RIPK1 Inhibitor and Method of Use

Abstract

In this specification, a compound of formula I or a pharmaceutically acceptable salt thereof is described. The compound of formula I acts as a RIPK1 inhibitor and may be useful in preventing, treating, or acting as a therapeutic agent for RIPK1-related diseases. 【Chemical 1】 TIFF2025521068000173.tif28165

Description

Technical Field

[0001] In this specification, RIPK1 inhibitors are disclosed. The RIPK1 inhibitors described in this specification may be useful as prophylactic, therapeutic, or treatment agents for RIPK1-related diseases.

Background Art

[0002] Receptor-interacting protein 1 kinase (RIPK1) belongs to the serine / threonine protein kinase family involved in innate immune signaling. RIPK1 has emerged as a promising therapeutic target in the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This is supported by extensive studies demonstrating that RIPK1 is an important mediator of apoptosis and necroptotic cell death, as well as inflammatory pathways.

[0003] For example, RIPK1 inhibition has been recognized as effective as a therapeutic agent for acute kidney injury (AKI), a destructive clinical symptom induced by multiple disorders such as ischemia-reperfusion, nephrotoxic drugs, and sepsis. It has been recognized that RIPK1-mediated necroptosis plays an important role in AKI, and RIPK1 inhibitors may be promising clinical candidates for AKI treatment. Wang JN, Liu MM, Wang F, Wei B, Yang Q, Cai YT, Chen X, Liu XQ, Jiang L, Li C, Hu XW, Yu JT, Ma TT, Jin J, Wu YG, Li J, Meng XM, RIPK1 Inhibitor Cpd-71 Attenuates Renal Dysfunction in Cisplatin-Treated Mice via Attenuating Necroptosis, Inflammation and Oxidative Stress. Clin Sci (Lond). 2019 Jul 25;133(14):1609-1627.

[0004] Furthermore, human genetic evidence has linked dysregulation of RIPK1 to 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] Moreover, since necroptosis has been demonstrated to be a delayed component of ischemic neuronal injury, RIPK1 inhibition may 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]

Non-Patent Literature 1

Non-Patent Literature 2

Non-Patent Literature 3

Non-Patent Literature 4

[0007] Therefore, there is a need for RIPK1 inhibitors that provide high selectivity to cross the blood-brain barrier and have the potential to target neuroinflammation and cell death that cause various neurological symptoms 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 Problems]

[0008] In the present specification, compounds of formula I and pharmaceutically acceptable salts thereof are described; [Chemical Formula] 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 diseases, and other RIPK1-related diseases.

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

[0011] Also described herein is the use of a compound described herein or a pharmaceutically acceptable salt thereof for treating neurodegenerative, autoimmune, and inflammatory diseases in a patient in need thereof.

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

[0013] Also described herein is a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

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

[0015] Also described herein is the treatment of a neurodegenerative, autoimmune, and inflammatory disease in a patient in need thereof with a compound described herein or a pharmaceutically acceptable salt thereof in combination with at least one additional agent.

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

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

DETAILED DESCRIPTION OF THE INVENTION

[0018] Described herein are compounds of formula I below; [Chemical formula] Wherein, R 1 is selected from C3-C6 cycloalkyl, aryl, and heteroaryl, and each of said C3-C6 cycloalkyl, aryl, and heteroaryl is 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 optionally substituted with 1 to 4 substituents selected from; R 2 is selected from C3-C 10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and each of said C3-C 10 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)-R a [R ais -OH, -C1-C6 alkyl, -O-C1-C6 alkyl and -NR b R c selected from, and R b and R c each of which is independently selected from hydrogen and -C1-C6 alkyl which may be substituted with heteroaryl.]; and (6) aryl which may be substituted with 1 to 3 halogens optionally substituted with 1 to 4 substituents selected from; R 3 and R 4 together with the atom to which they are attached form a 5- or 6-membered ring fused to the triazole ring, said 5- or 6-membered ring may contain a heteroatom selected from N, O or S and may be independently substituted with 1 to 4 substituents 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, 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 -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 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, and the cyclobutyl, cyclopentyl, phenyl, pyridyl, and pyrazinyl are (1) halogen; (2) -CN; (3) -CH3 which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (4) ethynyl; (5) cyclopropyl; and (6) -O-CH3 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 is (1) halogen; (2) -CN; and (3) phenyl which may be substituted with 1 to 3 substituents independently selected from halogen and -CN selected from the following.

[0022] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is bridged C5-C 10 selected from cycloalkyl, bridged heterocycloalkyl, phenyl and heteroaryl, said bridged C5-C 10 cycloalkyl or bridged heterocycloalkyl is unsubstituted or independently (1) halogen; (2) -CN; (3) -C1-C4 alkyl which may be independently substituted with 1 to 3 substituents selected from halogen, -CN, -OH, and -O-C1-C4 alkyl; (4) -O-C1-C4 alkyl which may be independently substituted with 1 to 3 substituents selected from halogen and -CN; (5) -C(O)-R a [R a is selected from -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NHR c and R c is -C1-C4 alkyl which may be substituted with heteroaryl selected from hydrogen and pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; and (6) phenyl which may be substituted with 1 to 3 halogen and is substituted with 1 to 3 substituents selected therefrom.

[0023] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is selected from C3-C 10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein the C3-C 10 cycloalkyl is selected from

Chemical formula

Chemical formula

[0024] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is

Chemical formula

[0025] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is [Chemical formula] and is independently, (1) halogen; (2) -CN; (3) -CH3 which may be 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 which may be substituted with 1 to 3 substituents selected from

[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, they form a 5-membered aliphatic ring fused to a triazole ring, and the 5-membered aliphatic ring may be independently substituted with 1 to 4 substituents selected from halogen, -OH, -CH3, -CH2CH3, and -CH2CH2CH3.

[0027] In one embodiment of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is of Formula Ia below;

Chemical formula

[0028] In one embodiment of the compound 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, and 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 which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (4) -CH2CH3 which may be 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, and the cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl and pyrazinyl are (1) halogen; (2) -CN; (3) -CH3 which may be 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 selected from C3-C 10 cycloalkyl, heterocycloalkyl, phenyl and heteroaryl, the C3-C 10 cycloalkyl is

Chemical formula

Chemical formula

[0032] In one embodiment of the compound of formula Ia or a pharmaceutically acceptable salt thereof, R 2 is

Chemical formula

Chemical formula

[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, and 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 which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (4) -CH2CH3 which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (5) ethynyl; (6) cyclopropyl; (7) -O-CH3; and (8) -O-CH2CH3 and may be substituted with 1 to 3 substituents selected therefrom; R 2 is

Chemical Structure

Chemical formula

[0034] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is (1) halogen; (2) -CN; (3) -CH3 which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (4) cyclopropyl; and (5) -O-CH3 is phenyl which may be substituted with 1 to 3 substituents selected from R 2 is

Chemical formula

[0035] In one embodiment of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is of the following Formula Ib;

Chemical formula

[0036] In one embodiment of the compound of formula Ib or a pharmaceutically acceptable salt thereof, R 1 is (1) halogen; (2) -CN; (3) phenyl which may be substituted with 1 to 3 substituents independently selected from halogen and -CN and may be substituted with -CH3; (4) cyclopropyl; and (5) -O-CH3 and is phenyl substituted with 1 to 3 substituents selected from R 2 is

Chemical Formula

[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 for treating 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, which comprises administering to a patient in need of treatment a compound described herein or a pharmaceutically acceptable salt thereof.

[0039] In one embodiment, the present specification discloses a method for treating amyotrophic lateral sclerosis, which includes administering to a patient in need of treatment a compound described in the present specification or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the present specification discloses a pharmaceutical composition comprising a compound disclosed in the present specification or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0041] In one embodiment, the present specification discloses a pharmaceutical composition comprising a compound disclosed in the present specification 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, and the C3-C6 cycloalkyl may be substituted with 1 to 4 substituents selected from (1) halogen; (2) -CN; (3) -C1-C6 alkyl which may be independently substituted with 1 to 3 substituents 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 is

Chemical formula

[0046] In one embodiment, R 1 is

Chemical formula

[0047] In one embodiment, R 1 is

Chemical formula

[0048] In one embodiment, R 1 is

Chemical formula

[0049] In one embodiment, R 1 is

Chemical formula

[0050] In one embodiment, R1 is [Chem.] a C3-C6 cycloalkyl selected from; said C3-C6 cycloalkyl is substituted with -C2-C6 alkynyl. In one embodiment, said C3-C6 cycloalkyl is substituted with ethynyl or propynyl. In one embodiment, said C3-C6 cycloalkyl is substituted with ethynyl.

[0051] In one embodiment, R 1 is [Chem.] a C3-C6 cycloalkyl selected from; said C3-C6 cycloalkyl is substituted with -C3-C6 cycloalkyl. In one embodiment, said C3-C6 cycloalkyl is substituted with cyclopropyl. In one embodiment, said C3-C6 cycloalkyl is substituted with cyclobutyl.

[0052] In one embodiment, R 1 is [Chem.] a C3-C6 cycloalkyl selected from; said C3-C6 cycloalkyl is substituted with -O-C1-C6 alkyl. In one embodiment, said C3-C6 cycloalkyl is substituted with -OCH3. In one embodiment, said C3-C6 cycloalkyl is substituted with -OCH2CH3. In one embodiment, said C3-C6 cycloalkyl is substituted with -OCH2CH2CH3. In one embodiment, said C3-C6 cycloalkyl is substituted with -OCH2CH2CH2CH3.

[0053] In one embodiment, R 1is aryl, which is independently selected from (1) halogen; (2) -CN; (3) -C1-C6 alkyl which may be 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 and may be substituted with 1 to 3 substituents.

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

[0055] In one embodiment, R 1 is phenyl, and the phenyl is independently substituted with 1 to 3 substituents selected from (1) halogen; (2) -CN; (3) -C1-C6 alkyl which may be 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, and the phenyl is substituted with 1 to 3 halogens. In one embodiment, R 1 is phenyl, and the phenyl is substituted with 1 to 3 fluorines. In one embodiment, R 1 is phenyl, and the phenyl is substituted with 1 to 3 chlorines.

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

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

[0059] In one embodiment, R 1is phenyl, and the phenyl is independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, and -CH2CN. In one embodiment, R 1 is phenyl, and the phenyl is independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 1 is phenyl, and the phenyl is independently substituted with 1 to 3 substituents selected from -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, and -CH2CN. In one embodiment, R 1 is phenyl, and the phenyl is independently substituted with 1 to 3 substituents selected from methyl and -CF3.

[0060] In one embodiment, R 1 is phenyl, and the phenyl is independently substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, -CH2F, -CHF2, and -CF3.

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

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

[0063] In one embodiment, R 1 is heteroaryl, and the heteroaryl is independently (1) halogen; (2) -CN; (3) -C1-C6 alkyl which may be 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 which may be substituted with 1 to 3 substituents selected therefrom.

[0064] In one embodiment, R 1 is 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 unsubstituted heteroaryl selected from pyridyl and pyrazinyl. In one embodiment, R 1 is unsubstituted pyridyl. In one embodiment, R 1 is 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, and the heteroaryl is independently (1) halogen; (2) -CN; (3) -C1-C6 alkyl which may be 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, and is substituted with 1 to 3 substituents selected therefrom.

[0067] 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, and the heteroaryl is substituted with 1 to 3 halogens.

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

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

[0070] In one embodiment, R 1 is pyrazinyl substituted with fluoro. R 1is pyrazinyl substituted with two fluoros. In one embodiment, R 1 is pyrazinyl substituted with chloro. In one embodiment, R 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, and the heteroaryl is substituted with -CN. In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, and 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, and the heteroaryl is substituted with one or two substituents independently selected from C1-C6 alkyl. In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, and the heteroaryl is substituted with one or two 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. In one embodiment, R 1 is pyridyl substituted with methyl.

[0074] In one embodiment, R 1 is pyrazinyl substituted with methyl, ethyl, propyl, butyl, pentyl or hexyl. In one embodiment, R 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, and the heteroaryl is substituted with -C2-C6 alkynyl. In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, and 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, and the heteroaryl is substituted with -C3-C6 cycloalkyl. In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, and the heteroaryl is substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, R 1 is pyridyl substituted with cyclopropyl or cyclobutyl. In one embodiment, R 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, and the heteroaryl is substituted with -O-C1-C6 alkyl. In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, and the heteroaryl is substituted with -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -O-pentyl or -O-hexyl. In one embodiment, R 1 is pyridyl substituted with -O-methyl, -O-ethyl, or -O-propyl. In one embodiment, R 1 is pyridyl substituted with -O-methyl. In one embodiment, R 1 is pyrazinyl substituted with -O-methyl, -O-ethyl, or -O-propyl. In one embodiment, R 1 is pyrazinyl substituted with -O-methyl.

[0078] In one embodiment, R 2 is C3-C 10 cycloalkyl, which is independently (1) halogen; (2) -CN; (3) -C1-C6 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-C1-C6 alkyl, and heteroaryl; (4) -O-C1-C6 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (5) -C(O)-R a [R a is selected from -OH, -C1-C6 alkyl, -O-C1-C6 alkyl, and -NR b R c is selected from, R b and R cEach of them is independently selected from -C1-C6 alkyl which may be substituted with hydrogen and heteroaryl.]; and (6) aryl which may be substituted with 1 to 3 halogens and may be substituted with 1 to 3 substituents selected from

[0079] In one embodiment, R 2 is

Chemical formula

[0080] In one embodiment, R 2 is

Chemical formula

[0081] In one embodiment, R 2 is unsubstituted

Chemical formula

[0082] In one embodiment, R 2 is unsubstituted

Chemical formula

[0083] In one embodiment, R 2 is unsubstituted

Chemical formula

[0084] In one embodiment, R 2 is unsubstituted

Chem.

[0085] In one embodiment, R 2 is unsubstituted

Chem.

[0086] In one embodiment, R 2 is unsubstituted

Chem.

[0087] In one embodiment, R 2 is unsubstituted

Chem.

[0088] In one embodiment, R 2 is

Chem.

[0089] In one embodiment, R 2 is

Chemical formula

[0090] In one embodiment, R 2 is [Chemical formula] A C3-C selected from 10 cycloalkyl, Said C3-C 10 cycloalkyl is independently (1) halogen; (2) -CN; (3) -C1-C4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-C1-C4 alkyl, and heteroaryl [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.]; (4) -O-C1-C4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; (5) -C(O)-R a [R a is selected from -OH, -C1-C4 alkyl, -O-C1-C4 alkyl, and -NR b R c selected from b and R c each of which is independently selected from hydrogen and -C1-C4 alkyl which may be substituted with heteroaryl, said heteroaryl being 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 which may be substituted with 1 to 3 halogens substituted with 1 to 3 substituents selected from

[0091] In one embodiment, R 2 is [Chemical formula] C3-C selected from 10 cycloalkyl, the C3-C 10 cycloalkyl is independently (1) halogen; (2) -CN; (3) -C1-C4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl [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, -CH3, -CH2CH3, -O-CH3, -CH2CH3, and -NH-CH2-heteroaryl, and the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl.]; and (6) phenyl substituted with 1 to 3 substituents selected from

[0092] In one embodiment, R 2 is [Chemical formula] C3-C selected from 10 cycloalkyl, the 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 said 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-CH2 - heteroaryl [wherein said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrazinyl, and pyrimidyl.]; and (15)phenyl is substituted with 1 to 3 substituents selected from

[0093] In one embodiment, R 2 is

Chemical formula

[0094] In one embodiment, R 2 is

Chemical formula

[0095] In one embodiment, R 2 is

Chemical formula

[0096] In one embodiment, R 2 is

Chemical formula

[0097] In one embodiment, R 2 is

Chemical formula

[0098] In one embodiment, R 2 is

Chemical formula

[0099] In one embodiment, R 2 is

Chemical formula

[0100] In one embodiment, R 2 is

Chemical formula

[0101] In one embodiment, R 2 is [Chemical formula] and it is independently (1) halogen; (2) -CN; (3) -C1-C4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, -OCH2CH3, and heteroaryl [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 [wherein R a is selected from -OH, -CH3, -CH2CH3, -O-CH3, -CH2CH3, and -NH-CH2-heteroaryl, and the heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, and indolizinyl.]; and (6) phenyl and is substituted with 1 to 3 substituents selected from

[0102] In one embodiment, R 2 is [Chemical formula] 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 [said heteroaryl is selected from furyl, triazinyl, and thienyl.]; (11) -O-CH3; (12) -C(O)-CH3; (13) -C(O)-O-CH3; (14) -C(O)-NH-CH2 - heteroaryl [said heteroaryl is selected from furyl, triazinyl, and thienyl.]; and (15) phenyl is substituted with 1 to 3 substituents selected from the following.

