RIPK1 inhibitors and methods of use

Abstract

Described herein are compounds of formula I or pharma- ceutically acceptable salts thereof. The compounds of formula I act as RIPK1 inhibitors and may be useful in preventing, treating, or acting as therapeutic agents for RIPK1-associated diseases. [Formula 1] TIFF0007680639000158.tif28165

Description

[Technical field]

[0001] The present specification discloses a RIPK1 inhibitor. The RIPK1 inhibitor described herein can be useful for preventing, treating, or as a therapeutic agent for RIPK1-related diseases. [Background technology]

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

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

[0004] Furthermore, human genetic evidence has implicated RIPK1 dysregulation in the development of amyotrophic lateral sclerosis (ALS), Alzheimer's disease and multiple sclerosis, as well as other inflammatory and neurodegenerative diseases. Alexei Degterev, Dimitry Ofengeim, and Junying Yuan, Targeting RIPK1 for the treatment of human diseases, PNAS, May 14, 2019, 116 (20), 9714-9722; Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al., RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS, Science, 2016, 353:603-8; Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, et al., Necroptosis activation in Alzheimer's disease, Nat Neurosci, 2017, 20:1236-46; Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, et al., Activation of necroptosis in multiple sclerosis, Cell Rep., 2015, 10:1836-49.

[0005] Also, necroptosis has been demonstrated to be a delayed component of ischemic neuronal injury, so RIPK1 inhibition may have a promising role in the treatment of stroke. Degterev A, et al., Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury, Nat Chem Biol 2005, 1(2):112-119. [Prior art documents]

Non-Patent Literature

[0006]

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

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

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

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

[0011] Also described herein is the use of the compounds described herein, or pharma- ceutically acceptable salts thereof, for treating neurodegenerative, autoimmune, and inflammatory diseases in a patient in need of such treatment.

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

[0013] Also described herein are pharmaceutical compositions that include a compound described herein and a pharma- ceutically acceptable carrier.

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

[0015] Also described herein is the treatment of a compound described herein, or a pharma- ceutically acceptable salt thereof, in combination with at least one additional agent to treat neurodegenerative, autoimmune, and inflammatory diseases in a patient in need of such treatment.

[0016] Also described herein are pharmaceutical compositions that include a compound described herein, or a pharma- ceutically acceptable salt thereof, at least one additional therapeutic agent, and a pharma- ceutically acceptable carrier.

[0017] Also described herein are pharmaceutical compositions that include a compound described herein, at least one additional therapeutic agent, and a pharma- ceutically acceptable carrier. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0019] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R 1 -C 4 -C 6cycloalkyl, phenyl, and 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; Said-C 4 -C 6 Cycloalkyl, phenyl and heteroaryl are (1) halogen; (2)-CN; (3) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; 3 ; (4) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 2 CH 3 ; (5) ethynyl; (6) cyclopropyl; (7)-O-CH 3 and (8)-O-CH 2 CH 3 It may be substituted with 1 to 3 substituents selected from the following.

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

[0021] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R 1 teeth, (1) halogen; (2)-CN; and (3) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 3 and phenyl which may be substituted by 1 to 3 substituents selected from the above.

[0022] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R 2 is crosslinked C 5 -C 10 selected from cycloalkyl, bridged heterocyclic alkyl, phenyl and heteroaryl; Said cross-linked C 5 -C 10 The cycloalkyl or bridged heterocycloalkyl is unsubstituted or independently (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, and -OC 1 -C 4 -C optionally substituted with 1 to 3 substituents selected from alkyl 1 -C 4 Alkyl; (4) -OC, 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 -OH, -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl and -NHR c Selected from R cis optionally substituted with hydrogen and a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; 1 -C 4 alkyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It is substituted with 1 to 3 substituents selected from:

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

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

[0025] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R 2 teeth [ka] and independently, (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, and -O-CH 3 -CH 3 ; (4)-C(O)-OCH 3 ; (5)-C(O)CH 2 -thiemyl; and (6) Phenyl It may be substituted with 1 to 3 substituents selected from the following.

[0026] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R 3 and R 4together with the atoms to which they are attached form a 5-membered aliphatic ring fused to the triazole ring, said 5-membered aliphatic ring independently containing halogen, -OH, -CH 3 , -CH 2 CH 3 , and -CH 2 CH 2 CH 3 It may be substituted with 1 to 4 substituents selected from the following.

[0027] In one embodiment of the compound of formula 1 or a pharma- ceutically acceptable salt thereof, the compound is of formula Ia: [ka] During the ceremony, n is 1 or 2; R 1 is C 3 -C 6 cycloalkyl, aryl, and heteroaryl; 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)-OC 1 -C 6 Alkyl may be substituted with 1 to 3 substituents selected from R 2 is C 3 -C 10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 3 -C 10Each of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently: (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, -OC 1 -C 6 -C optionally substituted with 1 to 4 substituents selected from alkyl and heteroaryl 1 -C 6 Alkyl; (4) -OC, 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 -OH, -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, and -NR b R c Selected from R b and R c each independently is hydrogen and optionally substituted with heteroaryl; 1 -C 6 alkyl; and (6) Aryl optionally substituted with 1 to 3 halogens may be substituted with 1 to 4 substituents selected from R 5 Each occurrence of is independently hydrogen, halogen, -C 1 -C 6 It is selected from alkyl and -OH.

[0028] In one embodiment of the compounds of formula Ia, or a pharma- ceutically acceptable salt thereof, n is 1.

[0029] In one embodiment of the compound of formula Ia or a pharma- ceutically acceptable salt thereof, R 1 -C 4 -C 6cycloalkyl, phenyl, and 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; Said-C 4 -C 6 Cycloalkyl, phenyl and heteroaryl are (1) halogen; (2)-CN; (3) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 3 ; (4) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 2 CH 3 ; (5) ethynyl; (6) cyclopropyl; (7)-O-CH 3 and (8)-O-CH 2 CH 3 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 pharma- ceutically acceptable salt thereof, 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; (3) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 3 ; (4) ethynyl; (5) cyclopropyl; and (6)-O-CH 3 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 pharma- ceutically acceptable salt thereof, R 2 is C 3 -C 10 selected from cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; Said C 3 -C 10 Cycloalkyl is [ka] Selected from; The heterocyclic alkyl is [ka] Selected from; said heteroaryl is selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl and isoquinolyl; Said C 3 -C 10 Each of cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is independently (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, and -OC 1 -C 4 -C optionally substituted with 1 to 3 substituents selected from alkyl 1 -C 4 Alkyl; (4) -OC, which may be substituted with 1 to 4 substituents independently selected from halogen and -CN; 1 -C 4 Alkyl; (5)-C(O)-R a [R a -OH, -C1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, and -NHR c Selected from R c is optionally substituted with hydrogen and a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl; 1 -C 4 alkyl; and (6) Phenyl optionally substituted with 1 to 3 halogens It may be substituted with 1 to 3 substituents selected from the following.

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

[0033] In one embodiment of the compound of formula Ia or a pharma- ceutically acceptable salt thereof, R 1 -C 4 -C 6 cycloalkyl, phenyl, and 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; Said-C 4 -C 6 Cycloalkyl, phenyl and heteroaryl are (1) halogen; (2)-CN; (3) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 3 ; (4) -CH, which may be substituted with 1 to 3 substituents independently 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 teeth, [ka] and phenyl, [ka] and phenyl are each independently (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, and -O-CH 3 -CH 3 ; (4) -O-CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 3 ; (5)-C(O)-R a [R a -OH, -CH 3 , -O-CH 3 , and -NHR c Selected from; R c is -CH, which may be substituted with hydrogen and thienyl 3 ]; and (6) Phenyl optionally substituted with 1 to 3 halogens may be substituted with 1 to 3 substituents selected from R 5 is hydrogen, halogen, -C 1 -C 4 It is selected from alkyl and -OH.

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

[0035] In one embodiment of the compound of formula 1 or a pharma- ceutically acceptable salt thereof, the compound is of formula Ib: [ka] During the ceremony, R 1 is C 3 -C 6 cycloalkyl, phenyl and heteroaryl, 3 -C 6 Each of cycloalkyl, phenyl and heteroaryl is independently (1) halogen; (2)-CN; (3) -C, which may be substituted with 1 to 3 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)-OC 1 -C 6Alkyl may be substituted with 1 to 3 substituents selected from R 2 is C 3 -C 10 cycloalkyl and heterocyclic alkyl, 3 -C 10 Each of cycloalkyl and heterocycloalkyl is independently (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, and -OC 1 -C 6 -C optionally substituted with 1 to 3 substituents selected from alkyl 1 -C 6 Alkyl; (4) -OC, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN; 1 -C 6 Alkyl; (5)-C(O)-R a [R a -OH, -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, and -NR b R c Selected from R b and R c each of which is independently substituted with hydrogen and heteroaryl; 1 -C 6 alkyl; and (6) Aryl optionally substituted with 1 to 3 halogens may be substituted with 1 to 3 substituents selected from R 5 is hydrogen, halogen, -C 1 -C 6 It is selected from alkyl and -OH.

[0036] In one embodiment of the compound of formula Ib or a pharma- ceutically acceptable salt thereof, R 1 teeth, (1) halogen; (2)-CN; (3) -CH, which may be substituted with 1 to 3 substituents independently selected from halogen and -CN. 3 ; (4) cyclopropyl; and (5)-O-CH 3 phenyl substituted with 1 to 3 substituents selected from R 2 teeth, [ka] and, independently, (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, and -O-CH 3 -CH 3 ; (4)-C(O)O-CH 3 ; (5)-C(O)CH 2 -thienyl; and (6) Phenyl is substituted with 1 to 3 substituents selected from; R 5 is hydrogen.

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

[0038] In one embodiment, disclosed herein is a method of treating RIPK1-dependent inflammation and cell death that occurs in genetic and sporadic diseases including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis, and acute tissue damage caused by stroke, traumatic brain injury, encephalitis, comprising administering to a patient in need of treatment a compound described herein or a pharma- ceutically acceptable salt thereof.

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

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

[0041] In one embodiment, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically 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 C 3 -C 6 cycloalkyl, 3 -C 6 Cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen; (2) —CN; and (3) —C 1 -C 6 Alkyl;(4)-C 2 -C 6 Alkynyl; (5)-C 3 -C 6 Cycloalkyl; and (6)-OC 1 -C 6 It may be substituted with 1 to 4 substituents selected from alkyl.

[0045] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 cycloalkyl, each of which is unsubstituted.

[0046] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 Cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen; (2) —CN; and (3) —C 1 -C 6Alkyl;(4)-C 2 -C 6 Alkynyl; (5)-C 3 -C 6 Cycloalkyl; and (6)-OC 1 -C 6 It is substituted with 1 to 4 substituents selected from alkyl.

[0047] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 The cycloalkyl is substituted with 1 to 3 halogens.

[0048] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 The cycloalkyl is substituted with -CN.

[0049] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 Cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and -CN. 1 -C 6 In one embodiment, the C 3 -C 6Cycloalkyl is independently methyl, ethyl, propyl, butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 , and -CH 2 It is substituted with 1 to 3 substituents selected from CN.

[0050] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 Cycloalkyl is -C 2 -C 6 In one embodiment, the C is substituted with alkynyl. 3 -C 6 The cycloalkyl is substituted with ethynyl or propynyl. 3 -C 6 The cycloalkyl is substituted with ethynyl.

[0051] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 Cycloalkyl is -C 3 -C 6 In one embodiment, the C 3 -C 6 In one embodiment, the C is substituted with cyclopropyl. 3 -C 6The cycloalkyl is substituted with cyclobutyl.

[0052] In one embodiment, R 1 teeth, [ka] C selected from 3 -C 6 is cycloalkyl; Said C 3 -C 6 Cycloalkyl is -OC 1 -C 6 In one embodiment, the C 3 -C 6 Cycloalkyl is -OCH 3 In one embodiment, the C 3 -C 6 Cycloalkyl is -OCH 2 CH 3 In one embodiment, the C 3 -C 6 Cycloalkyl is -OCH 2 CH 2 CH 3 In one embodiment, the C 3 -C 6 Cycloalkyl is -OCH 2 CH 2 CH 2 CH 3 has been replaced with.

[0053] In one embodiment, R 1 is aryl, which is optionally substituted with 1 to 3 substituents independently selected from (1) halogen; (2) -CN; (3) -C 1 -C 6 Alkyl;(4)-C 2 -C 6 Alkynyl; (5)-C 3 -C 6 Cycloalkyl; and (6)-OC 1 -C 6It may be substituted with 1 to 3 substituents selected from alkyl.

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

[0055] In one embodiment, R 1 is phenyl, and the phenyl is optionally substituted with 1 to 3 substituents independently selected from (1) halogen; (2) -CN; and (3) -C 1 -C 6 Alkyl;(4)-C 2 -C 6 Alkynyl; (5)-C 3 -C 6 Cycloalkyl; and (6)-OC 1 -C 6 It is substituted with 1 to 3 substituents selected from alkyl.

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

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

[0058] In one embodiment, R 1 is phenyl, which is optionally substituted with 1 to 3 substituents independently selected from halogen and -CN; 1 -C 6 It is substituted with alkyl.

[0059] In one embodiment, R 1is phenyl, which phenyl is independently methyl, ethyl, propyl, butyl, pentyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 , and -CH 2 In one embodiment, R is substituted with 1 to 3 substituents selected from CN. 1 is phenyl, which is substituted with 1 to 3 substituents independently selected from methyl, ethyl, propyl, butyl, and pentyl. 1 is phenyl, each of which is independently -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 , and -CH 2 In one embodiment, R is substituted with 1 to 3 substituents selected from CN. 1 is phenyl, the phenyl being independently selected from methyl and -CF 3 It is substituted with 1 to 3 substituents selected from:

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

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

[0062] In one embodiment, R 1 is phenyl, the phenyl independently being selected from halogen and -C 3-C 6 In one embodiment, R is substituted with 1 to 3 substituents selected from cycloalkyl. 1 is phenyl, which is substituted with cyclopropyl. 1 is phenyl, which is substituted with cyclobutyl. 1 is phenyl, which is substituted with cyclopentyl. 1 is phenyl, which is substituted with cyclohexyl.

[0063] In one embodiment, R 1 is a heteroaryl, the heteroaryl being optionally substituted with 1 to 4 substituents independently selected from (1) halogen; (2) -CN; (3) halogen and -CN; 1 -C 6 Alkyl;(4)-C 2 -C 6 Alkynyl; (5)-C 3 -C 6 Cycloalkyl; and (6)-OC 1 -C 6 It may be substituted with 1 to 3 substituents selected from alkyl.

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

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

[0066] In one embodiment, R 1 is a 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 optionally substituted with 1 to 4 substituents independently selected from (1) halogen; (2) -CN; and (3) -C independently selected from halogen and -CN. 1 -C 6 Alkyl;(4)-C 2 -C 6 Alkynyl; (5)-C 3 -C 6 Cycloalkyl; and (6)-OC 1 -C 6 It is substituted with 1 to 3 substituents selected from alkyl.

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

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

[0069] In one embodiment, R 1 R is pyridyl substituted with fluoro. 1 is pyridyl substituted with two fluoro. In one embodiment, R1 is pyridyl substituted with chloro. In one embodiment, R 1 is pyridyl substituted with two chloros.

[0070] In one embodiment, R 1 R is pyrazinyl substituted with fluoro. 1 is pyrazinyl substituted with two fluoro. 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, wherein the heteroaryl is substituted with -CN. 1 is a heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with -CN.

[0072] In one embodiment, R 1 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is independently selected from C 1 -C 6 In one embodiment, R 1is heteroaryl selected from pyridyl and pyrazinyl, which heteroaryl is independently substituted with 1 to 2 substituents selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

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

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

[0075] In one embodiment, R 1 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is selected from -C 2 -C 6 In one embodiment, R 1 is a heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is -C=CH 3 has been replaced with.

[0076] In one embodiment, R 1 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is selected from -C3 -C 6 In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is pyridyl substituted with cyclopropyl or cyclobutyl. 1 is pyrazinyl substituted with cyclopropyl or cyclobutyl.

[0077] In one embodiment, R 1 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl, wherein the heteroaryl is selected from -OC 1 -C 6 In one embodiment, R 1 is heteroaryl selected from pyridyl and pyrazinyl, wherein the heteroaryl is substituted with -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -O-pentyl, or -O-hexyl. 1 is pyridyl substituted with -O-methyl, -O-ethyl, or -O-propyl. 1 is pyridyl substituted with -O-methyl. 1 is pyrazinyl substituted with -O-methyl, -O-ethyl, or -O-propyl. 1 is pyrazinyl substituted with -O-methyl.

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

[0079] In one embodiment, R 2 teeth, [ka] unsubstituted C selected from 3 -C 10 It is cycloalkyl.

[0080] In one embodiment, R 2 teeth, [ka] unsubstituted C selected from 3 -C 10It is cycloalkyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0109] In one embodiment, R 2 is not replaced [ka] It is.

[0110] In one embodiment, R 2 teeth [ka] and that is, (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, -O-CH 3 , and -OCH 2 CH 3 -C 1 -C 4 Alkyl It is substituted with 1 to 3 substituents selected from:

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

[0112] In one embodiment, R 2 teeth, [ka] and it is -CH 3 has been replaced with.

