WO2025072451A1 - Ras-pi3k inhibitors for the treatment of cancer and immunological diseases - Google Patents

Ras-pi3k inhibitors for the treatment of cancer and immunological diseases Download PDF

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Publication number
WO2025072451A1
WO2025072451A1 PCT/US2024/048567 US2024048567W WO2025072451A1 WO 2025072451 A1 WO2025072451 A1 WO 2025072451A1 US 2024048567 W US2024048567 W US 2024048567W WO 2025072451 A1 WO2025072451 A1 WO 2025072451A1
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Prior art keywords
methylsulfonyl
carboxamide
pyrazine
fluorophenyl
chloro
Prior art date
Application number
PCT/US2024/048567
Other languages
French (fr)
Inventor
Cynthia BERRY
Owen HEARNE
Chung Mao Pan
Junko Tamiya
Hideki Miyatake Ondozabal
Igor Mochalkin
Robert MALMSTROM
Fabian GOERICKE
David Weinstein
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Vividion Therapeutics, Inc.
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Publication date
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Publication of WO2025072451A1 publication Critical patent/WO2025072451A1/en

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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions

  • a RAS- PI3K agonist Some aspects relate to a RAS-PI3K inhibitor. Some aspects relate to a RAS-PI3K inhibitor.
  • the RAS-PI3K modulators may include a compound described herein.
  • the RAS-PI3K modulators may be useful in a method described herein.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; and at least one pharmaceutically acceptable excipient.
  • a method of modulating RAS-PI3K comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.
  • the method comprises inhibition of RAS- PI3K.
  • the method comprises activation of RAS-PI3K.
  • a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.
  • the disease or condition is mediated by the 1 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC modulation of RAS-PI3K.
  • the disease is cancer.
  • the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the condition is wound healing.
  • each is a single bond when X 8 is CH 2 and is absent when X 8 is absent; each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N; or X 1 is C, X 4 is N or C, and X 1 and X 4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-3 R 10 , and each of X 2 and X 3 is independently CR 3 or N, wherein not more than one of X 2 and X 3 is N; R 1 is C 1 -C
  • each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N;
  • R 1 is C 1 -C 6 alkyl;
  • R 2 is hydrogen or C 1 -C 6 alkyl;
  • each R 3 is independently hydrogen, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -C(O)NR 4 R 5 , or -O-C1-C6 alkyl;
  • each of R 4 and R 5 is independently hydrogen or C 1 -C 6 alkyl;
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH
  • R 1 and R 2 are methyl.
  • one of X 1 and X 4 is N.
  • one of X 2 and X 3 is N.
  • X 1 is N.
  • X 3 is N.
  • X 2 and X 4 are each CR 3 .
  • each of X 1 , X 2 , X 3 and X 4 is CR 3 .
  • each R 3 is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy.
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 .
  • X 5 and X 6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R 8 .
  • each R 8 is independently chloro or fluoro.
  • each R 6 is independently chloro, fluoro, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, C 1 -C 3 haloalkyl, or C 1 -C 3 hydroxyalkyl.
  • each R 7 is independently chloro, fluoro or C 1 -C 3 alkyl.
  • ring A is phenyl.
  • the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X 5 and X 6 are each CH and together with one additional carbon atom form a
  • the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2;
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2;
  • X 5 and X 6 are each CH and together with one additional carbon
  • the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof: 6 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X
  • the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2;
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X 5 and X 6 are each CH and together with one additional carbon atom form a fuse
  • the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2;
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ;
  • X 5 and X 6 are each CH and together with one additional carbon atom form a fused cyclo
  • the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof: 8 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or
  • the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; 9 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or
  • the present disclosure provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) as disclosed above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.
  • the present disclosure provides a method of inhibiting RAS-PI3K in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa), or a pharmaceutically salt, solvate, or stereoisomer thereof.
  • the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the disease is cancer.
  • the cancer is selected from the group of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the disease or condition is an immunological disease or condition.
  • the immunological condition is wound healing deficiency.
  • the present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of cancer. 10 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [0041]
  • the use of the compound is to treat bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, or pancreatic cancer.
  • the present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of an immunological disease or condition.
  • the immunological condition addressed by the use is wound healing deficiency.
  • the present disclosure provides for a method treating cancer comprising administering a sufficient amount of a compound disclosed herein, such as a compound of Formula (I) or Formula I(a) to a subject in need thereof.
  • the subject is a human subject.
  • the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the present disclosure provides for methods of promoting wound healing, comprising administering to a subject in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing.
  • the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa) in the treatment of cancer or the promotion of wound healing. [0047] In some aspects, the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa) in the formulation of a medicament useful for the treatment of cancer or the promotion of wound healing. INCORPORATION BY REFERENCE [0048] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
  • RAS proteins are small GTPases known for their involvement in oncogenesis. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate cellular functions such as cell proliferation, differentiation, apoptosis, and senescence.
  • Phosphatidylinositol 3- kinase is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell 11 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC survival, cytoskeleton reorganization, and metabolism. It is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro. Mice with mutations in the PI3K catalytic subunit p110 ⁇ that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRAS-induced lung tumorigenesis and HRAS-induced skin carcinogenesis.
  • the compound is used for treatment of cancer.
  • Compounds of the Disclosure provides for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein: each is a single bond when X 8 is CH 2 and is absent when X 8 is absent; each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N; or X 1 is C, X 4 is N or C, and X 1 and X 4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-3 R 10 , and each of X 2 and X 3 is independently CR 3 or N, wherein not more than one of X 2 and X 3 is N; R 1 is C 1 -C 6 alkyl or
  • each of R 1 and R 2 is independently methyl or cyclopropyl.
  • one of X 1 and X 4 is N.
  • one of X 2 and X 3 is N.
  • X 3 is N. 13 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC
  • X 1 is N.
  • X 4 is N.
  • X 2 and X 4 are each CR 3 .
  • each of X 1 , X 2 , X 3 and X 4 is CR 3 .
  • X 1 is C
  • X 4 is N or C
  • X 1 and X 4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring, wherein the fused 5-membered aromatic ring is substituted with 0-1 R 10
  • X 2 and X 3 are each CR 3 .
  • each R 3 is independently hydrogen, chloro, fluoro, methyl, methoxy, -CF 2 , -CF 3 , or -CN.
  • X 5 and X 6 are each CH2, substituted with 0-2 R 6 , and X 7 and X 8 are each absent.
  • X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 , substituted with 0-2 R 6 , CH 2 NR 6 CH 2 , or C(O)NR 6 CH 2 , and X 8 is absent.
  • each X 5 and X 6 is independently CH or C, substituted with 0-1 R 6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R 8 , and X 7 and X 8 are each absent.
  • X 5 and X 6 are each CH, substituted with 0-1 R 6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R 8 .
  • X 5 is CH
  • X 6 is CH 2
  • X 7 is N
  • X 5 and X 7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring
  • X 8 is absent.
  • X 5 and X 6 are each CH
  • X 7 is CH 2 or O
  • X 8 is CH 2 .
  • each R 6 is independently fluoro, chloro, oxo, -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 heterocyclyl; or two R 6 together with a ring atom form a C 3 -C 6 spirocyclic ring or a C 3 -C 6 spiroheterocyclic ring.
  • each R 7 is independently fluoro, chloro, -OCH 3 , -CF 3 , -OCF 3 , or C 1 -C 3 alkyl.
  • each R 8 is independently fluoro, chloro, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxyl, cyclopropyl, oxetanyl, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -C 1 -C 3 alkylene-R 9 , or -C 1 -C 3 alkylene-O-R 9 .
  • ring A is phenyl. 14 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [0072] In some embodiments of Formula (I), ring A is pyridinyl or cyclohexyl. [0073] In some embodiments of Formula (I), R 10 is methyl.
  • the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(
  • the compound is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: 15 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(
  • the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof: 16 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2
  • the compound is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: 17 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C1-C3 alkyl or C3-C6 cycloalkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 ,
  • X 5 and X 6 are each CH, substituted with 0-1 R 6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R 8 .
  • the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; R 2 is hydrogen, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH
  • the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 SCH 2 CH 2 , CH
  • the compound is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof: 20 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; or X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 SCH 2 CH 2 , CH 2 SCH
  • the compound is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof: 21 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C1-C3 alkyl; X 4 is C or N; X 9 is CH or NR 10 ; X 5 and X 6 are each CH 2 , substituted with 0-2 R 6 , and X 7 and X 8 are each absent; each R 6 is independently halogen, hydroxyl, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 3 -C 6 cycloalkyl, or two R 6 together with a ring atom form a C 3 -C 6 spirocyclic ring or a C 3 -
  • the compound is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof: wherein: each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N; or 22 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC X 1 is C, X 4 is N or C, and X 1 and X 4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-1 R 10 , and each of X 2 and X 3 is independently CR 3 or N, wherein not more than one of X 2 and X 3 is N; R 1 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; R 2 is
  • each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N.
  • X 5 and X 6 are each CH, substituted with 0-1 R 6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R 8 .
  • ring A is phenyl.
  • the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof: wherein: each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N; R 1 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3 is independently hydrogen, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; X 5 , X 6 and X 7 together are CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2
  • the compound is a compound of Formula (XII), or a pharmaceutically acceptable salt or solvate thereof: 24 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N; R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3 is independently hydrogen, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 alkyl; X 5 and X 6 are each CH, X 7 is CH 2 or O, and X 8 is CH 2 ; ring A is aryl; each R 7 is independently halogen, C 1 -C 3 al
  • the compound is selected from the group of: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-
  • each of X 1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X 2 and X 3 is N;
  • R 1 is C 1 -C 6 alkyl;
  • R 2 is hydrogen or C 1 -C 6 alkyl;
  • each R 3 is independently hydrogen, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -C(O)NR 4 R 5 , or -O-C 1 -C 6 alkyl;
  • each of R 4 and R 5 is independently hydrogen or C 1 -C 6 alkyl;
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2
  • R 1 and R 2 are methyl.
  • one of X 1 and X 4 is N.
  • one of X 2 and X 3 is N.
  • X 1 is N.
  • X 3 is N.
  • X 2 and X 4 are each CR 3 .
  • each of X 1 , X 2 , X 3 and X 4 is CR 3 .
  • each R 3 is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy.
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 .
  • X 5 and X 6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R 8 .
  • each R 8 is independently chloro or fluoro.
  • each R 6 is independently chloro, fluoro, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, C 1 -C 3 haloalkyl, or C 1 -C 3 hydroxyalkyl.
  • each R 7 is independently chloro, fluoro or C 1 -C 3 alkyl.
  • ring A is phenyl.
  • the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: 51 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2
  • the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; 52 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X
  • the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2;
  • X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X 5 and X 6 are each CH and together with one additional carbon atom form a fuse
  • the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2;
  • X 5 is CH2, wherein X 5 and X 6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ;
  • X 5 and X 6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein: R 1
  • the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: 54 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X
  • the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; 55 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or
  • the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; each R 3a is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or -O-C 1 -C 3 alkyl; z is 0, 1, or 2; X 5 is CH 2 , wherein X 5 and X 6 together are CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 OCH 2 , CH 2 OCH 2 CH 2 , CH 2 CH 2 OCH 2 , CH 2 SCH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 C(O)CH 2 or CH 2 S(O)CH 2 ; or X 5 and X 6 are each CH and together with one additional carbon atom form a
  • the present disclosure provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) as disclosed above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.
  • the present disclosure provides a method of inhibiting RAS-PI3K in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa), or a pharmaceutically salt, solvate, or stereoisomer thereof.
  • the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the disease is cancer.
  • the cancer is selected from the group of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the disease or condition is an immunological disease or condition.
  • the immunological condition is wound healing deficiency.
  • the present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of cancer.
  • the use of the compound is to treat bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, or pancreatic cancer.
  • the present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of an immunological disease or condition.
  • the immunological condition addressed by the use is wound healing deficiency.
  • the present disclosure provides for a method treating cancer comprising administering a sufficient amount of a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) to a subject in need thereof.
  • the subject is a human subject.
  • the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck 57 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the present disclosure provides for methods of promoting wound healing, comprising administering to a subject in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing.
  • the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa) in the treatment of cancer or the promotion of wound healing. [00126] In some aspects, the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa)in the formulation of a medicament useful for the treatment of cancer or the promotion of wound healing. [00127] In some aspects, the present disclosure provides for a method treating cancer comprising administering a sufficient amount of a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) to a subject in need thereof. In some aspects, the subject is a human subject.
  • the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the present disclosure provides for methods of promoting wound healing, comprising administering to a subject in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing.
  • a compound disclosed herein such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing.
  • a compound disclosed herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Furthermore, the compounds may exist as atropisomers.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of 58 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • Jacques J., et al. “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981.
  • stereoisomers are obtained by stereoselective synthesis.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug.
  • prodrug may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions. Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.
  • the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon14 ( 14 C).
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 5 , R 6 , R 7 , R 8 groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R 1 , R 2 , R 3 , R 4 , R 5 , R 5 , R 6 , R 7 , R 8 .
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 5 , R 6 , R 7 , R 8 is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, 60 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [00145] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • “Pharmaceutically acceptable” as used herein refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with acids.
  • Pharmaceutically acceptable salts are also obtained by reacting a compound disclosed herein with a base to form a salt.
  • Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts.
  • the type of pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic
  • compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein may 61 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compositions [00150] in another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the manufacture of a medicament.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, 62 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC preservatives, or one or more combination thereof.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • compositions described herein are administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections
  • intranasal buccal
  • topical or transdermal administration routes e.g., topical or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • the compounds disclosed herein are administered orally.
  • the compounds disclosed herein are administered topically.
  • the compound disclosed herein is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments.
  • the compounds disclosed herein are administered topically to the skin.
  • the compounds disclosed herein are administered by inhalation.
  • the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.
  • the compounds disclosed herein are formulated as eye drops.
  • the effective amount of the compound disclosed herein is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non- systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) the compound is administered continually; or (iv) the compound is administered continuously.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the 63 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound disclosed herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the compound disclosed herein is administered in a local rather than systemic manner.
  • the compound disclosed herein is administered topically.
  • the compound disclosed herein is administered systemically.
  • the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds disclosed herein are in the form of a capsule.
  • liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.
  • a compound disclosed herein is formulated for use as an aerosol, a mist or a powder.
  • the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.
  • compounds disclosed herein are prepared as transdermal dosage forms.
  • a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.
  • the compound disclosed herein is be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.
  • the method comprises inhibiting RAS-PI3K.
  • the method comprises activating RAS-PI3K.
  • a method of treating a disease or condition comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.
  • the disease or condition is mediated by RAS-PI3K.
  • the disease is a cancer.
  • the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, lung cancer, colorectal cancer, cervical cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.
  • the immunological condition is a wound healing.
  • administration of a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof promotes wound healing.
  • the compounds disclosed herein are used in the preparation of medicaments for the treatment of diseases or conditions described herein.
  • a method for treating any of the diseases 65 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said subject.
  • the compositions containing the compound disclosed herein are administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. [00181] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • Doses employed for adult human treatment are typically in the range of 0.01mg - 5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.
  • Combination Treatments [00184] In certain instances, it is appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent.
  • a compound disclosed herein is co-administered with a second therapeutic agent, wherein the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth.
  • the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.
  • 66 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC Definitions
  • the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.
  • the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
  • Alkyl refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C 1 -C 10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C 1 -C 6 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly.
  • Alkyl groups include, but are not limited to, C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 - C 8 alkyl, C 1 -C 7 alkyl, C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl, C 2 -C 8 alkyl, C 3 -C 8 alkyl and C 4 -C 8 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, npropyl, 1methylethyl (ipropyl), nbutyl, i-butyl, s-butyl, npentyl, 1,1dimethylethyl (tbutyl), 3methylhexyl, 2methylhexyl, 1-ethyl-propyl, and the like.
  • the alkyl is methyl or ethyl.
  • an alkyl group may be optionally substituted as described below.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group.
  • the alkylene is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. In some embodiments, the alkylene is -CH 2 -. In some embodiments, the alkylene is -CH 2 CH 2 -. In some embodiments, the alkylene is -CH 2 CH 2 CH 2 -. [00193] “Alkoxy” refers to a radical of the formula OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy.
  • the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.
  • “Heteroalkyl” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N (i.e., NH, N-alkyl) or S atom.
  • “Heteroalkylene” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below.
  • heteroalkyl groups include, but are not limited to -OCH 2 OMe, - OCH 2 CH 2 OMe, or -OCH 2 CH 2 OCH 2 CH 2 NH 2 .
  • Representative heteroalkylene groups include, but are not limited to -OCH 2 CH 2 O-, -OCH 2 CH 2 OCH 2 CH 2 O-, or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O-. 67 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00195] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above.
  • an alkylamino group may be optionally substituted as described below.
  • aromatic refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • Aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted.
  • aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. [00198] “Carboxy” refers to -CO 2 H.
  • carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
  • a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
  • a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
  • a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
  • Cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms.
  • a cycloalkyl is a C 3 -C 6 cycloalkyl.
  • the cycloalkyl is monocyclic, bicyclic or polycyclic.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 68 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, decalinyl and adamantyl.
  • the cycloalkyl is monocyclic.
  • Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the cycloalkyl is bicyclic.
  • Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups.
  • cycloalkyl groups are selected from among spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalen- 1(2H)-one and decalinyl.
  • the cycloalkyl is polycyclic.
  • Polycyclic radicals include, for example, adamantyl, and.
  • the polycyclic cycloalkyl is adamantyl.
  • a cycloalkyl group may be optionally substituted.
  • “Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2trifluoroethyl, 1,2difluoroethyl, 3bromo2fluoropropyl, 1,2dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • Haloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2trifluoroethoxy, 1,2difluoroethoxy, 3bromo2fluoropropoxy, 1,2dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.
  • Heterocycloalkyl or “heterocyclyl” or “heterocyclic ring” refers to a stable 3 to 14 membered nonaromatic ring radical comprising 2 to 10 carbon atoms and from one to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic ring (which may include a fused bicyclic heterocycloalkyl (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), bridged heterocycloalkyl or spiro heterocycloalkyl), or polycyclic.
  • the heterocycloalkyl is monocyclic or bicyclic.
  • the heterocycloalkyl is monocyclic.
  • the heterocycloalkyl is bicyclic.
  • the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized.
  • the nitrogen atom may be optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • Examples of such heterocycloalkyl radicals 69 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
  • heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.
  • heterocycloalkyls have from 2 to 10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.
  • Heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl is monocyclic or bicyclic.
  • Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quin
  • monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0- 4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C 1 -C 9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C 1 -C 5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • a bicyclic heteroaryl is a C 6 - C 9 heteroaryl.
  • the term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, 70 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C 1 -C 6 alkylalkyne, halogen, acyl, acyloxy, -CO 2 H, -CO 2 alkyl, nitro, and amino, including mono and disubstituted amino groups (e.g., -
  • optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OH, -CO 2 H, and -CO 2 alkyl.
  • optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • tautomeric interconversions include: [00208]
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • effective amount or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, 71 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC or reduce one or more symptoms of a disease or condition).
  • an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a compound of Formula (I) or Formula (Ia) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g., a compound of Formula (I) or Formula (Ia) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • subject or patient encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Table 1 Compounds of the Disclosure.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols.
  • the reaction takes place in the presence of a ligand/catalyst system such as SPhos Pd G4, RuPhos Pd G4, XantPhos/Pd 2 (dba) 3 , and the like; a base such as Cs 2 CO 3 , and the like; in a suitable solvent such as toluene; and the like; at temperatures of 80-110 °C for a period of 16-24 hours to provide a compound of formula (IV).
  • a ligand/catalyst system such as SPhos Pd G4, RuPhos Pd G4, XantPhos/Pd 2 (dba) 3 , and the like
  • a base such as Cs 2 CO 3 , and the like
  • a suitable solvent such as toluene
  • a compound of formula (V) may be obtained directly.
  • a compound of formula (IV) can be synthesized from a compound of formula (II) and a compound of formula (III) under nucleophilic aromatic substitution (SNAr) conditions.
  • SNAr nucleophilic aromatic substitution
  • a compound of formula (II), wherein X 1 , X 2 , X 3 , and X 4 are independently nitrogen or a substituted or unsubstituted carbon and Y is F or Cl is reacted under conventional S N Ar coupling conditions in the presence of a commercially available or synthetically accessible compound of formula (III).
  • a compound of formula (V) is prepared from a compound of formula (IV).
  • a compound of formula (IV) is reacted with an appropriate hydroxide such as aqueous LiOH, and the like; in a suitable solvent such as MeOH, ACN, THF, and the like; at temperatures of 25-80 °C for a period of 1-16 hours to provide a compound of formula (V).
  • an appropriate hydroxide such as aqueous LiOH, and the like
  • a suitable solvent such as MeOH, ACN, THF, and the like
  • a compound of formula (I), as defined in Claim 1 is prepared from a compound of formula (V) under amide coupling conditions known to one skilled in the art.
  • a carboxylic acid such as a compound of formula (V) is reacted with a coupling agent such as HATU, T 3 P ® , T 4 P and the like; in the presence of an amine such as a compound of formula (VI), wherein R 2 is hydrogen, C 1 -C 6 -alkyl, or C 3 -C 6 -cycloalkyl and R 1 is C 1 -C 6 -alkyl or C 3 -C 6 - cycloalkyl, and a base such as DIPEA, TEA, and the like; in a solvent such as DMSO, DMF, DCM, and the like; at rt for a period of 30 minutes to 16 hours to provide a compound of formula (I).
  • a coupling agent such as HATU, T 3 P ® , T 4 P and
  • a compound of formula (VII), wherein R 2 and R 1 are independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, can be formed from a compound of formula (XXXIII) using the appropriate phosphonate such as diethyl ((methylsulfonyl)methyl)phosphonate, diethyl ((ethylsulfonyl)methyl)phosphonate, and the like; with an appropriate base such as NaH, and the like; in a solvent such as THF, and the like; at 0 °C for 30 min before addition of a compound of formula (XXXIII). Reaction at 0 °C for a period of 1 hour provides a compound of formula (VII).
  • a compound of formula (VII) is treated with an acid such as TsOH, TFA, HCl, and the like; in a solvent such as ACN, MeOH, 1,4-dioxane, DCM, and the like; at 25-60 °C for a period of 1-12 h to provide a compound of formula (VI), where R 2 and R 1 are independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
  • Scheme 3 151 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00221]
  • a compound of formula (V) can be formed from a compound of formula (VIII).
  • Scheme 4 [00222] According to Scheme 4, a compound of formula (X), wherein X 1 and X 3 are independently N or CH and R 3 and R 7 are independently H or F, can be made from a compound of formula (IX) under reducing conditions using BH 3 ⁇ Me 2 S in a suitable solvent such as THF, and the like; at rt for a period of 16 hours.
  • Scheme 5 [00223] According to Scheme 5, a compound of formula (XII), wherein R 7 is H or F, X 5 and X 6 are CH 2 , X 7 is O or is absent, and X 8 is absent, can be formed from a compound of formula (XI) in the presence of CsF in a solvent such as DMF, and the like; at a temperature of 80 °C for a period of 16 hours.
  • a solvent such as DMF, and the like
  • Scheme 6 152 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC
  • a compound of formula (XIV) wherein X 3 is CH or N and R 3 is H or F, can be formed from a compound of formula (XIII) in the presence of NaIO 4 and RuCl 3 in an appropriate solvent such as water/ethyl acetate, and the like; at rt for a period of 16 hours.
  • a compound of formula (XV) can be subjected to the same conditions to form a compound of formula (XVI).
  • Scheme 7 [00225] According to Scheme 7, a compound of formula (IV) can be formed in three steps from a compound of formula (XVII).
  • a triflating agent such as trifluoromethanesulfonic anhydride, 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)s
  • a compound of formula (XVII), wherein X 2 is N, X 3 is CH, X 8 is absent, X 5 and X 6 are CH2 and X 7 is - CH 2 CH 2 -, is treated with diphenyl phosphorochloridate in the presence of a suitable base such as KHMDS, and the like; in a solvent such as THF, and the like; at -78 °C for a period of 1 h to provide a compound of formula (XVIII), where R a is PO(OPh) 2 .
  • boronic acid of formula (XIX) wherein A is a substituted aromatic ring, and a ligand/catalyst system such as Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , and the like; and a base such as K 2 CO 3 , Na 2 CO 3 , and the like; in a solvent such as 1,4-dioxane/water, DME, EtOH, and the like; at temperatures of 70-100 °C for a period of 2-17 hours provides a compound of formula (XX).
  • a compound of formula (IV) is formed from a compound of formula (XX) under standard hydrogenation conditions known to one skilled in the art.
  • a compound of formula (XX) is treated with PtO 2 , Pd/C, and the like; in a suitable solvent such as THF, MeOH, EtOAc, EtOH, and the like; at rt for 3-12 hours to provide a compound of formula (IV), where X 1 is CH, X 4 is CF, X 2 and X 3 are independently N or CH, X 8 is absent, X 5 and X 6 are CH 2 , X 7 is CH 2 , O, or - CH 2 CH 2 -, and A is a substituted aromatic ring.
  • Scheme 8 (XXII) [00228] According to Scheme 8, a compound of formula (XXII), wherein each R 7 is independently F or H, is formed from a compound of formula (XXI).
  • a compound of formula (XXI) is reacted with a Grignard reagent formed from the treatment of an appropriate halobenzene such as 1-chloro-2-iodobenzene, 1-bromo-2-chloro-3-fluorobenzene, 2- chloro-4-fluoro-1-iodobenzene, and the like; with iPrMgCl ⁇ LiCl in a solvent such as THF, and the like; at temperatures of -20-25 °C for up to 2 hours.
  • an appropriate halobenzene such as 1-chloro-2-iodobenzene, 1-bromo-2-chloro-3-fluorobenzene, 2- chloro-4-fluoro-1-iodobenzene, and the like
  • a compound of formula (XVI) can be reacted under conventional Grignard coupling conditions using (2-chloro-4-fluorophenyl)magnesium bromide, (2-chloro-3- fluorophenyl)magnesium bromide, (2-chlorophenyl)magnesium bromide, (2,3-difluorophenyl)magnesium bromide, (3-fluoro-2-methylphenyl)magnesium bromide and the like; in an appropriate solvent such as THF, and the like; at a temperature of 0 °C for a period of 2 hours to provide a compound of formula (XXIII), where A is a substituted aromatic ring.
  • a compound of formula (XXIII) can be formed by treating an aryl bromide such as 2-bromo-3-chloropyridine, 2-bromochlorobenzene, 2,6- difluorobromobenzene, and the like; with n-butyllithium at -78 °C for 1 h followed by addition of a compound of formula (XVI) in an appropriate solvent such as THF, and the like; at -78-25 °C for a period of 4-12 hours to provide a compound of formula (XXIII), where A is a substituted aromatic or heteroaromatic ring.
  • an aryl bromide such as 2-bromo-3-chloropyridine, 2-bromochlorobenzene, 2,6- difluorobromobenzene, and the like
  • n-butyllithium at -78 °C for 1 h
  • a compound of formula (XVI) in an appropriate solvent such as THF, and the like
  • a compound of formula (XXIII) is subjected to Boc deprotection conditions previously described in Scheme 2 to provide a compound of formula (XXIV).
  • a compound of formula (XXIV) is reacted under reductive amination conditions using NaBH 3 CN, NaBH 4 , and the like; in a solvent such as MeOH, EtOH, and the like; with acetic acid at rt for a period of 2-16 hours to provide a compound of formula (III).
  • a Mitsunobu coupling is needed to form a compound of formula (III) after the steps described above.
  • a compound of formula (III) can be formed.
  • Scheme 10 [00231] According to Scheme 10, a compound of formula (III) can be synthesized in five steps from a compound of formula (XXV).
  • a compound of formula (XXV) is Boc protected under conditions known to one skilled in the art using di-tert-butyl dicarbonate, DMAP, and an appropriate base such as TEA, and the like; in a solvent such as DCM, and the like; at rt for a period of 2-17 hours to provide 155 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC a compound of formula (XVI).
  • a compound of formula (XVI) is reacted under conditions previously described in Scheme 7 to form a compound of formula (XXVI), where R a is SO 2 CF 3 or PO(OPh) 2 .
  • a third step standard boronic acid coupling conditions previously described in Scheme 7 are employed.
  • a compound of formula (XXVI) is reacted with a compound of formula (XIX), wherein A is a substituted aromatic ring, to provide a compound of formula (XXVII).
  • a compound of formula (XXVII) can undergo hydrogenation as previously described in Scheme 7 followed by Boc deprotection as previously described in Scheme 2 to provide a compound of formula (III).
  • a compound of formula (XXVII) can be subjected to Boc deprotection conditions then reacted under reducing conditions using NaBH 4 , and the like; in a solvent such as MeOH, and the like; at rt for a period of 2-16 hours to provide a compound of formula (III).
  • Boc deprotection conditions then reacted under reducing conditions using NaBH 4 , and the like; in a solvent such as MeOH, and the like; at rt for a period of 2-16 hours to provide a compound of formula (III).
  • a first step 2-chlorobenzaldehyde is treated with 2-methylpropane-2- sulfinamide and Ti(OiPr) 4 in an appropriate solvent such as THF, and the like; at rt for a period of 16 h to provide N-(2-chlorobenzylidene)-2-methylpropane-2-sulfinamide.
  • N-(2- chlorobenzylidene)-2-methylpropane-2-sulfinamide is reacted under conventional Grignard coupling conditions previously described in Scheme 9 using allylmagnesium chloride to form N-(1-(2- chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide.
  • 1-(2- chlorophenyl)but-3-en-1-amine Treatment with an acid such as HCl, and the like; in a suitable solvent such as MeOH, and the like; at rt for a period of 2 h provides 1-(2- chlorophenyl)but-3-en-1-amine.
  • 1-(2-chlorophenyl)but-3-en-1-amine is treated with acetic anhydride and an appropriate base such as TEA, and the like; in a solvent such as DCM, and the like; at 0 °C for a period of 3 hours to provide N-(1-(2-chlorophenyl)but-3-en-1-yl)acetamide.
  • Boc protection previously described in Scheme 10 is used to obtain tert-butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxylate.
  • tert- butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxyl is treated with a suitable base such as K 2 CO 3 , and the like; in a solvent such as MeOH, and the like; at rt for a period of 1 hour to provide tert-butyl 2-(2- chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate.
  • tert-butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1-carboxylate is formed using oxalyl chloride, DMSO, and TEA in a solvent such as DCM, and the like; at -78 °C warming to rt for 1 h.
  • tert-butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1-carboxylate is treated with methyllithium in the presence of trichlorocerium, in a suitable solvent such as THF, and the like; at -78 °C for a period of 3 h to provide tert-butyl 2-(2-chlorophenyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylate.
  • Boc deprotection as previously described in Scheme 2 provides 5-(2-chlorophenyl)-3-methylpyrrolidin-3-ol, a compound of formula (III).
  • a compound of formula (XXXVII) can be synthesized from a compound of formula (XXVIII), wherein R 3 is F or H, X 1 and X 3 are dependently CH or N, and R b is H or CH 3 , in two steps.
  • a compound of formula (XXVIII) is treated with a suitable base such as K 2 CO 3 , and the like; in a solvent such as MeOH, and the like; at rt for a period of 1 hour to provide a compound of formula (XXIX).
  • a compound of formula (XXIX) is subjected to standard methylation conditions using an appropriate base such as NaH, and the like; and iodomethane in a solvent such as THF, and the like; at 0-25 °C for a period of 1-16 h.
  • R 3 is F and X 1 and X 3 are CH
  • a compound of formula (XXXVII) is formed wherein R b is CH 3 .
  • R 3 is H and X 1 and X 3 are N
  • a compound of formula (XXXVII) is formed wherein R b is H.
  • a compound of formula (V) can be synthesized from a compound of formula (XXIX) in three steps.
  • a compound of formula (XXIX) wherein R 3 is H and X 1 and X 3 are CH, is oxidized under conventional Swern oxidation conditions previously described in Scheme 12 to provide methyl 4-(2-(2-chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate.
  • methyl 4-(2-(2- chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate is treated with a fluorinating agent such as DAST, and the like; in a solvent such as DCM, and the like; at a temperature of -78 °C warming to rt over 4 hours to provide methyl 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate.
  • a third step methyl 4-(2-(2- chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate is treated with HBr at a temperature of 110 °C over a period of 2 hours to provide a compound of formula (V), where X 1 , X 2 , X 3 , and X 4 are CH, X 7 and X 8 are absent, X 5 is CF 2 , X 6 is CH 2 , and A is 2-chlorophenyl.
  • Scheme 15 [00236] According to Scheme 15, a compound of formula (III) can be formed in four steps from tert-butyl 4-oxopyridine-1(4H)-carboxylate.
  • tert-butyl 4-oxopyridine-1(4H)-carboxylate is reacted under Grignard coupling conditions using an appropriately substituted Grignard reagent such as (2- chlorophenyl)magnesium bromide, (2-chloro-3-fluorophenyl)magnesium bromide, and the like; and chlorotrimethylsilane in a solvent such as THF, and the like; at temperatures of -10-25 °C for a period of 16 hours to provide a compound of formula (XXX), where R 7 is F or H.
  • an appropriately substituted Grignard reagent such as (2- chlorophenyl)magnesium bromide, (2-chloro-3-fluorophenyl)magnesium bromide, and the like
  • chlorotrimethylsilane in a solvent such as THF, and the like
  • a compound of formula (XXXI), wherein R 7 is H is treated with ethylene glycol and TsOH in toluene at 120 °C for 16 h to provide tert-butyl 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate.
  • tert-butyl 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate is subjected to Boc deprotection conditions previously described in Scheme 2 to provide 7-(2-chlorophenyl)-1,4-dioxa-8- azaspiro[4.5]decane.
  • methyl 4-(7-(2- chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-fluorobenzoate is treated with 10% H 2 SO 4 in a solvent such as THF, and the like; at rt for up to 96 hours to provide methyl 4-(2-(2-chlorophenyl)-4- oxopiperidin-1-yl)-2-fluorobenzoate, a compound of formula (IV).
  • Scheme 17 [00238] According to Scheme 17, a compound of formula (III) can be synthesized in three steps from a compound of formula (XXIII).
  • a compound of formula (XXXIII) can be reduced using an appropriate 159 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC reducing agent such as LiAlH 4 , NaBH 4 , and the like; in a solvent such as MeOH, and the like; at rt for a period of 2-16 hours to provide a compound of formula (XXXIV).
  • a compound of formula (XXXIV) is treated with tosyl chloride, DMAP, and a base such as TEA, and the like; in a solvent such as ACN, DCM, and the like; at 25-45 °C for 2-16 hours to provide a compound of formula (XXXV).
  • a compound of formula (XXXIV) can be subjected to Mitsunobu conditions as previously described in Scheme 9 to provide a compound of formula (XXXV).
  • employing Boc deprotection conditions previously described in Scheme 2 provides a compound of formula (III).
  • the final two steps can be reversed so that a compound of formula (XXXIV) undergoes Boc deprotection followed by S N 2 ring closure as previously described to provide a compound of formula (III).
  • Scheme 18 [00239] According to Scheme 18, a compound of formula (III) can be synthesized in five steps from tert- butyl (1-(2-chlorophenyl)-2-hydroxyethyl)carbamate.
  • tert-butyl (1-(2-chlorophenyl)-2- hydroxyethyl)carbamate is treated with methyl acrylate and an appropriate base such as Cs 2 CO 3 , and the like; in a solvent such as ACN, and the like; at rt for a period of 3 h to provide methyl 3-(2-((tert- butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate.
  • methyl 3-(2-((tert- butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate undergoes Boc deprotection previously described in Scheme 2 to provide methyl 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoate.
  • methyl 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoate is reacted under hydrolysis conditions previously described in Scheme 1 to provide 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoic acid.
  • Scheme 19 160 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00240] According to Scheme 19, methyl 4-(3-(2-chlorophenyl)thiomorpholino)-2-fluorobenzoate is reacted with 1 equivalent of Selectfluor ® and 2 equivalents of water in ACN at rt for 10 min to provide methyl 4-(3-(2-chlorophenyl)-1-oxidothiomorpholino)-2-fluorobenzoate, a compound of formula (IV).
  • tert-butyl rac-(1*S,5*S,6*S)-6-(dimethylcarbamoyl)-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XVI)) is formed from rac-(1*S,5*R,6*S)- 3-(tert-butoxycarbonyl)-2-oxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid under the same conditions.
  • Scheme 21 Boc Boc deprotection reduction (XXIII) [00242] According to Scheme 21, a compound of formula (XXIII) can be converted to a compound of formula (III) in two steps.
  • a compound of formula (XXIII) is treated with 2,6-lutidine and trimethylsilyl trifluoromethanesulfonate in DCM at rt for 1 h to provide a compound of formula (XXXVI).
  • Treating a compound of formula (XXXVI) with a reducing agent such as NaBH3CN in MeOH at rt for 3- 16 h provides a compound of formula (III).
  • Scheme 22 161 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC (XVI) (XXXVIII) [00243]
  • a compound of formula (XXXVI) can be formed from a compound of formula (XVI) in two steps.
  • tert- butyl N-(morpholin-3-ylmethyl)carbamate is reacted with 2-bromo-1-(2-chloro-3-fluorophenyl)ethanone and DIPEA in DMSO for 12 h at rt to give tert-butyl ((4-(2-(2-chloro-3-fluorophenyl)-2- oxoethyl)morpholin-3-yl)methyl)carbamate.
  • a compound of formula (XXXIX) is treated with Ir[dF(CF 3 )ppy]2(5,5’-dCF 3 bpy)PF 6 , CuI•DMS, 2,2'-dipyridyl ketone, tert-butylimino- tri(pyrrolidino)phosphorane, and 1,3-dihydro-3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole in EtOAc and water under irradiation at rt for 16 h to provide a compound of formula (XL), where R 7 is Cl or F.
  • a compound of formula (XL) can be Boc deprotected as previously described in Scheme 2 to provide a 162 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC compound of formula (III), where X 5 and X 6 are CH and form a fused 3-membered saturated ring with another CH that is substituted with CF 3 , and X 7 and X 8 are absent.
  • Scheme 25 [00246] According to Scheme 25, a compound of formula (III) can be prepared in four steps from a compound of formula (XLI), wherein R 7 is H or F.
  • a compound of formula (XLI) is treated with 2- chloroacetyl chloride and TEA in DCM at rt for 16 h to provide a compound of formula (XLII).
  • a compound of formula (XLII) can be cyclized using NaH in DMF at rt for 16 h to provide a compound of formula (XLIII).
  • a compound of formula (XLIII) can be methylated using standard conditions previously described in Scheme 13 to provide a compound of formula (XLIV), where R 6 is CH 3 .
  • a compound of formula (XLIV), wherein R 6 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and R 7 is F or H can be Boc deprotected as previously described in Scheme 2 to provide a compound of formula (III), where X 5 , X 6 and X 7 together are C(O)NR 6 CH 2 and X 8 is absent.
  • Scheme 26 [00247] According to Scheme 26, a compound of formula (XLIV) can be prepared from 2-amino-2-(2- chloro-3-fluorophenyl)acetic acid in five steps. In a first step, 2-amino-2-(2-chloro-3-fluorophenyl)acetic acid is Boc protected as previously described in Scheme 10.
  • tert-Butyl (1-(2-chloro-3-fluorophenyl)-2- (cyclopropylamino)-2-oxoethyl)carbamate is reduced using LiAlH 4 in THF at rt for 16 h to provide tert- butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)ethyl)carbamate.
  • tert-Butyl (1-(2-chloro-3- fluorophenyl)-2-(cyclopropylamino)ethyl)carbamate is treated with 2-chloroacetyl chloride as previously described in Scheme 25 to provide tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(2-chloro-N- cyclopropylacetamido)ethyl)carbamate.
  • tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(2-chloro-N- cyclopropylacetamido)ethyl)carbamate can be cyclized as previously described in Scheme 25 to provide a compound of formula (XLIV), where R 6 is cyclopropyl and R 7 is F.
  • Scheme 27 [00248] According to Scheme 27, a compound of formula (III) can be synthesized from tert-butyl 2-(2- chlorophenyl)pyrrolidine-1-carboxylate in two steps.
  • tert-butyl 2-(2-chlorophenyl)pyrrolidine-1- carboxylate is treated with TMEDA, n-BuLi, and iodomethane in THF at rt over a period of 12 h to provide tert-butyl 2-(2-chlorophenyl)-2-methyl-pyrrolidine-1-carboxylate.
  • tert-Butyl 2-(2-chlorophenyl)-2- methyl-pyrrolidine-1-carboxylate is reacted under Boc deprotection conditions previously described in Scheme 2 to provide a compound of formula (III), where X 7 and X 8 are absent, X 5 and X 6 are CH 2 , R 6 is CH 3 , and A is 2-chlorophenyl.
  • Scheme 28 [00249] According to Scheme 28, a compound of formula (III) can be formed in five steps from rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid.
  • Boc protection as previously described in Scheme 10 is used to obtain rac-(1*S,2*S,5*R,6*S)-3-tert- butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid.
  • tert-Butyl rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxycarbonyl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate is treated with tert-butyl nitrite in DCM at 15 °C for 1 h to provide tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxycarbonyl)(nitroso)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate.
  • tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)(nitroso)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate is treated with K 2 CO 3 in MeOH for 15 min at 15 °C to provide tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro- 3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate is reacted under Boc deprotection conditions previously described in Scheme 2 to provide a compound of formula (III), where X 5 and X 6 are CH and form a fused 3-membered saturated ring with another CH that is substituted with OCH 3 , and X 7 and X 8 are absent.
  • Scheme 29 [00250] According to Scheme 29, rac-(1*S,2*S,5*R)-2-(2-chloro-3-fluorophenyl)-6-oxa-3- azabicyclo[3.1.1]heptane (a compound of formula (III)) can be formed in eight steps from 2-chloro-3- fluorobenzaldehyde. First, 2-chloro-3-fluorobenzaldehyde is treated with 4-methoxybenzylamine and MgSO 4 in DCM at rt over a period of 20 h to provide (E)-1-(2-chloro-3-fluorophenyl)-N-(4- methoxybenzyl)methanimine.
  • Methyl 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylate is treated with NaBH 4 in THF at 40 °C over 12 h to provide 5-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4- methoxybenzyl)morpholin-3-one.
  • 5-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4- methoxybenzyl)morpholin-3-one is treated with imidazole, PPh 3 , and I 2 in THF at rt for 2 h to provide 5- (2-chloro-3-fluorophenyl)-6-(iodomethyl)-4-(4-methoxybenzyl)morpholin-3-one.
  • rac-(1*S,4*R,5*R)-4-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6- oxa-3-azabicyclo[3.1.1]heptan-2-one is treated with BH3 in THF at 15 °C over a period of 2 h to provide rac-(1*R,2*R,5*S)-2-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptane.
  • rac-(1*R,2*R,5*S)-2-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptane is treated with CAN in ACN/water at 15 °C for 12 h to provide rac-(1*S,2*S,5*R)- 2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane, a compound of formula (III).
  • Scheme 30 [00251] According to Scheme 30, tert-butyl 3-(2-chloro-3-fluorophenyl)piperazine-1-carboxylate (a compound of formula (III)) is synthesized in three steps from 2-chloropyrazine.
  • first step standard Suzuki coupling conditions known to those skilled in the art are employed with 2-chloropyrazine and (2- chloro-3-fluorophenyl)boronic acid using K 2 CO 3 and Pd(dppf)Cl 2 in 1,4-dioxane/water at 100 °C over a period of 16 h to provide 2-(2-chloro-3-fluorophenyl)pyrazine.
  • 2-(2-Chloro-3-fluorophenyl)pyrazine is reduced to 2-(2-chloro-3-fluorophenyl)piperazine using N-phenylaniline, pinacolborane, and tris(2,3,4,5,6- pentafluorophenyl)borane in toluene at 110 °C for 6 h.
  • 2-(2-chloro-3-fluorophenyl)piperazine is Boc protected as previously described in Scheme 10 to provide tert-butyl 3-(2-chloro-3- fluorophenyl)piperazine-1-carboxylate, a compound of formula (III).
  • tert-butyl exo-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate using PPh 3 , 1,2-diiodoethane, K 2 CO 3 , and trimethylsilyl chloride in DMF at rt over a period of 12 h.
  • tert-butyl exo-6-(((tert-butyldimethylsilyl)oxy)methyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate using tert-butyl chlorodimethylsilane and imidazole in DCM at rt over a period of 5 h.
  • Scheme 33 [00254] According to Scheme 33, tert-butyl exo-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate is subjected to standard methylation conditions as previously described in Scheme 13 with iodomethane or iodomethane-d 3 to provide a compound of formula (XV), where R 9 is CH 3 or CD 3 .
  • tert-butyl exo-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate employing the same conditions.
  • Methyl 7-fluoro-1H-indazole-4-carboxylate can also be methylated in an analogous manner to provide methyl 7-fluoro-2-methyl-indazole-4-carboxylate, a compound of formula (II).
  • tert-butyl exo-6-((difluoromethoxy)methyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate using CuI and 2,2-difluoro-2-(fluorosulfonyl)acetic acid in ACN at 45 °C over a period of 0.5 h.
  • tert-butyl exo-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate using a fluorinating reagent such as DAST, and the like; in an appropriate solvent such as DCM, and the like; at 0 °C over a period of 1 h.
  • tert-butyl exo-6-(difluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) from tert-butyl exo-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • Scheme 36 [00257] According to Scheme 36, tert-butyl exo-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared in two steps from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate.
  • tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate is reacted with methanesulfonic anhydride and TEA in DCM at rt over a period of 6 h to provide tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate.
  • tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate is reacted with LiAlH 4 in THF at temperatures of 0-20 °C for 0.5 h to provide tert-butyl exo-6- methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate, a compound of formula (XV).
  • tert-butyl exo-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-acetyl-3- azabicyclo[3.1.0]hexane-3-carboxylate using methylmagnesium bromide under Grignard conditions previously described in Scheme 8.
  • tert-butyl exo-(1*R,5*S)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) can be formed from tert-butyl exo- 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in two steps.
  • tert-butyl exo-6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate is treated with palladium(II) acetate and 2,2'- bipyridine in ethyl vinyl ether at 50 °C for 16 h to provide tert-butyl exo-6-(vinyloxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate.
  • tert-Butyl exo-6-(vinyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate is treated with diethylzinc and diiodomethane in DCM at rt for 2 h to provide tert-butyl exo- (1*R,5*S)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, a compound of formula (XV).
  • Scheme 39 [00260] According to Scheme 39, tert-butyl 1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate is protected with Fmoc using 9H-fluoren-9-ylmethyl chloroformate and DIPEA in DCM at rt for 16 h to provide 5-((9H-fluoren-9-yl)methyl) 2-(tert-butyl) 1-oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)- dicarboxylate, a compound of formula (XVI).
  • Scheme 40 [00261] According to Scheme 40, 2-chloro-5-fluoro-4-methyl-pyrimidine is treated with TEA and Pd(dppf)Cl 2 in DMF/MeOH under CO at 80 °C for a period of 16 h to provide a compound of formula (II), where X 3 and X 4 are N, X 1 is CH, X 2 is CCH 3 , and Y is F.
  • Scheme 41 [00262] According to Scheme 41, methyl 5-fluoropyrimidine-2-carboxylate is treated with zinc difluoromethanesulfinate, 2,2,2-trifluoroacetic acid, and tert-butyl hydroperoxide in DCM/water at rt for 16 h to provide methyl 4-(difluoromethyl)-5-fluoropyrimidine-2-carboxylate, a compound of formula (II).
  • methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate is prepared in three steps from 2-chlorobenzaldehyde.
  • the SNAP reaction is employed using 2- chlorobenzaldehyde and tert-butyl N-(2-aminoethyl)-N-(tributylstannylmethyl)carbamate in DCM with the addition of 2,6-lutidine and copper(II) trifluoromethanesulfonate in hexafluoroisopropanol at rt over a period of 12 h to provide tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate.
  • tert-Butyl 3-(2- chlorophenyl)piperazine-1-carboxylate is coupled to methyl 5-bromo-3-fluoropicolinate using Buchwald- Hartwig conditions previously described in Scheme 1.
  • Boc deprotection of tert-butyl 3-(2- chlorophenyl)-4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate as previously described in Scheme 2 provides methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate.
  • Scheme 45 [00266] According to Scheme 45, methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3- fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate can be prepared in nine steps from methyl 5-chloropyrazine-2-carboxylate. In a first step, standard Suzuki coupling conditions are employed as previously described in Scheme 30 to provide methyl 5-(2-chloro-3-fluorophenyl)pyrazine- 2-carboxylate.
  • Methyl 5-(2-chloro-3-fluorophenyl)pyrazine-2-carboxylate is reduced using CaCl 2 and NaBH 4 in MeOH at rt for 2 h to give (5-(2-chloro-3-fluorophenyl)pyrazin-2-yl)methanol.
  • Treatment with PtO 2 in MeOH under H 2 at 40 °C for 12 h provides (rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)piperazin- 2-yl)methanol.
  • tert-Butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2- (hydroxymethyl)piperazine-1-carboxylate is reacted under S N Ar conditions as previously described in Scheme 1 with methyl 5-fluoropyrazine-2-carboxylate to provide methyl 5-(rac-(2*S,5*R)-4-(tert- butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate.
  • Methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate is Boc deprotected as previously described in 171 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC Scheme 2 to provide methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1- yl)pyrazine-2-carboxylate.
  • Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3- fluorophenyl)-4-(2-chloroacetyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate can be cyclized using NaH in THF at rt for 2 h to give methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3-fluorophenyl)-4- oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate.
  • a compound of formula (V) can be prepared from a compound of formula (XLV) in two steps.
  • a compound of formula (XLV), wherein R 3 is CH 3 or OCH 3 is subjected to Buchwald- Hartwig coupling with a compound of formula (III) as described in Scheme 1 to provide a compound of formula (XLVI).
  • Treatment of a compound of formula (XLVI) with 10% aq. NaOH at 100 °C for 10 h provides a compound of formula (V), where X 1 is CH, X 3 and X 4 are N, and X 2 is CR 3 where R 3 is CH 3 or OCH 3 .
  • fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be alkylated with cyclopropyl using (1-ethoxycyclopropoxy)trimethylsilane and AcOH in MeOH at 60 oC for 16 h to provide methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol- 172 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC 2(1H)-yl)pyrazine-2-carboxylate.
  • a compound of formula (XLVII), where R 7 and R 3 are independently H or F and X 1 is CH or N, can be subjected to the same conditions to provide a compound of formula (XLVIII).
  • Scheme 48 [00269] According to Scheme 48, methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be acylated using acetyl chloride and TEA in DCM at rt for 1 h to provide methyl 5-((1*S,3a*S,6a*S)-5-acetyl-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate, a compound of formula (IV).
  • methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be alkylated using 2- bromoethyl methyl ether and K 2 CO 3 in ACN at 80 oC for 16 h to provide methyl 5-((1*S,3a*R,6a*S)-1-(2- chloro-3-fluorophenyl)-5-(2-methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2- carboxylate, a compound of formula (IV).
  • methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin- 1-yl)pyrazine-2-carboxylate can be subjected to the same conditions with iodomethane to provide 5-(2-(2- chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide, a compound of formula (IV).
  • Scheme 50 173 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00271] According to Scheme 50, methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be methylated using formaldehyde and sodium triacetoxyborohydride in MeOH at rt for 2 h to provide methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate, a compound of formula (IV).
  • methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2- carboxylate can be alkylated using oxetan-3-one and sodium triacetoxyborohydride with AcOH in a solvent such as DCM, MeOH, and the like; at rt for 2-16 h to provide 5-(2-(2-chloro-3-fluorophenyl)-4-(oxetan-3- yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide, a compound of formula (IV).
  • tert-butyl rac-(3a*R,6a*S)-1-oxohexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate can be converted to tert-butyl rac-(3a*R,6a*S)-5-(oxetan-3-yl)-1- oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, a compound of formula (XVI).
  • methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be alkylated with 2,2,2- trifluoroethyl trifluoromethanesulfonate, 2,2-difluoroethyl 1,1,1-trifluoromethanesulfonate, and the like; using DIPEA, TEA, and the like; in DMF, DCM, and the like; at 25-40 °C for 3-16 h to provide methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- 174 Q
  • tert-butyl rac-(3a*R,6a*S)- 1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate is converted to tert-butyl rac-(3a*R,6a*S)-1-oxo- 5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, a compound of formula (XVI). 175 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00274] All stereocenters labeled with (S) or (R) are known, absolute stereochemistry.
  • Step B (R,E)-4-Methylsulfonylbut-3-en-2-amine.
  • Step A tert-Butyl 5-oxo-1,4-oxazepane-4-carboxylate.
  • 1,4-oxazepan-5-one 2.0 g, 17.4 mmol, 1.0 eq
  • DCM 20 mL, 0.87 M
  • di-tert-butyl dicarbonate 4.5 g, 20.8 mmol, 1.2 eq
  • N,N-dimethylpyridin-4-amine 1.1 g, 8.69 mmol, 0.5 eq
  • triethylamine 5.3 g, 52.1 mmol, 3.0 eq.
  • Step B tert-Butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)- carboxylate.
  • Step C tert-Butyl 5-(2-chlorophenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate.
  • Step E 5-(2-Chlorophenyl)-1,4-oxazepane.
  • 5-(2-chlorophenyl)-2,3,6,7- tetrahydro-1,4-oxazepine 2.6 g, 12.4 mmol, 1.0 eq
  • methanol 30 mL, 0.48 M
  • sodium borohydride 1.4 g, 37.3 mmol, 3.0 eq
  • the mixture was stirred at 25°C for 16 h before being concentrated under vacuum.
  • Step B tert-Butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate.
  • Step A tert-Butyl 2-(2-chlorophenyl)-4,4-difluoropiperidine-1-carboxylate.
  • tert- butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate (Intermediate 8, 4.2 g, 13.6 mmol, 1.0 eq) in DCM (50 mL, 0.30 M) was added DEOXO-FLUOR ® (3.6 g, 16.3 mmol, 1.2 eq) at 0°C under N 2 .
  • the mixture was stirred at 25°C for 16 h before being poured into water and extracted with DCM.
  • Step B 2-(2-Chlorophenyl)-4,4-difluoropiperidine.
  • a solution of tert-butyl 2-(2-chlorophenyl)- 4,4-difluoropiperidine-1-carboxylate (1.5 g, 4.52 mmol, 1.0 eq) was taken up in HCl (20 mL, 4N in EtOAc). The mixture was stirred at 25°C for 1 h before being concentrated to provide 2-(2-chlorophenyl)-4,4- difluoropiperidine (700 mg, 67%) as a white solid, which was used without further purification.
  • Intermediate 10 2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidine.
  • Step A tert-Butyl 4,4-dimethyl-2-oxo-pyrrolidine-1-carboxylate.
  • DCM DCM
  • TEA 2.3 mL, 88.3 mmol, 2.0 eq
  • 4-(dimethylamino)pyridine 540 mg, 4.40 mmol, 0.1 eq
  • di-tert- butyl dicarbonate 14 g, 66.3 mmol, 1.5 eq.
  • Step B tert-Butyl 3,3-dimethyl-5-(trifluoromethylsulfonyloxy)-2H-pyrrole-1-carboxylate.
  • KHMDS 5.6 mL, 5.60 mmol, 1.2 eq
  • THF 33 mL
  • N 2 cooled to -78°C.
  • Step D tert-Butyl 2-(2-chlorophenyl)-4,4-dimethyl-pyrrolidine-1-carboxylate.
  • Step A Methyl 3-(2-((tert-butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate.
  • Step C 3-(2-Amino-2-(2-chlorophenyl)ethoxy)propanoic acid.
  • 2,2,2-trifluoroacetic acid (12.5 g, 48.3 mmol, 1.0 eq) in THF (120 mL, 0.24 M), H 2 O (40 mL, 0.24 M), and methanol (40 mL, 0.24 M) was added LiOH ⁇ H 2 O (6.1 g, 145 mmol, 3.0 eq).
  • Step B tert-Butyl 7-(2-chloro-4-fluorophenyl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate.
  • Step C 7-(2-Chloro-4-fluorophenyl)-3,4,5,6-tetrahydro-2H-azepine.
  • a solution of tert-butyl 7-(2- chloro-4-fluorophenyl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (8.0 g, 24.4 mmol, 1.0 eq) in HCl (80 mL, 4N in EtOAc) was stirred at 25°C for 0.5 h. The solvent was evaporated to afford 7-(2-chloro-4- fluorophenyl)-3,4,5,6-tetrahydro-2H-azepine (5.5 g, quant.
  • Step D 2-(2-Chloro-4-fluorophenyl)azepane.
  • 7-(2-chloro-4-fluorophenyl)- 3,4,5,6-tetrahydro-2H-azepine 5.5 g, 24.4 mmol, 1.0 eq
  • NaBH 4 1.9 g, 50.5 mmol, 2.1 eq
  • Step B tert-Butyl (2-((2-chlorophenyl)(hydroxy)methyl)benzyl)carbamate.
  • Step C tert-Butyl 1-(2-chlorophenyl)isoindoline-2-carboxylate.
  • Step D 1-(2-Chlorophenyl)isoindoline.
  • a solution of tert-butyl 1-(2-chlorophenyl)isoindoline-2- carboxylate (130 mg, 0.394 mmol, 1.0 eq) in DCM (2.0 mL, 0.15 M) and trifluoroacetic acid (0.70 mL, 186 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC 0.15 M) was stirred at 25°C for 3 h.
  • the solution was evaporated to provide 1-(2-chlorophenyl)isoindoline (100 mg, quant. yield) as a yellow oil, which was used in the next step without further purification.