[0103] In one embodiment, R 2 is

Chemical formula

[0104] In one embodiment, R 2 is

Chemical formula

[0105] In one embodiment, R 2 is

Chemical formula

[0106] In one embodiment, R 2 is

Chemical formula

[0107] In one embodiment, R 2 is

Chemical formula

[0108] In one embodiment, R 2 is

Chemical formula

[0109] In one embodiment, R2 is unsubstituted [Chemical formula] is as follows.

[0110] In one embodiment, R 2 is [Chemical formula] and it is (1) halogen; (2) -CN; (3) -C1-C4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, and -OCH2CH3 substituted with 1 to 3 substituents selected from the above.

[0111] In one embodiment, R 2 is [Chemical formula] and it is (1) halogen; (2) -CN; (3) -CH3; (4) -CH2CH3 substituted with 1 to 3 substituents selected from the above.

[0112] In one embodiment, R 2 is [Chemical formula] and it is substituted with -CH3.

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

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

[0115] In one embodiment, R 2 is phenyl, which (1) Halogen; (2) -CN; (3) -CH3; (4) -CH2CH3 is substituted with 1 to 3 substituents selected therefrom.

[0116] In one embodiment, R 2 is 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 (1) Halogen; (2) -CN; (3) -C1-C4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH, -O-CH3, and -OCH2CH3 is substituted with 1 to 3 substituents selected therefrom.

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

[0119] In one embodiment of formula Ia, each occurrence of 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, each occurrence of 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, each occurrence of R 5 is 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, each occurrence of R 5 is -OH.

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

[0125] The term "C1-C6 alkyl" includes straight-chain alkyls having 1 to 6 carbon atoms and branched alkyls 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 3 to 6 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0127] 「C3-C 10 The term "C3-C cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having 3 to 10 carbons. "Cycloalkyl" also includes non-aromatic rings and 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 described by structure include the following.

Chemical formula

[0128] The term "heteroaryl" means a monocyclic or polycyclic aromatic heterocyclic alkyl, including bicyclic, 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, etc.

[0129] The term "heterocyclic alkyl" means a monocyclic or bicyclic or bridged partially unsaturated and saturated ring containing at least one heteroatom selected from N, S, and O, each of said rings having 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, etc. This term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridone or n-substituted-(1H,3H)-pyrimidine-2,4-dione (N-substituted uracils) attached via 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 the structure include the following.

Chemical formula

[0130] The term "pharmaceutically acceptable salt" 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 included in the term "pharmaceutically acceptable salt" 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 the basic compounds of the present invention include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clubranate, citrate, dihydrochloride, edetate, edisylicate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, 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, subsulfate, succinate, tannate, tartrate, theocurate, tosylate, triethiodide, and valerate, etc. Further, when the compound of the present invention has 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, zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts.Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary amines and tertiary amines, cyclic amines and basic ion exchange resins, for example, salts of 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 resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

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

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

[0133] Some of the compounds described herein contain double bonds and, unless otherwise indicated, are to be construed 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 indicated, are to be construed to include both cis and trans geometric isomers.

[0135] The independent synthesis of these diastereomers or their chromatographic separation can be carried out according to methods known in the art by appropriately modifying the methods disclosed herein. Their absolute stereochemistry can be determined, if necessary, by X-ray crystallographic analysis of crystalline products or crystalline intermediates derivatized with reagents containing chiral centers of known absolute configuration. Optionally, a racemic mixture of the compounds can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, for example, by coupling a racemic mixture of the compounds with an enantiomerically pure compound to form a mixture of diastereomers, and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compound can also be separated directly by chromatography using a chiral stationary phase, which is known in the art.

[0136] Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known constitution by methods well known in the art.

[0137] It is understood that the present invention includes pharmaceutically acceptable salts and pharmaceutically unacceptable salts of the compounds described herein, when used as precursors of the free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

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

[0139] Some of the compounds described herein may exist as tautomers with different hydrogen bonding sites involving one or more double bond migrations. For example, a ketone and its enol form are keto-enol tautomers. The compounds of the present invention include not only individual tautomers but also mixtures thereof.

[0140] In the compounds described herein, atoms may exhibit their natural isotope abundances, or one or more of those atoms may be artificially enriched in specific isotopes having the same atomic number but different atomic masses or mass numbers from the atomic masses or mass numbers predominantly found in nature. This disclosure is intended to encompass all suitable isotope variants of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the major hydrogen isotope found in nature. Enriching deuterium may provide certain therapeutic advantages such as an extended half-life in vivo or a reduced required dosage, or may provide a useful compound as a standard for characterizing biological samples. 3 H, 11 C, 18 F-labeled compounds can be used in PET or SPECT and other imaging studies. Isotope-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by manufacturing methods similar to those described in the schemes and examples herein using appropriate isotope-enriched reagents and / or intermediates.

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

[0142] Therapeutic methods The compounds described herein may be particularly useful for preventing, treating, or ameliorating RIPK1-mediated diseases or disorders. Such RIPK1-mediated diseases or disorders may be controlled, at least in part, by programmed necrosis, apoptosis, or the production of inflammatory cytokines, and particularly inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic-onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / 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 injury / disorder (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, such as cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplanted organs, tissues, and cells), 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, ischemic 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, Behçet's disease, interleukin-I converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), tobacco smoke-induced injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO mutations (mutations in the NF-κB essential modulator gene (also known as IKK gamma or IKKG)), particularly NEMO deficiency syndrome,HOIL-1 deficiency (also known as RBCKI), heme-oxidized IRP2 ubiquitin ligase 1 deficiency, linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, malignant tumors of the hematopoietic and solid organs, bacterial and viral infections (such as 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, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, 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, ocular ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / mitigation, auditory disorders such as noise-induced hearing loss, and drugs related to ototoxicity such as cisplatin, or ex vivo cell therapy for maintaining viability and function.

[0143] The compounds of the formula described herein or pharmaceutically acceptable salts thereof are useful for treating the following RIPK1-mediated diseases or disorders: inflammatory bowel diseases (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), Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / 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 injury / disorder (nephritis, kidney transplantation, surgery, administration of nephrotoxic agents such as cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplanted organs, tissues and cells), solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), 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, Behçet's disease, interleukin-I converting enzyme (ICE, also known as caspase-1)-related fever syndrome, chronic obstructive pulmonary disease (COPD), tobacco 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, ocular ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, periodontitis, NEMO mutations (mutations in the NF-κB essential modulator gene (also known as IKK gamma or IKKG)), in particular, NEMO deficiency syndrome, HOIL-1 deficiency ((also known as RBCKI) heme-oxidized IRP2 ubiquitin ligase 1 deficiency),Linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, malignant tumors of hematopoietic and solid organs, bacterial and viral infections (such as 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 accumulation disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid accumulation disease, Tay-Sachs disease, and Wolman disease), spinal cord injury, Stevens-Johnson syndrome, fibrosis, complement-mediated cytotoxicity, treatment of toxic epidermal necrolysis, and / or ex vivo cell therapy for maintaining vitality and function may be particularly useful.

[0144] The compounds of the formula described herein or pharmaceutically acceptable salts thereof may be useful for the treatment of glaucoma.

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

[0146] The compounds of the formula described herein or pharmaceutically acceptable salts thereof may be particularly useful for 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 diseases / disorders may more specifically relate to the improvement of persistent organ injury or damage as a result of the above-mentioned diseases / disorders. For example, the compounds of the present invention may be useful for improving injury or damage to brain tissue after ischemic brain injury or traumatic brain injury, or improving injury or damage to heart tissue after myocardial infarction, or improving injury or damage to brain tissue associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or improving injury or damage to liver tissue associated with non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen.

[0148] The compounds of the present invention may be particularly useful for improving persistent organ injury or damage as a result of radiotherapy, or improving injury or damage to spinal cord tissue after spinal cord injury, or improving injury or damage to liver tissue associated with acute liver failure. The compounds of the present invention may be particularly useful for improving auditory disorders such as noise-induced hearing loss, or auditory disorders after administration of ototoxic drugs or substances such as cisplatin.

[0149] The compounds of the present invention may be particularly useful for improving injury or damage to solid organ tissues (especially kidneys, liver, heart and / or lungs) after transplantation or after administration of nephrotoxic agents or substances such as cisplatin. It is understood that such improvement of tissue damage can be achieved, if possible, by pretreatment with a compound of the formula described herein or a pharmaceutically acceptable salt thereof, for example, pretreatment of a patient before cisplatin administration, or pretreatment of an organ or organ recipient before transplantation surgery. Such improvement of tissue damage can be achieved by treating with a compound of the formula described herein or a pharmaceutically acceptable salt thereof during transplantation surgery.

[0150] Such improvement of tissue damage can also be achieved by treating the patient with a compound of the formula described herein or a pharmaceutically acceptable salt thereof for a short period of time after transplantation surgery.

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

[0152] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of multiple sclerosis.

[0153] In one embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of traumatic brain injury.

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

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

[0156] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of age-related macular degeneration.

[0157] The 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 relate to the improvement of sustained organ injury or damage as a result of these diseases / disorders. For example, the compounds described herein may be particularly useful for the improvement of brain tissue injury or damage after traumatic brain injury, or for the improvement of brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0158] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and for the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0159] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for 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, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative colitis.

[0161] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of lupus, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.

[0162] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher's disease, Niemann-Pick disease, and spinal cord injury.

[0163] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of amyotrophic lateral sclerosis (ALS).

[0164] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of multiple sclerosis.

[0165] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for 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 formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung cancer (NSCLC).

[0167] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC).

[0168] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.

[0169] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of type II diabetes and obesity.

[0170] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of atherosclerosis.

[0171] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of vasculitis.

[0172] In another embodiment, the compounds of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of hereditary 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 the treatment of dependent inflammation and cell death occurring in acute tissue damage caused by stroke, traumatic brain injury, and encephalitis.

[0173] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of ischemic kidney injury, ocular ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0174] In another embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be useful for the treatment of non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).

[0175] A compound of the formula described herein or a pharmaceutically acceptable salt thereof may be particularly useful for the treatment of RIPK1-mediated cancer-related diseases or disorders. Gong et al., The role of necroptosis in cancer biology and therapy, Molecular Cancer (2019) 18:100. In one aspect, the human has a solid tumor. In one aspect, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung cancer (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one aspect, 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 aspect, the human has a liquid tumor such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphocytic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myeloid leukemia.

[0176] The present disclosure also relates to methods for treating or significantly reducing cancer selected from brain (glioma), glioblastoma, astrocytoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple-negative breast cancer, inflammatory breast cancer, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, epithelioma, medulloblastoma, colon cancer, head and neck cancer (including head and neck squamous cell carcinoma), kidney cancer, lung cancer (lung squamous cell carcinoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer), 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, 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 lymphoma, non-Hodgkin lymphoma, lymphoblastic T cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvar cancer, cervical cancer, endometrial cancer, uterine cancer, kidney cancer (including renal clear cell carcinoma, renal papillary carcinoma, renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer (buccal cancer), oral cancer (cancer of the mouth), GIST (gastrointestinal stromal tumor), and testicular cancer.

[0177] Specific examples of clinical symptoms 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 Waldenström macroglobulinemia; lymphomas such as non-Hodgkin lymphoma and Hodgkin lymphoma.

[0178] Cancer can 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, including malignancies of both the lymphoid and myeloid lineages. Myeloid malignancies include, but are not limited to, acute myeloid (or myeloblastic, myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyeloblastic, promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryoblastic leukemia. These leukemias may collectively be referred to as acute myeloid (or myeloblastic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) such as chronic myeloid (or myelogenous) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV) (not limited to these). Myeloid malignancies include myelodysplasia (or myelodysplastic syndrome or MDS), also sometimes referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); and myelofibrosis (MFS) etc., regardless of the presence or absence of myelodysplasia of unknown origin.

[0179] Specific examples of clinical symptoms 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 Waldenström macroglobulinemia; lymphomas such as non-Hodgkin lymphoma and Hodgkin lymphoma. Hematopoietic cancers also include lymphoid malignancies that can affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extranodal sites. Lymphoid cancers include B-cell malignancies such as, but not limited to, B-cell non-Hodgkin lymphoma (B-NHL). B-NHL can be of low grade (or low malignancy), intermediate grade (or high malignancy), or high grade (very high malignancy). Low-grade B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) (including nodal MZL, extranodal MZL, splenic MZL, splenic MZL with villous lymphocytes); lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHL includes mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML) with or without leukemia involvement. High-grade B-NHL includes Burkitt lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHL 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), Waldenström macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoblastic (or lymphocytic or lymphoblastic) leukemia, and Castleman disease.NHL can include T-cell non-Hodgkin lymphoma (T-NHL), which can include, but is not limited to, T-cell non-Hodgkin lymphoma, not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disease (AILD), nasal natural killer (NK) / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0180] Hematopoietic cancers can also include Hodgkin lymphoma (or disease) such as classical Hodgkin lymphoma, nodular sclerosis Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte predominance (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocyte depletion Hodgkin lymphoma. Hematopoietic cancers can also include multiple myeloma (MM) such as smoldering MM, monoclonal gammopathy of undetermined (or unknown or indeterminate) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström 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", can include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues such as spleen, lymph nodes, mucosa-associated lymphoid tissue (such as gut-associated lymphoid tissue), tonsils, Peyer's patches and appendix, and other mucosa-associated lymphoid tissue such as the bronchial lining.

[0181] Pharmaceutical composition The compounds described herein can be administered orally or parenterally. Formulated into dosage forms suitable for administration, the compounds described herein can be used as pharmaceutical compositions for the prevention, treatment, or improvement of the above diseases.

[0182] In the clinical use of the compounds described in this specification, usually, the compounds can be formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form and then administered. "Pharmaceutically acceptable" means that the additives, carriers, diluents or excipients should be compatible with other components of the preparation and should not be harmful to the recipient. Therefore, various additives commonly used in the field of pharmaceutical preparations 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 ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

[0183] 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 formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in a form that can be dissolved or suspended in water or other suitable media at the time of use.

[0184] Particularly in the case of injections, if desired, the preparation can be dissolved or suspended in physiological saline or glucose solution, and buffers or preservatives can be optionally added thereto.

[0185] The pharmaceutical composition can 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 the number of administrations can be varied according to the sex, age, weight and medical condition of the patient, and the type and scope of the intended therapeutic effect. Generally, in the case of oral administration, 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 is about 0.05 to about 10 mg / kg / day. In the case of oral administration, the composition is preferably provided in the form of tablets or capsules containing 0.01 mg to 1,000 mg. In a specific embodiment, the dosage 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 the compound described herein. This method of administration can be adjusted to obtain an optimal therapeutic response.

[0187] Combination therapy The compounds of the present invention are also useful in methods for preventing or treating the aforementioned diseases, disorders and symptoms in combination with other therapeutic agents.

[0188] The compounds of the present invention can be used in combination with one or more other agents in the treatment, prevention, suppression or amelioration of diseases or conditions in which the compounds described herein or other agents may be useful, in which case the combination of agents is safer or more effective than either agent alone. Accordingly, such other agents can be administered in the amounts customarily used, simultaneously or sequentially, with the compounds described herein or pharmaceutically acceptable salts thereof. When the compounds described herein are used simultaneously with one or more other agents, in a specific embodiment, the pharmaceutical composition can contain such other agents and the compounds described herein or pharmaceutically acceptable salts thereof in unit dosage form. However, combination therapy can also include therapies in which the compounds described herein or pharmaceutically acceptable salts thereof and one or more other agents 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 can be used at lower dosages than when each is used alone. Accordingly, the 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 The abbreviations used herein have the meanings shown in the following table. Abbreviations not listed in the following table have the meanings of their generally used abbreviations, unless specifically otherwise indicated.