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

[0114] In one embodiment, R 2 is phenyl, which is (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, -O-CH 3 , and -OCH 2 CH 3 -C 1 -C 4 Alkyl It is substituted with 1 to 3 substituents selected from:

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

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

[0117] In one embodiment, R 2 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl and isoquinolyl, which is (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, -O-CH 3 , and -OCH 2 CH 3 -C 1 -C 4 Alkyl It is substituted with 1 to 3 substituents selected from:

[0118] In one embodiment, R 2 is a heteroaryl selected from pyridyl, oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, and pyridazinyl, which is (1) halogen; (2)-CN; (3) Independently, halogen, -CN, -OH, -O-CH 3 , and -OCH 2 CH 3 -C 1 -C 4 Alkyl It is substituted with 1 to 3 substituents selected from:

[0119] In one embodiment of Formula Ia, R 5 Each occurrence of is independently hydrogen, halogen, -C 1 -C 6 In one embodiment, n is selected from alkyl and -OH.

[0120] In one embodiment of Formula Ia, R 5 Each occurrence of is independently hydrogen, halogen, -CH 3 , -CH 2 CH 3 and -OH. In one embodiment, n is 1.

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

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

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

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

[0125] "C 1 -C 6The term "alkyl" includes linear alkyl having 1 to 6 carbon atoms and branched alkyl having 3 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-1-methylpropyl, and the like.

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

[0127] "C 3 -C 10 The term "cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having 3 to 10 carbons. "Cycloalkyl" also includes non-aromatic rings, as well as monocyclic non-aromatic rings fused to a saturated cycloalkyl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. Examples illustrated by structure include: [ka]

[0128] The term "heteroaryl" refers to a monocyclic or polycyclic, including bicyclic, aromatic heterocycloalkyl containing at least one ring heteroatom selected from O, S, and N. Examples of heteroaryl groups include pyridyl (pyridinyl), oxazolyl, azabenzothiazole, benzothiazole, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, and the like.

[0129] The term "heterocycloalkyl" refers to monocyclic or bicyclic or bridged partially unsaturated and saturated rings containing at least one heteroatom selected from N, S, and O, each of which has 3 to 10 atoms and where the point of attachment can be carbon or nitrogen. Examples include azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones or n-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through the nitrogen. The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. Examples illustrated by structure include: [ka]

[0130] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The salts of basic compounds included in the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothioate, lactate, lactobionate, laurate ... The preferred pharmaceutically acceptable salts include, but are not limited to, ammonium salts such as ammonium salts, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salts, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate. In addition, when the compound of the present invention contains 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, manganous, manganous, potassium, sodium, and zinc. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.Salts derived from pharma- ceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidinyl, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

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

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

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

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

[0135] The independent syntheses of these diastereomers or their chromatographic separation can be carried out according to methods known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry can be determined, if necessary, by X-ray crystallography of crystalline products or crystalline intermediates that have been derivatized with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. 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 diastereomeric mixture, 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 derivatives can then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixtures of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are known in the art.

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

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

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

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

[0140] In the compounds described herein, atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is intended to encompass all suitable isotopic variations of 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 predominant hydrogen isotope found in nature. Enriching with deuterium may confer certain therapeutic advantages, such as an increased half-life in vivo or reduced dosage requirements, or may provide compounds useful as standards for the characterization of biological samples. 3 H, 11 C. 18 F-labeled compounds can be used for PET or SPECT and other imaging studies. Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques well known to those of skill in the art, or by methods similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

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

[0142] Treatment method The compounds described herein may be particularly useful for preventing, treating, or ameliorating RIPK1-mediated diseases or disorders. Such RIPK1-mediated diseases or disorders may be controlled, at least in part, by programmed necrosis, apoptosis, or the production of inflammatory cytokines, and include, among others, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLEU), and other conditions that may be mediated by RIPK1-mediated disease or disorders. E), Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / disease (nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), kidney damage / failure (nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, e.g. systolic dysfunction, chronic kidney disease, chronic obstructive pulmonary disease, chronic myocardial infarction ... , 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 (asthma) and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-I converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic neoplasms, periodontitis, NEMO mutations (mutations in the NF-κB essential regulator gene (also known as IKK gamma or IKKG)), particularly NEMO deficiency syndrome,HOIL-1 deficiency (also known as RBCKI, heme-oxidizing IRP2 ubiquitin ligase 1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematopoietic and solid organ malignancies, bacterial and viral infections (influenza, staphylococcus, tuberculosis, etc.), and lysosomal storage diseases (especially Gaucher disease, GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, hyperchromatic osteodystrophy, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastasis, breast cancer, non-small cell lung cancer (NSCLC), radiation-induced necrosis, ischemic kidney injury, ophthalmic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure, and hearing disorders such as radiation protection / mitigation, noise-induced hearing loss, and drugs related to ototoxicity such as cisplatin, or ex vivo cell therapy to maintain vitality and function.

[0143] The compounds of the formulae described herein, or pharma- ceutically acceptable salts thereof, may be used to treat the following RIPK1 mediated diseases or disorders: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / disease (non-alcoholic), osteoarthritis, osteoporosis ... Nonalcoholic Steatohepatitis (NASH), Alcoholic Steatohepatitis (ASH), Autoimmune Hepatitis, Autoimmune Hepatobiliary Disease, Primary Sclerosing Cholangitis (PSC), Acetaminophen Toxicity, Hepatotoxicity), Nonalcoholic Steatohepatitis (NASH), Alcoholic Steatohepatitis (ASH), Autoimmune Hepatitis, Nonalcoholic Fatty Liver Disease (NAFLD), Kidney Damage / Injury (Nephritis, Kidney Transplant, Surgery, Administration of Nephrotoxic Drugs, e.g., Cisplatin, Acute Kidney Injury (AKI), Celiac Disease, Autoimmune Idiopathic Thrombocytopenic Purpura (Autoimmune ITP), Transplant Rejection (Rejection of Transplanted Organs, Tissues and Cells) , ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), arteriosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-I converting enzyme Inflammatory cell death syndrome (ICE, also known as caspase-1), chronic obstructive pulmonary disease (COPD), cigarette smoke-induced injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, melanoma, metastasis, breast cancer, non-small cell lung cancer (NSCLC), radiation-induced necrosis, ischemic kidney injury, ophthalmic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, periodontitis, NEMO mutations (mutations in the NF-κB essential regulator gene (also known as IKK gamma or IKKG)), especially NEMO deficiency syndrome, HOIL-1 deficiency ((also known as RBCKI) heme-oxidized IRP2 ubiquitin ligase 1 deficiency),Linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematopoietic and solid organ malignancies, bacterial and viral infections (influenza, staphylococcus, tuberculosis, etc.), and lysosomal storage diseases (especially Gaucher disease, GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acidosis, etc.) The compounds may be particularly useful in the treatment of conditions such as sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pigmented osteodysplasia, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease), spinal cord injury, Stevens-Johnson syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and / or ex vivo cell therapy to maintain vitality and function.

[0144] The compounds of the formulae described herein, or pharma- ceutically acceptable salts thereof, may be useful in the treatment of glaucoma.

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

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

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

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

[0149] The compounds of the present invention may be particularly useful in ameliorating injury or damage to solid organ tissues (particularly kidney, liver, heart and / or lung) after transplantation or administration of nephrotoxic drugs or substances such as cisplatin. It is understood that ameliorating such tissue damage can be achieved, if possible, by pre-treatment with a compound of the formulas described herein or a pharma- ceutically acceptable salt thereof, for example, by pre-treatment of the patient before administration of cisplatin, or pre-treatment of the organ or organ recipient before transplantation surgery. Ameliorating such tissue damage can be achieved by treatment with a compound of the formulas described herein or a pharma- ceutically acceptable salt thereof at the time of transplantation surgery.

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

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

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

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

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

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

[0156] In another embodiment, the compounds of the formulae described herein, or pharma- ceutically acceptable salts thereof, may be useful in 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 involve ameliorating organ injury or damage sustained as a result of these diseases / disorders. For example, the compounds described herein may be particularly useful in ameliorating brain tissue injury or damage following traumatic brain injury, or ameliorating brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

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

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

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

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

[0162] In another embodiment, the compounds of the formulae described herein or pharma- ceutically acceptable salts thereof may be useful in the treatment of cerebrovascular accidents (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, the compounds of the formulae described herein, or pharma- ceutically acceptable salts thereof, may be useful in the treatment of amyotrophic lateral sclerosis (ALS).

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

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

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

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

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

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

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

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

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

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

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

[0175] The compounds of the formulas described herein or pharma- ceutically acceptable salts thereof may be particularly useful for treating RIPK1-mediated cancer-related diseases or disorders. Gong et al., The role of necroptosis in cancer biology and therapy, Molecular Cancer (2019) 18:100. In one embodiment, the human has a solid tumor. In one embodiment, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung cancer (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one embodiment, the human has one or more of colorectal cancer (CRC), esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung cancer, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another embodiment, the human has a liquid tumor, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myelogenous leukemia.

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

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

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

[0179] Specific examples of hematological neoplasm-based clinical conditions include leukemias such as chronic myelogenous leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma and Hodgkin's lymphoma. Hematopoietic cancers also include lymphoid malignancies that may affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extra-lymphatic sites. Lymphoid cancers include B-cell malignancies, including but not limited to B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL may be low grade (or low grade), intermediate grade (or high grade), or high grade (highly aggressive). Low-grade B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) (including nodal MZL, extranodal MZL, splenic MZL, and splenic MZL with villous lymphocytes); lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt lymphoma (BL), Burkitt-like lymphoma, small noncleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocytic (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease.NHL can also include T-cell non-Hodgkin's lymphoma (T-NHL), which includes, but is not limited to, T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphopathy (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0180] Hematopoietic cancers also include Hodgkin lymphomas (or diseases) such as classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocytopenic Hodgkin lymphoma. Hematopoietic cancers also include multiple myeloma (MM), such as smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers can also include other cancers of additional hematopoietic cells, such as polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, red blood cells, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues such as the spleen, lymph nodes, mucosa-associated lymphoid tissues (such as gut-associated lymphoid tissue), tonsils, Peyer's patches and appendix, and other mucosa-associated lymphoid tissues such as the bronchial lining.

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

[0182] In the clinical use of the compounds described herein, the compounds are usually formulated into various preparations with pharma- ceutically acceptable additives according to the dosage form, and then can be administered. "Pharmaceutically acceptable" means that the additive, carrier, diluent or excipient must be compatible with other components of the preparation and not 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 esters, polysorbates, sucrose fatty acid esters, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, and hydroxypropylcyclodextrin.

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

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

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

[0186] When the compound of the present invention is used for the prevention or treatment of the above diseases, the dosage and the number of administrations can be varied according to the sex, age, weight and condition of the patient, as well as the type and extent of the intended therapeutic effect. In general, when administered orally, the dosage can be 0.001 to 50 mg / kg / day, which can be administered once or several times. In a specific embodiment, the dosage is about 0.01 to about 25 mg / kg / day, and in a particular embodiment, about 0.05 to about 10 mg / kg / day. When administered orally, the composition is preferably provided in the form of a tablet or capsule containing 0.01 mg to 1,000 mg. In specific embodiments, the 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 a compound described herein. This dosing regimen can be adjusted to provide the optimal therapeutic response.

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

[0188] The compounds of the present invention can be used in combination with one or more other drugs in the treatment, prevention, inhibition or amelioration of diseases or conditions for which the compounds described herein or other drugs may be useful, where the combination of drugs is safer or more effective than either drug alone. Thus, such other drugs can be administered simultaneously or sequentially with the compounds described herein or pharma- ceutically acceptable salts thereof, in amounts normally used. When the compounds described herein are used simultaneously with one or more other drugs, in specific embodiments, the pharmaceutical composition can include such other drugs and the compounds described herein or pharma- ceutically acceptable salts thereof in a unit dosage form. However, combination therapy can also include therapy in which the compounds described herein or pharma- ceutically acceptable salts thereof and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when each is used alone. Thus, pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds described herein or pharma- ceutically acceptable salts thereof. EXAMPLES

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

[0190] [Table 1] TIFF0007680639000064.tif116161

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

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

[0193] The two reactions were combined and worked up together. The mixture was washed with ice-H 2 O (25 L) and extracted with DCM (2 x 5.0 L) to give an organic layer. The organic layer was washed with saturated NaHCO 3 (15 L) and separated. The organic layer was then purified by flash silica gel chromatography (petroleum ether / ethyl acetate) to give 5-phenylpyrrolidin-2-one. 1 H NMR (400 MHz, CDCl 3 ) δ 7.28-7.41 (m, 5H), 6.11 (br, s, 1H), 4.78 (t, J = 7.2 Hz, 1H), 2.44-2.61 (m, 3H), 1.99-2.03 (m, 1H).

[0194] Step 2. Synthesis of 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole Five identical scale reactions were run in parallel. Trimethyloxonium tetrafluoroborate (109 g, 736 mmol) was dissolved in 5-phenylpyrrolidin-2-one (99.0 g, 614 mmol) and K 2 CO 3 (169 g, 1.23 mol) in DCM (990 mL) was added at 25-30 °C. The mixture was stirred at 25-30 °C for 12 h. The mixture was diluted with saturated NaHCO 3(5.0 L) and extracted with DCM (2 x 1.0 L) to give an organic layer. The organic layer was concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl) to give 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole. 1 H NMR (400 MHz, CDCl 3 ) 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 (4M, 180 mL) was added to a mixture of 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole (180 g, 1.03 mol) and compound methyl hydrazine carboxylate (97.1 g, 1.08 mol) in MeOH (1.8 L) at 25-30° C. The reaction was stirred at 80° C. for 3 h. Upon completion, the mixture was concentrated. The crude product was washed with MTBE (300 mL) to give methyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 1 H NMR (400 MHz, CD 3 OD) δ 7.33-7.40 (m, 5H), 5.07 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), 2.96-3.00 (m, 2H), 2.69-2.72 (m, 1H), 2.06-2.09 (m, 1H).

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

[0197] The compound 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (30.0 g, 149 mmol) was separated by preparative SFC (method column DAICEL AD; conditions MeOH / IPA) to give (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, the first eluting isomer and I-1A ((S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one), the second eluting isomer.

[0198] (R)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 HNMR (400 MHz, CD 3 OD) 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, CD 3 OD) δ 7.22-7.39 (m, 5H), 5.23 (dd, J = 8.0, 4.4 Hz, 1H), 2.92-3.06 (m, 1H), 2.82-2.90 (m, 2H), 2.40-2.42 (m, 1H).

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

[0200] Step 1. Synthesis of 5-(3,5-difluorophenyl)pyrrolidin-2-one To a solution of 1-bromo-3,5-difluorobenzene (906 g, 469 mmol) in THF (6.75 L) was added i-PrMgCl·LiCl (6 L) at 0 °C and the reaction was stirred at 50 °C for 1 h. To the mixture was then added succinimide (310 g, 313 mmol) and DCM (300 mL) at -78 °C. The mixture was stirred at 25 °C for 16 h. The mixture was added with NaBH 3 CN (236 g, 3750 mmol) was added at 25° C., and the mixture was then stirred at 25° C. for 1 h. The reaction was acidified to pH=3-4 with HCl (6 M), stirred for 30 min, and neutralized with aqueous NaOH (3 M). The mixture was quenched with water (5000 mL) and extracted with DCM (3×5000 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (hexanes / ethyl acetate) to give 5-(3,5-difluorophenyl)pyrrolidin-2-one. 10 H 10 F 2 NO[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 diluted with saturated NaHCO 3The reaction was quenched with aqueous solution (3000 mL) and extracted with DCM (3 x 2000 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(3,5-difluorocyclohexyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly in the next step. 11 H 12 F 2 NO[M+H] + Calculated value: 212; measured value: 212.

[0202] Step 3. Synthesis of N'-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide To a solution of 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (185 g, 876 mmol) in MeOH (2000 mL) was added hydrazine carboxylic acid methyl ester (103 g, 1140 mmol) and HCl / MeOH (240 mL, 4.0 M). The mixture was stirred at 80° C. for 3 h. The mixture was purified by flash silica gel chromatography (EtOAc / MeOH) to give N′-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide. 12 H 14 F 2 N 3 O 2 [M+H] + Calculated value: 270; Actual value: 270.

[0203] Steps 4-5. Synthesis of 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one and subsequent SFC to obtain I-2A A solution of N'-[5-(3,5-difluorophenyl)-4,5-dihydro-3H-pyrrol-2-yl]methoxycarbohydrazide (161 g) in DMF (1600 mL) was stirred at 145 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude product, which was then separated into CH 35-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (75 g) was obtained as a slurry with CN / PE (3:5). The compound 5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (75 g, 316 mmol, 1.00 equiv.) was separated by preparative SFC (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 eluting isomer, and I-2A, ((5S)-5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (25.7 g), the second eluting isomer.

[0204] (5R)-5-(3,5-difluorophenyl)-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -109.22. C 11 H 10 F 2 N 3 O[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): 1 H NMR (300 MHz, DMSO-d 6) δ 11.32 (s, 1H), 7.20 (tt, J = 9.3, 2.4 Hz, 1H), 7.10 - 6.96 (m, 2H), 5.20 (dd, J = 8.0, 4.8 Hz, 1H), 3.06 - 2.72 (m, 3H), 2.39 - 2.23 (m, 1H). 19 F NMR (282 MHz, DMSO-d 6 ) δ -109.22.C 11 H 10 F 2 N 3 O[M+H] + Calculated value: 238; Measured value: 238.