  • Step D N-(1-(2-Chlorophenyl)but-3-en-1-yl)acetamide.
  • TEA 6.7 g, 66.0 mmol, 1.5 eq
  • acetic anhydride 5.4 g, 52.8 mmol, 1.2 eq
  • Step A tert-Butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxylate.
  • DCM 100 mL, 0.29 M
  • triethylamine 4.4 g, 43.8 mmol, 1.5 eq
  • di-tert-butyl dicarbonate 7.6 g, 35.1 mmol, 1.2 eq.
  • the mixture was stirred at 25°C for 1 h before being diluted with H 2 O and extracted with DCM.
  • Step B tert-Butyl 2-(2-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate.
  • Step D tert-Butyl 2-(2-chlorophenyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylate.
  • Step A tert-Butyl ((2-(2-chloro-4-fluorobenzoyl)cyclopropyl)methyl)carbamate.
  • a solution of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 15.2 mmol, 1.0 eq) in THF (10 mL, 1.5 M) was degassed and purged with N 2 .
  • To the mixture was slowly added (2-chloro-4- fluorophenyl)magnesium bromide (11.4 mL, 22.8 mmol, 1.5 eq) at 0°C.
  • Step B (2-(Aminomethyl)cyclopropyl)(2-chloro-4-fluorophenyl)methanone.
  • Step A tert-Butyl rac-(((1*R,2*S)-2-(3-chloropicolinoyl)cyclopropyl)methyl)carbamate.
  • Step B rac-((1*S,2*R)-2-(Aminomethyl)cyclopropyl)(3-chloropyridin-2-yl)methanone.
  • Step C rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane.
  • Step D rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane.
  • TFA salt 1.9 g, 6.16 mmol, 1.0 eq
  • Na 2 CO 3 1.9 g, 18.4 mmol, 3.0 eq
  • Step A tert-Butyl rac-(((1*R,2*S)-2-(2-chloro-3-fluorobenzoyl)cyclopropyl)methyl)carbamate.
  • Step B tert-Butyl rac-(((1*R,2*S)-2-((2-chloro-3- fluorophenyl)(hydroxy)methyl)cyclopropyl)methyl)carbamate.
  • tert-butyl rac-(((1*R,2*S)- 2-(2-chloro-3-fluorobenzoyl)cyclopropyl)methyl)carbamate 500 mg, 1.52 mmol, 1.0 eq
  • methanol 5.0 mL, 0.30 M
  • sodium borohydride 115 mg, 3.05 mmol, 2.0 eq
  • Step C tert-Butyl 2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step D rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane.
  • Step A tert-Butyl (((1*R,3*S)-3-(2,3-difluorobenzoyl)-2,2- dimethylcyclopropyl)methyl)carbamate.
  • tert-butyl rac-(1*R,5*S)-6,6-dimethyl-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 44, 2.0 g, 8.88 mmol, 1.0 eq) in THF (30 mL, 0.3M) was added (2,3-difluorophenyl)magnesium bromide (13 mL, 13.3 mmol, 1.5 eq, 1M in THF) at 0 °C.
  • Step B rac-(1*R,5*S)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene.
  • tert-butyl (((1*R,3*S)-3-(2,3-difluorobenzoyl)-2,2-dimethylcyclopropyl)methyl)carbamate (1.9 g, 5.60 mmol, 1.0 eq) in DCM (50 mL, 0.1M) was added 2,6-lutidine (1.8 g, 16.8 mmol, 3.0 eq) and trimethylsilyl trifluoromethanesulfonate (5.0 g, 22.4 mmol, 4.0 eq).
  • Step C rac-(1*R,2*R,5*S)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.
  • rac-(1*R,5*S)-2-(2,3-difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene 1.2 g, 5.56 mmol, 1.0 eq
  • MeOH 30 mL, 0.2M
  • sodium cyanoborohydride 1.0 g, 16.7 mmol, 3.0 eq
  • Step A tert-Butyl rac-(1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-2-hydroxy-3- azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step B rac-(1*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hex-2-ene-6- carbonitrile.
  • tert-butyl (rac-1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-2- hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.8 g, 5.10 mmol, 1.0 eq) in ACN (20 mL, 0.26M) was added p-TsOH monohydrate (970 mg, 5.10 mmol, 1.0 eq).
  • Step C rac-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6- carbonitrile.
  • TsOH salt 2.0 g, 4.92 mmol, 1.0 eq
  • MeOH 20 mL, 0.24M
  • sodium cyanoborohydride 618 mg, 9.83 mmol, 2.0 eq
  • AcOH (3.0 mL).
  • tert-butyl rac- (1*R,5*S,6r)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 94% yield) as a yellow oil.
  • the title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (1*R,5*S,6r)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6- difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (5.0 g, 28.1 mmol, 2.0 eq) was added dropwise to the mixture over 30 min and the reaction was stirred for 0.5 h at 45 °C.
  • the mixture was concentrated under vacuum then diluted with sat. aq. NaHCO 3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under vacuum.
  • Step B tert-Butyl exo-(1*R,5*S)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate.
  • a solution of diethylzinc (2.0 mL, 2.01 mmol, 4.0 eq) in DCM (2.0 mL, 0.13M) was placed under N 2 and cooled to 0 °C.
  • Diiodomethane (671 mg, 2.51 mmol, 5.0 eq) in DCM (1.0 mL, 0.13M) was added dropwise and the mixture was stirred at 0 °C for 30 min.
  • Step D rac-(1*S,2*S,5*R,6*S)-3-tert-Butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid.
  • Step A tert-Butyl rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step B tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)(nitroso)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step C tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3- azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step D rac-(1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3- azabicyclo[3.1.0]hexane.
  • a solution of tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)- 6-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate 15 mg, 0.044 mmol, 1.0 eq) in DCM (0.5 mL, 0.08M) was added TFA (50 ⁇ L).
  • Step A tert-Butyl rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step B rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane.
  • tert-Butyl rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 50 mg, 0.132 mmol, 1.0 eq
  • DCM/TFA v/v 3:1, 0.40 mL, 0.3M
  • Step B tert-Butyl exo-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • Lithium aluminum hydride (9.1 mL, 22.7 mmol, 2.0 eq, 2.5M in THF) was added dropwise to the solution at 0 °C.
  • Step A (E)-1-(2-Chloro-3-fluorophenyl)-N-(4-methoxybenzyl)methanimine.
  • 2- chloro-3-fluorobenzaldehyde (10 g, 63.1 mmol, 1.0 eq)
  • 4-methoxybenzylamine (10 g, 75.7 mmol, 1.2 eq)
  • DCM 126 mL, 0.5M
  • MgSO 4 25 g, 212 mmol, 3.4 eq
  • Step B 3-(2-Chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylic acid.
  • a solution of (E)-1-(2-chloro-3-fluorophenyl)-N-(4-methoxybenzyl)methanimine (9.0 g, 32.4 mmol, 1.0 eq) and 1,4-dioxane-2,6-dione (4.1 g, 35.6 mmol, 1.1 eq) in o-xylene (90 mL, 0.4M) was stirred at 140 °C for 6 h. After cooling to rt, the mixture was concentrated under reduced pressure.
  • Step E 5-(2-Chloro-3-fluorophenyl)-6-(iodomethyl)-4-(4-methoxybenzyl)morpholin-3-one.
  • 5-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4-methoxybenzyl)morpholin-3-one 2.5 g, 6.58 mmol, 1.0 eq
  • THF 25 mL, 0.26M
  • imidazole 1.5 g, 21.7 mmol, 3.3 eq
  • triphenylphosphine 3.8 g, 14.5 mmol, 2.2 eq
  • iodine 4.2 g, 16.5 mmol, 2.5 eq
  • Step F rac-(1*S,4*R,5*R)-4-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptan-2-one.
  • a solution of 5-(2-chloro-3-fluorophenyl)-6-(iodomethyl)-4-(4- methoxybenzyl)morpholin-3-one (2.3 g, 4.70 mmol, 1.0 eq) in THF (40 mL, 0.1M) was placed under N 2 .
  • Step G rac-(1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptane.
  • Step A tert-Butyl (2-(2-chloroacetamido)-1-(2-chlorophenyl)ethyl)carbamate.
  • tert-butyl (2-amino-1-(2-chlorophenyl)ethyl)carbamate 4.0 g, 14.8 mmol, 1.0 eq
  • TEA 6.2 mL, 44.3 mmol, 3.0 eq
  • DCM 40 mL, 0.37M
  • 2-chloroacetyl chloride 1.2 mL, 14.8 mmol, 1.0 eq
  • Step B tert-Butyl 2-(2-chlorophenyl)-5-oxo-piperazine-1-carboxylate.
  • Step A 2-(tert-Butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)acetic acid.
  • 2- amino-2-(2-chloro-3-fluorophenyl)acetic acid 5.0 g, 20.8 mmol, 1.0 eq
  • DCM 50 mL, 0.4M
  • TEA 0.5 g, 104 mmol, 5.0 eq
  • the mixture was stirred at 0 °C for 5 minutes before Boc 2 O (5.45 g, 25.0 mmol, 1.2 eq) was added.
  • Step C tert-Butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)ethyl)carbamate.
  • Step E tert-Butyl 2-(2-chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazine-1-carboxylate.
  • Step F 5-(2-Chloro-3-fluorophenyl)-1-cyclopropylpiperazin-2-one.
  • tert-butyl 2- (2-chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazine-1-carboxylate 2.0 g, 5.70 mmol, 1.0 eq
  • EtOAc 2.0 mL, 2.9M
  • HCl 20 mL, 4M in EtOAc
  • Step A tert-Butyl ((4-(2-(2-chloro-3-fluorophenyl)-2-oxoethyl)morpholin-3-yl)methyl)carbamate.
  • Step B 7-(2-Chloro-3-fluorophenyl)-1,3,4,6,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine.
  • tert- Butyl ((4-(2-(2-chloro-3-fluorophenyl)-2-oxoethyl)morpholin-3-yl)methyl)carbamate 500 mg, 1.29 mmol, 1.0 eq
  • TFA/DCM v/v 1:3, 0.80 mL, 1.6M
  • Step C 7-(2-Chloro-3-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine.
  • Step A A solution of tert-butyl rac-(3a*S,6a*S)-4-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- carboxylate (Intermediate 40, 6.0 g, 26.4 mmol, 1 eq) in THF (3.0 mL, 0.9M) was placed under N 2 and cooled to 0 °C. To this was added (2-chloro-3-fluorophenyl)magnesium bromide (40 mL, 39.6 mmol, 1.5 eq, 1M in THF) dropwise.
  • reaction was stirred at 0 °C for 16 h before being slowly quenched with sat. aq. NH 4 Cl at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step B tert-Butyl ((rac-(3*R,4*R)-4-((2-chloro-3-fluorophenyl)(hydroxy)methyl)tetrahydrofuran- 3-yl)methyl)carbamate.
  • Step C tert-Butyl 4-rac-(3a*S,6a*R)-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrole- 5(3H)-carboxylate.
  • Step D rac-(3a*S,6a*R)-4-(2-Chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole.
  • Step B (9H-Fluoren-9-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-(2-chloro-3- fluorobenzoyl)pyrrolidine-1-carboxylate.
  • Step C (9H-Fluoren-9-yl)methyl 3-(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-1- carboxylate.
  • Step D rac-(9H-Fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
  • Step E rac-(9H-Fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)-5-(5- (methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
  • Step F Methyl 5-(rac-(1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate.
  • Step G tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
  • Step A tert-Butyl 3-(2-chlorophenyl)piperazine-1-carboxylate.
  • tert-butyl N-(2- aminoethyl)-N-(tributylstannylmethyl)carbamate 91 ⁇ L, 0.220 mmol, 1.0 eq
  • DCM 0.37 mL, 0.2M
  • 2-chlorobenzaldehyde 24 ⁇ L, 0.220 mmol, 1.0 eq
  • 4A molecular sieves ⁇ 100 mg/mmol
  • 2,6-lutidine (30 ⁇ L, 0.240 mmol, 1.1 eq) was added to a suspension of hexafluoroisopropanol (0.37 mL, 0.2M) and copper(II) trifluoromethanesulfonate (86 mg, 0.240 mmol, 1.1 eq) and this was stirred at rt for 1 h.
  • the imine was added and the reaction was stirred at rt for 12 h.
  • the reaction was quenched with 10% aq. NH 4 OH and stirred vigorously for 15 min.
  • the layers were separated and the aqueous layer was extracted with DCM.
  • Step B tert-Butyl 3-(2-chlorophenyl)-4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1- carboxylate.
  • Methyl 5-bromo-3-fluoropicolinate 243 mg, 1.04 mmol, 1.0 eq
  • tert-butyl 3-(2- chlorophenyl)piperazine-1-carboxylate (308 mg, 1.04 mmol, 1.0 eq)
  • RuPhos Pd G4 88 mg, 0.104 mmol, 0.1 eq
  • cesium carbonate 1.0 g, 3.11 mmol, 3.0 eq
  • Step C Methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate.
  • tert-Butyl 3-(2- chlorophenyl)-4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (214 mg, 0.477 mmol, 1.0 eq) was taken up in a 20% TFA solution in DCM (0.5 mL, 0.2M). The reaction was allowed to stir at rt for 1 h before being concentrated to provide methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3- fluoropicolinate (167 mg, quant. yield).
  • Step D Methyl 5-(4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2- carboxylate.
  • a mixture of tert-butyl 3-(2-chloro-3-fluorophenyl)piperazine-1-carboxylate (3.2 g, 10.1 mmol, 1.0 eq) in DMSO (35 mL, 0.3M) was added methyl 5-fluoro-2-pyrazinecarboxylate (1.9 g, 12.1 mmol, 1.2 eq) and TEA (3.1 g, 30.3 mmol, 3.0 eq).
  • Step E Methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate.
  • Methyl 5- (4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (1.5 g, 3.33 mmol, 1.0 eq) was taken up in DCM/TFA (v/v 3:1, 20 mL, 0.2M).
  • Step B Methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-(tert-butoxycarbonylamino)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate.
  • Step C Methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-amino-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate.
  • Step D Methyl 5-(rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(dimethylamino)-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate.
  • Step A Methyl 5-(rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate.
  • Step B Methyl 5-((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan- 3-yl)pyrimidine-2-carboxylate.
  • Step C 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)pyrimidine-2-carboxylic acid.
  • Methyl 5-((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate 500 mg, 1.30 mmol, 1.0 eq
  • MeOH 6.5 mL, 0.2M
  • Step B (5-(2-Chloro-3-fluorophenyl)pyrazin-2-yl)methanol.
  • Step D tert-Butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2-(hydroxymethyl)piperazine-1- carboxylate.
  • a solution of (rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)piperazin-2-yl)methanol (11 g, 36.0 mmol, 1.0 eq) in DCM (110 mL, 0.3M) was added Boc 2 O (7.8 g, 36.0 mmol, 1.0 eq). The reaction was stirred at 25 °C for 16 h before being filtered.
  • Step E Methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate.
  • Step F Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1- yl)pyrazine-2-carboxylate.
  • Step G Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-4-(2-chloroacetyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate.
  • Step H Methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate.
  • Step I Methyl 5-(rac-(7*R,9a*S)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate.
  • Example 1 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. 254 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00521] Step A: Methyl (S)-4-(2-(2-chlorophenyl)pyrrolidin-1-yl)benzoate. Methyl 4-bromobenzoate (75 mg, 0.342 mmol, 1.0 eq) was taken up in toluene (1.7 mL, 0.2 M).
  • Step C 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • (S)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)benzoic acid (26 mg, 0.086 mmol, 1.0 eq) and HATU (41 mg, 0.103 mmol, 1.2 eq) were taken up in DMF (0.4 mL, 0.2 M).
  • Example 2 4-((R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. 255 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00524] The title compound was prepared in a manner analogous to Example 1 using (R)-2-(2- chlorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A.
  • Example 3 4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide. [00525] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A.
  • Example 5 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 6 4-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide. 257 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00528] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)azepane instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A.
  • Example 7 4-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 8 4-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 9 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 10 (E)-4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-(3-(methylsulfonyl)allyl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A and (E)-3- (methylsulfonyl)prop-2-en-1-amine, 4-methylbenzenesulfonic acid instead of (R,E)-4-(methylsulfonyl)but- 3-en-2-amine, 4-methylbenzenesulfonic acid in Step C.
  • Example 11 4-(3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 12 4-((R)-3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 14 2-Fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 15 2-Fluoro-4-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 16 2-Fluoro-4-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 17 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2,6-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide. 262 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00539] The title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2,6- difluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 18 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4- bromobenzoate in Step A.
  • Example 19 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-2-(o-tolyl)piperidin-1- yl)benzamide.
  • Example 20 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)piperidin-1- yl)benzamide.
  • Example 21 2-Fluoro-4-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 22 2-Fluoro-4-((*S)-2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • Example 23 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)pyrrolidin-1- yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4- bromobenzoate in Step A.
  • Example 24 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)pyrrolidin-1- yl)benzamide.
  • Example 25 2-Fluoro-4-(3-(2-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 3-(2- fluorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 27 5-(2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 28 5-((S)-2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • Example 29 (S,E)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-(3-(methylsulfonyl)allyl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A and (E)-3-(methylsulfonyl)prop-2-en-1- amine, 4-methylbenzenesulfonic acid instead of (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4- methylbenzenesulfonic acid in Step C.
  • Example 30 3-Fluoro-5-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
  • Example 31 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2,6- difluorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 32 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
  • Example 33 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
  • Example 34 3-Fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide. 270 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00556] The title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 35 3-Fluoro-5-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • Example 36 3-Fluoro-5-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • Example 37 2-Fluoro-4-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(4-fluoro-2- methylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 38 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
  • Example 39 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
  • Example 40 2-Fluoro-4-((2*R,4*S)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
  • Example 41 2-Fluoro-4-((2*R,4*S)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using a mixture of 2-(2- fluorophenyl)-4-methylpyrrolidine and 4-methyl-2-phenylpyrrolidine instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 42 2-Fluoro-4-((2*S,4*R)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
  • Example 43 2-Fluoro-4-((2*S,4*R)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using a mixture of 2-(2- fluorophenyl)-4-methylpyrrolidine and 4-methyl-2-phenylpyrrolidine instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A.
  • Example 44 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)piperidin-1- yl)picolinamide. 275 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC [00566]
  • the title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4- bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 45 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)piperidin-1- yl)picolinamide.
  • Example 46 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2,3- difluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- 276 QB ⁇ 184200.00050 ⁇ 92364964.2 VVID-746PC fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 47 5-((*R)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
  • Example 48 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
  • Example 49 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1- yl)picolinamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4- bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 50 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1- yl)picolinamide.
  • Example 52 5-((*S)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
  • Example 54 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. [00576] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 56 4-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. [00578] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 58 4-((*R)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. [00580] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-6- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 60 5-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 62 4-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
  • the title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A.
  • Example 63 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.

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Abstract

The application relates to modulators of RAS-PI3K of formula (I) or (la) useful for the treatment of cancer and immunological diseases.

Description

VVID-746PC RAS-PI3K INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application claims the benefit of U.S. provisional application serial no. 63/585,907 filed September 27, 2023, the contents of which is incorporated by reference in its entirety. FIELD OF THE DISCLOSURE [002] The disclosure relates to compounds and methods for modulating RAS-PI3K. BACKGROUND OF THE DISCLOSURE [003] There is a need for improved cancer therapeutics and methods of treatment, particularly for modulation of RAS-PI3K. SUMMARY [004] Disclosed herein in some aspects are modulators of RAS-PI3K. Some such aspects relate to a RAS- PI3K agonist. Some aspects relate to a RAS-PI3K inhibitor. The RAS-PI3K modulators may include a compound described herein. The RAS-PI3K modulators may be useful in a method described herein. [005] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; and at least one pharmaceutically acceptable excipient. [006] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; and at least one pharmaceutically acceptable excipient. [007] In another aspect, provided herein is a method of modulating RAS-PI3K, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof. In some embodiments, the method comprises inhibition of RAS- PI3K. In some embodiments, the method comprises activation of RAS-PI3K. [008] In another aspect, provided herein is a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof. In some embodiments, the disease or condition is mediated by the 1 QB\184200.00050\92364964.2 VVID-746PC modulation of RAS-PI3K. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. In some embodiments, the condition is wound healing. [009] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. [0010] The present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000004_0001
wherein: each is a single bond when X8 is CH2 and is absent when X8 is absent; each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; or X1 is C, X4 is N or C, and X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-3 R10, and each of X2 and X3 is independently CR3 or N, wherein not more than one of X2 and X3 is N; R1 is C1-C6 alkyl or C3-C6 cycloalkyl; each R2 is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R3 is independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4 and R5 is independently hydrogen or C1-C6 alkyl; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or 2 QB\184200.00050\92364964.2 VVID-746PC X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-3 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8, and X7 and X8 are each absent; or X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with three to four additional atoms, form a fused 5 to 6-membered heterocyclic ring, wherein the fused 5 to 6-membered heterocyclic ring is substituted with 0-2 R8 , and X 8 is absent; or X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; each R6 is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl; or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7 cycloalkyl; each R7 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl or C1-C6 haloalkoxyl; y is 0, 1, 2 or 3; and each R8 is independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; and each R10 is independently C1-C3 alkyl. [0011] The present disclosure also provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000005_0001
3 QB\184200.00050\92364964.2 VVID-746PC (Ia) wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; R1 is C1-C6 alkyl; R2 is hydrogen or C1-C6 alkyl; each R3 is independently hydrogen, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4 and R5 is independently hydrogen or C1-C6 alkyl; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7 cycloalkyl; each R7 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; y is 0, 1, 2 or 3; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl. [0012] In some embodiments of Formula (Ia), R1 and R2 are methyl. [0013] In some embodiments of Formula (Ia), one of X1 and X4 is N. [0014] In some embodiments of Formula (Ia), one of X2 and X3 is N. [0015] In some embodiments of Formula (Ia), X1 is N. [0016] In some embodiments of Formula (Ia), X3 is N. [0017] In some embodiments of Formula (Ia), X2 and X4 are each CR3. [0018] In some embodiments of Formula (Ia), each of X1, X2, X3 and X4 is CR3. [0019] In some embodiments of Formula (Ia), each R3 is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy. [0020] In some embodiments of Formula (Ia), X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2. 4 QB\184200.00050\92364964.2 VVID-746PC [0021] In some embodiments of Formula (Ia), X5 and X6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8. [0022] In some embodiments of Formula (Ia), each R8 is independently chloro or fluoro. [0023] In some embodiments of Formula (Ia), each R6 is independently chloro, fluoro, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl. [0024] In some embodiments of Formula (Ia), each R7 is independently chloro, fluoro or C1-C3 alkyl. [0025] In some embodiments of Formula (Ia), ring A is phenyl. [0026] In some embodiments, the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 5 QB\184200.00050\92364964.2 VVID-746PC [0027] In some embodiments, the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [0028] In some embodiments, the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0002
6 QB\184200.00050\92364964.2 VVID-746PC wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [0029] In some embodiments, the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; 7 QB\184200.00050\92364964.2 VVID-746PC each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [0030] In some embodiments, the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is optionally substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [0031] In some embodiments, the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof: 8 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000011_0002
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [0032] In some embodiments, the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0001
wherein: R1 is C1-C3 alkyl; 9 QB\184200.00050\92364964.2 VVID-746PC R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [0033] The present disclosure provides for a pharmaceutical composition comprising a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) as disclosed above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. [0034] The present disclosure provides a method of inhibiting RAS-PI3K in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa), or a pharmaceutically salt, solvate, or stereoisomer thereof. [0035] The present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0036] In some embodiments, the disease is cancer. [0037] In some embodiments, the cancer is selected from the group of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. [0038] In some embodiments, the disease or condition is an immunological disease or condition. [0039] In some embodiments, the immunological condition is wound healing deficiency. [0040] The present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of cancer. 10 QB\184200.00050\92364964.2 VVID-746PC [0041] In some embodiments, the use of the compound is to treat bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, or pancreatic cancer. [0042] The present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of an immunological disease or condition. [0043] In some embodiments, the immunological condition addressed by the use is wound healing deficiency. [0044] In some aspects, the present disclosure provides for a method treating cancer comprising administering a sufficient amount of a compound disclosed herein, such as a compound of Formula (I) or Formula I(a) to a subject in need thereof. In some aspects, the subject is a human subject. In some aspects, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. [0045] In some aspects, the present disclosure provides for methods of promoting wound healing, comprising administering to a subject in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing. [0046] In some aspects, the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa) in the treatment of cancer or the promotion of wound healing. [0047] In some aspects, the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa) in the formulation of a medicament useful for the treatment of cancer or the promotion of wound healing. INCORPORATION BY REFERENCE [0048] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. DETAILED DESCRIPTION [0049] RAS proteins are small GTPases known for their involvement in oncogenesis. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3- kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell 11 QB\184200.00050\92364964.2 VVID-746PC survival, cytoskeleton reorganization, and metabolism. It is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro. Mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRAS-induced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature. [0050] Disclose herein are compounds and methods for modulating RAS-PI3K activity. Some embodiments relate to a compound or method of inhibiting RAS-PI3K activity. Some embodiments, relate to a compound or method of activating RAS-PI3K activity. The modulating of RAS-PI3K activity may be in vitro or in vivo. The compound for modulating RAS-PI3K may be formulated for administration to a subject. The RAS-PI3K modulation may be performed in a subject. [0051] The compounds disclosed herein may be useful for treatment of diseases where RAS-PI3K activity may be a concern. In some embodiments, the compound is used for wound healing. In some embodiments, the compound is used for treatment of cancer. Compounds of the Disclosure [0052] The present disclosure provides for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000014_0001
wherein: each is a single bond when X8 is CH2 and is absent when X8 is absent; each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; or X1 is C, X4 is N or C, and X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-3 R10, and each of X2 and X3 is independently CR3 or N, wherein not more than one of X2 and X3 is N; R1 is C1-C6 alkyl or C3-C6 cycloalkyl; each R2 is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; 12 QB\184200.00050\92364964.2 VVID-746PC each R3 is independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4 and R5 is independently hydrogen or C1-C6 alkyl; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-3 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8 , and X7 and X8 are each absent; or X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with three to four additional atoms, form a fused 5 to 6-membered heterocyclic ring, wherein the fused 5 to 6-membered heterocyclic ring is substituted with 0-2 R8, and X8 is absent; or X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; each R6 is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl; or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7 cycloalkyl; each R7 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl or C1-C6 haloalkoxyl; y is 0, 1, 2 or 3; and each R8 is independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; and each R10 is independently C1-C3 alkyl. [0053] In some embodiments of Formula (I), each of R1 and R2 is independently methyl or cyclopropyl. [0054] In some embodiments of Formula (I), one of X1 and X4 is N. [0055] In some embodiments of Formula (I), one of X2 and X3 is N. [0056] In some embodiments of Formula (I), X3 is N. 13 QB\184200.00050\92364964.2 VVID-746PC [0057] In some embodiments of Formula (I), X1 is N. [0058] In some embodiments of Formula (I), X4 is N. [0059] In some embodiments of Formula (I), X2 and X4 are each CR3. [0060] In some embodiments of Formula (I), each of X1, X2, X3 and X4 is CR3. [0061] In some embodiments of Formula (I), X1 is C, X4 is N or C, X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring, wherein the fused 5-membered aromatic ring is substituted with 0-1 R10, and X2 and X3 are each CR3. [0062] In some embodiments of Formula (I), each R3 is independently hydrogen, chloro, fluoro, methyl, methoxy, -CF2, -CF3, or -CN. [0063] In some embodiments of Formula (I), X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent. [0064] In some embodiments of Formula (I), X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent. [0065] In some embodiments of Formula (I), each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8, and X7 and X8 are each absent. For example, in some such embodiments, X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8. [0066] In some embodiments of Formula (I), X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8 is absent. [0067] In some embodiments of Formula (I), X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2. [0068] In some embodiments of Formula (I), each R6 is independently fluoro, chloro, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl; or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring. [0069] In some embodiments of Formula (I), each R7 is independently fluoro, chloro, -OCH3, -CF3, -OCF3, or C1-C3 alkyl. [0070] In some embodiments of Formula (I), each R8 is independently fluoro, chloro, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, cyclopropyl, oxetanyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9. [0071] In some embodiments of Formula (I), ring A is phenyl. 14 QB\184200.00050\92364964.2 VVID-746PC [0072] In some embodiments of Formula (I), ring A is pyridinyl or cyclohexyl. [0073] In some embodiments of Formula (I), R10 is methyl. [0074] In some embodiments of Formula (I), the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000017_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8, and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is independently halogen or C1-C3 alkyl. [0075] In some embodiments of Formula (I), the compound is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: 15 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000018_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is independently halogen or C1-C3 alkyl. [0076] In some embodiments of Formula (I), the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof: 16 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000019_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is independently halogen or C1-C3 alkyl. [0077] In some embodiments of Formula (I), the compound is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: 17 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000020_0001
wherein: R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8, and X7 and X8 are each absent; or X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8 is absent; or X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; each R6 is independently halogen, hydroxyl, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, or C1-C3 haloalkoxyl; y is 0, 1, 2 or 3; each R8 is independently halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; and 18 QB\184200.00050\92364964.2 VVID-746PC each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. [0078] In some embodiments of Formula (V), X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8. [0079] In some embodiments of Formula (I), the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000021_0001
wherein: R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; each R8 is independently halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -C1-C3 alkylene-O-R9; and R9 is C1-C3 alkyl. 19 QB\184200.00050\92364964.2 VVID-746PC [0080] In some embodiments of Formula (I), the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000022_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1, or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2, or 3; and each R8 is independently halogen or C1-C3 alkyl. [0081] In some embodiments of Formula (I), the compound is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof: 20 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000023_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1, or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2, or 3; and each R8 is independently halogen or C1-C3 alkyl. [0082] In some embodiments of Formula (I), the compound is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof: 21 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000024_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; X4 is C or N; X9 is CH or NR10; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and R10 is C1-C3 alkyl. [0083] In some embodiments of Formula (I), the compound is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000024_0002
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; or 22 QB\184200.00050\92364964.2 VVID-746PC X1 is C, X4 is N or C, and X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-1 R10, and each of X2 and X3 is independently CR3 or N, wherein not more than one of X2 and X3 is N; R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; each R3 is independently hydrogen, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; X5 and X6 are each CH2, substituted with 0-2 R6, or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1, or 2; ring A is aryl, 6-membered heteroaryl, or C6 cycloalkyl; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, or C1-C3 haloalkoxyl; y is 0, 1, 2, or 3; each R8 is independently halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; and R10 is C1-C3 alkyl. [0084] In some embodiments of Formula (X), each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N. [0085] In some embodiments of Formula (X), X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8. [0086] In some embodiments of Formula (X), ring A is phenyl. 23 QB\184200.00050\92364964.2 VVID-746PC [0087] In some embodiments of Formula (I), the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000026_0001
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen or C1-C3 alkyl; each R3 is independently hydrogen, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, or X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring; each R6 is independently halogen, hydroxyl, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; ring A is aryl, w is 0, 1, or 2; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxyl; and y is 0, 1, 2, or 3. [0088] In some embodiments of Formula (I), the compound is a compound of Formula (XII), or a pharmaceutically acceptable salt or solvate thereof: 24 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000027_0001
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3 is independently hydrogen, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; ring A is aryl; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxyl; and y is 0, 1, 2 or 3. [0089] In some embodiments of Formula (I), the compound is selected from the group of: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; (E)-4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-(3-(methylsulfonyl)allyl)benzamide; 4-(3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 25 QB\184200.00050\92364964.2 VVID-746PC 2-Fluoro-4-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2,6-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-4-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*S)-2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)pyrrolidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)pyrrolidin-1-yl)benzamide; 2-Fluoro-4-(3-(2-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-(2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((S)-2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; (S,E)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-(3-(methylsulfonyl)allyl)benzamide; 3-Fluoro-5-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 3-Fluoro-5-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-5-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 2-Fluoro-4-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 26 QB\184200.00050\92364964.2 VVID-746PC 2-Fluoro-4-((2*R,4*S)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 2-Fluoro-4-((2*R,4*S)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((2*S,4*R)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 2-Fluoro-4-((2*S,4*R)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)piperidin-1-yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)piperidin-1-yl)picolinamide; 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)picolinamide; 5-(3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((*S)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 27 QB\184200.00050\92364964.2 VVID-746PC 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(3-Chloropyridin-2-yl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 28 QB\184200.00050\92364964.2 VVID-746PC 4-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 29 QB\184200.00050\92364964.2 VVID-746PC 4-((*S)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 6-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-(2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-1-(2-Chlorophenyl)-3-oxoisoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-cyano-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(3-(2-Chlorophenyl)thiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2,5-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chlorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 30 QB\184200.00050\92364964.2 VVID-746PC 4-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2,4-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 5-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((*R)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2- carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)-2-fluorobenzamide; 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(rac-(2*R,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-(rac-(2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 31 QB\184200.00050\92364964.2 VVID-746PC 5-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide; 5-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*R)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1- yl)pyrazine-2-carboxamide; 32 QB\184200.00050\92364964.2 VVID-746PC N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1- yl)pyrazine-2-carboxamide; 5-(2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 6-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide; 5-(rac-(1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 33 QB\184200.00050\92364964.2 VVID-746PC 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamid;e 5-((*S)-2-(2-Fluoro-3-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-(2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 34 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 35 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 2-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5- carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R, E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((S)-2-(2-chlorophenyl)pyrrolidin-1-yl)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 36 QB\184200.00050\92364964.2 VVID-746PC 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(rac-(2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*R,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 37 QB\184200.00050\92364964.2 VVID-746PC 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 4-((*R)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 3-Fluoro-5-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-3-(2,3,4- trifluorophenyl)morpholino)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-3-(2,3,4- trifluorophenyl)morpholino)benzamide; 4-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(rac-(1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 6-((1*R,2*S,5*S)-2-(2-Chloro-4-fluoro-phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E,1R)-1-methyl-3- methylsulfonyl-allyl)pyridine-3-carboxamide; 4-(2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 38 QB\184200.00050\92364964.2 VVID-746PC 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-(2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(2-((*R)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(2-((*S)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 6-(2-(2-Chlorophenyl)azepan-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide; 4-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide; 5-(2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide; 39 QB\184200.00050\92364964.2 VVID-746PC 4-(2-(2-Chlorophenyl)-4-oxopiperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 4-((*R)-2-(2-Chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-3- (trifluoromethyl)picolinamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 8-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)imidazo[1,2- a]pyridine-5-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*S,2*R,5*R)-2-(2,3-difluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*R,2*S,5*S)-2-(2,3-difluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*S,2*R,5*R)-2-(3-fluoro-2-methylphenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; 40 QB\184200.00050\92364964.2 VVID-746PC N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*R,2*S,5*S)-2-(3-fluoro-2-methylphenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide 5-((1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 7-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-2H- indazole-4-carboxamide; 5-((3a*S,4*S,6a*R)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*R,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(2-(2-Chlorophenyl)-4-cyclopropylpiperazin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*S,6a*S)-5-Acetyl-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 41 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2-methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(((R,E)-4-(methylsulfonyl)but-3-en-2- yl)carbamoyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((7*S,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-6-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 42 QB\184200.00050\92364964.2 VVID-746PC (1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethoxy)phenyl)pyrrolidin-1-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((*S)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; (1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 5-((1*S,2*R,5*R)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((3a*S,4*R,6a*R)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 43 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,2*R,5*R)-2-(2,6-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1S,2S,5R,6S)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3*S,5*S)-3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3*R,5*S)-3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 44 QB\184200.00050\92364964.2 VVID-746PC 5-((3a*S,4*R,6a*R)-4-(2,3-Difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*S,6a*S)-4-(2,3-Difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((1*R,3a*S,6a*R)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,3a*S,6a*R)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((*S)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 45 QB\184200.00050\92364964.2 VVID-746PC 5-((rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-Cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1R,2S,5S,6S)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,4*R,5*S)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 46 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(3-Fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(3-Fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-1-(2,3-Difluorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-1-(2,3-Difluorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 47 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 4-(Difluoromethyl)-5-((1*R,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 4-(Difluoromethyl)-5-((1*S,2*R,5*R,6*R)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S,6*R)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(3-Chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(3-Chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((7*R,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((2*R,4*R)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((2*S,4*S)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((2*S,4*R)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(3-Fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 48 QB\184200.00050\92364964.2 VVID-746PC 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4- (trifluoromethyl)nicotinamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((1*S,2*R,5*R)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((3a*S,4*R,6a*R)-4-(2-Chlorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*S,6a*S)-4-(2-Chlorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((2*R,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 49 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E)-4- (methylsulfonyl)allyl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)pent-1-en-3-yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((S,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-1- cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; and 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. [0090] The present disclosure also provides for a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000052_0001
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; R1 is C1-C6 alkyl; R2 is hydrogen or C1-C6 alkyl; each R3 is independently hydrogen, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4 and R5 is independently hydrogen or C1-C6 alkyl; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or 50 QB\184200.00050\92364964.2 VVID-746PC X5 and X6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7 cycloalkyl; each R7 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; y is 0, 1, 2 or 3; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl. [0091] In some embodiments of Formula (Ia), R1 and R2 are methyl. [0092] In some embodiments of Formula (Ia), one of X1 and X4 is N. [0093] In some embodiments of Formula (Ia), one of X2 and X3 is N. [0094] In some embodiments of Formula (Ia), X1 is N. [0095] In some embodiments of Formula (Ia), X3 is N. [0096] In some embodiments of Formula (Ia), X2 and X4 are each CR3. [0097] In some embodiments of Formula (Ia), each of X1, X2, X3 and X4 is CR3. [0098] In some embodiments of Formula (Ia), each R3 is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy. [0099] In some embodiments of Formula (Ia), X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2. [00100] In some embodiments of Formula (Ia), X5 and X6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8. [00101] In some embodiments of Formula (Ia), each R8 is independently chloro or fluoro. [00102] In some embodiments of Formula (Ia), each R6 is independently chloro, fluoro, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl. [00103] In some embodiments of Formula (Ia), each R7 is independently chloro, fluoro or C1-C3 alkyl. [00104] In some embodiments of Formula (Ia), ring A is phenyl. [00105] In some embodiments, the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: 51 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000054_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00106] In some embodiments, the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000054_0002
wherein: R1 is C1-C3 alkyl; 52 QB\184200.00050\92364964.2 VVID-746PC R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00107] In some embodiments, the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000055_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; 53 QB\184200.00050\92364964.2 VVID-746PC w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00108] In some embodiments, the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000056_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00109] In some embodiments, the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: 54 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000057_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is optionally substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00110] In some embodiments, the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000057_0002
wherein: R1 is C1-C3 alkyl; 55 QB\184200.00050\92364964.2 VVID-746PC R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00111] In some embodiments, the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000058_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; 56 QB\184200.00050\92364964.2 VVID-746PC w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. [00112] The present disclosure provides for a pharmaceutical composition comprising a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) as disclosed above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. [00113] The present disclosure provides a method of inhibiting RAS-PI3K in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa), or a pharmaceutically salt, solvate, or stereoisomer thereof. [00114] The present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00115] In some embodiments, the disease is cancer. [00116] In some embodiments, the cancer is selected from the group of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. [00117] In some embodiments, the disease or condition is an immunological disease or condition. [00118] In some embodiments, the immunological condition is wound healing deficiency. [00119] The present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of cancer. [00120] In some embodiments, the use of the compound is to treat bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, or pancreatic cancer. [00121] The present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of an immunological disease or condition. [00122] In some embodiments, the immunological condition addressed by the use is wound healing deficiency. [00123] In some aspects, the present disclosure provides for a method treating cancer comprising administering a sufficient amount of a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) to a subject in need thereof. In some aspects, the subject is a human subject. In some aspects, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck 57 QB\184200.00050\92364964.2 VVID-746PC cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. [00124] In some aspects, the present disclosure provides for methods of promoting wound healing, comprising administering to a subject in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing. [00125] In some aspects, the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa) in the treatment of cancer or the promotion of wound healing. [00126] In some aspects, the present disclosure provides for the use of the compounds of Formula (I) through (XII) or Formula (Ia) through (VIIIa)in the formulation of a medicament useful for the treatment of cancer or the promotion of wound healing. [00127] In some aspects, the present disclosure provides for a method treating cancer comprising administering a sufficient amount of a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) to a subject in need thereof. In some aspects, the subject is a human subject. In some aspects, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. [00128] In some aspects, the present disclosure provides for methods of promoting wound healing, comprising administering to a subject in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (Ia) in an amount sufficient to promote wound healing. [00129] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. Further Forms of Compounds [00130] In some aspects, a compound disclosed herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Furthermore, the compounds may exist as atropisomers. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of 58 QB\184200.00050\92364964.2 VVID-746PC stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jacques J., et al., “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis. [00131] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [00132] In one aspect, prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacokinetic, pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is known, the design of prodrugs of the compound is possible. (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401, Rooseboom et al., Pharmacological Reviews, 56:53–102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series). [00133] In some embodiments, some of the herein-described compounds may be a prodrug for another derivative or active compound. [00134] In some embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions. Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group. 59 QB\184200.00050\92364964.2 VVID-746PC [00135] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00136] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514, and 6,334,997. As described in U.S. Patent Nos. 5,846,514, and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [00137] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [00138] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [00139] In some embodiments of a compound disclosed herein, one or more of R1, R2, R3, R4, R5, R5, R6, R7, R8 groups comprise deuterium at a percentage higher than the natural abundance of deuterium. [00140] In some embodiments of a compound disclosed herein, one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R1, R2, R3, R4, R5, R5, R6, R7, R8. [00141] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R1, R2, R3, R4, R5, R5, R6, R7, R8 is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. [00142] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [00143] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, 60 QB\184200.00050\92364964.2 VVID-746PC Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [00144] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [00145] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. [00146] “Pharmaceutically acceptable” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [00147] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound disclosed herein with a base to form a salt. [00148] Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’- methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may 61 QB\184200.00050\92364964.2 VVID-746PC form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. [00149] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Pharmaceutical Compositions [00150] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the manufacture of a medicament. [00151] In one aspect, the compounds described herein (e.g., compound of Formula (I) or Formula (Ia), or pharmaceutically acceptable salts thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof) are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00152] A pharmaceutical composition, as used herein, refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, 62 QB\184200.00050\92364964.2 VVID-746PC preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. [00153] Pharmaceutical formulations described herein are administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. [00154] In some embodiments, the compounds disclosed herein are administered orally. [00155] In some embodiments, the compounds disclosed herein are administered topically. In such embodiments, the compound disclosed herein is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. In one aspect, the compounds disclosed herein are administered topically to the skin. [00156] In another aspect, the compounds disclosed herein are administered by inhalation. [00157] In another aspect, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like. [00158] In another aspect, the compounds disclosed herein are formulated as eye drops. [00159] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound disclosed herein is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non- systemically or locally to the mammal. [00160] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) the compound is administered continually; or (iv) the compound is administered continuously. [00161] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the 63 QB\184200.00050\92364964.2 VVID-746PC compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound disclosed herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. [00162] In certain embodiments, the compound disclosed herein is administered in a local rather than systemic manner. [00163] In some embodiments, the compound disclosed herein is administered topically. In some embodiments, the compound disclosed herein is administered systemically. [00164] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds disclosed herein are in the form of a capsule. [00165] In one aspect, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. [00166] For administration by inhalation, a compound disclosed herein is formulated for use as an aerosol, a mist or a powder. [00167] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. [00168] In some embodiments, compounds disclosed herein are prepared as transdermal dosage forms. [00169] In one aspect, a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. [00170] In some embodiments, the compound disclosed herein is be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. [00171] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. Methods of Treatment [00172] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer 64 QB\184200.00050\92364964.2 VVID-746PC thereof, for use in a method of modulating RAS-PI3K. In some embodiments, the method comprises inhibiting RAS-PI3K. In some embodiments, the method comprises activating RAS-PI3K. [00173] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in a method of treating a disease or condition. In some embodiments, provided herein is a method of treating a disease or condition, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof. In some embodiments, the disease or condition is mediated by RAS-PI3K. [00174] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in treating cancer in a patient in need thereof. [00175] In some embodiments, the disease is a cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, lung cancer, colorectal cancer, cervical cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. [00176] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in a method of treating an immunological condition. In some embodiments, the immunological condition is a wound healing. [00177] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in a method of treating a disease or condition. [00178] In some embodiments, administration of a compound of Formula (I) or Formula (Ia), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, promotes wound healing. Dosing and Treatment Regimens [00179] In one aspect, the compounds disclosed herein are used in the preparation of medicaments for the treatment of diseases or conditions described herein. In addition, a method for treating any of the diseases 65 QB\184200.00050\92364964.2 VVID-746PC or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said subject. [00180] In some embodiments, the compositions containing the compound disclosed herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. [00181] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. [00182] In some embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). [00183] Doses employed for adult human treatment are typically in the range of 0.01mg - 5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses. Combination Treatments [00184] In certain instances, it is appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent. [00185] In one specific embodiment, a compound disclosed herein is co-administered with a second therapeutic agent, wherein the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [00186] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially. [00187] If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms. 66 QB\184200.00050\92364964.2 VVID-746PC Definitions [00188] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. [00189] The terms below, as used herein, have the following meanings, unless indicated otherwise: [00190] “Oxo” refers to the =O substituent. [00191] “Alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10 alkyl, C1-C9 alkyl, C1- C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, npropyl, 1methylethyl (ipropyl), nbutyl, i-butyl, s-butyl, npentyl, 1,1dimethylethyl (tbutyl), 3methylhexyl, 2methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below. [00192] “Alkylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-. [00193] “Alkoxy” refers to a radical of the formula OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy. [00194] “Heteroalkyl” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N (i.e., NH, N-alkyl) or S atom. “Heteroalkylene” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to -OCH2OMe, - OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. Representative heteroalkylene groups include, but are not limited to -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-. 67 QB\184200.00050\92364964.2 VVID-746PC [00195] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below. [00196] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl). [00197] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. [00198] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to: ,
Figure imgf000070_0001
, , [00199] “Cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic or polycyclic. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 68 QB\184200.00050\92364964.2 VVID-746PC spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, decalinyl and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups. In some embodiments, cycloalkyl groups are selected from among spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalen- 1(2H)-one and decalinyl. In some embodiments, the cycloalkyl is polycyclic. Polycyclic radicals include, for example, adamantyl, and. In some embodiments, the polycyclic cycloalkyl is adamantyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. [00200] “Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom. [00201] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. [00202] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2trifluoroethyl, 1,2difluoroethyl, 3bromo2fluoropropyl, 1,2dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted. [00203] “Haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2trifluoroethoxy, 1,2difluoroethoxy, 3bromo2fluoropropoxy, 1,2dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted. [00204] “Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” refers to a stable 3 to 14 membered nonaromatic ring radical comprising 2 to 10 carbon atoms and from one to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic ring (which may include a fused bicyclic heterocycloalkyl (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), bridged heterocycloalkyl or spiro heterocycloalkyl), or polycyclic. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic. In some embodiments, the heterocycloalkyl is bicyclic. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of such heterocycloalkyl radicals 69 QB\184200.00050\92364964.2 VVID-746PC include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1oxothiomorpholinyl, 1,1dioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted. [00205] “Heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0- 4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6- C9heteroaryl. [00206] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, 70 QB\184200.00050\92364964.2 VVID-746PC haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6alkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2alkyl, nitro, and amino, including mono and disubstituted amino groups (e.g., -NH2, -NHR, -NR2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). [00207] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:
Figure imgf000073_0001
[00208] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [00209] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, 71 QB\184200.00050\92364964.2 VVID-746PC or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [00210] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of Formula (I) or Formula (Ia) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound of Formula (I) or Formula (Ia) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. [00211] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human. [00212] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. Table 1. Compounds of the Disclosure. 72 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000075_0001
73 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000076_0001
74 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000077_0001
75 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000078_0001
76 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000079_0001
77 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000080_0001
78 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000081_0001
79 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000082_0001
80 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000083_0001
81 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000084_0001
82 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000085_0001
83 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000086_0001
84 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000087_0001
85 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000088_0001
86 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000089_0001
87 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000090_0001
88 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000091_0001
89 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000092_0001
90 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000093_0001
91 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000094_0001
92 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000095_0001
93 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000096_0001
94 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000097_0001
95 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000098_0001
96 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000099_0001
97 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000100_0001
98 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000101_0001
99 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000102_0001
100 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000103_0001
101 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000104_0001
102 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000105_0001
103 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000106_0001
104 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000107_0001
105 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000108_0001
106 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000109_0001
107 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000110_0001
108 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000111_0001
109 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000112_0001
110 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000113_0001
111 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000114_0001
112 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000115_0001
113 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000116_0001
114 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000117_0001
115 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000118_0001
116 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000119_0001
117 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000120_0001
118 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000121_0001
119 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000122_0001
120 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000123_0001
121 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000124_0001
122 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000125_0001
123 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000126_0001
124 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000127_0001
125 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000128_0001
126 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000129_0001
127 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000130_0001
128 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000131_0001
129 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000132_0001
130 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000133_0001
131 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000134_0001
132 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000135_0001
133 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000136_0001
134 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000137_0001
135 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000138_0001
136 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000139_0001
137 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000140_0001
138 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000141_0001
139 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000142_0001
140 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000143_0001
141 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000144_0001
142 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000145_0001
143 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000146_0001
144 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000147_0001
145 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000148_0001
146 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000149_0001
147 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000150_0001
148 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000151_0001
EXAMPLES [00213] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. [00214] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [00215] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized. Scheme 1 149 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000152_0002
Figure imgf000152_0001
[00216] According to Scheme 1, a compound of formula (I), fully defined in Claim 1, is prepared in three steps from a compound of formula (II) and a compound of formula (III). In a first step, a compound of formula (II), wherein X1, X2, X3, and X4 are independently nitrogen or a substituted or unsubstituted carbon and Y is Br or I, is reacted under conventional Buchwald-Hartwig coupling conditions in the presence of a commercially available or synthetically accessible compound of formula (III). The reaction takes place in the presence of a ligand/catalyst system such as SPhos Pd G4, RuPhos Pd G4, XantPhos/Pd2(dba)3, and the like; a base such as Cs2CO3, and the like; in a suitable solvent such as toluene; and the like; at temperatures of 80-110 °C for a period of 16-24 hours to provide a compound of formula (IV). In the case where X1 and X2 are CH and X3 and X4 are N, a compound of formula (V) may be obtained directly. [00217] Alternatively, a compound of formula (IV) can be synthesized from a compound of formula (II) and a compound of formula (III) under nucleophilic aromatic substitution (SNAr) conditions. In this case, a compound of formula (II), wherein X1, X2, X3, and X4 are independently nitrogen or a substituted or unsubstituted carbon and Y is F or Cl, is reacted under conventional SNAr coupling conditions in the presence of a commercially available or synthetically accessible compound of formula (III). The reaction takes place using a suitable base such as K2CO3, Cs2CO3, KOtBu, DIPEA, TEA, NaH, pyridine, and the like; in a solvent such as DMSO, DMF, NMP, 1,4-dioxane, THF, and the like; at temperatures of 25-160 °C for a period of 3-20 hours to provide a compound of formula (IV). [00218] In a second step, a compound of formula (V) is prepared from a compound of formula (IV). Using hydrolysis conditions known to one skilled in the art, a compound of formula (IV) is reacted with an appropriate hydroxide such as aqueous LiOH, and the like; in a suitable solvent such as MeOH, ACN, THF, and the like; at temperatures of 25-80 °C for a period of 1-16 hours to provide a compound of formula (V). 150 QB\184200.00050\92364964.2 VVID-746PC Alternatively, a compound of formula (V) can be prepared from a compound of formula (IV) in the presence of Me3SnOH in a suitable solvent such as DCE, and the like; at a temperature of 110 °C for a period of 16 h. [00219] In a third step, a compound of formula (I), as defined in Claim 1, is prepared from a compound of formula (V) under amide coupling conditions known to one skilled in the art. Employing conventional amide bond forming techniques, a carboxylic acid such as a compound of formula (V) is reacted with a coupling agent such as HATU, T3P®, T4P and the like; in the presence of an amine such as a compound of formula (VI), wherein R2 is hydrogen, C1-C6-alkyl, or C3-C6-cycloalkyl and R1 is C1-C6-alkyl or C3-C6- cycloalkyl, and a base such as DIPEA, TEA, and the like; in a solvent such as DMSO, DMF, DCM, and the like; at rt for a period of 30 minutes to 16 hours to provide a compound of formula (I). Scheme 2 Boc deprotection
Figure imgf000153_0001
Figure imgf000153_0002
[00220] According to Scheme 2, tert-butyl N-(1-cyclopropyl-2-hydroxyethyl)carbamate can be oxidized using Dess-Martin periodinane in DCM to provide a compound of formula (XXXIII), where R2 is cyclopropyl. A compound of formula (VII), wherein R2 and R1 are independently C1-C6 alkyl or C3-C6 cycloalkyl, can be formed from a compound of formula (XXXIII) using the appropriate phosphonate such as diethyl ((methylsulfonyl)methyl)phosphonate, diethyl ((ethylsulfonyl)methyl)phosphonate, and the like; with an appropriate base such as NaH, and the like; in a solvent such as THF, and the like; at 0 °C for 30 min before addition of a compound of formula (XXXIII). Reaction at 0 °C for a period of 1 hour provides a compound of formula (VII). A compound of formula (VII) is treated with an acid such as TsOH, TFA, HCl, and the like; in a solvent such as ACN, MeOH, 1,4-dioxane, DCM, and the like; at 25-60 °C for a period of 1-12 h to provide a compound of formula (VI), where R2 and R1 are independently C1-C6 alkyl or C3-C6 cycloalkyl. Scheme 3
Figure imgf000153_0003
151 QB\184200.00050\92364964.2 VVID-746PC [00221] According to Scheme 3, a compound of formula (V) can be formed from a compound of formula (VIII). A compound of formula (VIII), wherein R7 is H or F, is treated with iPrMgCl in a suitable solvent such as THF, and the like; at a temperature of 0 °C before being mixed with crushed CO2 and acidified with HCl to provide a compound of formula (V), where X1 and X3 are CH, X4 is CF, X2 is N, X5 and X6 are CH2, X7 and X8 are absent, and ring A is a substituted phenyl. Scheme 4
Figure imgf000154_0001
[00222] According to Scheme 4, a compound of formula (X), wherein X1 and X3 are independently N or CH and R3 and R7 are independently H or F, can be made from a compound of formula (IX) under reducing conditions using BH3·Me2S in a suitable solvent such as THF, and the like; at rt for a period of 16 hours. Scheme 5
Figure imgf000154_0002
[00223] According to Scheme 5, a compound of formula (XII), wherein R7 is H or F, X5 and X6 are CH2, X7 is O or is absent, and X8 is absent, can be formed from a compound of formula (XI) in the presence of CsF in a solvent such as DMF, and the like; at a temperature of 80 °C for a period of 16 hours. Scheme 6
Figure imgf000154_0003
152 QB\184200.00050\92364964.2 VVID-746PC [00224] According to Scheme 6, a compound of formula (XIV), wherein X3 is CH or N and R3 is H or F, can be formed from a compound of formula (XIII) in the presence of NaIO4 and RuCl3 in an appropriate solvent such as water/ethyl acetate, and the like; at rt for a period of 16 hours. Similarly, a compound of formula (XV) can be subjected to the same conditions to form a compound of formula (XVI). Scheme 7
Figure imgf000155_0001
Figure imgf000155_0002
[00225] According to Scheme 7, a compound of formula (IV) can be formed in three steps from a compound of formula (XVII). In a first step, a compound of formula (XVII), wherein X2 is CH, X3 is N or CH, X8 is absent, X5 and X6 are CH2 and X7 is CH2 or O, is treated with a triflating agent such as trifluoromethanesulfonic anhydride, 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide, and the like; in the presence of a base such as DIPEA, LiHMDS, KHMDS, and the like; in a solvent such as DCM, THF, and the like; at temperatures of -78-0 °C for a period of 2 hours to provide a compound of formula (XVIII), where Ra is SO2CF3. Alternatively, a compound of formula (XVII), wherein X2 is N, X3 is CH, X8 is absent, X5 and X6 are CH2 and X7 is - CH2CH2-, is treated with diphenyl phosphorochloridate in the presence of a suitable base such as KHMDS, and the like; in a solvent such as THF, and the like; at -78 °C for a period of 1 h to provide a compound of formula (XVIII), where Ra is PO(OPh)2. [00226] In a second step, a compound of formula (XX), wherein X2 and X3 are independently N or CH, X8 is absent, X5 and X6 are CH2, and X7 is CH2, O, or -CH2CH2-, and A is a substituted aromatic ring, is formed from a compound of formula (XVIII) under standard boronic acid coupling conditions. Using a boronic acid of formula (XIX), wherein A is a substituted aromatic ring, and a ligand/catalyst system such as Pd(PPh3)4, Pd(dppf)Cl2, and the like; and a base such as K2CO3, Na2CO3, and the like; in a solvent such as 1,4-dioxane/water, DME, EtOH, and the like; at temperatures of 70-100 °C for a period of 2-17 hours provides a compound of formula (XX). 153 QB\184200.00050\92364964.2 VVID-746PC [00227] In a third step, a compound of formula (IV) is formed from a compound of formula (XX) under standard hydrogenation conditions known to one skilled in the art. Under an atmosphere of hydrogen, a compound of formula (XX) is treated with PtO2, Pd/C, and the like; in a suitable solvent such as THF, MeOH, EtOAc, EtOH, and the like; at rt for 3-12 hours to provide a compound of formula (IV), where X1 is CH, X4 is CF, X2 and X3 are independently N or CH, X8 is absent, X5 and X6 are CH2, X7 is CH2, O, or - CH2CH2-, and A is a substituted aromatic ring. Scheme 8
Figure imgf000156_0001
(XXII) [00228] According to Scheme 8, a compound of formula (XXII), wherein each R7 is independently F or H, is formed from a compound of formula (XXI). Employing Grignard coupling conditions known to one skilled in the art, a compound of formula (XXI) is reacted with a Grignard reagent formed from the treatment of an appropriate halobenzene such as 1-chloro-2-iodobenzene, 1-bromo-2-chloro-3-fluorobenzene, 2- chloro-4-fluoro-1-iodobenzene, and the like; with iPrMgCl·LiCl in a solvent such as THF, and the like; at temperatures of -20-25 °C for up to 2 hours. Addition of a reducing agent such as NaBH3CN, and the like; along with an appropriate acid such as HCl, AcOH, and the like; at 10-25 °C reacting over a period of 16 hours provides a compound of formula (XXII). Scheme 9
Figure imgf000156_0003
(XXIII)
Figure imgf000156_0002
154 QB\184200.00050\92364964.2 VVID-746PC [00229] According to Scheme 9, a compound of formula (III) can formed in three steps from a compound of formula (XVI). In a first step, a compound of formula (XVI) can be reacted under conventional Grignard coupling conditions using (2-chloro-4-fluorophenyl)magnesium bromide, (2-chloro-3- fluorophenyl)magnesium bromide, (2-chlorophenyl)magnesium bromide, (2,3-difluorophenyl)magnesium bromide, (3-fluoro-2-methylphenyl)magnesium bromide and the like; in an appropriate solvent such as THF, and the like; at a temperature of 0 °C for a period of 2 hours to provide a compound of formula (XXIII), where A is a substituted aromatic ring. Alternatively, a compound of formula (XXIII) can be formed by treating an aryl bromide such as 2-bromo-3-chloropyridine, 2-bromochlorobenzene, 2,6- difluorobromobenzene, and the like; with n-butyllithium at -78 °C for 1 h followed by addition of a compound of formula (XVI) in an appropriate solvent such as THF, and the like; at -78-25 °C for a period of 4-12 hours to provide a compound of formula (XXIII), where A is a substituted aromatic or heteroaromatic ring. [00230] In a second step, a compound of formula (XXIII) is subjected to Boc deprotection conditions previously described in Scheme 2 to provide a compound of formula (XXIV). Finally, a compound of formula (XXIV) is reacted under reductive amination conditions using NaBH3CN, NaBH4, and the like; in a solvent such as MeOH, EtOH, and the like; with acetic acid at rt for a period of 2-16 hours to provide a compound of formula (III). In some instances, a Mitsunobu coupling is needed to form a compound of formula (III) after the steps described above. Using PPh3 and DEAD, and the like; in a solvent such as toluene, and the like; at 50 °C for 16 h, a compound of formula (III) can be formed. Scheme 10
Figure imgf000157_0001
[00231] According to Scheme 10, a compound of formula (III) can be synthesized in five steps from a compound of formula (XXV). In a first step, a compound of formula (XXV) is Boc protected under conditions known to one skilled in the art using di-tert-butyl dicarbonate, DMAP, and an appropriate base such as TEA, and the like; in a solvent such as DCM, and the like; at rt for a period of 2-17 hours to provide 155 QB\184200.00050\92364964.2 VVID-746PC a compound of formula (XVI). In a second step, a compound of formula (XVI) is reacted under conditions previously described in Scheme 7 to form a compound of formula (XXVI), where Ra is SO2CF3 or PO(OPh)2. In a third step, standard boronic acid coupling conditions previously described in Scheme 7 are employed. A compound of formula (XXVI) is reacted with a compound of formula (XIX), wherein A is a substituted aromatic ring, to provide a compound of formula (XXVII). A compound of formula (XXVII) can undergo hydrogenation as previously described in Scheme 7 followed by Boc deprotection as previously described in Scheme 2 to provide a compound of formula (III). Alternatively, a compound of formula (XXVII) can be subjected to Boc deprotection conditions then reacted under reducing conditions using NaBH4, and the like; in a solvent such as MeOH, and the like; at rt for a period of 2-16 hours to provide a compound of formula (III).