[0190]

Table 1

[0191] Synthesis of common intermediates (Table A) Production 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 produced from pyrrolidine-2,5-dione according to the method described below.

Chemical formula

[0192] Step 1. Synthesis of 5-Phenylpyrrolidin-2-one Two reactions of the same scale 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 N2 at -70 to -65 °C, and the reaction solution was stirred at 25 to 30 °C for 12 h. To the mixture was added NaBH3CN (1.28 kg, 6.06 mol) at 5 to 10 °C, and it was stirred for 1 h. The reaction solution was acidified to pH = 3 - 4 with TFA (2.31 kg, 20.3 mol). It was stirred at 25 to 30 °C for 2 h.

[0193] The two reaction solutions were combined and worked up together. The mixture was added to ice-H2O (25 L) and extracted with DCM (2 times with 5.0 L) to obtain an organic layer. The organic layer was washed with saturated NaHCO3 (15 L) and separated. Next, the organic layer was purified by flash silica gel chromatography (petroleum ether / ethyl acetate) to obtain 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 reactions of the same scale were carried out 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 (twice with 1.0 L) to obtain an organic layer. The organic layer was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl) 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 methylhydrazine carboxylate (97.1 g, 1.08 mol) in MeOH (1.8 L) at 25 - 30 °C. The reaction solution was stirred at 80 °C for 3 h. Upon completion, the mixture was concentrated. The crude product was washed with MTBE (300 mL) to obtain 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] Steps 4-5. Synthesis of 5-Phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and subsequent acquisition of I-1A by SFC Two reactions of the same scale were carried out in parallel. A solution of methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (50.0 g, 214 mmol) in DMF (500 mL) was stirred at 145 °C for 1 hour. After completion, the two reaction solutions were combined and worked up together. The mixture was concentrated to remove DMF to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) and washed with MTBE (100 mL) to obtain 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (30.0 g).

[0197] The compound of 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (30.0 g, 149 mmol) was separated by preparative SFC (method column DAICEL AD; conditions MeOH / IPA) to obtain (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, the first eluted 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 eluted 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] Production of Intermediate I-2A ((5S)-5-(3,5-Difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one) According to the method described below, Intermediate I-2A was prepared from 1-bromo-3,5-difluorobenzene.

Chemical formula

[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) at 0 °C was added i-PrMgCl·LiCl (6 L), and the reaction mixture was stirred at 50 °C for 1 hour. Next, succinimide (310 g, 313 mmol) and DCM (300 mL) were added to the mixture at -78 °C. The mixture was stirred at 25 °C for 16 hours. To the mixture was added NaBH3CN (236 g, 3750 mmol) at 25 °C, and then the mixture was stirred at 25 °C for 1 hour. The reaction solution was acidified to pH = 3 - 4 with HCl (6 M), stirred for 30 minutes, and neutralized with aqueous NaOH (3 M). The mixture was quenched with water (5000 mL) and extracted with DCM (3 times with 5000 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel chromatography (hexane / ethyl acetate) to obtain 5-(3,5-difluorophenyl)pyrrolidin-2-one. C 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 NaHCO3 (3000 mL) and extracted with DCM (3×2000 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude 2-(3,5-difluorocyclohexyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly in the next step. C 11 H 12 F2NO[M+H] + Calculated: 212; Found: 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) were added methyl hydrazinecarboxylate (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 afford N′-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide. C 12 H 14 F2N3O2[M+H] + Calculated: 270; Found: 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 acquisition of I-2A by SFC 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 a crude product, which was slurried with CH3CN / PE (3:5) to give 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (75 g). 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) of the compound was separated by preparative SFC (method column CHIRALPAK IC-3; condition 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 eluted 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 eluted 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): 11H 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 19F NMR (282 MHz, DMSO-d6) δ -109.22.C 11 H 10 F2N3O[M+H] + Calculated value: 238; Measured value: 238.

[0206] Production 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.

Chemical Structure

[0207] Step 1. Synthesis of Ethyl 4-(2-Fluorophenyl)-4-oxobutanoate A stirred solution of 1-(2-fluorophenyl)ethan-1-one (10.0 g, 72.4 mmol) in THF (150 mL) and DMPU (50 mL, 72.4 mmol) was added with LiHMDS (72.4 mL, 72.4 mmol) (solution in 1 M THF) at about -60 °C (dry ice - acetone bath). After the addition was complete, the reaction mixture was stirred at -60 °C for 30 minutes. Next, ethyl 2-bromoacetate (12.7 g, 76 mmol) was added to the mixture at -60 °C in one portion. The resulting mixture was continuously stirred at -60 °C for an additional 30 minutes. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. 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 Na2SO4, 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. C 12 H 14 FO3[M+H] + Calculated value: 225; Found 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) were added ammonium acetate (5.50 g, 71.4 mmol) and sodium cyanotrihydroborate (3.74 g, 59.5 mmol) at room temperature. Next, the mixture was stirred at 80 °C for 12 hours. The reaction mixture was quenched with HCl (2 M, about 5 mL) and concentrated. The residue was purified by flash silica gel chromatography (DCM / MeOH) to give 5-(2-fluorophenyl)pyrrolidin-2-one. C 10 H 11 FNO[M+H] + Calculated value: 180; Found value: 180.

[0209] Step 3.2 - Synthesis of (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 h. The reaction mixture was quenched with saturated NaHCO3 (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole. The crude product was used in the next step without further purification. C 11 H 13 FNO[M+H] + Calculated: 194; Found: 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 methylhydrazinecarboxylate (1.21 g, 13.5 mmol) at 20 °C, and the addition was complete. The reaction solution was stirred at 80 °C for 2 h and concentrated under reduced pressure. The residue was purified by p-HPLC (Boston Green ODS 150×30 mm×5 μm; condition: water (0.1% TFA)-MeCN) to give methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 12 H 15 FN3O2[M+H] + Calculated: 252; Found: 252.

[0211] Steps 5 - 6. Synthesis of 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and 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 N2 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. A 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 (SFC-P1, ee = 100%) and 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%).

[0212] (R)-5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 1 H NMR (400 MHz, 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) 11H NMR (400 MHz, 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] (S)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-4A) The intermediate I-4A was prepared from 3-bromo-5-fluoropyridine according to the method described below. [Chemical formula]

[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 (solution in 1.3 M THF) (192 mL, 250 mmol) at 0 °C and the mixture was allowed to stir for 2 hours. Next, the mixture was added to a solution of dihydrofuran-2,5-dione (27.3 g, 273 mmol) in THF (450 mL) at -20 °C and the resulting mixture was stirred at -20 °C for 3 hours. Saturated NH4Cl (200 mL) and aqueous NaOH solution (2 M) were added to the reaction solution until the pH reached about 11. After stirring for 30 minutes, the reaction solution was extracted with EtOAc (100 mL), HCl (2 M) was added to the aqueous layer until the pH reached about 5, and then it was extracted with EtOAc (3 times with 100 mL). The combined organic layers were dehydrated over Na2SO4, filtered, concentrated, and 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid was obtained and 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 H2SO4 (12 mL, 225 mmol), and the resulting mixture was stirred at 70 °C for 12 h. The mixture was concentrated directly. The residue was dissolved in DCM (100 mL) and water (50 mL), saturated NaHCO3 was added until pH was about 8, and the mixture was extracted with DCM (3 times with 100 mL). The combined organic layers were dried over Na2SO4, 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 = 6.4 Hz, 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 NaBH3CN (8.03 g, 128 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction solution was concentrated, and the residue was purified by flash silica gel chromatography (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 A solution of 5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (4.1 g, 22.75 mmol) in toluene (40 mL) was added to Lawesson's reagent (4.60 g, 11.4 mmol), and the resulting mixture was stirred at 110 °C for 12 h. The reaction solution was concentrated directly, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to obtain 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione. 1 1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 7.64 (td, J = 2.0, 9.2 Hz, 1H), 5.16 (t, J = 7.2 Hz, 1H), 2.88 - 3.09 (m, 2H), 2.72 (dtd, J = 5.6, 8.4, 13.25 Hz, 1H), 2.03 - 2.14 (m, 1H).

[0218] Step 5. Preparation of 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine A solution of 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione (4.0 g, 20.4 mmol) in THF (70 mL) was added to MeI (1.91 mL, 30.6 mmol), and the resulting mixture was stirred at 20 °C for 12 h. The reaction solution was concentrated. The residue was washed with saturated NaHCO3 (40 mL), and the aqueous layer was extracted with DCM (3 times with 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain 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 hydrazinecarboxylate (2.44 g, 27.1 mmol), and the resulting mixture was stirred at 80 °C for 5 h. The reaction solution was concentrated directly, 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 h. 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 A mixture of enantiomers of 5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1.8 g, 8.17 mmol) was resolved by chiral-SFC (method: column DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); conditions: 0.1% NH₃H₂O / EtOH) to obtain (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) 11H 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] Production of Intermediate I-5A ((S)-5-(3-Fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) The intermediate I-5A was prepared from pyrrolidine-2,5-dione according to the method described below.

Chemical Structure

[0224] Step 1. Production 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) at -78 °C by syringe under N2. After the addition was complete, the reaction mixture was warmed to 25 °C and reacted for an additional 16 h. Next, NaBH3CN (10.2 g, 161 mmol) was added to the mixture and reacted for an additional 3 h. 6 M HCl was added and the pH was adjusted to 3. It was reacted for an additional 1 h. Aqueous NaOH was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 times with 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. Production 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 h to obtain a brown mixture. Aqueous NaHCO3 was added to adjust the pH to neutral. The organic layer was separated, the aqueous layer was re-extracted with DCM (3 times with 30 mL), the combined organic layers were washed with brine (2 times with 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly. C 11 H 13 FNO[M+H] + Calculated value: 194; Measured value: 194.

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

[0227] Step 4. Production 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 for 3 h under N2. Next, the reaction mixture was concentrated to obtain a solid. The solid was suspended in EtOAc, the turbid liquid was filtered, and concentrated to obtain 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 11 Calculated for FN3O [M+H]: 220; Found: 220. +

[0228] Step 5. Production 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% NH3H2O / EtOH) to obtain (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 (400 MHz, 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) 1 ​1H NMR (400 MHz, 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] Production 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) The intermediate I - 6A was prepared from pyrrolidine - 2,5 - dione and 3 - bromo - 5 - chloropyridine according to the method described below.

Chemical Structure

[0231] Step 1. Production of 4-(5-Chloropyridin-3-yl)-4-oxobutanoic acid Isopropylmagnesium chloride (48.0 mL, 52.0 mmol) was added via syringe to a solution of 3 - bromo - 5 - chloropyridine (10 g, 52.0 mmol) in THF (100 mL) at 0 °C over 5 minutes. After stirring for 1 hour, the mixture was added via cannula to a solution of dihydrofuran - 2,5 - dione (6.76 g, 67.6 mmol) in THF (100 mL) at - 20 °C over a period of 30 minutes and then stirred at - 20 °C for 3 hours. The pH was adjusted to approximately 9 by slowly adding NaHCO3 solution. The aqueous layer was acidified with aqueous HCl and extracted with EtOAc (5 times with 100 mL). The combined organic layers were dried over Na2SO4 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. Production 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 h. After 3 h of stirring, the pH was adjusted to approximately 9 by gradually adding NaHCO3 solution. The combined aqueous layers were extracted with DCM (3 times with 50 mL) to remove neutral impurities. The combined organic layers were dried over NaSO4 and concentrated. The solvent was distilled off, and the residue was purified by flash silica gel chromatography (hexane / ethyl acetate) to obtain methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate. C 10 H 11 ClNO3[M+H] + Calculated value: 228; Found value: 228.

[0233] Step 3. Production 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) were added ammonium acetate (3.45 g, 44.8 mmol) and NaBH3CN (2.82 g, 44.8 mmol), and the mixture was stirred at 80 °C for 12 h. The combined aqueous layers were extracted with DCM (4 times with 30 mL) to remove neutral impurities. The combined organic layers were dried over Na2SO4 and concentrated. The organic layer was concentrated, and the residue was purified by flash silica gel chromatography (EtOAc / EtOH) to obtain 5-(5-chloropyridin-3-yl)pyrrolidin-2-one. C9H 10 ClN2O[M+H] + Calculated value: 197; Found value: 197.

[0234] Step 4. Production 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 h. The reaction solution was concentrated directly, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to obtain 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione. C9H 10ClN2S[M+H] + Calculated value: 213; Measured value: 213.

[0235] Step 5. Production 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 h. 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. C 10 H 12 ClN2S[M+H] + Calculated value: 227; Measured value: 227.

[0236] Step 6. Production 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 methylhydrazinecarboxylate (0.775 g, 8.60 mmol), and the resulting mixture was stirred at 80 °C for 5 h. The reaction solution was concentrated directly, 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. C 11 H 14 ClN4O2[M+H] + Calculated value: 269; Measured value: 269.

[0237] Step 7. Production 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 h. The reaction solution was concentrated directly. 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. C 10 H 10 ClN4O [M+H] + Calculated value: 237; Found: 237.

[0238] Step 8. Obtaining of I-6A by chiral separation A mixture of enantiomers of 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (700 mg, 2.96 mmol) was separated by chiral-SFC (Method: column DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Conditions: 0.1% NH3H2O / EtOH) to give 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 (400 MHz, 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 1H NMR (400 MHz, 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] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: Intermediate I-7A was prepared from methyl 5-oxopyrrolidine-2-carboxylate according to the method described below.

Chemical Structure

[0241] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: To a solution of methyl 5-oxopyrrolidine-2-carboxylate (50 g, 349 mmol) in CH2Cl2 (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 NaHCO3 (400 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were dried over Na2SO4, 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. C7H 12 NO3[M + H] + Calculated value: 158; Found: 158.

[0242] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: To a solution of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (55 g, 350 mmol) in MeOH (800 mL) were added methyl hydrazinecarboxylate (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 h. The reaction solution was concentrated directly, and the residue was slurried with ethyl acetate and MeOH to give methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. C8H 14 N3O4[M+H] + Calculated value: 216; Found 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] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 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 methoxide (15.1 g, 279 mmol), and the resulting mixture was stirred at 80 °C for 8 h. To the reaction solution was added HCl (solution in 4.0 M MeOH) until pH was about 5, and the mixture was stirred at 80 °C for 2 h. The solid was filtered off, 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; Found value: 184. 11H 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] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: The intermediate I-8A was produced from pyrrolidine-2,5-dione according to the method described below.

Chemical Structure

[0245] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: (4-Fluorophenyl)magnesium bromide in THF (404 mL, 404 mmol) was added dropwise to pyrrolidine-2,5-dione (20 g, 202 mmol) by syringe at -78 °C under N2. After the addition was complete, the reaction mixture was warmed to 25 °C and reacted for an additional 2.5 hours. Next, NaBH3CN (12.68 g, 202 mmol) was added to the mixture and reacted for an additional 16 hours. HCl (6 M aqueous solution) was added to adjust the pH to 3. The reaction mixture was stirred for an additional 1 hour. NaOH (25 mL EtOH + 5 mL water) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 times with 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 / hexane) to obtain 5-(4-fluorophenyl)pyrrolidin-2-one. C 10 H 11 FNO[M+H] + Calculated value: 180; Measured value: 180. 1 1H NMR (400 MHz, 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] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 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 h. The residue was diluted with a mixture of saturated aqueous NaHCO3 (10 mL) and DCM (10 mL). The organic layer was separated, the aqueous layer was re-extracted with DCM (3 times with 10 mL), the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly in the next step without further purification. C 11 H 13 FNO[M+H] + Calculated: 194; Found: 194.