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

[0207] Step 1. Synthesis of ethyl 4-(2-fluorophenyl)-4-oxobutanoate To a stirred solution of 1-(2-fluorophenyl)ethan-1-one (10.0 g, 72.4 mmol) in THF (150 mL) and DMPU (50 mL, 72.4 mmol) was added LiHMDS (72.4 mL, 72.4 mmol) (1 M solution in THF) at approximately -60°C (dry ice-acetone bath). After the addition was complete, the reaction was stirred at -60°C for 30 min. Ethyl 2-bromoacetate (12.7 g, 76 mmol) was then added in one portion to the mixture at -60°C. The resulting mixture was stirred continuously at -60°C for an additional 30 min. The reaction was allowed to warm to room temperature and stirred at room temperature for 2 h. The mixture was diluted with tert-butyl methyl ether (300 mL) and washed with saturated NH 4 The reaction was quenched with aqueous Cl (250 mL). The mixture was extracted with tert-butyl methyl ether (2 x 300 mL). The combined organic portions were washed with brine (200 mL) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give ethyl 4-(2-fluorophenyl)-4-oxobutanoate. 12 H 14 FO 3 [M+H] + Calculated value: 225; Measured value: 225.

[0208] Step 2. Synthesis of 5-(2-fluorophenyl)pyrrolidin-2-one To a solution of methyl 4-(2-fluorophenyl)-4-oxobutanoate (5 g, 23.8 mmol) in MeOH (100 mL) was added ammonium acetate (5.50 g, 71.4 mmol) and sodium cyanotrihydroborate (3.74 g, 59.5 mmol) at room temperature. The mixture was then stirred at 80° C. for 12 h. The reaction mixture was quenched with HCl (2 M, ca. 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; Actual value: 180.

[0209] Step 3. Synthesis of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A mixture of 5-(2-fluorophenyl)pyrrolidin-2-one (2.0 g, 11.2 mmol) and trimethyloxonium tetrafluoroborate (2.15 g, 14.5 mmol) in DCM (50 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with saturated NaHCO 3 (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 13 FNO[M+H] + Calculated value: 194; Measured value: 194.

[0210] Step 4. Synthesis of methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a stirred solution of 2-(2-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.0 g, 10.4 mmol) in MeOH (20 mL) was added methyl hydrazine carboxylate (1.21 g, 13.5 mmol) at 20° C. until the addition was complete. The reaction was stirred at 80° C. for 2 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. 12 H 15 FN 3 O 2 [M+H] + Calculated value: 252; measured value: 252.

[0211] Step 5-6. Synthesis of 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one and isolation of I-3A by chiral separation A stirred solution of methyl 2-(2-(2-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (450 mg, 1.80 mmol) in DMF (30 mL) was diluted with N 2 Heat to 145°C under atmosphere and stir at 145°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method: Column Boston Green ODS 150 x 30 mm x 5 μm; Condition: Water (0.1% TFA)-MeCN) to give 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. The racemic mixture of 5-(2-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (320 mg, 1.46 mmol) was purified by SFC (Method: Column (S,S) WHELK-O1 (250 mm x 30 mm, 5 μm); Condition: 0.1% NH 3 H 2Separation by elution with 0.05% hexane / EtOH gave (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 (400MHz, CD 3 OD) 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): 1 H NMR (400MHz, CD 3 OD) δ 7.37 - 7.36 (m, 1H), 7.22 - 7.11 (m, 3H), 5.45 - 5.42 (m, 1H), 3.13 - 3.09 (m, 1H), 2.98 - 2.85 (m, 2H), 2.46 - 2.44 (m, 1H).

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

[0214] Step 1. Preparation of 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid To a solution of 3-bromo-5-fluoropyridine (40 g, 227 mmol) in THF (250 mL) was added iPrMgCl·LiCl (1.3 M in THF) (192 mL, 250 mmol) at 0 °C for 2 h. The mixture was then added to a solution of dihydrofuran-2,5-dione (27.3 g, 273 mmol) in THF (450 mL) at -20 °C, and the resulting mixture was stirred at -20 °C for 3 h. The reaction mixture was diluted with saturated NH 4 Cl (200 mL) and aqueous NaOH (2 M) were added until pH 11. After stirring for 30 min, the reaction was extracted with EtOAc (100 mL) and the aqueous layer was added HCl (2 M) until pH 5, then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 4° C., filtered and concentrated to give 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid, which was used in the next step without further purification.

[0215] Step 2. Preparation of methyl 4-(5-fluoropyridin-3-yl)-4-oxobutanoate To a solution of 4-(5-fluoropyridin-3-yl)-4-oxobutanoic acid (34 g, 172 mmol) in MeOH (300 mL), 2 SO 4 (12 mL, 225 mmol) was added and the resulting mixture was stirred at 70° C. for 12 h. The mixture was directly concentrated. The residue was dissolved in DCM (100 mL), water (50 mL) and saturated NaHCO 3 was added until the pH was about 8 and extracted with DCM (3 x 100 mL). The combined organic layers were washed with Na 2 SO 4 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, CDCl 3) 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) was added ammonium acetate (9.85 g, 128 mmol), NaBH 3 CN (8.03 g, 128 mmol) was added and the mixture was stirred for 12 h at 80° C. 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, CD 3 OD) δ 8.35-8.46 (m, 2H), 7.66 (td, J = 2.0, 9.6 Hz, 1H), 4.90-4.94 (m, 1H), 2.60-2.74 (m, 1H), 2.43-2.50 (m, 2H), 1.91-2.03 (m, 1H).

[0217] Step 4. Preparation of 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione To a solution of 5-(5-fluoropyridin-3-yl)pyrrolidin-2-one (4.1 g, 22.75 mmol) in toluene (40 mL) was added Lawesson's reagent (4.60 g, 11.4 mmol) and the resulting mixture was stirred for 12 h at 110° C. The reaction solution was directly concentrated and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione. 1 H NMR (400 MHz, CD 3OD) δ 8.46 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 7.64 (td, J = 2.0, 9.2 Hz, 1H), 5.16 (t, J = 7.2 Hz, 1H), 2.88-3.09 (m, 2H), 2.72 (dtd, J = 5.6, 8.4, 13.25 Hz, 1H), 2.03-2.14 (m, 1H).

[0218] Step 5. Preparation of 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine To a solution of 5-(5-fluoropyridin-3-yl)pyrrolidine-2-thione (4.0 g, 20.4 mmol) in THF (70 mL) was added MeI (1.91 mL, 30.6 mmol), and the resulting mixture was stirred at 20° C. for 12 h. The reaction solution was concentrated. The residue was dissolved in saturated NaHCO 3 (40 mL) and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with Na 2 SO 4 Drying at 40° C., filtration and concentration afforded 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine which was used in the next step without further purification.

[0219] Step 6. Preparation of methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 3-fluoro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (3.8 g, 18.1 mmol) in MeOH (60 mL) was added methyl hydrazine carboxylate (2.44 g, 27.1 mmol) and the resulting mixture was stirred at 80° C. for 5 h. The reaction solution was directly concentrated and the residue was purified by flash silica gel chromatography (MeOH / DCM) to give methyl 2-(2-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 11 H NMR (400 MHz, CDCl 3) 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, CD 3 OD) δ 8.46 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 7.64 (td, J = 2.0, 9.2 Hz, 1H), 5.34 (dd, J = 5.6, 8.0 Hz, 1H), 3.06-3.18 (m, 1H), 2.93-3.03 (m, 1H), 2.83-2.93 (m, 1H), 2.53 - 2.47 (m, 1H).

[0221] Step 8. Obtaining I-4A by chiral separation 5-(5-Fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1.8 g, 8.17 mmol) The mixture of enantiomers was purified by chiral-SFC (Method: Column DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm)); Conditions: 0.1% NH 3 H 2O / EtOH) to give (R)-5-(5-fluoropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (806 mg) (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, CD 3 OD) 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): 1 H NMR (500 MHz, CD 3 OD) δ 8.45 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 7.63 (td, J = 2.0, 9.5 Hz, 1H), 5.34 (dd, J = 5.5, 8.0 Hz, 1H), 3.12 (dddd, J = 5.5, 8.0, 9.0, 13.47 Hz, 1H), 2.94-3.02 (m, 1H), 2.84-2.92 (m, 1H), 2.50 (tdd, J = 6.0, 9.0, 13.5 Hz, 1H).

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

[0224] Step 1. Preparation of 5-(3-fluorophenyl)pyrrolidin-2-one (3-Fluorophenyl)magnesium bromide (323 mL, 323 mmol) was dissolved in N 2 Pyrrolidine-2,5-dione (16 g, 161 mmol) was added dropwise via syringe at −78° C. After the addition was complete, the reaction was warmed to 25° C. and allowed to react for an additional 16 hours. NaBH 3 CN (10.2 g, 161 mmol) was added to the mixture and reacted for another 3 h. 6M HCl was added and the pH was adjusted to 3. It was reacted for another 1 h. Aqueous NaOH was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (hexanes / ethyl acetate) to give 5-(3-fluorophenyl)pyrrolidin-2-one. 10 H 11 FNO[M+H] + Calculated value: 180; Actual value: 180.

[0225] Step 2. Preparation of 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A mixture of 5-(3-fluorophenyl)pyrrolidin-2-one (10 g, 55.8 mmol) and trimethyloxonium tetrafluoroborate (10.7 g, 72.5 mmol) in DCM (100 mL) was stirred at 25° C. for 16 h to give a brown mixture. 3 The pH was adjusted to neutral by adding aqueous solution. The organic layer was separated and the aqueous solution was re-extracted with DCM (3×30 mL), and the combined organic layers were washed with brine (2×30 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give crude 2-(3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly. 11 H 13 FNO[M+H] +Calculated value: 194; Measured value: 194.

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

[0227] Step 4. Preparation of 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one A mixture of methyl 2-(2-(3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.3 g, 5.17 mmol) in DMF (100 mL) was diluted with N 2 The mixture was stirred at 145° C. for 3 hours under reduced pressure. The reaction mixture was then concentrated to give a solid. The solid was suspended in EtOAc and the cloudy liquid was filtered and concentrated to give 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 11 FN 3 O[M+H] + Calculated value: 220; measured value: 220.

[0228] Step 5. Preparation of 5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 5-(3-Fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (3.7 g, 16.9 mmol) was purified by SFC (Method: Column DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 μm); Conditions: 0.1% NH 3 H 2 C.O / EtOH) to give (R)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (ee=99.6%) and I-5A ((S)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (ee=98.9%).

[0229] (R)-5-(3-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one 1 H NMR (400MHz, CD 3 OD) 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 H NMR (400MHz, CD 3 OD) δ 7.32-7.43 (m, 1H), 6.96-7.07 (m, 3H), 5.23 (dd, J = 4.4, 8.0 Hz, 1H), 3.00-3.11 (m, 1H), 2.86-2.95 (m, 1H), 2.76-2.85 (m, 1H), 2.34-2.46 (m, 1H).

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

[0231] Step 1. Preparation of 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid Isopropylmagnesium chloride (48.0 mL, 52.0 mmol) was added via syringe over 5 min at 0° C. to a solution of 3-bromo-5-chloropyridine (10 g, 52.0 mmol) in THF (100 mL). After stirring for 1 h, this mixture was added via cannula over a period of 30 min at −20° C. to a solution of dihydrofuran-2,5-dione (6.76 g, 67.6 mmol) in THF (100 mL), then stirred at −20° C. for 3 h. 3 The pH was adjusted to about 9 by slow addition of aq. The aqueous layer was acidified with aqueous HCl and extracted with EtOAc (5 x 100 mL). The combined organic layers were diluted with NaSO 4 The crude product, 4-(5-chloropyridin-3-yl)-4-oxobutanoic acid, was obtained after drying at 4°C and concentration. 9 H 9 ClNO 3 [M+H] + Calculated value: 214; Measured value: 214.

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

[0233] Step 3. Preparation of 5-(5-chloropyridin-3-yl)pyrrolidin-2-one A solution of methyl 4-(5-chloropyridin-3-yl)-4-oxobutanoate (3.4 g, 14.9 mmol) in MeOH (50 mL) was added with ammonium acetate (3.45 g, 44.8 mmol), NaBH 3 CN (2.82 g, 44.8 mmol) was added and the mixture was stirred at 80° C. for 12 h. The combined aqueous layers were extracted with DCM (4×30 mL) to remove neutral impurities. The combined organic layers were washed with Na 2 SO 4 The organic layer was concentrated and the residue was purified by flash silica gel chromatography (EtOAc / EtOH) to give 5-(5-chloropyridin-3-yl)pyrrolidin-2-one. 9 H 10 ClN 2 O[M+H] + Calculated value: 197; Measured value: 197.

[0234] Step 4. Preparation of 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione To a solution of 5-(5-chloropyridin-3-yl)pyrrolidin-2-one (700 mg, 3.56 mmol) in toluene (15 mL) was added Lawesson's reagent (720 mg, 1.78 mmol) and the resulting mixture was stirred at 110° C. for 12 h. The reaction solution was directly concentrated and the residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione. 9 H 10 ClN 2 S[M+H] + Calculated value: 213; Measured value: 213.

[0235] Step 5. Preparation of 3-chloro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine To a solution of 5-(5-chloropyridin-3-yl)pyrrolidine-2-thione (1.45 g, 6.82 mmol) in THF (20 mL) was added iodomethane (1.20 mL, 19.2 mmol) and the resulting mixture was stirred at 20° C. for 12 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. 10 H 12 ClN 2 S[M+H] + Calculated value: 227; Measured value: 227.

[0236] Step 6. Preparation of methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 3-chloro-5-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyridine (1.3 g, 5.73 mmol) in MeOH (15 mL) was added methyl hydrazine carboxylate (0.775 g, 8.60 mmol) and the resulting mixture was stirred at 80° C. for 5 h. The reaction solution was directly concentrated and the residue was purified by flash silica gel chromatography (EtOAc / EtOH) to give methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 11 H 14 ClN 4 O 2 [M+H] + Calculated value: 269; Measured value: 269.

[0237] Step 7. Preparation of 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one A solution of methyl 2-(2-(5-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.1 g, 4.09 mmol) in DMF (50 mL) was stirred at 145° C. for 12 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 H10 ClN 4 O[M+H] + Calculated value: 237; Measured value: 237.

[0238] Step 8. Obtaining I-6A by chiral separation The mixture of 5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (700 mg, 2.96 mmol) enantiomers was purified by chiral-SFC (method: column DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); conditions: 0.1% NH 3 H 2 O / 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 (400MHz, CD 3 OD) δ = 8.54 (d, J=2.3 Hz, 1H), 8.47 (d, J=1.9 Hz, 1H), 7.86 (t, J=2.1 Hz, 1H), 5.31 (dd, J=5.6, 8.1 Hz, 1H), 3.19 - 3.05 (m, 1H), 3.04 - 2.82 (m, 2H), 2.50 (tdd, J=6.1, 9.0, 13.2 Hz, 1H). (R)-5-(5-chloropyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H NMR (400MHz, CD 3OD) δ = 8.54 (d, J=2.3 Hz, 1H), 8.47 (d, J=1.9 Hz, 1H), 7.86 (t, J=2.1 Hz, 1H), 5.31 (dd, J=5.7, 8.0 Hz, 1H), 3.19 - 3.05 (m, 1H), 3.04 - 2.82 (m, 2H), 2.57 - 2.44 (m, 1H).

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

[0241] Step 1. Preparation of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate CH of methyl 5-oxopyrrolidine-2-carboxylate (50 g, 349 mmol) 2 Cl 2 To a solution in (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 diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (400 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., 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. 7 H 12 NO 3 [M+H] + Calculated value: 158; Measured value: 158.

[0242] Step 2. Preparation of methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate To a solution of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (55 g, 350 mmol) in MeOH (800 mL) was added methyl hydrazine carboxylate (47.3 g, 525 mmol) and HCl / MeOH (4 M) (50 mL) at 20° C., and the resulting mixture was stirred at 80° C. for 4 h. The reaction was directly concentrated, and the residue was slurried with ethyl acetate and MeOH to give methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. 8 H 14 N 3 O 4 [M+H] + Calculated value: 216; Measured value: 216. 1 H NMR (400 MHz, CD 3 OD) δ 4.73 (dd, J = 4.8, 9.2 Hz, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 2.99-3.09 (m, 2H), 2.68 (qd, J = 8.8, 13.2 Hz, 1H), 2.35-2.43 (m, 1H).

[0243] Step 3. Preparation of I-7A (Methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate) To a solution of methyl 5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (20.0 g, 93.0 mmol) in MeOH (400 mL) was added sodium methanolate (15.1 g, 279 mmol) and the resulting mixture was stirred at 80° C. for 8 h. HCl (4.0 M in MeOH) was added to the reaction until pH ∼5 and stirred at 80° C. for 2 h. The solids were filtered and the filtrate was purified by flash silica gel chromatography (MeOH / DCM) to give methyl 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate. 7 H 10 N 3 O 3 [M+H] + Calculated value: 184; Measured value: 184. 1 H NMR (400 MHz, CD 3OD) δ 4.74 (dd, J = 3.2, 9.2 Hz, 1H), 3.80 (s, 3H), 2.93-3.05 (m, 1H), 2.75-2.88 (m, 2H), 2.57-2.67 (m, 1H).