Figure imgf000158_0001
[00232] According to Scheme 11, 5-(2-chlorophenyl)pyrrolidin-3-yl acetate can be formed from 2- chlorobenzaldehyde in five steps. In a first step, 2-chlorobenzaldehyde is treated with 2-methylpropane-2- sulfinamide and Ti(OiPr)4 in an appropriate solvent such as THF, and the like; at rt for a period of 16 h to provide N-(2-chlorobenzylidene)-2-methylpropane-2-sulfinamide. In a second step, N-(2- chlorobenzylidene)-2-methylpropane-2-sulfinamide is reacted under conventional Grignard coupling conditions previously described in Scheme 9 using allylmagnesium chloride to form N-(1-(2- chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide. Treatment with an acid such as HCl, and the like; in a suitable solvent such as MeOH, and the like; at rt for a period of 2 h provides 1-(2- chlorophenyl)but-3-en-1-amine. In a fourth step, 1-(2-chlorophenyl)but-3-en-1-amine is treated with acetic anhydride and an appropriate base such as TEA, and the like; in a solvent such as DCM, and the like; at 0 °C for a period of 3 hours to provide N-(1-(2-chlorophenyl)but-3-en-1-yl)acetamide. Reaction of N-(1-(2- chlorophenyl)but-3-en-1-yl)acetamide with iodine in a solvent such as THF/water, and the like; at rt for a period of 16 hours provides 5-(2-chlorophenyl)pyrrolidin-3-yl acetate, a compound of formula (III). Scheme 12 156 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000159_0001
[00233] According to Scheme 12, 5-(2-chlorophenyl)-3-methylpyrrolidin-3-ol can be formed in five steps from 5-(2-chlorophenyl)pyrrolidin-3-yl acetate. First, Boc protection previously described in Scheme 10 is used to obtain tert-butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxylate. In a second step, tert- butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxyl is treated with a suitable base such as K2CO3, and the like; in a solvent such as MeOH, and the like; at rt for a period of 1 hour to provide tert-butyl 2-(2- chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate. Employing Swern oxidation conditions known to one skilled in the art, tert-butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1-carboxylate is formed using oxalyl chloride, DMSO, and TEA in a solvent such as DCM, and the like; at -78 °C warming to rt for 1 h. In a fourth step, tert-butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1-carboxylate is treated with methyllithium in the presence of trichlorocerium, in a suitable solvent such as THF, and the like; at -78 °C for a period of 3 h to provide tert-butyl 2-(2-chlorophenyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylate. Finally, Boc deprotection as previously described in Scheme 2 provides 5-(2-chlorophenyl)-3-methylpyrrolidin-3-ol, a compound of formula (III). Scheme 13
Figure imgf000159_0002
[00234] According to Scheme 13, a compound of formula (XXXVII) can be synthesized from a compound of formula (XXVIII), wherein R3 is F or H, X1 and X3 are dependently CH or N, and Rb is H or CH3, in two steps. In a first step, a compound of formula (XXVIII) is treated with a suitable base such as K2CO3, and the like; in a solvent such as MeOH, and the like; at rt for a period of 1 hour to provide a compound of formula (XXIX). In a second step, a compound of formula (XXIX) is subjected to standard methylation conditions using an appropriate base such as NaH, and the like; and iodomethane in a solvent such as THF, and the like; at 0-25 °C for a period of 1-16 h. In the case where R3 is F and X1 and X3 are CH, a compound of formula (XXXVII) is formed wherein Rb is CH3. In the case where R3 is H and X1 and X3 are N, a compound of formula (XXXVII) is formed wherein Rb is H. 157 QB\184200.00050\92364964.2 VVID-746PC Scheme 14
Figure imgf000160_0001
[00235] According to Scheme 14, a compound of formula (V) can be synthesized from a compound of formula (XXIX) in three steps. In a first step, a compound of formula (XXIX), wherein R3 is H and X1 and X3 are CH, is oxidized under conventional Swern oxidation conditions previously described in Scheme 12 to provide methyl 4-(2-(2-chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate. In a second step, methyl 4-(2-(2- chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate is treated with a fluorinating agent such as DAST, and the like; in a solvent such as DCM, and the like; at a temperature of -78 °C warming to rt over 4 hours to provide methyl 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate. In a third step, methyl 4-(2-(2- chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate is treated with HBr at a temperature of 110 °C over a period of 2 hours to provide a compound of formula (V), where X1, X2, X3, and X4 are CH, X7 and X8 are absent, X5 is CF2, X6 is CH2, and A is 2-chlorophenyl. Scheme 15
Figure imgf000160_0002
Figure imgf000160_0003
[00236] According to Scheme 15, a compound of formula (III) can be formed in four steps from tert-butyl 4-oxopyridine-1(4H)-carboxylate. In a first step, tert-butyl 4-oxopyridine-1(4H)-carboxylate is reacted under Grignard coupling conditions using an appropriately substituted Grignard reagent such as (2- chlorophenyl)magnesium bromide, (2-chloro-3-fluorophenyl)magnesium bromide, and the like; and chlorotrimethylsilane in a solvent such as THF, and the like; at temperatures of -10-25 °C for a period of 16 hours to provide a compound of formula (XXX), where R7 is F or H. Reduction of a compound of formula (XXX) using L-selectride, and the like; in a solvent such as THF, and the like; at rt for 16 hours provides a compound of formula (XXXI). Treatment of a compound of formula (XXXI) with a fluorinating 158 QB\184200.00050\92364964.2 VVID-746PC agent such as Deoxo-Fluor®, DAST, and the like; in an appropriate solvent such as DCM, and the like; at temperatures of 0-25 °C for a period of 16 hours provides a compound of formula (XXXII). Boc deprotection of a compound of formula (XXXII) as previously described in Scheme 2 provides a compound of formula (III), where X8 is absent, X5 and X6 are CH2, X7 is CF2 and A is a substituted aromatic ring.
Figure imgf000161_0001
[00237] According to Scheme 16, methyl 4-(2-(2-chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoate is prepared in four steps from a compound of formula (XXXI), wherein R7 is H. In a first step, a compound of formula (XXXI), wherein R7 is H, is treated with ethylene glycol and TsOH in toluene at 120 °C for 16 h to provide tert-butyl 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate. In a second step, tert-butyl 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate is subjected to Boc deprotection conditions previously described in Scheme 2 to provide 7-(2-chlorophenyl)-1,4-dioxa-8- azaspiro[4.5]decane. In a third step, 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane is subjected to Buchwald-Hartwig coupling conditions as previously described in Scheme 1 to provide methyl 4-(7-(2- chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-fluorobenzoate. In a fourth step, methyl 4-(7-(2- chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-fluorobenzoate is treated with 10% H2SO4 in a solvent such as THF, and the like; at rt for up to 96 hours to provide methyl 4-(2-(2-chlorophenyl)-4- oxopiperidin-1-yl)-2-fluorobenzoate, a compound of formula (IV). Scheme 17
Figure imgf000161_0002
[00238] According to Scheme 17, a compound of formula (III) can be synthesized in three steps from a compound of formula (XXIII). A compound of formula (XXXIII) can be reduced using an appropriate 159 QB\184200.00050\92364964.2 VVID-746PC reducing agent such as LiAlH4, NaBH4, and the like; in a solvent such as MeOH, and the like; at rt for a period of 2-16 hours to provide a compound of formula (XXXIV). A compound of formula (XXXIV) is treated with tosyl chloride, DMAP, and a base such as TEA, and the like; in a solvent such as ACN, DCM, and the like; at 25-45 °C for 2-16 hours to provide a compound of formula (XXXV). Alternatively, a compound of formula (XXXIV) can be subjected to Mitsunobu conditions as previously described in Scheme 9 to provide a compound of formula (XXXV). Finally, employing Boc deprotection conditions previously described in Scheme 2 provides a compound of formula (III). Alternatively, the final two steps can be reversed so that a compound of formula (XXXIV) undergoes Boc deprotection followed by SN2 ring closure as previously described to provide a compound of formula (III). Scheme 18
Figure imgf000162_0003
Figure imgf000162_0001
Figure imgf000162_0004
Figure imgf000162_0002
[00239] According to Scheme 18, a compound of formula (III) can be synthesized in five steps from tert- butyl (1-(2-chlorophenyl)-2-hydroxyethyl)carbamate. In a first step, tert-butyl (1-(2-chlorophenyl)-2- hydroxyethyl)carbamate is treated with methyl acrylate and an appropriate base such as Cs2CO3, and the like; in a solvent such as ACN, and the like; at rt for a period of 3 h to provide methyl 3-(2-((tert- butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate. In a second step, methyl 3-(2-((tert- butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate undergoes Boc deprotection previously described in Scheme 2 to provide methyl 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoate. In a third step, methyl 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoate is reacted under hydrolysis conditions previously described in Scheme 1 to provide 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoic acid. In a fourth step, 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoic acid is reacted under amide coupling conditions previously described in Scheme 1 to provide 3-(2-chlorophenyl)-1,4-oxazepan-5-one. Finally, 3-(2- chlorophenyl)-1,4-oxazepan-5-one is reacted under reducing conditions described in Scheme 17 to provide a compound of formula (III), where X8 is absent, X5 and X6 are CH2, X7 is -CH2O-, and A is 2-chlorophenyl. Scheme 19 160 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000163_0001
[00240] According to Scheme 19, methyl 4-(3-(2-chlorophenyl)thiomorpholino)-2-fluorobenzoate is reacted with 1 equivalent of Selectfluor® and 2 equivalents of water in ACN at rt for 10 min to provide methyl 4-(3-(2-chlorophenyl)-1-oxidothiomorpholino)-2-fluorobenzoate, a compound of formula (IV). Scheme 20
Figure imgf000163_0002
[00241] According to Scheme 20, 5-(2-(2-chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3- fluoropicolinic acid (a compound of formula (V)) is formed from 5-(((2-carboxycyclopropyl)(2-chloro-3- fluorophenyl)methyl)amino)-3-fluoropicolinic acid under standard amide coupling conditions previously described in Scheme 1. Similarly, tert-butyl rac-(1*S,5*S,6*S)-6-(dimethylcarbamoyl)-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XVI)) is formed from rac-(1*S,5*R,6*S)- 3-(tert-butoxycarbonyl)-2-oxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid under the same conditions. Scheme 21 Boc Boc deprotection reduction
Figure imgf000163_0003
Figure imgf000163_0004
Figure imgf000163_0005
Figure imgf000163_0006
(XXIII) [00242] According to Scheme 21, a compound of formula (XXIII) can be converted to a compound of formula (III) in two steps. In a first step, a compound of formula (XXIII) is treated with 2,6-lutidine and trimethylsilyl trifluoromethanesulfonate in DCM at rt for 1 h to provide a compound of formula (XXXVI). Treating a compound of formula (XXXVI) with a reducing agent such as NaBH3CN in MeOH at rt for 3- 16 h provides a compound of formula (III). Scheme 22 161 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000164_0005
Figure imgf000164_0001
(XVI) (XXXVIII)
Figure imgf000164_0002
[00243] According to Scheme 22, a compound of formula (XXXVI) can be formed from a compound of formula (XVI) in two steps. Subjecting a compound of formula (XVI) to standard Grignard coupling conditions as previously described in Scheme 8 can provide a compound of formula (XXXVIII). Under Boc deprotection conditions previously described in Scheme 2, a compound of formula (XXXVIII) can be converted to compound of formula (XXXVI). Scheme 23
Figure imgf000164_0003
[00244] According to Scheme 23, 7-(2-chloro-3-fluorophenyl)-1,3,4,6,9,9a-hexahydropyrazino[2,1- c][1,4]oxazine is prepared in two steps from tert-butyl N-(morpholin-3-ylmethyl)carbamate. First, tert- butyl N-(morpholin-3-ylmethyl)carbamate is reacted with 2-bromo-1-(2-chloro-3-fluorophenyl)ethanone and DIPEA in DMSO for 12 h at rt to give tert-butyl ((4-(2-(2-chloro-3-fluorophenyl)-2- oxoethyl)morpholin-3-yl)methyl)carbamate. tert-Butyl ((4-(2-(2-chloro-3-fluorophenyl)-2- oxoethyl)morpholin-3-yl)methyl)carbamate is subjected to Boc deprotection conditions as previously described in Scheme 2 to provide 7-(2-chloro-3-fluorophenyl)-1,3,4,6,9,9a-hexahydropyrazino[2,1- c][1,4]oxazine, a compound of formula (XXXVI). Scheme 24
Figure imgf000164_0004
[00245] According to Scheme 24, a compound of formula (III) can be synthesized in two steps from a compound of formula (XXXIX), wherein R7 is Cl or F. In a first step, a compound of formula (XXXIX) is treated with Ir[dF(CF3)ppy]2(5,5’-dCF3bpy)PF6, CuI•DMS, 2,2'-dipyridyl ketone, tert-butylimino- tri(pyrrolidino)phosphorane, and 1,3-dihydro-3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole in EtOAc and water under irradiation at rt for 16 h to provide a compound of formula (XL), where R7 is Cl or F. A compound of formula (XL) can be Boc deprotected as previously described in Scheme 2 to provide a 162 QB\184200.00050\92364964.2 VVID-746PC compound of formula (III), where X5 and X6 are CH and form a fused 3-membered saturated ring with another CH that is substituted with CF3, and X7 and X8 are absent. Scheme 25
Figure imgf000165_0001
[00246] According to Scheme 25, a compound of formula (III) can be prepared in four steps from a compound of formula (XLI), wherein R7 is H or F. First, a compound of formula (XLI) is treated with 2- chloroacetyl chloride and TEA in DCM at rt for 16 h to provide a compound of formula (XLII). A compound of formula (XLII) can be cyclized using NaH in DMF at rt for 16 h to provide a compound of formula (XLIII). A compound of formula (XLIII) can be methylated using standard conditions previously described in Scheme 13 to provide a compound of formula (XLIV), where R6 is CH3. Finally, a compound of formula (XLIV), wherein R6 is C1-C6 alkyl or C3-C6 cycloalkyl and R7 is F or H, can be Boc deprotected as previously described in Scheme 2 to provide a compound of formula (III), where X5, X6 and X7 together are C(O)NR6CH2 and X8 is absent. Scheme 26
Figure imgf000165_0002
[00247] According to Scheme 26, a compound of formula (XLIV) can be prepared from 2-amino-2-(2- chloro-3-fluorophenyl)acetic acid in five steps. In a first step, 2-amino-2-(2-chloro-3-fluorophenyl)acetic acid is Boc protected as previously described in Scheme 10. In a second step, 2-(tert- butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)acetic acid undergoes amide coupling as previously described in Scheme 1 with cyclopropylamine to provide tert-butyl (1-(2-chloro-3-fluorophenyl)-2- 163 QB\184200.00050\92364964.2 VVID-746PC (cyclopropylamino)-2-oxoethyl)carbamate. tert-Butyl (1-(2-chloro-3-fluorophenyl)-2- (cyclopropylamino)-2-oxoethyl)carbamate is reduced using LiAlH4 in THF at rt for 16 h to provide tert- butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)ethyl)carbamate. tert-Butyl (1-(2-chloro-3- fluorophenyl)-2-(cyclopropylamino)ethyl)carbamate is treated with 2-chloroacetyl chloride as previously described in Scheme 25 to provide tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(2-chloro-N- cyclopropylacetamido)ethyl)carbamate. Finally, tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(2-chloro-N- cyclopropylacetamido)ethyl)carbamate can be cyclized as previously described in Scheme 25 to provide a compound of formula (XLIV), where R6 is cyclopropyl and R7 is F. Scheme 27
Figure imgf000166_0001
[00248] According to Scheme 27, a compound of formula (III) can be synthesized from tert-butyl 2-(2- chlorophenyl)pyrrolidine-1-carboxylate in two steps. First, tert-butyl 2-(2-chlorophenyl)pyrrolidine-1- carboxylate is treated with TMEDA, n-BuLi, and iodomethane in THF at rt over a period of 12 h to provide tert-butyl 2-(2-chlorophenyl)-2-methyl-pyrrolidine-1-carboxylate. tert-Butyl 2-(2-chlorophenyl)-2- methyl-pyrrolidine-1-carboxylate is reacted under Boc deprotection conditions previously described in Scheme 2 to provide a compound of formula (III), where X7 and X8 are absent, X5 and X6 are CH2, R6 is CH3, and A is 2-chlorophenyl. Scheme 28
Figure imgf000166_0002
[00249] According to Scheme 28, a compound of formula (III) can be formed in five steps from rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid. First, Boc protection as previously described in Scheme 10 is used to obtain rac-(1*S,2*S,5*R,6*S)-3-tert- butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid. In a second step, rac-(1*S,2*S,5*R,6*S)-3-tert-butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3- 164 QB\184200.00050\92364964.2 VVID-746PC azabicyclo[3.1.0]hexane-6-carboxylic acid is treated with diphenyl phosphoryl azide and TEA in toluene followed by treatment with MeOH at 86 °C for 16 h to provide tert-butyl rac-(1*S,2*S,5*S,6*S)-2-(2- chloro-3-fluorophenyl)-6-((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate. tert-Butyl rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxycarbonyl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate is treated with tert-butyl nitrite in DCM at 15 °C for 1 h to provide tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxycarbonyl)(nitroso)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate. tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)(nitroso)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate is treated with K2CO3 in MeOH for 15 min at 15 °C to provide tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate. Finally, tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro- 3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate is reacted under Boc deprotection conditions previously described in Scheme 2 to provide a compound of formula (III), where X5 and X6 are CH and form a fused 3-membered saturated ring with another CH that is substituted with OCH3, and X7 and X8 are absent. Scheme 29
Figure imgf000167_0001
[00250] According to Scheme 29, rac-(1*S,2*S,5*R)-2-(2-chloro-3-fluorophenyl)-6-oxa-3- azabicyclo[3.1.1]heptane (a compound of formula (III)) can be formed in eight steps from 2-chloro-3- fluorobenzaldehyde. First, 2-chloro-3-fluorobenzaldehyde is treated with 4-methoxybenzylamine and MgSO4 in DCM at rt over a period of 20 h to provide (E)-1-(2-chloro-3-fluorophenyl)-N-(4- methoxybenzyl)methanimine. (E)-1-(2-Chloro-3-fluorophenyl)-N-(4-methoxybenzyl)methanimine is reacted with 1,4-dioxane-2,6-dione in o-xylene at 140 °C for 6 h to provide 3-(2-chloro-3-fluorophenyl)-4- (4-methoxybenzyl)-5-oxo-morpholine-2-carboxylic acid. 3-(2-Chloro-3-fluorophenyl)-4-(4- methoxybenzyl)-5-oxo-morpholine-2-carboxylic acid is treated with HCl in MeOH at 60 °C for 5 h to 165 QB\184200.00050\92364964.2 VVID-746PC provide methyl 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylate. Methyl 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylate is treated with NaBH4 in THF at 40 °C over 12 h to provide 5-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4- methoxybenzyl)morpholin-3-one. 5-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4- methoxybenzyl)morpholin-3-one is treated with imidazole, PPh3, and I2 in THF at rt for 2 h to provide 5- (2-chloro-3-fluorophenyl)-6-(iodomethyl)-4-(4-methoxybenzyl)morpholin-3-one. 5-(2-Chloro-3- fluorophenyl)-6-(iodomethyl)-4-(4-methoxybenzyl)morpholin-3-one is treated with LiHMDS in THF at - 70 °C for 2 h to provide rac-(1*S,4*R,5*R)-4-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptan-2-one. rac-(1*S,4*R,5*R)-4-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6- oxa-3-azabicyclo[3.1.1]heptan-2-one is treated with BH3 in THF at 15 °C over a period of 2 h to provide rac-(1*R,2*R,5*S)-2-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptane. Finally, rac-(1*R,2*R,5*S)-2-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptane is treated with CAN in ACN/water at 15 °C for 12 h to provide rac-(1*S,2*S,5*R)- 2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane, a compound of formula (III). Scheme 30
Figure imgf000168_0001
[00251] According to Scheme 30, tert-butyl 3-(2-chloro-3-fluorophenyl)piperazine-1-carboxylate (a compound of formula (III)) is synthesized in three steps from 2-chloropyrazine. In the first step, standard Suzuki coupling conditions known to those skilled in the art are employed with 2-chloropyrazine and (2- chloro-3-fluorophenyl)boronic acid using K2CO3 and Pd(dppf)Cl2 in 1,4-dioxane/water at 100 °C over a period of 16 h to provide 2-(2-chloro-3-fluorophenyl)pyrazine. 2-(2-Chloro-3-fluorophenyl)pyrazine is reduced to 2-(2-chloro-3-fluorophenyl)piperazine using N-phenylaniline, pinacolborane, and tris(2,3,4,5,6- pentafluorophenyl)borane in toluene at 110 °C for 6 h. Finally, 2-(2-chloro-3-fluorophenyl)piperazine is Boc protected as previously described in Scheme 10 to provide tert-butyl 3-(2-chloro-3- fluorophenyl)piperazine-1-carboxylate, a compound of formula (III). Scheme 31
Figure imgf000168_0002
[00252] According to Scheme 31, tert-butyl exo-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate using PPh3, 1,2-diiodoethane, K2CO3, and trimethylsilyl chloride in DMF at rt over a period of 12 h. 166 QB\184200.00050\92364964.2 VVID-746PC Scheme 32
Figure imgf000169_0001
[00253] According to Scheme 32, tert-butyl exo-6-(((tert-butyldimethylsilyl)oxy)methyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate using tert-butyl chlorodimethylsilane and imidazole in DCM at rt over a period of 5 h. Scheme 33
Figure imgf000169_0002
[00254] According to Scheme 33, tert-butyl exo-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate is subjected to standard methylation conditions as previously described in Scheme 13 with iodomethane or iodomethane-d3 to provide a compound of formula (XV), where R9 is CH3 or CD3. Likewise, tert-butyl exo-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate employing the same conditions. Methyl 7-fluoro-1H-indazole-4-carboxylate can also be methylated in an analogous manner to provide methyl 7-fluoro-2-methyl-indazole-4-carboxylate, a compound of formula (II). Scheme 34
Figure imgf000169_0003
[00255] According to Scheme 34, tert-butyl exo-6-((difluoromethoxy)methyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate using CuI and 2,2-difluoro-2-(fluorosulfonyl)acetic acid in ACN at 45 °C over a period of 0.5 h. Scheme 35 167 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000170_0001
[00256] According to Scheme 35, tert-butyl exo-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate using a fluorinating reagent such as DAST, and the like; in an appropriate solvent such as DCM, and the like; at 0 °C over a period of 1 h. Likewise, these conditions can be used to prepare tert-butyl exo-6-(difluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) from tert-butyl exo-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate. Scheme 36
Figure imgf000170_0002
[00257] According to Scheme 36, tert-butyl exo-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) is prepared in two steps from tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate. In the first step, tert-butyl exo-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate is reacted with methanesulfonic anhydride and TEA in DCM at rt over a period of 6 h to provide tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate. In the second step, tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate is reacted with LiAlH4 in THF at temperatures of 0-20 °C for 0.5 h to provide tert-butyl exo-6- methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate, a compound of formula (XV). Scheme 37
Figure imgf000170_0003
[00258] According to Scheme 37, tert-butyl exo-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (a compound of formula (XV)) is prepared from tert-butyl exo-6-acetyl-3- azabicyclo[3.1.0]hexane-3-carboxylate using methylmagnesium bromide under Grignard conditions previously described in Scheme 8. Scheme 38
Figure imgf000170_0004
168 QB\184200.00050\92364964.2 VVID-746PC [00259] According to Scheme 38, tert-butyl exo-(1*R,5*S)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (a compound of formula (XV)) can be formed from tert-butyl exo- 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in two steps. First, tert-butyl exo-6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate is treated with palladium(II) acetate and 2,2'- bipyridine in ethyl vinyl ether at 50 °C for 16 h to provide tert-butyl exo-6-(vinyloxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate. tert-Butyl exo-6-(vinyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate is treated with diethylzinc and diiodomethane in DCM at rt for 2 h to provide tert-butyl exo- (1*R,5*S)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, a compound of formula (XV). Scheme 39
Figure imgf000171_0001
[00260] According to Scheme 39, tert-butyl 1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate is protected with Fmoc using 9H-fluoren-9-ylmethyl chloroformate and DIPEA in DCM at rt for 16 h to provide 5-((9H-fluoren-9-yl)methyl) 2-(tert-butyl) 1-oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)- dicarboxylate, a compound of formula (XVI). Scheme 40
Figure imgf000171_0002
[00261] According to Scheme 40, 2-chloro-5-fluoro-4-methyl-pyrimidine is treated with TEA and Pd(dppf)Cl2 in DMF/MeOH under CO at 80 ℃ for a period of 16 h to provide a compound of formula (II), where X3 and X4 are N, X1 is CH, X2 is CCH3, and Y is F. Scheme 41
Figure imgf000171_0003
[00262] According to Scheme 41, methyl 5-fluoropyrimidine-2-carboxylate is treated with zinc difluoromethanesulfinate, 2,2,2-trifluoroacetic acid, and tert-butyl hydroperoxide in DCM/water at rt for 16 h to provide methyl 4-(difluoromethyl)-5-fluoropyrimidine-2-carboxylate, a compound of formula (II). Scheme 42 169 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000172_0001
[00263] According to Scheme 42, rac-(9H-fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3- fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate is deprotected using piperidine in DCM at rt for 2 h to give methyl 5-(rac-(1*R,3a*S,6a*R)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate. Scheme 43
Figure imgf000172_0002
[00264] According to Scheme 43, methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate is prepared in three steps from 2-chlorobenzaldehyde. In a first step, the SNAP reaction is employed using 2- chlorobenzaldehyde and tert-butyl N-(2-aminoethyl)-N-(tributylstannylmethyl)carbamate in DCM with the addition of 2,6-lutidine and copper(II) trifluoromethanesulfonate in hexafluoroisopropanol at rt over a period of 12 h to provide tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate. tert-Butyl 3-(2- chlorophenyl)piperazine-1-carboxylate is coupled to methyl 5-bromo-3-fluoropicolinate using Buchwald- Hartwig conditions previously described in Scheme 1. Finally, Boc deprotection of tert-butyl 3-(2- chlorophenyl)-4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate as previously described in Scheme 2 provides methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate. Scheme 44
Figure imgf000172_0003
[00265] According to Scheme 44, methyl 5-(rac-(1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- (dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate is prepared in three steps from rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-(5-methoxycarbonylpyrazin-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid. First, rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3- (5-methoxycarbonylpyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid is treated with diphenylphosphoryl azide and TEA in t-BuOH at 90 °C for 16 h to give methyl 5-(rac-(1*S,2*S,5*S,6*S)- 170 QB\184200.00050\92364964.2 VVID-746PC 6-(tert-butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2- carboxylate. Methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-(tert-butoxycarbonylamino)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate undergoes Boc deprotection as previously described in Scheme 2 to afford methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-amino-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate. Finally, methyl 5-(rac- (1*S,2*S,5*S,6*S)-6-amino-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2- carboxylate is treated with formaldehyde and NaBH3CN in MeOH/AcOH at rt for 2 h to afford methyl 5- (rac-(1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3- yl)pyrazine-2-carboxylate, a compound of formula (IV). Scheme 45
Figure imgf000173_0001
[00266] According to Scheme 45, methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3- fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate can be prepared in nine steps from methyl 5-chloropyrazine-2-carboxylate. In a first step, standard Suzuki coupling conditions are employed as previously described in Scheme 30 to provide methyl 5-(2-chloro-3-fluorophenyl)pyrazine- 2-carboxylate. Methyl 5-(2-chloro-3-fluorophenyl)pyrazine-2-carboxylate is reduced using CaCl2 and NaBH4 in MeOH at rt for 2 h to give (5-(2-chloro-3-fluorophenyl)pyrazin-2-yl)methanol. Treatment with PtO2 in MeOH under H2 at 40 °C for 12 h provides (rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)piperazin- 2-yl)methanol. (rac-(2*R,5*S)-5-(2-Chloro-3-fluorophenyl)piperazin-2-yl)methanol is Boc protected as previously described in Scheme 10 to provide tert-butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2- (hydroxymethyl)piperazine-1-carboxylate. tert-Butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2- (hydroxymethyl)piperazine-1-carboxylate is reacted under SNAr conditions as previously described in Scheme 1 with methyl 5-fluoropyrazine-2-carboxylate to provide methyl 5-(rac-(2*S,5*R)-4-(tert- butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate. Methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate is Boc deprotected as previously described in 171 QB\184200.00050\92364964.2 VVID-746PC Scheme 2 to provide methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1- yl)pyrazine-2-carboxylate. Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate is reacted with 2-chloroacetyl chloride and TEA in DCM at rt for 2 h to give methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-4-(2-chloroacetyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate. Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3- fluorophenyl)-4-(2-chloroacetyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate can be cyclized using NaH in THF at rt for 2 h to give methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3-fluorophenyl)-4- oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate. Methyl 5-(rac-(7*S,9*aR)-7- (2-chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate is reduced using BH3 in THF at rt for 2 h to give methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3- fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate, a compound of formula (IV). Scheme 46
Figure imgf000174_0001
(XLVI) (V) [00267] According to Scheme 46, a compound of formula (V) can be prepared from a compound of formula (XLV) in two steps. A compound of formula (XLV), wherein R3 is CH3 or OCH3, is subjected to Buchwald- Hartwig coupling with a compound of formula (III) as described in Scheme 1 to provide a compound of formula (XLVI). Treatment of a compound of formula (XLVI) with 10% aq. NaOH at 100 °C for 10 h provides a compound of formula (V), where X1 is CH, X3 and X4 are N, and X2 is CR3 where R3 is CH3 or OCH3. Scheme 47
Figure imgf000174_0002
fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be alkylated with cyclopropyl using (1-ethoxycyclopropoxy)trimethylsilane and AcOH in MeOH at 60 ºC for 16 h to provide methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol- 172 QB\184200.00050\92364964.2 VVID-746PC 2(1H)-yl)pyrazine-2-carboxylate. Similarly, a compound of formula (XLVII), where R7 and R3 are independently H or F and X1 is CH or N, can be subjected to the same conditions to provide a compound of formula (XLVIII). Scheme 48
Figure imgf000175_0001
[00269] According to Scheme 48, methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be acylated using acetyl chloride and TEA in DCM at rt for 1 h to provide methyl 5-((1*S,3a*S,6a*S)-5-acetyl-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate, a compound of formula (IV). Scheme 49
Figure imgf000175_0002
[00270] According to Scheme 49, methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be alkylated using 2- bromoethyl methyl ether and K2CO3 in ACN at 80 ºC for 16 h to provide methyl 5-((1*S,3a*R,6a*S)-1-(2- chloro-3-fluorophenyl)-5-(2-methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2- carboxylate, a compound of formula (IV). Analogously, methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin- 1-yl)pyrazine-2-carboxylate can be subjected to the same conditions with iodomethane to provide 5-(2-(2- chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide, a compound of formula (IV). Scheme 50 173 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000176_0001
[00271] According to Scheme 50, methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be methylated using formaldehyde and sodium triacetoxyborohydride in MeOH at rt for 2 h to provide methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate, a compound of formula (IV). Scheme 51
Figure imgf000176_0002
[00272] According to Scheme 51, methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2- carboxylate can be alkylated using oxetan-3-one and sodium triacetoxyborohydride with AcOH in a solvent such as DCM, MeOH, and the like; at rt for 2-16 h to provide 5-(2-(2-chloro-3-fluorophenyl)-4-(oxetan-3- yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide, a compound of formula (IV). Under the same conditions tert-butyl rac-(3a*R,6a*S)-1-oxohexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate can be converted to tert-butyl rac-(3a*R,6a*S)-5-(oxetan-3-yl)-1- oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, a compound of formula (XVI). Scheme 52
Figure imgf000176_0003
[00273] According to Scheme 52, methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate can be alkylated with 2,2,2- trifluoroethyl trifluoromethanesulfonate, 2,2-difluoroethyl 1,1,1-trifluoromethanesulfonate, and the like; using DIPEA, TEA, and the like; in DMF, DCM, and the like; at 25-40 °C for 3-16 h to provide methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- 174 QB\184200.00050\92364964.2 VVID-746PC yl)pyrazine-2-carboxylate, a compound of formula (IV). In the same manner, tert-butyl rac-(3a*R,6a*S)- 1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate is converted to tert-butyl rac-(3a*R,6a*S)-1-oxo- 5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, a compound of formula (XVI).
Figure imgf000177_0001
175 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000178_0002
[00274] All stereocenters labeled with (S) or (R) are known, absolute stereochemistry. In cases where the stereochemistry is pure but unknown, the stereocenter is drawn and defined as (*S) or (*R). Stereochemistry that is drawn but not labeled is in the correct cis or trans configuration but are racemic and designated as “rac”. Stereocenters that are not defined are racemic. Intermediate 1: (R,E)-4-Methylsulfonylbut-3-en-2-amine.
Figure imgf000178_0001
[00275] Step A: tert-Butyl (R,E)-(4-(methylsulfonyl)but-3-en-2-yl)carbamate. To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (2.7 g, 11.5 mmol, 1.0 eq) in THF (60 mL, 0.19 M) was added NaH (462 mg, 11.5 mmol, 1.0 eq, 60% in mineral oil) at 0°C. The mixture was stirred at 0°C for 30 min before addition of (R)-tert-butyl (1-oxopropan-2-yl)carbamate (2.0 g, 11.5 mmol, 1.0 eq) in THF (10 mL). The reaction was stirred at 0°C for 1 h before being quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to give tert-butyl (R,E)-(4-(methylsulfonyl)but-3-en-2- yl)carbamate (950 mg, 33% yield) as a white solid. [00276] Step B: (R,E)-4-Methylsulfonylbut-3-en-2-amine. To a solution of tert-butyl (R,E)-(4- (methylsulfonyl)but-3-en-2-yl)carbamate (200 mg, 0.800 mmol, 1.0 eq) in ACN (3.0 mL, 0.27 M) was added 4-methylbenzenesulfonic acid (138 mg, 0.800 mmol, 1.0 eq). The mixture was stirred at 60°C for 12 h. After cooling to rt, the reaction was concentrated to give (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (200 mg, 78% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.92 - 7.01 (m, 1H), 6.81 - 6.89 (m, 1H), 4.18 (q, J = 6.5 Hz, 1H), 3.02 (s, 3H), 2.37 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H). Intermediate 2: (R,E)-4-Ethylsulfonylbut-3-en-2-amine. 176 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000179_0001
[00277] The title compound was prepared in a manner analogous to Intermediate 1 using diethyl ((ethylsulfonyl)methyl)phosphonate instead of diethyl ((methylsulfonyl)methyl)phosphonate in Step A and HCl instead of 4-methylbenzenesulfonic acid in Step B. Intermediate 3: tert-Butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000179_0002
[00278] To a solution of NaIO4 (741 mg, 3.47 mmol, 3.8 eq) in H2O (2.0 mL, 0.23 M) was added RuCl3 (9.5 mg, 0.046 mmol, 0.05 eq). The mixture was stirred for 5 min before a solution of tert-butyl 6,6- difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.912 mmol, 1.0 eq) in EtOAc (2.0 mL, 0.23 M) was added. The reaction was stirred at 25°C for 16 h before being filtered then poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to give tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 94% yield) as a colorless oil. MS (ESI): mass calcd. for C 10H13F2NO3, 233.1; m/z found, 178.2 [M+2H-tBu] + . 1H NMR (400 MHz, CDCl3) δ 3.91 - 4.10 (m, 2H), 2.76 - 2.91 (m, 1H), 2.52 (td, J = 8.6, 7.1 Hz, 1H), 1.53 (s, 9H). Intermediate 4: tert-Butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate.
Figure imgf000179_0003
[00279] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl 2-oxa- 7-azaspiro[3.5]nonane-7-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3- carboxylate. 1H NMR (400 MHz, CDCl3) δ 4.48 - 4.53 (m, 4H), 3.60 - 3.70 (m, 2H), 2.83 (s, 2H), 2.14 - 2.21 (m, 2H), 1.53 (s, 9H). Intermediate 5: 5-(2-Chlorophenyl)-1,4-oxazepane. 177 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000180_0001
[00280] Step A: tert-Butyl 5-oxo-1,4-oxazepane-4-carboxylate. To a solution of 1,4-oxazepan-5-one (2.0 g, 17.4 mmol, 1.0 eq) in DCM (20 mL, 0.87 M) was added di-tert-butyl dicarbonate (4.5 g, 20.8 mmol, 1.2 eq), N,N-dimethylpyridin-4-amine (1.1 g, 8.69 mmol, 0.5 eq), and triethylamine (5.3 g, 52.1 mmol, 3.0 eq). The mixture was stirred at 25°C for 2 h before being quenched with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give crude product. Purification by FCC on silica (0-25% EtOAc in PE) afforded tert-butyl 5- oxo-1,4-oxazepane-4-carboxylate (2.4 g, 64% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.93 - 3.98 (m, 2H), 3.83 - 3.88 (m, 2H), 3.78 - 3.82 (m, 2H), 2.83 - 2.89 (m, 2H), 1.53 (s, 9H). [00281] Step B: tert-Butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)- carboxylate. To a solution of tert-butyl 5-oxo-1,4-oxazepane-4-carboxylate (2.4 g, 11.1 mmol, 1.0 eq) in THF (30 mL, 0.37 M) at -78°C under N2 was added LiHMDS (14.5 mL, 14.5 mmol, 1.3 eq). The mixture was stirred at -78°C for 1.5 h before a solution of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (5.2 g, 14.5 mmol, 1.3 eq) in THF (4.0 mL) was added. The mixture was stirred at 25°C for 16 h before being quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)- carboxylate as a yellow oil, which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 5.67 (br t, J = 5.8 Hz, 1H), 4.14 - 4.17 (m, 2H), 3.64 - 3.80 (m, 4H), 1.51 (s, 9H). [00282] Step C: tert-Butyl 5-(2-chlorophenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate. To a solution of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (4.0 g, 11.5 mmol, 1.0 eq) in 1,4-dioxane/water (10:1 v/v, 44 mL, 0.26 M) under N2 was added (2-chlorophenyl)boronic acid (2.0 g, 12.7 mmol, 1.1 eq), Pd(PPh3)4 (665 mg, 0.570 mmol, 0.05 eq) and potassium carbonate (4.8 g, 34.5 mmol, 3.0 eq). The mixture was stirred at 80°C for 16 h. After cooling to rt, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude mixture was purified by FCC on silica (0- 20% EtOAc in PE) to afford tert-butyl 5-(2-chlorophenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (2.1 g, 59% yield) as a white oil. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.42 (m, 2H), 7.23 (dd, J = 5.8, 3.5 Hz, 2H), 5.60 (d, J = 5.4 Hz, 1H), 4.29 (d, J = 5.6 Hz, 2H), 3.84 - 3.97 (m, 4H), 1.08 (br s, 9H). [00283] Step D: 5-(2-Chlorophenyl)-2,3,6,7-tetrahydro-1,4-oxazepine. A solution of tert-butyl 5-(2- chlorophenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (3.9 g, 12.6 mmol, 1.0 eq) in trifluoroacetic acid/DCM (1:3 v/v, 40 mL, 0.31 M) was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to give 5-(2-chlorophenyl)-2,3,6,7-tetrahydro-1,4-oxazepine (2.6 g, 98% yield) as a white oil, which was used in the next step without further purification. 178 QB\184200.00050\92364964.2 VVID-746PC [00284] Step E: 5-(2-Chlorophenyl)-1,4-oxazepane. To a solution of 5-(2-chlorophenyl)-2,3,6,7- tetrahydro-1,4-oxazepine (2.6 g, 12.4 mmol, 1.0 eq) in methanol (30 mL, 0.48 M) at 0°C under N2 was added sodium borohydride (1.4 g, 37.3 mmol, 3.0 eq). The mixture was stirred at 25°C for 16 h before being concentrated under vacuum. The crude mixture was purified by RP-HPLC (10-40% ACN in 0.01% aqueous TFA) to afford 5-(2-chlorophenyl)-1,4-oxazepane (530 mg, 20% yield) as a white oil. MS (ESI): mass calcd. for C11H14ClNO, 211.1; m/z found, 212.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 1.7 Hz, 1H), 7.42 (dd, J = 7.8, 1.4 Hz, 1H), 7.27 - 7.32 (m, 1H),7.21 - 7.27 (m, 1H), 4.94 (br d, J = 9.4 Hz, 1H), 3.92 - 3.99 (m, 4H), 3.15 - 3.27 (m, 2H), 2.66 - 2.78 (m, 1H), 2.08 - 2.17 (m, 1H). Intermediate 6: 2-(2-Chlorophenyl)-5-methylpyrrolidine.
Figure imgf000181_0001
[00285] The title compound was prepared in a manner analogous to Intermediate 5 using 5- methylpyrrolidin-2-one instead of 1,4-oxazepan-5-one in Step A and triflic anhydride instead of 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide in Step B. 1H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.80 (m, 1H), 7.28 - 7.55 (m, 3H), 4.66 - 5.01 (m, 1H), 3.51 - 3.80 (m, 1H), 2.29 - 2.45 (m, 1H), 2.01 - 2.28 (m, 1H), 1.75 - 1.97 (m, 1H), 1.44 - 1.68 (m, 1H), 1.21 - 1.36 (m, 3H). Intermediate 7: 6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane.
Figure imgf000181_0002
[00286] The title compound was prepared in a manner analogous to Intermediate 5, Steps B-E using tert- butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 4) instead of tert-butyl 5-oxo-1,4- oxazepane-4-carboxylate and triflic anhydride instead of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide in Step B and using (2-chloro-3-fluorophenyl)boronic acid instead of (2-chlorophenyl)boronic acid in Step C. MS (ESI): mass calcd. for C13H15ClFNO, 255.1; m/z found, 256.1 [M+H]+. Intermediate 8: tert-Butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate. 179 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000182_0001
[00287] Step A: tert-Butyl 2-(2-chlorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate. To a solution of tert-butyl 4-oxopyridine-1(4H)-carboxylate (15 g, 76.8 mmol, 1.0 eq) in THF (150 mL, 0.51 M) under N2 was added chlorotrimethylsilane (25 g, 230 mmol, 3.0 eq). The mixture was cooled to -10°C before (2-chlorophenyl)magnesium bromide (33 g, 154 mmol, 2.0 eq) was added. The mixture was stirred at 25°C for 16 h before being quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-50% EtOAc in PE) provided tert-butyl 2-(2-chlorophenyl)-4-oxo-3,4-dihydropyridine- 1(2H)-carboxylate (6.3 g, 27% yield) as a pale yellow oil. MS (ESI): mass calcd. for C16H18ClNO3, 307.1; m/z found, 252.1 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 8.15 (br d, J = 8.3 Hz, 1H), 7.33 - 7.43 (m, 1H), 7.12 - 7.23 (m, 3H), 5.97 (br d, J = 8.4 Hz, 1H), 5.41 (d, J = 8.4 Hz, 1H), 3.14 (dd, J = 16.7, 8.7 Hz, 1H), 2.77 (br d, J = 16.5 Hz, 1H), 1.37 (br s, 9H). [00288] Step B: tert-Butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate. To a solution of tert-butyl 2-(2-chlorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (6.4 g, 20.7 mmol, 1.0 eq) in THF (70 mL, 0.30 M) was added L-selectride (21.7 mL, 21.7 mmol, 1.1 eq) at 0°C under N2. The mixture was stirred at 25°C for 16 h before being quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-30% EtOAc in PE) provided tert-butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate (5.0 g, 78% yield) as a pale yellow oil. MS (ESI): mass calcd. for C16H20ClNO3, 309.1; m/z found, 254.0 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.39 (m, 1H), 7.21 - 7.29 (m, 3H), 5.56 - 5.69 (m, 1H), 4.25 - 4.40 (m, 1H), 3.63 - 3.80 (m, 1H), 2.96 (dd, J = 15.6, 6.4 Hz, 1H), 2.75 (br dd, J = 15.5, 7.4 Hz, 1H), 2.50 - 2.66 (m, 2H), 1.26 - 1.33 (m, 9H). Intermediate 9: 2-(2-Chlorophenyl)-4,4-difluoropiperidine.
Figure imgf000182_0002
[00289] Step A: tert-Butyl 2-(2-chlorophenyl)-4,4-difluoropiperidine-1-carboxylate. To a solution of tert- butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate (Intermediate 8, 4.2 g, 13.6 mmol, 1.0 eq) in DCM (50 mL, 0.30 M) was added DEOXO-FLUOR® (3.6 g, 16.3 mmol, 1.2 eq) at 0°C under N2. The mixture was stirred at 25°C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-30% EtOAc in PE) to give tert-butyl 2-(2-chlorophenyl)- 180 QB\184200.00050\92364964.2 VVID-746PC 4,4-difluoropiperidine-1-carboxylate (1.5 g, 33% yield) as a yellow oil. MS (ESI): mass calcd. for C16H20ClF2NO2, 331.1; m/z found, 276.1 [M+2H-tBu]+. [00290] Step B: 2-(2-Chlorophenyl)-4,4-difluoropiperidine. A solution of tert-butyl 2-(2-chlorophenyl)- 4,4-difluoropiperidine-1-carboxylate (1.5 g, 4.52 mmol, 1.0 eq) was taken up in HCl (20 mL, 4N in EtOAc). The mixture was stirred at 25°C for 1 h before being concentrated to provide 2-(2-chlorophenyl)-4,4- difluoropiperidine (700 mg, 67%) as a white solid, which was used without further purification. Intermediate 10: 2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidine.
Figure imgf000183_0001
[00291] The title compound was prepared in a manner analogous to Intermediate 9 using (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chlorophenyl)magnesium bromide in Step A of Intermediate 8 and DAST instead of DEOXO-FLUOR® in Step A of Intermediate 9. 1H NMR (400 MHz, Methanol-d4) δ 7.33 - 7.44 (m, 2H), 7.19 (ddd, J = 9.2, 7.7, 1.9 Hz, 1H), 4.31 (br d, J = 12.0 Hz, 1H), 3.20 - 3.28 (m, 1H), 2.93 (td, J = 12.9, 3.1 Hz, 1H), 2.29 (dddt, J = 13.6, 10.9, 5.6, 2.8 Hz, 1H), 2.06 - 2.17 (m, 1H), 1.70 - 2.04 (m, 2H). Intermediate 11: 2-(2-Chlorophenyl)-4,4-dimethylpyrrolidine.
Figure imgf000183_0002
[00292] Step A: tert-Butyl 4,4-dimethyl-2-oxo-pyrrolidine-1-carboxylate. To a solution of 4,4- dimethylpyrrolidin-2-one (5.0 g, 44.2 mmol, 1.0 eq) in DCM (50 mL, 0.90 M) at 20°C under N2 was added TEA (12.3 mL, 88.3 mmol, 2.0 eq), 4-(dimethylamino)pyridine (540 mg, 4.40 mmol, 0.1 eq), and di-tert- butyl dicarbonate (14 g, 66.3 mmol, 1.5 eq). The reaction was stirred at 20°C for 17 h before being poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-65% EtOAc in PE) to give tert-butyl 4,4-dimethyl-2-oxo-pyrrolidine-1-carboxylate (2.7 g, 29% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.45 (s, 2H), 2.33 (s, 2H), 1.52 (s, 9H), 1.16 (s, 6H). [00293] Step B: tert-Butyl 3,3-dimethyl-5-(trifluoromethylsulfonyloxy)-2H-pyrrole-1-carboxylate. KHMDS (5.6 mL, 5.60 mmol, 1.2 eq) was taken up in THF (33 mL) under N2 and cooled to -78°C. tert- Butyl 4,4-dimethyl-2-oxo-pyrrolidine-1-carboxylate (1.0 g, 4.70 mmol, 1.0 eq) in THF (20 mL, 0.23 M) 181 QB\184200.00050\92364964.2 VVID-746PC was added dropwise and the solution was stirred at -78°C for 1 h. The solution was slowly warmed to - 40°C and stirred for 1 h. The reaction was cooled to -78°C before a solution of N- phenylbis(trifluoromethanesulfonimide) (2.0 g, 5.60 mmol, 1.2 eq) in THF (30 mL) was added. This was stirred at -78°C for 1 h then 25°C for 1 h before the reaction mixture was concentrated under reduced pressure to give tert-butyl 3,3-dimethyl-5-(trifluoromethylsulfonyloxy)-2H-pyrrole-1-carboxylate (1.2 g, 74% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.85 (s, 1H), 3.59 (s, 2H), 1.52 (s, 9H), 1.18 (s, 6H). [00294] Step C: tert-Butyl 5-(2-chlorophenyl)-3,3-dimethyl-2H-pyrrole-1-carboxylate. To a solution of tert-butyl 3,3-dimethyl-5-(trifluoromethylsulfonyloxy)-2H-pyrrole-1-carboxylate (1.2 g, 3.50 mmol, 1.0 eq) in 1,4-dioxane/water (3:1 v/v, 12 mL, 0.20 M) at 20°C under N 2 was added 2-chlorophenylboronic acid (1.6 g, 10.4 mmol, 3.0 eq), potassium carbonate (1.4 g, 10.4 mmol, 3.0 eq), and Pd(dppf)Cl2 (0.50 g, 0.700 mmol, 0.2 eq). The reaction was stirred at 70°C for 17 h. After cooling to rt, the reaction mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica (0-20% EtOAc in PE) to give tert-butyl 5-(2-chlorophenyl)-3,3-dimethyl-2H-pyrrole-1-carboxylate (800 mg, 75% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.36 (m, 2H), 7.19 - 7.24 (m, 2H), 4.94 (s, 1H), 3.69 (s, 2H), 1.22 (s, 6H), 0.86 - 1.18 (m, 9H). [00295] Step D: tert-Butyl 2-(2-chlorophenyl)-4,4-dimethyl-pyrrolidine-1-carboxylate. To a solution of tert-butyl 5-(2-chlorophenyl)-3,3-dimethyl-2H-pyrrole-1-carboxylate (800 mg, 2.60 mmol, 1.0 eq) in ethyl acetate (9.0 mL, 0.29 M) and ethanol (3.0 mL, 0.87 M) was added PtO2 (400 mg). The reaction was stirred at 20°C under H2 (15 psi) for 17 h. The reaction mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (10% EtOAc in PE) to give tert-butyl 2- (2-chlorophenyl)-4,4-dimethyl-pyrrolidine-1-carboxylate (600 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.43 (m, 2H), 7.09 - 7.26 (m, 2H), 4.99 - 5.43 (m, 1H), 3.44 - 3.64 (m, 1H), 3.38 (br s, 1H), 2.68 - 3.19 (m, 1H), 2.25 (br dd, J = 12.6, 7.1 Hz, 1H), 1.41 - 1.50 (m, 6H), 1.07 - 1.18 (m, 9H). [00296] Step E: 2-(2-Chlorophenyl)-4,4-dimethylpyrrolidine. To a solution of tert-butyl 2-(2- chlorophenyl)-4,4-dimethyl-pyrrolidine-1-carboxylate (600 mg, 1.90 mmol, 1.0 eq) in DCM (6.0 mL, 0.32 M) was added 2,2,2-trifluoroacetic acid (221 mg, 1.90 mmol, 1.0 eq) under N2. The reaction was stirred at 20°C for 2 h before being filtered. The filtrate was concentrated to provide 2-(2-chlorophenyl)-4,4- dimethyl-pyrrolidine (600 mg, 96% yield) as colorless oil, which was used in subsequent steps without further purification. Intermediate 12: 3-(2-Chlorophenyl)-1,4-oxazepane. 182 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000185_0001
[00297] Step A: Methyl 3-(2-((tert-butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate. A solution of tert-butyl (1-(2-chlorophenyl)-2-hydroxyethyl)carbamate (8.0 g, 29.4 mmol, 1.0 eq), methyl acrylate (12.7 g, 147 mmol, 5.0 eq), and Cs2CO3 (19.2 g, 58.9 mmol, 2.0 eq) in ACN (80 mL, 0.37 M) was stirred for 3 h at 25°C. The reaction mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FCC on silica (0-75% EtOAc in PE) to obtain methyl 3-(2- ((tert-butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate (6.0 g, 57% yield) as a yellow oil. MS (ESI): mass calcd. for C17H24ClNO5, 357.1; m/z found, 258.1 [M+H-Boc]+. 1H NMR (400 MHz, CDCl3) δ 7.33 (br dd, J = 1.5, 7.6 Hz, 2H), 7.21 (ddd, J = 1.6, 7.5, 11.5 Hz, 2H), 5.41 - 5.64 (m, 1H), 5.24 (br s, 1H), 3.53 - 3.83 (m, 7H), 2.54 (br t, J = 6.1 Hz, 2H), 1.28 - 1.57 (m, 9H). [00298] Step B: Methyl 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoate. A solution of methyl 3-(2- ((tert-butoxycarbonyl)amino)-2-(2-chlorophenyl)ethoxy)propanoate (12 g, 33.5 mmol, 1.0 eq) and TFA (11.5 g, 101 mmol, 3.0 eq) in DCM (120 mL, 0.28 M) was stirred for 1 h at 25°C. The reaction mixture was concentrated under reduced pressure to give methyl 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoate, 2,2,2-trifluoroacetic acid (12.5 g, quant. yield), which was used in the next step without further purification. [00299] Step C: 3-(2-Amino-2-(2-chlorophenyl)ethoxy)propanoic acid. To a solution of methyl 3-(2- amino-2-(2-chlorophenyl)ethoxy)propanoate, 2,2,2-trifluoroacetic acid (12.5 g, 48.3 mmol, 1.0 eq) in THF (120 mL, 0.24 M), H2O (40 mL, 0.24 M), and methanol (40 mL, 0.24 M) was added LiOH·H2O (6.1 g, 145 mmol, 3.0 eq). The reaction mixture was stirred at 25°C for 12 h then filtered and concentrated under reduced pressure to provide 3-(2-amino-2-(2-chlorophenyl)ethoxy)propanoic acid (12 g, 89% yield) as a yellow solid. MS (ESI): mass calcd. for C11H14ClNO3, 243.1; m/z found, 244.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (dd, J = 1.3, 7.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29 - 7.35 (m, 1H), 7.23 - 7.27 (m, 1H), 4.39 - 4.48 (m, 1H),3.60 - 3.69 (m, 1H), 3.48 - 3.57 (m, 1H), 3.44 (br dd, J = 4.0, 9.8 Hz, 2H), 2.17 (t, J = 7.1 Hz, 2H), 1.88 - 1.95 (m, 2H). [00300] Step D: 3-(2-Chlorophenyl)-1,4-oxazepan-5-one. To a solution of 3-(2-amino-2-(2- chlorophenyl)ethoxy)propanoic acid (5.0 g, 20.5 mmol, 1.0 eq) in DMF (50 mL, 0.41 M) was added TEA (8.0 g, 61.5 mmol, 3.0 eq) and HATU (9.4 g, 24.6 mmol, 1.2 eq). The resulting mixture was stirred at 20°C for 12 h before being poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (50-100% EtOAc in PE) to give 3-(2-chlorophenyl)-1,4-oxazepan-5-one (800 mg, 17% yield) as a yellow oil. MS (ESI): mass calcd. for C11H12ClNO2, 225.1; m/z found, 226.2 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.90 - 8.05 (m, 1H), 7.49 (dt, J = 1.9, 7.0 Hz, 2H), 7.30 - 7.41 (m, 2H), 5.20 - 5.29 (m, 1H), 3.98 - 4.06 (m, 1H), 3.85 - 3.90 (m, 2H), 3.73 - 3.82 (m, 1H), 3.03 - 3.14 (m, 2H). 183 QB\184200.00050\92364964.2 VVID-746PC [00301] Step E: 3-(2-Chlorophenyl)-1,4-oxazepane. A solution of 3-(2-chlorophenyl)-1,4-oxazepan-5-one (800 mg, 3.55 mmol, 1.0 eq) in THF (9.0 mL, 0.39 M) was added dropwise into LiAlH4 (269 mg, 7.09 mmol, 2.0 eq) in THF (3.0 mL) at 0°C under N2. The reaction mixture was stirred for 3 h at 20°C before being quenched with H2O and 15% aq. NaOH. The mixture was filtered and the filtrate was extracted with H2O and EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (20-50% ACN in 10 mM aqueous NH4HCO3) to obtain 3-(2-chlorophenyl)-1,4-oxazepane (150 mg, 20% yield) as a pale yellow oil. MS (ESI): mass calcd. for C11H14ClNO, 211.1; m/z found, 212.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.40 (m, 2H), 7.30 (br s, 1H), 7.18 - 7.26 (m, 1H), 3.84 - 3.95 (m, 1H), 3.40 - 3.82 (m, 6H), 2.36 - 2.60 (m, 1H), 1.75 - 1.93 (m, 2H). Intermediate 13: 2-(2-Chloro-4-fluorophenyl)azepane.