[0247] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: A mixture of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.9 g, crude) and methyl hydrazinecarboxylate (1.76 g, 19.51 mmol) in MeOH (32 mL) and HCl (solution in 4 M MeOH, 0.5 mL) was stirred at 80 °C for 4 h. 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. C 12 H 15 FN3O2[M+H] + Calculated: 252; Found: 252. 11H NMR (500 MHz, 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] (R)-5-(5-Chloropyridin-3-yl)-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 h. The solvent was evaporated and the residue was purified by flash silica gel chromatography (EtOAc / hexane) to give 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 11 FN3O [M+H] + Calculated: 220; Found: 220. 1 1H NMR (500 MHz, 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] (R)-5-(5-Chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 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% NH3H2O / EtOH) to obtain (R)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (t = 0.991 min) as the first elution peak and (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (t = 1.100 min) as the second elution peak.

[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] (S)-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. [Chem.]

[0252] Step 1. Production 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) was added lithium bis(trimethylsilyl)amide (32.0 mL, 32.0 mmol) (solution in 1M THF) at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 minutes. Next, ethyl 2-bromoacetate (3.73 mL, 33.6 mmol) was added to the above mixture at -78 °C in one portion. After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. LCMS indicated that the reaction was complete. The mixture was diluted with tert-butyl methyl ether (200 mL) and quenched with saturated aqueous NH4Cl solution (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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to afford ethyl 4-(2,6-difluorophenyl)-4-oxobutanoate. C 12 H 13 F2O3[M+H] + Calculated value: 243; Found value: 243.

[0253] Step 2. Production of 5-(2,6-Difluorophenyl)pyrrolidin-2-one A solution of ethyl 4-(2,6-difluorophenyl)-4-oxobutanoate (2.8 g, 11.6 mmol) in EtOH (20 mL) was added with ammonium acetate (13.4 g, 173 mmol) and sodium cyanoborohydride (1.45 g, 23.1 mmol), and the reaction mixture was stirred at 90 °C for 12 h. 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 times with 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to obtain 5-(2,6-difluorophenyl)pyrrolidin-2-one. C 10 H 10 F2NO[M+H] + Calculated value: 198; Measured value: 198.

[0254] Step 3. Production 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) was added trimethyloxonium tetrafluoroborate (2.03 g, 13.7 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO3 solution (50 mL) and extracted with DCM (2 times with 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-(2,6-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0255] Step 4. Production of Methyl 2-(2-(2,6-Difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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 with methylhydrazinecarboxylate (0.761 g, 8.45 mmol) and HCl (1 mL, solution in 4M MeOH) at 20 °C, and the resulting mixture was stirred at 80 °C for 2 h under N₂. The mixture was concentrated under reduced pressure, and the crude residue was washed with EtOAc and hexane and filtered to obtain 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. C 12 H 14 F2N3O2[M+H] + Calculated value: 270; Measured value: 270.

[0256] Step 5. Production of I-9A (5-(2,6-Difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) Sodium methoxide (0.662 g, 12.3 mmol) was added 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), and the resulting mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and made acidic to pH = 7 with HCl (solution in 4M MeOH). Next, the mixture was filtered, and the solid was dehydrated by vacuum distillation to obtain 5-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 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] Production of Intermediate I-10A (5-(3,4-Difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) The intermediate I-10A was prepared from pyrrolidine-2,5-dione and (3,4-difluorophenyl)magnesium bromide according to the method described below. [Chemical formula]

[0258] Step 1. Production 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) at -78 °C under N2 was added a solution of isopropylmagnesium chloride lithium chloride complex (17.47 mL, 22.71 mmol). Next, the reaction mixture was stirred at -78 °C for 1 hour. To a separate solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (50 mL) at -78 °C under N2 was added the above mixture. The mixture was stirred at 25 °C for 16 hours. Next, NaBH3CN (1.74 g, 27.8 mmol) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was acidified to pH = 3 - 4 with HCl (6 M aqueous solution), the resulting mixture was stirred for 1 hour, and neutralized with NaOH (4 M aqueous solution). The mixture was quenched with water (20 mL) and extracted with EtOAc (3 times with 10 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to obtain 5-(3,4-difluorophenyl)pyrrolidin-2-one. C 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. Production 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) was added trimethyloxonium tetrafluoroborate (1.13 g, 7.61 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4, 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. C 11 H 12 F2NO[M+H] + Calculated: 212; Found: 212.

[0260] Step 3. Production 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) were added methylhydrazinecarboxylate (0.448 g, 4.97 mmol) and HCl (2 mL, solution in 4M MeOH) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction solution was concentrated directly, 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. C 12 H 14 F2N3O2[M+H] + Calculated: 270; Found: 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] Step 4. Production of I-10A 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 with sodium methoxide (0.662 g, 12.3 mmol), and the resulting mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and acidified to pH = 7 with HCl (solution in 4M MeOH). Next, the mixture was filtered, and the solid was dehydrated by vacuum distillation to obtain 5-(3,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 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] Production 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.

Chemical Structure

[0263] Step 1. Production of 5-(4-Chlorophenyl)pyrrolidin-2-one A solution of (4-chlorophenyl)magnesium bromide (60.6 mL, 60.6 mmol) in THF (200 mL) was added dropwise with isopropylmagnesium chloride-lithium chloride complex solution (34.9 mL, 45.4 mmol) at 0 °C under N₂. Next, the reaction mixture was stirred at 0 °C for 1 h. Another solution of pyrrolidine-2,5-dione (5 g, 50.5 mmol) in THF (100 mL) was added dropwise to the above solution at -78 °C under N₂. The mixture was stirred at 25 °C for 16 h. Then, NaBH₃CN (3.49 g, 55.5 mmol) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction solution 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 times with 500 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to obtain 5-(4-chlorophenyl)pyrrolidin-2-one. 1 H NMR (CDCl₃, 400 MHz) 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. Production of 2-(4-Chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-(4-chlorophenyl)pyrrolidin-2-one (12 g, 61.3 mmol) in DCM (300 mL) was added dropwise with trimethyloxonium tetrafluoroborate (13.6 g, 92 mmol) at 0 °C under N₂. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated NaHCO₃ aqueous solution (50 mL) and extracted with DCM (2 times with 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated under reduced pressure to obtain crude 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 11 H 13 ClNO[M+H] +Calculated value: 210; Measured value: 210.

[0265] Step 3. Production 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 methylhydrazinecarboxylate (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 h under N2. The mixture was concentrated under reduced pressure, and then the residue was washed with EtOAc / PE (1:1) to give methyl 2-(2-(4-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 12 H 15 ClN3O2 [M+H] + Calculated value: 268; Measured value: 268.

[0266] Step 4. Production 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 h. The mixture was cooled to room temperature and made acidic to pH = 7 with HCl (4 M solution in MeOH). Next, the mixture was filtered, and the solid was dehydrated by vacuum distillation to give 5-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 11 ClN3O [M+H] + Calculated value: 236; Measured value: 236.

[0267] Production 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.

Chemical Structure

[0268] Step 1. Production 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), lithium bis(trimethylsilyl)amide (64.0 mL, 64.0 mmol, 1 M solution in THF) was added at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 minutes. Next, ethyl 2-bromoacetate (7.46 mL, 67.3 mmol) was added in one portion at -78 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. The mixture was diluted with tert-butyl methyl ether (200 mL) and quenched with saturated aqueous NH4Cl solution (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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to give ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate. C 12 H 13 F2O3[M+H] + Calculated value: 243; Found: 243.

[0269] Step 2. Production 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), ammonium acetate (11.9 g, 155 mmol) and sodium cyanoborohydride (1.30 g, 20.6 mmol) were added, 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 Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to give 5-(2,4-difluorophenyl)pyrrolidin-2-one. C10 H 10 F2NO[M+H] + Calculated value: 198; measured value: 198.

[0270] Step 3. Production 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) was added trimethyloxonium tetrafluoroborate (2.25 g, 15.21 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (3 times with 50 mL). The combined organic layers were dried over Na2SO4, 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. C 11 H 12 F2NO[M+H] + Calculated value: 212; measured value: 212.

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

[0272] Production of (2,4-Difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-12A) at Step 5.5 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 h. The residue was purified by RP-HPLC (column Boston Green ODS 150×30 mm×5 μm; conditions: 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. C 11 H 10 F2N3O[M+H] + Calculated value: 238; Found: 238.

[0273] Production 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.

Chemical formula

[0274] Production of 5-(3-(Trifluoromethyl)phenyl)pyrrolidin-2-one at Step 1 A solution of the first 1-bromo-3-(trifluoromethyl)benzene (4.54 g, 20.2 mmol) in THF (40 mL) was added dropwise with i-PrMgCl·LiCl (21.7 mL, 28.3 mmol) at 0 °C under N₂. Next, the reaction mixture was stirred at 25 °C for 1 h. A solution of the second pyrrolidine-2,5-dione (2 g, 20.2 mmol) in THF (60 mL) was added dropwise with i-PrMgCl·LiCl (14.0 mL, 18.2 mmol) at 0 °C under N₂, and the reaction mixture was stirred at 0 °C for 1 h. The first solution was added to the second mixture at -78 °C. The resulting mixture was stirred at 25 °C for 16 h. Next, NaBH₃CN (1.40 g, 22.2 mmol) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction solution was acidified to pH = 3 - 4 with HCl (6 M aqueous solution) and stirred for 1 h, then basified with NaOH (4 M aqueous solution). The mixture was quenched with water (500 mL) and extracted with EtOAc (3 times with 500 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexane) to obtain 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one. C 11 H 11 F3NO[M+H] + Calculated value: 230; Found 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] Production of 5-Methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole at Step 2 To a solution of 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one (2.1 g, 9.16 mmol) in DCM (40 mL) was added trimethyloxonium tetrafluoroborate (2.03 g, 13.7 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NaHCO3 (80 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over Na2SO4, 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. C 12 H 13 F3NO[M+H] + Calculated: 244; Found: 244.

[0276] Production of Methyl 2-(2-(3-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate at Step 3 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 hydrazinecarboxylate (0.815 g, 9.04 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (EtOAc / hexane) to give methyl 2-(2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 13 H 15 F3N3O2[M+H] + Calculated: 302; Found: 302.

[0277] Production of 5-(3-(Trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one at Step 4 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 h. The mixture was cooled to room temperature and acidified with HCl (solution in 4M MeOH) to pH = 7. Next, the mixture was filtered, washed with water (80 mL), and the solid was dehydrated 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. C 12 H 11 F3N3O[M+H] + Calculated value: 270; Found 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] Chiral Separation for 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) at Step 5 A 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 separated by chiral-SFC (method: column DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); conditions: 0.1% NH₃·H₂O / IPA) to obtain (R)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (t = 2.878 min) as the first elution peak and (S)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (t = 3.317 min) as the second elution peak.

[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] Production 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.

Chemical Structure

[0281] Production of 5-(4-(Trifluoromethyl)phenyl)pyrrolidin-2-one at Step 1 A solution of the first 1-bromo-4-(trifluoromethyl)benzene (9.08 g, 40.4 mmol) in THF (70 mL) was added dropwise with i-PrMgCl·LiCl (43.5 mL, 56.5 mmol) at 0 °C under N₂. Next, the reaction mixture was stirred at 25 °C for 1 h. A solution of the second pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (70 mL) was added dropwise with i-PrMgCl·LiCl (27.9 mL, 36.3 mmol) at 0 °C under N₂, and the reaction mixture was stirred at 0 °C for 1 h. The first solution was added to the second mixture at -78 °C. The mixture was stirred at 25 °C for 16 h. Next, NaBH₃CN (3.04 g, 48.4 mmol) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction solution was acidified to pH = 3 - 4 with HCl (6 M aqueous solution), 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 times with 500 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to obtain 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one. C 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] Production of 5-Methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole at Step 2 To a solution of 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (900 mg, 3.93 mmol) in DCM (20 mL) was added trimethyloxonium tetrafluoroborate (1450 mg, 9.82 mmol) at 0 °C under N₂. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO₃ (80 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over Na₂SO₄, 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. C 12 H 13 F3NO[M+H] + Calculated value: 244; Found value: 244.

[0283] Production of Methyl 2-(2-(4-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate at Step 3 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) were added methylhydrazinecarboxylate (1.24 g, 13.7 mmol) and HCl (2 mL, solution in 4M MeOH) at 20 °C, and the resulting mixture was stirred at 80 °C for 3 h under N₂. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexane) to give methyl 2-(2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 13 H 15 F3N3O2[M+H] + Calculated value: 302; Found value: 302.

[0284] Production of 5-(4-(Trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one at Step 4 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 to sodium methoxide (385 mg, 7.12 mmol), and the resulting mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and acidified to pH = 7 with HCl (solution in 4M MeOH). The resulting mixture was filtered, and the filtrate was purified by RP-HPLC (column: Boston Green ODS 150×30 mm×5 μm, mobile phase A - B: 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. C 12 H 11 F3N3O[M+H] + Calculated value: 270; Found: 270.

[0285] Production 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.

Chemical formula

[0286] Step 1. Production 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) was added i-PrMgCl·LiCl (6.52 mL, 8.48 mmol) at 0 °C under N₂. Next, the reaction solution was stirred at 25 °C for 1 hour. To a solution of the second pyrrolidine-2,5-dione (600 mg, 6.06 mmol) in THF (15 mL) was added i-PrMgCl·LiCl (4.19 mL, 5.45 mmol) at 0 °C under N₂, and the reaction solution was stirred at 0 °C for 1 hour. Next, the first solution was added to the second mixture at -78 °C. The reaction solution was warmed to 25 °C and stirred at 25 °C for 12 hours. Next, NaBH₃CN (419 mg, 6.66 mmol) was added, and the resulting mixture was stirred for 1 hour. The reaction mixture was acidified to pH ~3 with HCl (6 M aqueous solution) and stirred for 1 hour. Next, NaOH (4 M aqueous solution) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 times with 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 (EtOAc / hexane) to obtain 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one. C 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. Production 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 h. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude 2-(3,5-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 12 H 14 F2NO[M+H] + Calculated: 226; Found: 226.

[0288] Step 3. Production 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 hydrazinecarboxylate (96 mg, 1.07 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was added to EtOAc (10 mL). The resulting mixture was stirred for 10 min and filtered to afford methyl 2-(2-(3,5-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 13 H 16 F2N3O2[M+H] + Calculated: 284; Found: 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] Step 4. Production of I-15A 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 treated with sodium methoxide (62.9 mg, 1.16 mmol) at 20 °C and the resulting mixture was stirred at 80 °C for 12 h. HCl (0.3 mL, 4 M solution in MeOH) was added to the reaction mixture to adjust the pH to about 6, then the mixture was filtered and the filtrate was purified by RP-HPLC (method: column: Boston Green ODS (150×30 mm×5 μm); conditions: mobile phase A - B: water (0.01% TFA) - ACN) to afford 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; found: 252.

[0290] Production 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.

Chemical formula

[0291] Step 1. Production of ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate A stirred solution of 1-(3,5-difluorophenyl)propan-1-one (5 g, 29.4 mmol) in THF (30 mL) was added with 1,3-dimethyltetrahydropyrimidin-2(1H)-one (7.53 g, 58.8 mmol) and LHMDS (29.4 mL, 29.4 mmol) at -78 °C under N₂. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 minutes. Next, ethyl 2-bromoacetate (3.44 mL, 30.9 mmol) was added to the above mixture at -78 °C in one portion. After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. The mixture was diluted with tert-butyl methyl ether (10 mL) and quenched with saturated aqueous NH₄Cl solution (20 mL). The mixture was extracted with tert-butyl methyl ether (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to give ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate. C 13 H 15 F2O3[M+H] + Calculated value: 257; Found: 257.

[0292] Step 2. Production 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) were added ammonium acetate (8.12 g, 105 mmol) and sodium cyanoborohydride (2.65 g, 42.1 mmol), and the reaction mixture 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 layer was re-extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc / hexane) to give 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one. C 11 H 12 F2NO[M+H] + Calculated value: 212; Found: 212.