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

[0245] Step 1-2. Preparation of 5-(4-fluorophenyl)pyrrolidin-2-one (4-Fluorophenyl)magnesium bromide in THF (404 mL, 404 mmol) was heated at -78 °C with N 2 Pyrrolidine-2,5-dione (20 g, 202 mmol) was added dropwise via syringe. After the addition was complete, the reaction was warmed to 25° C. and allowed to react for an additional 2.5 hours. NaBH 3 CN (12.68 g, 202 mmol) was added to the mixture and reacted for an additional 16 h. HCl (6 M aqueous solution) was added to adjust the pH to 3. The reaction was stirred for an additional 1 h. NaOH (25 mL EtOH + 5 mL water) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(4-fluorophenyl)pyrrolidin-2-one. 10 H 11 FNO[M+H] + Calculated value: 180; Actual value: 180. 1 H NMR (400MHz, CDCl 3) δ 7.31 - 7.24 (m, 2H), 7.10 - 7.02 (m, 2H), 6.30 (br s, 1H), 4.75 (t, J = 7.1 Hz, 1H), 2.65 - 2.34 (m, 3H), 2.01 - 1.86 (m, 1H).

[0246] Step 3. Preparation of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A mixture of 5-(4-fluorophenyl)pyrrolidin-2-one (3.2 g, 17.9 mmol) and trimethyloxonium tetrafluoroborate (3.43 g, 23.2 mmol) in DCM (10 mL) was stirred at 25° C. for 16 h. The residue was washed with saturated NaHCO 3 The mixture was diluted with a mixture of aqueous (10 mL) and DCM (10 mL). The organic layer was separated, the aqueous layer was re-extracted with DCM (3 x 10 mL), and the combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used directly in the next step without further purification. 11 H 13 FNO[M+H] + Calculated value: 194; Measured value: 194.

[0247] Step 4. Preparation of methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate A mixture of 2-(4-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.9 g, crude) and methyl hydrazine carboxylate (1.76 g, 19.51 mmol) in MeOH (32 mL) and HCl (4 M in 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. 12 H 15 FN 3 O 2 [M+H] + Calculated value: 252; measured value: 252. 1H NMR (500MHz, DMSO-d 6 ) δ 8.85 (br s, 1H), 7.45 - 7.28 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 7.02 (br s, 1H), 3.57 (s, 3H), 3.33 (br s, 1H), 2.48 - 2.39 (m, 2H), 2.37 - 2.28 (m, 1H), 2.37 - 2.28 (m, 1H), 1.76 - 1.58 (m, 1H).

[0248] Step 5. Preparation of 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one A mixture of methyl 2-(2-(4-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (2.2 g, 8.76 mmol) in DMF (100 mL) was stirred at 145° C. for 16 h. The solvent was evaporated and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 11 FN 3 O[M+H] + Calculated value: 220; measured value: 220. 1 H NMR (500MHz, DMSO-d 6 ) δ 11.26 (s, 1H), 7.35 - 7.26 (m, 2H), 7.24 - 7.14 (m, 2H), 5.17 (dd, J = 4.5, 8.2 Hz, 1H), 3.00 - 2.88 (m, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.68 (m, 1H), 2.31 - 2.21 (m, 1H).

[0249] Step 6. Chiral SFC to obtain (S)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-8A) 5-(4-Fluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (2.5 g, 11.40 mmol) was subjected to SFC (Method: Column DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 μm); Conditions: 0.1% NH 3 H 2 0 / EtOH) to give (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 eluting 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 eluting 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-d 6 ) 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-d 6 ) δ 11.26 (s, 1 H) 7.26 - 7.32 (m, 2 H) 7.17 - 7.23 (m, 2 H) 5.17 (dd, J = 8.09, 4.58 Hz, 1 H) 2.90 - 2.99 (m, 1 H) 2.78 - 2.87 (m, 1 H) 2.69 - 2.77 (m, 1 H) 2.26 (qd, J = 8.90, 5.04 Hz, 1 H).

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

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

[0253] Step 2. Preparation of 5-(2,6-difluorophenyl)pyrrolidin-2-one To a solution of ethyl 4-(2,6-difluorophenyl)-4-oxobutanoate (2.8 g, 11.6 mmol) in EtOH (20 mL) was added ammonium acetate (13.4 g, 173 mmol), sodium cyanoborohydride (1.45 g, 23.1 mmol) and the reaction 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 (3×50 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(2,6-difluorophenyl)pyrrolidin-2-one. 10 H 10 F 2 NO[M+H] + Calculated value: 198; Measured value: 198.

[0254] Step 3. Preparation of 2-(2,6-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-(2,6-difluorophenyl)pyrrolidin-2-one (1.8 g, 9.13 mmol) in DCM (50 mL) was added at 0° C. with N 2 Trimethyloxonium tetrafluoroborate (2.03 g, 13.7 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(2,6-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 F 2 NO[M+H] + Calculated value: 212; Measured value: 212.

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

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

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

[0258] Step 1. Preparation of 5-(3,4-difluorophenyl)pyrrolidin-2-one A solution of (3,4-difluorophenyl)magnesium bromide (60.6 mL, 30.3 mmol) in THF (15 mL) was cooled to -78 °C with N 2 Isopropylmagnesium chloride lithium chloride complex solution (17.47 mL, 22.71 mmol) was added under reduced pressure. The reaction mixture was then stirred at -78°C for 1 h. Another solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (50 mL) was added at -78°C with N 2 The mixture was stirred at 25° C. for 16 hours. The mixture was then added with NaBH 3 CN (1.74 g, 27.8 mmol) was added and the mixture was stirred at 25° C. for 1 h. The reaction was acidified with HCl (6 M aq.) to pH=3-4, the resulting mixture was stirred for 1 h, and neutralized with NaOH (4 M aq.). The mixture was quenched with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to give 5-(3,4-difluorophenyl)pyrrolidin-2-one. 10 H 10 F 2 NO[M+H] +Calculated value: 198; Measured value: 198. 1 H NMR (400 MHz, CD 3 OD) δ 7.20-7.32 (m, 2H), 7.14 (ddd, J = 4.0 Hz, 1H), 4.79 (t, J = 7.6 Hz, 1H), 2.53-2.66 (m, 1H), 2.38-2.47 (m, 2H), 1.85-1.97 (m, 1H).

[0259] Step 2. Preparation of 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-(3,4-difluorophenyl)pyrrolidin-2-one (1 g, 5.07 mmol) in DCM (10 mL) was added at 0° C. with N 2 Trimethyloxonium tetrafluoroborate (1.13 g, 7.61 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 F 2 NO[M+H] + Calculated value: 212; Measured value: 212.

[0260] Step 3. Preparation of methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(3,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (1 g, 4.73 mmol) in MeOH (10 mL) was added methyl hydrazine carboxylate (0.448 g, 4.97 mmol) and HCl (2 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was stirred at 80° C. for 12 h. The reaction was directly concentrated, and the residue was purified by recrystallization to give methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 14 F2 N 3 O 2 [M+H] + Calculated value: 270; Actual value: 270. 1 H NMR (400 MHz, CD 3 OD) 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] Phase 4. Construction of I-10A To a solution of methyl 2-(2-(3,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.1 g, 4.09 mmol) in MeOH (20 mL) was added sodium methoxide (0.662 g, 12.3 mmol) and the resulting mixture was stirred at 80° C. for 8 h. The mixture was cooled to room temperature and acidified to pH=7 with HCl (4 M in MeOH). The mixture was then filtered and the solid was dried by distillation under reduced pressure to give 5-(3,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 10 F 2 N 3 O[M+H] + Calculated value: 238; Measured value: 238. 11 H NMR (500 MHz, CD 3 OD) δ 7.20-7.32 (m, 2H), 7.09 (ddd, J = 4.5 Hz, 1H), 5.22 (dd, J = 5.5 Hz, 1H), 3.02-3.13 (m, 1H), 2.90-2.98 (m, 1H), 2.79-2.88 (m, 1H), 2.43 (tdd, J = 13.5 Hz, 1H), 1.90-2.08 (m, 1H).

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

[0263] Step 1. Preparation of 5-(4-chlorophenyl)pyrrolidin-2-one A solution of (4-chlorophenyl)magnesium bromide (60.6 mL, 60.6 mmol) in THF (200 mL) was added to 10 mL of THF at 0 °C with N 2 The isopropylmagnesium chloride-lithium chloride complex solution (34.9 mL, 45.4 mmol) was added to the reaction mixture and stirred at 0° C. for 1 h. The mixture was then added to a solution of pyrrolidine-2,5-dione (5 g, 50.5 mmol) in THF (100 mL) at -78° C. with N 2 The mixture was stirred at 25° C. for 16 hours. The mixture was then added with NaBH 3 CN (3.49 g, 55.5 mmol) was added and the mixture was stirred at 25° C. for 1 h. The reaction was acidified with HCl (6 M aq.) to pH=3-4, the resulting mixture was stirred for 1 h, and neutralized with NaOH (4 M aq.). The mixture was quenched with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with Na 2 SO 4 After drying at 40° C., filtering, and concentrating in vacuo, the residue was purified by flash silica gel chromatography (EtOAc) to give 5-(4-chlorophenyl)pyrrolidin-2-one. 1 H NMR (CDCl 3 , 400MHz) δ 7.31-7.37 (m, 2H), 7.20-7.26 (m, 2H), 4.73 (t, J = 7.2 Hz, 1H), 2.49-2.62 (m, 1H), 2.30-2.46 (m, 2H), 1.83-1.98 ppm (m, 1H).

[0264] Step 2. Preparation of 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-(4-chlorophenyl)pyrrolidin-2-one (12 g, 61.3 mmol) in DCM (300 mL) was added at 0° C. with N2 Trimethyloxonium tetrafluoroborate (13.6 g, 92 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 13 ClNO[M+H] + Calculated value: 210; measured value: 210.

[0265] Step 3. Preparation of methyl 2-(2-(4-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(4-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (6 g, 28.6 mmol) in MeOH (200 mL) was added methyl hydrazine carboxylate (3.35 g, 37.2 mmol) and HCl (15 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was cooled to 10° C. with N 2 The mixture was stirred at 80° C. for 6 h under reduced pressure. The mixture was concentrated under reduced pressure, and the residue was then washed with EtOAc / PE (1:1) to give methyl 2-(2-(4-chlorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 15 ClN 3 O 2 [M+H] + Calculated value: 268; Measured value: 268.

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

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

[0268] Step 1. Preparation of ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate To a stirred solution of 1-(2,4-difluorophenyl)ethan-1-one (10 g, 64.0 mmol) in THF (300 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (16.4 g, 128 mmol) at -78 °C was added lithium bis(trimethylsilyl)amide (64.0 mL, 64.0 mmol, 1 M solution in THF). After the addition was complete, the reaction was stirred at -78 °C for 30 min. Then, 2-bromoethyl acetate (7.46 mL, 67.3 mmol) was added in one portion at -78 °C. After the addition was complete, the reaction was stirred at 20 °C for 2 h. The mixture was diluted with tert-butyl methyl ether (200 mL) and washed with saturated NH 4 The reaction was quenched with aqueous Cl (200 mL). The mixture was extracted with tert-butyl methyl ether (2 x 200 mL). The combined organic portions were washed with brine (200 mL) and anhydrous Na 2 SO4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate. 12 H 13 F 2 O 3 [M+H] + Calculated value: 243; Measured value: 243.

[0269] Step 2. Preparation of 5-(2,4-difluorophenyl)pyrrolidin-2-one To a solution of ethyl 4-(2,4-difluorophenyl)-4-oxobutanoate (2.5 g, 10.3 mmol) in EtOH (100 mL) was added ammonium acetate (11.9 g, 155 mmol), sodium cyanoborohydride (1.30 g, 20.6 mmol) and the reaction mixture was stirred at 90° C. for 12 h. 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) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(2,4-difluorophenyl)pyrrolidin-2-one. 10 H 10 F 2 NO[M+H] + Calculated value: 198; Measured value: 198.

[0270] Step 3. Preparation of 2-(2,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-(2,4-difluorophenyl)pyrrolidin-2-one (2 g, 10.1 mmol) in DCM (50 mL) was added at 0 °C with N 2 Trimethyloxonium tetrafluoroborate (2.25 g, 15.21 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(2,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 F 2 NO[M+H] + Calculated value: 212; measured value: 212.

[0271] Step 4. Preparation of methyl 2-(2-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(2,4-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2 g, 9.47 mmol) in MeOH (50 mL) was added methyl hydrazine carboxylate (0.896 g, 9.94 mmol) and HCl (1 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was cooled to 10° C. with N 2 The mixture was stirred at 80° C. for 3 h under reduced pressure. The mixture was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give methyl 2-(2-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 14 F 2 N 3 O 2 [M+H] + Calculated value: 270; Actual value: 270.

[0272] Step 5. Preparation of 5-(2,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-12A) To a solution of methyl 2-(2-(2,4-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (900 mg, 3.34 mmol) in MeOH (20 mL), sodium methoxide (542 mg, 10.0 mmol) was added 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; condition: water (TFA)-ACN) to give 5-(2,4-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 10 F2 N 3 O[M+H] + Calculated value: 238; Measured value: 238.

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

[0274] Step 1. Preparation of 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one First, a solution of 1-bromo-3-(trifluoromethyl)benzene (4.54 g, 20.2 mmol) in THF (40 mL) was added to the flask at 0 °C with N 2 i-PrMgCl LiCl (21.7 mL, 28.3 mmol) was added under reduced pressure. The reaction was then 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 at 0 °C with N 2 i-PrMgCl LiCl (14.0 mL, 18.2 mmol) was added 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. The mixture was then added with NaBH 3 CN (1.40 g, 22.2 mmol) was added and the mixture was stirred at 25° C. for 1 h. The reaction was acidified to pH=3-4 with HCl (6 M aq.), stirred for 1 h, and made basic with NaOH (4 M aq.). The mixture was quenched with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one. 11 H 11 F 3 NO[M+H] + Calculated value: 230; Actual value: 230. 1H NMR (500 MHz, CDCl 3 ) δ 7.43-7.63 (m, 4H), 4.83 (t, J=7.17 Hz, 1H), 2.56-2.68 (m, 1H), 2.38-2.50 (m, 2H), 1.90-2.00 (m, 1H).

[0275] Step 2. Preparation of 5-methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole A solution of 5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one (2.1 g, 9.16 mmol) in DCM (40 mL) was added at 0 °C with N 2 Trimethyloxonium tetrafluoroborate (2.03 g, 13.7 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (80 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 5-methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 13 F 3 NO[M+H] + Calculated value: 244; Actual value: 244.

[0276] Step 3. Preparation of methyl 2-(2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-methoxy-2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole (2 g, 8.22 mmol) in MeOH (40 mL) at 20° C. was added methyl hydrazine carboxylate (0.815 g, 9.04 mmol), 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 / hexanes) to give methyl 2-(2-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 15 F 3 N 3 O 2[M+H] + Calculated value: 302; Actual value: 302.

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

[0278] Step 5. Chiral separation for the isolation of (S)-5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (I-13A) The racemic mixture of 5-(3-(trifluoromethyl)phenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (900 mg, 3.34 mmol) was subjected to chiral-SFC (method: column DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); conditions: 0.1% NH 3 H 2O / IPA) to give (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 eluting 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 eluting 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 F 3 N 3 O[M+H] + Calculated value: 270; Actual 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 F 3 N 3 O[M+H] + Calculated value: 270; Actual value: 270.

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

[0281] Step 1. Preparation of 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one First, a solution of 1-bromo-4-(trifluoromethyl)benzene (9.08 g, 40.4 mmol) in THF (70 mL) was added to the flask at 0 °C with N 2 i-PrMgCl LiCl (43.5 mL, 56.5 mmol) was added under reduced pressure. The reaction was then 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 at 0 °C with N 2i-PrMgCl LiCl (27.9 mL, 36.3 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. To the second mixture was added the first solution at -78 °C. The mixture was stirred at 25 °C for 16 h. The mixture was then added with NaBH 3 CN (3.04 g, 48.4 mmol) was added and the mixture was stirred at 25° C. for 1 h. The reaction was acidified to pH=3-4 with HCl (6 M aq.), stirred for 1 h, and neutralized with NaOH (4 M aq.). The mixture was quenched with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc) to give 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one. 11 H 11 F 3 NO[M+H] + Calculated value: 230; Actual value: 230. 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.21 ( dd, J=4.53, 2.28 Hz, 2 H) 1.98 ( d, J=2.15 Hz, 2 H) 4.06 (d, J=6.92 Hz, 1 H) 7.28 - 7.91 (m, 4 H) 8.51 - 8.54 (m, 1 H).

[0282] Step 2. Preparation of 5-methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole A solution of 5-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (900 mg, 3.93 mmol) in DCM (20 mL) was added at 0 °C with N 2 Trimethyloxonium tetrafluoroborate (1450 mg, 9.82 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (80 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 5-methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 13 F 3 NO[M+H] + Calculated value: 244; Actual value: 244.

[0283] Step 3. Preparation of methyl 2-(2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-methoxy-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrole (3.18 g, 13.1 mmol) in MeOH (50 mL) was added methyl hydrazine carboxylate (1.24 g, 13.7 mmol) and HCl (2 mL, 4 M solution in MeOH) at 20° C., and the resulting mixture was cooled to 10° C. with N 2 The mixture was stirred at 80° C. for 3 h under reduced pressure. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give methyl 2-(2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 13 H 15 F 3 N 3 O 2 [M+H] + Calculated value: 302; Actual value: 302.

