-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitride, (S)-2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5-(5-fluoropyridine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(3-chloro-5-fluoro-4-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(3,5-difluoro-4-hydroxyphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(2,6-difluoro-4-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(4-chloro-3-fluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-5-(4-chloro-3,5-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (R)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one, (R)-3-(5-(3,5-difluorophenyl)-3-oxo-5,6-dihydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-2(8H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one, 3-[(5S)-5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]-2,2-difluorobicyclo[1.1.1]pentan-1-carbonitride, Methyl(S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carboxylate, 2,2-difluoro-3-[(5S)-3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl]bicyclo[1.1.1]pentan-1-carbonitrile, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(o-tolyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (S)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(5-(trifluoromethyl)pyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, (5S,7S)-7-fluoro-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-(pyrazine-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one, and (S)-3-(5-(4-(difluoromethyl)phenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)bicyclo[1.1.1]pentan-1-carbonitrile A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

20. A pharmaceutical composition comprising the compound described in claim 1 or 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising the compound described in claim 1 or 19 and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 20, for the treatment of RIPK1-dependent inflammation and cell death occurring in hereditary 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, and acute tissue injury caused by stroke, traumatic brain injury, and encephalitis.

23. The pharmaceutical composition according to claim 20, for the treatment of amyotrophic lateral sclerosis.

24. Use of the compound according to claim 1 or 19, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical for the treatment of amyotrophic lateral sclerosis.

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