[0293] Step 3. Production 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) was added trimethyloxonium tetrafluoroborate (2.21 g, 14.9 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 15 h. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude 2-(3,5-difluorophenyl)-5-methoxy-3-methyl-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 12 H 14 F2NO[M+H] + Calculated: 226; Found: 226.

[0294] Step 4. Production 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) were added methylhydrazinecarboxylate (0.840 g, 9.32 mmol) and HCl (2 mL, solution in 4 M MeOH) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction solution was concentrated directly, and the residue was purified by recrystallization to afford methyl 2-(2-(3,5-difluorophenyl)-3-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 13 H 16 F2N3O2[M+H] + Calculated: 284; Found: 284.

[0295] Step 5. Production 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) 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 h. The mixture was cooled to room temperature and made acidic to pH = 7 with HCl (solution in 4M MeOH). The mixture was concentrated and the residue was purified by recrystallization to give I-16A. C 12 H 12 F2N3O[M+H] + Calculated value: 252; Found: 252.

[0296] Production 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.

Chemical formula

[0297] Step 1. Production of 6-(3,5-difluorophenyl)piperidin-2-one A solution of 1-bromo-3,5-difluorobenzene (5.12 g, 26.5 mmol) in THF (50 mL) was added dropwise with iPrMgCl·LiCl (solution in 1.3 M 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 to the mixture at -78 °C. The mixture was stirred at 20 °C for 12 h. Sodium cyanoborohydride (1.33 g, 21.2 mmol) was added to the mixture at 20 °C, and then the mixture was stirred at 25 °C for 1 h. The reaction solution was acidified to pH = 3 - 4 with HCl (6 M), then 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 times with 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 obtain 6-(3,5-difluorophenyl)piperidin-2-one. C 11 H 12 F2NO[M+H] + Calculated value: 212; Measured value: 212.

[0298] Step 2. Production of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine Dimethyloxonium tetrafluoroborate (475 mg, 3.55 mmol) was added to a solution of 6-(3,5-difluorophenyl)piperidin-2-one (500 mg, 2.37 mmol) in DCM (10 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2 times with 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine, which was used in the next step without further purification. C 12 H 14 F2NO[M+H] + Calculated value: 226; Measured value: 226.

[0299] Step 3. Production of methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate 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 with methylhydrazinecarboxylate (294 mg, 3.26 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction solution was directly concentrated, and the residue was purified by flash silica gel chromatography (MeOH / DCM) to obtain methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate. C 13 H 16 F2N3O2[M+H] + Calculated value: 284; Found: 284.

[0300] Steps 4 - 5. Production 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 h. The reaction solution was directly concentrated to obtain 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% NH3H2O / EtOH) to obtain 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): 11H 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 1H NMR (400 MHz, CD3OD) δ 6.87 (tt, J=2.20, 9.15 Hz, 1H), 6.68-6.76 (m, 2H), 5.13 (t, J=5.28 Hz, 1H), 2.79-2.89 (m, 1H), 2.65-2.77 (m, 1H), 2.29 (dddd, J=3.13, 5.87, 11.00, 14.04 Hz, 1H), 2.01 (tdd, J=3.33, 6.65, 14.09 Hz, 1H), 1.64-1.87 (m, 2H).

[0302] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: The intermediate I-18A was prepared from cyclopentylmagnesium bromide and pyrrolidine-2,5-dione according to the method described below.

Chemical Structure

[0303] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: To a solution of pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (150 mL) was added cyclopentylmagnesium bromide (121 mL, 121 mmol) dropwise via syringe under N₂ at -78 °C. After the addition was complete, the reaction mixture was warmed to 25 °C and reacted for an additional 16 hours. Next, NaBH₃CN (3.04 g, 48.4 mmol) was added to the mixture and reacted for an additional 2 hours. 6 M HCl was added to adjust the pH to 4. It was stirred for an additional 1 hour. Aqueous NaOH was added to neutralize the pH. The reaction mixture was extracted with EtOAc (3 times with 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 obtain 5-cyclopentylpyrrolidin-2-one. C₉H 16 NO[M+H] + Calculated value: 154; Observed value: 154.

[0304] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: To a solution of 5-cyclopentylpyrrolidin-2-one (520 mg, 3.39 mmol) in DCM (20 mL) was added trimethyloxonium tetrafluoroborate (753 mg, 5.09 mmol) under N₂ at 0 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with saturated NaHCO₃ (800 mL) until foaming ceased completely and extracted with DCM (2 times with 300 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 10 H 18 NO[M+H] + Calculated value: 168; Observed value: 168.

[0305] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: A solution of 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole (520 mg, 3.11 mmol) in MeOH (20 mL) was added with methylhydrazinecarboxylate (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 h. The reaction solution was concentrated directly, and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to obtain methyl 2-(2-cyclopentyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 11 H 20 N3O2[M+H] + Calculated value: 226; Found value: 226.

[0306] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: Sodium methoxide (144 mg, 2.66 mmol) was added 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), and the resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature and acidified with HCl / MeOH (4 M) to pH = 7. Next, the mixture was filtered and purified by preparative HPLC (method: column Boston Green ODS 150×30 mm×5 μm; conditions: water (0.01% TFA)-CAN) to obtain 5-cyclopentyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 10 H 16 N3O[M+H] + Calculated value: 194; Found 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] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: The intermediate I-19A was prepared from cyclohexylmagnesium bromide and pyrrolidine-2,5-dione according to the method described below.

Chemical formula

[0308] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: To a solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (100 mL) was added dropwise cyclohexylmagnesium bromide (76 mL, 76 mmol) via syringe under N2 at -78 °C. After the addition was complete, the reaction mixture was warmed to 25 °C and stirred for 16 h. Next, NaBH3CN (2.378 g, 37.8 mmol) was added to the mixture and stirring was continued for an additional 2 h. 6 M HCl was added to adjust the pH to 4. It was stirred for an additional 1 h. Aqueous NaOH was added to adjust the pH to 7. The reaction mixture was extracted with EtOAc (3 times with 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; Observed value: 168.

[0309] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: 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 foaming ceased and extracted with DCM (2 × 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. C 11 H 20 NO[M+H] + Calculated: 182; Found: 182.

[0310] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: To a solution of 2-cyclohexyl-5-methoxy-3,4-dihydro-2H-pyrrole (1.3 g, 5.74 mmol) in MeOH (20 mL) were added methylhydrazinecarboxylate (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 h. The reaction solution was concentrated directly, 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. C 12 H 22 N3O2[M+H] + Calculated: 240; Found: 240.

[0311] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: 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 with sodium methoxide (474 mg, 8.77 mmol), and the resulting mixture was stirred at 80 °C for 24 h. The mixture was cooled to room temperature and made acidic to pH = 7 with HCl / MeOH (4 M). Next, the mixture was filtered and purified by preparative HPLC (method: column Boston Uni C18 150×40 mm×5 μm; conditions: water (0.01% TFA)-CAN) to obtain 5-cyclohexyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 18 N3O[M+H] + Calculated value: 208; Found 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] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: Intermediate I-20A was prepared from pyrrolidine-2,5-dione and 3-bromo-5-chloropyridine according to the method described below.

Chemical Structure

[0313] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: A solution 1 of 1-bromo-3-chlorobenzene (10.1 g, 52.5 mmol) in THF (100 mL) was added dropwise with i-PrMgCl·LiCl (56.5 mL, 73.5 mmol) at 0 °C under N₂. Next, the reaction solution was stirred at 25 °C for 1 h. A solution 2 of pyrrolidine-2,5-dione (5.2 g, 52.5 mmol) in THF (200 mL) was added dropwise with isopropylmagnesium (II) lithium chloride (36.3 mL, 47.2 mmol) at 0 °C under N₂, and the reaction solution was stirred at 25 °C for 1 h. The first solution was added to the second solution at -78 °C under N₂, and the mixture was stirred at 25 °C for 12 h. Next, NaBH₃CN (3.63 g, 57.7 mmol) was added, and the reaction solution was stirred for 1 h. HCl (6 M) was added to the reaction solution until the pH reached about 3, and the mixture was stirred for 1 h. An aqueous NaOH solution (4 M) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (250 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g silica gel, eluent with a gradient of 100% ethyl acetate / petroleum ether) to obtain 5-(3-chlorophenyl)pyrrolidin-2-one. C 10 H 11 ClNO[M+H] + Calculated value: 196; Measured value: 196.

[0314] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: To a solution of 5-(3-chlorophenyl)pyrrolidin-2-one (7.0 g, 35.8 mmol) in DCM (180 mL) was added dropwise 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 foaming ceased completely and extracted with DCM (2 × 200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 11 H 13 ClNO[M+H] + Calculated value: 210; Measured value: 210.

[0315] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: A mixture of 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (7.5 g, 35.8 mmol) and methyl hydrazinecarboxylate (3.22 g, 35.8 mmol) in MeOH (180 mL) and HCl·MeOH (2 mL) was stirred at 80 °C for 12 h to obtain a yellow solution. The solvent was distilled off, and the residue was purified by recrystallization to obtain methyl 2-(2-(3-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 12 H 15 ClN3O2 [M+H] + Calculated value: 268; Found value: 268.

[0316] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: Sodium methoxide (3.03 g, 56.0 mmol) was added 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), and the resulting mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and acidified to pH = 7 with HCl / MeOH (4 M). Next, the mixture was filtered, and the solid was dehydrated by vacuum distillation to obtain I-20A, (S and R)-5-(3-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 11 ClN3O [M+H] + Calculated value: 236; Found value: 236.

[0317] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: Intermediate I-21A was prepared from pyrazine-2-carbaldehyde according to the method described below.

Chemical formula

[0318] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: 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 times with 1.00 L). The organic layer was washed with saturated NaHCO3 (1.00 L) and brine (0.50 L), and dried over Na2SO4. The organic layer was dried in vacuo, 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] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-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, ammonium acetate (592 g, 7.68 mol) and molecular sieves (320 g, 1.32 mol) were added. The resulting mixture was stirred at 20 °C for 12 h. The reaction solution was concentrated to dryness, and the resulting brown liquid was used in the next step without further purification.

[0321] In the subsequent step, two reactions of the same scale were carried out in parallel.

[0322] Sodium cyanoborohydride (145 g, 2.31 mol) was added to 4-oxo-4-(pyrazin-2-yl)butanamide (138 g, 768 mmol) in EtOH (960 mL) at 20 °C, and the resulting mixture was stirred at 80 °C for 5 hours. 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, concentrated, and the resulting residue was dissolved in DCM (1.00 liter). 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 (400 MHz, 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] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: Lawesson's reagent (95.4 g, 236 mmol) was added to a solution of 5-(pyrazin-2-yl)pyrrolidin-2-one (77.0 g, 472 mmol) in toluene (3.85 liters) at 20 °C. The resulting mixture was stirred at 80 °C for 0.5 hour. The reaction solution 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. 11H NMR (400 MHz, 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] (R)-5-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: A solution of 5-(pyrazin-2-yl)pyrrolidine-2-thione (84.0 g, 469 mmol) in acetone (494 mL) was added with K2CO3 (194 g, 1.41 mol) at 20 °C. The mixture was stirred at 20 °C for 1 hour. MeI (133 g, 937 mmol, 58.3 mL) was added dropwise, and the reaction solution was stirred at 20 °C for 11 hours. The reaction solution was filtered, and the filter cake was washed with acetone (200 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by column chromatography (petroleum ether / 30% EtOAc:EtOH). The fractions containing the desired product portion were collected and concentrated to obtain 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine. 1 1H NMR (400 MHz, 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] Manufacture of Step 6-7.I-21A Two reactions of the same scale were carried out in parallel.

[0326] A solution of 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine (22.0 g, 114 mmol) in MeOH (440 mL) was added to methylhydrazinecarboxylate (15.4 g, 171 mmol) at 20 °C. The reaction mixture was heated to 80 °C and allowed to stir for 2 hours. The reaction solution was concentrated to dryness to obtain 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 hours. The two batches were combined and poured into H2O (500 mL) at room temperature. The mixture was filtered and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated to obtain the desired crude residue, which was purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH) to obtain 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 (400 MHz, 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] Manufacture of Intermediate I-22A ((S and R)-5-(3,5-Difluorophenyl)-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one) The intermediate I-22A was prepared from 2-amino-2-(3,5-difluorophenyl)ethan-1-ol according to the method described below.

Chemical formula

[0330] Step 1. Manufacture of 2-((tert-Butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethane-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 N2. 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 × 30 mL), washed with brine (40 mL), the organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica gel, eluent with a gradient of 4% EtOAc / petroleum ether) to give 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine. C 14 H 24 F2NOSi [M+H] + Calculated value: 288; Found: 288.

[0331] Step 2. Manufacture 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 NaHCO3 (5 mL) was stirred at 25 °C for 15 minutes. 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 hours. The reaction was quenched with brine and the mixture was extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SO4 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. C 15 H 22 F2NOSSi[M+H] + Calculated: 330; Found: 330.

[0332] Step 3. Manufacture of Methyl 6-(3,5-difluorophenyl)-9,9,10,10-tetramethyl-4-thioxo-8-oxo-2,3,5-triaza-9-siloundecanoate A mixture of tert-butyl (2-(3,5-difluorophenyl)-2-isothiocyanatoethoxy)dimethylsilane (680 mg, 2.06 mmol), Et3N (0.863 mL, 6.19 mmol) and methylhydrazinecarboxylate (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 with 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-siloundecanoate. C 17 H 28 F2N3O3SSi[M+H] + Calculated: 420; Found: 420.

[0333] Step 4. Manufacture 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-siloundecanoate (630 mg, 1.50 mmol) in sodium hydroxide (10 mL, 1.000 mmol) was stirred at 25 °C for 3 h. 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; Found: 274.

[0334] Step 5. Manufacture 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 triphenylphosphine (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 h. 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. C 10 H8F2N3OS[M+H] + Calculated value: 274; Found: 274.

[0335] Intermediate I-23A ((S and R) - Manufacture 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.

Chemical formula

[0336] Step 1. Manufacture of 5-(4-Methoxyphenyl)pyrrolidin-2-one To a solution of pyrrolidine-2,5-dione (2 g, 20.2 mmol) in THF (100 mL) was added dropwise 4-methoxyphenylmagnesium bromide (89 mL, 44.4 mmol) via syringe at 78 °C under N₂. After the addition was complete, the reaction mixture was warmed to 25 °C and stirred for an additional 16 h. Next, NaBH₃CN (1.52 g, 24.2 mmol) was added to the mixture and stirred for an additional 2 h. Aqueous HCl (4 M) was added to adjust the pH to 4. The mixture was stirred at room temperature for an additional 1 h. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (2 × 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 with a gradient of 80% to 100% EtOAc) to give 5-(4-methoxyphenyl)pyrrolidin-2-one. C 11 H 14 NO₂[M+H] + Calculated: 192; Found: 192.

[0337] Step 2. Manufacture 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) was added trimethyloxonium tetrafluoroborate (696 mg, 4.71 mmol) at 0 °C under N₂. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated NaHCO₃ (20 mL) until effervescence ceased and extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, 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. C 12 H 16 NO₂[M+H] + Calculated: 206; Found: 206.

[0338] Step 3. Manufacture of Methyl 2-(2-(4-Methoxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate A solution of 5-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole (600 mg, 2.92 mmol) in MeOH (20 mL) was added with methylhydrazinecarboxylate (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 h. The reaction solution was directly concentrated, and the residue was washed with petroleum ether / EtOAc = 1:1 to obtain methyl 2-(2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. C 13 H 18 N3O3[M+H] + Calculated value: 264; Found value: 264.

[0339] Step 3. Manufacture 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 h. The mixture was cooled to room temperature and acidified with HCl / MeOH (4 M) to pH = 7. Next, the mixture was filtered and purified by preparative HPLC (column; Boston Uni C18, condition; water (0.01% TFA)-ACN) to obtain I-23A (S and R)-5-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 12 H 14 N3O2[M+H] + Calculated value: 232; Found value: 232.