Figure imgf000186_0001
[00302] Step A: tert-Butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate. To a solution of tert-butyl 2-oxoazepane-1-carboxylate (5.0 g, 23.4 mmol, 1.0 eq) in THF (50 mL, 0.47 M) was added KHMDS (35 mL, 35.2 mmol, 1.5 eq, 1.0 M) at -78°C under N2. The mixture was stirred at - 78°C for 1 h. A solution of diphenyl phosphorochloridate (9.45 g, 35.2 mmol, 1.5 eq) in THF (10 mL) was added at -78°C. The reaction was stirred at -78°C for 1 h before being quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-50% EtOAc in PE) provided tert-butyl 7- ((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (6.4 g, 61% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.39 (m, 4H), 7.15 - 7.27 (m, 6H), 5.43 (td, J = 6.7, 2.9 Hz, 1H), 3.04 - 3.94 (m, 2H), 2.04 - 2.13 (m, 2H), 1.66 - 1.79 (m, 2H), 1.53 (br s, 2H), 1.40 - 1.44 (m, 9H). [00303] Step B: tert-Butyl 7-(2-chloro-4-fluorophenyl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate. To a solution of tert-butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (12 g, 27.0 mmol, 1.0 eq) in DME (268 mL, 0.10 M) was added Pd(PPh3)4 (1.56 g, 1.35 mmol, 0.05 eq) under N2. The mixture was stirred at 25°C for 5 min before a solution of (2-chloro-4-fluorophenyl)boronic acid (7.05 g, 40.4 mmol, 1.5 eq) and sodium carbonate (4.6 mL, 9.23 mmol, 2.0 eq) in EtOH (5.0 mL) was added. The mixture was stirred at 90°C for 2 h under N2. After cooling to rt, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-50% EtOAc in PE) to give tert-butyl 7-(2-chloro-4-fluorophenyl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (8.0 g, 91% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.24 (br s, 1H), 7.03 - 7.11 (m, 1H), 6.93 (td, J = 8.3, 2.5 Hz, 184 QB\184200.00050\92364964.2 VVID-746PC 1H), 5.58 (t, J = 6.2 Hz, 1H), 3.70 - 3.80 (m, 2H), 2.30 - 2.36 (m, 2H), 1.85 (quin, J = 5.8 Hz, 2H), 1.58 - 1.68 (m, 2H), 1.13 (s, 9H). [00304] Step C: 7-(2-Chloro-4-fluorophenyl)-3,4,5,6-tetrahydro-2H-azepine. A solution of tert-butyl 7-(2- chloro-4-fluorophenyl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (8.0 g, 24.4 mmol, 1.0 eq) in HCl (80 mL, 4N in EtOAc) was stirred at 25°C for 0.5 h. The solvent was evaporated to afford 7-(2-chloro-4- fluorophenyl)-3,4,5,6-tetrahydro-2H-azepine (5.5 g, quant. yield) as a pale yellow oil. This was used in the next step without further purification. [00305] Step D: 2-(2-Chloro-4-fluorophenyl)azepane. To a solution of 7-(2-chloro-4-fluorophenyl)- 3,4,5,6-tetrahydro-2H-azepine (5.5 g, 24.4 mmol, 1.0 eq) in methanol (50 mL, 0.49 M) was added NaBH4 (1.9 g, 50.5 mmol, 2.1 eq) and the mixture was stirred at 25°C for 2 h. The reaction was quenched with MeOH and concentrated to provide 2-(2-chloro-4-fluorophenyl)azepane (5.3 g, 95% yield) as a yellow oil. This was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.6, 6.3 Hz, 1H), 7.08 (dd, J = 8.6, 2.6 Hz, 1H), 6.97 (td, J = 8.4, 2.6 Hz, 1H), 4.14 - 4.22 (m, 1H), 3.07 - 3.19 (m, 1H), 2.84 - 2.99 (m, 1H), 2.00 (ddd, J = 10.6, 6.9, 3.8 Hz, 1H), 1.58 - 1.83 (m, 7H). Intermediate 14: 2-(2-Chloro-3-fluorophenyl)azepane.
Figure imgf000187_0001
[00306] The title compound was prepared in a manner analogous to Intermediate 13 using (2-chloro-3- fluorophenyl)boronic acid instead of (2-chloro-4-fluorophenyl)boronic acid in Step B. MS (ESI): mass calcd. for C12H15ClFN, 227.1; m/z found, 228.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.8 Hz, 1H), 7.22 (td, J = 8.0, 5.4 Hz, 1H), 7.02 (td, J = 8.5, 1.4 Hz, 1H), 4.26 (dd, J = 9.2, 3.5 Hz, 1H), 3.11 - 3.22 (m, 1H), 2.88 - 3.04 (m, 1H), 2.00 - 2.07 (m, 1H), 1.60 - 1.89 (m, 7H). Intermediate 15: 5-(2-Chloro-3-fluorophenyl)-1,4-oxazepane.
Figure imgf000187_0002
[00307] The title compound was prepared in a manner analogous to Intermediate 13 using tert-butyl 5-oxo- 1,4-oxazepane-4-carboxylate instead of tert-butyl 2-oxoazepane-1-carboxylate in Step A and using (2- chloro-3-fluorophenyl)boronic acid instead of (2-chloro-4-fluorophenyl)boronic acid in Step B. MS (ESI): 185 QB\184200.00050\92364964.2 VVID-746PC mass calcd. for C11H13ClFNO, 229.1; m/z found, 230.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.41 (m, 1H), 7.10 - 7.26 (m, 2H), 4.92 (br d, J = 10.2 Hz, 1H), 3.90 - 4.07 (m, 3H), 3.48 (s, 1H), 3.28 - 3.36 (m, 1H), 3.14 - 3.26 (m, 1H), 2.61 - 2.77 (m, 1H), 2.13 (br d, J = 15.8 Hz, 1H). Intermediate 16: 1-(2-Chlorophenyl)isoindoline.
Figure imgf000188_0001
[00308] Step A: tert-Butyl (2-(2-chlorobenzoyl)benzyl)carbamate. To a solution of 2-bromochlorobenzene (4.0 g, 20.6 mmol, 1.0 eq) in THF (50 mL, 0.41 M) was added n-butyllithium (9.9 mL, 24.7 mmol, 2.5 M, 1.2 eq) at -78°C under N2. The mixture was stirred at -78°C for 1 h before a solution of tert-butyl 1- oxoisoindoline-2-carboxylate (4.8 g, 20.6 mmol, 1.0 eq) in THF (10 mL) was added. The reaction was stirred at -78°C for 4 h before being quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC on silica (0-50% EtOAc in PE) to give tert-butyl (2-(2-chlorobenzoyl)benzyl)carbamate (3.0 g, 42% yield) as a white solid. [00309] Step B: tert-Butyl (2-((2-chlorophenyl)(hydroxy)methyl)benzyl)carbamate. To a solution of tert- butyl (2-(2-chlorobenzoyl)benzyl)carbamate (3.0 g, 8.68 mmol, 1.0 eq) in methanol (10 mL, 0.87 M) was added LiAlH4 (658 mg, 17.3 mmol, 2.0 eq). The mixture was stirred at 25°C for 2 h before water (5.0 mL) was added dropwise at 0°C. This was stirred for 5 min, then 15% aq. NaOH (10 mL) was added. The resulting mixture was stirred at 20°C for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (2-((2-chlorophenyl)(hydroxy)methyl)benzyl)carbamate (2.8 g, 93% yield) as a yellow oil. [00310] Step C: tert-Butyl 1-(2-chlorophenyl)isoindoline-2-carboxylate. To a solution of tert-butyl (2-((2- chlorophenyl)(hydroxy)methyl)benzyl)carbamate (1.6 g, 4.60 mmol, 1.0 eq) in MeCN (10 mL, 0.46 M) was added p-toluenesulfonyl chloride (877 mg, 4.60 mmol, 1.0 eq), 4-(dimethylamino)pyridine (1.1 g, 9.20 mmol, 2.0 eq), and TEA (930 mg, 9.20 mmol, 2.0 eq). The mixture was stirred at 45°C for 2 h. After cooling to rt, the solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by RP-HPLC (65-85% ACN in 10 mM aqueous NH4HCO3) to give tert-butyl 1-(2- chlorophenyl)isoindoline-2-carboxylate (150 mg, 10% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.40 (m, 2H), 7.11 - 7.23 (m, 6H), 6.49 (d, J = 1.5 Hz, 1H), 4.92 - 5.02 (m, 1H), 4.92 (s, 1H), 1.22 (s, 9H). [00311] Step D: 1-(2-Chlorophenyl)isoindoline. A solution of tert-butyl 1-(2-chlorophenyl)isoindoline-2- carboxylate (130 mg, 0.394 mmol, 1.0 eq) in DCM (2.0 mL, 0.15 M) and trifluoroacetic acid (0.70 mL, 186 QB\184200.00050\92364964.2 VVID-746PC 0.15 M) was stirred at 25°C for 3 h. The solution was evaporated to provide 1-(2-chlorophenyl)isoindoline (100 mg, quant. yield) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C14H12ClN, 229.1; m/z found, 230.1 [M+H]+. Intermediate 17: 5-(2-Chlorophenyl)pyrrolidin-3-yl acetate.
Figure imgf000189_0001
[00312] Step A: (Z)-N-(2-Chlorobenzylidene)-2-methylpropane-2-sulfinamide. To a solution of 2- chlorobenzaldehyde (8.5 g, 60.4 mmol, 1.0 eq) in DCM (80 mL, 0.75 M) was added 2-methylpropane-2- sulfinamide (9.5 g, 78.6 mmol, 1.3 eq) and cesium carbonate (24 g, 72.5 mmol, 1.2 eq). The mixture was stirred at 45°C for 1.5 h. After cooling to rt, the reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford (Z)-N-(2-chlorobenzylidene)-2-methylpropane-2-sulfinamide (13 g, 88% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.01 - 8.10 (m, 1H), 7.40 - 7.50 (m, 2H), 7.32 - 7.38 (m, 1H), 1.28 (s, 9H). [00313] Step B: N-(1-(2-Chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide. To a solution of (Z)-N-(2-chlorobenzylidene)-2-methylpropane-2-sulfinamide (13 g, 53.3 mmol, 1.0 eq) in DCM (100 mL, 0.53 M) at -78°C under N2 was added allylmagnesium chloride (80 mL, 80.0 mmol, 1.5 eq). The mixture was stirred at -78°C for 1 h before being quenched with sat. aq. NH4Cl and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford N-(1-(2-chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (15 g, 98% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.27 - 7.36 (m, 2H), 7.08 - 7.21 (m, 2H), 5.60 - 5.73 (m, 1H), 5.08 - 5.19 (m, 2H), 4.93 (ddd, J = 8.1, 5.0, 3.4 Hz, 1H), 3.54 - 3.74 (m, 1H), 2.56 - 2.65 (m, 1H), 2.35 - 2.47 (m, 1H), 1.13 (s, 9H). [00314] Step C: 1-(2-Chlorophenyl)but-3-en-1-amine. To a solution of N-(1-(2-chlorophenyl)but-3-en-1- yl)-2-methylpropane-2-sulfinamide (10 g, 35.0 mmol, 1.0 eq) in methanol (60 mL, 0.58 M) was added HCl (4N in MeOH, 30 mL) at 0°C. The mixture was stirred at 0°C for 3 h. The pH of the mixture was adjusted to ~9 with 10% aq. NaOH and the product was concentrated under vacuum. The resulting residue was diluted with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford 1-(2-chlorophenyl)but-3-en-1- amine (6.0 g, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.8, 1.5 Hz, 1H), 7.32 - 7.38 (m, 1H), 7.23 - 7.28 (m, 1H), 7.12 - 7.20 (m, 1H), 5.69 - 5.96 (m, 1H), 5.04 - 5.20 (m, 2H), 4.39 - 4.54 (m, 1H), 2.47 - 2.63 (m, 1H), 2.18 - 2.38 (m, 1H). 187 QB\184200.00050\92364964.2 VVID-746PC [00315] Step D: N-(1-(2-Chlorophenyl)but-3-en-1-yl)acetamide. To a solution of 1-(2-chlorophenyl)but-3- en-1-amine (8.0 g, 44.0 mmol, 1.0 eq) in DCM (50 mL, 0.88 M) at 0°C was added TEA (6.7 g, 66.0 mmol, 1.5 eq) and acetic anhydride (5.4 g, 52.8 mmol, 1.2 eq). The mixture was stirred at 0°C for 3 h before being diluted with sat. aq. NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford N-(1-(2-chlorophenyl)but-3- en-1-yl)acetamide (7.0 g, 71% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.47 (m, 1H), 7.21 - 7.37 (m, 3H), 6.34 (br d, J = 4.9 Hz, 1H), 5.66 - 5.89 (m, 1H), 5.41 - 5.50 (m, 1H), 5.07 - 5.25 (m, 2H), 2.53 - 2.74 (m, 2H), 2.03 - 2.09 (m, 3H). [00316] Step E: 5-(2-Chlorophenyl)pyrrolidin-3-yl acetate. To a solution of N-(1-(2-chlorophenyl)but-3- en-1-yl)acetamide (6.0 g, 26.8 mmol, 1.0 eq) in THF/water (4:1 v/v, 75 mL, 0.35 M) was added iodine (20 g, 80.5 mmol, 3.0 eq). The mixture was stirred at 20°C for 16 h before being diluted with sat. aq. NaHCO3, quenched with sat. aq. Na2S2O3, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford 5-(2-chlorophenyl)pyrrolidin- 3-yl acetate (5.0 g, 77% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 - 7.83 (m, 1H), 7.27 - 7.43 (m, 2H), 7.26 (br d, J = 1.8 Hz, 1H), 5.22 - 5.43 (m, 1H), 4.68 (t, J = 8.1 Hz, 1H), 3.47 - 3.62 (m, 1H), 3.19 - 3.42 (m, 1H), 2.53 (dd, J = 14.3, 6.8 Hz, 1H), 1.99 - 2.15 (m, 4H). Intermediate 18: 5-(2-Chlorophenyl)-3-methylpyrrolidin-3-ol.
Figure imgf000190_0001
[00317] Step A: tert-Butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxylate. To a solution of 5-(2- chlorophenyl)pyrrolidin-3-yl acetate (Intermediate 17, 7.0 g, 29.2 mmol, 1.0 eq) in DCM (100 mL, 0.29 M) was added triethylamine (4.4 g, 43.8 mmol, 1.5 eq) and di-tert-butyl dicarbonate (7.6 g, 35.1 mmol, 1.2 eq). The mixture was stirred at 25°C for 1 h before being diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give tert-butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxylate (9.0 g, 91% yield) as a brown oil, which was used in the next step directly. [00318] Step B: tert-Butyl 2-(2-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate. To a solution of tert- butyl 4-acetoxy-2-(2-chlorophenyl)pyrrolidine-1-carboxylate (9.0 g, 26.5 mmol, 1.0 eq) in methanol (90 mL, 0.29 M) was added potassium carbonate (3.7 g, 26.5 mmol, 1.0 eq). The mixture was stirred at 25°C for 1 h before being filtered. The filtrate was concentrated under vacuum and purified by FCC on silica (0- 50% EtOAc in PE) to give tert-butyl 2-(2-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (5.8 g, 74% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.6 Hz, 1H), 7.08 - 7.26 (m, 3H), 5.14 - 188 QB\184200.00050\92364964.2 VVID-746PC 5.43 (m, 1H), 4.51 (br s, 1H), 3.59 - 3.83 (m, 2H), 2.44 - 2.73 (m, 1H), 1.86 - 2.00 (m, 1H), 1.46 (br s, 2H), 1.06 - 1.23 (m, 9H). [00319] Step C: tert-Butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1-carboxylate. A solution of oxalyl chloride (5.2 g, 40.9 mmol, 2.1 eq) in DCM (50 mL, 0.39 M) was degassed and purged with N2. After cooling to -78°C, DMSO (6.4 g, 81.8 mmol, 4.2 eq) was added slowly and the reaction was stirred at -78°C for 0.5 h. A solution of tert-butyl 2-(2-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (5.8 g, 19.5 mmol, 1.0 eq) in DCM (60 mL) was added and the mixture was stirred at -78°C for 1 h. TEA (13.5 mL, 97.4 mmol, 5.0 eq) was added at -78°C and the mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-20% EtOAc in PE) to give tert-butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1- carboxylate (4.0 g, 69% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.42 (m, 1H), 7.11 - 7.26 (m, 3H), 5.65 (br s, 1H), 3.90 - 4.24 (m, 2H), 3.11 - 3.35 (m, 1H), 2.54 (br d, J = 19.0 Hz, 1H), 1.22 - 1.48 (m, 9H). [00320] Step D: tert-Butyl 2-(2-chlorophenyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylate. A solution of tert-butyl 2-(2-chlorophenyl)-4-oxo-pyrrolidine-1-carboxylate (500 mg, 1.69 mmol, 1.0 eq) and trichlorocerium (917 mg, 3.72 mmol, 2.2 eq) in THF (5.0 mL, 0.34 M) was degassed and purged with N2. After cooling to -78°C, methyllithium solution (3.7 mL, 3.72 mmol, 2.2 eq) was added dropwise and the mixture was stirred at -78°C for 3 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 3:1) to give tert-butyl 2-(2-chlorophenyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylate (300 mg, 57% yield) as a pale yellow oil. MS (ESI): mass calcd. for C16H22ClNO3, 311.1; m/z found, 256.2 [M+2H-tBu]+. [00321] Step E: 5-(2-Chlorophenyl)-3-methylpyrrolidin-3-ol. To a solution of tert-butyl 2-(2- chlorophenyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylate (300 mg, 0.962 mmol, 1.0 eq) in DCM (3.0 mL, 0.32 M) was added TFA (1.0 mL). The reaction was stirred at 25°C for 1 h before being concentrated under reduced pressure to give 5-(2-chlorophenyl)-3-methyl-pyrrolidin-3-ol (200 mg, 98% yield) as a brown oil, which was used in the next step directly. Intermediate 19: 5-(2-Chlorophenyl)pyrrolidin-2-one.
Figure imgf000191_0001
[00322] To a solution of iPrMgCl·LiCl (20 mL, 26.2 mmol, 2.6 eq) in THF (10 mL) was added 1-chloro-2- iodobenzene (6.3 g, 26.2 mmol, 2.6 eq) at -20°C under N2. This was stirred for 45 min then allowed to 189 QB\184200.00050\92364964.2 VVID-746PC warm to 20°C and stirred for 2 h. This mixture was then added to a suspension of pyrrolidine-2,5-dione (1.0 g, 10.1 mmol, 1.0 eq) in THF (20 mL, 0.50 M) at -10°C. The reaction was stirred at 20°C for 1 h. Sodium cyanoborohydride (1.1 g, 18.2 mmol, 1.8 eq) and HCl (1.5M, 34 mL) were added slowly at 10°C. The mixture was stirred at 20°C for 16 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (5-42% ACN in 0.1% aqueous TFA) to provide 5-(2-chlorophenyl)pyrrolidin-2-one (400 mg, 20% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.35 - 7.40 (m, 2H), 7.29 - 7.34 (m, 1H), 4.97 (dd, J = 7.9, 5.6 Hz, 1H), 2.53 - 2.64 (m, 1H), 2.17 - 2.25 (m, 2H), 1.63 - 1.75 (m, 1H). Intermediate 20: 3-(2-Chlorophenyl)isoindolin-1-one.
Figure imgf000192_0001
[00323] The title compound was prepared in a manner analogous to Intermediate 19 using isoindoline-1,3- dione instead of pyrrolidine-2,5-dione. 1H NMR (400 MHz, CDCl3) δ 7.86 - 7.95 (m, 1H), 7.41 - 7.58 (m, 4H), 7.27 - 7.33 (m, 1H), 7.20 (td, J = 7.5, 1.2 Hz, 1H), 7.07 - 7.14 (m, 1H), 6.64 (br s, 1H) 6.27 (s, 1H). Intermediate 21: rac-(1*R,4*R,5*S)-4-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-2-one.
Figure imgf000192_0002
[00324] The title compound was prepared in a manner analogous to Intermediate 19 using 3- azabicyclo[3.1.0]hexane-2,4-dione instead of pyrrolidine-2,5-dione. MS (ESI): mass calcd for C11H10ClNO, 207.1; found 208.0 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.46 (m, 1H), 7.31 (ddd, J = 7.2, 4.9, 1.9 Hz, 2H), 7.21 - 7.25 (m, 1H), 5.34 (d, J = 5.9 Hz, 1H), 2.57 (dtd, J = 7.7, 5.9, 4.2 Hz, 1H), 1.93 (ddd, J = 8.8, 5.7, 3.3 Hz, 1H), 0.86 (td, J = 8.2, 4.9 Hz, 1H), 0.57 - 0.61 (m, 1H). Intermediate 22: rac-(1*R,4*R,5*S)-4-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one.
Figure imgf000192_0003
190 QB\184200.00050\92364964.2 VVID-746PC [00325] The title compound was prepared in a manner analogous to Intermediate 19 using 3- azabicyclo[3.1.0]hexane-2,4-dione instead of pyrrolidine-2,5-dione and 2-chloro-4-fluoro-1-iodobenzene instead of 1-chloro-2-iodobenzene. 1H NMR (400 MHz, CDCl3) δ 7.15 - 7.19 (m, 1H), 7.11 (dd, J = 8.3, 2.6 Hz, 1H), 6.94 (td, J = 8.3, 2.6 Hz, 1H), 5.53 (br s, 1H), 5.23 (d, J = 5.9 Hz, 1H), 2.40 - 2.43 (m, 1H), 1.85 - 1.93 (m, 1H), 0.79 - 0.90 (m, 1H), 0.57 - 0.70 (m, 1H). Intermediate 23: rac-(1*S,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one.
Figure imgf000193_0001
[00326] The title compound was prepared in a manner analogous to Intermediate 19 using 3- azabicyclo[3.1.0]hexane-2,4-dione instead of pyrrolidine-2,5-dione and 1-bromo-2-chloro-3-fluorobenzene instead of 1-chloro-2-iodobenzene. 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.14 (dt, J = 1.3, 8.4 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 5.94 (br s, 1H), 5.34 (d, J = 5.9 Hz, 1H), 2.42 - 2.62 (m, 1H), 1.88 - 2.03 (m, 1H), 0.82 - 0.97 (m, 1H), 0.62 - 0.77 (m, 1H). Intermediate 24: rac-(1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000193_0002
[00327] Step A: tert-Butyl ((2-(2-chloro-4-fluorobenzoyl)cyclopropyl)methyl)carbamate. A solution of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 15.2 mmol, 1.0 eq) in THF (10 mL, 1.5 M) was degassed and purged with N2. To the mixture was slowly added (2-chloro-4- fluorophenyl)magnesium bromide (11.4 mL, 22.8 mmol, 1.5 eq) at 0°C. The reaction was stirred at 0°C for 2 h before being quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-15% EtOAc in PE) to give tert-butyl ((2-(2-chloro-4- fluorobenzoyl)cyclopropyl)methyl)carbamate (3.9 g, 78% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.27 - 7.32 (m, 1H), 7.14 - 7.21 (m, 1H), 6.91 - 7.01 (m, 1H), 3.75 - 3.82 (m, 1H), 3.65 - 3.71 (m, 1H), 1.97 - 2.10 (m, 1H), 1.54 - 1.67 (m, 1H), 1.43 - 1.47 (m, 9H), 0.92 - 0.98 (m, 1H), 0.84 - 0.88 (m, 1H). [00328] Step B: (2-(Aminomethyl)cyclopropyl)(2-chloro-4-fluorophenyl)methanone. To a solution of tert- butyl ((2-(2-chloro-4-fluorobenzoyl)cyclopropyl)methyl)carbamate (2.3 g, 7.01 mmol, 1.0 eq) in DCM (15 mL, 0.35 M) was added TFA (5.0 mL, 0.35 M) dropwise. The reaction was stirred at 20℃ for 2 h before 191 QB\184200.00050\92364964.2 VVID-746PC being concentrated under reduced pressure to give (2-(aminomethyl)cyclopropyl)(2-chloro-4- fluorophenyl)methanone (TFA salt, 2.3 g, 95% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.8, 5.6 Hz, 1H), 7.38 (dd, J = 8.1, 2.4 Hz, 1H), 7.21 - 7.26 (m, 1H), 4.26 - 4.43 (m, 2H), 2.98 - 3.09 (m, 1H), 2.65 - 2.74 (m, 1H), 1.94 (td, J = 8.3, 5.5 Hz, 1H), 1.04 - 1.15 (m, 1H). [00329] Step C: rac-(1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexane. To a solution of (2-(aminomethyl)cyclopropyl)(2-chloro-4-fluorophenyl)methanone (TFA salt, 1.7 g, 4.86 mmol, 1.0 eq) in ethanol (14 mL, 0.35 M) was added acetic acid (0.50 mL) dropwise and NaBH3CN (519 mg, 8.25 mmol, 1.7 eq). The reaction was stirred at 20℃ for 2 h before being quenched by sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give rac-(1*R,2*S,5*S)-2-(2-chloro-4-fluorophenyl)-3- azabicyclo[3.1.0]hexane (800 mg, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 8.6, 6.3 Hz, 1H), 7.13 (dd, J =8.5, 2.6 Hz, 1H), 6.98 (td, J = 8.3, 2.6 Hz, 1H), 4.70 (d, J = 3.5 Hz, 1H), 3.22 - 3.29 (m, 2H), 1.74 - 1.82 (m, 1H), 1.52 - 1.62 (m, 1H), 0.72 (q, J = 4.2 Hz, 1H), 0.54 (td, J = 7.8, 5.4 Hz, 1H). Intermediate 25: rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000194_0001
[00330] The title compound was prepared in a manner analogous to Intermediate 24 using (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C11H11ClFN, 211.0; m/z found, 212.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.20 (dt, J = 1.1, 8.4 Hz, 1H), 5.19 (d, J = 3.5 Hz, 1H), 3.63 - 3.45 (m, 2H), 2.05 - 1.96 (m, 1H), 1.83 (dt, J = 4.0, 7.3 Hz, 1H), 1.19 - 1.06 (m, 1H), 0.96 (q, J = 7.8 Hz, 1H). Intermediate 26: (1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000194_0002
[00331] The title compound was prepared via separation of rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)- 3-azabicyclo[3.1.0]hexane (Intermediate 25) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2 with 0.1% NH4OH; Rt = 4.70 min, second eluting product). Absolute stereochemistry was determined by single crystal x-ray. MS (ESI): mass calcd. for C11H11ClFN, 211.0; m/z found, 212.1 [M+H]+. 192 QB\184200.00050\92364964.2 VVID-746PC Intermediate 27: rac-(1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000195_0001
[00332] The title compound was prepared in a manner analogous to Intermediate 24 using (2- chlorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C11H12ClN, 193.1; m/z found, 194.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.74 - 7.65 (m, 1H), 7.40 - 7.33 (m, 1H), 7.27 - 7.16 (m, 2H), 4.70 - 4.62 (m, 1H), 3.25 - 3.13 (m, 2H), 1.81 - 1.74 (m, 1H), 1.56 - 1.46 (m, 1H), 0.72 - 0.63 (m, 1H), 0.49 - 0.38 (m, 1H). Intermediate 28: rac-(1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000195_0002
[00333] The title compound was prepared in a manner analogous to Intermediate 24 using (2,3- difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.37 (m, 1H), 7.00 - 7.10 (m, 2H), 4.60 (d, J = 3.5 Hz, 1H), 3.11 - 3.22 (m, 2H), 1.67 - 1.73 (m, 2H), 1.52 (tt, J = 7.1, 3.6 Hz, 1H), 0.59 (q, J = 4.2 Hz, 1H), 0.46 (td, J = 7.7, 5.1 Hz, 1H). Intermediate 29: rac-(1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane.
Figure imgf000195_0003
[00334] The title compound was prepared in a manner analogous to Intermediate 24 using (2- chlorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)manesium bromide and tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C11H10ClF2N, 229.1; m/z found, 230.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (br d, J = 7.0 Hz, 1H), 7.32 - 7.47 (m, 3H), 5.61 (br t, J = 4.4 Hz, 1H), 3.89 - 4.02 (m, 1H), 3.80 (br d, J = 12.3 Hz, 1H), 2.75 (td, J = 10.1, 4.4 Hz, 1H), 2.62 (td, J = 9.8, 5.1 Hz, 1H). 193 QB\184200.00050\92364964.2 VVID-746PC Intermediate 30: rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane.
Figure imgf000196_0001
[00335] The title compound was prepared in a manner analogous to Intermediate 24 using (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide and tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate in Step A. 1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.55 (m, 1H), 7.31 - 7.42 (m, 2H), 4.76 - 4.89 (m, 1H), 3.36 - 3.45 (m, 2H), 2.58 - 2.64 (m, 1H), 2.36 - 2.43 (m, 1H). Intermediate 31: rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000196_0002
[00336] Step A: tert-Butyl rac-(((1*R,2*S)-2-(3-chloropicolinoyl)cyclopropyl)methyl)carbamate. A solution of 2-bromo-3-chloropyridine (8.9 g, 46.2 mmol, 1.2 eq) in THF (80 mL, 0.29 M) was degassed and purged with N2. After cooling to -78°C, n-BuLi (23 mL, 57.8 mmol, 1.5 eq, 2.5 M) was added over 30 min. Finally, a solution of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (7.6 g, 38.5 mmol, 1.0 eq) in THF (50 mL, 0.29 M) was added and the reaction was stirred at 25°C for 12 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-50% EtOAc in PE) to afford tert-butyl rac-(((1*R,2*S)-2-(3- chloropicolinoyl)cyclopropyl)methyl)carbamate (4.0 g, 33% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.56 (br d, J = 4.1 Hz, 1H), 7.82 (dd, J = 8.3, 1.3 Hz, 1H), 7.39 (dd, J = 8.2, 4.6 Hz, 1H), 5.30 (br d, J = 2.0 Hz, 1H), 3.66 - 3.78 (m, 1H), 2.98 - 3.06 (m, 1H), 2.80 - 2.90 (m, 1H), 1.93 - 2.02 (m, 1H), 1.50 (br dd, J = 4.8, 2.1 Hz, 2H), 1.42 (s, 9H). [00337] Step B: rac-((1*S,2*R)-2-(Aminomethyl)cyclopropyl)(3-chloropyridin-2-yl)methanone. To a mixture of tert-butyl rac-(((1*R,2*S)-2-(3-chloropicolinoyl)cyclopropyl)methyl)carbamate (2.0 g, 6.43 mmol, 1.0 eq) in DCM (16 mL, 0.26 M) was added trifluoroacetic acid (8.0 mL, 0.26 M) under N2. The reaction mixture was stirred at 20°C for 2 h before being concentrated under reduced pressure to give rac- ((1*S,2*R)-2-(aminomethyl)cyclopropyl)(3-chloropyridin-2-yl)methanone (2.0 g, 96% yield) as a yellow oil. This was used directly without purification. 194 QB\184200.00050\92364964.2 VVID-746PC [00338] Step C: rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane. To a solution of rac-((1*S, 2*R)-2-(aminomethyl) cyclopropyl)(3-chloropyridin-2-yl)methanone (2.0 g, 6.16 mmol, 1.0 eq) in methanol (20 mL, 0.30 M) was added NaBH3CN (503 mg, 8.01 mmol, 1.3 eq). The reaction was stirred at 25°C for 16 h before being concentrated under reduced pressure. The crude mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0- 30% EtOAc in PE) to give rac-(1*S,2*R,5*R)-2-(3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane (TFA salt, 1.9 g, quant. yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 4.7, 1.1 Hz, 1H), 7.83 (dd, J = 8.1, 1.2 Hz, 1H), 7.35 (dd, J = 7.8, 4.7 Hz, 1H), 5.45 (d, J = 4.1 Hz, 1H), 3.73 (s, 1H), 3.62 (s, 1H), 2.31 - 2.44 (m, 1H), 1.86 - 1.99 (m, 2H), 0.69 (q, J = 7.8 Hz, 1H), 0.53 (dt, J = 6.8, 4.4 Hz, 1H). [00339] Step D: rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane. To a solution of rac-(1*S,2*R,5*R)-2-(3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane (TFA salt, 1.9 g, 6.16 mmol, 1.0 eq) in water (30 mL, 0.20 M) was added Na2CO3 (1.9 g, 18.4 mmol, 3.0 eq). The mixture was stirred at 25°C for 1 h before being extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give rac-(1*S,2*R,5*R)-2-(3- chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane (1.4 g, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 4.7, 1.3 Hz, 1H), 7.68 (dd, J = 8.0, 1.5 Hz, 1H), 7.16 (dd, J = 8.0, 4.7 Hz, 1H), 4.75 (d, J = 3.5 Hz, 1H), 3.15 - 3.19 (m, 2H), 1.83 - 1.97 (m, 2H), 0.29 - 0.33 (m, 1H), 0.24 (td, J = 7.6, 5.3 Hz, 1H). Intermediate 32: 6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octane.
Figure imgf000197_0001
[00340] The title compound was prepared in a manner analogous to Intermediate 31 using 2- bromochlorobenzene instead of 2-bromo-3-chloropyridine and tert-butyl 6-oxo-4-oxa-7- azaspiro[2.5]octane-7-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C12H14ClNO, 223.1; m/z found, 224.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 1.6, 7.8 Hz, 1H), 7.37 (dd, J = 1.4, 7.9 Hz, 1H), 7.28 - 7.31 (m, 1H), 7.19 - 7.25 (m, 1H), 4.48 (dd, J = 3.1, 9.8 Hz, 1H), 3.94 (dd, J = 3.1, 10.8 Hz, 1H), 3.62 (dd, J = 2.1, 12.0 Hz, 1H), 3.45 - 3.54 (m, 1H), 2.50 (d, J = 12.0 Hz, 1H), 0.87 - 0.97 (m, 1H), 0.79 (dddd, J = 2.4, 4.5, 6.3, 8.4 Hz, 1H), 0.58 - 0.69 (m, 2H). Intermediate 33: rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane. 195 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000198_0001
[00341] Step A: tert-Butyl rac-(((1*R,2*S)-2-(2-chloro-3-fluorobenzoyl)cyclopropyl)methyl)carbamate. A solution of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.3 g, 16.7 mmol, 1.0 eq) in THF (40 mL, 0.42 M) was degassed and purged with N2. To the solution was added (2-chloro-3- fluorophenyl)magnesium bromide (25.1 mL, 25.1 mmol, 1.5 eq) dropwise at 0°C. The reaction was stirred at 0-25°C for 16 h before being quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-15% EtOAc in PE) to give tert-butyl rac- (((1*R,2*S)-2-(2-chloro-3-fluorobenzoyl)cyclopropyl)methyl)carbamate (5.1 g, 92% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.37 (m, 2H), 7.28 - 7.30 (m, 1H), 4.63 - 5.01 (m, 1H), 3.46 - 3.62 (m, 1H), 3.20 - 3.36 (m, 1H), 2.52 - 2.64 (m, 1H), 2.05 - 2.14 (m, 1H), 1.47 - 1.50 (m, 1H), 1.42 - 1.46 (m, 9H), 1.34 (br d, J = 4.3 Hz, 1H). [00342] Step B: tert-Butyl rac-(((1*R,2*S)-2-((2-chloro-3- fluorophenyl)(hydroxy)methyl)cyclopropyl)methyl)carbamate. To a solution of tert-butyl rac-(((1*R,2*S)- 2-(2-chloro-3-fluorobenzoyl)cyclopropyl)methyl)carbamate (500 mg, 1.52 mmol, 1.0 eq) in methanol (5.0 mL, 0.30 M) was added sodium borohydride (115 mg, 3.05 mmol, 2.0 eq) at 0°C. The mixture was stirred at 0-25°C for 16 h before being concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to give tert-butyl rac-(((1*R,2*S)-2-((2-chloro-3- fluorophenyl)(hydroxy)methyl)cyclopropyl)methyl)carbamate (428 mg, 85% yield) as a white solid, which was used in the next step directly. [00343] Step C: tert-Butyl 2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of tert-butyl rac-(((1*R,2*S)-2-((2-chloro-3- fluorophenyl)(hydroxy)methyl)cyclopropyl)methyl)carbamate (428 mg, 1.30 mmol, 1.0 eq) in DCM (15 mL, 0.086 M) was added TEA (0.36 mL, 2.59 mmol, 2.0 eq), p-toluenesulfonyl chloride (371 mg, 1.95 mmol, 1.5 eq) and 4-(dimethylamino)pyridine (158 mg, 1.30 mmol, 1.0 eq). The reaction mixture was stirred at 25°C for 16 h before being concentrated under reduced pressure. Purification by FCC on silica (0-15% EtOAc in PE) provided tert-butyl 2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (300 mg, 74% yield). MS (ESI): mass calcd. for C16H19ClFNO2, 311.1; m/z found, 256.1 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.16 - 7.26 (m, 1H), 6.99 - 7.11 (m, 1H), 6.83 - 6.97 (m, 1H), 5.17 (s, 1H), 3.66 - 3.85 (m, 2H), 1.59 - 1.69 (m, 1H), 1.49 - 1.56 (m, 1H), 1.45 (s, 3H), 1.23 (s, 9H), 0.86 (td, J = 7.8, 5.4 Hz, 1H), 0.37 - 0.49 (m, 1H). [00344] Step D: rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane. A solution of tert-butyl 2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 0.962 mmol, 1.0 196 QB\184200.00050\92364964.2 VVID-746PC eq) in HCl (5.0 mL, 4N in EtOAc) was stirred at 25°C for 3 h. The reaction was concentrated under reduced pressure to give rac-(1*S,2*S,5*R)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (238 mg, quant. yield) as a white solid, which was used in the next step directly. Intermediate 34: (S,E)-4-Methylsulfonylbut-3-en-2-amine.
Figure imgf000199_0001
[00345] The title compound was prepared in a manner analogous to Intermediate 1 using (S)-tert-butyl (1- oxopropan-2-yl)carbamate instead of (R)-tert-butyl (1-oxopropan-2-yl)carbamate in Step A. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (br s, 3H), 7.49 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.99 (dd, J = 15.4, 1.3 Hz, 1H), 6.75 (dd, J = 15.4, 5.8 Hz, 1H), 4.11 (br s, 1H), 3.05 (s, 3H), 2.29 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H). Intermediate 35: (R,E)-1-(Methylsulfonyl)pent-1-en-3-amine.
Figure imgf000199_0002
[00346] The title compound was prepared in a manner analogous to Intermediate 1 using (R)-tert-butyl (1- formylpropyl)carbamate instead of (R)-tert-butyl (1-oxopropan-2-yl)carbamate in Step A. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (br s, 3H), 7.49 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 7.02 (dd, J = 15.4, 0.8 Hz, 1H), 6.64 (dd, J = 15.4, 7.3 Hz, 1H), 3.91 (q, J = 6.9 Hz, 1H), 3.06 (s, 3H), 2.29 (s, 3H), 1.81 - 1.58 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H). Intermediate 36: (R,E)-1-Cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine.
Figure imgf000199_0003
[00347] To a solution of tert-butyl
Figure imgf000199_0004
1-cyclopropyl-2-hydroxyethyl)carbamate (500 mg, 2.48 mmol, 1.0 eq) in DCM (8 mL, 0.3M) was added Dess-Martin periodinane (2.1 g, 4.97 mmol, 2.0 eq). The reaction was stirred at rt for 1 h under N2 before being filtered and rinsed with DCM. The combined filtrates were concentrated under reduced pressure and purified by FCC (0-8% EtOAc in PE) to afford tert-butyl N-((R)- 1-cyclopropyl-2-oxoethyl)carbamate (300 mg, 61% yield). [00348] The title compound was prepared in a manner analogous to Intermediate 1 using tert-butyl N-((R)- 1-cyclopropyl-2-oxoethyl)carbamate instead of (R)-tert-butyl (1-oxopropan-2-yl)carbamate in Step A. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (br s, 3H), 7.48 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.03 (dd, 197 QB\184200.00050\92364964.2 VVID-746PC J = 15.4, 1.0 Hz, 1H), 6.75 (dd, J = 15.4, 6.1 Hz, 1H), 3.06 (s, 3H), 2.29 (s, 3H), 1.10 - 1.00 (m, 1H), 0.67 - 0.58 (m, 2H), 0.56 - 0.38 (m, 2H). Intermediate 37: (R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-amine.
Figure imgf000200_0001
[00349] A solution of sodium cyclopropanesulfinate (922 mg, 7.19 mmol, 2.0 eq) in DMSO (6.0 mL, 0.6M) was stirred for 1 hour at rt. Diethyl iodomethylphosphonate (0.60 mL, 3.60 mmol, 1.0 eq) was added and the reaction was heated to 80 °C for 16 hours. Another aliquot of sodium cyclopropanesulfinate (922 mg, 7.19 mmol, 2.0 eq) was added and the reaction was heated to 100 °C for 1 hour. After cooling to rt, the reaction was diluted with EtOAc, washed with 1M HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-10% MeOH in DCM) to afford diethoxyphosphorylmethylsulfonylcyclopropane (432 mg, 47% yield) as a yellow oil. [00350] The title compound was prepared in a manner analogous to Intermediate 1 using diethoxyphosphorylmethylsulfonylcyclopropane instead of diethyl ((methylsulfonyl)methyl)phosphonate in Step A. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (br s, 2H), 6.98 (d, J = 15.5 Hz, 1H), 6.72 (dd, J = 15.4, 5.6 Hz, 1H), 4.12 (br d, J = 5.0 Hz, 1H), 2.59 - 2.73 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H), 0.93 - 1.10 (m, 4H). Intermediate 38: tert-Butyl 4-oxo-5-azaspiro[2.4]heptane-5-carboxylate.
Figure imgf000200_0002
[00351] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl 5- azaspiro[2.4]heptane-5-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3- carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.87 - 3.78 (m, 2H), 2.11 - 2.05 (m, 2H), 1.55 (s, 9H), 1.26 - 1.23 (m, 2H), 0.87 - 0.83 (m, 2H). Intermediate 39: 4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptane.
Figure imgf000200_0003
[00352] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 4-oxo- 5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 38) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2- chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.9 Hz, 198 QB\184200.00050\92364964.2 VVID-746PC 1H), 7.23 (td, J = 8.0, 5.4 Hz, 1H), 7.02 (td, J = 8.5, 1.5 Hz, 1H), 4.62 (s, 1H), 3.39 - 3.19 (m, 2H), 2.14 - 2.09 (m, 2H), 0.77 - 0.67 (m, 1H), 0.67 - 0.61 (m, 1H), 0.53 - 0.41 (m, 1H), 0.32 - 0.21 (m, 1H). Intermediate 40: tert-Butyl rac-(3a*S,6a*S)-4-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate.
Figure imgf000201_0001
[00353] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (3a*R,6a*S)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 4.29 (dd, J = 9.3, 1.9 Hz, 1H), 3.97 (dd, J = 11.3, 8.9 Hz, 1H), 3.91 - 3.78 (m, 3H), 3.59 (dd, J = 11.4, 3.3 Hz, 1H), 3.30 - 3.19 (m, 1H), 2.94 (ddt, J = 9.1, 6.0, 3.1 Hz, 1H), 1.54 (s, 9H). Intermediate 41: rac-(3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole.
Figure imgf000201_0002
[00354] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (3a*S,6a*S)-4-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (Intermediate 40) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.07 (t, J = 8.5 Hz, 1H), 4.47 (d, J = 6.6 Hz, 1H), 4.02 (t, J = 8.2 Hz, 1H), 3.58 (dd, J = 8.7, 5.4 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.36 - 3.25 (m, 1H), 3.17 - 3.07 (m, 3H), 2.99 - 2.89 (m, 1H). Intermediate 42: rac-(3a*R,4*S,6a*S)-4-(2-Chlorophenyl)hexahydro-1H-furo[3,4-c]pyrrole.
Figure imgf000201_0003
[00355] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (3a*S,6a*S)-4-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (Intermediate 40) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chlorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H14ClNO, 223.1; m/z found, 224.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 7.5, 1.2 Hz, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.23 - 7.17 (m, 1H), 4.47 (d, J = 6.6 Hz, 1H), 4.02 (t, J = 8.2 Hz, 1H), 199 QB\184200.00050\92364964.2 VVID-746PC 3.59 (dd, J = 8.7, 5.4 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.37 - 3.28 (m, 1H), 3.18 - 3.06 (m, 3H), 2.98 - 2.88 (m, 1H). Intermediate 43: rac-(3a*R,4*S,6a*S)-4-(2,3-Difluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole.
Figure imgf000202_0001
[00356] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (3a*S,6a*S)-4-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (Intermediate 40) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13F2NO, 225.1; m/z found, 226.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.42 - 7.32 (m, 1H), 7.17 - 7.03 (m, 2H), 4.53 (br d, J = 5.8 Hz, 1H), 3.98 (br t, J = 8.3 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.56 - 3.45 (m, 1H), 3.30 - 3.17 (m, 4H), 3.07 - 2.95 (m, 1H). Intermediate 44: tert-Butyl rac-(1*R,5*S)-6,6-dimethyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000202_0002
[00357] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.82 (dd, J = 11.8, 6.6 Hz, 1H), 3.60 (d, J = 11.9 Hz, 1H), 1.89 (dd, J = 6.5, 1.4 Hz, 1H), 1.67 (t, J = 6.6 Hz, 1H), 1.52 (s, 9H), 1.14 (d, J = 3.3 Hz, 6H). Intermediate 45: rac-(1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.
Figure imgf000202_0003
[00358] Step A: tert-Butyl (((1*R,3*S)-3-(2,3-difluorobenzoyl)-2,2- dimethylcyclopropyl)methyl)carbamate. To a solution of tert-butyl rac-(1*R,5*S)-6,6-dimethyl-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 44, 2.0 g, 8.88 mmol, 1.0 eq) in THF (30 mL, 0.3M) was added (2,3-difluorophenyl)magnesium bromide (13 mL, 13.3 mmol, 1.5 eq, 1M in THF) at 0 ℃. The reaction was stirred at 0 ℃ for 2 h before being quenched with sat. aq. NH4Cl and extracted with EtOAc. 200 QB\184200.00050\92364964.2 VVID-746PC The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (10-25% EtOAc in PE) to give tert-butyl (((1*R,3*S)-3-(2,3-difluorobenzoyl)-2,2-dimethylcyclopropyl)methyl)carbamate (2.0 g, 66% yield) as a colorless oil. [00359] Step B: rac-(1*R,5*S)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene. To a solution of tert-butyl (((1*R,3*S)-3-(2,3-difluorobenzoyl)-2,2-dimethylcyclopropyl)methyl)carbamate (1.9 g, 5.60 mmol, 1.0 eq) in DCM (50 mL, 0.1M) was added 2,6-lutidine (1.8 g, 16.8 mmol, 3.0 eq) and trimethylsilyl trifluoromethanesulfonate (5.0 g, 22.4 mmol, 4.0 eq). The reaction was stirred at 20 ℃ for 1 h before being concentrated under vacuum to give rac-(1*R,5*S)-2-(2,3-difluorophenyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hex-2-ene (1.2 g, quant. yield) as a pale yellow solid, which was used in the next step directly. MS (ESI): mass calcd. for C13H13F2N, 221.1; m/z found, 222.1 [M+H]+. [00360] Step C: rac-(1*R,2*R,5*S)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane. To a solution of rac-(1*R,5*S)-2-(2,3-difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene (1.2 g, 5.56 mmol, 1.0 eq) in MeOH (30 mL, 0.2M) was added sodium cyanoborohydride (1.0 g, 16.7 mmol, 3.0 eq). The reaction was stirred at 20 ℃ for 3 h before being diluted with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give rac-(1*R,2*R,5*S)-2-(2,3-difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane (1.0 g, 81% yield, 50% purity) as a brown oil. MS (ESI): mass calcd. for C13H15F2N, 223.1; m/z found, 224.1 [M+H]+. Intermediate 46: rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane.
Figure imgf000203_0001
[00361] The title compound was prepared in a manner analogous to Intermediate 45 using (2-chloro-3- fluorophenyl)magnesium bromide instead of (2,3-difluorophenyl)magnesium bromide in Step A and ZnBr2 instead of trimethylsilyl trifluoromethanesulfonate in Step B. MS (ESI): mass calcd. for C13H15ClFN, 239.1; m/z found, 240.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 7.6 Hz, 1H), 7.36 - 7.21 (m, 2H), 4.68 (d, J = 4.1 Hz, 1H), 3.26 (dd, J = 9.4, 5.1 Hz, 1H), 3.04 (d, J = 9.4 Hz, 1H), 2.68 (br d, J = 9.3 Hz, 1H), 1.68 (dd, J = 7.4, 4.5 Hz, 1H), 1.29 (dd, J = 7.4, 5.0 Hz, 1H), 1.11 (s, 3H), 0.90 (s, 3H). Intermediate 47: tert-Butyl rac-(1*R,5*S)-2-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate. 201 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000204_0001
[00362] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl 3- azabicyclo[3.2.0]heptane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3- carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.80 (dd, J = 11.3, 7.3 Hz, 1H), 3.64 (d, J = 11.3 Hz, 1H), 3.16 - 3.06 (m, 1H), 2.97 - 2.85 (m, 1H), 2.51 (qd, J = 11.9, 9.5 Hz, 1H), 2.42 - 2.29 (m, 1H), 2.22 - 2.12 (m, 1H), 2.08 - 1.97 (m, 1H), 1.56 (s, 9H). Intermediate 48: rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptane
Figure imgf000204_0002
[00363] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*S)-2-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate (Intermediate 47) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2- chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13ClFN, 225.1; m/z found, 226.0 [M+H]+. Intermediate 49: tert-Butyl rac-(1*S,5*S,6*S)-6-cyano-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000204_0003
[00364] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (1*S,5*S,6*S)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.99 - 3.79 (m, 2H), 2.65 (ddd, J = 6.6, 2.8, 1.1 Hz, 1H), 2.53 (br d, J = 3.6 Hz, 1H), 1.73 (t, J = 3.2 Hz, 1H), 1.50 (s, 9H). Intermediate 50: rac-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6- carbonitrile.
Figure imgf000204_0004
202 QB\184200.00050\92364964.2 VVID-746PC [00365] Step A: tert-Butyl rac-(1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-2-hydroxy-3- azabicyclo[3.1.0]hexane-3-carboxylate. A solution of tert-butyl rac-(1*S,5*S,6*S)-6-cyano-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 49, 1.5 g, 6.75 mmol, 1.0 eq) in THF (10 mL, 0.7M) was placed under N2 and cooled to 0 °C. To the solution was added (2-chloro-3-fluorophenyl)magnesium bromide (7.4 mL, 7.42 mmol, 1.1 eq, 1M in THF) and the reaction was stirred at 0 °C for 1 h. The mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (30-50% EtOAc in PE) to give tert-butyl rac-(1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)- 6-cyano-2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.2 g, 92% yield) as a yellow oil. MS (ESI): mass calcd. for C17H18ClFN2O3, 352.1; m/z found, 235.1 [M-Boc-H2O]+. [00366] Step B: rac-(1*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hex-2-ene-6- carbonitrile. To a solution of tert-butyl (rac-1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-2- hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.8 g, 5.10 mmol, 1.0 eq) in ACN (20 mL, 0.26M) was added p-TsOH monohydrate (970 mg, 5.10 mmol, 1.0 eq). The reaction was stirred at 50 °C for 1 h before being concentrated under reduced pressure to give rac-(1*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hex-2-ene-6-carbonitrile (TsOH salt, 2.0 g, 96% yield) as a white solid. MS (ESI): mass calcd. for C12H8ClFN2, 234.0; m/z found, 235.2 [M+H]+. [00367] Step C: rac-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6- carbonitrile. To a solution of rac-(1*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hex-2- ene-6-carbonitrile (TsOH salt, 2.0 g, 4.92 mmol, 1.0 eq) in MeOH (20 mL, 0.24M) was added sodium cyanoborohydride (618 mg, 9.83 mmol, 2.0 eq) and AcOH (3.0 mL). The reaction was stirred at 20 °C for 1 h before being quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford rac-((1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (1.0 g, 86% yield) as a yellow oil. MS (ESI): mass calcd. for C12H10ClFN2, 236.1; m/z found, 237.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.12 (br d, J = 1.1 Hz, 1H), 4.72 (d, J = 3.3 Hz, 1H), 3.37 - 3.22 (m, 2H), 2.52 (td, J = 6.8, 3.4 Hz, 1H), 2.21 (td, J = 6.8, 3.3 Hz, 1H), 1.74 (br t, J = 3.3 Hz, 1H). Intermediate 51: rac-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexane-6- carbonitrile.
Figure imgf000205_0001
203 QB\184200.00050\92364964.2 VVID-746PC [00368] The title compound was prepared in a manner analogous to Intermediate 50 using (2,3- difluorophenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H10F2N2, 220.1; m/z found, 221.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.21 (m, 1H), 7.15 - 7.07 (m, 2H), 4.67 (d, J = 3.0 Hz, 1H), 3.33 - 3.28 (m, 1H), 3.28 - 3.23 (m, 1H), 2.43 (dq, J = 3.4, 2.5 Hz, 1H), 2.22 (td, J = 6.8, 3.3 Hz, 1H), 1.92 (s, 1H), 1.73 (t, J = 3.3 Hz, 1H). Intermediate 52: rac-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-6- carbonitrile.
Figure imgf000206_0001
[00369] The title compound was prepared in a manner analogous to Intermediate 50 using (3-fluoro-2- methylphenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C13H13FN2, 216.1; m/z found, 217.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.36 - 7.29 (m, 1H), 7.28 - 7.19 (m, 1H), 7.14 - 7.02 (m, 1H), 4.33 (br s, 1H), 3.13 - 3.02 (m, 1H), 3.00 - 2.88 (m, 1H), 2.44 (br d, J = 2.0 Hz, 1H), 2.39 (td, J = 6.6, 3.3 Hz, 1H), 2.29 (d, J = 2.1 Hz, 3H), 2.21 (td, J = 6.6, 3.2 Hz, 1H), 1.84 (t, J = 3.4 Hz, 1H). Intermediate 53: rac-((1*S,2*S,5*R,6*S)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6- carbonitrile.
Figure imgf000206_0002
[00370] The title compound was prepared in a manner analogous to Intermediate 50 using 3-chloro-2- iodopyridine and isopropylmagnesium chloride·LiCl instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C11H10ClN3, 219.1; m/z found, 220.0 [M+H]+. Intermediate 54: tert-Butyl rac-(1*R,5*S,6*S)-6-(cyanomethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate.