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

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

[0286] Step 1. Preparation of 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one First, a solution of 5-bromo-1,3-difluoro-2-methylbenzene (1250 mg, 6.06 mmol) in THF (10 mL) was added to the flask at 0 °C with N 2 i-PrMgCl LiCl (6.52 mL, 8.48 mmol) was added under reduced pressure. The reaction was then stirred at 25 °C for 1 h. A solution of the second pyrrolidine-2,5-dione (600 mg, 6.06 mmol) in THF (15 mL) was added at 0 °C with N 2i-PrMgCl LiCl (4.19 mL, 5.45 mmol) was added and the reaction was stirred at 0 °C for 1 h. The first solution was then added to the second mixture at -78 °C. The reaction was warmed to 25 °C and stirred at 25 °C for 12 h. NaBH 3 CN (419 mg, 6.66 mmol) was added and the resulting mixture was stirred for 1 h. The reaction mixture was acidified with HCl (6 M aq.) to pH approx. 3 and stirred for 1 h. NaOH (4 M aq.) was then added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL) and Na 2 SO 4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one. 11 H 12 F 2 NO[M+H] + Calculated value: 212; measured value: 212. 1 H NMR (400 MHz, CD 3 OD) δ 6.82-6.95 (m, 2H), 4.77 (t, J=7.09 Hz, 1H), 2.54-2.66 (m, 1H), 2.36-2.44 (m, 2H), 2.16 (t, J=1.55 Hz, 3H), 1.82-1.96 (m, 1H).

[0287] Step 2. Preparation of 2-(3,5-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(3,5-difluoro-4-methylphenyl)pyrrolidin-2-one (150 mg, 0.710 mmol) in DCM (3 mL) was added dimethyloxonium tetrafluoroborate (143 mg, 1.07 mmol) at 0° C. The mixture was stirred at 30° C. for 12 h. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (10 mL) and extracted with DCM (2 x 5 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(3,5-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 F 2 NO[M+H] + Calculated value: 226; Measured value: 226.

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

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

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

[0291] Step 1. Preparation of ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate A stirred solution of 1-(3,5-difluorophenyl)propan-1-one (5 g, 29.4 mmol) in THF (30 mL) was cooled to -78 °C with N 2 1,3-Dimethyltetrahydropyrimidin-2(1H)-one (7.53 g, 58.8 mmol) and LHMDS (29.4 mL, 29.4 mmol) were added under the conditions below. After the addition was complete, the reaction was stirred at -78°C for 30 minutes. Ethyl 2-bromoacetate (3.44 mL, 30.9 mmol) was then added to the above mixture at -78°C in one portion. After the addition was complete, the reaction was stirred at 20°C for 2 hours. The mixture was diluted with tert-butyl methyl ether (10 mL) and washed with saturated NH 4The reaction was quenched with aqueous Cl (20 mL). The mixture was extracted with tert-butyl methyl ether (2 x 30 mL). The combined organic portions were washed with brine (10 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate. 13 H 15 F 2 O 3 [M+H] + Calculated value:,257;Measured value:257.

[0292] Step 2. Preparation of 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one To a solution of ethyl 4-(3,5-difluorophenyl)-3-methyl-4-oxobutanoate (5.4 g, 21.07 mmol) in EtOH (30 mL) was added ammonium acetate (8.12 g, 105 mmol), sodium cyanoborohydride (2.65 g, 42.1 mmol) and the reaction was stirred at 80° 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 solution was re-extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (EtOAc / hexanes) to give 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one. 11 H 12 F 2 NO[M+H] + Calculated value: 212; measured value: 212.

[0293] Step 3. Preparation of 2-(3,5-difluorophenyl)-5-methoxy-3-methyl-3,4-dihydro-2H-pyrrole A solution of 5-(3,5-difluorophenyl)-4-methylpyrrolidin-2-one (2.1 g, 9.94 mmol) in DCM (30 mL) was added at 0 °C with N 2Trimethyloxonium tetrafluoroborate (2.21 g, 14.9 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(3,5-difluorophenyl)-5-methoxy-3-methyl-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 F 2 NO[M+H] + Calculated value: 226; Measured value: 226.

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

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

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

[0297] Step 1. Preparation of 6-(3,5-difluorophenyl)piperidin-2-one To a solution of 1-bromo-3,5-difluorobenzene (5.12 g, 26.5 mmol) in THF (50 mL) was added iPrMgCl·LiCl (1.3 M in THF) (34.0 mL, 44.2 mmol) at 0 °C, and the mixture was stirred at 50 °C for 1 h. Then, piperidine-2,6-dione (2 g, 17.7 mmol) in DCM (2 mL) was added at -78 °C to the mixture. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with NaBH 3 CN (1.33 g, 21.2 mmol) was added and the mixture was then stirred at 25° C. for 1 h. The reaction was acidified with HCl (6 M) to pH=3-4, the mixture was then stirred for 30 min, and neutralized with aqueous NaOH (3 M). The mixture was washed with saturated NH 4 The reaction was quenched with Cl (200 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL) and Na 2 SO 4The mixture was dried over 1000 ml, filtered and concentrated. The residue was added to ethyl acetate (20 mL) and stirred for 0.5 h. The solid was filtered to give 6-(3,5-difluorophenyl)piperidin-2-one. 11 H 12 F 2 NO[M+H] + Calculated value: 212; Measured value: 212.

[0298] Step 2. Preparation of 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine To a solution of 6-(3,5-difluorophenyl)piperidin-2-one (500 mg, 2.37 mmol) in DCM (10 mL) was added dimethyloxonium tetrafluoroborate (475 mg, 3.55 mmol) at 25° C. The mixture was stirred at 25° C. for 12 h. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (20 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give crude 2-(3,5-difluorophenyl)-6-methoxy-2,3,4,5-tetrahydropyridine, which was used in the next step without further purification. 12 H 14 F 2 NO[M+H] + Calculated value: 226; Measured value: 226.

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

[0300] Steps 4-5. Preparation of intermediate I-17A A solution of methyl 2-(6-(3,5-difluorophenyl)-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate (300 mg, 1.06 mmol) in DMF (15 mL) was stirred at 145° C. for 12 h. The reaction solution was directly concentrated to give 5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (220 mg, 0.841 mmol). 5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was purified by chiral-SFC (Method: Column DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); Conditions: 0.1% NH 3 H 2 O / EtOH) to give 5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (ee%=97.6%) and 5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (ee%=97.3%).

[0301] ( S)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (I-17A): 1 H NMR (400 MHz, CD 3 OD) δ 6.87 (tt, J=2.35, 9.00 Hz, 1H), 6.67-6.77 (m, 2H), 5.13 (t, J=5.09 Hz, 1H), 2.79-2.91 (m, 1H), 2.65-2.78 (m, 1H), 2.29 (dddd, J=2.74, 6.06, 10.86, 13.99 Hz, 1H), 2.01 (tdd, J=3.42, 6.55, 13.99 Hz, 1H), 1.63-1.88 (m, 2H). (R)-5-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one: 1 H NMR (400 MHz, CD 3 OD) δ 6.87 (tt, J=2.20, 9.15 Hz, 1H), 6.68-6.76 (m, 2H), 5.13 (t, J=5.28 Hz, 1H), 2.79-2.89 (m, 1H), 2.65-2.77 (m, 1H), 2.29 (dddd, J=3.13, 5.87, 11.00, 14.04 Hz, 1H), 2.01 (tdd, J=3.33, 6.65, 14.09 Hz, 1H), 1.64-1.87 (m, 2H).

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

[0303] Step 1. Preparation of 5-cyclopentylpyrrolidin-2-one A solution of pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (150 mL) was cooled to -78 °C with N 2 Cyclopentylmagnesium bromide (121 mL, 121 mmol) was added dropwise via syringe. After the addition was complete, the reaction was warmed to 25° C. and allowed to react for an additional 16 hours. NaBH 3 CN (3.04 g, 48.4 mmol) was added to the mixture and reacted for another 2 h. 6M HCl was added to adjust the pH to 4. It was stirred for another 1 h. Aqueous NaOH was added to neutralize the pH. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (hexanes / ethyl acetate) to give 5-cyclopentylpyrrolidin-2-one. 9 H 16 NO[M+H]+ Calculated value: 154; Measured value: 154.

[0304] Step 2. Preparation of 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-cyclopentylpyrrolidin-2-one (520 mg, 3.39 mmol) in DCM (20 mL) was added at 0° C. with N 2 Trimethyloxonium tetrafluoroborate (753 mg, 5.09 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was diluted with saturated NaHCO 3 until no effervescence was observed. 3 (800 mL) and extracted with DCM (2 x 300 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-cyclopentyl-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 10 H 18 NO[M+H] + Calculated value: 168; Measured value: 168.

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

[0306] Phase 4. Construction of I-18A To a solution of methyl 2-(2-cyclopentyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (200 mg, 0.888 mmol) in MeOH (6 mL) was added sodium methoxide (144 mg, 2.66 mmol) and the resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled to room temperature and acidified with HCl / MeOH (4 M) to pH=7. The mixture was then filtered and purified by preparative HPLC (Method: Column Boston Green ODS 150×30 mm×5 μm; Condition: Water (0.01% TFA)-CAN) to give 5-cyclopentyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 10 H 16 N 3 O[M+H] + Calculated value: 194; Measured value: 194. 1 H NMR (400 MHz, CD 3 OD) δ 4.12-4.19 (m, 1H), 2.81 (d, J = 8.1 Hz, 1H), 2.59-2.75 (m, 2H), 2.27-2.46 (m, 2H), 1.79-1.88 (m, 1H), 1.65-1.77 (m, 3H), 1.60 (ddd, J = 10.4, 5.4, 2.4 Hz, 2H), 1.42 (br d, J = 9.2 Hz, 2H).

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

[0308] Step 1. Preparation of 5-cyclohexylpyrrolidin-2-one A solution of pyrrolidine-2,5-dione (2.5 g, 25.2 mmol) in THF (100 mL) was cooled to -78 °C with N 2Cyclohexylmagnesium bromide (76 mL, 76 mmol) was added dropwise via syringe. After addition was complete, the reaction was warmed to 25° C. and stirred for 16 hours. NaBH 3 CN (2.378 g, 37.8 mmol) was added to the mixture and allowed to stir for another 2 h. 6M HCl was added to adjust the pH to 4. It was stirred for another 1 h. Aqueous NaOH was added to adjust the pH to 7. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., 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. 10 H 18 NO[M+H] + Calculated value: 168; Measured value: 168.

[0309] Step 2. Preparation of 2-cyclohexyl-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-cyclohexylpyrrolidin-2-one (1.3 g, 7.77 mmol) in DCM (30 mL) was added at 0° C. with N 2 Trimethyloxonium tetrafluoroborate (1.72 g, 11.7 mmol) was added. The mixture was stirred at 35° C. for 12 hours. The mixture was diluted with saturated NaHCO 3 until no effervescence was observed. 3 (40 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-cyclohexyl-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 20 NO[M+H] + Calculated value: 182; Measured value: 182.

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

[0311] Phase 4. Construction of I-19A To a solution of methyl 2-(2-cyclohexyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (700 mg, 2.92 mmol) in MeOH (20 mL) was added sodium methoxide (474 ​​mg, 8.77 mmol) and the resulting mixture was stirred at 80° C. for 24 h. The mixture was cooled to room temperature and acidified to pH=7 with HCl / MeOH (4 M). The mixture was then filtered and purified by preparative HPLC (Method: Column Boston Uni C18 150×40 mm×5 μm; Conditions: Water (0.01% TFA)-CAN) to give 5-cyclohexyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 18 N 3 O[M+H] + Calculated value: 208; measured value: 208. 1 H NMR (500 MHz, CD 3OD) δ 4.06 (dt, J = 8.4, 4.1 Hz, 1H), 2.66-2.80 (m, 2H), 2.51-2.60 (m, 1H), 2.41 (dt, J = 8.9, 4.4 Hz, 1H), 1.98 (br d, J = 4.4 Hz, 1H), 1.76-1.84 (m, 2H), 1.67-1.75 (m, 2H), 1.46-1.52 (m, 1H), 1.25-1.37 (m, 2H), 1.17-1.24 (m, 2H), 1.09 (dd, J = 12.6, 3.6 Hz, 1H).

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

[0313] Step 1. Preparation of 5-(3-chlorophenyl)pyrrolidin-2-one A solution of 1-bromo-3-chlorobenzene (10.1 g, 52.5 mmol) in THF (100 mL) was added to 1.2 mL of THF at 0 °C. 2 i-PrMgCl LiCl (56.5 mL, 73.5 mmol) was added under reduced pressure. The reaction mixture was then stirred at 25 °C for 1 h. A solution of pyrrolidine-2,5-dione (5.2 g, 52.5 mmol) in THF (200 mL) was added at 0 °C with N 2 Isopropylmagnesium(II) lithium chloride (36.3 mL, 47.2 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h. The first solution was cooled to −78° C. with N 2 The mixture was added to the second solution and stirred at 25° C. for 12 hours. Then, NaBH 3 CN (3.63 g, 57.7 mmol) was added and the reaction was stirred for 1 h. HCl (6 M) was added to the reaction until the pH was about 3 and stirred for 1 h. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (250 mL) and Na 2SO 4 The residue was purified by flash silica gel chromatography (12 g silica gel, 100% ethyl acetate / petroleum ether gradient eluent) to give 5-(3-chlorophenyl)pyrrolidin-2-one. 10 H 11 ClNO[M+H] + Calculated value: 196; Measured value: 196.

[0314] Step 2. Preparation of 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A solution of 5-(3-chlorophenyl)pyrrolidin-2-one (7.0 g, 35.8 mmol) in DCM (180 mL) was added to 10 mL of DCM at 0° C. with N 2 Trimethyloxonium tetrafluoroborate (7.94 g, 53.7 mmol) was added. The mixture was stirred at 25° C. for 15 hours. The mixture was diluted with saturated NaHCO 3 until no effervescence was observed. 3 (150 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(3-chlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 13 ClNO[M+H] + Calculated value: 210; measured value: 210.

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

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

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

[0318] Step 1. Preparation of ethyl 4-oxo-4-(pyrazin-2-yl)butanoate Two reactions of identical scale were performed 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 diluted with saturated NH 4Cl (1.00 L) and the aqueous layer was extracted with EtOAc (4 x 1.00 L). The organic layer was washed with saturated NaHCO 3 (1.00 L), washed with brine (0.50 L), and then washed with Na 2 SO 4 The organic layer was dried in vacuum and the crude residue was purified by flash column chromatography (petroleum ether / EtOAc). Fractions containing the desired product were pooled and concentrated to give ethyl 4-oxo-4-(pyrazin-2-yl)butanoate. 1 H (400 MHz, CDCl 3 ) δ 9.13 (s, 1H), 8.69 (d, J = 2.00 Hz, 1H), 8.58 (d, J = 0.80 Hz, 1H), 4.04-4.09 (m, 2H), 3.43 (t, J = 6.40 Hz, 2H), 2.68 (d, J = 6.80 Hz, 2H), 1.17 (t, J = 7.20 Hz, 2H).

[0320] Step 2-3. Preparation of 5-(pyrazin-2-yl)pyrrolidin-2-one To a solution of ethyl 4-oxo-4-(pyrazin-2-yl)butanoate (160 g, 768 mmol) in EtOH (1.04 L) at 20° C. was added ammonium acetate (592 g, 7.68 mol) and molecular sieves (320 g, 1.32 mol). The resulting mixture was stirred at 20° C. for 12 h. The reaction was concentrated to dryness and the resulting brown liquid was used in the next step without further purification.

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

[0322] 4-Oxo-4-(pyrazin-2-yl)butanamide (138 g, 768 mmol) in EtOH (960 mL) was added to NaBH 3CN (145 g, 2.31 mol) was added and the mixture was stirred at 80° C. for 5 h. The two batches were combined and worked up together. The suspension was filtered and the filter cake was washed with EtOH (500 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH). Fractions containing the desired product portion were pooled and concentrated to give a residue that was dissolved in DCM (1.00 L). The solution was filtered and the filter cake was washed with DCM (200 mL). The filtrate was concentrated to give 5-(pyrazin-2-yl)pyrrolidin-2-one. 1 H NMR (400MHz, CDCl 3 ) δ 8.62-8.64 (m, 2H), 8.58 (d, J = 2.40 Hz, 1H), 8.14 (s, 1H), 4.79-4.82 (m, 1H), 2.49-2.50 (m, 1H), 2.23-2.30 (m, 2H), 1.98-2.21 (m, 1H).

[0323] Step 4. Preparation of 5-(pyrazin-2-yl)pyrrolidine-2-thione To a solution of 5-(pyrazin-2-yl)pyrrolidin-2-one (77.0 g, 472 mmol) in toluene (3.85 L) at 20° C. was added Lawesson's reagent (95.4 g, 236 mmol). The resulting mixture was stirred at 80° C. for 0.5 h. The reaction was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH). Fractions containing the desired product portion were pooled and concentrated to give 5-(pyrazin-2-yl)pyrrolidine-2-thione. 1 H NMR (400MHz, CDCl 3) δ 8.61 (d, J = 1.20 Hz, 1H), 8.46 (t, J = 1.60 Hz, 1H), 8.40 (d, J = 2.40 Hz, 1H), 7.74-7.77 (m, 1H), 5.20 (t, J = 7.20 Hz, 1H), 4.17-4.21 (m, 1H), 2.70-2.79 (m, 2H), 2.52-2.55 (m, 1H), 2.46 (s, 3H), 2.06-2.10 (m, 2H).