[0340] Manufacture 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) According to the method described below, intermediate I-24A was prepared from I-11A.

Chemical formula

[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) were added potassium ferricyanide trihydrate (358 mg, 0.849 mmol), potassium acetate (250 mg, 2.55 mmol) and Brettphos Pd G3 (115 mg, 0.127 mmol) at 20 °C. After the addition was complete, the reaction mixture was stirred at 100 °C under a N2 atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (column; Phenomenex Gemini-NX, conditions; water (7 mM NH4HCOO)-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. C 12 H 11 N4O[M+H] + Calculated value: 227; found value: 227.

[0342] Manufacture 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.

Chemical formula

[0343] Step 1. Production 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 Cs2CO3 (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 h. The reaction mixture 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. C 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 N2, 2-chloro-6-methylpyrazine (429 mg, 3.34 mmol), Cs2CO3 (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) were added, and the resulting mixture was stirred under 450 nm blue light for 12 hours. Water (50 mL) was added to the mixture, and the mixture was extracted with EtOAc (3 times with 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 (eluent with a gradient of 100% ethyl acetate / petroleum ether) to obtain 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. C 16 H 26 N5O2Si[M+H] + Calculated value: 348; Measured value: 348.

[0345] Step 3. Production 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 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 treated with TFA (1.5 mL), and the resulting mixture was stirred at 20 °C for 2 h. The reaction solution was concentrated directly. The residue was dissolved in MeOH (5 mL), NH3·H2O (0.5 mL) was added to adjust the pH to about 8, and the mixture was stirred for 1 h. Then the solution was concentrated, and the residue was purified by preparative HPLC (column: Boston Uni C18, condition: 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. C 10 H 12 Calculated for N5O[M+H]: 218; found: 218. + The intermediates I-26A and I-27A were prepared from 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoic acid according to the method described below.

[0346] Production 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

Chemical formula

[0347] Step 1. Synthesis of methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate ​A solution of 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoic acid (21 g, 92 mmol) in MeOH (20 mL) was added to HCl / MeOH (200 mL). The resulting mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure, and the obtained residue was diluted with saturated aqueous NaHCO3 (150 mL) and extracted with EtOAc (3 times with 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate containing impurities. The obtained product 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 elution 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 A solution of methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate (2.5 g, 10.3 mmol) in MeOH (25 mL) was added with ammonium acetate (0.796 g, 10.3 mmol) and sodium cyanoborohydride (0.649 g, 10.3 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was heated to 70 °C and allowed to stand for 12 h. The mixture was cooled to ambient temperature, poured into ice water (100 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one. C 11 H 12 F2NO[M+H] + Calculated value: 212; Found value: 212.

[0349] Step 3. Synthesis of 2-(3,5-difluorophenyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole A solution of 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one (1.5 g, 7.1 mmol) in DCM (15 mL) was added with trimethyloxonium tetrafluoroborate (1.58 g, 10.6 mmol) at 0 °C under nitrogen. The resulting mixture was stirred at 45 °C for 16 h. The reaction was quenched by dropping the mixture into saturated aqueous NaHCO3 (100 mL) at 5 - 10 °C, and the mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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. C 12 H 14 F2NO[M+H] + Calculated value: 226; Found 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) was added methylhydrazinecarboxylate (0.672 g, 7.46 mmol) at 25 °C under nitrogen. The resulting mixture was stirred at 80 °C for 3 h. The reaction solution 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. C 13 H 16 F2N3O2[M+H] + Calculated: 284; Found: 284.

[0351] Steps 5-6. Synthesis of 5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and subsequent acquisition of I-26A and I-27A by SFC 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) was added with sodium methylate (3.58 g, 21.2 mmol) at 0 °C under nitrogen. The resulting mixture was heated to 80 °C and allowed to stand for 12 hours. The mixture was cooled to 0 °C and acidified to pH = 7 with HCl / MeOH (4M). The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70mm*10μm; conditions: water (NH4HCO3)-MeCN) to obtain 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 (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); conditions: 0.1% NH3H2O / IPA) to obtain 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 elution peak. The second and third elution peaks were poorly soluble. These peaks were combined, concentrated under reduced pressure, and the resulting residue was re-purified by preparative SFC (column: (s,s)WHELK-O1 (250 mm×30 mm, 5 μm) conditions: 0.1% NH3H2O / EtOH) to obtain 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 The 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.

Chemical Structure

[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 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) was added with 2-bromo-5-fluoropyridine (411 mg, 2.34 mmol), Cs2CO3 (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) under N2. The resulting mixture was stirred for 12 h under 450 nm blue light. The mixture was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 μm; 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. C 16 H 24 FN4O2Si [M+H] + Calculated value: 351; Found 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 TFA (2 mL) was added 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). The resulting mixture was stirred at ambient temperature for 2 h. The reaction solution was concentrated, and the obtained residue was dissolved in MeOH (10 mL). Ammonium hydroxide was added until pH was about 8, and the resulting solution was stirred for 1 h. The solution was concentrated, and the obtained residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; condition: water (10 mM-NH4HCO3)-MeCN) to obtain I-28A, 5-(5-fluoropyridin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C10 H 10 Calculated value of FN4O[M+H]: 221; Measured value: 221. + 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.

Chemical formula

[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) was added iPrMgCl·LiCl (solution in 1.3 M THF) (18.63 mL, 24.22 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 20 °C for 1 hour. To a separate solution of pyrrolidine-2,5-dione (2.00 g, 20.2 mmol) in THF (100 mL) was added iPrMgCl·LiCl (solution in 1.3 M THF) (13.97 mL, 18.17 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 1 hour. The first solution was added to the second solution at -78 °C. The resulting mixture was warmed to ambient temperature and stirred for 16 hours. NaBH3CN (1.78 g, 28.3 mmol) was added to the reaction mixture at ambient temperature, and the reaction solution was stirred for 1 hour. The reaction solution 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 times with 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 obtain 5-(3-chloro-5-fluoro-4-methylphenyl)pyrrolidin-2-one. C 11 H 12 Calculated value of ClFNO[M+H]: 228; Measured value: 228. + 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) was added trimethyloxonium tetrafluoroborate (1.559 g, 10.54 mmol) at 0 °C under nitrogen. The mixture was stirred at 40 °C for 24 h under nitrogen. The mixture was cooled to ambient temperature and quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 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. C 12 H 14 ClFNO [M+H] + Calculated: 242; Found: 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) were added methyl hydrazinecarboxylate (0.451 g, 5.01 mmol) and HCl / MeOH (3 mL) at ambient temperature. The resulting mixture was heated to 80 °C and stirred for 2 h under nitrogen. The mixture was concentrated under reduced pressure. The resulting residue was slurried with ethyl acetate for 15 min and filtered to afford 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. C 13 H 15 ClFN3O2 [M+H] + Calculated: 300; Found: 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 at 145 °C for 4 h under nitrogen. The mixture was cooled to ambient temperature, washed with ethyl acetate (10 mL), filtered, and purified by preparative HPLC (column Boston Prime C18 150*40mm*5μm; conditions: 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 ClFN3O [M+H] + Calculated: 268; Found: 268.

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

Chemical Structure

[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) were 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 then the solution was extracted with EtOAc (3 times with 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, eluent 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 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 dropwise with iPrMgCl·LiCl (solution in 1.3 M 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 (solution in 1.3 M 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 the mixture was stirred at 0 °C for 1 h. This 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 mixture was stirred for 1 h. HCl (6 M) was added until the pH was about 4, and the mixture was stirred for 1 h. An aqueous NaOH solution (4 M) was added to adjust the pH to neutral. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 times with 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 (registered trademark); 40 g SepaFlash (registered trademark) silica flash column, eluent with a gradient of 100% ethyl acetate / petroleum ether, at 35 mL / min) to obtain 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 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and then extracted with DCM (3 times with 15 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, 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. C 11 H 12 F2NO2[M+H] + Calculated value: 228; found: 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) was added methylhydrazinecarboxylate (1.249 g, 13.86 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 5 h. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent with 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. C 12 H 14 F2N3O3[M+H] + Calculated value: 286; found: 286.

[0368] Step 5. Preparation of Intermediate I-30A 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 with sodium methoxide (1.515 g, 28.0 mmol), and the resulting mixture was stirred at 80 °C for 12 h. The reaction solution was allowed to cool to room temperature, and HCl / MeOH (4 M) was added until pH was about 5, followed by stirring 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, eluent 5% MeOH / DCM gradient, at 35 mL / min) to obtain I-30A, 5-(3,5-difluoro-4-hydroxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 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.

Chemical Structure

[0370] Step 1.1 - Synthesis of (2,6-difluoro-4-methylphenyl)ethan-1-one 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) was added with Pd(dppf)Cl2 (1.868 g, 2.55 mmol) under nitrogen. 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 (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 1-(2,6-difluoro-4-methylphenyl)ethan-1-one. 1 1H 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: 171; Found: 171.

[0371] Step 2 - Synthesis of ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate 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) was treated with lithium bis(trimethylsilyl)amide (1 M solution in THF) (18.75 mL, 18.75 mmol) at -78 °C. The mixture was stirred at -78 °C for 30 min and then ethyl 2-bromoacetate (2.183 mL, 19.68 mmol) was added. The reaction mixture was warmed to ambient temperature and held for 2 h. 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 Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to afford 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: 257; Found: 257.

[0372] Step 3 - Synthesis of 5-(2,6-difluoro-4-methylphenyl)pyrrolidin-2-one A solution of ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate (2.2 g, 8.6 mmol) and AcONH4 (1.985 g, 25.8 mmol) in EtOH (40 mL) was added with NaBH3(CN) (1.349 g, 21.46 mmol) at ambient temperature. 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 times with 100 mL). The combined organic layers were 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-(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 was added trimethyloxonium tetrafluoroborate (637 mg, 4.31 mmol) at 0 °C under nitrogen. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and extracted with DCM (3 times with 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, 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. C 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) were added methyl hydrazinecarboxylate (167 mg, 1.86 mmol) and HCl / MeOH (1 mL) at 20 °C under nitrogen. 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: 284; Found: 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 Sodium methoxide (143 mg, 2.65 mmol) was added 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). The resulting mixture was heated to 80 °C for 5 h. The reaction mixture was cooled to ambient temperature and HCl / MeOH (4M) was added until pH ~6 was reached, 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] Production 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 The intermediate I-32A was prepared from 4-bromo-1-chloro-2-fluorobenzene according to the method described below.

Chemical formula

[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) was added iPrMgCl·LiCl (solution in 1.3 M THF) (27.2 mL, 35.3 mmol) at 0 °C under nitrogen. The resulting solution was stirred at ambient temperature for 1 hour. To a separate solution of pyrrolidine-2,5-dione (2.5 g, 25 mmol) in THF (100 mL) was added iPrMgCl·LiCl (solution in 1.3 M THF) (17.47 mL, 22.71 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 1 hour. The first solution was added to the second solution at -78 °C. The resulting solution was warmed to ambient temperature and stirred for 12 hours. NaBH3(CN) (1.744 g, 27.8 mmol) was added to the reaction mixture at ambient temperature and stirred for 1 hour. The reaction solution was acidified to pH about 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 times with 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 obtain 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 A solution of 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one (1.00 g, 4.68 mmol) in DCM (23.4 mL) was added with trimethyloxonium tetrafluoroborate (1.039 g, 7.02 mmol) at 0 °C under nitrogen. The mixture was stirred at ambient temperature for 15 h. The mixture was quenched with saturated aqueous NaHCO3 (150 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 11 H 12 ClFNO[M+H] + Calculated value: 228; Found value: 228.

[0379] Step 3 - Synthesis of methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate 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) was added with methylhydrazinecarboxylate (0.422 g, 4.68 mmol) and HCl / MeOH (1 mL) at ambient temperature. The resulting mixture was heated to 80 °C and stirred for 12 h. The mixture was concentrated under reduced pressure. The obtained residue was slurried with ethyl acetate for 15 min and filtered to afford 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. C 12 H 14 ClFN3O2[M+H] + Calculated value: 286; Found value: 286.

[0380] Step 4 - Synthesis of I-32A 5-(4-chloro-3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 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 treated with sodium methoxide (0.945 g, 17.5 mmol). The resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to ambient temperature and HCl / MeOH (4 M) was added until pH ~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 ClFN3O [M+H] + Calculated: 254; Found: 254.

[0381] Production 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.

Chem.

[0382] Step 1 - Synthesis of 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one 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 dropwise with iPrMgCl·LiCl (solution in 1.3 M THF) (25 mL, 32.5 mmol) at 0 °C under nitrogen. The resulting solution was stirred at ambient temperature for 1 h. Another solution of pyrrolidine-2,5-dione (2.3 g, 23 mmol) in THF (100 mL) was added dropwise with iPrMgCl·LiCl (solution in 1.3 M 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 h. The reaction solution was acidified to pH ca. 3 with HCl (6 M), stirred for 1 h, and neutralized with aqueous NaOH (4 M). The mixture was diluted with water (20 mL) and extracted with EtOAc (3 times with 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 obtain 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one. C 10 H9F3NO[M+H] + Calculated value: 216; Found value: 216.

[0383] Step 2 - Synthesis of 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole A solution of 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one (1.00 g, 4.65 mmol) in DCM (20 mL) was added dropwise with trimethyloxonium tetrafluoroborate (1.031 g, 6.97 mmol) at 0 °C under nitrogen. The mixture was stirred at ambient temperature for 15 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (2 times with 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. C 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) were added methylhydrazinecarboxylate (0.413 g, 4.58 mmol) and HCl / MeOH (1 mL) at ambient temperature. The resulting mixture was heated to 80 °C and stirred under nitrogen for 3 h. The mixture was concentrated under reduced pressure. The residue obtained 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. C 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 methoxide (0.940 g, 17.4 mmol). The resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to ambient temperature and HCl / MeOH (4 M) was added until pH ~6 was reached, and the solution was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give I-33A, 5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H9F3N3O[M+H] + Calculated value: 256; measured value: 256.

[0386] Production of Intermediate I-34A The intermediate I-34A was prepared from 5-bromo-2-chloro-1,3-difluorobenzene according to the method described below. [Chemical formula]

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

[0388] Step 2. Production 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 h to give a brown mixture. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and extracted with DCM (3 times with 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, 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. C 11 H 11 ClF2NO[M+18+H] + Calculated value: 264; Measured value: 264.

[0389] Step 3. Production 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) were added methylhydrazinecarboxylate (1.613 g, 17.91 mmol) and HCl / MeOH (4 mL) at 20 °C, and the resulting mixture was stirred under N2 at 80 °C 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, eluent 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. C 12 H 13 ClF2N3O2[M+H] + Calculated value: 304; Measured value: 304.

[0390] Step 4. Production of I-34A 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 treated with sodium methoxide (89 mg, 1.646 mmol), and the resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature and then HCl / MeOH (4 M) was added until pH ∼6. The solution was concentrated, the residue was dissolved in MeOH (50 mL), filtered, and the filtrate was concentrated to afford I-34A, 5-(4-chloro-3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H9ClF2N3O [M+H] + Calculated: 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] Production of intermediate I-35A Intermediate I-35A was prepared from (R)-2-amino-2-phenylethan-1-ol according to the method described below.

Chemical Structure

[0392] Step 1. Production of (R)-5-phenylmorpholin-3-one (R)-2-Amino-2-phenylethan-1-ol (5 g, 36.4 mmol) and TEA (12.70 mL, 91 mmol) in THF (100 mL) were added 2-chloroacetyl chloride (2.90 mL, 36.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×20 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 solution (50 mL) and extracted with EtOAc (2×20 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, eluent with 5% MeOH / DCM gradient, at 35 mL / min) to give (R)-5-phenylmorpholin-3-one. C 10 H 12 NO2[M+H] + Calculated value: 178; found: 178.

[0393] Step 2. Production of (R)-5-methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxazine (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 NaHCO3 solution (30 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude (R)-5-methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxazine, which was used in the next step without further purification.