Figure imgf000206_0003
[00371] To a solution of tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (2.0 g, 9.38 mmol, 1.0 eq) in DMF (80 mL, 0.12M) under N2 was added 1,2-diiodoethane (3.2 g, 11.2 mmol, 1.2 eq) and triphenylphosphine (2.9 g, 11.2 mmol, 1.2 eq). When the solid was dissolved 204 QB\184200.00050\92364964.2 VVID-746PC completely, potassium carbonate (3.9 g, 28.1 mmol, 3.0 eq) and trimethylsilyl cyanide (3.7 g, 37.5 mmol, 4.0 eq) was added. The reaction was stirred at 15 °C under N2 for 12 h before being quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE:EtOAc = 2:1) to give tert-butyl exo-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.8 g, 85% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.70 - 3.55 (m, 2H), 3.40 - 3.29 (m, 2H), 2.59 - 2.30 (m, 2H), 1.53 (t, J = 2.8 Hz, 2H), 1.44 (s, 9H), 0.97 - 0.89 (m, 1H). [00372] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl exo-6- (cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.90 - 3.76 (m, 2H), 2.75 (dd, J = 17.4, 5.1 Hz, 1H), 2.43 (dd, J = 17.5, 6.8 Hz, 1H), 2.13 - 2.07 (m, 1H), 2.02 - 1.95 (m, 1H), 1.51 (s, 9H), 1.47 - 1.41 (m, 1H). Intermediate 55: 2-(rac-(1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6- yl)acetonitrile.
Figure imgf000207_0001
[00373] The title compound was prepared in a manner analogous to Intermediate 50 using tert-butyl rac- (1*R,5*S,6*S)-6-(cyanomethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 54) instead of tert-butyl rac-(1*S,5*S,6*S)-6-cyano-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.8 Hz, 1H), 7.36 - 7.22 (m, 2H), 4.45 - 4.35 (m, 2H), 3.19 - 3.13 (m, 2H), 3.02 - 2.96 (m, 2H), 1.56 (td, J = 6.8, 3.4 Hz, 1H), 1.37 - 1.31 (m, 1H), 1.18 - 1.14 (m, 1H). Intermediate 56: tert-Butyl rac-(1*R,5*R)-1-cyano-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000207_0002
[00374] To a solution of rac-3-azabicyclo[3.1.0]hexane-1-carbonitrile (500 mg, 2.64 mmol, 1.0 eq) and Boc2O (693 mg, 3.17 mmol, 1.2 eq) in MeOH (5.0 mL, 0.5M) was added sodium carbonate (841 mg, 7.93 mmol, 3.0 eq). The reaction was stirred at rt for 16 h before being quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give crude tert-butyl rac-(1*R,5*R)-1-cyano-3- azabicyclo[3.1.0]hexane-3-carboxylate (550 mg, quant. yield) as a colorless oil. 205 QB\184200.00050\92364964.2 VVID-746PC [00375] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (1*R,5*R)-1-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 4.05 - 3.98 (m, 1H), 3.97 (d, J = 1.0 Hz, 1H), 2.64 - 2.57 (m, 1H), 1.91 - 1.84 (m, 2H), 1.52 (s, 9H). Intermediate 57: rac-(1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-1- carbonitrile.
Figure imgf000208_0001
[00376] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*R)-1-cyano-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 56) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 1H), 7.23 (td, J = 8.0, 5.4 Hz, 1H), 7.11 (td, J = 8.4, 1.5 Hz, 1H), 4.82 (d, J = 3.5 Hz, 1H), 3.50 - 3.36 (m, 2H), 2.53 (ddd, J = 8.4, 5.0, 3.6 Hz, 1H), 1.43 (t, J = 5.3 Hz, 1H), 1.16 (dd, J = 8.3, 5.4 Hz, 1H). Intermediate 58: tert-Butyl 2-oxo-3-azabicyclo[3.1.1]heptane-3-carboxylate.
Figure imgf000208_0002
[00377] The title compound was prepared in a manner analogous to Intermediate 56 using 3- azabicyclo[3.1.1]heptane instead of rac-3-azabicyclo[3.1.0]hexane-1-carbonitrile in Step A. 1H NMR (400 MHz, CDCl3) δ 3.73 (d, J = 2.4 Hz, 2H), 2.88 (q, J = 5.8 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.39 - 2.29 (m, 2H), 1.75 - 1.67 (m, 2H), 1.55 (s, 9H). Intermediate 59: 2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptane.
Figure imgf000208_0003
[00378] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 2-oxo- 3-azabicyclo[3.1.1]heptane-3-carboxylate (Intermediate 58) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2- chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13ClFN, 225.1; m/z 206 QB\184200.00050\92364964.2 VVID-746PC found, 226.2 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.51 - 7.39 (m, 2H), 7.38 - 7.32 (m, 1H), 5.15 (s, 1H), 3.58 (s, 2H), 2.81 - 2.72 (m, 1H), 2.64 - 2.54 (m, 2H), 2.51 - 2.42 (m, 1H), 1.95 (dd, J = 10.6, 8.5 Hz, 1H), 1.81 - 1.71 (m, 1H). Intermediate 60: tert-Butyl 2-oxo-6-oxa-3-azabicyclo[3.1.1]heptane-3-carboxylate. Boc
Figure imgf000209_0001
O [00379] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl 6-oxa- 3-azabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3- carboxylate. 1H NMR (400 MHz, CDCl3) δ 4.91 (td, J = 6.7, 3.5 Hz, 1H), 4.51 (dd, J = 6.6, 3.7 Hz, 1H), 4.07 (dd, J = 12.7, 3.1 Hz, 1H), 3.80 (d, J = 12.8 Hz, 1H), 3.42 (td, J = 9.5, 6.8 Hz, 1H), 2.16 (d, J = 9.6 Hz, 1H), 1.58 (s, 9H). Intermediate 61: rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane.
Figure imgf000209_0002
[00380] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 2-oxo- 6-oxa-3-azabicyclo[3.1.1]heptane-3-carboxylate (Intermediate 60) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2- chloro-4-fluorophenyl)magnesium bromide in Step A. (4-(Aminomethyl)oxetan-2-yl)(2-chloro-3- fluorophenyl)methanol was isolated from Step C as the first eluting product of RP-HPLC (5-35% ACN in 0.1% aq. TFA). 1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 7.9 Hz, 1H), 7.33 (dt, J = 8.0, 5.4 Hz, 1H), 7.24 - 7.12 (m, 1H), 5.11 (d, J = 2.3 Hz, 1H), 5.02 - 4.88 (m, 2H), 3.28 (d, J = 5.0 Hz, 1H), 3.23 - 3.16 (m, 1H), 2.81 - 2.71 (m, 2H). [00381] Step D: To a solution of (4-(aminomethyl)oxetan-2-yl)(2-chloro-3-fluorophenyl)methanol (220 mg, 0.895 mmol, 1.0 eq) in toluene (1.0 mL, 0.9M) was added triphenylphosphine (470 mg, 1.79 mmol, 2.0 eq) at 0 °C. The solution was stirred at 0 °C for 10 min before addition of DEAD (311 mg, 1.79 mmol, 2.0 eq). The reaction was stirred at 50 °C for 16 h. After cooling to rt, the mixture was acidified with TFA to pH = 5 then extracted with EtOAc. The aqueous phase was concentrated under reduced pressure to give rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (50 mg, 25% yield) as a colorless oil. MS (ESI): mass calcd. for C11H11ClFNO, 227.1; m/z found, 228.2 [M+H]+. Intermediate 62: tert-Butyl rac-(1*S,5*S,6*S)-6-(2-hydroxypropan-2-yl)-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate. 207 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000210_0001
[00382] tert-Butyl exo-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 4.44 mmol, 1.0 eq) in THF (10 mL, 0.44M) was placed under N2 and cooled to 0 °C. To the mixture was added methylmagnesium bromide (3.7 mL, 11.1 mmol, 2.5 eq, 3M in THF) dropwise. The reaction was allowed to warm to rt over 2 h before being poured into sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (0-50% EtOAc in PE) to afford tert-butyl exo-6-(2-hydroxypropan-2-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 93% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.66 - 3.44 (m, 2H), 3.43 - 3.26 (m, 2H), 1.53 (br t, J = 3.0 Hz, 2H), 1.45 (s, 9H), 1.26 - 1.20 (m, 6H), 0.74 (t, J = 3.8 Hz, 1H). [00383] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl exo-6- (2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.87 - 3.78 (m, 1H), 3.74 - 3.67 (m, 1H), 2.09 - 2.06 (m, 1H), 1.97 (dt, J = 6.0, 4.3 Hz, 1H), 1.51 (s, 9H), 1.32 (d, J = 6.5 Hz, 6H), 1.25 - 1.22 (m, 1H). Intermediate 63: 2-(rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6- yl)propan-2-ol.
Figure imgf000210_0002
[00384] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-(2-hydroxypropan-2-yl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 62) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C14H17ClFNO, 269.1; m/z found, 270.1 [M+H]+. Intermediate 64: tert-Butyl rac-(1*S,5*S,6*S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000210_0003
208 QB\184200.00050\92364964.2 VVID-746PC [00385] To a solution of tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (500 mg, 2.34 mmol, 1.0 eq) in DCM (10 mL, 0.2M) was added imidazole (319 mg, 4.69 mmol, 2.0 eq) and tert-butyl chlorodimethylsilane (707 mg, 4.69 mmol, 2.0 eq). The reaction was stirred at 25 °C for 5 h before being diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE:EtOAc = 1:9) to give tert-butyl rac-(1*R,5*S,6r)-6-(((tert- butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (760 mg, quant. yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.56 (br d, J = 6.9 Hz, 4H), 3.34 (br d, J = 10.5 Hz, 2H), 1.44 (s, 9H), 1.43 - 1.40 (m, 2H), 0.89 (s, 9H), 0.87 - 0.81 (m, 1H), 0.05 (s, 6H). [00386] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (1*R,5*S,6r)-6-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.85 - 3.77 (m, 2H), 3.75 - 3.71 (m, 1H), 3.59 (dd, J = 10.8, 4.9 Hz, 1H), 1.99 (dd, J = 6.2, 1.3 Hz, 1H), 1.94 - 1.87 (m, 1H), 1.51 (s, 9H), 1.37 - 1.31 (m, 1 H), 0.88 (s, 9H), 0.05 (s, 6H). Intermediate 65: rac-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-
Figure imgf000211_0001
[00387] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 64) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.8 Hz, 1H), 7.36 - 7.22 (m, 2H), 4.45 - 4.35 (m, 2H), 3.19 - 3.13 (m, 2H), 3.02 - 2.96 (m, 2H), 1.56 (td, J = 6.8, 3.4 Hz, 1H), 1.37 - 1.31 (m, 1H), 1.18 - 1.14 (m, 1H). Intermediate 66: tert-Butyl rac-(1*S,5*S,6*S)-6-(methoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate.
Figure imgf000211_0002
[00388] A solution of tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (3.0 g, 14.1 mmol, 1.0 eq) in THF (30 mL, 0.47M) was degassed and purged with N2. NaH (1.1 g, 28.1 mmol, 2.0 eq, 60% in mineral oil) was added to the solution at 0 °C portionwise. The solution 209 QB\184200.00050\92364964.2 VVID-746PC was stirred at 25 °C for 40 min before iodomethane (4.4 g, 30.9 mmol, 2.2 eq) was added. The reaction was stirred at 25 °C for 12 h before being quenched with NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl rac- (1*R,5*S,6r)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 94% yield) as a yellow oil. [00389] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (1*R,5*S,6r)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6- difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.88 - 3.70 (m, 2H), 3.51 (dd, J = 10.4, 5.3 Hz, 1H), 3.34 (s, 3H), 3.21 (dd, J = 10.4, 6.6 Hz, 1H), 2.00 - 1.94 (m, 1H), 1.92 - 1.85 (m, 1H), 1.50 (s, 9H), 1.42 (br dd, J = 5.4, 2.7 Hz, 1H). Intermediate 67: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000212_0001
[00390] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-(methoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 66) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 7.15 (td, J = 8.0, 5.4 Hz, 1H), 6.99 (td, J = 8.5, 1.4 Hz, 1H), 4.60 (d, J = 3.6 Hz, 1H), 3.15 - 3.22 (m, 7H), 1.98 (s, 1H), 1.64 (dt, J = 6.8, 3.5 Hz, 1H), 1.43 (dt, J = 6.7, 3.3 Hz, 1H), 1.33 (tt, J = 6.8, 3.4 Hz, 1H). Intermediate 68: rac-(1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000212_0002
[00391] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-(methoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 66) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for 210 QB\184200.00050\92364964.2 VVID-746PC C13H15F2NO, 239.1; m/z found, 240.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.36 (m, 1H), 7.19 - 7.03 (m, 2H), 4.68 (d, J = 3.5 Hz, 1H), 4.41 (br s, 1H), 3.37 - 3.23 (m, 7H), 1.73 (td, J = 6.7, 3.4 Hz, 1H), 1.58 (td, J = 6.7, 3.3 Hz, 1H), 1.38 (qd, J = 6.8, 3.4 Hz, 1H). Intermediate 69: tert-Butyl rac-(1*S,5*S,6*S)-6-((methoxy-d3)methyl)-2-oxo-3-azabicyclo[3.1.0]hexane- 3-carboxylate.
Figure imgf000213_0001
[00392] The title compound was prepared in a manner analogous to Intermediate 66 using iodomethane-d3 instead of iodomethane in Step A. 1H NMR (400 MHz, CDCl3) δ 3.86 - 3.71 (m, 2H), 3.51 (dd, J = 10.4, 5.3 Hz, 1H), 3.21 (dd, J = 10.4, 6.7 Hz, 1H), 1.99 - 1.94 (m, 1H), 1.89 (br d, J = 3.8 Hz, 1H), 1.50 (s, 9H), 1.42 (br dd, J = 5.6, 2.9 Hz, 1H). Intermediate 70: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000213_0002
[00393] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-((methoxy-d3)methyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 69) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C13H12D3ClFNO, 258.1; m/z found, 259.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.80 - 7.74 (m, 1H), 7.57 - 7.46 (m, 2H), 5.25 (br d, J = 3.4 Hz, 1H), 3.61 (br dd, J = 11.4, 3.9 Hz, 1H), 3.49 - 3.37 (m, 2H), 3.26 (dd, J = 10.3, 7.4 Hz, 1H), 2.02 (td, J = 7.1, 3.7 Hz, 1H), 1.85 (td, J = 7.1, 3.6 Hz, 1H), 1.58 - 1.47 (m, 1H). Intermediate 71: tert-Butyl rac-(1*R,5*R)-1-(methoxymethyl)-4-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate.
Figure imgf000213_0003
[00394] The title compound was prepared in a manner analogous to Intermediate 66 using tert-butyl rac- (1*R,5*R)-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl rac- 211 QB\184200.00050\92364964.2 VVID-746PC (1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. The above regioisomer was recovered as the second eluting product from Step B, FCC (25-50% EtOAc in PE). 1H NMR (400 MHz, CDCl3) δ 3.83 - 3.71 (m, 2H), 3.53 - 3.43 (m, 2H), 3.38 (s, 3H), 1.98 - 1.92 (m, 1H), 1.50 (s, 9H), 1.26 (dd, J = 8.8, 5.1 Hz, 1H), 1.01 (dd, J = 4.7, 3.6 Hz, 1H). Intermediate 72: rac-(1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000214_0001
[00395] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*R)-1-(methoxymethyl)-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 71) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C13H15ClFNO, 255.1; m/z found, 256.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 1H), 7.22 (dt, J = 8.0, 5.4 Hz, 1H), 7.10 - 7.03 (m, 1H), 4.75 (d, J = 3.4 Hz, 1H), 3.61 (d, J = 10.4 Hz, 1H), 3.48 (d, J = 10.4 Hz, 1H), 3.40 (s, 3H), 3.26 (s, 2H), 2.20 - 2.08 (m, 1H), 1.70 (td, J = 7.8, 3.8 Hz, 1H), 0.99 (t, J = 4.4 Hz, 1H), 0.56 (dd, J = 8.0, 5.0 Hz, 1H). Intermediate 73: tert-Butyl rac-(1*S,5*R)-1-(methoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate.
Figure imgf000214_0002
[00396] The title compound was prepared in a manner analogous to Intermediate 66 using tert-butyl rac- (1*R,5*R)-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl rac- (1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. The above regioisomer was recovered as the first eluting product from Step B, FCC (25-50% EtOAc in PE). 1H NMR (400 MHz, CDCl3) δ 4.09 (d, J = 10.8 Hz, 1H), 3.80 - 3.75 (m, 1H), 3.70 - 3.62 (m, 1H), 3.36 (s, 3H), 3.27 (d, J = 10.6 Hz, 1H), 1.99 (td, J = 8.1, 5.0 Hz, 1H), 1.51 (s, 9H), 1.25 - 1.18 (m, 1H), 0.88 (t, J = 4.7 Hz, 1H). Intermediate 74: rac-(1*S,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3- azabicyclo[3.1.0]hexane. 212 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000215_0001
[00397] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*R)-1-(methoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 73) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 1H), 7.22 (dt, J = 8.0, 5.5 Hz, 1H), 7.07 (dt, J = 8.5, 1.4 Hz, 1H), 4.79 (s, 1H), 3.67 - 3.60 (m, 1H), 3.32 (d, J = 10.4 Hz, 1H), 3.29 (s, 3H), 3.26 (d, J = 3.5 Hz, 1H), 3.13 (d, J = 9.6 Hz, 1H), 1.51 (td, J = 7.9, 3.9 Hz, 1H), 1.10 (t, J = 4.6 Hz, 1H), 0.65 (dd, J = 7.9, 5.1 Hz, 1H). Intermediate 75: tert-Butyl rac-(1*S,5*S,6*S)-6-((difluoromethoxy)methyl)-2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000215_0002
[00398] A solution of tert-butyl exo-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 14.1 mmol, 1.0 eq) and CuI (536 mg, 2.81 mmol, 0.2 eq) in ACN (60 mL, 0.2M) was placed under N2 and heated to 45 °C. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (5.0 g, 28.1 mmol, 2.0 eq) was added dropwise to the mixture over 30 min and the reaction was stirred for 0.5 h at 45 °C. The mixture was concentrated under vacuum then diluted with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC (0-10% EtOAc in PE) to give tert-butyl exo-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, 54% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.21 (t, J = 74.7 Hz, 1H), 3.87 - 3.51 (m, 4H), 3.36 (br d, J = 10.5 Hz, 2H), 1.54 - 1.41 (m, 11H), 1.07 - 0.94 (m, 1H). The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl exo-6- ((difluoromethoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 6.21 (t, J = 73.7 Hz, 1H), 4.00 - 3.67 (m, 4H), 2.04 (br s, 1H), 1.97 - 1.91 (m, 1H), 1.59 (s, 1H), 1.51 (s, 9H). Intermediate 76: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexane. 213 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000216_0001
[00399] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-((difluoromethoxy)methyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 75) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.8 Hz, 1H), 7.23 (dt, J = 8.0, 5.5 Hz, 1H), 7.07 (dt, J = 8.5, 1.4 Hz, 1H), 6.17 (t, J = 74.9 Hz, 1H), 4.67 (d, J = 3.5 Hz, 1H), 3.72 (d, J = 7.3 Hz, 2H), 3.29 - 3.19 (m, 2H), 1.79 (td, J = 6.8, 3.3 Hz, 1H), 1.56 (td, J = 6.5, 3.0 Hz, 1H), 1.52 - 1.45 (m, 1H). Intermediate 77: rac-(1*S,2*S,5*R,6*S)-6-((Difluoromethoxy)methyl)-2-(3-fluoro-2-methylphenyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000216_0002
[00400] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-((difluoromethoxy)methyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 75) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (3-fluoro-2- methylphenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C14H16F3NO, 271.3; m/z found, 272.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.15 - 7.07 (m, 1H), 6.88 - 6.43 (m, 1H), 4.57 (br s, 1H), 3.80 (dq, J = 11.1, 7.3 Hz, 2H), 3.12 (br s, 2H), 2.28 (d, J = 2.0 Hz, 3H), 1.83 - 1.72 (m, 1H), 1.62 (br s, 1H), 1.49 - 1.37 (m, 1H). Intermediate 78: tert-Butyl rac-(1*S,5*S,6*S)-6-(cyclopropoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane- 3-carboxylate.
Figure imgf000216_0003
[00401] Step A: tert-Butyl exo-(1*R,5*S)-6-(vinyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a mixture of tert-butyl exo-(1*R,5*S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.938 mmol, 1.0 eq) in ethyl vinyl ether (4.0 mL) was added palladium(II) acetate (8.4 mg, 0.037 mmol, 0.04 eq) and 2,2'-bipyridine (5.9 mg, 0.037 mmol, 0.04 eq). The reaction was purged with N2 and 214 QB\184200.00050\92364964.2 VVID-746PC stirred at 50 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl exo- (1*R,5*S)-6-(vinyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 53% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.46 (dd, J = 14.4, 6.8 Hz, 1H), 4.16 (dd, J = 14.4, 1.7 Hz, 1H), 4.00 (dd, J = 6.7, 1.8 Hz, 1H), 3.71 - 3.46 (m, 4H), 3.36 (br t, J = 9.0 Hz, 2H), 1.49 (br s, 2H), 1.44 (s, 9H), 1.01 (tt, J = 6.8, 3.2 Hz, 1H). [00402] Step B: tert-Butyl exo-(1*R,5*S)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate. A solution of diethylzinc (2.0 mL, 2.01 mmol, 4.0 eq) in DCM (2.0 mL, 0.13M) was placed under N 2 and cooled to 0 °C. Diiodomethane (671 mg, 2.51 mmol, 5.0 eq) in DCM (1.0 mL, 0.13M) was added dropwise and the mixture was stirred at 0 °C for 30 min. tert-Butyl exo-(1*R,5*S)-6- (vinyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 0.501 mmol, 1.0 eq) in DCM (1.0 mL, 0.13M) was added to the mixture and the reaction was stirred at 25 °C for 2 h. The mixture was quenched with sat. aq. NH4Cl and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-30% EtOAc in PE) to give tert-butyl exo-(1*R,5*S)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 79% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.69 - 3.42 (m, 3H), 3.39 - 3.25 (m, 4H), 1.46 - 1.39 (m, 11H), 0.97 - 0.88 (m, 1H), 0.60 - 0.53 (m, 2H), 0.50 - 0.43 (m, 2H). [00403] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl exo- (1*R,5*S)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6- difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.84 - 3.71 (m, 2H), 3.61 (dd, J = 10.6, 5.5 Hz, 1H), 3.36 - 3.25 (m, 2H), 1.96 (dd, J = 6.3, 1.6 Hz, 1H), 1.91 - 1.83 (m, 1H), 1.50 (s, 9H), 1.43 (dt, J = 6.1, 3.1 Hz, 1H), 0.59 - 0.52 (m, 2H), 0.51 - 0.44 (m, 2H). Intermediate 79: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000217_0001
[00404] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-(cyclopropoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 78) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C15H17ClFNO, 281.1; m/z found, 282.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.56 215 QB\184200.00050\92364964.2 VVID-746PC (d, J = 7.9 Hz, 1H), 7.23 (dt, J = 8.0, 5.5 Hz, 1H), 7.08 (dt, J = 8.5, 1.5 Hz, 1H), 4.73 (d, J = 3.5 Hz, 1H), 3.38 (d, J = 6.9 Hz, 2H), 3.31 - 3.24 (m, 2H), 3.20 (tt, J = 6.0, 3.0 Hz, 1H), 1.74 (td, J = 6.8, 3.5 Hz, 1H), 1.53 (td, J = 6.6, 3.1 Hz, 1H), 1.46 (dt, J = 6.8, 3.3 Hz, 1H), 0.55 - 0.46 (m, 2H), 0.45 - 0.37 (m, 2H). Intermediate 80: rac-(1*S,5*R,6*S)-3-(tert-Butoxycarbonyl)-2-oxo-3-azabicyclo[3.1.0]hexane-6- carboxylic acid.
Figure imgf000218_0001
[00405] The title compound was prepared in a manner analogous to Intermediate 3 using rac-(1*R,5*S,6r)- 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.95 - 3.88 (m, 1H), 3.86 - 3.79 (m, 1H), 2.62 - 2.56 (m, 1H), 2.45 (td, J = 5.9, 3.3 Hz, 1H), 1.94 (t, J = 2.9 Hz, 1H), 1.52 (s, 9H). Intermediate 81: rac-(1*S,2*S,5*R,6*S)-3-tert-Butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid.
Figure imgf000218_0002
[00406] The title compound was prepared in a manner analogous to Intermediate 24 using rac- (1*S,5*R,6*S)-3-(tert-butoxycarbonyl)-2-oxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 80) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A to provide rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid. MS (ESI): mass calcd. for C12H11ClFNO2, 255.1; m/z found, 256.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.52 - 7.45 (m, 1H), 7.39 (dt, J = 8.0, 5.7 Hz, 1H), 7.34 - 7.29 (m, 1H), 4.55 (d, J = 3.3 Hz, 1H), 3.18 - 3.05 (m, 2H), 2.19 (td, J = 6.7, 3.2 Hz, 1H), 1.96 (td, J = 6.6, 3.1 Hz, 1H), 1.67 (t, J = 2.9 Hz, 1H). [00407] Step D: rac-(1*S,2*S,5*R,6*S)-3-tert-Butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid. To a solution of rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (320 mg, 1.25 mmol, 1.0 eq) in DCM (5.0 mL, 0.25M) was added Boc2O (410 mg, 1.88 mmol, 1.5 eq) and TEA (253 mg, 2.50 mmol, 2.0 eq) at 0 ℃. The reaction was stirred at 15 ℃ for 3 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give rac-(1*S,2*S,5*R,6*S)-3-tert-butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid (440 mg, quant. yield) as a yellow oil. MS (ESI): mass calcd. 216 QB\184200.00050\92364964.2 VVID-746PC for C17H19ClFNO4, 355.1; m/z found, 299.9 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.17 (m, 1H), 7.15 - 7.08 (m, 1H), 7.00 (br t, J = 8.3 Hz, 1H), 5.46 - 5.43 (m, 1H), 3.85 - 3.78 (m, 2H), 2.56 (br s, 1H), 2.37 - 2.25 (m, 1H), 2.20 - 2.07 (m, 1H), 1.54 (s, 9H). Intermediate 82: rac-(1*S,2*S,5*R,6*S)-3-tert-Butoxycarbonyl-2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid.
Figure imgf000219_0001
[00408] The title compound was prepared in a manner analogous to Intermediate 81 using (2,3- difluorophenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C17H19F2NO4, 339.1; m/z found, 284.1 [M+2H-tBu]+. Intermediate 83: rac-(1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3- azabicyclo[3.1.0]hexane.
Figure imgf000219_0002
[00409] Step A: tert-Butyl rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of rac- (1*S,2*S,5*R,6*S)-3-tert-butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6- carboxylic acid (Intermediate 81, 220 mg, 0.618 mmol, 1.0 eq) in toluene (6.0 mL, 0.1M) was added TEA (400 mg, 3.09 mmol, 5.0 eq) and diphenyl phosphoryl azide (255 mg, 0.928 mmol, 1.5 eq). The reaction was stirred at 86 °C for 2 h. The mixture was cooled to 15 °C before MeOH (396 mg, 12.4 mmol, 20 eq) was added. The reaction was stirred at 86 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (40- 70% ACN in 10 mM aq. NH4HCO3) to give tert-butyl rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)- 6-((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 8% yield) as a white solid. MS (ESI): mass calcd. for C18H22ClFN2O4, 384.1; m/z found, 328.9 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.01 (m, 3H), 5.41 (br d, J = 5.3 Hz, 1H), 4.67 - 4.50 (m, 1H), 3.83 (br s, 2H), 3.56 (br s, 3H), 2.30 (br d, J = 3.6 Hz, 2H), 1.93 (br s, 1H), 1.33 - 0.97 (m, 9H). [00410] Step B: tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)(nitroso)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of tert-butyl 217 QB\184200.00050\92364964.2 VVID-746PC rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxycarbonyl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.260 mmol, 1.0 eq) in DCM (3.0 mL, 0.09M) was added tert-butyl nitrite (268 mg, 2.60 mmol, 10 eq). The reaction was stirred at 15 °C for 1 h before being evaporated under N2. tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)(nitroso)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 93% yield) was obtained as a colorless oil. MS (ESI): mass calcd. for C18H21ClFN3O5, 413.1; m/z found, 358.0 [M+2H- tBu]+. [00411] Step C: tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3- azabicyclo[3.1.0]hexane-3-carboxylate. tert-Butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6- ((methoxycarbonyl)(nitroso)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.242 mmol, 1.0 eq) was taken up in anhydrous MeOH (2.0 mL, 0.1M). To this was added potassium carbonate (334 mg, 2.42 mmol, 10 eq) and the reaction was stirred at 15 °C for 15 min. The mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 3:1) to give tert-butyl rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 36% yield) as a colorless oil. MS (ESI): mass calcd. for C17H21ClFNO3, 341.1; m/z found, 286.0 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.20 (dt, J = 8.0, 5.4 Hz, 1H), 7.13 - 6.98 (m, 1H), 6.92 - 6.78 (m, 1H), 5.39 (br d, J = 5.8 Hz, 1H), 3.95 - 3.80 (m, 1H), 3.67 (br d, J = 11.3 Hz, 1H), 3.07 (s, 3H), 2.90 (br s, 1H), 2.44 - 2.25 (m, 1H), 1.93 (br t, J = 7.5 Hz, 1H), 1.47 - 1.08 (m, 9H). [00412] Step D: rac-(1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3- azabicyclo[3.1.0]hexane. To a solution of tert-butyl rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)- 6-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (15 mg, 0.044 mmol, 1.0 eq) in DCM (0.5 mL, 0.08M) was added TFA (50 µL). The reaction was stirred at 15 °C for 0.5 h before being evaporated under N2. rac- (1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexane (10 mg, 94% yield) was obtained as a colorless oil. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m/z found, 242.1 [M+H]+. Intermediate 84: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000220_0001
[00413] Step A: tert-Butyl rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate. Ir[dF(CF3)ppy]2(5,5’-dCF3bpy)PF6 (13 mg, 0.011 mmol, 0.02 eq), CuI•DMS (107 mg, 0.112 mmol, 0.2 eq), 2,2'-dipyridyl ketone (31 mg, 0.169 mmol, 0.3 eq), rac- (1*S,2*S,5*R,6*S)-3-tert-butoxycarbonyl-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6- 218 QB\184200.00050\92364964.2 VVID-746PC carboxylic acid (Intermediate 81, 200 mg, 0.560 mmol, 1.0 eq) and 1,3-dihydro-3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (232 mg, 0.703 mmol, 1.25 eq) were combined. Ethyl acetate (22 mL, 0.03M) was added followed by addition of tert-butylimino-tri(pyrrolidino)phosphorane (88 mg, 0.281 mmol, 0.5 eq) and water (304 mg, 16.9 mmol, 30 eq). The reaction was purged with nitrogen, sonicated, and wrapped with parafilm before being stirred and irradiated using 34 W blue LED lamps at 20 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by RP-HPLC (50-80% ACN in 10 mM aq. NH4HCO3) to afford tert-butyl rac-(1*S,2*S,5*R,6*S)- 2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 42% yield) as a white solid. MS (ESI): mass calcd. for C17H18ClF4NO2, 379.1; m/z found, 324.0 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.15 (m, 1H), 7.11 - 7.01 (m, 1H), 6.89 (br d, J = 7.4 Hz, 1H), 5.44 (br d, J = 4.9 Hz, 1H), 3.92 - 3.71 (m, 2H), 2.53 (br d, J = 1.6 Hz, 1H), 2.13 (td, J = 7.8, 4.0 Hz, 1H), 1.48 - 1.01 (m, 10H). [00414] Step B: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane. tert-Butyl rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 0.132 mmol, 1.0 eq) was taken up in DCM/TFA (v/v 3:1, 0.40 mL, 0.3M). The reaction was stirred at 20 °C for 0.5 h before being concentrated in vacuo to afford rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane (TFA salt, 50 mg, 96% yield) as a yellow oil. This was used directly in the next step. MS (ESI): mass calcd. for C12H10ClF4N, 279.0; m/z found, 280.0 [M+H]+. Intermediate 85: rac-(1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000221_0001
[00415] The title compound was prepared in a manner analogous to Intermediate 84 using rac- (1*S,2*S,5*R,6*S)-3-tert-butoxycarbonyl-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 82) instead of rac-(1*S,2*S,5*R,6*S)-3-tert-butoxycarbonyl-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid in Step A. MS (ESI): mass calcd. for C12H10F5N, 263.1; m/z found, 264.0 [M+H]+. Intermediate 86: tert-Butyl rac-(1*S,5*S,6*S)-6-(dimethylcarbamoyl)-2-oxo-3-azabicyclo[3.1.0]hexane- 3-carboxylate. 219 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000222_0001
[00416] To a solution of rac-(1*S,5*R,6*S)-3-(tert-butoxycarbonyl)-2-oxo-3-azabicyclo[3.1.0]hexane-6- carboxylic acid (Intermediate 80, 3.0 g, 12.4 mmol, 1.0 eq) in DCM (30 mL, 0.4M) was added HATU (7.1 g, 18.7 mmol, 1.5 eq), DIPEA (4.8 g, 37.3 mmol, 3.0 eq), and dimethylamine (HCl salt, 2.0 g, 24.9 mmol, 2.0 eq). The reaction was stirred at 25 °C for 2 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (PE:EtOAc = 0:1) to give tert-butyl rac-(1*S,5*S,6*S)- 6-(dimethylcarbamoyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 30% yield) as a white solid. MS (ESI): mass calcd. for C13H20N2O4, 268.1; m/z found, 169.1 [M+2H-Boc]+. 1H NMR (400 MHz, CDCl3) δ 3.91 (dd, J = 11.8, 5.0 Hz, 1H), 3.80 - 3.73 (m, 1H), 3.17 (s, 3H), 2.97 (s, 3H), 2.51 - 2.41 (m, 2H), 2.03 (t, J = 2.9 Hz, 1H), 1.51 (s, 9H). Intermediate 87: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3- azabicyclo[3.1.0]hexane-6-carboxamide.
Figure imgf000222_0002
[00417] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*S,6*S)-6-(dimethylcarbamoyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 86) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C14H16ClFN2O, 282.1; m/z found, 283.1 [M+H]+. Intermediate 88: 2-(3-Fluoro-2-methoxyphenyl)pyrrolidine.
Figure imgf000222_0003
[00418] The title compound was prepared in a manner analogous to Intermediate 5, Steps B-E, using tert- butyl 2-oxopyrrolidine-1-carboxylate instead of tert-butyl 5-oxo-1,4-oxazepane-4-carboxylate and triflic anhydride instead of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide in Step B and using (3-fluoro-2-methoxyphenyl)boronic acid instead of (2-chlorophenyl)boronic acid in Step C. 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.15 (m, 1H), 7.06 – 6.86 (m, 2H), 4.43 (t, J = 7.8 Hz, 1H), 3.94 (d, J = 220 QB\184200.00050\92364964.2 VVID-746PC 1.9 Hz, 3H), 3.19 (ddd, J = 10.2, 7.3, 5.6 Hz, 1H), 3.10 - 2.96 (m, 1H), 2.22 (dt, J = 12.5, 7.7, 5.1 Hz, 1H), 1.98 - 1.78 (m, 2H), 1.63 (qd, J = 12.3, 8.3 Hz, 1H). Intermediate 89: tert-Butyl rac-(1*S,5*R,6*S)-6-(fluoromethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate.
Figure imgf000223_0001
[00419] To tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 4.69 mmol, 1.0 eq) in DCM (20 mL, 0.23M) was added DAST (1.5 g, 9.37 mmol, 2.0 eq) at 0 ℃. The reaction was stirred at 0 ℃ for 1 h before being poured into sat. aq. NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl rac- (1*R,5*S,6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (450 mg, 45% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.48 - 4.08 (m, 2H), 3.61 (br s, 2H), 3.37 (br d, J = 10.3 Hz, 2H), 1.54 (br s, 2H), 1.44 (s, 9H), 1.15 - 1.03 (m, 1H). [00420] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl rac- (1*R,5*S,6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro- 3-azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 4.60 - 4.37 (m, 1H), 4.35 - 4.12 (m, 1H), 3.90 - 3.74 (m, 2H), 2.09 - 2.03 (m, 1H), 2.01 - 1.93 (m, 1H), 1.66 (s, 1H), 1.61 - 1.45 (m, 9H). Intermediate 90: rac-(1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000223_0002
[00421] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*R,6*S)-6-(fluoromethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 89) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.33 (m, 1H), 7.14 - 7.06 (m, 2H), 4.73 - 4.63 (m, 1H), 4.39 - 4.13 (m, 2H), 3.31 - 3.25 (m, 2H), 1.83 (dt, J = 6.8, 3.4 Hz, 1H), 1.65 (br dd, J = 6.3, 2.7 Hz, 1H), 1.59 - 1.52 (m, 1H). Intermediate 91: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexane. 221 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000224_0001
[00422] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*R,6*S)-6-(fluoromethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 89) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H12ClF2N, 243.1; m/z found, 244.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.52 (br d, J = 7.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.12 - 7.04 (m, 1H), 4.70 (br s, 1H), 4.45 - 4.17 (m, 2H), 3.26 (s, 2H), 1.84 (br d, J = 3.8 Hz, 1H), 1.61 (br d, J = 4.6 Hz, 2H). Intermediate 92: rac-(1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000224_0002
[00423] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*R,6*S)-6-(fluoromethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 89) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (3-fluoro-2-methylphenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C13H15F2N, 223.1; m/z found, 224.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.20 - 7.13 (m, 1H), 7.00 (t, J = 8.9 Hz, 1H), 4.62 (t, J = 2.4 Hz, 1H), 4.35 (br dd, J = 9.6, 7.5 Hz, 2H), 3.32 - 3.25 (m, 2H), 2.32 (d, J = 2.1 Hz, 3H), 1.83 - 1.76 (m, 1H), 1.70 - 1.65 (m, 1H), 1.60 (br dd, J = 7.0, 3.5 Hz, 1H). Intermediate 93: tert-Butyl rac-(1*S,5*R,6*S)-6-(difluoromethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-
Figure imgf000224_0003
[00424] The title compound was prepared in a manner analogous to Intermediate 89 using tert-butyl rac- (1*R,5*S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl rac-(1*R,5*S,6r)-6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. 1H NMR (400 MHz, CDCl3) δ 6.05 222 QB\184200.00050\92364964.2 VVID-746PC - 5.68 (m, 1H), 3.93 - 3.84 (m, 1H), 3.83 - 3.74 (m, 1H), 2.28 (dd, J = 6.6, 1.8 Hz, 1H), 2.22 - 2.14 (m, 1H), 1.68 - 1.58 (m, 1H), 1.51 (s, 9H). Intermediate 94: rac-(1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000225_0001
[00425] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*S,5*R,6*S)-6-(difluoromethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 93) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H11F4N, 245.1; m/z found, 246.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.25 (m, 2H), 7.23 - 7.14 (m, 1H), 5.80 (dt, J = 56.7, 5.9 Hz, 1H), 4.44 (br s, 1H), 3.08 - 2.94 (m, 2H), 2.66 (br s, 1H), 1.97 - 1.91 (m, 1H), 1.77 (td, J = 6.7, 3.1 Hz, 1H), 1.60 - 1.50 (m, 1H). Intermediate 95: tert-Butyl rac-(1*R,5*S,6*S)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate.
Figure imgf000225_0002
[00426] Step A: tert-Butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of tert-butyl exo-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 14.1 mmol, 1.0 eq) in DCM (20 mL, 0.7M) was added methanesulfonic anhydride (3.7 g, 21.1 mmol, 1.5 eq) and TEA (4.3 g, 42.2 mmol, 3.0 eq) at 0 ℃. The reaction was stirred at 20 ℃ for 6 h before being quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-50% EtOAc in PE) to give tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (3.3 g, 81% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.24 - 3.97 (m, 2H), 3.71 - 3.54 (m, 2H), 3.42 - 3.30 (m, 2H), 3.03 (s, 3H), 1.60 (s, 1H), 1.46 - 1.42 (m, 10H), 1.16 - 1.07 (m, 1H). [00427] Step B: tert-Butyl exo-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate. A solution of tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.3 g, 11.3 mmol, 1.0 eq) in THF (30 mL, 0.4M) was placed under N2. Lithium aluminum hydride (9.1 mL, 22.7 mmol, 2.0 eq, 2.5M in THF) was added dropwise to the solution at 0 ℃. The reaction was stirred at 20 ℃ for 0.5 h before being quenched with water and 15% aq. NaOH dropwise at 0 ℃. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (0-10% EtOAc in PE) to give tert-butyl exo- 223 QB\184200.00050\92364964.2 VVID-746PC 6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (700 mg, 31% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.52 (br s, 2H), 3.31 (br d, J = 10.6 Hz, 2H), 1.44 (s, 9H), 1.18 (br s, 2H), 1.02 (d, J = 6.1 Hz, 3H), 0.57 - 0.46 (m, 1H). [00428] The title compound was prepared in a manner analogous to Intermediate 3 using tert-butyl exo-6- methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 3.81 - 3.66 (m, 2H), 1.81 - 1.73 (m, 1H), 1.68 - 1.59 (m, 1H), 1.50 (s, 9H), 1.17 - 1.11 (m, 4H). Intermediate 96: rac-(1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane.
Figure imgf000226_0001
[00429] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*S,6*S)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 95) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13F2N, 209.1; m/z found, 210.2 [M+H]+. Intermediate 97: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3- azabicyclo[3.1.0]hexane.
Figure imgf000226_0002
[00430] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*S,6*S)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 95) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13ClFN, 225.1; m/z found, 226.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.12 - 7.06 (m, 1H), 4.69 (d, J = 3.6 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.85 - 2.76 (m, 1H), 1.52 (td, J = 6.7, 3.3 Hz, 1H), 1.32 (td, J = 6.5, 3.0 Hz, 1H), 1.09 - 1.01 (m, 4H). Intermediate 98: rac-(1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-methyl-3- azabicyclo[3.1.0]hexane. 224 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000227_0001
[00431] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*S,6*S)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 95) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (3-fluoro-2-methylphenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C13H16FN, 205.1; m/z found, 206.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.18 - 7.09 (m, 1H), 6.95 (t, J = 8.8 Hz, 1H), 4.38 (d, J = 3.3 Hz, 1H), 3.17 - 3.02 (m, 2H), 2.35 (d, J = 2.3 Hz, 3H), 1.58 - 1.40 (m, 1H), 1.35 - 1.29 (m, 1H), 1.25 (td, J = 6.4, 3.3 Hz, 1H), 1.11 (d, J = 6.0 Hz, 3H), 0.90 (dt, J = 6.1, 3.0 Hz, 1H). Intermediate 99: rac-(1*R,2*S,5*S,6*S)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexane.
Figure imgf000227_0002
[00432] The title compound was prepared in a manner analogous to Intermediate 31 using tert-butyl rac- (1*R,5*S,6*S)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 95) instead of tert- butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C11H13ClN2, 208.1; m/z found, 209.1 [M+H]+. Intermediate 100: tert-Butyl rac-(1*R,5*S,6*R)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate.
Figure imgf000227_0003
[00433] The title compound was prepared in a manner analogous to Intermediate 95 using tert-butyl endo- 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl exo-6-(hydroxymethyl)- 3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. 1H NMR (400 MHz, CDCl3) δ 3.85 (dd, J = 11.8, 6.5 Hz, 1H), 3.61 (d, J = 11.8 Hz, 1H), 2.10 (ddd, J = 8.9, 6.4, 1.5 Hz, 1H), 1.87 (q, J = 6.5 Hz, 1H), 1.52 (s, 9H), 1.41 (dd, J = 15.0, 8.3 Hz, 1H), 1.10 (d, J = 6.5 Hz, 3H). Intermediate 101: rac-(1*R,2*S,5*S,6*R)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane. 225 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000228_0001
[00434] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (1*R,5*S,6*R)-6-methyl-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 100) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13F2N, 209.1; m/z found, 210.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.35 (br t, J = 6.8 Hz, 1H), 7.10 - 6.99 (m, 2H), 4.88 (d, J = 4.3 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.22 (d, J = 10.0 Hz, 1H), 1.83 - 1.79 (m, 1H), 1.64 - 1.56 (m, 1H), 1.09 - 1.05 (m, 3H), 0.98 (br dd, J = 13.4, 6.6 Hz, 1H). Intermediate 102: 2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidine.
Figure imgf000228_0002
[00435] To a solution of 4-(trifluoromethyl)pyrrolidin-2-one (2.1 g, 13.7 mmol, 1.0 eq) in DCM (15 mL, 0.9M) was added DIPEA (7.2 mL, 41.2 mmol, 3.0 eq), DMAP (168 mg, 1.37 mmol, 0.1 eq) and Boc2O (3.3 g, 15.1 mmol, 1.1 eq). The reaction was stirred at 25 °C for 12 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (0-15% EtOAc in PE) to give tert- butyl 2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (1.2 g, 35% yield) as a colorless oil. MS (ESI): mass calcd. for C10H14F3NO3, 253.1; m/z found, 198.1 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 3.97 (dd, J = 11.8, 9.0 Hz, 1H), 3.83 (dd, J = 11.8, 6.3 Hz, 1H), 3.05 (br dd, J = 15.5, 7.9 Hz, 1H), 2.84 - 2.65 (m, 2H), 1.55 (s, 9H). [00436] The title compound was prepared in a manner analogous to Intermediate 24 using (2,3- difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide and tert- butyl 2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C11H10F5N, 251.1; m/z found, 252.0 [M+H]+. Intermediate 103: rac-(1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane. 226 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000229_0001
[00437] The title compound was prepared in a manner analogous to Intermediate 24 using (2,3- difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide and tert- butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3) instead of tert-butyl 2- oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C11H9F4N, 231.1; m/z found, 232.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.24 (br t, J = 6.8 Hz, 1H), 7.18 - 7.05 (m, 2H), 4.87 (br d, J = 2.8 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.44 - 3.33 (m, 1H), 2.48 - 2.38 (m, 1H), 2.31 (ddd, J = 13.6, 8.8, 4.4 Hz, 1H). Intermediate 104: rac-(1*R,2*S,5*S)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000229_0002
[00438] The title compound was prepared in a manner analogous to Intermediate 24 using (2- fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide and tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C11H10F3N, 213.1; m/z found, 214.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.47 (br t, J = 7.6 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.21 - 7.13 (m, 1H), 7.12 - 7.03 (m, 1H), 4.91 - 4.82 (m, 1H), 3.56 (br d, J = 12.4 Hz, 1H), 3.44 - 3.33 (m, 1H), 2.47 - 2.37 (m, 1H), 2.29 (ddd, J = 13.5, 9.0, 4.3 Hz, 1H), 1.77 (br s, 1H). Intermediate 105: rac-(1*R,2*S,5*S)-2-(3-Fluoro-2-methylphenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexane.
Figure imgf000229_0003
[00439] The title compound was prepared in a manner analogous to Intermediate 24 using (3-fluoro-2- methylphenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide and tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3) instead of tert-butyl 2-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C12H12F3N, 227.1; m/z found, 228.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.22 (m, 1H), 7.21 - 7.14 (m, 1H), 7.01 (t, J = 8.9 Hz, 227 QB\184200.00050\92364964.2 VVID-746PC 1H), 4.75 - 4.60 (m, 1H), 3.52 (d, J = 12.8 Hz, 1H), 3.39 - 3.25 (m, 1H), 2.37 (d, J = 2.4 Hz, 3H), 2.36 - 2.23 (m, 2H), 1.97 - 1.86 (m, 1H). Intermediate 106: rac-(1*R,2*S,5*S)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000230_0001
[00440] The title compound was prepared in a manner analogous to Intermediate 24 using (3-fluoro-2- methylphenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H14FN, 191.1; m/z found, 192.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.13 (dt, J = 6.1, 7.8 Hz, 1H), 6.95 (t, J = 8.8 Hz, 1H), 4.42 (d, J = 3.1 Hz, 1H), 3.19 - 3.02 (m, 2H), 2.36 (d, J = 2.3 Hz, 3H), 1.65 - 1.56 (m, 1H), 1.54 - 1.44 (m, 1H), 0.63 - 0.50 (m, 2H). Intermediate 107: rac-(1*R,2*S,5*S)-2-(2,6-Difluorophenyl)-3-azabicyclo[3.1.0]hexane.
Figure imgf000230_0002
[00441] The title compound was prepared in a manner analogous to Intermediate 31, Steps A-C, using 1,3- difluorobenzene instead of 2-bromo-3-chloropyridine in Step A. MS (ESI): mass calcd. for C11H11F2N, 195.1; m/z found, 196.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.01 - 6.78 (m, 2H), 5.77 (br s, 1H), 4.86 (d, J = 3.5 Hz, 1H), 3.36 - 3.21 (m, 2H), 1.89 - 1.81 (m, 1H), 1.70 - 1.62 (m, 1H), 0.91 - 0.80 (m, 1H), 0.67 (q, J = 7.6 Hz, 1H). Intermediate 108: 6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptane.
Figure imgf000230_0003
[00442] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 6-oxo- 5-azaspiro[2.4]heptane-5-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13ClFN, 225.1; m/z found, 226.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.8 Hz, 1H), 7.23 (dt, J = 8.0, 5.4 Hz, 1H), 7.08 - 6.98 (m, 1H), 4.81 (t, J = 7.5 Hz, 1H), 3.12 - 3.02 (m, 2H), 2.24 (dd, J = 12.4, 7.4 Hz, 1H), 1.72 (dd, J = 12.4, 7.6 Hz, 1H), 0.71 - 0.49 (m, 4H). 228 QB\184200.00050\92364964.2 VVID-746PC Intermediate 109: 6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptane.
Figure imgf000231_0001
[00443] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 6-oxo- 5-azaspiro[2.4]heptane-5-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C12H13F2N, 209.1; m/z found, 210.1 [M+H]+. Intermediate 110: 1-(2,3-Difluorophenyl)isoindoline.
Figure imgf000231_0002
[00444] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 1- oxoisoindoline-2-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C14H11F2N, 231.2; m/z found, 232.1 [M+H]+. Intermediate 111: 3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexane.
Figure imgf000231_0003
[00445] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl 3-oxo- 2-azabicyclo[3.1.0]hexane-2-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3- carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4- fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C11H11ClFN, 211.1; m/z found, 212.2 [M+H]+. Intermediate 112: rac-(1*S,3a*S,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)octahydropyrrolo[3,4- c]pyrrole. 229 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000232_0001
[00446] To a solution of tert-butyl rac-(3a*R,6a*S)-1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (2.8 g, 12.4 mmol, 1.0 eq) in DCM (30 mL, 0.4M) was added oxetan-3-one (2.7 g, 37.1 mmol, 3.0 eq) and AcOH (0.10 mL). The mixture was stirred at 20 °C for 2 h before sodium triacetoxyborohydride (7.9 g, 37.1 mmol, 3.0 eq) was added. The reaction was stirred at 20 °C for 16 h then poured into sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0- 5% MeOH in DCM) to give tert-butyl rac-(3a*R,6a*S)-5-(oxetan-3-yl)-1-oxohexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (2.0 g, 57% yield) as a yellow oil. MS (ESI): mass calcd. for C14H22N2O4, 282.2; m/z found, 283.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.70 - 4.66 (m, 2H), 4.60 (q, J = 5.8 Hz, 2H), 3.97 (dd, J = 11.0, 9.4 Hz, 1H), 3.61 (br t, J = 6.3 Hz, 1H), 3.53 (dd, J = 11.1, 3.6 Hz, 1H), 3.16 (br d, J = 8.6 Hz, 1H), 3.12 - 3.06 (m, 1H), 2.82 (ddd, J = 9.4, 6.4, 2.9 Hz, 1H), 2.72 (dd, J = 9.2, 1.4 Hz, 1H), 2.46 - 2.38 (m, 2H), 1.54 (s, 9H). [00447] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (3a*R,6a*S)-5-(oxetan-3-yl)-1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C15H18ClFN2O, 296.1; m/z found, 297.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.15 - 7.03 (m, 1H), 4.58 (q, J = 6.4 Hz, 2H), 4.54 - 4.48 (m, 1H), 4.47 - 4.37 (m, 2H), 3.41 (q, J = 6.2 Hz, 1H), 3.36 - 3.26 (m, 1H), 3.22 - 3.03 (m, 2H), 3.01 - 2.89 (m, 1H), 2.88 - 2.76 (m, 1H), 2.31 (dd, J = 8.8, 5.4 Hz, 1H), 2.24 - 2.11 (m, 1H), 1.77 (dd, J = 9.4, 5.8 Hz, 1H). Intermediate 113: rac-(1*S,3a*S,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2- trifluoroethyl)octahydropyrrolo[3,4-c]pyrrole.
Figure imgf000232_0002
[00448] To a solution of tert-butyl rac-(3a*R,6a*S)-1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (500 mg, 2.21 mmol, 1.0 eq) in DMF (5.0 mL, 0.4M) was added DIPEA (857 mg, 6.63 mmol, 3.0 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (615 mg, 2.65 mmol, 1.2 eq). The reaction was stirred at 20 °C for 16 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The 230 QB\184200.00050\92364964.2 VVID-746PC resulting residue was purified by FCC (0-50% EtOAc in PE) to give tert-butyl rac-(3a*R,6a*S)-1-oxo-5- (2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (300 mg, 44% yield) as a yellow oil. MS (ESI): mass calcd. for C13H19F3N2O3, 308.1; m/z found, 209.1 [M-Boc+H]+. 1H NMR (400 MHz, CDCl3) δ 3.95 (dd, J = 11.1, 8.9 Hz, 1H), 3.53 (dd, J = 11.2, 3.6 Hz, 1H), 3.30 (dd, J = 9.4, 1.6 Hz, 1H), 3.18 - 2.95 (m, 3H), 2.92 - 2.70 (m, 4H), 1.54 (s, 9H). [00449] The title compound was prepared in a manner analogous to Intermediate 24 using tert-butyl rac- (3a*R,6a*S)-1-oxo-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate and (2-chloro-3-fluorophenyl)magnesium bromide instead of (2-chloro-4-fluorophenyl)magnesium bromide in Step A. MS (ESI): mass calcd. for C14H15ClF4N2, 322.1; m/z found, 323.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.38 (br d, J = 7.9 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.11 - 7.04 (m, 1H), 4.37 (d, J = 6.9 Hz, 1H), 3.28 (dt, J = 15.1, 7.5 Hz, 2H), 3.15 - 3.10 (m, 1H), 3.08 - 3.04 (m, 2H), 2.95 - 2.87 (m, 2H), 2.85 (s, 1H), 2.46 - 2.41 (m, 2H), 1.96 (dd, J = 9.0, 6.4 Hz, 1H). Intermediate 114: (1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane.
Figure imgf000233_0001
[00450] Separation of Intermediate 30 via SFC (Stationary phase: AD (5x25 cm); Mobile phase: 11% MeOH/CO2 with 0.1% NH4OH; Rt = 3.83 min) provided the title compound. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C11H9ClF3N, 247.1; m/z found, 247.9 [M+H]+. Intermediate 115: (1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane.
Figure imgf000233_0002
[00451] Separation of Intermediate 30 via SFC (Stationary phase: AD (5x25 cm); Mobile phase: 11% MeOH/CO2 with 0.1% NH4OH; Rt = 4.84 min) provided the title compound. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C11H9ClF3N, 247.1; m/z found, 248.0 [M+H]+. Intermediate 116: rac-(1*R,2*S,5*S)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexane. 231 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000234_0001
[00452] The title compound was prepared in a manner analogous to Intermediate 31, Steps A-C, using 1- bromo-2-fluorobenzene instead of 2-bromo-3-chloropyridine in Step A. MS (ESI): mass calcd. for C11H12FN, 177.1; m/z found, 178.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.63 - 7.55 (m, 1H), 7.27 - 7.23 (m, 1H), 7.16 - 7.09 (m, 1H), 7.09 - 7.01 (m, 1H), 4.65 - 4.61 (m, 1H), 3.24 - 3.13 (m, 2H), 2.60 - 2.57 (m, 1H), 1.79 - 1.69 (m, 1H), 1.61 - 1.51 (m, 1H), 0.63 (q, J = 4.2 Hz, 1H), 0.60 - 0.51 (m, 1H). Intermediate 117: rac-(1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexane.
Figure imgf000234_0002
[00453] The title compound was prepared in a manner analogous to Intermediate 33 using tert-butyl rac- (1*S,5*S,6*S)-6-(methoxymethyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 66) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and methanesulfonyl anhydride instead of p-toluenesulfonyl chloride in Step C. Intermediate 118: rac-(1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3- azabicyclo[3.1.0]hexane-6-carboxamide.
Figure imgf000234_0003
[00454] The title compound was prepared in a manner analogous to Intermediate 33 using tert-butyl rac- (1*S,5*S,6*S)-6-(dimethylcarbamoyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 86) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. Intermediate 119: rac-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6- yl)methanol. 232 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000235_0001
[00455] The title compound was prepared in a manner analogous to Intermediate 33 using tert-butyl rac- (1*S,5*S,6*S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 64) instead of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and methanesulfonyl anhydride instead of p-toluenesulfonyl chloride in Step C. 1H NMR (400 MHz, DMSO- d6) δ 7.57 - 7.51 (m, 2H), 7.49 - 7.43 (m, 1H), 5.16 (s, 1H), 4.44 - 4.31 (m, 2H), 3.44 - 3.33 (m, 2H), 2.30 (td, J = 7.0, 3.6 Hz, 1H), 2.13 (dd, J = 6.8, 3.3 Hz, 1H), 1.61 (td, J = 7.2, 3.7 Hz, 1H). Intermediate 120: rac-(1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane.