[0324] Step 5. Preparation of 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine A solution of 5-(pyrazin-2-yl)pyrrolidine-2-thione (84.0 g, 469 mmol) in acetone (494 mL) was added at 20° C. to K 2 CO 3 (194 g, 1.41 mol) was added. The mixture was stirred at 20° C. for 1 h. MeI (133 g, 937 mmol, 58.3 mL) was added dropwise and the reaction was stirred at 20° C. for 11 h. The reaction was filtered and the filter cake was washed with acetone (200 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography (petroleum ether / 30% EtOAc:EtOH). Fractions containing the desired product portion were pooled and concentrated to give 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine. 1 H NMR (400MHz, CDCl 3 ) δ 8.61 (d, J = 1.20 Hz, 1H), 8.46 (t, J = 0.8 Hz, 1H), 8.40 (d, J = 2.40 Hz, 1H), 7.74-7.77 (m, 1H), 5.20 (t, J = 7.20 Hz, 1H), 4.17-4.21 (m, 1H), 2.70-2.79 (m, 2H), 2.52-2.55 (m, 1H), 2.46 (s, 3H), 2.06-2.10 (m, 2H).

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

[0326] To a solution of 2-(5-(methylthio)-3,4-dihydro-2H-pyrrol-2-yl)pyrazine (22.0 g, 114 mmol) in MeOH (440 mL) at 20° C. was added methyl hydrazine carboxylate (15.4 g, 171 mmol). The reaction mixture was heated to 80° C. for 2 h. The reaction was concentrated to dryness to give methyl 2-(2-(pyrazin-2-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without further purification.

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

[0328] To a solution of methyl 2-(2-(pyrazin-2-yl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (26.0 g, 111 mmol) in MeOH (485 mL) was added MeONa (25.6 g, 332 mmol) at 20° C. The resulting mixture was stirred at 80° C. for 12 h. The two batches were combined and heated to 30° C. with H at room temperature. 2 2H 3 O (500 mL). The mixture was filtered and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated to give the desired crude residue, which was purified by flash column chromatography (petroleum ether / 30% EtOAc:EtOH) to give 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. After another purification cycle by preparative HPLC (Method: Welch Xtimate C18; Conditions: water (TFA)-ACN), I-21A, 5-(pyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, was obtained. 1 H NMR (400MHz, CDCl 3 ) δ 9.26 (s, 1H), 8.69 (s, 1H), 8.57 (d, J = 2.40 Hz, 2H), 5.31-5.33 (m, 1H), 3.00-3.07 (m, 2H), 2.85-2.87 (m, 1H), 2.73-2.80 (m, 1H).

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

[0330] Step 1. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine A mixture of 2-amino-2-(3,5-difluorophenyl)ethan-1-ol (800 mg, 4.62 mmol) in DCM (20 mL) was added at 0 °C with N 2 Imidazole (472 mg, 6.93 mmol) and TBSCl (836 mg, 5.54 mmol) were added. 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), and the organic layer was diluted with Na 2 SO 4 The mixture was dried at 40° C. and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica gel, eluent of 4% EtOAc / petroleum ether gradient) to give 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine. 14 H 24 F 2 NOSi[M+H] + Calculated value: 288; Measured value: 288.

[0331] Step 2. Preparation of tert-butyl(2-(3,5-difluorophenyl)-2-isothiocyanatoethoxy)dimethylsilane 2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethan-1-amine (700 mg, 2.435 mmol) in DCM (5 mL) and aqueous NaHCO 3 The solution in (5 mL) was stirred at 25° C. for 15 min. To the bottom layer of the mixture was added thiophosgene (0.355 mL, 4.87 mmol) via syringe at 25° C., and the mixture was stirred at 25° C. for 1.5 h. The mixture was quenched with brine and extracted with DCM (2×20 mL). The combined organic layers were washed with Na2 SO 4 The filtrate was concentrated under reduced pressure to give crude tert-butyl(2-(3,5-difluorophenyl)-2-isothiocyanatoethoxy)dimethylsilane, which was used directly in the next step without further purification. 15 H 22 F 2 NOSSi [M+H] + Calculated value: 330; Actual value: 330.

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

[0333] Step 4. Preparation of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-5-mercapto-2,4-dihydro-3H-1,2,4-triazol-3-one A mixture of methyl 6-(3,5-difluorophenyl)-9,9,10,10-tetramethyl-4-thioxo-8-oxo-2,3,5-triaza-9-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, condition: 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 F 2 N 3 O 2 S[M+H] + Calculated value: 274; Measured value: 274.

[0334] Step 5. Preparation of I-22A, (S and R)-5-(3,5-difluorophenyl)-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one To a solution of 4-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-5-mercapto-2,4-dihydro-3H-1,2,4-triazol-3-one (200 mg, 0.183 mmol) and triphenylphosphane (96 mg, 0.366 mmol) in THF (4 mL) was added DIAD (0.071 mL, 0.366 mmol) at 25 °C, and the mixture was heated at 40 °C with N 2 The mixture was stirred under reduced pressure for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Green ODS, condition: water (0.01% TFA)-CAN) to obtain I-22A, (S and R)-5-(3,5-difluorophenyl)-5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3(2H)-one. 10 H 8 F 2 N 3 OS[M+H] + Calculated value: 274; Measured value: 274.

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

[0336] Step 1. Preparation of 5-(4-methoxyphenyl)pyrrolidin-2-one A solution of pyrrolidine-2,5-dione (2 g, 20.2 mmol) in THF (100 mL) was heated at 78 °C with N 2 4-Methoxyphenylmagnesium bromide (89 mL, 44.4 mmol) was added dropwise via syringe to the bottom of the flask. After the addition was complete, the reaction was warmed to 25° C. and stirred for an additional 16 hours. NaBH 3 CN (1.52 g, 24.2 mmol) was added to the mixture and stirred for another 2 h. Aqueous HCl (4 M) was added to adjust the pH to 4. The mixture was stirred at room temperature for another 1 h. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (40 g silica gel, eluent gradient 80% to 100% EtOAc) to give 5-(4-methoxyphenyl)pyrrolidin-2-one. 11 H 14 NO 2 [M+H] + Calculated value: 192; Measured value: 192.

[0337] Step 2. Preparation of 5-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole A solution of 5-(4-methoxyphenyl)pyrrolidin-2-one (600 mg, 3.14 mmol) in DCM (20 mL) was added at 0° C. with N 2 Trimethyloxonium tetrafluoroborate (696 mg, 4.71 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was diluted with saturated NaHCO 3 until no effervescence was observed. 3 (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 5-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 16 NO 2 [M+H] + Calculated value: 206; Actual value: 206.

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

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

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

[0341] To a stirred solution of 5-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (200 mg, 0.849 mmol) in dioxane (5 mL) and water (5 mL) was added potassium ferrocyanide trihydrate (358 mg, 0.849 mmol), potassium acetate (250 mg, 2.55 mmol) and Brettphos Pd G3 (115 mg, 0.127 mmol) at 20 °C. After the addition was complete, the reaction was incubated at 100 °C with N 2 The mixture was stirred under atmospheric pressure for 12 hours. 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 HCOONH 4 )-ACN) to give I-24A, (S and R)-4-(3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-yl)benzonitrile. 12 H 11 N 4 O[M+H] + Calculated value: 227; Measured value: 227.

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

[0343] Step 1. Preparation of methyl 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate 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), Cs 2 CO 3 To a solution of (13.3 g, 40.9 mmol) in DMF (136 mL) at 0° C. was added SEM-Cl (5.81 mL, 32.8 mmol) and the resulting mixture was stirred at 20° C. for 12 h. The reaction was filtered and the filtrate was concentrated to give methyl 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate, which was used in the next step without further purification. 12 H 22 N 3 O 4 Si[M+H] + Calculated value: 300; Actual 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), 2 Below, 2-chloro-6-methylpyrazine (429 mg, 3.34 mmol), Cs 2 CO 3 (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 for 12 h under 450 nm blue light. Water (50 mL) was added to the mixture, and it was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (50 mL) and Na 2 SO 4The residue was purified by flash silica gel chromatography (100% ethyl acetate / petroleum ether gradient elution) to give 5-(6-methylpyrazin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 16 H 26 N 5 O 2 Si[M+H] + Calculated value: 348; Measured value: 348.

[0345] Step 3. Preparation of I-25A, (S and R)-5-(6-methylpyrazin-2-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a mixture of 5-(6-methylpyrazin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (320 mg, 0.921 mmol) in DCM (4.5 mL) was added TFA (1.5 mL) and the resulting mixture was stirred at 20° C. for 2 h. The reaction solution was concentrated directly. The residue was dissolved in MeOH (5 mL) and NH 3 H 2 2H2O (0.5 mL) was added to adjust the pH to about 8 and stirred for 1 h. The solution was then 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. 10 H 12 N 5 O[M+H] + Calculated value: 218; measured value: 218.

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

[0347] Step 1. Synthesis of methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate To a solution of 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoic acid (21 g, 92 mmol) in MeOH (20 mL) was added HCl / MeOH (200 mL). The resulting mixture was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the resulting residue was purified with saturated NaHCO 3 The mixture was diluted with aqueous solution (150 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give impure methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate. The material was purified by preparative SFC (method: column DAICEL CHIRALPAK AD; conditions: MeOH (0.1% NH 3 H 2 Further purification by HPLC) afforded methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate as a combination of the first and second eluting peaks. 1 H NMR (400 MHz, MeOD) δ 7.54-7.62 (m, 2H), 7.20-7.29 (m, 1H), 3.67 (s, 3H), 3.44 (dd, J = 18.24, 8.70 Hz, 1H), 3.09-3.17 (m, 1H), 2.99-3.09 (m, 1H), 1.27 (d, J = 7.27 Hz, 3H).

[0348] Step 2. Synthesis of 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one To a solution of methyl 4-(3,5-difluorophenyl)-2-methyl-4-oxobutanoate (2.5 g, 10.3 mmol) in MeOH (25 mL) was added ammonium acetate (0.796 g, 10.3 mmol) and sodium cyanoborohydride (0.649 g, 10.3 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was aged at 70° C. 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) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one. 11 H 12 F 2 NO[M+H] + Calculated value: 212; measured value: 212.

[0349] Step 3. Synthesis of 2-(3,5-difluorophenyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole To a solution of 5-(3,5-difluorophenyl)-3-methylpyrrolidin-2-one (1.5 g, 7.1 mmol) in DCM (15 mL) was added trimethyloxonium tetrafluoroborate (1.58 g, 10.6 mmol) under nitrogen at 0° C. The resulting mixture was stirred at 45° C. for 16 h. The mixture was diluted with saturated NaHCO 3 The reaction was quenched by dropwise addition to aqueous solution (100 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give 2-(3,5-difluorophenyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole, which was used in the next step without purification. 12 H 14 F 2 NO[M+H] + Calculated value: 226; Measured value: 226.

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

[0351] Step 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 SFC to obtain I-26A and I-27A To a solution of methyl 2-(2-(3,5-difluorophenyl)-4-methyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (2 g, 7.06 mmol) in MeOH (20 mL) at 0° C. under nitrogen was added sodium methylate (3.58 g, 21.2 mmol). The resulting mixture was aged at 80° C. for 12 h. 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*70 mm*10 μm; condition: water (NH 4 HCO 3 The mixture was purified by preparative SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); condition: 0.1% NH 3 H 2The elution peak was separated by HPLC using a 50 mL hexane / IPA column to give I-27A, (5S,7S)-5-(3,5-difluorophenyl)-7-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, as the fourth elution peak. The second and third elution peaks were poorly soluble. These peaks were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative SFC (column: (s,s)WHELK-O1 (250 mm × 30 mm, 5 μm) conditions: 0.1% NH 3 H 2 Repurification by elution with 300 mL of 1H-pyrrolo[2,1-c][1,2,4]triazol-3-one gave 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 eluting 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 H 12 F 2 N 3 O[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 F 2 N 3 O[M+H] + Calculated value: 252; measured value: 252.

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

[0355] Step 1. Synthesis of 5-(5-fluoropyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of 3-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid (700 mg, 2.34 mmol) in DMF (14 mL), 2 Below, 2-bromo-5-fluoropyridine (411 mg, 2.34 mmol), Cs 2 CO 3 (1143mg, 3.51mmol), 2,2′-bipyridine (82mg, 0.53mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (77mg, 0.35mmol) and 4CzIPN (92mg, 0.12mmol) were added. The resulting mixture was stirred under 450nm blue light for 12 hours. The mixture was purified by preparative HPLC (column: Boston Green ODS150*30mm*5μm; condition: water (0.1% TFA)-MeCN) to obtain 5-(5-fluoropyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 16 H 24 FN 4 O 2 Si[M+H] + Calculated value: 351; Measured value: 351.

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

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

[0358] Step 1. Synthesis of 5-(3-chloro-5-fluoro-4-methylphenyl)pyrrolidin-2-one To a solution of 5-bromo-1-chloro-3-fluoro-2-methylbenzene (4.96 g, 22.2 mmol) in THF (100 mL) was added iPrMgCl·LiCl (1.3 M in THF) (18.63 mL, 24.22 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 20 °C for 1 h. To another solution of pyrrolidine-2,5-dione (2.00 g, 20.2 mmol) in THF (100 mL) was added iPrMgCl·LiCl (1.3 M in THF) (13.97 mL, 18.17 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 mixture was allowed to warm to ambient temperature and stirred for 16 h. NaBH 3 CN (1.78 g, 28.3 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 1 h. The reaction was acidified to pH=3-4 with HCl (6 M), stirred for 1 h, and neutralized with aqueous NaOH (4 M). The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate) to give 5-(3-chloro-5-fluoro-4-methylphenyl)pyrrolidin-2-one. 11 H 12 ClFNO[M+H] + Calculated value: 228; Measured value: 228.

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

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

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

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

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

[0364] Step 1. Preparation of 2-(benzyloxy)-5-bromo-1,3-difluorobenzene A solution of 4-bromo-2,6-difluorophenol (5 g, 23.92 mmol) in DMF (100 mL) was added to the 2 CO 3 (4.96 g, 35.9 mmol) and (bromomethyl)benzene (3.41 mL, 28.7 mmol) were added 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 (3×80 mL). The combined organic layers were washed with brine (100 mL) and Na 2 SO 4The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 2% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 2-(benzyloxy)-5-bromo-1,3-difluorobenzene. 1 H NMR (400 MHz, CD 3 OD) 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 heated at 0 °C with N 2 iPrMgCl LiCl (1.3 M in THF) (21.74 mL, 28.3 mmol) was added to the reaction mixture and stirred at 45 °C for 1 h. Separately, iPrMgCl LiCl (1.3 M in THF) (13.97 mL, 18.17 mmol) was added at 0 °C with N 2 The mixture was cooled to -78°C and solution-1 was added. The reaction mixture was warmed to 25°C and stirred at 25°C for 12 hours. NaBH 3 CN (1.395 g, 22.20 mmol) was added and the reaction was stirred for 1 h. HCl (6 M) was added until pH 4 and stirred for 1 h. Aqueous NaOH (4 M) was added to adjust the pH to neutral. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL) and Na 2 SO 4The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 100% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 5-(4-(benzyloxy)-3,5-difluorophenyl)pyrrolidin-2-one. 17 H 16 F 2 NO 2 [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 diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (50 mL) and then extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 2,6-difluoro-4-(5-methoxy-3,4-dihydro-2H-pyrrol-2-yl)phenol, which was used in the next step without further purification. 11 H 12 F 2 NO 2 [M+H] + Calculated value: 228; Measured value: 228.

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

[0368] Step 5. Preparation of Intermediate I-30A To a solution of methyl 2-(2-(3,5-difluoro-4-hydroxyphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.6 g, 5.61 mmol) in MeOH (30 mL) was added sodium methanolate (1.515 g, 28.0 mmol) and the resulting mixture was stirred at 80° C. for 12 h. The reaction was allowed to cool to room temperature and HCl / MeOH (4M) was added until pH approx. 5 and stirred for 10 min. The reaction mixture was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluting with a 5% MeOH / DCM gradient at 35 mL / min) to give I-30A, 5-(3,5-difluoro-4-hydroxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. 11 H 10 F 2 N 3 O 2 [M+H] + Calculated value: 254; Measured value: 254.1 H NMR (400 MHz, CD 3 OD) δ 6.85 (d, J = 7.6 Hz, 2H), 5.13 (dd, J = 4.8, 7.6 Hz, 1H), 2.99-3.09 (m, 1H), 2.74-2.98 (m, 2H), 2.41 (tdd, J = 5.2, 8.4, 13.2 Hz, 1H).