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

[0395] Step 4. Production of I-35A A solution of (R)-2-(5-phenyl-5,6-dihydro-2H-1,4-oxazin-3-yl)hydrazine-1-carboxylate (1.2 g, 4.81 mmol) in DMF (40 mL) was stirred at 145 °C for 12 h. The reaction mixture 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 min. The mixture was filtered, and the filtrate was purified by preparative HPLC (method: Boston Green ODS, conditions: water (0.01% TFA)-ACN) to obtain I-35A, (R)-5-phenyl-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one. C 11 H 12 N3O2[M+H] + Calculated value for: 218; Found: 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] Production 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 According to the method described below, intermediate I-36A was prepared from 2-((tert-butyldimethylsilyl)oxy)acetaldehyde.

Chemical formula

[0397] Step 1. Production of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropan-2-sulfinamide To a stirred mixture of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (10 g, 57.4 mmol) in THF (250 mL) was added (S)-2-methylpropan-2-sulfinamide (9.04 g, 74.6 mmol) and Ti(iPrO)4 (22.5 mL, 86 mmol) at 20 °C, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into brine (300 mL) and filtered. The mixture was extracted with EtOAc (3 times with 100 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% to 20% EtOAc / petroleum ether) to give (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropan-2-sulfinamide. C 12 H 28 NO2SSi[M+H] + Calculated value: 278; Measured value: 278.

[0398] Step 2. Production of (S)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropan-2-sulfinamide A solution of 1-bromo-3,5-difluorobenzene (8.80 g, 45.6 mmol) in THF (100 mL) was added with i-PrMgCl·LiCl (47.8 mL, 62.2 mmol) at 0 °C under N2, and the mixture was stirred at 40 °C for 1 hour. Next, the reaction mixture was added at 0 °C under N2 to a solution of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropan-2-sulfinamide (11.5 g, 41.4 mmol) in THF (150 mL). The reaction mixture was stirred at 25 °C for 5 hours. The mixture was quenched with saturated NH4Cl (300 mL) and extracted with EtOAc (3 times with 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 obtain (S)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropan-2-sulfinamide. C 18 H 32 F2NO2SSi[M+H] + Calculated value: 392; Measured value: 392.

[0399] Steps 3 - 4. Production of 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide (S)-N-((R)-2-((tert-Butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropan-2-sulfinamide (3 g, 7.66 mmol) in HCl / MeOH (50 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 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) at 0 °C was added 2-chloroacetyl chloride (0.459 mL, 5.77 mmol), and the resulting mixture was stirred at 20 °C for 2 h. The mixture was added to water (20 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40% EtOAc:petroleum ether) to give 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide. C 10 H 11 ClF2NO2[M+H] + Calculated value: 250; Found value: 250.

[0400] Step 5. Production 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) at 0 °C was added NaH (224 mg, 5.61 mmol), and the mixture was stirred at 20 °C for 1 h. 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. Production of 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxazine 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 h. The mixture was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxazine, which was used in the next step without further purification. C 11 H 12 F2NO2[M+H+H2O] + Calculated value: 246; Measured value: 246.

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

[0403] Step 8. Production of I-36A A solution of methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)hydrazine-1-carboxylate (480 mg, 1.68 mmol) in DMF (40 mL) was stirred at 145 °C for 12 h. The reaction solution was concentrated directly. The residue was purified again 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; Found 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] Production 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.

Chemical Structure

[0405] Step 1. Production of 6-phenylpiperidin-2-one A solution of piperidine-2,6-dione (5 g, 44.2 mmol) in THF (100 mL) was added dropwise with phenylmagnesium bromide (30.9 mL, 93 mmol) via syringe under N₂ at -78 °C. After the addition was complete, the reaction solution was warmed to 25 °C and stirred for 16 h. NaBH₃(CN) (3.06 g, 48.6 mmol) was added to the mixture, and it 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 to a neutral pH. The mixture was quenched with water (200 mL) and extracted with EtOAc (3 times with 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow oil. It was purified by flash silica gel chromatography (100% EtOAc) to obtain 6-phenylpiperidin-2-one. C 11 H 14 NO[M+H] + Calculated value: 176; Measured value: 176.

[0406] Step 2. Production of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine Dimethyloxonium tetrafluoroborate (2.87 g, 21.4 mmol) was added to a solution of 6-phenylpiperidin-2-one (2.5 g, 14.3 mmol) in CH₂Cl₂(100 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated NaHCO₃(50 mL) and extracted with DCM (2 times with 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine, which was used in the next step without further purification. C 12 H 16 NO[M+H] + Calculated value: 190; Measured value: 190.

[0407] Step 3. Production 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 methylhydrazinecarboxylate (1.64 g, 18.2 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. The reaction solution was concentrated directly. The residue was added to EtOAc (20 mL) and stirred for 0.5 h. The solid was filtered to obtain methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate. C 13 H 18 N3O2[M+H] + Calculated value: 248; Found 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 at 145 °C for 12 h. The reaction solution was concentrated directly to obtain (±)-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, Condition: 0.1% NH3H2O EtOH) to obtain (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: 11H 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 1H NMR (500 MHz, CD3OD) δ 7.32 - 7.38 (m, 2H), 7.24 - 7.30 (m, 1H), 7.04 (d, J = 7.5 Hz, 2H), 5.18 (dd, J = 3.5 Hz, 1H), 2.80 - 2.87 (m, 1H), 2.66 - 2.77 (m, 1H), 2.27 (dddd, J = 3.5 Hz, 1H), 1.98 - 2.07 (m, 1H), 1.63 - 1.81 (m, 2H).

[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 According to the method described below, Intermediate I-38A was prepared from (2S,4S)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid.

Chemical Structure

[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 K2CO3 (11.85 g, 86 mmol) at 0 °C, and then iodomethane (8.01 mL, 129 mmol). The mixture was stirred at 30 °C under a N2 atmosphere for 2 h. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (petroleum ether:EtOAc = 3:1) to give 1-(tert-butyl) 2-methyl-4-fluoropyrrolidine-1,2-dicarboxylate. C 11 H 19 FNO4[M+H] + Calculated value: 248; Found: 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 min. 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 mixture was stirred at 25 °C for 12 h. IPA (100 mL) was added to the mixture, and the reaction mixture was stirred at 25 °C for 3 h. The mixture was filtered, and the filtrate was extracted with EtOAc (2 times with 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 120 g SepaFlash (registered trademark) silica flash column, eluent 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; Found: 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 h. 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 NaHCO3 (100 mL) and extracted with DCM (3 times with 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude methyl-4-fluoro-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate. The crude product 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 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) was added with methylhydrazinecarboxylate (1.018 g, 11.30 mmol) and HCl / MeOH (0.5 mL) at 20 °C. The resulting mixture was stirred at 80 °C for 2 h under N2. The reaction solution was cooled to room temperature and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 12 g SepaFlash (registered trademark) silica flash column, eluent with a gradient of 10% MeOH / EtOAc, at 60 mL / min) to obtain methyl 4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. C8H 13 FN3O4[M+H] + Calculated value: 234; Found 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 for 12 h under N2. The reaction solution was cooled to room temperature and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 12 g SepaFlash (registered trademark) silica flash column, eluent with a gradient of 10% MeOH / EtOAc, at 60 mL / min) to obtain 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; Found value: 202. 1 1H 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] TIFF2025521068000103.tif255153

[0418] Synthesis of Common Intermediates (Table B) Preparation of Intermediate I-2B (Mesityl-l3-iodandiylbis(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. [Chemical formula]

[0419] A mixture of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (143 mg, 1.098 mmol) and mesityl-13-iododiacetate (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), 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 obtain crude mesityl-13-iododiacetylbis(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-l3-iodandiylbis(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. [Chemical formula]

[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 mixture was stirred at 20 °C for 12 h. TLC indicated consumption of the starting material and the appearance of new spots. Water (4 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1×2 mL). The aqueous layer was acidified to pH ~4 with 2 M HCl and extracted with EtOAc (3×2 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid, which was used in the next step without further purification.

[0422] Step 2. Preparation of 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-l3-iodane diacetate (133 mg, 0.365 mmol), and the resulting mixture was concentrated 4 times at 55 °C using a rotary evaporator, with fresh toluene (20 mL) used each time. The crude product was concentrated under reduced pressure to afford mesityl-l3-iodane 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 - I-19B were prepared in the same manner as the procedure used to prepare I-2B, using the corresponding commercially available acids and mesityl-l3-iodane diacetate reagent.

[0424] Table B. Chemical structures of intermediates I-1B - I-19B [Table 3] TIFF2025521068000107.tif164168

[0425] General Schematic Diagram 1 [Chem.]

[0426] In General Schematic Diagram 1, the intermediates in Table A and Table B were coupled under photooxidation-reduction conditions in the presence of a copper and iridium catalyst to obtain 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. [Chem.]

[0428] Four individual 40 mL vials were charged with 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-l3-iodandiylbis(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). Each mixture was purged with nitrogen gas and placed in a photoreactor (fan rpm 4700, stirring rpm 1000, 450 nm, 100% light intensity) for 5 h. The reaction solution was diluted with CAN, filtered through a celite layer, 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 accumulated and concentrated to dryness to afford Compound 1-2. The desired product can be recrystallized by dissolving it in a minimum amount of EtOAc over 24 - 48 h. The product can be isolated with >99.9% purity by filtration and washing with hexane. C 16 H 15 F3N3O[M+H] + Calculated: 322; Found: 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] Example 1.2. Preparation of 1-40 Compound 1-40 was prepared from Intermediates I-9A and I-2B according to the method described below.

Chemical formula

[0430] A mixture of Intermediate I-9A (20 mg, 0.084 mmol), Cu(OAc)2 (11.04 mg, 0.042 mmol), Ir(ppy)3 (1.104 mg, 1.69 μmol), and Intermediate I-2B (85 mg, 0.169 mmol) in MeCN (2 mL) was stirred at 25 °C for 2 h under N2 while irradiating with a 450 nm blue LED lamp. LCMS indicated that the product was 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 obtain 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% NH3H2O / EtOH) to obtain (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 1H 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

[0433] Synthesis of Common Intermediate (TABLEC) (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 (I-1C)) Intermediate I-1C was prepared from Compound 1-18 according to the method described below.

Chemical Structure

[0434] To a solution of compound 1-18 (240 mg, 0.664 mmol) in THF (5 mL) was added lithium borohydride (0.664 mL, 1.33 mmol) dropwise at 25 °C under N₂, and the reaction mixture was stirred at 25 °C for 1 h. LCMS indicated the completion of the reaction. The mixture was added to H₂O (20 mL). The mixture was extracted with EtOAc (3 times with 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to obtain 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; found value: 334.

[0435] (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 (I-2C)) Intermediate I-2C was prepared from compound 1-18 according to the method described below.

Chemical formula

[0436] To a solution of compound 1-18 (300 mg, 0.830 mmol) in MeOH / THF / H₂O (3 / 3 / 1, v / v / v) (10 mL) was added lithium hydroxide (23.86 mg, 0.996 mmol) at 25 °C, and the resulting mixture was stirred at 25 °C for 16 h. Water (30 mL) and EtOAc (10 mL) were added, and the mixture was extracted with EtOAc (2 times with 8 mL). The organic layer was discarded. The pH of the aqueous layer was adjusted to about 4.0 by adding aqueous HCl solution (3 M), and the mixture was extracted with EtOAc (2 times with 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to obtain 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. C 17H 16 F2N3O3[M+H] + Calculated value: 348; Measured value: 348.

[0437] (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 (I-3C)) According to the method described below, Intermediate I-3C was prepared from Compound I-1C by mesylation.

Chemical Structure

[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 indicated that the reaction was complete. Water (10 mL) and DCM (10 mL) were added, and the mixture was extracted with DCM (3 times with 6 mL), dried over Na2SO4, filtered, and concentrated to give a 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. C 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] (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)) Compound 2-1 was prepared from Intermediate I-1C according to the method described below.

Chemical Structure

[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 times with 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: column Boston Green ODS 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. C 18 H 20 F2N3O2 [M+H] + Calculated: 348; Found: 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] (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)) Compound 2-2 was prepared from intermediate I-2C according to the method described below.

Chemical Structure

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

[0444] (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)) Compound 2-4 was prepared from Intermediate I-3C according to the method described below.

Chemical formula

[0445] Sodium cyanide (20 mg, 0.408 mmol) was added to a solution of Intermediate I-2C (23 mg, 0.056 mmol) in DMF (1 mL) at 20 °C. The resulting mixture was stirred at 60 °C for 16 hours. LCMS indicated that the reaction was complete. H2O (10 mL) and EtOAc (10 mL) were added. The aqueous layer was extracted with EtOAc (2 times with 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by preparative HPLC (Instrument Eh; Method: Column Welch Xtimate C18 150 mm×25 mm×5 μm; Conditions: water (NH4HCO3)-ACN) to obtain Compound 2-4. C 18 H 17 F2N4O[M+H] + Calculated value: 343; Observed value: 343. 11H 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] (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 (Compound 2-5))

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

[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) were 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 a solution of 1 - propanephosphonic anhydride (685 mg, 1.08 mmol) was slowly added under N2. 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 times with 10 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give a residue, which 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. C 19 H 21 F2N4O3[M + H] + Calculated value: 391; Found: 391.

[0449] Step 2. Preparation of Compound 2-5 (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 with methylmagnesium bromide (0.236 mL, 0.707 mmol) at -5 °C, and the resulting mixture was stirred at -5 °C for 2 h. The mixture was slowly warmed to 25 °C and the reaction solution was stirred at 25 °C for 16 h. Saturated NH4Cl (20 mL) and EtOAc (10 mL) were added, and the mixture was extracted with EtOAc (2 times with 8 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to obtain an oil, which was purified by preparative TLC (SiO2, petroleum ether / EtOAc = 1 / 2) to obtain Compound 2-5. C 18 H 18 F2N3O2[M+H] + Calculated value: 346; Found 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

Chemical formula

[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 glove box, into two 20 mL red cap vials containing Intermediate I-2A (80 mg, 0.337 mmol), 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) were added. The vials were placed in the glove box, then DMF (5620 μL) and MeCN (5620 μL) were added to form a homogeneous solution, which was then sealed and taken out of the glove box. 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 / hexane) to obtain a crude mixture containing the product, and EKB purification (with TFA as the modifier) was performed on it. The sample was lyophilized to obtain (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. C 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 Into a 20 mL red cap 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) were 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 hours. The reaction mixture was carefully quenched to approximately pH 3 with 2N HCl (110 μL) and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, 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. C 17 H 14 F4N3O3[M+H] + Calculated value: 384; Found: 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 (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 a stirred solution of DCM (408 μL) was charged with isobutyl chloroformate (21.7 μL, 0.166 mmol) at 0 °C, and then TEA (42.2 μL, 0.303 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 30 minutes, 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 hour. The reaction mixture was purified directly by silica gel flash column chromatography (ethyl acetate / EtOH / hexane) 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. C 17 H 15 F4N4O2[M+H] + Calculated: 383; Found: 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 (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 placed in a 20 mL red cap vial and charged with ClCH2CH2Cl (2800 μL), then POCl3 (500 μL, 5.36 mmol) was added in one portion, and the reaction mixture was stirred at 90 °C for 4 hours. The reaction mixture was purified directly by silica gel flash column chromatography (ethyl acetate / EtOH / hexane) and, after lyophilization, gave (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. C 17H 13 F4N4O[M+H] + Calculated value: 365; Measured value: 365.

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

Chem.