Figure imgf000235_0002
[00456] Step A: (E)-1-(2-Chloro-3-fluorophenyl)-N-(4-methoxybenzyl)methanimine. To a solution of 2- chloro-3-fluorobenzaldehyde (10 g, 63.1 mmol, 1.0 eq) and 4-methoxybenzylamine (10 g, 75.7 mmol, 1.2 eq) in DCM (126 mL, 0.5M) was added MgSO4 (25 g, 212 mmol, 3.4 eq) and the reaction was stirred at 25 °C for 20 h. The mixture was filtered and concentrated to give (E)-1-(2-chloro-3-fluorophenyl)-N-(4- methoxybenzyl)methanimine (17 g, quant. yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.89 (br d, J = 7.8 Hz, 1H), 7.28 (br s, 1H), 7.27 - 7.16 (m, 3H), 6.91 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H), 3.86 - 3.74 (m, 3H). [00457] Step B: 3-(2-Chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylic acid. A solution of (E)-1-(2-chloro-3-fluorophenyl)-N-(4-methoxybenzyl)methanimine (9.0 g, 32.4 mmol, 1.0 eq) and 1,4-dioxane-2,6-dione (4.1 g, 35.6 mmol, 1.1 eq) in o-xylene (90 mL, 0.4M) was stirred at 140 °C for 6 h. After cooling to rt, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in methyl tert-butyl ether and washed with sat. aq. Na2CO3. The combined water phases were acidified with 2N HCl to pH 2. The product was extracted with EtOAc and the combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylic acid (8.8 g, 67% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.30 (m, 1H), 7.25 - 7.15 (m, 2H), 7.11 - 7.00 (m, 2H), 6.97 - 6.78 (m, 2H), 5.51 - 5.36 (m, 1H), 4.89 - 4.77 (m, 1H), 4.53 - 4.37 (m, 2H), 4.26 - 4.16 (m, 2H), 3.84 (s, 1H), 3.82 - 3.73 (m, 3H). [00458] Step C: Methyl 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2- carboxylate. To a solution of 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2- 233 QB\184200.00050\92364964.2 VVID-746PC carboxylic acid (8.8 g, 22.3 mmol, 1.0 eq) in MeOH (90 mL, 0.25M) was added conc. HCl (2.0 mL) and the reaction was stirred at 60 °C for 5 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (15- 30% EtOAc in PE) to give methyl 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2- carboxylate (3.7 g, 40% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (dt, J = 8.0, 5.4 Hz, 1H), 7.28 - 7.01 (m, 4H), 6.99 - 6.83 (m, 2H), 5.57 - 5.44 (m, 1H), 4.88 (dd, J = 17.2, 1.7 Hz, 1H), 4.71 - 4.36 (m, 2H), 4.32 - 4.25 (m, 1H), 3.82 (d, J = 11.4 Hz, 4H), 3.71 - 3.53 (m, 3H). [00459] Step D: 5-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4-methoxybenzyl)morpholin-3-one. A solution of methyl 3-(2-chloro-3-fluorophenyl)-4-(4-methoxybenzyl)-5-oxo-morpholine-2-carboxylate (3.5 g, 8.58 mmol, 1.0 eq) in THF (35 mL, 0.25M) was placed under N2. Sodium borohydride (812 mg, 21.5 mmol, 2.5 eq) was added in portions at 0 °C. The reaction was stirred at 40 °C for 12 h before being quenched with MeOH and concentrated under reduced pressure. The resulting residue was purified by FCC (50-100% EtOAc in PE) to give 5-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4- methoxybenzyl)morpholin-3-one (2.5 g, 76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.29 (m, 1H), 7.23 - 7.12 (m, 2H), 7.11 - 6.96 (m, 3H), 6.93 - 6.78 (m, 3H), 5.45 - 5.24 (m, 1H), 4.65 - 4.36 (m, 3H), 3.90 - 3.78 (m, 5H), 1.93 - 1.77 (m, 1H). [00460] Step E: 5-(2-Chloro-3-fluorophenyl)-6-(iodomethyl)-4-(4-methoxybenzyl)morpholin-3-one. To a solution of 5-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-4-(4-methoxybenzyl)morpholin-3-one (2.5 g, 6.58 mmol, 1.0 eq) in THF (25 mL, 0.26M) was added imidazole (1.5 g, 21.7 mmol, 3.3 eq), triphenylphosphine (3.8 g, 14.5 mmol, 2.2 eq), and iodine (4.2 g, 16.5 mmol, 2.5 eq) at 0 °C. The reaction was stirred at 20 °C for 2 h before being diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC to give 5-(2-chloro-3-fluorophenyl)-6-(iodomethyl)- 4-(4-methoxybenzyl)morpholin-3-one (2.3 g, 71% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.33 (br d, J = 5.3 Hz, 1H), 7.22 (dd, J = 8.3, 1.7 Hz, 1H), 7.11 - 7.02 (m, 3H), 6.99 - 6.80 (m, 2H), 5.53 - 5.24 (m, 1H), 4.87 (br d, J = 4.4 Hz, 1H), 4.64 - 4.35 (m, 2H), 3.91 - 3.85 (m, 1H), 3.83 (d, J = 9.3 Hz, 3H), 3.57 - 3.26 (m, 1H), 3.25 - 3.00 (m, 2H). [00461] Step F: rac-(1*S,4*R,5*R)-4-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptan-2-one. A solution of 5-(2-chloro-3-fluorophenyl)-6-(iodomethyl)-4-(4- methoxybenzyl)morpholin-3-one (2.3 g, 4.70 mmol, 1.0 eq) in THF (40 mL, 0.1M) was placed under N2. LiHMDS (5.2 mL, 5.17 mmol, 1.1 eq, 1M in THF) was added dropwise at -70 °C and the reaction was stirred at -70 °C for 2 h. The mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (25-35% EtOAc in PE) to give rac- (1*S,4*R,5*R)-4-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptan-2-one (920 mg, 54% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.32 (m, 2H), 7.23 - 7.15 (m, 234 QB\184200.00050\92364964.2 VVID-746PC 1H), 7.13 - 7.01 (m, 2H), 6.90 - 6.78 (m, 2H), 5.51 (d, J = 14.4 Hz, 1H), 4.88 (s, 1H), 4.61 (ddd, J = 16.1, 6.3, 3.8 Hz, 2H), 3.81 (s, 3H), 3.43 (td, J = 9.2, 6.5 Hz, 1H), 3.34 (d, J = 14.4 Hz, 1H), 2.08 (d, J = 9.3 Hz, 1H). [00462] Step G: rac-(1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptane. To a solution of rac-(1*S,4*R,5*R)-4-(2-chloro-3-fluorophenyl)-3-(4- methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptan-2-one (920 mg, 2.54 mmol, 1.0 eq) in THF (10 mL, 0.25M) was added BH3 (7.6 mL, 7.63 mmol, 3.0 eq, 1M in THF) dropwise at 0 °C under N2. The reaction was stirred at 15 °C for 2 h before being quenched with MeOH and concentrated under reduced pressure. rac-(1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptane (880 mg, quant. yield) was used in the next step directly. MS (ESI): mass calcd. for C19H19ClFNO2, 347.1; m/z found, 348.0 [M+H]+. [00463] Step H: rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane. To a solution of rac-(1*R,2*R,5*S)-2-(2-chloro-3-fluorophenyl)-3-(4-methoxybenzyl)-6-oxa-3- azabicyclo[3.1.1]heptane (920 mg, 2.65 mmol, 1.0 eq) in ACN/water (v/v 1:1, 20 mL, 0.1M) was added ceric ammonium nitrate (4.9 g, 10.6 mmol, 4.0 eq). The reaction was stirred at 15 °C for 12 h before being concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (0-30% ACN in 0.1% aq. TFA) to give rac-(1*S,2*S,5*R)-2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (250 mg, 41% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.33 (dt, J = 8.1, 5.5 Hz, 1H), 7.23 - 7.16 (m, 1H), 5.16 (s, 1H), 4.78 (br d, J = 6.0 Hz, 1H), 4.69 (br d, J = 6.5 Hz, 1H), 3.94 (br d, J = 12.1 Hz, 1H), 3.61 - 3.45 (m, 2H), 2.52 (br d, J = 10.4 Hz, 1H). Intermediate 121: 5-(2-Chlorophenyl)-1-methylpiperazin-2-one.
Figure imgf000237_0001
[00464] Step A: tert-Butyl (2-(2-chloroacetamido)-1-(2-chlorophenyl)ethyl)carbamate. To a solution of tert-butyl (2-amino-1-(2-chlorophenyl)ethyl)carbamate (4.0 g, 14.8 mmol, 1.0 eq) and TEA (6.2 mL, 44.3 mmol, 3.0 eq) in DCM (40 mL, 0.37M) was added 2-chloroacetyl chloride (1.2 mL, 14.8 mmol, 1.0 eq) dropwise over 5 min at 0 °C. The reaction was stirred at 20 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-25% EtOAc in PE) to give tert-butyl (2-(2-chloroacetamido)-1-(2-chlorophenyl)ethyl)carbamate (2.7 g, 53% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.32 (m, 2H), 7.27 - 7.20 (m, 1H), 7.10 (br s, 1H), 6.12 - 5.64 (m, 2H), 5.32 - 5.19 (m, 1H), 4.03 (s, 2H), 3.75 - 3.54 (m, 2H), 1.41 (s, 9H). [00465] Step B: tert-Butyl 2-(2-chlorophenyl)-5-oxo-piperazine-1-carboxylate. A solution of tert-butyl (2- (2-chloroacetamido)-1-(2-chlorophenyl)ethyl)carbamate (2.7 g, 7.78 mmol, 1.0 eq) in DMF (30 mL, 235 QB\184200.00050\92364964.2 VVID-746PC 0.26M) was placed under N2. To the mixture was added NaH (933 mg, 23.3 mmol, 3.0 eq) at 0 °C. The reaction was stirred at 20 °C for 16 h under N2 before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-50% EtOAc in PE) to give tert-butyl 2-(2- chlorophenyl)-5-oxo-piperazine-1-carboxylate (640 mg, 26% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.34 (m, 1H), 7.26 - 7.22 (m, 2H), 7.20 - 7.12 (m, 1H), 6.28 (br s, 1H), 5.49 (br s, 1H), 4.28 (d, J = 2.9 Hz, 2H), 3.82 (br d, J = 13.0 Hz, 1H), 3.52 (br d, J = 1.5 Hz, 1H), 1.41 - 1.20 (m, 9H). [00466] Step C: tert-Butyl 2-(2-chlorophenyl)-4-methyl-5-oxo-piperazine-1-carboxylate. A solution of tert-butyl 2-(2-chlorophenyl)-5-oxo-piperazine-1-carboxylate (440 mg, 1.42 mmol, 1.0 eq) in DMF (5.0 mL, 0.3M) was placed under N 2. To the mixture was added NaH (68 mg, 1.70 mmol, 1.2 eq) at 0°C then iodomethane (603 mg, 4.25 mmol, 3.0 eq) dropwise. The reaction was stirred at 20 °C for 16 h under N2 before being concentrated and poured into ice water. The product was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-chlorophenyl)-4-methyl-5-oxo-piperazine-1-carboxylate (440 mg, 96% yield) as a yellow oil. MS (ESI): mass calcd. for C16H21ClN2O3, 324.1; m/z found, 269.1 [M-tBu+2H]+. [00467] Step D: 5-(2-Chlorophenyl)-1-methylpiperazin-2-one. To a solution of tert-butyl 2-(2- chlorophenyl)-4-methyl-5-oxo-piperazine-1-carboxylate (440 mg, 1.35 mmol, 1.0 eq) in EtOAc (2.0 mL, 0.7M) was added HCl (5.0 mL, 4M in EtOAc). The reaction was stirred at 20 °C for 2 h before being concentrated under reduced pressure to give 5-(2-chlorophenyl)-1-methylpiperazin-2-one (353 mg, quant. yield) as a white solid. The product was used in the next step without purification. Intermediate 122: 5-(2-Chloro-3-fluorophenyl)-1-methylpiperazin-2-one.
Figure imgf000238_0001
[00468] The title compound was prepared in a manner analogous to Intermediate 121 using tert-butyl (2- amino-1-(2-chloro-3-fluorophenyl)ethyl)carbamate instead of tert-butyl (2-amino-1-(2- chlorophenyl)ethyl)carbamate in Step A. MS (ESI): mass calcd. for C11H12ClFN2O, 242.1; m/z found, 243.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 7.4 Hz, 1H), 7.62 - 7.54 (m, 2H), 5.19 (dd, J = 11.4, 4.3 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.94 - 3.68 (m, 2H), 3.61 (dd, J = 13.0, 4.4 Hz, 1H), 2.90 (s, 3H). Intermediate 123: 5-(2-Chloro-3-fluorophenyl)-1-cyclopropylpiperazin-2-one. 236 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000239_0001
[00469] Step A: 2-(tert-Butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)acetic acid. To a solution of 2- amino-2-(2-chloro-3-fluorophenyl)acetic acid (5.0 g, 20.8 mmol, 1.0 eq) in DCM (50 mL, 0.4M) was added TEA (10.5 g, 104 mmol, 5.0 eq) at 0 °C. The mixture was stirred at 0 °C for 5 minutes before Boc2O (5.45 g, 25.0 mmol, 1.2 eq) was added. The reaction was stirred at 15 °C for 16 h before being filtered and concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-2-(2-chloro-3- fluorophenyl)acetic acid (5.2 g, 82% yield) as a yellow oil. The crude product was used in the next step without purification. MS (ESI): mass calcd. for C13H15ClFNO4, 303.1; m/z found, 248.0 [M+2H-tBu]+. [00470] Step B: tert-Butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)-2-oxoethyl)carbamate. To a solution of 2-(tert-butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)acetic acid (5.0 g, 16.5 mmol, 1.0 eq) in DCM (50 mL, 0.3M) was added cyclopropylamine (1.1 g, 19.8 mmol, 1.2 eq), DIPEA (8.6 mL, 49.4 mmol, 3.0 eq) and T4P (17.8 g, 24.7 mmol, 1.5 eq). The reaction was stirred at 15 °C for 2 h before being poured into sat. aq. NaHCO3 and extracted with 10% MeOH in DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was filtered and the filter cake was washed with methyl tert-butyl ether then dried under vacuum to give tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)-2-oxoethyl)carbamate (4.2 g, 74% yield) as a white solid. MS (ESI): mass calcd. for C16H20ClFN2O3, 342.1; m/z found, 287.0 [M+2H-tBu]+. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (br d, J = 4.1 Hz, 1H), 7.56 (br d, J = 8.3 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.21 (br d, J = 7.0 Hz, 1H), 5.39 (br d, J = 8.3 Hz, 1H), 2.65 (dt, J = 7.3, 3.8 Hz, 1H), 1.37 (s, 9H), 0.64 - 0.58 (m, 2H), 0.48 - 0.37 (m, 2H). [00471] Step C: tert-Butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)ethyl)carbamate. A solution of tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(cyclopropylamino)-2-oxoethyl)carbamate (4.2 g, 12.3 mmol, 1.0 eq) in THF (40 mL, 0.3M) was placed under N2 and cooled to 0 °C. LiAlH4 (19.6 mL, 49.0 mmol, 4.0 eq, 2.5M in THF) was added dropwise and the mixture was stirred at 20 °C for 16 h. The reaction was cooled to 0 °C before water (1.8 mL) was added slowly followed by 10% aq. NaOH (1.8 mL). The reaction was stirred at 0 °C for 0.5 h before Na2SO4 (1.0 g) was added and the reaction was stirred at 15 °C for 0.5 h. The suspension was filtered through Celite and washed with THF. The combined filtrates were concentrated under reduced pressure to give tert-butyl (1-(2-chloro-3-fluorophenyl)-2- (cyclopropylamino)ethyl)carbamate (3.8 g, 94% yield) as a yellow solid. The product was used in the next step without purification. MS (ESI): mass calcd. for C16H22ClFN2O2, 328.1; m/z found, 329.1 [M+H]+. [00472] Step D: tert-Butyl (1-(2-chloro-3-fluorophenyl)-2-(2-chloro-N- cyclopropylacetamido)ethyl)carbamate. To a solution of tert-butyl (1-(2-chloro-3-fluorophenyl)-2- (cyclopropylamino)ethyl)carbamate (3.0 g, 9.12 mmol, 1.0 eq) and TEA (2.8 g, 27.4 mmol, 3.0 eq) in DCM 237 QB\184200.00050\92364964.2 VVID-746PC (30 mL, 0.3M) was added 2-chloroacetyl chloride (1.0 mL, 10.0 mmol, 1.1 eq) dropwise over 5 mins at 0 °C. The mixture was stirred at 15 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl (1- (2-chloro-3-fluorophenyl)-2-(2-chloro-N-cyclopropylacetamido)ethyl)carbamate (2.3 g, 62% yield) as a yellow solid. MS (ESI): mass calcd. for C18H23Cl2FN2O3, 404.1; m/z found, 349.0 [M+2H-tBu]+. 1H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.25 (m, 4H), 5.41 (br d, J = 5.3 Hz, 1H), 4.54 - 4.44 (m, 2H), 3.89 - 3.64 (m, 1H), 3.25 (br dd, J = 13.5, 5.1 Hz, 1H), 2.61 (br s, 1H), 1.36 (s, 9H), 0.87 - 0.65 (m, 4H). [00473] Step E: tert-Butyl 2-(2-chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazine-1-carboxylate. A solution of tert-butyl (1-(2-chloro-3-fluorophenyl)-2-(2-chloro-N-cyclopropylacetamido)ethyl)carbamate (2.3 g, 5.94 mmol, 1.0 eq) in THF (20 mL, 0.3M) was placed under N2 and cooled to 0 °C. NaH (713 mg, 17.8 mmol, 3.0 eq, 60% in mineral oil) was added. The reaction was stirred at 15 °C for 16 h before being poured into sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-40% EtOAc in PE) to give tert-butyl 2-(2-chloro-3-fluorophenyl)-4-cyclopropyl-5- oxopiperazine-1-carboxylate (2.0 g, 95% yield) as a white solid. MS (ESI): mass calcd. for C18H22ClFN2O3, 368.1; m/z found, 313.0 [M+2H-tBu]+. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (br dd, J = 7.8, 3.3 Hz, 2H), 6.90 (br s, 1H), 5.22 (br s, 1H), 4.24 - 4.15 (m, 1H), 4.13 - 4.06 (m, 1H), 3.99 - 3.77 (m, 1H), 3.32 (br dd, J = 13.6, 4.5 Hz, 1H), 2.51 (br s, 1H), 1.50 - 1.24 (m, 4H), 1.10 (br s, 5H), 0.70 - 0.45 (m, 2H), 0.39 - 0.07 (m, 1H), -0.12 - -0.56 (m, 1H). [00474] Step F: 5-(2-Chloro-3-fluorophenyl)-1-cyclopropylpiperazin-2-one. To a solution of tert-butyl 2- (2-chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazine-1-carboxylate (2.0 g, 5.70 mmol, 1.0 eq) in EtOAc (2.0 mL, 2.9M) was added HCl (20 mL, 4M in EtOAc). The reaction was stirred at 15 °C for 16 h before being filtered, washed with EtOAc, and dried under vacuum to give product as an HCl salt. The salt was dissolved in water and the pH was adjusted to ~9 with solid NaHCO3. The solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-(2-chloro-3-fluorophenyl)-1-cyclopropylpiperazin-2-one (800 mg, 55%) as a colorless oil. Intermediate 124: 2-(2-Chlorophenyl)-2-methylpyrrolidine.
Figure imgf000240_0001
[00475] Step A: tert-Butyl 2-(2-chlorophenyl)-2-methyl-pyrrolidine-1-carboxylate. A solution of tert-butyl 2-(2-chlorophenyl)pyrrolidine-1-carboxylate (800 mg, 2.84 mmol, 1.0 eq) in THF (15 mL, 0.2M) was placed under N2. TMEDA (660 mg, 5.68 mmol, 2.0 eq) was added and the mixture stirred at 25 ℃ for 10 238 QB\184200.00050\92364964.2 VVID-746PC min. The reaction was cooled to -40 ℃ before n-butyllithium (2.3 mL, 5.68 mmol, 2.5M in THF, 2.0 eq) was added dropwise. The reaction was stirred at 0 ℃ for 2 h then cooled to -40 ℃. Iodomethane (806 mg, 5.68 mmol, 2.0 eq) was added dropwise and the reaction was stirred at 25 ℃ for 12 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl 2-(2-chlorophenyl)-2-methyl-pyrrolidine-1-carboxylate (200 mg, 24% yield) as a pale yellow oil. MS (ESI): mass calcd. for C16H22ClNO2, 295.1; m/z found, 240.1 [M+2H-tBu]+. 1H NMR (400 MHz, CDCl3) δ 7.44 - 7.31 (m, 2H), 7.25 - 7.14 (m, 2H), 3.72 - 3.57 (m, 2H), 2.66 - 2.51 (m, 1H), 2.04 - 1.94 (m, 1H), 1.93 (s, 1H), 1.91 - 1.83 (m, 2H), 1.80 (s, 2H), 1.44 (s, 2H), 1.10 (s, 7H). [00476] Step B: 2-(2-Chlorophenyl)-2-methylpyrrolidine. To a solution of tert-butyl 2-(2-chlorophenyl)-2- methyl-pyrrolidine-1-carboxylate (200 mg, 0.676 mmol, 1.0 eq) in DCM (3.0 mL, 0.2M) was added TFA (1.0 mL). The reaction was stirred at 25 ℃ for 6 h before being diluted with water, quenched with sat. aq. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 2-(2-chlorophenyl)-2-methylpyrrolidine (130 mg, 98% yield) as a yellow oil. MS (ESI): mass calcd. for C11H14ClN, 195.1; m/z found, 196.0 [M+H]+. Intermediate 125: 7-(2-Chloro-3-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine.
Figure imgf000241_0001
[00477] Step A: tert-Butyl ((4-(2-(2-chloro-3-fluorophenyl)-2-oxoethyl)morpholin-3-yl)methyl)carbamate. To a mixture of tert-butyl N-(morpholin-3-ylmethyl)carbamate (500 mg, 2.31 mmol, 1.0 eq) in DMSO (5.0 mL, 0.46M) was added 2-bromo-1-(2-chloro-3-fluorophenyl)ethanone (698 mg, 2.77 mmol, 1.2 eq) and DIPEA (701 mg, 6.94 mmol, 3.0 eq). The reaction was stirred for 12 h at 25 °C under N2 before being poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (25% EtOAc in PE) to give tert-butyl ((4-(2-(2-chloro-3-fluorophenyl)-2- oxoethyl)morpholin-3-yl)methyl)carbamate (330 mg, 37% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.12 (m, 3H), 4.89 (br s, 1H), 4.02 (br d, J = 18.0 Hz, 1H), 3.75 - 3.63 (m, 3H), 3.61 - 3.50 (m, 1H), 3.43 (dd, J = 11.3, 8.1 Hz, 1H), 3.32 - 3.20 (m, 1H), 3.18 - 3.07 (m, 1H), 2.80 (br d, J = 11.8 Hz, 1H), 2.69 (br d, J = 2.4 Hz, 1H), 2.62 - 2.52 (m, 1H), 1.36 (s, 9H). [00478] Step B: 7-(2-Chloro-3-fluorophenyl)-1,3,4,6,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine. tert- Butyl ((4-(2-(2-chloro-3-fluorophenyl)-2-oxoethyl)morpholin-3-yl)methyl)carbamate (500 mg, 1.29 mmol, 1.0 eq) was taken up in TFA/DCM (v/v 1:3, 0.80 mL, 1.6M). The reaction was stirred at 20 °C for 2 h. The 239 QB\184200.00050\92364964.2 VVID-746PC mixture was concentrated under reduced pressure to give 7-(2-chloro-3-fluorophenyl)-1,3,4,6,9,9a- hexahydropyrazino[2,1-c][1,4]oxazine (TFA salt, 494 mg, quant. yield) as a light yellow oil, which was used in the next step directly. MS (ESI): mass calcd. for C13H14ClFN2O, 268.1; m/z found, 269.1 [M+H]+. [00479] Step C: 7-(2-Chloro-3-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine. A solution of 7-(2- chloro-3-fluorophenyl)-1,3,4,6,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine (TFA salt, 494 mg, 1.29 mmol, 1.0 eq) in methanol (5.0 mL, 0.26M) was cooled to 0 °C. To this was added sodium cyanoborohydride (162 mg, 2.58 mmol, 2.0 eq). The reaction was stirred at 25 °C for 16 h before being concentrated under reduced pressure. The crude product was washed with sat. aq. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (30% EtOAc in PE with 0.1% NH4OH) to give 7-(2-chloro-3- fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine (180 mg, 52% yield) as a colorless oil. MS (ESI): mass calcd. for C13H16ClFN2O, 270.1; m/z found, 271.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.10 - 7.04 (m, 1H), 4.46 (dd, J = 10.1, 2.4 Hz, 1H), 3.88 - 3.83 (m, 1H), 3.80 - 3.73 (m, 2H), 3.34 (t, J = 10.7 Hz, 1H), 3.00 - 2.92 (m, 2H), 2.74 - 2.65 (m, 2H), 2.47 - 2.35 (m, 2H), 2.10 (t, J = 10.6 Hz, 1H). Intermediate 126: Methyl 7-fluoro-2-methyl-indazole-4-carboxylate.
Figure imgf000242_0001
[00480] In an oven-dried flask under N2, sodium hydride (448 mg, 11.2 mmol, 3.0 eq) was taken up in THF (18.7 mL, 0.2M) and cooled to 0 °C. To this was added methyl 7-fluoro-1H-indazole-4-carboxylate (725 mg, 3.73 mmol, 1.0 eq) and the reaction was allowed to stir for 10 min. Finally, iodomethane (0.70 mL, 11.2 mmol, 3.0 eq) was added and the reaction was stirred at 0 °C for 10 min then rt for 7 h. The reaction was cooled to 0 ºC, quenched with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (0-100% EtOAc in heptanes) provided methyl 7-fluoro-1-methyl-indazole-4-carboxylate (first eluting, 180 mg, 23% yield) and methyl 7-fluoro-2-methyl-indazole-4-carboxylate (second eluting, 180 mg, 23% yield). MS (ESI): mass calcd. for C10H9N2O2, 208.1; m/z found, 209.2 [M+H]+. Intermediate 127: Methyl 5-fluoro-4-methylpyrimidine-2-carboxylate.
Figure imgf000242_0002
[00481] To a solution of 2-chloro-5-fluoro-4-methyl-pyrimidine (2.0 g, 13.6 mmol, 1.0 eq) in DMF/MeOH (v/v 1:1, 30 mL, 0.45M) was added TEA (4.1 g, 40.9 mmol, 3.0 eq) and Pd(dppf)Cl2 (494 mg, 0.680 mmol, 240 QB\184200.00050\92364964.2 VVID-746PC 0.05 eq). The mixture was degassed and purged with CO then stirred at 80 ℃ for 16 h under CO (50 psi). After cooling to rt, the mixture was concentrated under reduced pressure then poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE:EtOAc = 1:1) to give methyl 5-fluoro-4-methylpyrimidine-2-carboxylate (950 mg, 41% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 0.8 Hz, 1H), 4.06 (s, 3H), 2.67 (d, J = 2.6 Hz, 3H). Intermediate 128: Methyl 4-(difluoromethyl)-5-fluoropyrimidine-2-carboxylate.
Figure imgf000243_0001
[00482] To a solution of methyl 5-fluoropyrimidine-2-carboxylate (1.0 g, 6.41 mmol, 1.0 eq) and zinc difluoromethanesulfinate (5.1 g, 17.3 mmol, 2.7 eq) in DCM (4.0 mL, 1.1M) and water (1.6 mL, 1.1M) was added 2,2,2-trifluoroacetic acid (730 mg, 6.41 mmol, 1.0 eq) followed by slow addition of tert-butyl hydroperoxide (70% in water, 4.1 g, 32.0 mmol, 5.0 eq). The reaction was stirred at 20 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give methyl 4-(difluoromethyl)-5-fluoropyrimidine-2-carboxylate (700 mg, 53% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.02 - 6.64 (m, 1H), 4.08 (s, 3H). Intermediate 129: Methyl 5-(rac-(3a*S,4*S,6a*R)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4- c]pyrrol-5(3H)-yl)pyrazine-2-carboxylate.
Figure imgf000243_0002
[00483] Step A: A solution of tert-butyl rac-(3a*S,6a*S)-4-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- carboxylate (Intermediate 40, 6.0 g, 26.4 mmol, 1 eq) in THF (3.0 mL, 0.9M) was placed under N2 and cooled to 0 °C. To this was added (2-chloro-3-fluorophenyl)magnesium bromide (40 mL, 39.6 mmol, 1.5 eq, 1M in THF) dropwise. The reaction was stirred at 0 °C for 16 h before being slowly quenched with sat. aq. NH4Cl at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (25-50% EtOAc in PE) to give a mixture of tert-butyl ((rac-(3*R,4*R)-4-(2-chloro-3- 241 QB\184200.00050\92364964.2 VVID-746PC fluorobenzoyl)tetrahydrofuran-3-yl)methyl)carbamate and tert-butyl 4-(rac-(3a*R,6a*R)-2-chloro-3- fluorophenyl)-4-hydroxytetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (6.0 g, 64% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.63 - 7.30 (m, 1H), 7.25 - 7.18 (m, 1H), 7.16 - 7.03 (m, 1H), 5.21 - 5.01 (m, 1H), 4.46 - 4.22 (m, 1H), 4.06 - 3.73 (m, 4H), 3.68 - 3.56 (m, 1H), 3.32 - 2.87 (m, 2H), 1.56 - 1.29 (m, 5H), 1.11 (br s, 3H). [00484] Step B: tert-Butyl ((rac-(3*R,4*R)-4-((2-chloro-3-fluorophenyl)(hydroxy)methyl)tetrahydrofuran- 3-yl)methyl)carbamate. To a mixture of tert-butyl ((rac-(3*R,4*R)-4-(2-chloro-3- fluorobenzoyl)tetrahydrofuran-3-yl)methyl)carbamate and tert-butyl 4-(rac-(3a*R,6a*R)-2-chloro-3- fluorophenyl)-4-hydroxytetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (4.5 g, 12.6 mmol, 1.0 eq) in MeOH (20 mL, 0.6M) was added sodium borohydride (952 mg, 25.2 mmol, 2.0 eq) in portions at 0 °C under N2. The reaction was stirred at 20 °C for 16 h before being quenched with sat. aq. NH4Cl at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give tert-butyl ((rac-(3*R,4*R)-4-((2-chloro-3- fluorophenyl)(hydroxy)methyl)tetrahydrofuran-3-yl)methyl)carbamate (4.0 g, 88% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.33 (m, 1H), 7.33 - 7.27 (m, 1H), 7.08 (t, J = 8.4 Hz, 1H), 5.35 - 5.22 (m, 1H), 3.95 - 3.84 (m, 1H), 3.77 (br dd, J = 8.4, 2.3 Hz, 1H), 3.51 (br s, 1H), 3.45 - 3.26 (m, 3H), 2.76 (td, J = 17.1, 8.6 Hz, 1H), 2.69 - 2.53 (m, 1H), 1.52 - 1.38 (m, 9H). [00485] Step C: tert-Butyl 4-rac-(3a*S,6a*R)-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrole- 5(3H)-carboxylate. To a solution of tert-butyl ((rac-(3*R,4*R)-4-((2-chloro-3- fluorophenyl)(hydroxy)methyl)tetrahydrofuran-3-yl)methyl)carbamate (3.5 g, 9.73 mmol, 1.0 eq) in toluene (30 mL, 0.3M) was added PPh3 (3.8 g, 14.6 mmol, 1.5 eq) at 0 °C under N2. DEAD (2.5 g, 14.6 mmol, 1.5 eq) was added and the reaction was stirred at 50 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (25-35% EtOAc in PE) to give tert-butyl 4-rac-(3a*S,6a*R)-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- carboxylate (3.1 g, 93% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (dt, J = 8.0, 5.4 Hz, 1H), 7.11 - 6.82 (m, 2H), 5.44 (br d, J = 8.6 Hz, 1H), 4.24 (br s, 1H), 4.02 - 3.70 (m, 2H), 3.67 - 3.31 (m, 3H), 3.24 - 2.71 (m, 2H), 1.34 - 1.05 (m, 9H). [00486] Step D: rac-(3a*S,6a*R)-4-(2-Chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole. tert- Butyl 4-rac-(3a*S,6a*R)-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (3.1 g, 9.07 mmol, 1.0 eq) was taken up in DCM/TFA (v/v 3:1, 20 mL, 0.4M). The reaction was stirred at 20 °C for 5 h before being concentrated in vacuo. The resulting residue was purified by RP-HPLC (15- 45% ACN in 10 mM aq. NH4HCO3) to afford rac-(3a*S,6a*R)-4-(2-chloro-3-fluorophenyl)hexahydro-1H- furo[3,4-c]pyrrole (170 mg, 8% yield) as a colorless oil. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m/z found, 242.2 [M+H]+. 242 QB\184200.00050\92364964.2 VVID-746PC Step E: Methyl 5-(rac-(3a*S,4*S,6a*R)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol- 5(3H)-yl)pyrazine-2-carboxylate. To the solution of rac-(3a*S,6a*R)-4-(2-chloro-3- fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (170 mg, 0.703 mmol, 1.0 eq) in DMSO (1.0 mL, 0.7M) was added TEA (214 mg, 2.11 mmol, 3.0 eq) and methyl 5-fluoropyrazine-2-carboxylate (110 mg, 0.703 mmol, 1.0 eq). The reaction was stirred at 100 °C for 1 h. After cooling to rt, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- TLC (PE:EtOAc = 0:1) to give methyl 5-(rac-(3a*S,6a*R)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H- furo[3,4-c]pyrrol-5(3H)-yl)pyrazine-2-carboxylate. Separation via SFC (Stationary phase: OJ (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.62 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C18H17ClFN3O3, 377.1; m/z found, 378.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.76 (br s, 1H), 7.23 - 7.04 (m, 2H), 6.73 (d, J = 7.6 Hz, 1H), 5.43 (br s, 1H), 4.26 - 4.16 (m, 2H), 4.04 - 3.86 (m, 7H), 3.18 (ddd, J = 8.3, 5.6, 2.7 Hz, 1H), 3.08 - 2.92 (m, 1H). Intermediate 130: Methyl 5-(rac-(3a*R,4*R,6a*S)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4- c]pyrrol-5(3H)-yl)pyrazine-2-carboxylate.
Figure imgf000245_0001
[00487] The title compound was isolated from Intermediate 129, Step E, SFC (Stationary phase: OJ (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 15.6 min, fourth eluting product). MS (ESI): mass calcd. for C18H17ClFN3O3, 377.1; m/z found, 378.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.76 (br s, 1H), 7.17 - 7.04 (m, 2H), 6.73 (d, J = 7.7 Hz, 1H), 5.43 (br s, 1H), 4.26 - 4.17 (m, 2H), 4.02 - 3.83 (m, 7H), 3.26 - 3.10 (m, 1H), 3.06 - 2.94 (m, 1H). Intermediate 131: tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5- (methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
Figure imgf000245_0002
243 QB\184200.00050\92364964.2 VVID-746PC [00488] Step A: 5-((9H-Fluoren-9-yl)methyl) 2-(tert-butyl) 1-oxotetrahydropyrrolo[3,4-c]pyrrole- 2,5(1H,3H)-dicarboxylate. To a solution of tert-butyl 1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (13 g, 57.5 mmol, 1.0 eq) in DCM (130 L, 0.44M) was added DIPEA (22 g, 172 mmol, 3.0 eq) and 9H-fluoren-9-ylmethyl chloroformate (22 g, 86.2 mmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h before being quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC (0-50% EtOAc in PE) to give 5-((9H-fluoren-9-yl)methyl) 2-(tert-butyl) 1- oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate (8.0 g, 31% yield) as a white solid. MS (ESI): mass calcd. for C26H28N2O5, 448.2; m/z found, 349.1 [M+2H-Boc]+. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 2H), 7.60 (br d, J = 7.4 Hz, 2H), 7.49 - 7.38 (m, 2H), 7.38 - 7.29 (m, 2H), 4.49 - 4.30 (m, 2H), 4.27 - 4.20 (m, 1H), 4.05 - 3.80 (m, 3H), 3.67 (br dd, J = 11.4, 8.3 Hz, 2H), 3.32 - 3.11 (m, 2H), 3.06 - 2.91 (m, 1H), 1.56 (s, 9H). [00489] Step B: (9H-Fluoren-9-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-(2-chloro-3- fluorobenzoyl)pyrrolidine-1-carboxylate. A mixture of 5-((9H-fluoren-9-yl)methyl) 2-(tert-butyl) 1- oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate (2.6 g, 5.80 mmol, 1.0 eq) in THF (30 mL, 0.2M) was placed under N2. (2-Chloro-3-fluorophenyl)magnesium bromide (8.7 mL, 8.69 mmol, 1.5 eq, 1M in THF) was added dropwise at 0 °C. The reaction was stirred at 0-25 °C for 16 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by FCC (0-50% EtOAc in PE) to give (9H-fluoren-9-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-(2-chloro-3- fluorobenzoyl)pyrrolidine-1-carboxylate (2.7 g, 80% yield) as a colorless oil. [00490] Step C: (9H-Fluoren-9-yl)methyl 3-(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-1- carboxylate. To a solution of (9H-fluoren-9-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-(2- chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (2.7 g, 4.66 mmol, 1.0 eq) in DCM (21 mL, 0.2M) was added TFA (7.0 mL). The reaction was stirred at 20 °C for 2 h then concentrated in vacuo to give (9H- fluoren-9-yl)methyl 3-(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (TFA salt, 2.7 g, 98% yield) as a yellow oil. The crude product was used in the next step without further purification. [00491] Step D: rac-(9H-Fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. To a solution of (9H-fluoren-9- yl)methyl 3-(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (TFA salt, 2.7 g, 4.55 mmol, 1.0 eq) in MeOH (50 mL, 0.1M) was added sodium cyanoborohydride (572 mg, 9.11 mmol, 2.0 eq). The reaction was stirred at 20 °C for 16 h before being poured into sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give rac-(9H-fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.1 g, quant. yield) as a yellow oil. MS (ESI): mass calcd. for C27H24ClFN2O2, 462.2; m/z found, 463.2 [M+H]+. 244 QB\184200.00050\92364964.2 VVID-746PC [00492] Step E: rac-(9H-Fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)-5-(5- (methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. To a solution of rac- (9H-fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate (2.1 g, 4.54 mmol, 1.0 eq) in DMF (25 mL, 0.18M) was added methyl 5-fluoro-2- pyrazinecarboxylate (850 mg, 5.44 mmol, 1.2 eq) and DIPEA (1.8 g, 13.6 mmol, 3.0 eq). The reaction was stirred at 25 °C for 16 h under N2 before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (0-100% EtOAc in PE) to give rac-(9H-fluoren-9-yl)methyl (3a*R,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.5 g, 92% yield) as a colorless oil. MS (ESI): mass calcd. for C33H28ClFN4O4, 598.2; m/z found, 599.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 (br s, 1H), 7.85 - 7.56 (m, 4H), 7.50 - 7.31 (m, 4H), 7.28 - 7.23 (m, 1H), 7.21 - 7.01 (m, 2H), 6.89 - 6.71 (m, 1H), 5.63 (br d, J = 6.6 Hz, 1H), 4.43 - 4.06 (m, 4H), 3.95 (s, 3H), 3.84 - 3.60 (m, 3H), 3.59 - 3.44 (m, 1H), 3.39 - 3.06 (m, 3H). [00493] Step F: Methyl 5-(rac-(1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate. To a solution of rac-(9H-fluoren-9-yl)methyl (3a*R,4*R,6a*R)- 4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (500 mg, 0.835 mmol, 1.0 eq) in DCM (6.0 mL, 0.14M) was added piperidine (1.5 mL, 15.1 mmol, 18 eq). The reaction was stirred at 25 °C for 2 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give methyl 5-(rac-(1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate (300 mg, 95% yield) as a yellow oil. MS (ESI): mass calcd. for C18H18ClFN4O2, 376.1; m/z found, 377.1 [M+H]+. [00494] Step G: tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. To a solution of methyl 5-(rac-(1*R,3a*S,6a*R)- 1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate (300 mg, 0.796 mmol, 1.0 eq) in DCM (6.0 mL, 0.13M) was added Boc2O (209 mg, 0.955 mmol, 1.2 eq) and TEA (242 mg, 2.39 mmol, 3.0 eq). The reaction was stirred at 25 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by FCC (50-100% EtOAc in PE) to give tert- butyl rac-(3a*R,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. Separation of tert-butyl rac-(3a*R,4*R,6a*R)-4-(2- chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate via SFC (Stationary phase: WHELK-O1 (25x5 cm); Mobile phase: 50% MeOH/CO2; Rt = 10.9 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4, 476.2; m/z found, 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (br s, 1H), 8.07 - 7.78 (m, 1H), 245 QB\184200.00050\92364964.2 VVID-746PC 7.41 - 7.13 (m, 2H), 7.04 - 6.93 (m, 1H), 5.58 (d, J = 8.6 Hz, 1H), 4.16 - 3.98 (m, 1H), 3.96 - 3.82 (m, 1H), 3.77 (s, 3H), 3.54 - 3.41 (m, 2H), 3.30 - 2.88 (m, 4H), 1.34 - 1.15 (m, 9H). Intermediate 132: Methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)pyrazine-2-carboxylate.
Figure imgf000248_0001
[00495] tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate 131, 500 mg, 1.05 mmol, 1.0 eq) was taken up in MeOH (5.2 mL, 0.2M). To this was added HCl (0.26 mL, 1.05 mmol, 1.0 eq, 4N in dioxane) and the reaction was allowed to stir at 60 °C for 1 hr. Upon cooling to rt, the mixture was concentrated under reduced pressure to provide methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate (395 mg, quant. yield) as a white solid. MS (ESI): mass calcd. for C18H18ClFN4O2, 376.1; m/z found, 377.0 [M+H]+. Intermediate 133: Methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate.
Figure imgf000248_0002
[00496] Step A: tert-Butyl 3-(2-chlorophenyl)piperazine-1-carboxylate. To a solution of tert-butyl N-(2- aminoethyl)-N-(tributylstannylmethyl)carbamate (91 µL, 0.220 mmol, 1.0 eq) in DCM (0.37 mL, 0.2M) was added 2-chlorobenzaldehyde (24 µL, 0.220 mmol, 1.0 eq) and 4A molecular sieves (~100 mg/mmol). The reaction was stirred at rt for 2 h then filtered through Celite with DCM. The filtrate was concentrated under reduced pressure to afford the imine. Separately, 2,6-lutidine (30 µL, 0.240 mmol, 1.1 eq) was added to a suspension of hexafluoroisopropanol (0.37 mL, 0.2M) and copper(II) trifluoromethanesulfonate (86 mg, 0.240 mmol, 1.1 eq) and this was stirred at rt for 1 h. The imine was added and the reaction was stirred at rt for 12 h. The reaction was quenched with 10% aq. NH4OH and stirred vigorously for 15 min. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by RP-HPLC (0-100% ACN in 0.1% aq. HCOOH) provided tert-butyl 3-(2-chlorophenyl)piperazine-1- 246 QB\184200.00050\92364964.2 VVID-746PC carboxylate (19 mg, 30 % yield). MS (ESI): mass calcd. for C15H21ClN2O2, 296.1; m/z found, 297.0 [M+H]+. [00497] Step B: tert-Butyl 3-(2-chlorophenyl)-4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1- carboxylate. Methyl 5-bromo-3-fluoropicolinate (243 mg, 1.04 mmol, 1.0 eq), tert-butyl 3-(2- chlorophenyl)piperazine-1-carboxylate (308 mg, 1.04 mmol, 1.0 eq), RuPhos Pd G4 (88 mg, 0.104 mmol, 0.1 eq), and cesium carbonate (1.0 g, 3.11 mmol, 3.0 eq) were taken up in toluene (5.2 mL, 0.2M). The reaction was placed under N2 and heated to 100 °C for 24 hours. After cooling to rt, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (0-100% EtOAc in heptanes) provided tert-butyl 3-(2-chlorophenyl)-4-(5-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (210 mg, 45% yield). MS (ESI): mass calcd. for C22H25ClFN3O4, 449.2; m/z found, 450.0 [M+H]+. [00498] Step C: Methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3-fluoropicolinate. tert-Butyl 3-(2- chlorophenyl)-4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (214 mg, 0.477 mmol, 1.0 eq) was taken up in a 20% TFA solution in DCM (0.5 mL, 0.2M). The reaction was allowed to stir at rt for 1 h before being concentrated to provide methyl 5-(2-(2-chlorophenyl)piperazin-1-yl)-3- fluoropicolinate (167 mg, quant. yield). MS (ESI): mass calcd. for C17H17ClFN3O2, 349.1; m/z found, 350.0 [M+H]+. Intermediate 134: Methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate.
Figure imgf000249_0001
[00499] Step A: 2-(2-Chloro-3-fluorophenyl)pyrazine. To a solution of 2-chloropyrazine (2.0 g, 17.5 mmol, 1.0 eq) in 1,4-dioxane/water (v/v 10:1, 22 mL, 0.8M) was added (2-chloro-3-fluorophenyl)boronic acid (3.0 g, 17.5 mmol, 1.0 eq), potassium carbonate (6.0 g, 43.7 mmol, 2.5 eq) and Pd(dppf)Cl 2 (632 mg, 0.873 mmol, 0.05 eq). The reaction was placed under N2 and stirred at 100 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (15-25% EtOAc in PE) to give 2-(2-chloro-3-fluorophenyl)pyrazine (2.2 g, 60% yield) as a yellow solid. MS (ESI): mass calcd. for C10H6ClFN2, 208.0; m/z found, 209.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 1.5 Hz, 1H), 8.64 (dd, J = 2.4, 1.6 Hz, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.22 - 7.17 (m, 1H). 247 QB\184200.00050\92364964.2 VVID-746PC [00500] Step B: 2-(2-Chloro-3-fluorophenyl)piperazine. To a solution of 2-(2-chloro-3- fluorophenyl)pyrazine (2.0 g, 9.59 mmol, 1.0 eq) in toluene (30 mL, 0.3M) was added N-phenylaniline (3.2 g, 19.2 mmol, 2.0 eq) and pinacolborane (6.1 g, 47.9 mmol, 5.0 eq). The mixture was placed under N2 before tris(2,3,4,5,6-pentafluorophenyl)borane (491 mg, 0.959 mmol, 0.1 eq) was added. The reaction was stirred at 110 °C for 6 hrs. After cooling to rt, the mixture was quenched with MeOH and stirred for 30 min. After concentrating under reduced pressure, 2-(2-chloro-3-fluorophenyl)piperazine (2.0 g, 97% yield) was obtained as a yellow solid, which was used directly without further purification. MS (ESI): mass calcd. for C10H12ClFN2, 214.1; m/z found, 214.9 [M+H]+. [00501] Step C: tert-Butyl 3-(2-chloro-3-fluorophenyl)piperazine-1-carboxylate. To a solution of 2-(2- chloro-3-fluorophenyl)piperazine (2.0 g, 9.32 mmol, 1.0 eq) in DCM (50 mL, 0.2M) was added DIPEA (3.6 g, 28.0 mmol, 3.0 eq) and Boc2O (1.8 g, 8.39 mmol, 0.9 eq). The reaction was stirred at 25 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (30-60% EtOAc in PE) to give tert-butyl 3-(2-chloro-3-fluorophenyl)piperazine-1-carboxylate (3.0 g, 92% yield) as a yellow oil. MS (ESI): mass calcd. for C15H20ClFN2O2, 314.1; m/z found, 315.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.44 (br d, J = 7.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.09 (dt, J = 8.5, 1.3 Hz, 1H), 4.30 - 3.97 (m, 3H), 3.09 (br d, J = 6.0 Hz, 1H), 3.02 - 2.83 (m, 2H), 2.63 (dd, J = 12.6, 10.0 Hz, 1H), 1.48 (s, 9H). [00502] Step D: Methyl 5-(4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2- carboxylate. To a mixture of tert-butyl 3-(2-chloro-3-fluorophenyl)piperazine-1-carboxylate (3.2 g, 10.1 mmol, 1.0 eq) in DMSO (35 mL, 0.3M) was added methyl 5-fluoro-2-pyrazinecarboxylate (1.9 g, 12.1 mmol, 1.2 eq) and TEA (3.1 g, 30.3 mmol, 3.0 eq). The mixture was placed under N2 and stirred at 100 °C for 16 h. After cooling to rt, the residue was purified by FCC (50-100% EtOAc in PE) to give methyl 5-(4- (tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (3.7 g, 81% yield) as a pale yellow solid. MS (ESI): mass calcd. for C21H24ClFN4O4, 450.2; m/z found, 451.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 1.1 Hz, 1H), 7.77 (br s, 1H), 7.20 - 7.08 (m, 2H), 7.05 - 6.92 (m, 1H), 5.52 - 5.42 (m, 1H), 4.74 - 4.36 (m, 1H), 4.16 (br s, 1H), 4.01 - 3.91 (m, 5H), 3.88 - 3.73 (m, 1H), 3.66 - 3.52 (m, 1H), 1.41 - 1.14 (m, 9H). [00503] Step E: Methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate. Methyl 5- (4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (1.5 g, 3.33 mmol, 1.0 eq) was taken up in DCM/TFA (v/v 3:1, 20 mL, 0.2M). The reaction was stirred at 20 °C for 2 h before being concentrated under reduced pressure to provide methyl 5-(2-(2-chloro-3- fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (1.1 g, 94% yield) as a yellow oil, which was used directly without further purification. MS (ESI): mass calcd. for C16H16ClFN4O2, 350.1; m/z found, 351.1 [M+H]+. 248 QB\184200.00050\92364964.2 VVID-746PC Intermediate 135: Methyl 5-(rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(dimethylamino)-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate.
Figure imgf000251_0001
[00504] Step A: rac-(1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-(5-methoxycarbonylpyrazin-2-yl)- 3-azabicyclo[3.1.0]hexane-6-carboxylic acid. To a solution of rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 81 Step C, 1.0 g, 3.91 mmol, 1.0 eq) in DMSO (10 mL, 0.4M) was added TEA (1.6 mL, 11.7 mmol, 3.0 eq) and methyl 5-fluoro-2- pyrazinecarboxylate (672 mg, 4.30 mmol, 1.1 eq). The reaction was stirred at 100 °C for 5 h. After cooling to rt, the mixture was diluted with water and extracted with MTBE. The aqueous layer was adjusted to pH 6 with 0.5M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3- fluorophenyl)-3-(5-methoxycarbonylpyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1.5 g, 98% yield) as a yellow solid. MS (ESI): mass calcd. for C18H15ClFN3O4, 391.1; m/z found, 392.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1H), 7.85 - 7.78 (m, 1H), 7.26 - 7.19 (m, 2H), 6.87 - 6.73 (m, 1H), 5.66 - 5.58 (m, 1H), 4.16 (d, J = 10.9 Hz, 1H), 3.96 - 3.87 (m, 2H), 3.74 (s, 3H), 2.69 - 2.64 (m, 1H), 2.42 - 2.36 (m, 1H), 1.46 (t, J = 3.1 Hz, 1H). [00505] Step B: Methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-(tert-butoxycarbonylamino)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate. To a solution of rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-(5-methoxycarbonylpyrazin-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid (1.2 g, 3.06 mmol, 1.0 eq) in t-BuOH (13 mL, 0.24M) was added TEA (1.5 g, 15.3 mmol, 5.0 eq), 4A molecular sieve (1.3 g), and diphenylphosphoryl azide (1.0 g, 3.68 mmol, 1.2 eq). The reaction was stirred at 90 °C for 16 h. After cooling to rt, the mixture was filtered and concentrated in vacuo. The resulting residue was purified by FCC (10-40% EtOAc in PE) to give methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-(tert-butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (160 mg, 11% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.70 - 7.48 (m, 1H), 7.15 - 7.03 (m, 2H), 6.63 (br d, J = 6.6 Hz, 1H), 5.62 (d, J = 5.5 Hz, 1H), 4.61 - 4.47 (m, 1H), 4.26 - 4.17 (m, 1H), 4.08 - 3.96 (m, 1H), 3.92 (s, 3H), 2.51 (ddd, J = 7.9, 5.7, 2.1 Hz, 1H), 2.44 (br s, 1H), 2.23 - 2.14 (m, 1H), 1.38 (s, 9H). [00506] Step C: Methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-amino-2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate. A solution of methyl 5-(rac-(1*S,2*S,5*S,6*S)-6- (tert-butoxycarbonylamino)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2- 249 QB\184200.00050\92364964.2 VVID-746PC carboxylate (220 mg, 0.475 mmol, 1.0 eq) in DCM/TFA (v/v 3:1, 4.0 mL, 0.1M) was stirred at 20 °C for 16 h. The mixture was concentrated in vacuo to afford methyl 5-(rac-(1*S,2*S,5*S,6*S)-6-amino-2-(2- chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (TFA salt, 200 mg, 88% yield) as a yellow oil. MS (ESI): mass calcd. for C17H16ClFN4O2, 362.1; m/z found, 363.1 [M+H]+. [00507] Step D: Methyl 5-(rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(dimethylamino)-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate. To a solution of methyl 5-(rac-(1*S,2*S,5*S,6*S)-6- amino-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (200 mg, 0.420 mmol, 1.0 eq) in MeOH/AcOH (v/v 10:1, 1.1 mL, 0.4M) was added formaldehyde (37% in water, 340 mg, 4.19 mmol, 10 eq). The mixture was stirred at 20 °C for 5 min before NaBH3CN (132 mg, 2.10 mmol, 5.0 eq) was added. The reaction was stirred at 20 °C for 2 h then quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by prep-TLC (EtOAc:MeOH = 10:1) to afford methyl 5-(rac-(1*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3- yl)pyrazine-2-carboxylate (40 mg, 24% yield) as a colorless oil. MS (ESI): mass calcd. for C19H20ClFN4O2, 390.1; m/z found, 391.1 [M+H]+. Intermediate 136: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)pyrimidine-2-carboxylic acid.
Figure imgf000252_0001
[00508] Step A: Methyl 5-(rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate. To a mixture of rac-(1*R,2*S,5*S)-2-(2-chloro-3- fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 30, 10 g, 40.4 mmol, 1.0 eq) in 1,4- dioxane (200 mL, 0.2M) was added methyl 5-bromopyrimidine-2-carboxylate (13 g, 60.6 mmol, 1.5 eq), cesium carbonate (39 g, 121 mmol, 3.0 eq) and RuPhos Pd G4 (6.9 g, 8.08 mmol, 0.2 eq). The reaction was placed under N2 and stirred at 100 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (50-100% EtOAc in PE) to give methyl 5-(rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)pyrimidine-2-carboxylate (9.8 g, 63% yield) as a yellow solid. MS (ESI): mass calcd. for C17H13ClF3N3O2, 383.1; m/z found, 384.1 [M+H]+. 250 QB\184200.00050\92364964.2 VVID-746PC [00509] Step B: Methyl 5-((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan- 3-yl)pyrimidine-2-carboxylate. Separation of methyl 5-(rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)- 6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate via SFC (Stationary phase: AD (25x5 cm); Mobile phase: 40% MeOH/CO2; Rt = 3.82 min (first eluting product)) afforded methyl 5- ((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2- carboxylate. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C17H13ClF3N3O2, 383.1; m/z found, 384.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 7.19 - 7.08 (m, 2H), 6.93 - 6.85 (m, 1H), 5.58 (dd, J = 5.9, 3.0 Hz, 1H), 4.34 (d, J = 9.9 Hz, 1H), 3.99 (s, 3H), 3.96 - 3.87 (m, 1H), 3.08 (ddd, J = 11.8, 9.8, 5.9 Hz, 1H), 2.62 (dt, J = 10.6, 6.3 Hz, 1H). [00510] Step C: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)pyrimidine-2-carboxylic acid. Methyl 5-((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate (500 mg, 1.30 mmol, 1.0 eq) was taken up in MeOH (6.5 mL, 0.2M). To this was added LiOH (5.2 mL, 10.4 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60 °C for 3 hours. After cooling to rt, the reaction was adjusted to pH∼2 with 1N HCl. The precipitated product was collected by filtration to provide the title compound (452 mg, 94% yield), which was used directly in the following steps. MS (ESI): mass calcd. for C16H11ClF3N3O2, 369.1; m/z found, 370.0 [M+H]+. Intermediate 137: 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)pyrimidine-2-carboxylic acid.