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

[0370] Step 1. Synthesis of 1-(2,6-difluoro-4-methylphenyl)ethan-1-one 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 K 2 CO 3 A solution of (10.58 g, 77 mmol) in dioxane (10 mL) and water (1 mL) was added under nitrogen to Pd(dppf)Cl 2 (1.868 g, 2.55 mmol) was added. The resulting mixture was brought 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) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 1-(2,6-difluoro-4-methylphenyl)ethan-1-one. 1 H NMR (400 MHz, CDCl 3 ) δ 6.74 (d, J = 8.8 Hz, 2H), 2.55 (t, J = 2.0 Hz, 3H), 2.35 (s, 3H).C9 H 9 F 2 O[M+H] + Calculated value: 171; Measured value: 171.

[0371] Step 2. Synthesis of ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate To a stirred solution of 1-(2,6-difluoro-4-methylphenyl)ethan-1-one (3.19 g, 18.7 mmol) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (4.81 g, 37.5 mmol) in THF (20 mL) at -78°C was added lithium bis(trimethylsilyl)amide (1 M solution in THF) (18.75 mL, 18.75 mmol). The mixture was stirred at -78°C for 30 minutes, then 2-bromoethyl acetate (2.183 mL, 19.68 mmol) was added. The reaction was allowed to warm to ambient temperature and held for 2 hours. The mixture was diluted with tert-butyl methyl ether (100 mL) and saturated NH 4 The reaction was quenched with aqueous Cl (100 mL). The mixture was extracted with tert-butyl methyl ether (2 x 50 mL). The combined organic layers were washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate. 1 H NMR (400 MHz, CDCl 3 ) 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 F 2 O 3 [M+H] + Calculated value: 257; measured value: 257.

[0372] Step 3. Synthesis of 5-(2,6-difluoro-4-methylphenyl)pyrrolidin-2-one Ethyl 4-(2,6-difluoro-4-methylphenyl)-4-oxobutanoate (2.2 g, 8.6 mmol) and AcONH 4 A solution of (1.985 g, 25.8 mmol) in EtOH (40 mL) was added to NaBH 3 (CN) (1.349 g, 21.46 mmol) was added. The mixture was brought 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 (3×100 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue which 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, CDCl 3 ) 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 F 2 NO[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 under nitrogen at 0° C., trimethyloxonium tetrafluoroborate (637 mg, 4.31 mmol) was added. The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with saturated NaHCO 3 (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(2,6-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 12 H 14 F 2 NO[M+H] + Calculated value: 226; Measured value: 226.

[0374] Step 5. Synthesis of methyl 2-(2-(2,6-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(2,6-difluoro-4-methylphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (380 mg, 1.69 mmol) in MeOH (20 mL) at 20° C. under nitrogen was added methyl hydrazine carboxylate (167 mg, 1.86 mmol) and HCl / MeOH (1 mL). The resulting mixture was aged at 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, CD 3 OD) 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 F 2 N 3 O 2 [M+H] + Calculated value: 284; Measured value: 284.

[0375] Step 6. Synthesis of I-31A 5-(2,6-difluoro-4-methylphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(2,6-difluoro-4-methylphenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (250 mg, 0.883 mmol) in MeOH (10 mL) was added sodium methanolate (143 mg, 2.65 mmol). The resulting mixture was aged 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-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 H 12 F 2 N 3 O[M+H] + Calculated value: 252; measured value: 252.

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

[0377] Step 1. Synthesis of 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one To a solution of 4-bromo-1-chloro-2-fluorobenzene (5.28 g, 25.2 mmol) in THF (100 mL) was added iPrMgCl·LiCl (1.3 M in THF) (27.2 mL, 35.3 mmol) at 0 °C under nitrogen. The resulting solution was stirred at ambient temperature for 1 h. To another solution of pyrrolidine-2,5-dione (2.5 g, 25 mmol) in THF (100 mL) was added iPrMgCl·LiCl (1.3 M in THF) (17.47 mL, 22.71 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. NaBH 3(CN) (1.744 g, 27.8 mmol) was added to the reaction mixture at ambient temperature and stirred for 1 h. The reaction was acidified to pH 3 with HCl (6 M), stirred for 1 h, and neutralized with aqueous NaOH (4 M). The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one. 10 H 10 ClFNO[M+H] + Calculated value: 214; Measured value: 214.

[0378] Step 2. Synthesis of 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole To a solution of 5-(4-chloro-3-fluorophenyl)pyrrolidin-2-one (1.00 g, 4.68 mmol) in DCM (23.4 mL) was added trimethyloxonium tetrafluoroborate (1.039 g, 7.02 mmol) under nitrogen at 0° C. The mixture was stirred at ambient temperature for 15 h. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (150 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 12 ClFNO[M+H] + Calculated value: 228; Measured value: 228.

[0379] Step 3. Synthesis of methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(4-chloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (1.00 g, 3.51 mmol) in MeOH (20 mL) at ambient temperature was added methyl hydrazine carboxylate (0.422 g, 4.68 mmol) and HCl / MeOH (1 mL). The resulting mixture was brought to 80° C. and stirred for 12 h. The mixture was concentrated under reduced pressure. The resulting residue was slurried in ethyl acetate for 15 min and filtered to give methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate, which was used in the next step without further purification. C 12 H 14 ClFN 3 O 2 [M+H] + Calculated value: 286; Measured 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 To a solution of methyl 2-(2-(4-chloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.00 g, 3.50 mmol) in MeOH (20 mL) was added sodium methanolate (0.945 g, 17.5 mmol). The resulting mixture was stirred at 80° C. for 5 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 ClFN 3 O[M+H] + Calculated value: 254; Measured value: 254.

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

[0382] Step 1. Synthesis of 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one To a solution of 5-bromo-1,2,3-trifluorobenzene (4.90 g, 23.2 mmol) in THF (60 mL) (designated as solution-1) was added iPrMgCl·LiCl (1.3 M in THF) (25 mL, 32.5 mmol) at 0 °C under nitrogen. The resulting solution was stirred at ambient temperature for 1 h. To another solution of pyrrolidine-2,5-dione (2.3 g, 23 mmol) in THF (100 mL) was added iPrMgCl·LiCl (1.3 M in THF) (16.07 mL, 20.89 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 1 h. The first solution was added to the second solution at -78 °C. The resulting solution was allowed to warm to ambient temperature and stirred for 12 h. NaBH 3 (CN) (1.605 g, 25.5 mmol) was added to the reaction mixture at ambient temperature and stirred for 1 h. The reaction was acidified to pH 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 x 10 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one. 10 H 9 F 3 NO[M+H] + Calculated value: 216; Measured value: 216.

[0383] Step 2. Synthesis of 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole To a solution of 5-(3,4,5-trifluorophenyl)pyrrolidin-2-one (1.00 g, 4.65 mmol) in DCM (20 mL) at 0° C. under nitrogen was added trimethyloxonium tetrafluoroborate (1.031 g, 6.97 mmol). The mixture was stirred at ambient temperature for 15 h. The mixture was diluted with saturated NaHCO 3The reaction was quenched with aqueous solution (50 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 5-methoxy-2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 11 F 3 NO[M+H] + Calculated value: 230; Actual value: 230.

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

[0385] Step 4. Synthesis of I-33A 5-(3,4,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a solution of methyl 2-(2-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (1.00 g, 3.48 mmol) in MeOH (16 mL) was added sodium methanolate (0.940 g, 17.4 mmol). The resulting mixture was stirred at 80° C. for 5 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 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 H 9 F 3 N 3 O[M+H] + Calculated value: 256; measured value: 256.

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

[0387] Step 1. Preparation of 5-(4-chloro-3,5-difluorophenyl)pyrrolidin-2-one A solution of 5-bromo-2-chloro-1,3-difluorobenzene (10.10 g, 44.4 mmol) in THF (40 mL) was cooled to 0 °C with N 2 iPrMgCl LiCl (1.3 M in THF) (37.3 mL, 48.4 mmol) was added under reduced pressure. The reaction was stirred at 20 °C for 1 h to give mixture #1. Separately, iPrMgCl LiCl (1.3 M in THF) (27.9 mL, 36.3 mmol) was added to another solution of pyrrolidine-2,5-dione (4 g, 40.4 mmol) in THF (40 mL) at 0 °C with N 2The reaction was stirred at 0° C. for 1 hour to give mixture #2. Mixture #2 was added to mixture #1 at −78° C. The reaction was stirred at 25° C. for 16 hours. The reaction was warmed to 25° C. and NaBH 3 (CN) (3.81 g, 60.6 mmol) was added and then stirred at 25° C. for 1 h. The reaction was acidified with HCl (6 M) to pH=3-4, stirred for 1 h, and neutralized with aqueous NaOH (4 M). The mixture was quenched with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®, 40 g Agela flash column, 100% EtOAc) to give 5-(4-chloro-3,5-difluorophenyl)pyrrolidin-2-one. 10 H 9 ClF 2 NO[M+H] + Calculated value: 232; Measured value: 232.

[0388] Step 2. Preparation of 2-(4-chloro-3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole A mixture of 5-(4-chloro-3,5-difluorophenyl)pyrrolidin-2-one (4.4 g, 19.00 mmol) and trimethyloxonium tetrafluoroborate (3.65 g, 24.69 mmol) in DCM (50 mL) was stirred at 40° C. for 16 h to give a brown mixture. The reaction mixture was diluted with saturated NaHCO 3 (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(4-chloro-3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole, which was used in the next step without further purification. 11 H 11 ClF 2 NO[M+18+H] + Calculated value: 264; Actual value: 264.

[0389] Step 3. Preparation of methyl 2-(2-(4-chloro-3,5-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 2-(4-chloro-3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (4 g, 16.28 mmol) in MeOH (60 mL) was added methyl hydrazine carboxylate (1.613 g, 17.91 mmol) and HCl / MeOH (4 mL) at 20° C., and the resulting mixture was cooled to 10° C. with N 2 The mixture was stirred at 80° C. under reduced pressure 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 of DCM / EtOAc gradient at 60 mL / min) to give methyl 2-(2-(4-chloro-3,5-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate. 12 H 13 ClF 2 N 3 O 2 [M+H] + Calculated value: 304; Measured value: 304.

[0390] Phase 4. Construction of the I-34A To a solution of methyl 2-(2-(4-chloro-3,5-difluorophenyl)-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (100 mg, 0.329 mmol) in MeOH (5 mL) was added sodium methanolate (89 mg, 1.646 mmol) and the resulting mixture was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and then HCl / MeOH (4 M) was added until pH was about 6. The solution was concentrated, the residue was dissolved in MeOH (50 mL), filtered, and the filtrate was concentrated to give I-34A, 5-(4-chloro-3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one. C 11 H 9 ClF 2 N 3 O[M+H] + Calculated value: 272; Found value: 272. 1H NMR (400 MHz, CD 3OD) δ 6.71-7.15 (m, 2H), 5.20-5.26 (m, 1H), 3.02-3.13 (m, 1H), 2.89-2.99 (m, 1H), 2.78-2.88 (m, 1H), 2.78-2.88 (m, 1H), 2.38-2.50 (m, 1H).

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

[0392] Step 1. Preparation of (R)-5-phenylmorpholin-3-one To a mixture of (R)-2-amino-2-phenylethan-1-ol (5 g, 36.4 mmol) and TEA (12.70 mL, 91 mmol) in THF (100 mL) was added 2-chloroacetyl chloride (2.90 mL, 36.4 mmol) at 0° C. The reaction was stirred at 0° C. for 2 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The crude product was dissolved in THF (70 mL), NaH (1.749 g, 43.7 mmol) was added, and the resulting mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 5% MeOH / DCM gradient at 35 mL / min) to give (R)-5-phenylmorpholin-3-one. 10 H 12 NO 2 [M+H] +Calculated value: 178; Measured value: 178.

[0393] Step 2. Preparation of (R)-5-Methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxidine To a solution of (R)-5-phenylmorpholin-3-one (1 g, 5.64 mmol) in DCM (20 mL) was added dimethyloxonium tetrafluoroborate (1.133 g, 8.46 mmol) at 25° C. The mixture was stirred at 25° C. for 12 h. The mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (30 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give crude (R)-5-methoxy-3-phenyl-3,6-dihydro-2H-1,4-oxidine which was used in the next step without further purification.

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

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

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

[0397] Step 1. Preparation of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide To a stirred mixture of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (10 g, 57.4 mmol) in THF (250 mL) at 20 °C was added (S)-2-methylpropane-2-sulfinamide (9.04 g, 74.6 mmol), Ti(iPrO) 4(22.5 mL, 86 mmol) was added and the mixture was stirred at 20° C. for 12 h. The mixture was poured into brine (300 mL) and filtered. The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (250 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (0% to 20% EtOAc / petroleum ether) to give (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide. 12 H 28 NO 2 SSi[M+H] + Calculated value: 278; Measured value: 278.

[0398] Step 2. Preparation of (S)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide A solution of 1-bromo-3,5-difluorobenzene (8.80 g, 45.6 mmol) in THF (100 mL) was cooled to 0 °C with N 2 i-PrMgCl LiCl (47.8 mL, 62.2 mmol) was added to the reaction mixture and the mixture was stirred at 40 °C for 1 h. Next, the reaction mixture was added to a solution of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (11.5 g, 41.4 mmol) in THF (150 mL) at 0 °C with N 2 The reaction mixture was stirred at 25° C. for 5 h. The mixture was diluted with saturated NH 4 The reaction was quenched with Cl (300 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with Na 2 SO 4 The residue was purified by flash silica gel chromatography (100% EtOAc) to give (S)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide. 18 H 32 F 2 NO 2 SSi[M+H] +Calculated value: 392; Measured value: 392.

[0399] Steps 3-4. Preparation of 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide A solution of (S)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3 g, 7.66 mmol) in HCl / MeOH (50 mL) was stirred at 25° C. for 12 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) was added 2-chloroacetyl chloride (0.459 mL, 5.77 mmol) at 0° C., and the resulting mixture was stirred at 20° C. for 2 h. The mixture was added to water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (15 mL) and diluted with Na 2 SO 4 The residue was purified by flash silica gel chromatography (40% EtOAc:petroleum ether) to give 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide. 10 H 11 ClF 2 NO 2 [M+H] + Calculated value: 250; Actual value: 250.

[0400] Step 5. Preparation of 5-(3,5-difluorophenyl)morpholin-3-one To a solution of 2-chloro-N-(1-(3,5-difluorophenyl)-2-hydroxyethyl)acetamide (560 mg, 2.243 mmol) in THF (44 mL) was added NaH (224 mg, 5.61 mmol) at 0° C., and the mixture was stirred at 20° C. for 1 h. The mixture was diluted with saturated NH 4 Cl (30 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL) and2 SO 4 The residue was purified by flash silica gel chromatography (100% ethyl acetate / petroleum ether) to give 5-(3,5-difluorophenyl)morpholin-3-one. 10 H 10 F 2 NO 2 [M+H] + Calculated value: 214; Measured value: 214.

[0401] Step 6. Preparation of 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxidine 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 diluted with saturated NaHCO 3 (20 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (10 mL) and 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give crude 3-(3,5-difluorophenyl)-5-methoxy-3,6-dihydro-2H-1,4-oxidine, which was used in the next step without further purification. 11 H 12 F 2 NO 2 [M+H+H 2 O] + Calculated value: 246; Measured value: 246.

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

[0403] Phase 8. Construction of I-36A A solution of methyl 2-(5-(3,5-difluorophenyl)-5,6-dihydro-2H-1,4-oxozin-3-yl)hydrazine-1-carboxylate (480 mg, 1.68 mmol) in DMF (40 mL) was stirred at 145° C. for 12 h. The reaction solution was directly concentrated. The residue was repurified by preparative HPLC (Method: Boston Green ODS, Conditions: water (0.01% TFA)-ACN) to give I-36A, 5-(3,5-difluorophenyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one. C 11 H 10 F 2 N 3 O 2 [M+H] + Calculated value: 286; Measured value: 286. 1 H NMR (400 MHz, CD 3 OD) δ 6.82-6.98 (m, 3H), 5.05 (t, J = 3.6 Hz, 1H), 4.84 (s, 1H), 4.67 (d, J = 15.6 Hz, 1H), 4.17 (dd, J = 4.0, 12.4 Hz, 1H), 4.02 (dd, J = 3.2, 12.4 Hz, 1H).

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

[0405] Step 1. Preparation of 6-phenylpiperidin-2-one A solution of piperidine-2,6-dione (5 g, 44.2 mmol) in THF (100 mL) was cooled to -78 °C with N 2 Phenylmagnesium bromide (30.9 mL, 93 mmol) was added dropwise via syringe to the bottom of the flask. After the addition was complete, the reaction was warmed to 25° C. and stirred for 16 h. The mixture was then diluted with NaBH 3 (CN) (3.06 g, 48.6 mmol) was added and it was stirred at 25° C. for another 2 h. 4M HCl was added to adjust the pH to 4. The resulting mixture was stirred for 1 h. Aqueous NaOH was added to adjust to neutral pH. The mixture was quenched with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give the crude product as a yellow oil, which was purified by flash silica gel chromatography (100% EtOAc) to give 6-phenylpiperidin-2-one. 11 H 14 NO[M+H] + Calculated value: 176; Measured value: 176.

[0406] Step 2. Preparation of 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine CH of 6-phenylpiperidin-2-one (2.5 g, 14.3 mmol) 2 Cl 2 To the solution in (100 mL) was added dimethyloxonium tetrafluoroborate (2.87 g, 21.4 mmol) at 25° C. The mixture was stirred at 25° C. for 12 h. The mixture was diluted with saturated NaHCO 3 (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 6-methoxy-2-phenyl-2,3,4,5-tetrahydropyridine, which was used in the next step without further purification. 12 H 16 NO[M+H] + Calculated value: 190; Actual value: 190.