[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)2 (39.0 mg, 0.149 mmol), Ir(ppy)3 (3.90 mg, 5.96 μmol) and I-19B (391 mg, 0.596 mmol) in MeCN (5960 μL) was stirred at 25 °C for 1 h under irradiation with a 450 nm blue LED lamp under N2. The mixture was concentrated under reduced pressure. Next, the residue was purified by preparative HPLC (method: column Boston Green ODS 150×30 mm×5 μm; conditions: water (0.01% TFA)-CAN) to obtain 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). C 18 H 18 F2N3O3[M+H] + Calculated value: 362; Measured value: 362. 1 1H 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 (7M) (2 mL) was stirred at 60 °C for 12 h. 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. C 17 H 17 Calculated for F2N4O2[M+H]: 347; Found: 347. + to

[0459] Step 3. Preparation of Compound 3-3 (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) was treated with trifluoroacetic anhydride (109 mg, 0.520 mmol), and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Method: column Boston Prime C18 150×30 mm×5 μm; Conditions: water (10 mM-NH4HCO3)-ACN) to give Compound 3-3. C 17 H 15 Calculated for F2N4O[M+H]: 329; Found: 329. + to 1 1H 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.

Chemical formula

[0462] Step 1. Production 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 To a vial were added intermediate I-7A (325 mg, 1.77 mmol), I-5B (1840 mg, 3.55 mmol), Ir(ppy)3 (23.2 mg, 0.035 mmol), Cu(OAc)2 (232 mg, 0.887 mmol) and MeCN (17 mL). The mixture was purged with nitrogen gas and placed in a photoreactor (fan rpm 4700, stirring rpm 1000, 450 nm, 100% light intensity) for 3 hours. The reaction solution was diluted with MeCN and filtered through a celite layer. 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). The fractions containing the desired product were collected, concentrated to dryness, and 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 was obtained. C 13 H 15 N4O3 [M+H] + Calculated value: 275; Observed value: 275.

[0463] Step 2. Production 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 THF / water = 3 / 1 was added LiOH (51.1 mg, 2.133 mmol). 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 pH < 7. The aqueous layer was re-extracted with DCM (2 times with 20 mL), the combined organic layers were washed with brine (2 times with 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 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. C 12 H 13 N4O3[M+H] + Calculated value: 261; Measured value: 261.

[0464] Intermediate I-2D was prepared in the same manner as the procedure used to prepare I-1D from I-7A and I-2B. Intermediate I-3D was prepared in the same manner as the procedure used to prepare I-1D from I-38A and I-2B.

[0465] Table D [Table 8]

[0466] General Scheme 2a [Chemical Formula]

[0467] In General Scheme 2a, Intermediate I-7A and the intermediate in Table B were coupled under photoreductive oxidation conditions in the presence of a copper and iridium catalyst. Hydrolysis was then performed on the resulting product to obtain the corresponding acid. Treatment with the desired aryl halide under Ni catalyst conditions gave the desired products listed in Table 4.

[0468] General Scheme 2b [Chem.]

[0469] In General Scheme 2b, the products listed in Table 4 are obtained by treatment of the intermediate from Table D with the desired aryl halide under Ni catalyst conditions.

[0470] Example 4.1. Production of Compound 4-2 [Chem.]

[0471] DMSO (1.25 mL) was added to a 2-drum vial containing I-2D (12.7 mg, 0.05 mmol), 1-bromo-3-fluoro-5-methoxybenzene (15.4 mg, 0.075 mmol), isatin (7.4 mg, 0.05 mmol), DTBPYNiCl2·4H2O (4.7 mg, 0.01 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (17.1 mg, 0.1 mmol), and (Ir[DF(CF3)PPY]2(DTBPY))PF6 (1.1 mg, 1.0 μmol). The reaction mixture was degassed by bubbling nitrogen through the solution while stirring for 15 minutes. Next, the reaction mixture was irradiated for 18 hours under irradiation with a 450 nm LED lamp in a PennOC / Merck photoreactor with 100% LED power, 2500 rpm fan, and 630 rpm stirring. The reaction solution was filtered and purified by reverse phase chromatography (MeCN / water + 0.1% TFA) to obtain 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. C 17 H 18 F2N3O2[M+H] + Calculated value: 334; Measured value: 334.

[0472] Example 4.2. Production 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)

Chem.

[0473] Step 1-2. Production 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 and subsequent acquisition of 4-7 by SFC To a 2-drum vial containing I-1D (30 mg, 0.115 mmol), 1-bromo-4-methylbenzene (29.6 mg, 0.173 mmol), isatin (17.0 mg, 0.115 mmol), DTBPYNiCl2·4H2O (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(CF3)PPY]2(DTBPY))PF6 (2.59 mg, 2.31 μmol), DMSO (2880 μL) was added. The reaction mixture was degassed by bubbling nitrogen through the solution while stirring for 15 minutes. Next, the reaction mixture was irradiated for 14 hours under irradiation with a 450 nm LED lamp in a PennOC / Merck photoreactor with 100% LED power, a 1000 rpm fan, and stirring at 4700 rpm. The reaction solution was diluted with DCM and H2O, transferred to a separatory funnel, and shaken. The resulting mixture was extracted three times with DCM, dried over Na2SO4, 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-toly...

Claims

1. A compound of formula I below or a pharmaceutically acceptable salt thereof. 【Chemical 1】 [Wherein, R １ is selected from C ３ -C ６ cycloalkyl, aryl and heteroaryl, wherein each of said C ３ -C ６ cycloalkyl, aryl and heteroaryl is independently (1) halogen; (2) -CN; (3) -C which may be independently substituted with 1 to 4 substituents selected from halogen 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 may be substituted with 1 to 4 substituents selected from; R ２ is selected from C ３ -C １０ cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of said C ３ -C １０ cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently (1) halogen; (2) -CN; (3) Independently, halogen, -CN, -OH, -O-C １ -C ６ -C which may be substituted with 1 to 4 substituents selected from alkyl and heteroaryl １ -C ６ alkyl; (4) -O-C which may be substituted with 1 to 4 substituents independently selected from halogen 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 is selected from, and each of R ｂ and R ｃ may each independently be hydrogen and heteroaryl-substituted -C １ -C ６ alkyl.]; and (6) aryl which may be 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, where the 5- or 6-membered ring may contain a heteroatom selected from N, O or S, and, independently, is substituted with 1 to 4 substituents selected from halogen, -OH, and -C １ -C ６ alkyl.]

2. R １ is selected from -C ４ -C ６ cycloalkyl, phenyl and 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; Here, the -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 halogen and -CN ３ ; -CH, which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ２ CH ３ ; (5) ethynyl; (6) cyclopropyl; (7)-O-CH ３ ; and (8)-O-CH ２ CH ３ The compound or a pharmaceutically acceptable salt thereof according to claim 1, which may be substituted with 1 to 3 substituents selected from.

3. R １ is selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl, wherein said cyclobutyl, cyclopentyl, phenyl, pyridyl, and pyrazinyl are (1) halogen; (2) -CN; -CH which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ３ ; (4) ethynyl; (5) cyclopropyl; and (6)-O-CH ３ The compound or a pharmaceutically acceptable salt thereof according to claim 1, which may be substituted with 1 to 3 substituents selected from.

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

5. R ２ is selected from C ３ -C １０ cycloalkyl, heterocycloalkyl, phenyl and heteroaryl, Here, the C ３ -C １０ cycloalkyl is [Chemical 2] selected from; Here, the heterocyclic alkyl is 【Chemical 3】 selected from; and 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; Here, the C ３ -C １０ Each of cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is independently (1) halogen; (2) -CN; (3) Independently, halogen, -CN, -OH and -O-C １ -C ４ -C which may be substituted with 1 to 3 substituents selected from alkyl １ -C ４ alkyl; (4) -O-C which may be substituted with 1 to 3 substituents independently selected from halogen 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 is hydrogen, and may be substituted with a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl and isoquinolyl -C １ -C ４ alkyl, selected from.]; and (6) phenyl which may be substituted with 1 to 3 halogens The compound or a pharmaceutically acceptable salt thereof according to claim 1, which may be substituted with 1 to 3 substituents selected from.

6. R ２ is 【Chemical Formula 4】 and phenyl, where 【Chemical Formula 5】 and each of phenyl is independently (1) halogen; (2) -CN; (3) -CH which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH and -O-CH ３ ; ３ ; (4) -O-CH which may be independently substituted with 1 to 3 substituents selected from halogen 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 or a pharmaceutically acceptable salt thereof according to claim 1, which may be substituted with 1 to 3 substituents selected from.

7. R ２ is 【Chemical Formula 6】 and is independently (1) halogen; (2) -CN; (3) -CH which may be substituted with 1 to 3 substituents independently selected from halogen, -CN, -OH and -O-CH ３ ; ３ ; (4) -C(O)OMe; (5)-C(O)CH ２ -thienyl; and (6) phenyl The compound or a pharmaceutically acceptable salt thereof according to claim 1, which may be substituted with 1 to 3 substituents selected from.

8. R ３ and R ４ form a 5-membered aliphatic ring fused to the 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 or a pharmaceutically acceptable salt thereof according to claim 1 of formula Ia below. 【Chemical Formula 7】 [Wherein, n is 1 or 2; R １ is selected from C ３ -C ６ cycloalkyl, aryl and heteroaryl, wherein said C ３ -C ６ each of cycloalkyl, aryl and heteroaryl is independently (1) halogen; (2) -CN; (3) -C which may be substituted with 1 to 4 substituents independently selected from halogen and -CN １ -C ６ alkyl; (4)-C ２ -C ６ alkynyl; (5)-C ３ -C ６ cycloalkyl; and (6)-O-C １ -C ６ Alkyl may be substituted with 1 to 3 substituents selected from; R ２ is selected from C ３ -C １０ cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of said C ３ -C １０ cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently: (1) halogen; (2) -CN; (3) Independently, halogen, -CN, -OH, -O-C １ -C ６ -C which may be substituted with 1 to 4 substituents selected from alkyl and heteroaryl １ -C ６ alkyl; (4) -O-C may be optionally substituted with 1 to 4 substituents independently selected from halogen 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 is selected from; and R ｂ and R ｃ each is independently hydrogen and -C １ -C ６ alkyl which may be substituted with heteroaryl; and (6) aryl which may be substituted with 1 to 3 halogens may be substituted with 1 to 4 substituents selected from; and, R ５ Each occurrence of １ -C ６ is independently selected from hydrogen, halogen, -C alkyl and -OH.]

10. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein n is 1.

11. R １ is selected from -C ４ -C ６ cycloalkyl, phenyl and heteroaryl, where 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; Here, the -C ４ -C ６ Cycloalkyl, phenyl and heteroaryl are (1) halogen; (2) -CN; -CH which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ３ ; -CH, which may be independently substituted with 1 to 3 substituents selected from halogen 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 1 to 3 substituents selected from.

12. R １ is selected from cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl, wherein the cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, and pyrazinyl are (1) halogen; (2) -CN; -CH which may be independently substituted with 1 to 3 substituents selected from halogen 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 1 to 3 substituents selected from.

13. R ２ is selected from C ３ -C １０ cycloalkyl, heterocycloalkyl, phenyl and heteroaryl, Here, the C ３ -C １０ The cycloalkyl is 【Chemical Formula 8】 selected from; The heterocyclic alkyl is 【Chemical Formula 9】 selected from; and 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; Here, the C ３ -C １０ Each of cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is independently (1) halogen; (2) -CN; (3) Independently, halogen, -CN, -OH, and -O-C １ -C ４ -C which may be substituted with 1 to 3 substituents selected from alkyl １ -C ４ alkyl; (4) -O-C may be optionally substituted with 1 to 4 substituents independently selected from halogen 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 is selected from, and R ｃ is hydrogen and -C 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 １ -C ４ alkyl, 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 1 to 3 substituents selected from.

14. R ２ is 【Chemical 10】 and selected from phenyl, wherein said 【Chemical Formula 11】 and each of phenyl are independently (1) halogen; (2) -CN; (3) Independently, -CH which may be substituted with 1 to 3 substituents selected from halogen, -CN, -OH and -O-CH ３ ; ３ ; -O-CH which may be independently substituted with 1 to 3 substituents selected from halogen 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 optionally substituted with thienyl ３ ].; 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 1 to 3 substituents selected from.

15. R １ is selected from -C ４ -C ６ cycloalkyl, phenyl and 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; Here, the -C ４ -C ６ Cycloalkyl, phenyl, and heteroaryl are (1) halogen; (2) -CN; -CH which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ３ ; -CH, which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ２ CH ３ ; (5) ethynyl; (6) cyclopropyl; (7)-O-CH ３ ; and (8)-O-CH ２ CH ３ may be substituted with 1 to 3 substituents selected from; R ２ is 【Chemical Formula 12】 and selected from phenyl, wherein said 【Chemical 13】 and each of phenyl are independently (1) halogen; (2) -CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogen, -CN, -OH and -O-CH ３ ; ３ ; -O-CH which may be optionally substituted with 1 to 3 substituents independently selected from halogen 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 optionally substituted with thienyl ３ ; and (6) phenyl which may be substituted with 1 to 3 halogens may be substituted with 1 to 3 substituents selected from; and, R ５ is hydrogen, halogen, -C １ -C ４ alkyl and -OH, the compound according to claim 10 or a pharmaceutically acceptable salt thereof.

16. R １ is (1) halogen; (2) -CN; -CH which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ３ ; (4) cyclopropyl; and (5)-O-CH ３ phenyl, which may be substituted with 1 to 3 substituents selected from: R ２ is 【Chemical Formula 14】 and which is independently (1) halogen; (2) -CN; (3) Independently, -CH which may be substituted with 1 to 3 substituents selected from halogen, -CN, -OH and -O-CH ３ ３ ​ which may be substituted with 1 to 3 substituents selected from: and R ５ is hydrogen, halogen, -CH ３ , and -OH, and the compound according to claim 10 or a pharmaceutically acceptable salt thereof. **Claim 17** The compound according to claim 1 of formula Ib or a pharmaceutically acceptable salt thereof. 【Chemical 15】 [wherein, R １ is selected from C ３ -C ６ cycloalkyl, phenyl and heteroaryl, wherein said C ３ -C ６ each of cycloalkyl, phenyl and heteroaryl is independently (1) halogen; (2) -CN; (3) -C which may be independently substituted with 1 to 3 substituents selected from halogen and -CN １ -C ６ alkyl; (4)-C ２ -C ６ alkynyl; -(5)-C ３ -C ６ cycloalkyl; and (6)-O-C １ -C ６ Alkyl which may be substituted with 1 to 3 substituents selected from: R ２ is selected from C ３ -C １０ cycloalkyl and heterocycloalkyl, wherein each of said C ３ -C １０ cycloalkyl and heterocycloalkyl is independently (1) halogen; (2) -CN; (3) Independently, halogen, -CN, -OH, and -O-C １ -C ６ -C which may be substituted with 1 to 3 substituents selected from alkyl １ -C ６ -alkyl; (4) -O-C which may be independently substituted with 1 to 3 substituents selected from halogen 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 is selected from, and R ｂ and R ｃ each of which may independently be hydrogen and heteroaryl-substituted -C １ -C ６ alkyl.]; and (6) aryl which may be substituted with 1 to 3 halogens which may be substituted with 1 to 3 substituents selected from: and R ５ is selected from hydrogen, halogen, -C １ -C ６ alkyl and -OH.] **Claim 18** R １ is (1) halogen; (2) -CN; -CH which may be independently substituted with 1 to 3 substituents selected from halogen and -CN ３ ; (4) cyclopropyl; and (5)-O-CH ３ phenyl, which is substituted with 1 to 3 substituents selected from: R ２ is 【Chemical Formula 16】 and which is independently (1) halogen; (2) -CN; (3) -CH which may be independently substituted with 1 to 3 substituents selected from halogen, -CN, -OH, and -O-CH ３ ; ３ ; (4)-C(O)O-CH ３ ; (5)-C(O)CH ２ -thienyl; and (6) phenyl which is substituted with 1 to 3 substituents selected from: and R ５ The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen. **Claim 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]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, (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, (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, (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, (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, (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 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

20. A method for treating 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 damage caused by stroke, traumatic brain injury, and encephalitis, comprising administering to a patient in need thereof the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

21. A method for treating amyotrophic lateral sclerosis, comprising administering to a patient in need thereof the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

22. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for treating amyotrophic lateral sclerosis in a patient in need of treatment.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier.

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