Figure imgf000253_0001
[00511] The title compound was prepared in a manner analogous to Intermediate 136 using the second eluting product from Step B (Rt = 5.75 min). MS (ESI): mass calcd. for C16H11ClF3N3O2, 369.1; m/z found, 370.0 [M+H]+. Intermediate 138: Methyl 5-(rac-(7*R,9a*S)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate. 251 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000254_0001
[00512] Step A: Methyl 5-(2-chloro-3-fluorophenyl)pyrazine-2-carboxylate. To a solution of methyl 5- chloropyrazine-2-carboxylate (5.0 g, 29.0 mmol, 1.0 eq) in 1,4-dioxane/water (v/v 5:1, 60 mL, 0.5M) was added (2-chloro-3-fluorophenyl)boronic acid (5.1 g, 29.0 mmol, 1.0 eq), potassium carbonate (10 g, 72.4 mmol, 2.5 eq), and Pd(dppf)Cl2 (1.1 g, 1.45 mmol, 0.05 eq). The reaction was placed under N2 and stirred at 100 °C for 2 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was slurried with MTBE and purified by FCC (100% DCM) to give methyl 5-(2-chloro-3-fluorophenyl)pyrazine-2-carboxylate (18 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 1.5 Hz, 1H), 9.10 (d, J = 1.5 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.43 (dt, J = 7.9, 4.9 Hz, 1H), 7.33 (dt, J = 8.3, 1.7 Hz, 1H), 4.09 (s, 3H). [00513] Step B: (5-(2-Chloro-3-fluorophenyl)pyrazin-2-yl)methanol. To a solution of methyl 5-(2-chloro- 3-fluorophenyl)pyrazine-2-carboxylate (25 g, 93.8 mmol, 1.0 eq) in MeOH (50 mL, 1.9M) was added CaCl2 (47 g, 422 mmol, 4.5 eq) and NaBH4 (25 g, 656 mmol, 7.0 eq). The reaction was stirred at 25 °C for 2 h under N2. The mixture was quenched with water at 0 °C and concentrated under reduced pressure. The residue was extracted with EtOAc and the combined organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (5-(2-chloro-3- fluorophenyl)pyrazin-2-yl)methanol (20 g, 89% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 1.1 Hz, 1H), 8.76 (s, 1H), 7.46 - 7.36 (m, 2H), 7.32 - 7.27 (m, 1H), 4.94 (d, J = 4.6 Hz, 2H). [00514] Step C: (rac-(2*R,5*S)-5-(2-Chloro-3-fluorophenyl)piperazin-2-yl)methanol. To a solution of PtO2 (1.9 g, 8.38 mmol, 0.1 eq) in MeOH (200 mL, 0.4M) was added (5-(2-chloro-3-fluorophenyl)pyrazin- 2-yl)methanol (20 g, 83.8 mmol, 1.0 eq). The reaction was placed under H2 (30 psi) and stirred at 40 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give (rac-(2*R,5*S)-5-(2-chloro-3- fluorophenyl)piperazin-2-yl)methanol (17 g, 83% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.44 (t, J = 8.2 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.10 - 7.03 (m, 1H), 4.25 - 4.19 (m, 1H), 4.18 - 4.11 (m, 1H), 3.55 (dd, J = 10.8, 6.7 Hz, 1H), 3.27 - 3.17 (m, 1H), 3.16 - 3.06 (m, 1H), 3.03 - 2.94 (m, 2H), 2.89 - 2.82 (m, 1H), 2.81 - 2.74 (m, 1H), 2.63 (dd, J = 11.9, 10.2 Hz, 1H). [00515] Step D: tert-Butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2-(hydroxymethyl)piperazine-1- carboxylate. To a solution of (rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)piperazin-2-yl)methanol (11 g, 36.0 mmol, 1.0 eq) in DCM (110 mL, 0.3M) was added Boc2O (7.8 g, 36.0 mmol, 1.0 eq). The reaction was stirred at 25 °C for 16 h before being filtered. The filtrate was concentrated under reduced pressure 252 QB\184200.00050\92364964.2 VVID-746PC and purified by FCC (PE:EtOAc = 3:1) to give tert-butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2- (hydroxymethyl)piperazine-1-carboxylate (8.0 g, 65% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.34 (m, 1H), 7.27 - 7.19 (m, 1H), 7.14 - 7.06 (m, 1H), 4.31 - 4.17 (m, 1H), 4.16 - 4.02 (m, 3H), 4.00 - 3.95 (m, 1H), 3.40 - 3.31 (m, 1H), 3.18 (dd, J = 11.9, 4.1 Hz, 1H), 3.08 - 2.95 (m, 1H), 1.47 (d, J = 5.5 Hz, 9H). [00516] Step E: Methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate. To a mixture of tert-butyl rac-(2*R,5*S)-5-(2- chloro-3-fluorophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate (8.0 g, 23.2 mmol, 1.0 eq) in DMSO (80 mL, 0.3M) was added methyl 5-fluoropyrazine-2-carboxylate (5.4 g, 34.8 mmol, 1.5 eq) and TEA (7.0 g, 69.6 mmol, 3.0 eq). The reaction was placed under N2 and stirred for 16 h at 80 °C. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (PE:EtOAc = 1:1) to give methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2- chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate (6.0 g, 54% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 0.8 Hz, 1H), 7.65 (br s, 1H), 7.24 - 7.17 (m, 1H), 7.16 - 7.09 (m, 1H), 6.99 (br d, J = 7.4 Hz, 1H), 5.39 - 5.21 (m, 2H), 4.87 - 4.44 (m, 1H), 4.36 - 4.19 (m, 1H), 3.97 - 3.83 (m, 5H), 3.79 - 3.71 (m, 1H), 3.61 - 3.46 (m, 1H), 3.35 - 3.22 (m, 1H), 1.51 (s, 9H). [00517] Step F: Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1- yl)pyrazine-2-carboxylate. To a solution of methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2-chloro- 3-fluorophenyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate (1.6 g, 2.70 mmol, 1.0 eq) in ACN (15 mL, 0.2M) was added TsOH·H2O (626 mg, 3.30 mmol, 1.2 eq). The reaction was stirred at 40 °C for 12 h. The mixture was concentrated under reduced pressure to give methyl 5-(rac-(2*S,5*R)-2-(2- chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate (1.5 g, quant. yield) as a light yellow oil. MS (ESI): mass calcd. for C17H18ClFN4O3, 380.1; m/z found, 381.0 [M+H]+. [00518] Step G: Methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-4-(2-chloroacetyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate. To a solution of methyl 5-(rac-(2*S,5*R)-2-(2- chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate (1.5 g, 2.70 mmol, 1.0 eq, TsOH salt) and TEA (829 mg, 8.19 mmol, 3.0 eq) in DCM (15 mL, 0.2M) was added 2-chloroacetyl chloride (308 mg, 2.73 mmol, 1.0 eq) dropwise over 5 mins at 0 °C. The reaction was stirred at 20 °C for 2 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (100% EtOAc) to give methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-4-(2-chloroacetyl)-5- (hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate (900 mg, 72% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 1.0 Hz, 1H), 7.70 (d, J = 0.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.17 (dt, J = 8.3, 1.3 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 5.46 (dd, J = 11.3, 5.9 Hz, 1H), 5.32 (dd, J = 14.5, 6.5 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.32 (dd, J = 14.8, 5.8 Hz, 1H), 4.20 (d, J = 5.8 Hz, 2H), 4.03 (dd, J = 11.4, 3.7 Hz, 1H), 3.93 (s, 3H), 3.82 - 3.66 (m, 3H). 253 QB\184200.00050\92364964.2 VVID-746PC [00519] Step H: Methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate. A solution of methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3- fluorophenyl)-4-(2-chloroacetyl)-5-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate (870 mg, 1.90 mmol, 1.0 eq) in THF (9.0 mL, 0.2M) was placed under N2 and cooled to 0 °C. To the mixture was added sodium hydride (60% in mineral oil, 228 mg, 5.70 mmol, 3.0 eq) in portions. The reaction was stirred at 25 °C for 2 h. The mixture was quenched with MeOH and stirred for 20 min then concentrated under reduced pressure. The residue was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (PE:EtOAc = 1:1) to give methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3-fluorophenyl)-4- oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate (470 mg, 59% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.1 Hz, 1H), 7.18 (dd, J = 7.9, 5.4 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.04 (d, J = 7.7 Hz, 1H), 5.84 (br d, J = 3.6 Hz, 1H), 4.99 (dd, J = 14.1, 1.9 Hz, 1H), 4.53 (dd, J = 13.6, 3.5 Hz, 1H), 4.20 (d, J = 9.3 Hz, 2H), 4.16 - 4.08 (m, 3H), 3.96 (s, 3H), 3.87 - 3.79 (m, 1H), 3.71 (dd, J = 12.0, 6.3 Hz, 1H). [00520] Step I: Methyl 5-(rac-(7*R,9a*S)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate. A solution of methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3- fluorophenyl)-4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2-carboxylate (470 mg, 1.12 mmol, 1.0 eq) in THF (5.0 mL, 0.2M) was placed under N2 and cooled to 0 °C. To the solution was added BH3 (0.34 mL, 3.35 mmol, 3.0 eq, 10M in Me2S) dropwise. The reaction was stirred at rt for 2 h. The mixture was quenched with MeOH (3.0 mL) dropwise at 20 °C under N2 and stirred at 0 °C for 15 min. After concentrating under reduced pressure, the residue was purified by FCC (PE:EtOAc = 1:1) to give methyl 5-(rac-(7*S,9*aR)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)pyrazine-2-carboxylate (170 mg, 37% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.99 (s, 1H), 7.23 - 7.19 (m, 1H), 7.15 (dt, J = 7.9, 5.3 Hz, 1H), 7.11 - 7.04 (m, 1H), 5.71 (br s, 1H), 4.41 - 4.27 (m, 1H), 3.94 (s, 3H), 3.92 - 3.83 (m, 2H), 3.70 (dt, J = 11.4, 2.1 Hz, 1H), 3.40 (t, J = 10.5 Hz, 1H), 3.20 - 3.09 (m, 2H), 2.83 (dd, J = 12.1, 5.2 Hz, 1H), 2.62 (br d, J = 11.7 Hz, 1H), 2.52 - 2.43 (m, 1H), 2.34 (dt, J = 11.5, 3.3 Hz, 1H). Example 1: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000256_0001
254 QB\184200.00050\92364964.2 VVID-746PC [00521] Step A: Methyl (S)-4-(2-(2-chlorophenyl)pyrrolidin-1-yl)benzoate. Methyl 4-bromobenzoate (75 mg, 0.342 mmol, 1.0 eq) was taken up in toluene (1.7 mL, 0.2 M). To this was added (S)-2-(2- chlorophenyl)pyrrolidine (86 mg, 0.376 mmol, 1.1 eq), cesium carbonate (341 mg, 1.03 mmol, 3.0 eq), and SPhos Pd G4 (27 mg, 0.034 mmol, 0.1 eq). The vial was capped, purged with N2, and heated to 100°C for 24 hours. After cooling to rt, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-10% EtOAc in heptanes) provided methyl (S)-4-(2-(2- chlorophenyl)pyrrolidin-1-yl)benzoate (38 mg, 35% yield). MS (ESI): mass calcd. for C18H18ClNO2, 315.1; m/z found, 316.0 [M+H]+. [00522] Step B: (S)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)benzoic acid. Methyl (S)-4-(2-(2- chlorophenyl)pyrrolidin-1-yl)benzoate (38 mg, 0.120 mmol, 1.0 eq) was taken up in methanol (0.5 mL, 0.25 M). To this was added lithium hydroxide (0.50 mL, 0.963 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60°C for 2 hours. After cooling to rt, the reaction was adjusted to pH ~2 with 1N HCl. The precipitate was collected by filtration to provide (S)-4-(2-(2-chlorophenyl)pyrrolidin-1-yl)benzoic acid (26 mg, 72% yield) as a white solid. MS (ESI): mass calcd. for C17H16ClNO2, 301.1; m/z found, 302.0 [M+H]+. [00523] Step C: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. (S)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)benzoic acid (26 mg, 0.086 mmol, 1.0 eq) and HATU (41 mg, 0.103 mmol, 1.2 eq) were taken up in DMF (0.4 mL, 0.2 M). To this was added N,N- diisopropylethylamine (36 µL, 0.207 mmol, 2.4 eq) and the reaction was stirred at rt for 20 min. Finally, (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 30 mg, 0.095 mmol, 1.1 eq) was added and the reaction was stirred at rt overnight. The crude material was filtered through a PTFE filter with MeOH. Purification by RP-HPLC (5-95% ACN in 0.1% HCOOH water) provided 4- ((S)-2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (29 mg, 77% yield) as a white solid. MS (ESI): mass calcd. for C22H25ClN2O3S, 432.1; m/z found, 433.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 7.9, 1.4 Hz, 1H), 7.18 (td, J = 7.6, 1.8 Hz, 1H), 7.11 (td, J = 7.5, 1.4 Hz, 1H), 6.98 (dd, J = 7.6, 1.8 Hz, 1H), 6.90 (dd, J = 15.1, 4.6 Hz, 1H), 6.45 (dd, J = 15.1, 1.7 Hz, 1H), 6.40 (d, J = 8.8 Hz, 2H), 6.05 (d, J = 7.8 Hz, 1H), 5.12 (dd, J = 8.2, 1.6 Hz, 1H), 5.00 – 4.89 (m, 1H), 3.82 – 3.73 (m, 1H), 3.55 – 3.46 (m, 1H), 2.89 (s, 3H), 2.53 – 2.39 (m, 1H), 2.10 – 1.94 (m, 3H), 1.37 (d, J = 7.1 Hz, 3H). Example 2: 4-((R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. 255 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000258_0001
[00524] The title compound was prepared in a manner analogous to Example 1 using (R)-2-(2- chlorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C22H25ClN2O3S, 432.1; m/z found, 433.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.7 Hz, 2H), 7.40 (dd, J = 7.8, 1.3 Hz, 1H), 7.17 (td, J = 7.6, 1.8 Hz, 1H), 7.10 (td, J = 7.5, 1.3 Hz, 1H), 6.96 (dd, J = 7.7, 1.8 Hz, 1H), 6.88 (dd, J = 15.1, 4.5 Hz, 1H), 6.46 – 6.34 (m, 3H), 6.28 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 8.2, 1.6 Hz, 1H), 4.99 – 4.88 (m, 1H), 3.80 – 3.70 (m, 1H), 3.55 – 3.44 (m, 1H), 2.85 (s, 3H), 2.52 – 2.38 (m, 1H), 2.11 – 1.92 (m, 3H), 1.36 (d, J = 7.1 Hz, 3H). Example 3: 4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000258_0002
[00525] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C23H27ClN2O3S, 446.1; m/z found, 447.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.53 (m, 2H), 7.36 – 7.29 (m, 1H), 7.21 – 7.14 (m, 1H), 7.06 (pd, J = 7.3, 1.8 Hz, 2H), 6.87 (ddd, J = 15.1, 4.6, 2.5 Hz, 1H), 6.78 – 6.71 (m, 2H), 6.43 (ddd, J = 15.1, 4.2, 1.7 Hz, 1H), 6.20 (dd, J = 8.0, 3.0 Hz, 1H), 4.99 – 4.87 (m, 2H), 3.69 – 3.58 (m, 1H), 3.50 – 3.40 (m, 1H), 2.87 (d, J = 1.5 Hz, 3H), 2.19 – 2.06 (m, 1H), 2.01 – 1.87 (m, 1H), 1.89 – 1.75 (m, 2H), 1.73 – 1.63 (m, 1H), 1.65 – 1.48 (m, 1H), 1.35 (dd, J = 7.1, 2.3 Hz, 3H). Example 4: 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. 256 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000259_0001
[00526] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 3) by SFC (Stationary phase: A6-5 (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 6.61 min). MS (ESI): mass calcd. for C23H27ClN2O3S, 446.1; m/z found, 447.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.53 (m, 2H), 7.35 – 7.29 (m, 1H), 7.18 (dd, J = 7.3, 2.2 Hz, 1H), 7.06 (pd, J = 7.3, 1.8 Hz, 2H), 6.89 (dd, J = 15.1, 4.6 Hz, 1H), 6.79 – 6.73 (m, 2H), 6.44 (dd, J = 15.1, 1.7 Hz, 1H), 6.02 (d, J = 7.7 Hz, 1H), 4.97 – 4.88 (m, 2H), 3.70 – 3.59 (m, 1H), 3.46 – 3.38 (m, 1H), 2.89 (s, 3H), 2.18 – 2.06 (m, 1H), 1.99 – 1.89 (m, 1H), 1.89 – 1.75 (m, 2H), 1.73 – 1.63 (m, 2H), 1.64 – 1.49 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H). Example 5: 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000259_0002
[00527] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 3) by SFC (Stationary phase: A6-5 (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 7.43 min). MS (ESI): mass calcd. for C23H27ClN2O3S, 446.1; m/z found, 447.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.52 (m, 2H), 7.35 – 7.30 (m, 1H), 7.18 (dd, J = 7.3, 2.1 Hz, 1H), 7.11 – 7.01 (m, 2H), 6.87 (dd, J = 15.1, 4.6 Hz, 1H), 6.79 – 6.70 (m, 2H), 6.42 (dd, J = 15.1, 1.7 Hz, 1H), 6.12 (d, J = 7.9 Hz, 1H), 4.99 – 4.87 (m, 2H), 3.64 (ddd, J = 12.3, 7.6, 4.7 Hz, 1H), 3.43 (ddd, J = 12.2, 7.1, 4.7 Hz, 1H), 2.86 (s, 3H), 2.17 – 2.07 (m, 1H), 2.00 – 1.89 (m, 1H), 1.89 – 1.76 (m, 2H), 1.76 – 1.60 (m, 2H), 1.61 – 1.49 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H). Example 6: 4-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000259_0003
257 QB\184200.00050\92364964.2 VVID-746PC [00528] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)azepane instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C24H29ClN2O3S, 460.2; m/z found, 461.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.5 Hz, 2H), 7.42 – 7.35 (m, 1H), 7.21 – 7.08 (m, 3H), 6.89 (ddd, J = 15.1, 4.5, 2.8 Hz, 1H), 6.58 – 6.50 (m, 2H), 6.43 (ddd, J = 15.1, 4.1, 1.8 Hz, 1H), 6.01 (d, J = 7.8 Hz, 1H), 5.02 – 4.88 (m, 1H), 4.86 (ddd, J = 11.9, 5.0, 2.0 Hz, 1H), 4.03 – 3.94 (m, 1H), 3.72 (dd, J = 15.5, 11.2 Hz, 1H), 2.88 (d, J = 2.7 Hz, 3H), 2.57 (ddd, J = 14.9, 8.4, 5.0 Hz, 1H), 2.08 – 1.97 (m, 1H), 1.99 – 1.85 (m, 2H), 1.75 – 1.59 (m, 2H), 1.50 – 1.39 (m, 2H), 1.36 (dd, J = 7.1, 3.2 Hz, 3H). Example 7: 4-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000260_0001
[00529] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Example 6) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 27% MeOH/CO2; Rt = 3.12 min). MS (ESI): mass calcd. for C24H29ClN2O3S, 460.2; m/z found, 461.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.9 Hz, 2H), 7.41 – 7.36 (m, 1H), 7.21 – 7.13 (m, 2H), 7.13 – 7.09 (m, 1H), 6.90 (dd, J = 15.1, 4.5 Hz, 1H), 6.54 (d, J = 8.8 Hz, 2H), 6.44 (dd, J = 15.1, 1.8 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 5.02 – 4.89 (m, 1H), 4.87 (dd, J = 11.8, 5.0 Hz, 1H), 3.99 (dd, J = 15.4, 4.6 Hz, 1H), 3.72 (dd, J = 15.5, 11.2 Hz, 1H), 2.89 (s, 3H), 2.57 (ddd, J = 14.9, 8.4, 5.0 Hz, 1H), 2.10 – 1.98 (m, 1H), 1.98 – 1.86 (m, 1H), 1.76 – 1.57 (m, 3H), 1.50 – 1.38 (m, 2H), 1.36 (d, J = 7.1 Hz, 3H). Example 8: 4-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000260_0002
[00530] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Example 6) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 27% MeOH/CO2; Rt = 3.99 min). MS (ESI): mass calcd. for C24H29ClN2O3S, 460.2; m/z found, 258 QB\184200.00050\92364964.2 VVID-746PC 461.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.8 Hz, 2H), 7.42 – 7.36 (m, 1H), 7.21 – 7.14 (m, 2H), 7.14 – 7.08 (m, 1H), 6.90 (dd, J = 15.1, 4.5 Hz, 1H), 6.54 (d, J = 8.7 Hz, 2H), 6.43 (dd, J = 15.1, 1.7 Hz, 1H), 5.96 (d, J = 7.8 Hz, 1H), 5.02 – 4.90 (m, 1H), 4.86 (dd, J = 11.8, 4.9 Hz, 1H), 3.99 (dd, J = 15.5, 4.7 Hz, 1H), 3.72 (dd, J = 15.5, 11.2 Hz, 1H), 2.88 (s, 3H), 2.57 (ddd, J = 15.0, 8.4, 5.0 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.99 – 1.87 (m, 1H), 1.76 – 1.57 (m, 3H), 1.50 – 1.39 (m, 2H), 1.37 (d, J = 7.1 Hz, 3H). Example 9: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000261_0001
[00531] The title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.83 (t, J = 9.1 Hz, 1H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.4 Hz, 1H), 6.98 – 6.88 (m, 2H), 6.58 – 6.49 (m, 1H), 6.49 – 6.42 (m, 1H), 6.25 (dd, J = 8.9, 2.3 Hz, 1H), 6.07 (dd, J = 16.1, 2.3 Hz, 1H), 5.12 (dd, J = 8.1, 1.6 Hz, 1H), 5.05 – 4.91 (m, 1H), 3.80 – 3.70 (m, 1H), 3.56 – 3.45 (m, 1H), 2.92 (s, 3H), 2.55 – 2.41 (m, 1H), 2.13 – 1.96 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 10: (E)-4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-(3-(methylsulfonyl)allyl)benzamide.
Figure imgf000261_0002
[00532] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A and (E)-3- (methylsulfonyl)prop-2-en-1-amine, 4-methylbenzenesulfonic acid instead of (R,E)-4-(methylsulfonyl)but- 3-en-2-amine, 4-methylbenzenesulfonic acid in Step C. MS (ESI): mass calcd. for C22H25ClN2O3S, 432.1; m/z found, 433.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.54 (m, 2H), 7.36 – 7.30 (m, 1H), 7.19 (dd, J = 7.2, 2.2 Hz, 1H), 7.07 (pd, J = 7.3, 1.8 Hz, 2H), 6.93 (dt, J = 15.1, 4.3 Hz, 1H), 6.81 – 6.72 (m, 2H), 6.45 (dt, J = 15.2, 2.0 Hz, 1H), 6.30 (s, 1H), 4.96 (dd, J = 7.0, 5.1 Hz, 1H), 4.23 (ddd, J = 6.2, 4.4, 2.0 259 QB\184200.00050\92364964.2 VVID-746PC Hz, 2H), 3.65 (ddd, J = 12.5, 7.7, 4.7 Hz, 1H), 3.46 (ddd, J = 12.2, 7.0, 4.8 Hz, 1H), 2.89 (s, 3H), 2.13 (ddt, J = 12.8, 8.4, 4.5 Hz, 1H), 2.02 – 1.90 (m, 1H), 1.91 – 1.78 (m, 2H), 1.64 – 1.50 (m, 2H). Example 11: 4-(3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000262_0001
[00533] The title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H24ClFN2O4S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.84 (td, J = 9.1, 2.4 Hz, 1H), 7.38 (ddd, J = 7.8, 2.6, 1.5 Hz, 1H), 7.22 (dd, J = 7.5, 2.0 Hz, 1H), 7.19 – 7.08 (m, 2H), 6.89 (ddd, J = 15.1, 4.6, 2.0 Hz, 1H), 6.63 (ddd, J = 8.8, 6.3, 2.4 Hz, 1H), 6.55 (dd, J = 14.1, 7.7 Hz, 1H), 6.49 – 6.39 (m, 2H), 5.03 – 4.90 (m, 2H), 4.14 – 4.03 (m, 2H), 3.95 (ddd, J = 11.3, 7.2, 3.9 Hz, 1H), 3.85 (ddd, J = 11.7, 5.3, 1.3 Hz, 1H), 3.73 (ddd, J = 12.3, 7.2, 4.0 Hz, 1H), 3.49 – 3.39 (m, 1H), 2.91 (d, J = 0.7 Hz, 3H), 1.38 (dd, J = 7.1, 2.5 Hz, 3H). Example 12: 4-((R)-3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000262_0002
[00534] The title compound was prepared via separation of 4-(3-(2-chlorophenyl)morpholino)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 11) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 18% MeOH/CO2; Rt = 3.21 min (first eluting product)). MS (ESI): mass calcd. for C22H24ClFN2O4S, 466.1; m/z found, 467.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 9.1 Hz, 1H), 7.39 (dd, J = 7.8, 1.5 Hz, 1H), 7.26 – 7.08 (m, 3H), 6.91 (dd, J = 15.1, 4.6 Hz, 1H), 6.70 – 6.52 (m, 2H), 6.47 (ddd, J = 15.8, 6.2, 2.1 Hz, 2H), 5.06 – 4.90 (m, 2H), 4.10 (ddd, J = 16.2, 9.8, 3.1 Hz, 2H), 3.96 (ddd, J = 11.3, 7.2, 3.9 Hz, 1H), 3.86 (dd, J = 11.8, 5.2 Hz, 1H), 3.74 (ddd, J = 12.3, 7.2, 4.0 Hz, 1H), 3.55 – 3.38 (m, 3H), 2.92 (s, 3H), 1.39 (d, J = 7.1 Hz, 3H). 260 QB\184200.00050\92364964.2 VVID-746PC Example 13: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide.
Figure imgf000263_0001
[00535] The title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C24H30N2O3S, 426.2; m/z found, 427.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.50 (m, 2H), 7.18 – 7.08 (m, 2H), 7.10 – 6.97 (m, 2H), 6.88 (ddd, J = 15.2, 4.6, 1.7 Hz, 1H), 6.76 – 6.68 (m, 2H), 6.44 (ddd, J = 15.1, 3.0, 1.7 Hz, 1H), 6.11 – 6.00 (m, 1H), 4.98 – 4.88 (m, 1H), 4.68 (dd, J = 7.1, 5.0 Hz, 1H), 3.71 – 3.59 (m, 1H), 3.51 – 3.41 (m, 1H), 2.89 (d, J = 1.1 Hz, 3H), 2.42 (s, 3H), 2.09 – 1.99 (m, 1H), 1.99 – 1.89 (m, 1H), 1.89 – 1.68 (m, 3H), 1.63 – 1.48 (m, 1H), 1.36 (dd, J = 7.1, 2.1 Hz, 3H). Example 14: 2-Fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000263_0002
[00536] The title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.78 (m, 1H), 7.24 – 7.14 (m, 1H), 7.10 – 6.95 (m, 3H), 6.91 (ddd, J = 15.1, 4.5, 1.1 Hz, 1H), 6.60 (dt, J = 9.0, 2.8 Hz, 1H), 6.54 (dd, J = 14.5, 7.7 Hz, 1H), 6.46 (dt, J = 15.1, 2.0 Hz, 1H), 6.40 (ddd, J = 16.8, 4.0, 2.4 Hz, 1H), 5.15 – 5.07 (m, 1H), 5.03 – 4.91 (m, 1H), 3.74 – 3.64 (m, 1H), 3.56 – 3.43 (m, 1H), 2.91 (s, 3H), 2.17 – 2.01 (m, 2H), 1.97 – 1.87 (m, 1H), 1.88 – 1.74 (m, 1H), 1.67 – 1.47 (m, 2H), 1.38 (dd, J = 7.1, 2.1 Hz, 3H). Example 15: 2-Fluoro-4-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. 261 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000264_0001
[00537] The title compound was prepared via separation of 2-fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 14) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 20% EtOH/CO2; Rt = 2.82 min). MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.83 (t, J = 9.3 Hz, 1H), 7.24 – 7.14 (m, 1H), 7.10 – 6.95 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.60 (dd, J = 9.0, 2.5 Hz, 1H), 6.53 (dd, J = 14.6, 7.7 Hz, 1H), 6.49 – 6.36 (m, 2H), 5.12 (t, J = 5.3 Hz, 1H), 5.04 – 4.92 (m, 1H), 3.70 (dt, J = 12.7, 5.2 Hz, 1H), 3.57 – 3.46 (m, 1H), 2.92 (s, 3H), 2.18 – 2.01 (m, 2H), 1.98 – 1.88 (m, 1H), 1.89 – 1.75 (m, 1H), 1.69 – 1.48 (m, 2H), 1.38 (d, J = 7.2 Hz, 3H). Example 16: 2-Fluoro-4-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000264_0002
[00538] The title compound was prepared via separation of 2-fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 14) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 20% EtOH/CO2; Rt = 3.84 min). MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.83 (t, J = 9.3 Hz, 1H), 7.25 – 7.15 (m, 1H), 7.10 – 6.95 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.61 (dd, J = 9.0, 2.5 Hz, 1H), 6.53 (dd, J = 14.6, 7.7 Hz, 1H), 6.49 – 6.33 (m, 2H), 5.04 – 4.93 (m, 1H), 3.70 (dt, J = 12.7, 4.9 Hz, 1H), 3.57 – 3.46 (m, 1H), 2.92 (s, 3H), 2.19 – 2.01 (m, 2H), 1.98 – 1.86 (m, 1H), 1.89 – 1.76 (m, 1H), 1.68 – 1.49 (m, 2H), 1.39 (d, J = 7.1 Hz, 3H). Example 17: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2,6-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide. 262 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000265_0001
[00539] The title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2,6- difluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 7.8, 1.3 Hz, 1H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.15 (td, J = 7.5, 1.4 Hz, 1H), 6.94 – 6.84 (m, 2H), 6.51 (dd, J = 15.1, 1.8 Hz, 1H), 6.11 – 6.01 (m, 1H), 5.97 - 5.87 (m, 2H), 5.05 (dd, J = 8.1, 1.7 Hz, 1H), 4.99 – 4.89 (m, 1H), 3.74 – 3.65 (m, 1H), 3.51 – 3.40 (m, 1H), 2.91 (s, 3H), 2.54 – 2.41 (m, 1H), 2.11 – 1.96 (m, 4H), 1.37 (d, J = 7.1 Hz, 3H). Example 18: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide.
Figure imgf000265_0002
[00540] The title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4- bromobenzoate in Step A. MS (ESI): mass calcd. for C24H29FN2O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 9.3 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.12 – 6.99 (m, 3H), 6.89 (ddd, J = 15.1, 4.5, 1.0 Hz, 1H), 6.61 – 6.48 (m, 2H), 6.45 (dt, J = 15.1, 1.5 Hz, 1H), 6.29 (dd, J = 16.9, 2.4 Hz, 1H), 5.01 – 4.88 (m, 1H), 4.80 (td, J = 5.8, 1.6 Hz, 1H), 3.66 – 3.55 (m, 2H), 2.88 (s, 3H), 2.42 (s, 3H), 2.11 – 2.00 (m, 1H), 1.97 – 1.89 (m, 1H), 1.92 – 1.76 (m, 2H), 1.72 – 1.60 (m, 1H), 1.60 – 1.50 (m, 1H), 1.36 (dd, J = 7.2, 2.5 Hz, 3H). Example 19: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-2-(o-tolyl)piperidin-1- yl)benzamide.
Figure imgf000265_0003
263 QB\184200.00050\92364964.2 VVID-746PC [00541] The title compound was prepared via separation of 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide (Example 18) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 2.59 min). MS (ESI): mass calcd. for C24H29FN2O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.75 (m, 1H), 7.18 – 7.13 (m, 1H), 7.13 – 7.01 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.56 – 6.41 (m, 3H), 6.30 (dd, J = 16.9, 2.4 Hz, 1H), 5.03 – 4.91 (m, 1H), 4.81 (t, J = 5.8 Hz, 1H), 3.67 – 3.58 (m, 2H), 2.91 (s, 3H), 2.43 (s, 3H), 2.13 – 2.02 (m, 1H), 2.01 – 1.89 (m, 1H), 1.91 – 1.78 (m, 2H), 1.75 – 1.61 (m, 1H), 1.63 – 1.52 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H). Example 20: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)piperidin-1- yl)benzamide.
Figure imgf000266_0001
[00542] The title compound was prepared via separation of 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide (Example 18) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% MeOH/CO 2; Rt = 3.02 min). MS (ESI): mass calcd. for C24H29FN2O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 9.7, 9.0 Hz, 1H), 7.19 – 7.13 (m, 1H), 7.13 – 7.01 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.56 – 6.41 (m, 3H), 6.30 (dd, J = 16.9, 2.4 Hz, 1H), 5.03 – 4.91 (m, 1H), 4.81 (t, J = 5.8 Hz, 1H), 3.67 – 3.57 (m, 2H), 2.91 (s, 3H), 2.43 (s, 3H), 2.13 – 2.02 (m, 1H), 2.01 – 1.88 (m, 1H), 1.91 – 1.78 (m, 2H), 1.75 – 1.62 (m, 1H), 1.64 – 1.50 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H). Example 21: 2-Fluoro-4-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000266_0002
[00543] The title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H24F2N2O3S, 434.2; m/z found, 435.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.81 (td, J = 9.1, 1.5 Hz, 1H), 7.28 – 7.17 (m, 1H), 7.13 – 7.03 (m, 1H), 7.00 (tt, J = 7.4, 1.4 Hz, 1H), 6.95 – 6.85 (m, 2H), 6.63 – 6.52 (m, 1H), 6.46 264 QB\184200.00050\92364964.2 VVID-746PC (dt, J = 15.2, 2.0 Hz, 1H), 6.30 (dt, J = 9.0, 2.8 Hz, 1H), 6.10 (ddd, J = 16.1, 3.9, 2.3 Hz, 1H), 5.06 (d, J = 8.1 Hz, 1H), 5.02 – 4.91 (m, 1H), 3.74 – 3.64 (m, 1H), 3.52 – 3.40 (m, 1H), 2.90 (d, J = 0.8 Hz, 3H), 2.51 – 2.35 (m, 1H), 2.12 – 1.92 (m, 3H), 1.38 (dd, J = 7.1, 2.3 Hz, 3H). Example 22: 2-Fluoro-4-((*S)-2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000267_0001
[00544] The title compound was prepared via separation of 2-fluoro-4-(2-(2-fluorophenyl)pyrrolidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 21) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 3.01 min (first eluting product)). MS (ESI): mass calcd. for C22H24F2N2O3S, 434.2; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.85 (t, J = 9.2 Hz, 1H), 7.26 – 7.19 (m, 1H), 7.09 (ddd, J = 10.5, 8.2, 1.2 Hz, 1H), 7.01 (td, J = 7.4, 1.2 Hz, 1H), 6.97 – 6.87 (m, 2H), 6.58 – 6.50 (m, 1H), 6.47 (dd, J = 15.1, 1.7 Hz, 1H), 6.32 (dd, J = 8.9, 2.4 Hz, 1H), 6.12 (dd, J = 16.1, 2.3 Hz, 1H), 5.08 (d, J = 8.1 Hz, 1H), 5.04 – 4.92 (m, 1H), 3.76 – 3.66 (m, 1H), 3.54 – 3.42 (m, 1H), 2.92 (s, 3H), 2.53 – 2.38 (m, 1H), 2.14 – 1.95 (m, 3H), 1.39 (d, J = 7.2 Hz, 3H). Example 23: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)pyrrolidin-1- yl)benzamide.
Figure imgf000267_0002
[00545] The title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4- bromobenzoate in Step A. MS (ESI): mass calcd. for C23H27FN2O3S, 430.2; m/z found, 431.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 9.2 Hz, 1H), 7.25 – 7.18 (m, 1H), 7.15 (tt, J = 7.4, 1.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.96 – 6.85 (m, 2H), 6.53 (dd, J = 14.8, 7.7 Hz, 1H), 6.46 (dt, J = 15.2, 1.4 Hz, 1H), 6.28 – 6.17 (m, 1H), 6.08 – 5.96 (m, 1H), 5.04 – 4.93 (m, 1H), 4.92 (dt, J = 8.4, 1.7 Hz, 1H), 3.78 – 3.69 265 QB\184200.00050\92364964.2 VVID-746PC (m, 1H), 3.50 (q, J = 8.6 Hz, 1H), 2.91 (s, 3H), 2.51 – 2.36 (m, 4H), 2.13 – 2.01 (m, 2H), 1.96 – 1.85 (m, 1H), 1.38 (dd, J = 7.1, 2.3 Hz, 3H). Example 24: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)pyrrolidin-1- yl)benzamide.
Figure imgf000268_0001
[00546] The title compound was prepared via separation of 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)-4-(2-(o-tolyl)pyrrolidin-1-yl)benzamide (Example 23) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 2.71 min (first eluting product)). MS (ESI): mass calcd. for C23H27FN2O3S, 430.2; m/z found, 431.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 9.2 Hz, 1H), 7.24 – 7.19 (m, 1H), 7.15 (td, J = 7.4, 1.4 Hz, 1H), 7.11 – 7.03 (m, 1H), 6.95 – 6.85 (m, 2H), 6.56 – 6.43 (m, 2H), 6.27 – 6.19 (m, 1H), 6.03 (d, J = 15.6 Hz, 1H), 5.04 – 4.93 (m, 1H), 4.92 (dd, J = 8.4, 2.0 Hz, 1H), 3.79 – 3.66 (m, 1H), 3.54 – 3.44 (m, 1H), 2.92 (s, 3H), 2.49 - 2.38 (m, 4H), 2.13 – 2.00 (m, 2H), 1.96 – 1.86 (m, 1H), 1.38 (d, J = 7.1 Hz, 3H). Example 25: 2-Fluoro-4-(3-(2-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000268_0002
[00547] The title compound was prepared in a manner analogous to Example 1 using 3-(2- fluorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H24F2N2O4S, 450.1; m/z found, 451.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.85 (td, J = 9.2, 1.5 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.09 – 6.96 (m, 2H), 6.89 (ddd, J = 15.2, 4.6, 1.5 Hz, 1H), 6.67 (dt, J = 8.9, 2.6 Hz, 1H), 6.58 (dd, J = 13.9, 7.7 Hz, 1H), 6.52 – 6.42 (m, 2H), 5.01 – 4.91 (m, 2H), 4.10 (dt, J = 11.5, 4.2 Hz, 1H), 4.08 – 3.98 (m, 2H), 3.88 (ddd, J = 11.4, 8.9, 3.7 Hz, 1H), 3.65 (ddd, J = 12.8, 8.9, 4.0 Hz, 1H), 3.50 – 3.40 (m, 1H), 2.89 (d, J = 0.8 Hz, 3H), 1.37 (dd, J = 7.2, 2.1 Hz, 3H). 266 QB\184200.00050\92364964.2 VVID-746PC Example 26: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000269_0001
[00548] The title compound was prepared in a manner analogous to Example 1 using methyl 5- bromopicolinate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C21H24ClN3O3S, 433.1; m/z found, 434.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.4 Hz, 1H), 6.99 – 6.89 (m, 2H), 6.74 (dd, J = 8.7, 2.9 Hz, 1H), 6.46 (dd, J = 15.1, 1.8 Hz, 1H), 5.17 (dd, J = 8.2, 1.8 Hz, 1H), 4.99 – 4.88 (m, 1H), 3.81 (ddd, J = 9.8, 5.9, 2.9 Hz, 1H), 3.54 (td, J = 9.4, 7.0 Hz, 1H), 2.90 (s, 3H), 2.57 – 2.44 (m, 1H), 2.16 – 2.01 (m, 3H), 1.40 (d, J = 7.2 Hz, 3H). Example 27: 5-(2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000269_0002
[00549] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H25ClFN3O3S, 465.1; m/z found, 466.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.79 (ddd, J = 5.9, 2.5, 1.5 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.39 (ddd, J = 7.6, 2.7, 1.4 Hz, 1H), 7.21 – 7.06 (m, 3H), 6.90 (ddd, J = 15.1, 4.6, 3.1 Hz, 1H), 6.68 (ddd, J = 14.1, 4.5, 2.4 Hz, 1H), 6.46 (dt, J = 15.1, 1.9 Hz, 1H), 5.12 (dt, J = 6.0, 3.0 Hz, 1H), 4.98 – 4.87 (m, 1H), 3.72 – 3.59 (m, 2H), 2.91 (d, J = 1.4 Hz, 3H), 2.24 – 2.11 (m, 1H), 2.08 – 1.82 (m, 3H), 1.70 – 1.58 (m, 2H), 1.39 (dd, J = 7.1, 1.1 Hz, 3H). Example 28: 5-((S)-2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide. 267 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000270_0001
[00550] The title compound was prepared via separation of 5-(2-(2-chlorophenyl)piperidin-1-yl)-3-fluoro- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 27) by SFC (Stationary phase: A6-5 (3x25 cm); Mobile phase: 40% MeOH/CO2 with 0.05% DEA; Rt = 11.1 min (second eluting product)). Absolute stereochemistry was determined by single crystal x-ray diffraction. MS (ESI): mass calcd. for C22H25ClFN3O3S, 465.1; m/z found, 466.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 2.5, 1.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.43 – 7.33 (m, 1H), 7.22 – 7.06 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.68 (dd, J = 14.2, 2.4 Hz, 1H), 6.47 (dd, J = 15.1, 1.7 Hz, 1H), 5.11 (t, J = 5.7 Hz, 1H), 4.98 – 4.85 (m, 1H), 3.72 – 3.59 (m, 2H), 2.91 (s, 3H), 2.27 – 2.10 (m, 1H), 2.09 – 1.82 (m, 3H), 1.63 (p, J = 6.4 Hz, 2H), 1.39 (d, J = 7.1 Hz, 3H). Example 29: (S,E)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-(3-(methylsulfonyl)allyl)benzamide.
Figure imgf000270_0002
[00551] The title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A and (E)-3-(methylsulfonyl)prop-2-en-1- amine, 4-methylbenzenesulfonic acid instead of (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4- methylbenzenesulfonic acid in Step C. MS (ESI): mass calcd. for C21H22ClFN2O3S, 436.1; m/z found, 437.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.86 (t, J = 9.1 Hz, 1H), 7.43 (dd, J = 7.8, 1.4 Hz, 1H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.15 (td, J = 7.5, 1.4 Hz, 1H), 7.02 – 6.91 (m, 2H), 6.80 (dt, J = 13.4, 5.8 Hz, 1H), 6.49 (dt, J = 15.1, 2.0 Hz, 1H), 6.27 (dd, J = 9.0, 2.3 Hz, 1H), 6.07 (dd, J = 16.1, 2.3 Hz, 1H), 5.12 (dd, J = 8.2, 1.6 Hz, 1H), 4.33 – 4.25 (m, 2H), 3.80 – 3.70 (m, 1H), 3.57 – 3.45 (m, 1H), 2.92 (s, 3H), 2.55 – 2.41 (m, 1H), 2.12 – 1.96 (m, 3H). Example 30: 3-Fluoro-5-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide. 268 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000271_0001
[00552] The title compound was prepared in a manner analogous to Example 1 using 2-(4-fluoro-2- methylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H25F2N3O3S, 449.2; m/z found, 450.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 6.7 Hz, 1H), 6.96 – 6.86 (m, 2H), 6.85 – 6.70 (m, 2H), 6.47 (ddd, J = 15.1, 5.0, 1.8 Hz, 1H), 6.37 (d, J = 13.5 Hz, 1H), 4.98 – 4.84 (m, 2H), 3.81 – 3.70 (m, 1H), 3.57 – 3.45 (m, 1H), 2.89 (d, J = 1.6 Hz, 3H), 2.51 – 2.38 (m, 4H), 2.15 – 2.02 (m, 2H), 1.95 – 1.84 (m, 1H), 1.38 (dd, J = 7.1, 2.6 Hz, 3H). Example 31: 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000271_0002
[00553] The title compound was prepared in a manner analogous to Example 1 using 2-(2,6- difluorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C21H23F3N3O3S, 453.1; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 2H), 7.26 – 7.17 (m, 1H), 6.97 – 6.80 (m, 3H), 6.52 – 6.39 (m, 2H), 5.24 (dd, J = 8.0, 4.6 Hz, 1H), 4.93 (q, J = 7.0 Hz, 1H), 3.79 – 3.46 (m, 2H), 2.91 (d, J = 0.7 Hz, 3H), 2.65 – 2.48 (m, 1H), 2.32 – 2.06 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 32: 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide. 269 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000272_0001
[00554] The title compound was prepared via separation of 5-(2-(2,6-difluorophenyl)pyrrolidin-1-yl)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 31) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 2.66 min). MS (ESI): mass calcd. for C21H22F3N3O3S, 453.1; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.56 (m, 2H), 7.25 – 7.18 (m, 1H), 6.95 – 6.82 (m, 3H), 6.45 (td, J = 14.3, 2.1 Hz, 2H), 5.24 (dd, J = 8.0, 4.5 Hz, 1H), 4.97 – 4.86 (m, 1H), 3.72 – 3.63 (m, 1H), 3.59 – 3.49 (m, 1H), 2.91 (s, 3H), 2.62 – 2.50 (m, 1H), 2.32 – 2.19 (m, 1H), 2.21 – 2.07 (m, 2H), 1.39 (d, J = 7.2 Hz, 3H). Example 33: 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
Figure imgf000272_0002
[00555] The title compound was prepared via separation of 5-(2-(2,6-difluorophenyl)pyrrolidin-1-yl)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 31) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 3.11 min). MS (ESI): mass calcd. for C21H22F3N3O3S, 453.1; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.57 (m, 2H), 7.28 – 7.17 (m, 1H), 6.95 – 6.83 (m, 3H), 6.46 (ddd, J = 13.7, 9.9, 2.1 Hz, 2H), 5.24 (dd, J = 8.0, 4.6 Hz, 1H), 4.97 – 4.87 (m, 1H), 3.71 – 3.62 (m, 1H), 3.59 – 3.46 (m, 1H), 2.91 (s, 3H), 2.64 – 2.49 (m, 1H), 2.32 – 2.19 (m, 1H), 2.22 – 2.05 (m, 2H), 1.39 (d, J = 7.2 Hz, 3H). Example 34: 3-Fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000272_0003
270 QB\184200.00050\92364964.2 VVID-746PC [00556] The title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H25F2N3O3S, 449.2; m/z found, 450.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.88 (ddd, J = 4.0, 2.4, 1.4 Hz, 1H), 7.70 – 7.55 (m, 1H), 7.28 – 7.16 (m, 1H), 7.14 – 6.98 (m, 3H), 6.91 (ddd, J = 15.1, 4.6, 2.9 Hz, 1H), 6.73 (dt, J = 14.2, 2.6 Hz, 1H), 6.48 (dt, J = 15.1, 1.9 Hz, 1H), 5.14 (t, J = 5.3 Hz, 1H), 5.01 – 4.85 (m, 1H), 3.72 (dt, J = 12.7, 5.1 Hz, 1H), 3.66 – 3.51 (m, 1H), 2.91 (d, J = 1.5 Hz, 3H), 2.22 – 2.02 (m, 2H), 1.98 (dt, J = 13.5, 5.3 Hz, 1H), 1.92 – 1.77 (m, 1H), 1.73 – 1.52 (m, 2H), 1.40 (dd, J = 7.2, 1.3 Hz, 3H). Example 35: 3-Fluoro-5-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000273_0001
[00557] The title compound was prepared via separation of 3-fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 34) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 2.87 min). MS (ESI): mass calcd. for C22H25F2N3O3S, 449.2; m/z found, 450.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.83 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.27 – 7.16 (m, 1H), 7.12 – 6.98 (m, 3H), 6.92 (dd, J = 15.1, 4.5 Hz, 1H), 6.73 (dd, J = 14.2, 2.4 Hz, 1H), 6.47 (dd, J = 15.1, 1.8 Hz, 1H), 5.13 (t, J = 5.3 Hz, 1H), 4.98 – 4.85 (m, 1H), 3.72 (dt, J = 12.7, 5.1 Hz, 1H), 3.56 (ddd, J = 12.6, 10.0, 4.8 Hz, 1H), 2.91 (s, 3H), 2.22 – 2.03 (m, 2H), 2.03 – 1.91 (m, 1H), 1.94 – 1.79 (m, 1H), 1.71 – 1.52 (m, 2H), 1.39 (d, J = 7.1 Hz, 3H). Example 36: 3-Fluoro-5-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000273_0002
271 QB\184200.00050\92364964.2 VVID-746PC [00558] The title compound was prepared via separation of 3-fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 34) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 4.25 min). MS (ESI): mass calcd. for C22H25F2N3O3S, 449.2; m/z found, 450.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.84 (m, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.27 – 7.17 (m, 1H), 7.11 – 6.98 (m, 3H), 6.91 (dd, J = 15.0, 4.5 Hz, 1H), 6.73 (dd, J = 14.2, 2.5 Hz, 1H), 6.47 (dd, J = 15.1, 1.8 Hz, 1H), 5.13 (t, J = 5.3 Hz, 1H), 4.99 – 4.86 (m, 1H), 3.72 (dt, J = 12.6, 5.1 Hz, 1H), 3.56 (ddd, J = 12.7, 10.0, 4.7 Hz, 1H), 2.91 (s, 3H), 2.20 – 2.03 (m, 2H), 2.03 – 1.91 (m, 1H), 1.92 – 1.78 (m, 1H), 1.71 – 1.52 (m, 2H), 1.40 (d, J = 7.1 Hz, 3H). Example 37: 2-Fluoro-4-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000274_0001
[00559] The title compound was prepared in a manner analogous to Example 1 using 2-(4-fluoro-2- methylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C 23H26F2N2O3S, 448.2; m/z found, 449.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 9.1 Hz, 1H), 6.95 – 6.87 (m, 2H), 6.83 (dd, J = 8.6, 5.9 Hz, 1H), 6.74 (td, J = 8.4, 2.7 Hz, 1H), 6.55 (dd, J = 14.8, 7.7 Hz, 1H), 6.46 (ddd, J = 15.1, 1.8, 0.7 Hz, 1H), 6.25 – 6.17 (m, 1H), 6.01 (d, J = 15.7 Hz, 1H), 5.04 – 4.92 (m, 1H), 4.86 (d, J = 8.4 Hz, 1H), 3.76 – 3.68 (m, 1H), 3.54 – 3.43 (m, 1H), 2.91 (s, 3H), 2.47 - 2.37 (m, 4H), 2.11 – 2.00 (m, 2H), 1.91 – 1.81 (m, 1H), 1.38 (dd, J = 7.2, 2.1 Hz, 3H). Example 38: 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000274_0002
272 QB\184200.00050\92364964.2 VVID-746PC [00560] The title compound was prepared via separation of 2-fluoro-4-(2-(4-fluoro-2- methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 37) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 40% EtOH/CO2 with 0.1% DEA; Rt = 3.94 min). MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.82 (t, J = 9.2 Hz, 1H), 6.96 – 6.88 (m, 2H), 6.84 (dd, J = 8.6, 5.9 Hz, 1H), 6.75 (td, J = 8.4, 2.7 Hz, 1H), 6.57 – 6.42 (m, 2H), 6.22 (dd, J = 9.0, 2.2 Hz, 1H), 6.01 (dd, J = 16.4, 2.2 Hz, 1H), 5.05 – 4.93 (m, 1H), 4.87 (dd, J = 8.3, 2.0 Hz, 1H), 3.78 – 3.66 (m, 1H), 3.54 – 3.43 (m, 1H), 2.92 (s, 3H), 2.48 - 2.37 (m, 4H), 2.11 – 1.99 (m, 2H), 1.92 – 1.82 (m, 1H), 1.38 (d, J = 7.1 Hz, 3H). Example 39: 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000275_0001
[00561] The title compound was prepared via separation of 2-fluoro-4-(2-(4-fluoro-2- methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 37) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 40% EtOH/CO2 with 0.1% DEA; Rt = 5.33 min). MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.82 (t, J = 9.2 Hz, 1H), 6.96 – 6.88 (m, 2H), 6.84 (dd, J = 8.6, 5.9 Hz, 1H), 6.75 (td, J = 8.4, 2.7 Hz, 1H), 6.56 – 6.43 (m, 2H), 6.22 (dd, J = 8.9, 2.3 Hz, 1H), 6.06 – 5.96 (m, 1H), 5.04 – 4.94 (m, 1H), 4.86 (dd, J = 8.2, 2.1 Hz, 1H), 3.78 – 3.67 (m, 1H), 3.53 – 3.45 (m, 1H), 2.92 (s, 3H), 2.48 - 2.37 (m, 4H), 2.11 – 1.99 (m, 2H), 1.91 – 1.81 (m, 1H), 1.39 (d, J = 7.1 Hz, 3H). Example 40: 2-Fluoro-4-((2*R,4*S)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000275_0002
[00562] The title compound was prepared in a manner analogous to Example 1 using a mixture of 2-(2- fluorophenyl)-4-methylpyrrolidine and 4-methyl-2-phenylpyrrolidine instead of (S)-2-(2- 273 QB\184200.00050\92364964.2 VVID-746PC chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. The mixture of four compounds was carried through the synthesis together before being separated by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 2.68 min). MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.79 (t, J = 9.2 Hz, 1H), 7.24 – 7.16 (m, 1H), 7.12 – 6.97 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.57 – 6.42 (m, 2H), 6.27 (dd, J = 8.9, 2.4 Hz, 1H), 6.08 (dd, J = 16.2, 2.4 Hz, 1H), 5.05 – 4.92 (m, 2H), 3.75 (dd, J = 9.6, 7.4 Hz, 1H), 3.32 (t, J = 9.2 Hz, 1H), 2.91 (s, 3H), 2.75 (dt, J = 13.3, 7.0 Hz, 1H), 2.51 – 2.37 (m, 1H), 1.64 (ddd, J = 12.6, 10.2, 8.2 Hz, 1H), 1.37 (d, J = 7.2 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H). Example 41: 2-Fluoro-4-((2*R,4*S)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000276_0001
[00563] The title compound was prepared in a manner analogous to Example 1 using a mixture of 2-(2- fluorophenyl)-4-methylpyrrolidine and 4-methyl-2-phenylpyrrolidine instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. The mixture of four compounds was carried through the synthesis together before being separated by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 3.20 min). MS (ESI): mass calcd. for C23H27FN2O3S, 430.2; m/z found, 431.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 9.2 Hz, 1H), 7.33 – 7.24 (m, 2H), 7.24 – 7.11 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.56 – 6.41 (m, 2H), 6.29 (dd, J = 8.9, 2.4 Hz, 1H), 6.07 (dd, J = 16.4, 2.3 Hz, 1H), 5.03 – 4.90 (m, 1H), 4.74 (dd, J = 8.8, 7.0 Hz, 1H), 3.76 (dd, J = 9.6, 7.5 Hz, 1H), 3.34 (t, J = 9.4 Hz, 1H), 2.90 (s, 3H), 2.65 (dt, J = 13.0, 6.7 Hz, 1H), 2.49 – 2.35 (m, 1H), 1.63 (ddd, J = 12.6, 10.8, 8.8 Hz, 1H), 1.36 (d, J = 7.1 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H). Example 42: 2-Fluoro-4-((2*S,4*R)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000276_0002
274 QB\184200.00050\92364964.2 VVID-746PC [00564] The title compound was prepared in a manner analogous to Example 1 using a mixture of 2-(2- fluorophenyl)-4-methylpyrrolidine and 4-methyl-2-phenylpyrrolidine instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. The mixture of four compounds was carried through the synthesis together before being separated by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 3.89 min). MS (ESI): mass calcd. for C23H26F2N2O3S, 448.2; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.80 (t, J = 9.2 Hz, 1H), 7.24 – 7.16 (m, 1H), 7.09 – 6.98 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.56 – 6.40 (m, 2H), 6.29 (dd, J = 8.9, 2.3 Hz, 1H), 6.07 (dd, J = 16.3, 2.3 Hz, 1H), 5.05 – 4.92 (m, 2H), 3.76 (dd, J = 9.6, 7.5 Hz, 1H), 3.32 (t, J = 9.2 Hz, 1H), 2.91 (s, 3H), 2.75 (dt, J = 13.3, 7.0 Hz, 1H), 2.50 – 2.37 (m, 1H), 1.65 (ddd, J = 12.7, 10.2, 8.3 Hz, 2H), 1.38 (d, J = 7.2 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H). Example 43: 2-Fluoro-4-((2*S,4*R)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000277_0001
[00565] The title compound was prepared in a manner analogous to Example 1 using a mixture of 2-(2- fluorophenyl)-4-methylpyrrolidine and 4-methyl-2-phenylpyrrolidine instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. The mixture of four compounds was carried through the synthesis together before being separated by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 4.60 min). MS (ESI): mass calcd. for C23H27FN2O3S, 430.2; m/z found, 431.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 9.2 Hz, 1H), 7.29 (dd, J = 8.1, 6.6 Hz, 2H), 7.25 – 7.13 (m, 3H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.55 – 6.39 (m, 2H), 6.29 (dd, J = 8.9, 2.3 Hz, 1H), 6.07 (dd, J = 16.4, 2.3 Hz, 1H), 5.04 – 4.92 (m, 1H), 4.77 – 4.67 (m, 1H), 3.80 – 3.72 (m, 1H), 3.33 (t, J = 9.4 Hz, 1H), 2.90 (s, 3H), 2.66 (dt, J = 13.0, 6.8 Hz, 1H), 2.49 – 2.34 (m, 1H), 1.63 (ddd, J = 12.6, 10.7, 8.8 Hz, 1H), 1.37 (d, J = 7.1 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H). Example 44: 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)piperidin-1- yl)picolinamide.
Figure imgf000277_0002
275 QB\184200.00050\92364964.2 VVID-746PC [00566] The title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4- bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C23H28FN3O3S, 445.2; m/z found, 446.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.71 (m, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.18 – 7.09 (m, 1H), 7.10 – 7.00 (m, 2H), 6.91 (ddd, J = 15.1, 4.5, 3.1 Hz, 1H), 6.63 (ddd, J = 14.3, 2.6, 1.2 Hz, 1H), 6.46 (dt, J = 15.1, 1.6 Hz, 1H), 4.97 – 4.87 (m, 1H), 4.84 (t, J = 5.7 Hz, 1H), 3.67 (dd, J = 7.4, 5.1 Hz, 2H), 2.91 (d, J = 1.4 Hz, 3H), 2.44 (s, 3H), 2.19 – 2.05 (m, 1H), 2.08 – 1.94 (m, 1H), 1.95 – 1.82 (m, 2H), 1.76 – 1.64 (m, 1H), 1.65 – 1.59 (m, 1H), 1.39 (dd, J = 7.1, 2.3 Hz, 3H). Example 45: 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)piperidin-1- yl)picolinamide.