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

[0408] Steps 4 and 5. Preparation of Intermediate I-37A A solution of methyl 2-(6-phenyl-3,4,5,6-tetrahydropyridin-2-yl)hydrazine-1-carboxylate (2.5 g, 10.1 mmol) in DMF (25 mL) was stirred at 145° C. for 12 h. The reaction solution was directly concentrated to give (±)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2 g, 7.43 mmol). The enantiomers were separated by SFC (method: column DAICEL CHIRALCEL OD, conditions: 0.1% NH 3 H 2 Separation with O (EtOH) afforded (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: 1 H NMR (500 MHz, CD 3OD) δ 7.31-7.38 (m, 2H), 7.24-7.30 (m, 1H), 7.04 (d, J = 7.5 Hz, 2H), 5.18 (dd, J = 3.5 Hz, 1H), 2.80-2.89 (m, 1H), 2.66-2.76 (m, 1H), 2.27 (dddd, J = 2.5 Hz, 1H), 1.98-2.08 (m, 1H), 1.62-1.82 (m, 2H). (S)-5-Phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (I-37A): 1 H NMR (500 MHz, CD 3 OD) δ 7.32-7.38 (m, 2H), 7.24-7.30 (m, 1H), 7.04 (d, J = 7.5 Hz, 2H), 5.18 (dd, J = 3.5 Hz, 1H), 2.80-2.87 (m, 1H), 2.66-2.77 (m, 1H), 2.27 (dddd, J = 3.5 Hz, 1H), 1.98-2.07 (m, 1H), 1.63-1.81 (m, 2H).

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

[0411] Step 1. Preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate A solution of 1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (10 g, 42.9 mmol) in DMF (100 mL) was added to the flask at 0° C. 2 CO 3 (11.85 g, 86 mmol) and then iodomethane (8.01 mL, 129 mmol) were added. The mixture was heated at 30 °C for 2 h under N 2 The mixture was stirred under atmospheric pressure for 2 hours. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated NH 4Cl aqueous solution and brine, and then anhydrous Na 2 SO 4 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. 11 H 19 FNO 4 [M+H] + Calculated value: 248; Measured value: 248.

[0412] Step 2. Preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate A solution of sodium periodate (55.0 g, 257 mmol) and ruthenium(iii) chloride hydrate (9.66 g, 42.9 mmol) in water (450 mL) was stirred at 25° C. for 5 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 was stirred at 25° C. for 12 h. To the mixture was added IPA (100 mL) and the reaction was stirred at 25° C. for 3 h. The mixture was filtered, the filtrate was extracted with EtOAc (2×500 mL) and the combined organic layers were washed with brine and diluted with Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 50% EtOAc / petroleum ether gradient at 60 mL / min) to give 1-(tert-butyl)-2-methyl-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate. 6 H 8 FNO 3 [M-Boc+H] + Calculated value: 162; Measured value: 162.

[0413] Step 3. Preparation of methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-2-carboxylate A mixture of 1-(tert-butyl)-2-methyl-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate (5 g, 19.14 mmol) in DCM (45 mL) and TFA (15 mL) was stirred at 25° C. for 1 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. 6 H 8 FNO 3 [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 diluted with saturated NaHCO 3 (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude methyl-4-fluoro-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate, which was used in the next step without further purification. 7 H 11 FNO 3 [M+H] + Calculated value: 176; Measured value: 176.

[0415] Step 5. Preparation of methyl (2S,4S)-4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate To a solution of methyl-4-fluoro-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (1.8 g, 10.28 mmol) in MeOH (6 mL) was added methyl hydrazine carboxylate (1.018 g, 11.30 mmol) and HCl / MeOH (0.5 mL) at 20° C. The resulting mixture was diluted with N 2The mixture was stirred at 80° C. under reduced pressure for 2 hours. The reaction was cooled to room temperature and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 10% MeOH / EtOAc gradient at 60 mL / min) to give methyl 4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. 8 H 13 FN 3 O 4 [M+H] + Calculated value: 234; Measured value: 234.

[0416] Step 6. Preparation of intermediate I-38A A mixture of methyl (2S,4S)-4-fluoro-5-(2-(methoxycarbonyl)hydrazinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (600 mg, 2.57 mmol) in DMF (20 mL) was diluted with N 2 The mixture was stirred at 145° C. under reduced pressure for 12 hours. The reaction was cooled to room temperature and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 10% MeOH / EtOAc gradient at 60 mL / min) to give I-38A, methyl (5S,7S)-7-fluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate. 7 H 9 FN 3 O 3 [M+H] + Calculated value: 202; measured value: 202. 1 H NMR (400 MHz, CD 3 OD) 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] TIFF0007680639000103.tif255153

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

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

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

[0421] Step 1. Preparation of 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid To a solution of methyl 3-cyanobicyclo[1.1.1]pentane-1-carboxylate (170 mg, 1.13 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (81 mg, 3.37 mmol). The reaction was stirred at 20° C. for 12 h. TLC showed the starting material was consumed and a new spot was observed. To the reaction was added water (4 mL) and the mixture was extracted with ethyl acetate (1×2 mL). The aqueous layer was acidified to pH 4 with 2M HCl and extracted with EtOAc (3×2 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid, which was used in the next step without further purification.

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

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

[0424] Table B. Chemical structures of intermediates I-1B to I-19B [Table 3] TIFF0007680639000107.tif164168

[0425] General diagram 1 [ka]

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

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

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

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

[0430] Intermediate I-9A (20mg, 0.084mmol), Cu(OAc) 2 (11.04mg, 0.042mmol), Ir(ppy) 3A mixture of I-2B (1.104 mg, 1.69 μmol) and intermediate I-2B (85 mg, 0.169 mmol) in MeCN (2 mL) was irradiated with a 450 nm blue LED lamp and heated with N 2 The mixture was stirred at 25° C. for 2 h under reduced pressure. LCMS showed 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 (NH 3 H 2 O+NH 4 HCO 3 The enantiomers were purified by SFC (method: column DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); conditions: 0.1% NH 3 H 2 O / EtOH) to give (R)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (SFC-P1, ee=100%) and compound 1-40 ((S)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one) (SFC-P2, ee=100%).

[0431] (R)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one: 1 H NMR (400 MHz, CDCl 3 ) 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 = 2.0Hz, 6H). (S)-5-(2,6-difluorophenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (1-40): 1 H NMR (400 MHz, CDCl 3 ) 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 = 2.0Hz, 6H).

[0432] Table 1. [Table 4] TIFF0007680639000112.tif255161TIFF0007680639000113.tif255167TIFF0007680639000114.tif255167 TIFF0007680639000115.tif255160TIFF0007680639000116.tif255163TIFF0007680639000117.tif255164 TIFF0007680639000118.tif253169TIFF0007680639000119.tif255166TIFF0007680639000120.tif255160 TIFF0007680639000121.tif250169TIFF0007680639000122.tif254170TIFF0007680639000123.tif154168

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

[0434] A solution of compound 1-18 (240 mg, 0.664 mmol) in THF (5 mL) was added to 25 °C with N 2Lithium borohydride (0.664 mL, 1.33 mmol) was added dropwise and the reaction was stirred at 25° C. for 1 h. LCMS showed the reaction was complete. The mixture was diluted with H 2 The mixture was added to 200 mL of EtOAc (20 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C. for 1 hour, filtered, and concentrated to give intermediate I-3A (S)-5-(3,5-difluorophenyl)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, which was used directly. 17 H 18 F 2 N 3 O 2 [M+H] + Calculated value: 334; Measured value: 334.

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

[0436] Compound 1-18 (300 mg, 0.830 mmol) in MeOH / THF / H 2 To a solution in 2H2O (3 / 3 / 1, by volume) (10 mL) was added lithium hydroxide (23.86 mg, 0.996 mmol) at 25 °C, and the resulting mixture was stirred for 16 h at 25 °C. Water (30 mL) and EtOAc (10 mL) were added, and the mixture was extracted with EtOAc (2 x 8 mL). The organic layer was discarded. The pH of the aqueous layer was adjusted to about 4.0 by adding aqueous HCl (3 M) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (30 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and the filtrate was evaporated under reduced pressure to give intermediate I-2C(S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid. 17 H 16 F 2 N 3 O 3 [M+H] + Calculated value: 348; Measured value: 348.

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

[0438] To a solution of intermediate I-1C (35 mg, 0.100 mmol) in DCM (2 mL) was added DIEA (0.035 mL, 0.199 mmol) and Ms-Cl (0.014 mL, 0.175 mmol) at 0° C. and the mixture was stirred at 25° C. for 1 h. LCMS showed the reaction was complete. Water (10 mL) and DCM (10 mL) were added and the mixture was extracted with DCM (3×6 mL) and Na 2 SO 4 The mixture was dried over 4000 K, filtered, and concentrated to give the crude product, which was purified by preparative TLC (SiO 2 , petroleum ether / EtOAc) to give I-3C(S)-(3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate. 18 H 20 F 2 N 3 O 4 S[M+H] + Calculated value: 412; Measured value: 412.

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

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

[0441] CH of I-1C (50 mg, 0.150 mmol) 2 Cl 2 To the solution in (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 diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (10 mL) and extracted with DCM (3 x 6 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., 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; condition: water (TFA)-ACN) to give compound 2-1 ((5S)-5-(3,5-difluorophenyl)-2-[3-(methoxymethyl)bicyclo[1.1.1]pentan-1-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one). 18 H 20 F 2 N 3 O 2 [M+H] + Calculated value: 348; Measured value: 348. 1 H NMR (400 MHz, CD 3OD) δ 6.87-6.97 (m, 3H), 5.21 (dd, J = 4.8, 8.0 Hz, 1H), 3.53 (s, 2H), 3.36 (s, 3H), 2.78-3.10 (m, 3H), 2.35-2.45 (m, 1H), 2.19 (s, 6H).

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

[0443] A stock solution of 0.3M I-2C in DMSO (10 μL, 3 μmol) was added to a 384-well plate, followed by a solution of 0.5M thiophen-2-ylmethanamine in DMSO (24 μL, 12 μmol). A solution of 0.8M n-propylphosphonic anhydride in DMF (7.5 μL, 6 μmol) was then added, the reaction plate was sealed, and stirred overnight at room temperature. After 16 h, the reaction was diluted to 100 μL with DMSO, filtered, and analyzed by RP-HPLC (Method: Column XBridge BEH C18 OBD Prep Column, 130A, 5 μm, 10 mm × 50 mm; Conditions: 0.16% TFA, 20% to 55% ACN / H2O ... 2 O) to give compound 2-2. 22 H 21 F 2 N 4 O 2 S[M+H] + Calculated value: 443; Measured value: 443.

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

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

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

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

[0448] Step 1. Preparation of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide To a solution of I-2C (220 mg, 0.633 mmol) in DCM (6 mL) was added TEA (0.309 mL, 2.217 mmol) and N,O-dimethylhydroxylamine hydrochloride (93 mg, 0.950 mmol) at 25° C. The mixture was cooled to 0° C. and a solution of 1-propanephosphonic anhydride (685 mg, 1.08 mmol) was added to N 2 The mixture was stirred at 25° C. for 16 h. Water (30 mL) and EtOAc (10 mL) were added. The mixture was extracted with EtOAc (2×10 mL), washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was evaporated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide. 19 H 21 F 2 N 4 O 3 [M+H] + Calculated value: 391; Measured value: 391.

[0449] Step 2. Preparation of Compound 2-5 To a solution of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (230 mg, 0.589 mmol) in THF (8 mL) was added methylmagnesium bromide (0.236 mL, 0.707 mmol) at -5°C and the resulting mixture was stirred at -5°C for 2 h. The mixture was allowed to warm slowly to 25°C and the reaction was stirred at 25°C for 16 h. Saturated NH 4 Cl (20 mL) and EtOAc (10 mL) were added, and the mixture was extracted with EtOAc (2 x 8 mL), washed with brine (20 mL), and anhydrous Na 2 SO4 The mixture was dried at 400 C and filtered, and the filtrate was evaporated under reduced pressure to give an oil, which was separated by preparative TLC (SiO 2 , petroleum ether / EtOAc=1 / 2) to give compound 2-5. 18 H 18 F 2 N 3 O 2 [M+H] + Calculated value: 346; Measured value: 346. 1 H NMR (400 MHz, CDCl 3 ) δ 6.71-6.81 (m, 3H), 5.12 (dd, J = 4.4, 8.0 Hz, 1H), 2.76-3.07 (m, 3H), 2.55 (s, 6H), 2.42 (tdd, J = 4.8, 8.4a, 13.2 Hz, 1H), 2.20 (s, 3H).

[0450] Table 2 [Table 6]

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

[0452] Step 1. Preparation of methyl (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate In a glove box, two 20 mL red capped vials containing intermediate I-2A (80 mg, 0.337 mmol) were charged with I-19B (568 mg, 0.675 mmol), Ir(ppy) 3 (2.21mg, 3.37μmol), and Cu(OAc) 2(22.1 mg, 0.084 mmol). The vial was placed in a 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 / hexanes) to give a crude mixture containing the product, which was subjected to EKB purification (TFA as modifier). The sample was lyophilized to give (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate. 18 H 16 F 4 N 3 O 3 [M+H] + Calculated value:,398; Measured value:398.

[0453] Step 2. Preparation of (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylic acid To a 20 mL red 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) was added MeOH (658 μL), MeOH (658 μL), and LiOH (219 μL, 0.219 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was carefully quenched with 2N HCl (110 μL) to pH approx. 3 and extracted 3 times with EtOAc. The combined organic layers were washed with MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered, and concentrated to give crude (S)-3-(5-(3,5-difluorophenyl)-3-oxo-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylic acid, which was used directly without further purification. 17 H 14 F4 N 3 O 3 [M+H] + Calculated value: 384; Measured value: 384.

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

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

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

[0457] Step 1. Preparation of methyl (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylate 3-2 Intermediate I-1A (60mg, 0.298mmol), Cu(OAc) 2 (39.0mg, 0.149mmol), Ir(ppy) 3 A mixture of I-19B (3.90 mg, 5.96 μmol) and I-19B (391 mg, 0.596 mmol) in MeCN (5960 μL) was stirred at 4° C. for 1 hour at 4° C. for 24 hours. 2 The mixture was stirred at 25° C. for 1 hour under irradiation with a 450 nm blue LED lamp. The mixture was concentrated under reduced pressure. The residue was then purified by preparative HPLC (method: column Boston Green ODS 150×30 mm×5 μm; condition: water (0.01% TFA)-CAN) to give methyl (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxylate (3-2). 18 H 18 F 2 N 3 O 3 [M+H] + Calculated value: 362; Measured value: 362.1 H NMR (400 MHz, CDCl 3 ): 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 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) NH 3 The solution in 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. 17 H 17 F 2 N 4 O 2 [M+H] + Calculated value: 347; Measured value: 347.

[0459] Step 3. Preparation of compound 3-3 To a solution of (S)-2,2-difluoro-3-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)bicyclo[1.1.1]pentane-1-carboxamide (45 mg, 0.130 mmol) in pyridine (2 mL), 2,2,2-trifluoroacetic anhydride (109 mg, 0.520 mmol) was added and the mixture was stirred at 25° C. for 1 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-NH 4HCO 3 )-ACN) to give compound 3-3. 17 H 15 F 2 N 4 O[M+H] + Calculated value: 329; Measured value: 329. 1 H NMR (400 MHz, CDCl 3 ): δ 7.32-7.43 (m, 3H), 7.20-7.25 (m, 2H), 5.17 (dd, J = 7.6, 4.4 Hz, 1H), 2.99-3.06 (m, 1H), 2.98 (s, 2H), 2.91-2.97 (m, 1H), 2.80-2.90 (m, 1H), 2.53-2.60 (m, 2H), 2.51 (dd, J = 9.2, 4.4 Hz, 1H).

[0460] Table 3 [Table 7]

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

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

[0463] Step 2. Preparation of 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid To a mixture of methyl 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (195 mg, 0.711 mmol) in THF / water = 3 / 1 was added LiOH (51.1 mg, 2.133 mmol). The mixture was stirred at room temperature for 1 h. 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 x 20 mL) and the combined organic layers were washed with brine (2 x 5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give 2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid. 12 H 13 N 4 O 3 [M+H] +Calculated value: 261; Measured value: 261.

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

[0465] Table D [Table 8]

[0466] General diagram 2a [ka]

[0467] In general scheme 2a, intermediate I-7A and intermediate I-7B in Table B are coupled under photoreduction-oxidation conditions in the presence of copper and iridium catalysts. Subsequent hydrolysis of the product affords the corresponding acid. Treatment with the desired aryl halide under Ni catalysis affords the desired product listed in Table 4.

[0468] General diagram 2b [ka]

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

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

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

Claims

1. (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; 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

3. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable carrier.

4. A pharmaceutical composition according to claim 2 or 3 for the treatment of RIPK1-dependent inflammation and cell death that occurs in genetic and sporadic diseases including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis and acute tissue damage caused by stroke, traumatic brain injury, encephalitis.

5. The pharmaceutical composition according to claim 2 for the treatment of amyotrophic lateral sclerosis.

6. The pharmaceutical composition according to claim 4 for the treatment of amyotrophic lateral sclerosis.

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