Figure imgf000278_0001
[00567] The title compound was prepared via separation of 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)-5-(2-(o-tolyl)piperidin-1-yl)picolinamide (Example 44) by SFC (Stationary phase: A6-5 (3x25 cm); Mobile phase: 40% MeOH/CO2 with 0.2% DEA; Rt = 11.2 min (second eluting product)). MS (ESI): mass calcd. for C23H28FN3O3S, 445.2; m/z found, 446.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.10 – 6.99 (m, 2H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.63 (dd, J = 14.3, 2.4 Hz, 1H), 6.51 – 6.40 (m, 1H), 4.98 – 4.87 (m, 1H), 4.84 (t, J = 5.7 Hz, 1H), 3.66 (dd, J = 7.4, 5.2 Hz, 2H), 2.90 (s, 3H), 2.44 (s, 3H), 2.18 – 2.05 (m, 1H), 2.06 – 1.95 (m, 1H), 1.95 – 1.79 (m, 2H), 1.77 – 1.52 (m, 2H), 1.38 (d, J = 7.1 Hz, 3H). Example 46: 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000278_0002
[00568] The title compound was prepared in a manner analogous to Example 1 using 2-(2,3- difluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- 276 QB\184200.00050\92364964.2 VVID-746PC fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C21H22F3N3O3S, 453.1; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.54 (m, 2H), 7.15 – 7.03 (m, 1H), 7.03 – 6.92 (m, 1H), 6.90 (ddd, J = 15.1, 4.6, 3.2 Hz, 1H), 6.69 (ddd, J = 8.0, 6.3, 1.5 Hz, 1H), 6.51 – 6.40 (m, 2H), 5.10 (d, J = 8.1 Hz, 1H), 4.99 – 4.85 (m, 1H), 3.79 – 3.67 (m, 1H), 3.58 – 3.47 (m, 1H), 2.90 (d, J = 1.9 Hz, 3H), 2.57 – 2.42 (m, 1H), 2.19 – 1.99 (m, 3H), 1.39 (dd, J = 7.1, 1.5 Hz, 3H). Example 47: 5-((*R)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
Figure imgf000279_0001
[00569] The title compound was prepared via separation of 5-(2-(2,3-difluorophenyl)pyrrolidin-1-yl)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 46) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 15% EtOH/CO2 with 0.1% DEA; Rt = 3.04 min). MS (ESI): mass calcd. for C21H22F3N3O3S, 453.1; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.57 (m, 2H), 7.15 – 7.03 (m, 1H), 7.01 – 6.95 (m, 1H), 6.92 (dd, J = 15.0, 4.5 Hz, 1H), 6.73 – 6.67 (m, 1H), 6.51 – 6.41 (m, 2H), 5.11 (d, J = 8.1 Hz, 1H), 4.99 – 4.86 (m, 1H), 3.78 – 3.71 (m, 1H), 3.57 – 3.48 (m, 1H), 2.91 (s, 3H), 2.58 – 2.45 (m, 1H), 2.19 – 2.01 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 48: 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
Figure imgf000279_0002
[00570] The title compound was prepared via separation of 5-(2-(2,3-difluorophenyl)pyrrolidin-1-yl)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 46) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 15% EtOH/CO2 with 0.1% DEA; Rt = 3.93 min). MS (ESI): mass calcd. for C21H22F3N3O3S, 453.1; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.14 – 7.04 (m, 1H), 7.02 – 6.94 (m, 1H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.73 – 6.66 (m, 277 QB\184200.00050\92364964.2 VVID-746PC 1H), 6.50 – 6.42 (m, 2H), 5.10 (d, J = 8.1 Hz, 1H), 4.97 – 4.88 (m, 1H), 3.78 – 3.69 (m, 1H), 3.58 – 3.47 (m, 1H), 2.91 (s, 3H), 2.57 – 2.45 (m, 1H), 2.20 – 2.00 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 49: 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1- yl)picolinamide.
Figure imgf000280_0001
[00571] The title compound was prepared in a manner analogous to Example 1 using 2-(o-tolyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4- bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H26FN3O3S, 431.2; m/z found, 432.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 6.7 Hz, 1H), 7.24 – 7.19 (m, 1H), 7.16 (tt, J = 7.5, 1.8 Hz, 1H), 7.08 (tt, J = 7.4, 2.0 Hz, 1H), 6.94 – 6.82 (m, 2H), 6.47 (ddd, J = 15.1, 5.9, 1.7 Hz, 1H), 6.43 – 6.31 (m, 1H), 5.00 – 4.86 (m, 2H), 3.77 (dt, J = 10.1, 5.2 Hz, 1H), 3.53 (qd, J = 8.6, 4.0 Hz, 1H), 2.89 (d, J = 3.1 Hz, 3H), 2.53 – 2.39 (m, 4H), 2.17 – 2.05 (m, 2H), 1.97 – 1.89 (m, 1H), 1.38 (dd, J = 7.2, 3.2 Hz, 3H). Example 50: 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1- yl)picolinamide.
Figure imgf000280_0002
[00572] The title compound was prepared via separation of 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)picolinamide (Example 49) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 20% EtOH/CO2 with 0.1% DEA; Rt = 4.83 min (second eluting product)). MS (ESI): mass calcd. for C22H26FN3O3S, 431.2; m/z found, 432.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.25 – 7.19 (m, 1H), 7.16 (td, J = 7.4, 1.4 Hz, 1H), 7.12 – 7.05 (m, 1H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.85 (dd, J = 7.7, 1.5 Hz, 1H), 6.48 (dd, J = 15.0, 1.8 Hz, 1H), 6.42 – 6.32 (m, 1H), 5.00 – 4.87 (m, 2H), 3.81 – 3.73 (m, 1H), 3.53 (q, J = 8.6 Hz, 1H), 2.89 (s, 3H), 2.54 – 2.45 (m, 1H), 2.43 (s, 3H), 2.15 – 2.06 (m, 2H), 1.99 – 1.89 (m, 1H), 1.38 (d, J = 7.1 Hz, 3H). 278 QB\184200.00050\92364964.2 VVID-746PC Example 51: 5-(3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000281_0001
[00573] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C21H23ClFN3O4S, 467.1; m/z found, 468.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 7.90 – 7.85 (m, 1H), 7.64 (dd, J = 8.4, 3.4 Hz, 1H), 7.42 (ddd, J = 7.8, 3.8, 1.4 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.15 (tt, J = 7.6, 1.7 Hz, 1H), 6.91 (ddd, J = 15.1, 4.6, 2.5 Hz, 1H), 6.77 (ddd, J = 13.4, 8.1, 2.4 Hz, 1H), 6.47 (dd, J = 15.1, 1.7 Hz, 1H), 5.05 – 5.01 (m, 1H), 4.97 – 4.88 (m, 1H), 4.17 – 4.07 (m, 2H), 4.02 – 3.96 (m, 1H), 3.88 (dd, J = 11.9, 5.2 Hz, 1H), 3.80 – 3.73 (m, 1H), 3.51 – 3.45 (m, 1H), 2.91 (s, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 52: 5-((*S)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000281_0002
[00574] The title compound was prepared via separation of 5-(3-(2-chlorophenyl)morpholino)-3-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 51) by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% DEA; Rt = 5.83 min). MS (ESI): mass calcd. for C21H23ClFN3O4S, 467.1; m/z found, 468.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 7.88 (dd, J = 2.5, 1.2 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.15 (td, J = 7.5, 1.4 Hz, 1H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.77 (dd, J = 13.4, 2.4 Hz, 1H), 6.47 (dd, J = 15.1, 1.8 Hz, 1H), 5.03 (t, J = 4.7 Hz, 1H), 4.96 – 4.87 (m, 1H), 4.15 (ddd, J = 11.5, 6.0, 4.0 Hz, 1H), 4.10 (dd, J = 11.9, 4.3 Hz, 1H), 3.99 (ddd, J = 11.5, 7.3, 3.9 Hz, 1H), 3.88 (dd, J = 11.9, 5.2 Hz, 1H), 3.77 (ddd, J = 11.7, 7.3, 4.1 Hz, 1H), 3.48 (ddd, J = 12.3, 6.0, 4.0 Hz, 1H), 2.91 (s, 3H), 1.40 (d, J = 7.1 Hz, 3H). 279 QB\184200.00050\92364964.2 VVID-746PC Example 53: 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000282_0001
[00575] The title compound was prepared via separation of 5-(3-(2-chlorophenyl)morpholino)-3-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 51) by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% DEA; Rt = 7.93 min). MS (ESI): mass calcd. for C21H23ClFN3O4S, 467.1; m/z found, 468.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 7.86 (dd, J = 2.4, 1.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 7.9, 1.3 Hz, 1H), 7.24 – 7.19 (m, 2H), 7.15 (td, J = 7.5, 1.4 Hz, 1H), 6.90 (dd, J = 15.1, 4.6 Hz, 1H), 6.78 (dd, J = 13.4, 2.4 Hz, 1H), 6.47 (dd, J = 15.1, 1.7 Hz, 1H), 5.03 (t, J = 4.7 Hz, 1H), 4.97 – 4.87 (m, 1H), 4.15 (ddd, J = 11.7, 5.9, 4.1 Hz, 1H), 4.10 (dd, J = 11.9, 4.3 Hz, 1H), 3.99 (ddd, J = 11.5, 7.4, 4.0 Hz, 1H), 3.88 (dd, J = 11.9, 5.2 Hz, 1H), 3.77 (ddd, J = 11.7, 7.4, 4.1 Hz, 1H), 3.48 (ddd, J = 12.3, 6.0, 4.0 Hz, 1H), 2.91 (s, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 54: 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000282_0002
[00576] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 1.17 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 - 8.23 (m, 1H), 7.64 - 7.73 (m, 2H), 7.47 - 7.55 (m, 1H), 6.98 - 7.17 (m, 2H) 6.65 - 6.83 (m, 2H), 6.31 - 6.40 (m, 2H), 4.97 - 5.05 (m, 1H), 4.72 - 4.84 (m, 1H), 3.73 - 3.85 (m, 1H), 3.40 - 3.48 (m, 1H), 2.96 - 3.04 (m, 3H), 2.40 - 2.46 (m, 1H), 1.78 - 2.11 (m, 3H), 1.21 - 1.32 (m, 3H). 280 QB\184200.00050\92364964.2 VVID-746PC Example 55: 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000283_0001
[00577] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 1.25 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.12 - 8.24 (m, 1H), 7.63 - 7.74 (m, 2H), 7.46 - 7.56 (m, 1H), 7.00 - 7.17 (m, 2H), 6.62 - 6.83 (m, 2H), 6.29 - 6.43 (m, 2H), 4.97 - 5.06 (m, 1H), 4.73 - 4.87 (m, 1H), 3.75 - 3.85 (m, 1H), 3.40 - 3.49 (m, 1H), 2.95 - 3.01 (m, 3H), 2.39 - 2.46 (m, 1H), 1.79 - 2.08 (m, 3H), 1.23 - 1.31 (m, 3H). Example 56: 4-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000283_0002
[00578] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) by SFC (Stationary phase: AD (5x25 cm); Mobile phase: 11% EtOH/CO2; Rt = 1.17 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (br d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.57 (dd, J = 8.7, 5.1 Hz, 1H), 7.17 (td, J = 8.4, 3.1 Hz, 1H) 6.79 - 6.85 (m, 1H), 6.76 (d, J = 4.5 Hz, 1H), 6.65 - 6.73 (m, 1H), 6.36 (br d, J = 8.6 Hz, 2H), 5.00 (br d, J = 7.6 Hz, 1H), 4.79 (br dd, J = 11.5, 6.5 Hz, 1H), 3.86 (br t, J = 7.4 Hz, 1H), 3.39 - 3.48 (m, 1H), 2.99 (s, 3H), 2.40 - 2.47 (m, 1H), 2.03 (br dd, J = 6.4, 2.8 Hz, 1H), 1.82 - 1.96 (m, 2H), 1.27 (d, J = 7 Hz, 3H). 281 QB\184200.00050\92364964.2 VVID-746PC Example 57: 4-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000284_0001
[00579] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) by SFC (Stationary phase: AD (5x25 cm); Mobile phase: 11% EtOH/CO2; Rt = 1.28 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6 ) δ 8.20 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.57 (dd, J = 8.8, 5.0 Hz, 1H), 7.17 (td, J = 8.4, 3.1 Hz, 1H), 6.74 - 6.87 (m, 2H), 6.62 - 6.73 (m, 1H), 6.36 (br d, J = 8.6 Hz, 2H), 5.00 (br d, J = 7.9 Hz, 1H), 4.73 - 4.84 (m, 1H), 3.86 (br t, J = 7.6 Hz, 1H), 3.37 - 3.49 (m, 1H), 2.99 (s, 3H), 2.41 - 2.47 (m, 1H), 1.82 - 2.08 (m, 3H), 1.27 (d, J = 7.1 Hz, 3H). Example 58: 4-((*R)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000284_0002
[00580] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-6- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 1.38 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (br d, J = 7.6 Hz, 1H), 7.64 (br d, J = 8.5 Hz, 2H), 7.24 - 7.40 (m, 2H), 7.05 - 7.19 (m, 1H), 6.62 - 6.84 (m, 2H), 6.34 (br d, J = 8.3 Hz, 2H), 5.23 - 5.36 (m, 1H), 4.70 - 4.86 (m, 1H), 3.46 - 3.65 (m, 2H), 2.99 (s, 3H), 2.53 - 2.59 (m, 1H), 1.91 - 2.18 (m, 3H), 1.25 (br d, J = 7.0 Hz, 3H). 282 QB\184200.00050\92364964.2 VVID-746PC Example 59: 4-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000285_0001
[00581] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-6- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 1.47 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (br d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.28 - 7.42 (m, 2H), 7.12 (br s, 1H), 6.59 - 6.84 (m, 2H), 6.34 (br d, J = 8.7 Hz, 2H), 5.30 (br t, J = 6.1 Hz, 1H), 4.69 - 4.88 (m, 1H), 3.45 - 3.62 (m, 2H), 2.98 (s, 3H), 2.54 - 2.58 (m, 1H), 1.93 - 2.22 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 60: 5-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
Figure imgf000285_0002
[00582] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 8.6, 3.1 Hz, 1H), 7.54 (dd, J = 8.6, 2.3 Hz, 1H), 7.46 (br d, J = 5.0 Hz, 1H), 7.07 - 7.19 (m, 2H), 6.64 - 6.80 (m, 3H), 5.14 (br d, J = 8.3 Hz, 1H), 4.66 - 4.79 (m, 1H), 3.86 (br t, J = 7.8 Hz, 1H), 3.44 - 3.54 (m, 1H), 2.98 (d, J = 4.3 Hz, 3H), 2.47 (br d, J =3.8 Hz, 1H), 1.79 - 2.13 (m, 3H), 1.27 (dd, J = 7.0, 2.7 Hz, 3H). 283 QB\184200.00050\92364964.2 VVID-746PC Example 61: 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000286_0001
[00583] The title compound was prepared via separation of 5-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1-yl)- 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 60) by SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 56% iPrOH/CO2; Rt = 12.7 min (second eluting product)). MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.45 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.6, 2.3 Hz, 1H), 7.46 (br d, J = 5.0 Hz, 1H), 7.07 - 7.18 (m, 2H), 6.58 - 6.83 (m, 3H), 5.14 (br d, J =6.4 Hz, 1H), 4.67 - 4.81 (m, 1H), 3.81 - 3.93 (m, 1H), 3.44 - 3.56 (m, 1H), 2.99 (s, 3H), 2.47 (br d, J = 3.8 Hz, 1H), 1.83 - 2.11 (m, 3H), 1.27 (d, J =7.0 Hz, 3H). Example 62: 4-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000286_0002
[00584] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C 22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91 - 8.04 (m, 1H), 7.42 - 7.59 (m, 2H), 6.98 - 7.19 (m, 2H), 6.63 - 6.82 (m, 2H), 6.07 - 6.22 (m, 2H), 5.01(br d, J = 8.3 Hz, 1H), 4.76 (br dd, J = 11.4, 5.9 Hz, 1H), 3.79 (br t, J = 7.5 Hz, 1H), 3.39 - 3.48 (m, 1H), 2.99 (s, 3H), 1.82 - 2.07 (m, 3H), 1.55 (s, 1H),1.26 (br d, J = 6.6 Hz, 3H). Example 63: 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide. 284 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000287_0001
[00585] The title compound was prepared via separation of 4-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1-yl)- 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 62) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 5.87 min). MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 7.9, 3.3 Hz, 1H), 7.38 - 7.60 (m, 2H), 6.98 - 7.22 (m, 2H), 6.63 - 6.83 (m, 2H), 6.06 - 6.23 (m, 2H), 5.01 (br d, J = 7.5 Hz, 1H), 4.69 - 4.82 (m, 1H), 3.79 (br t, J = 7.7 Hz, 1H), 3.43 (br d, J = 7.1 Hz, 1H), 3.00 (s, 3H), 2.40 - 2.48 (m, 1H), 1.79 - 2.11(m, 3H), 1.26 (d, J = 7.1 Hz, 3H). Example 64: 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000287_0002
[00586] The title compound was prepared via separation of 4-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1-yl)- 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 62) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 7.82 min). MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (br dd, J = 7.9, 3.4 Hz, 1H), 7.43 - 7.55 (m, 2H), 6.98 - 7.17 (m, 2H), 6.74 - 6.81 (m, 2H), 6.65 - 6.72 (m, 2H), 6.07 - 6.21 (m, 2H), 5.01 (br d, J = 7.8 Hz, 1H), 4.70 - 4.83 (m, 1H), 3.79 (br t, J = 8.1 Hz, 1H), 3.37 - 3.49 (m, 1H), 2.99 (s, 3H), 2.38 - 2.48 (m, 1H), 1.81 - 2.07 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 65: 4-((*R)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide. 285 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000288_0001
[00587] The title compound was prepared in a manner analogous to Example 1 using 5-(2-chlorophenyl)- 1,4-oxazepane (Intermediate 5) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(5-(2-chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 3.74 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (br dd, J = 7.7, 2.4 Hz, 1H), 7.42 - 7.55 (m, 2H), 7.21 - 7.37 (m, 3H), 6.58 - 6.82 (m, 2H), 6.24 - 6.39 (m, 2H), 4.67 - 4.95 (m, 2H), 3.90 - 4.22 (m, 4H), 3.44 (br t, J = 10.6 Hz, 2H), 2.99 (s, 3H), 2.04 - 2.10 (m, 1H), 1.25 (br d, J = 7.0 Hz, 3H). Example 66: 4-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000288_0002
[00588] The title compound was prepared in a manner analogous to Example 1 using 5-(2-chlorophenyl)- 1,4-oxazepane (Intermediate 5) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(5-(2-chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 5.90 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (br dd, J = 7.9, 2.8 Hz, 1H), 7.43 - 7.56 (m, 2H), 7.24 - 7.32 (m, 3H), 6.62 - 6.82 (m, 2H), 6.24 - 6.41 (m, 2H), 4.70 - 4.93 (m, 2H), 4.14 - 4.23 (m, 1H), 3.93 - 4.12 (m, 3H), 3.44 (br t, J = 10.8 Hz, 2 H), 2.99 (s, 3H), 2.43 - 2.48 (m, 1H), 2.04 - 2.10 (m, 1H), 1.26 (d, J = 7.1 Hz, 3H). Example 67: 4-(3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide. 286 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000289_0001
[00589] The title compound was prepared in a manner analogous to Example 1 using 3-(2-chloro-4- fluorophenyl) morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.10 - 8.23 (m, 1H), 7.43 - 7.55 (m, 2H), 7.32 (dd, J = 8.8, 6.2 Hz, 1H), 7.11 (td, J = 8.5, 2.7 Hz, 1H), 6.73 - 6.81 (m, 1H), 6.66 - 6.72 (m, 1H), 6.51 - 6.65 (m, 2H), 4.93 (t, J = 4.2 Hz, 1H), 4.70 - 4.81 (m, 1H), 3.94 - 4.07 (m, 2H), 3.83 (ddd, J = 11.4, 7.9, 3.8 Hz, 1H), 3.65 - 3.79 (m, 2H), 3.44 (dt, J = 12.4, 4.2 Hz, 1H), 3.00 (d, J = 2.0 Hz, 3H), 1.26 (dd, J = 7.0, 3.0 Hz, 3H). Example 68: 4-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide.
Figure imgf000289_0002
[00590] The title compound was prepared via separation of 4-(3-(2-chloro-4-fluorophenyl)morpholino)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 67) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 6.37 min). MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (br dd, J = 7.9, 1.9 Hz, 1H), 7.41 - 7.58 (m, 2H), 7.32 (dd, J = 8.8, 6.3 Hz, 1H), 7.12 (td, J = 8.5, 2.6 Hz, 1H), 6.73 - 6.80 (m, 1H), 6.66 - 6.72 (m, 1H), 6.61 (br d, J = 11.6 Hz, 2H), 4.93 (t, J = 4.2 Hz, 1H), 4.68 - 4.81 (m, 1H), 3.93 - 4.08 (m, 2H), 3.83 (ddd, J = 11.4, 7.9, 3.6 Hz, 1H), 3.65 - 3.79 (m, 2H), 3.44 (dt, J = 12.6, 4.3 Hz, 1H), 3.00 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H). Example 69: 4-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide. 287 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000290_0001
[00591] The title compound was prepared via separation of 4-(3-(2-chloro-4-fluorophenyl)morpholino)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 67) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 9.32 min). MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (br dd, J = 7.9, 2.0 Hz, 1H), 7.40 - 7.57 (m, 2H), 7.32 (dd, J = 8.8, 6.2 Hz, 1H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 6.72 - 6.85 (m, 1H), 6.65 - 6.72 (m, 1H), 6.54 - 6.65 (m, 2H), 4.93 (s, 1H), 4.69 - 4.81 (m, 1H), 3.93 - 4.08 (m, 2H), 3.83 (ddd, J = 11.3, 7.9, 3.6 Hz, 1H), 3.64 - 3.79 (m, 2H), 3.44 (dt, J = 12.5, 4.2 Hz, 1H), 2.99 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 70: 4-(2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000290_0002
[00592] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chlorophenyl)- 4,4-difluoropiperidine (Intermediate 9) instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C23H25ClF2N2O3S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.28 - 7.50 (m, 2 H), 7.14 - 7.24 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.64 - 6.79 (m, 2H), 4.93 (br dd, J = 8.7, 3.6 Hz, 1H), 4.68 - 4.83 (m, 1H), 3.71 - 3.81 (m, 1H), 3.34 - 3.47 (m, 1H), 2.97 - 3.00 (m, 3H), 2.14 - 2.48 (m, 4H), 1.20 - 1.31 (m, 3H). Example 71: 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide. 288 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000291_0001
[00593] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4,4-difluoropiperidin-1- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 70) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 1.11 min). MS (ESI): mass calcd. for C23H25ClF2N2O3S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.32 - 7.46 (m, 2H), 7.14 - 7.25 (m, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.72 - 6.80 (m, 1H), 6.66 - 6.72 (m, 1H), 4.92 (dd, J = 9.3, 4.4 Hz, 1H), 4.72 - 4.82 (m, 1H), 3.70 - 3.82 (m, 1H), 3.36 - 3.43 (m, 1H), 2.99 (s, 3H), 2.13 - 2.49 (m, 4H), 1.25 (d, J = 7.0 Hz, 3H). Example 72: 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000291_0002
[00594] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4,4-difluoropiperidin-1- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 70) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 1.34 min). MS (ESI): mass calcd. for C23H25ClF2N2O3S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.29 - 7.45 (m, 2H), 7.13 - 7.24 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.64 - 6.78 (m, 2H), 4.93 (br dd, J = 9.2, 4.6 Hz, 1H), 4.69 - 4.85 (m, 1H), 3.69 - 3.82 (m, 1H), 3.36 - 3.46 (m, 1H), 2.98 (s, 3H), 2.13 - 2.49 (m, 4H), 1.26 (d, J = 7.1 Hz, 3H). Example 73: 4-(3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide. 289 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000292_0001
[00595] The title compound was prepared in a manner analogous to Example 1 using 3-(2-chloro-3- fluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.20 (m, 1H), 7.48 (t, J = 8.6 Hz, 1H), 7.23 - 7.37 (m, 2H) 7.09 - 7.17 (m, 1H), 6.55 - 6.83 (m, 4H), 5.02 (t, J = 4.0 Hz, 1H), 4.66 - 4.82 (m, 1H), 3.94 - 4.10 (m, 2H), 3.78 - 3.88 (m, 2H), 3.71 (ddd, J = 12.4, 8.4, 3.9 Hz, 1H), 3.40 - 3.53 (m, 1H), 2.99 (d, J = 2.0 Hz, 3H), 1.25 (dd, J = 7.0, 3.1 Hz, 3H). Example 74: 4-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide.
Figure imgf000292_0002
[00596] The title compound was prepared via separation of 4-(3-(2-chloro-3-fluorophenyl)morpholino)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 73) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 35% EtOH/CO2; Rt = 2.55 min). MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (dd, J = 7.9, 1.9 Hz, 1H), 7.43 - 7.53 (m, 1H), 7.20 - 7.37 (m, 2H), 7.10 - 7.18 (m, 1H), 6.52 - 6.82 (m, 4H), 5.02(t, J = 4.1 Hz, 1H), 4.70 - 4.81 (m, 1H), 3.96 - 4.07 (m, 2H), 3.77 - 3.89 (m, 2H), 3.71 (ddd, J = 12.4, 8.2, 3.9 Hz, 1H), 3.48 (dt, J = 12.6, 4.3 Hz, 1H), 2.99 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H). Example 75: 4-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide. 290 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000293_0001
[00597] The title compound was prepared via separation of 4-(3-(2-chloro-3-fluorophenyl)morpholino)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 73) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 35% EtOH/CO 2; Rt = 2.74 min). MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (dd, J = 7.9, 1.9 Hz, 1H) 7.44 - 7.51 (m, 1H) 7.19 - 7.34 (m, 2H) 7.10 - 7.15 (m, 1H) 6.52 - 6.80 (m, 4H) 4.99 - 5.07 (m, 1H) 4.64 - 4.82 (m, 1H) 3.98 - 4.10 (m, 2H) 3.76 - 3.91 (m, 2H) 3.71 (ddd, J = 12.4, 8.4, 4.0 Hz, 1H) 3.42 - 3.54 (m, 1H) 2.99 (s, 3H) 1.25 (d, J = 7.0 Hz, 3H). Example 76: 4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000293_0002
[00598] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-3-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 7.9 Hz, 1 H), 7.42 - 7.58 (m, 3H), 7.19 - 7.32 (m, 2H), 7.10 (dd, J = 6.3, 2.1 Hz, 1H), 6.65 - 6.84 (m, 2H), 6.54 (t, J = 8.8 Hz, 1H), 5.27 - 5.36 (m, 1H), 4.70 - 4.85 (m, 1H), 3.91 - 4.02 (m, 1H), 3.59 (q, J = 7.1 Hz, 1H), 2.99 (d, J = 2.6 Hz, 3H), 2.41 - 2.48 (m, 1H), 1.84 - 2.06 (m, 2H), 1.73 - 1.83 (m, 1H), 1.27 (dd, J = 7.1, 1.3 Hz, 3H). Example 77: 4-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. 291 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000294_0001
[00599] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-3-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluorobenzoic acid (Step B) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 3.70 min) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 7.9 Hz, 1H), 7.41 - 7.57 (m, 3H), 7.18 - 7.29 (m, 2H), 7.10 (dd, J = 7.1, 2.3 Hz, 1H), 6.65 - 6.83 (m, 2H), 6.54 (t, J = 8.8 Hz, 1H), 5.26 - 5.36 (m, 1H), 4.70 - 4.83 (m, 1H), 3.91 - 4.02 (m, 1H), 3.53 - 3.66 (m, 1H), 2.99 (s, 3H), 2.39 - 2.48 (m, 1H), 1.70 - 2.04 (m, 3H), 1.27 (d, J = 7.0 Hz, 3H). Example 78: 4-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000294_0002
[00600] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-3-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluorobenzoic acid (Step B) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 4.70 min) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.1 [M+H]+. .1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.0 Hz, 1H), 7.43 - 7.57 (m, 3H), 7.19 - 7.29 (m, 2H), 7.07 - 7.13 (m, 1H), 6.73 - 6.81 (m, 1H), 6.65 - 6.73 (m, 1H), 6.54 (t, J = 8.9 Hz, 1H), 5.28 - 5.34 (m, 1H), 4.72 - 4.84 (m, 1H), 3.92 - 4.02 (m, 1H), 3.52 - 3.65 (m, 1H), 2.98 (s, 3H), 2.38 - 2.48 (m, 1H), 1.84 - 2.05 (m, 2H), 1.78 (dq, J = 11.0, 5.6 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). 292 QB\184200.00050\92364964.2 VVID-746PC Example 79: 4-((*S)-2-(3-Chloropyridin-2-yl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000295_0001
[00601] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-2-pyrrolidin- 2-yl-pyridine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluorobenzoic acid (Step B) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 35% iPrOH/CO2; Rt = 8.04 min (second eluting product)) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.1; m/z found, 452.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J = 4.6, 1.2 Hz, 1H), 7.85 - 8.00 (m, 2H), 7.43 (t, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.1, 4.6 Hz, 1H), 6.74 - 6.84 (m, 1H), 6.62 - 6.71 (m, 1H), 6.07 - 6.18 (m, 2H), 5.29 (dd, J = 8.2, 2.4 Hz, 1H), 4.76 (br d, J = 5.5 Hz, 1H), 3.68 (td, J = 8.7, 3.9 Hz, 1H), 3.47 - 3.57 (m, 1H), 3.00 (s, 3H), 2.47 (br d, J = 4.3 Hz, 1H), 2.02 - 2.15 (m, 2H), 1.90 - 1.99 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 80: 4-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000295_0002
[00602] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of methyl 4-(2-(2-chloro-3-fluoro-phenyl)pyrrolidin-1-yl)benzoate (Step A) via SFC (Stationary phase: OJ (3x25 cm); Mobile phase: 25% iPrOH/CO2; Rt = 1.21 min (second eluting product)) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C22H24ClFN2O3S, 450.1; m/z found, 451.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.9 Hz, 2H), 7.20 - 7.37 (m, 2H), 6.63 - 6.91 (m, 3H), 6.36 (br d, J = 8.6 Hz, 2H), 5.07 (br d, J = 7.9 Hz, 1H), 4.71 - 4.87 (m, 1H), 3.76 - 3.88 (m, 1H), 3.35 - 3.40 (m, 1H), 2.99 (s, 3H), 2.42 - 2.49 (m, 1H), 1.81 - 2.12 (m, 3H), 1.27 (d, J = 7.1 Hz, 3H). 293 QB\184200.00050\92364964.2 VVID-746PC Example 81: 4-(2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000296_0001
[00603] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chlorophenyl)- 4,4-dimethylpyrrolidine (Intermediate 11) instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C24H29ClN2O3S, 460.1; m/z found, 461.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (br d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.41 - 7.50 (m, 1H), 7.10 - 7.30 (m, 3H), 6.58 - 6.81 (m, 2H), 6.34 (br d, J = 8.8 Hz, 2H), 5.09 (t, J = 7.8 Hz, 1H), 4.63 - 4.87 (m, 1H), 3.60 (d, J = 9.8 Hz, 1H), 3.40 (br d, J = 9.6 Hz, 1H), 2.98 (d, J = 2.5 Hz, 3H), 2.42 (br dd, J = 12.4, 8.0 Hz, 1H), 1.68 (br dd, J = 12.4, 8.0 Hz, 1H), 1.26 (dd, J = 7.0, 1.6 Hz, 3H), 1.14 (s, 3H), 1.08 (s, 3H). Example 82: 4-((*R)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000296_0002
[00604] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chlorophenyl)- 4,4-dimethylpyrrolidine (Intermediate 11) instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-4,4-dimethylpyrrolidin-1- yl)benzoic acid (Step B) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 1.83 min) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C24H29ClN2O3S, 460.1; m/z found, 461.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.40 - 7.51 (m, 1H), 7.09 - 7.30 (m, 3H), 6.59 - 6.81 (m, 2H), 6.34 (d, J = 8.8 Hz, 2H), 5.09 (t, J = 7.8 Hz, 1H), 4.69 - 4.87 (m, 1H), 3.60 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 9.6 Hz, 1H), 2.98 (s, 3H), 2.42 (br dd, J = 12.1, 7.8 Hz, 1H), 1.68 (dd, J = 12.4, 7.8 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H). 294 QB\184200.00050\92364964.2 VVID-746PC Example 83: 4-((*S)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000297_0001
[00605] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chlorophenyl)- 4,4-dimethylpyrrolidine (Intermediate 11) instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-4,4-dimethylpyrrolidin-1- yl)benzoic acid (Step B) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 2.14 min) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C24H29ClN2O3S, 460.1; m/z found, 461.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.40 - 7.53 (m, 1H), 7.09 - 7.29 (m, 3H), 6.54 - 6.84 (m, 2H), 6.34 (d, J = 8.9 Hz, 2H), 5.09 (t, J = 7.8 Hz, 1H), 4.65 - 4.85 (m, 1H), 3.60 (d, J = 9.6 Hz, 1H), 3.40 (d, J = 9.6 Hz, 1H), 2.99 (s, 3H), 2.42 (dd, J = 12.4, 7.6 Hz, 1H), 1.68 (dd, J = 12.6, 7.9 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H), 1.14 (s, 3H), 1.08 (s, 3H). Example 84: 4-(3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000297_0002
[00606] The title compound was prepared in a manner analogous to Example 1 using 3-(2-chlorophenyl)- 1,4-oxazepane (Intermediate 12) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 7.93 - 8.00 (m, 1H), 7.45 - 7.56 (m, 2H), 7.31 - 7.37 (m, 3H), 6.73 - 6.82 (m, 1H), 6.67 (s, 1H), 6.36 (s, 2H), 4.96 (s, 1H),4.72 - 4.79 (m, 1H), 4.10 - 4.19 (m, 2H), 3.93 - 4.05 (m, 2H), 3.74 - 3.82 (m, 1H), 3.53 - 3.61 (m, 1H), 2.99 (d, J = 1.6 Hz, 3H), 1.75 - 1.89 (m, 2H), 1.24 - 1.28 (m, 3H). Example 85: 4-((*S)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide. 295 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000298_0001
[00607] The title compound was prepared in a manner analogous to Example 1 using 3-(2-chlorophenyl)- 1,4-oxazepane (Intermediate 12) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(3-(2-chlorophenyl)-1,4-oxazepan-4-yl)-2-fluorobenzoic acid (Step B) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 1.95 min) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (dd, J = 3.2, 7.9 Hz, 1H), 7.45 - 7.56 (m, 2H), 7.31 - 7.37 (m, 3H), 6.73 - 6.81 (m, 1H), 6.64 - 6.71 (m, 1H), 6.27 -6.42 (m, 2H), 4.96 (dd, J = 5.0, 10.4 Hz, 1H), 4.69 - 4.82 (m, 1H), 4.09 - 4.21 (m, 2H), 3.91 - 4.07 (m, 2H), 3.78 (dd, J = 10.5, 13.6 Hz, 1H), 3.50 - 3.64 (m,1H), 2.99 (s, 3H), 1.71 - 1.89 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H). Example 86: 4-((*R)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000298_0002
[00608] The title compound was prepared in a manner analogous to Example 1 using 3-(2-chlorophenyl)- 1,4-oxazepane (Intermediate 12) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(3-(2-chlorophenyl)-1,4-oxazepan-4-yl)-2-fluorobenzoic acid (Step B) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 2.19 min) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (dd, J = 3.1, 8.0 Hz, 1H), 7.45 - 7.57 (m, 2H), 7.31 - 7.38 (m, 3H), 6.73 - 6.81 (m, 1H), 6.64 - 6.71 (m, 1H), 6.36 - 6.42 (m, 1H), 6.27 - 6.35 (m, 1H), 4.96 (dd, J = 5.0, 10.4 Hz, 1H), 4.70 - 4.81 (m, 1H), 4.09 - 4.21 (m, 2H), 3.92 - 4.07 (m, 2H), 3.78 (dd, J = 10.5, 13.5 Hz, 1H), 3.52 - 3.62 (m, 1H), 2.99 (s, 3H), 1.82 (br s, 2H), 1.26 (d, J = 7.0 Hz, 3H). 296 QB\184200.00050\92364964.2 VVID-746PC Example 87: 5-(2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
Figure imgf000299_0001
[00609] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 8.5, 3.4 Hz, 1H), 7.60 (dd, J = 8.6, 5.1 Hz, 1H), 7.45 (br d, J = 6.6 Hz, 1H), 7.20 (td, J = 8.5, 3.3 Hz, 1H), 6.96 (dd, J = 9.2, 2.6 Hz, 1H), 6.62 - 6.85 (m, 3H), 5.13 (br d, J = 7.5 Hz, 1H), 4.69 - 4.79 (m, 1H), 3.88 - 3.97 (m, 1H), 3.41 - 3.55 (m, 1H), 2.98 (d, J = 4.4 Hz, 3H), 1.82 - 2.13 (m, 4H), 1.22 - 1.33 (m, 3H). Example 88: 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000299_0002
[00610] The title compound was prepared via separation of 5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)- 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 87) by SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 12.9 min (second eluting product)). MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.45 (d, J =8.5 Hz, 1H), 7.59 (dd, J = 8.8, 5.1 Hz, 1H), 7.47 (br s, 1H), 7.20 (td, J = 8.4, 3.1 Hz, 1H), 6.96 (dd, J = 9.5, 3.0 Hz, 1H), 6.74 - 6.83 (m, 1H), 6.61 - 6.72 (m, 2H), 5.13 (br d, J = 7.8 Hz, 1H), 4.69 - 4.79 (m, 1H), 3.88 - 3.98 (m, 1H), 3.42 - 3.53 (m, 1H), 2.99 (s, 3H), 1.83 - 2.11 (m, 4H), 1.27 (d, J = 7.0 Hz, 3H). Example 89: 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)picolinamide. 297 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000300_0001
[00611] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 13.0 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 8.6 Hz, 1H), 7.48 (br s, 1H), 7.23 - 7.41 (m, 2H), 6.92 (d, J = 7.4 Hz, 1H), 6.74 - 6.82 (m, 1H), 6.59 - 6.74 (m, 2H), 5.11 - 5.29 (m, 1H), 4.64 - 4.85 (m, 1H), 3.74 - 3.98 (m, 1H), 3.43 - 3.61 (m, 1H), 2.99 (s, 3H), 2.51 - 2.61 (m, 1H), 2.01 - 2.13 (m, 1H), 1.86 - 2.01 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H). Example 90: 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000300_0002
[00612] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) via SFC (Stationary phase: AY-H (3x25 cm); Mobile phase: 70% EtOH/CO2; Rt = 5.50 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (br dd, J = 7.9, 3.4 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.21 - 7.39 (m, 2H), 6.86 (br d, J = 6.9 Hz, 1H), 6.63 - 6.82(m, 2H), 6.10 - 6.23 (m, 2H), 5.07 (br d, J = 7.6 Hz, 1H), 4.69 - 4.83 (m, 1H), 3.73 - 3.85 (m, 1H), 3.38 - 3.52 (m, 1H), 2.99 (s, 3H), 2.50-2.42 (m, 1H), 1.81 - 2.11 (m, 3H), 1.26 (d, J = 7.1 Hz, 3H). 298 QB\184200.00050\92364964.2 VVID-746PC Example 91: 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000301_0001
[00613] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) via SFC (Stationary phase: AY-H (3x25 cm); Mobile phase: 70% EtOH/CO2; Rt = 13.8 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 8.0, 3.5 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.23 - 7.37 (m, 2H), 6.86 (d, J = 6.7 Hz, 1H), 6.73 - 6.82 (m, 1H), 6.63 - 6.72 (m, 1H), 6.09 - 6.24 (m, 2H), 5.07 (d, J = 7.7 Hz, 1H), 4.70 - 4.82 (m, 1H), 3.74 - 3.84 (m, 1H), 3.40 - 3.50 (m, 1H), 2.99 (s, 3H), 1.98 - 2.11 (m, 1H), 1.82 - 1.97 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H). Example 92: 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000301_0002
[00614] The title compound was prepared in a manner analogous to Example 1 using 2-(4-fluoro-2- methylphenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 2-fluoro-4-(2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 1.50 min) provided the title compound. MS (ESI): mass calcd. for C24H28F2N2O3S, 462.2; m/z found 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.01 - 8.09 (m, 1H), 7.42 (t, J = 8.9 Hz, 1H), 6.98 - 7.08 (m, 2H), 6.85 (dt, J = 2.8, 8.6 Hz, 1H), 6.72 - 6.80 (m, 1H), 6.64 - 6.71 (m, 1H), 6.46 - 6.59 (m, 2H), 4.83 (t, J = 5.6 Hz, 1H), 4.69 - 4.79 (m, 1H), 3.50 - 3.58 (m, 2H), 2.99 (s, 3H), 2.40 (s, 3H), 1.93 - 2.04 (m, 1H), 1.80 - 1.91 (m, 1H), 1.64 - 1.79 (m, 2H), 1.47 - 1.59 (m, 2H), 1.24 (d, J = 7.0 Hz, 3H). 299 QB\184200.00050\92364964.2 VVID-746PC Example 93: 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000302_0001
[00615] The title compound was prepared in a manner analogous to Example 1 using 2-(4-fluoro-2- methylphenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 2-fluoro-4-(2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 2.03 min) provided the title compound. MS (ESI): mass calcd. for C24H28F2N2O3S, 462.2; m/z found 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J = 2.8, 7.9 Hz, 1H), 7.42 (t, J = 8.9 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.85 (dt, J = 2.7, 8.6 Hz, 1H), 6.79 - 6.72 (m,1H), 6.70 - 6.64 (m, 1H), 6.59 - 6.54 (m, 1H), 6.49 (dd, J = 2.0, 15.1 Hz, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.79 - 4.69 (m, 1H), 3.60 - 3.46 (m, 2H), 2.99 (s, 3H), 2.40 (s, 3H), 1.98 (br dd, J = 7.4, 12.9 Hz, 1H), 1.85 (br dd, J = 6.1, 12.1 Hz, 1H), 1.72 (dt, J = 6.9, 13.9 Hz, 2H), 1.57 - 1.48 (m, 2H), 1.25 (d, J = 7.1 Hz, 3H). Example 94: 4-((*S)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide.
Figure imgf000302_0002
[00616] The title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2,5- difluorobenzoate instead of methyl 4-bromobenzoate, and Pd2(dba)3/XantPhos instead of SPhos Pd G4 in Step A. Separation of 4-(3-(2-chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 23% MeOH/CO2; Rt = 5.20 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (br d, J = 7.5 Hz, 1H), 7.38 - 7.47 (m, 3H), 7.20 - 300 QB\184200.00050\92364964.2 VVID-746PC 7.26 (m, 2H), 6.64 - 6.76 (m, 3H), 4.68 - 4.81 (m, 2H), 3.81 - 3.97 (m, 3H), 3.37 - 3.44 (m, 2H), 2.99 (s, 4H), 1.23 (d, J = 7.0 Hz, 3H). Example 95: 4-((*R)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide.
Figure imgf000303_0001
[00617] The title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2,5- difluorobenzoate instead of methyl 4-bromobenzoate, and Pd2(dba)3/XantPhos instead of SPhos Pd G4 in Step A. Separation of 4-(3-(2-chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 23% MeOH/CO2; Rt = 6.20 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N2O4S, 484.1; m/z found, 485.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (br d, J = 7.9 Hz, 1H), 7.35 - 7.49 (m, 3H), 7.18 - 7.28 (m, 2H), 6.59 - 6.80 (m, 3H), 4.67 - 4.83 (m, 2H), 3.78 - 3.99 (m, 3H), 3.35 - 3.47 (m, 2H), 2.99 (s, 4H), 1.24 (d, J = 7.0 Hz, 3H). Example 96: 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000303_0002
[00618] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chloro-4-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide (Step C) via SFC (Stationary phase: WK (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 11.8 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C22H24ClF2N3O3S, 483.1; m/z found, 484.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.51 (dd, J = 8.8, 2.6 Hz, 1H), 7.27 (dd, J = 8.5, 6.3 Hz, 1H), 7.00 - 7.17 (m, 2H), 6.72 - 301 QB\184200.00050\92364964.2 VVID-746PC 6.81 (m, 1H), 6.59 - 6.70 (m, 1H), 5.14 (br t, J = 5.5 Hz, 1H), 4.73 (br d, J = 7.2 Hz, 1H), 3.70 - 3.79 (m, 1H), 3.58 - 3.68 (m, 1H), 2.98 (s, 3H), 2.04 - 2.15 (m, 1H), 1.88 - 1.97 (m, 1H), 1.71 - 1.87 (m, 2H), 1.55 (br d, J = 4.5 Hz, 2H), 1.26 (d, J = 6.9 Hz, 3H). Example 97: 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)picolinamide.
Figure imgf000304_0001
[00619] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)azepane (Intermediate 13) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)picolinamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 5.71 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClF2N3O3S, 497.0; m/z found, 498.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.6 Hz, 1H), 7.49 - 7.64 (m, 2H), 7.26 - 7.32 (m, 1H), 7.17 - 7.23 (m, 1H), 6.87 (br d, J = 14.9 Hz, 1H), 6.74 - 6.82 (m, 1H), 6.60 - 6.70 (m, 1H), 4.68 - 4.85 (m, 2H), 4.01 (br dd, J = 15.3, 3.2 Hz, 1H), 3.79 (br dd, J = 15.6, 10.2 Hz, 1H), 2.99 (s, 3H), 2.22 - 2.36 (m, 1H), 1.71 - 2.12 (m, 4H), 1.30 - 1.57 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 98: 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)picolinamide.
Figure imgf000304_0002
[00620] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)azepane (Intermediate 13) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)picolinamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 9.20 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClF2N3O3S, 497.0; m/z found, 302 QB\184200.00050\92364964.2 VVID-746PC 498.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.6 Hz, 1H), 7.57 (br s, 1H), 7.53 (dd, J = 8.7, 2.6 Hz, 1H), 7.26 - 7.33 (m, 1H), 7.20 (td, J = 8.5, 2.6 Hz, 1H), 6.87 (br d, J = 14.4 Hz, 1H), 6.73 - 6.79 (m, 1H), 6.61 - 6.68 (m, 1H), 4.69 - 4.85 (m, 2H), 4.00 (br dd, J = 15.3, 3.9 Hz, 1H), 3.79 (br dd, J = 15.4, 10.1 Hz, 1H), 2.97 (s, 3H), 2.24 - 2.35 (m, 1H), 1.72 - 2.04 (m, 4H), 1.31 - 1.55 (m, 3H), 1.27 (d, J = 7.0 Hz, 3H). Example 99: 4-((*S)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide.
Figure imgf000305_0001
[00621] The title compound was prepared in a manner analogous to Example 1 using 3-(2,4- dichlorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(3-(2,4-dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 6.92 min) provided the title compound. MS (ESI): mass calcd. for C22H23Cl2FN2O4S, 500.1; m/z found, 501.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (dd, J = 7.9, 2.0 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.43 - 7.52 (m, 1H), 7.23 - 7.36 (m, 2H), 6.65 - 6.82 (m, 2H), 6.55 - 6.65 (m, 2H), 4.95 (t, J = 4.3 Hz, 1H), 4.68 - 4.81 (m, 1H), 3.95 - 4.07 (m, 2H), 3.64 - 3.89 (m, 3H), 3.45 (dt, J = 12.8, 4.3 Hz, 1H), 3.00 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H). Example 100: 4-((*R)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide.
Figure imgf000305_0002
[00622] The title compound was prepared in a manner analogous to Example 1 using 3-(2,4- dichlorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(3-(2,4-dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- 303 QB\184200.00050\92364964.2 VVID-746PC yl)benzamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 10.1 min) provided the title compound. MS (ESI): mass calcd. for C22H23Cl2FN2O4S, 500.1; m/z found, 501.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (br d, J = 7.4 Hz, 1H), 7.67 (s, 1H), 7.48 (br t, J = 8.8 Hz, 1H), 7.25 - 7.35 (m, 2H), 6.66 - 6.81 (m, 2H), 6.55 - 6.64 (m, 2H), 4.94 (br s, 1H), 4.74 (br dd, J = 11.2, 6.1 Hz, 1H), 3.96 - 4.11 (m, 2H), 3.64 - 3.90 (m, 3H), 3.40 - 3.51 (m, 1H), 2.99 (s, 3H), 1.26 (br d, J = 6.9 Hz, 3H). Example 101: 4-((*R)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000306_0001
[00623] The title compound was prepared in a manner analogous to Example 1 using 1-(2- chlorophenyl)isoindoline (Intermediate 16) instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(1-(2-chlorophenyl)isoindolin-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 48% iPrOH/CO2; Rt = 2.98 min) provided the title compound. MS (ESI): mass calcd. for C26H25ClN2O3S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (br d, J = 7.6 Hz, 1H), 7.73 (br d, J = 8.4 Hz, 2H), 7.47 - 7.60 (m, 2H), 7.10 - 7.41 (m, 6H), 6.65 - 6.85 (m, 2H), 6.55 (br d, J = 8.4 Hz, 2H), 6.47 (br s, 1H), 5.17 (br d, J = 13.9 Hz, 1H), 4.72 - 4.90 (m, 2H), 2.99 (s, 3H), 1.26 (br d, J = 7.0 Hz, 3H). Example 102: 4-((*S)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000306_0002
[00624] The title compound was prepared in a manner analogous to Example 1 using 1-(2- chlorophenyl)isoindoline (Intermediate 16) instead of (S)-2-(2-chlorophenyl)pyrrolidine and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(1-(2-chlorophenyl)isoindolin-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 48% iPrOH/CO2; Rt = 4.60 min) provided the title compound. MS (ESI): mass calcd. for C26H25ClN2O3S, 304 QB\184200.00050\92364964.2 VVID-746PC 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (br d, J = 8.0 Hz, 1H), 7.74 (br d, J = 8.6 Hz, 2H), 7.47 - 7.57 (m, 2H), 7.13 - 7.39 (m, 6H), 6.63 - 6.82 (m, 2H), 6.55 (br d, J = 8.6 Hz, 2H), 6.47 (br s, 1H), 5.11 - 5.23 (m, 1H), 4.74 - 4.88 (m, 2H), 2.98 (s, 3H), 1.27 (d, J = 7.0 Hz, 3H). Example 103: 6-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide.
Figure imgf000307_0001
[00625] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 6-bromo-4-fluoronicotinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 6-(2-(2-chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 8.10 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClF2N3O3S, 483.1; m/z found, 484.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 11.1 Hz, 1H), 8.27 (br d, J = 7.9 Hz, 1H), 7.44 (dd, J = 8.6, 2.3 Hz, 1H), 7.15 - 7.25 (m, 1H), 7.10 (td, J = 8.6, 2.6 Hz, 1H), 6.67 - 6.82 (m, 2H), 6.43 (d, J = 14.5 Hz, 1H), 5.67 (br t, J = 5.1 Hz, 1H), 4.67 - 4.81 (m, 1H), 4.21 (br dd, J = 13.2, 3.8 Hz, 1H), 3.52 (td, J = 12.3, 4.8 Hz, 1H), 3.00 (s, 3H), 1.83 - 2.09 (m, 3H), 1.52 - 1.77 (m, 2H), 1.36 - 1.49 (m, 1H), 1.24 (d, J = 7.0 Hz, 3H). Example 104: 6-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide.
Figure imgf000307_0002
[00626] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-4- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 6-bromo-4-fluoronicotinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 6-(2-(2-chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 305 QB\184200.00050\92364964.2 VVID-746PC 12.0 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClF2N3O3S, 483.1; m/z found, 484.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 11.1 Hz, 1H), 8.25 (br d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H), 7.21 (dd, J = 8.7, 6.2 Hz, 1H), 7.10 (td, J = 8.5, 2.4 Hz, 1H), 6.66 - 6.82 (m, 2H), 6.41 (d, J = 14.5 Hz, 1H), 5.64 (t, J = 5.1 Hz, 1H), 4.67 - 4.80 (m, 1H), 4.16 - 4.29 (m, 1H), 3.52 (td, J = 12.5, 4.8 Hz, 1H), 2.99 (s, 3H), 1.84 - 2.12 (m, 3H), 1.52 - 1.76 (m, 2H), 1.37 - 1.51 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H). Example 105: 5-(2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide.
Figure imgf000308_0001
[00627] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-3- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H24ClF2N3O3S, 483.1; m/z found, 484.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 8.5, 2.8 Hz, 1H), 7.73 (br d, J = 1.4 Hz, 1H), 7.25 - 7.35 (m, 2H), 7.03 - 7.13 (m, 2H), 6.71 - 6.80 (m, 1H), 6.62 - 6.69 (m, 1H), 5.23 (q, J = 5.2 Hz, 1H), 4.73 (ddt, J = 8.4, 7.1, 3.5, 3.5 Hz, 1H), 3.77 (dt, J = 12.7, 5.1 Hz, 1H), 3.57 - 3.68 (m, 1H), 2.98 (d, J = 5.9 Hz, 3H), 2.13 (dddd, J = 13.7, 9.7, 5.5, 4.3 Hz, 1H), 1.72 - 1.99 (m, 3H), 1.43 - 1.64 (m, 2H), 1.20 - 1.31 (m, 3H). Example 106: 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000308_0002
[00628] The title compound was prepared via separation of 5-(2-(2-chloro-3-fluorophenyl)piperidin-1-yl)- 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 105) by SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 46% EtOH/CO2; Rt = 9.94 min (second eluting product)). MS (ESI): mass calcd. for C22H24ClF2N3O3S, 483.1; m/z found, 484.0 [M+H]+. 1H NMR (400 MHz, DMSO- 306 QB\184200.00050\92364964.2 VVID-746PC d6) δ 8.53 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 7.22 - 7.36 (m, 2H), 7.01 - 7.15 (m, 2H), 6.72 - 6.81 (m, 1H), 6.59 - 6.71 (m, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.68 - 4.79 (m, 1H), 3.77 (dt, J = 12.7, 5.0 Hz, 1H), 3.57 - 3.69 (m, 1H), 2.98 (s, 3H), 2.06 - 2.20 (m, 1H), 1.72 - 2.00 (m, 3H), 1.43 - 1.65 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H). Example 107: 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000309_0001
[00629] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chlorophenyl)- 4,4-difluoropiperidine (Intermediate 9) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)picolinamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% iPrOH/CO2; Rt = 7.50 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF3N3O3S, 501.1; m/z found, 502.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.56 (m, 1H), 7.79 - 7.73 (m, 1H), 7.55 - 7.46 (m, 1H), 7.37 - 7.24 (m, 3H), 7.20 (dd, J = 2.2, 14.2 Hz, 1H), 6.80 - 6.73 (m, 1H), 6.70 - 6.63 (m, 1H), 5.23 - 5.14 (m, 1H), 4.79 - 4.66 (m, 1H), 3.97 - 3.79 (m, 2H), 3.01 - 2.96 (m, 3H), 2.68 - 2.57 (m, 1H), 2.47 - 2.31 (m, 3H), 1.29 - 1.22 (m, 3H). Example 108: 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000309_0002
[00630] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chlorophenyl)- 4,4-difluoropiperidine (Intermediate 9) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but- 307 QB\184200.00050\92364964.2 VVID-746PC 3-en-2-yl)picolinamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% iPrOH/CO2; Rt = 10.8 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF3N3O3S, 501.1; m/z found, 502.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.55 (m, 1H), 7.79 - 7.71 (m, 1H), 7.54 - 7.48 (m, 1H), 7.37 - 7.18 (m, 4H), 6.79 - 6.71 (m, 1H), 6.70 - 6.62 (m,1H), 5.25 - 5.15 (m, 1H), 4.79 - 4.65 (m, 1H), 3.97 - 3.79 (m, 2H), 3.00 - 2.94 (m, 3H), 2.68 - 2.56 (m, 1H), 2.47 - 2.31 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 109: 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000310_0001
[00631] The title compound was prepared in a manner analogous to Example 1 using 2-(2-chloro-6- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chloro-6-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 7.82 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.32 - 7.42 (m, 2H), 7.14 - 7.25 (m, 1H), 6.73 - 6.81 (m, 1H), 6.61 - 6.70 (m, 2H), 5.38 (t, J = 6.75 Hz, 1H), 4.65 - 4.80 (m, 1H), 3.52 - 3.66 (m, 2H), 2.98 (s, 3H), 2.53 - 2.62 (m, 1H), 1.95 - 2.22 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 110: 4-((*R)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000310_0002
[00632] The title compound was prepared in a manner analogous to Example 1 using 5-(2- chlorophenyl)pyrrolidin-2-one (Intermediate 19) instead of (S)-2-(2-chlorophenyl)pyrrolidine and XantPhos/Pd2(dba)3 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-5- oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Step C) via SFC (Stationary 308 QB\184200.00050\92364964.2 VVID-746PC phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.67 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClN2O4S, 446.1; m/z found, 447.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.50 (br d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.44 - 7.57 (m, 3H), 7.15 - 7.30 (m, 3H), 6.68 - 6.82 (m, 2H), 5.76 - 5.86 (m, 1H), 4.79 (td, J = 6.8, 3.9 Hz, 1H), 2.99 (s, 3H), 2.59 - 2.75 (m, 3H), 1.82 - 1.93 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H). Example 111: 4-((*S)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000311_0001
[00633] The title compound was prepared in a manner analogous to Example 1 using 5-(2- chlorophenyl)pyrrolidin-2-one (Intermediate 19) instead of (S)-2-(2-chlorophenyl)pyrrolidine and XantPhos/Pd2(dba)3 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-5- oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.96 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClN2O4S, 446.1; m/z found, 447.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.51 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.44 - 7.57 (m, 3H), 7.13 - 7.31 (m, 3H), 6.66 - 6.82 (m, 2H), 5.82 (dd, J = 7.3, 4.8 Hz, 1H), 4.79 (td, J = 7.3, 3.8 Hz, 1H), 2.98 (s, 3H), 2.58 - 2.72 (m, 3H), 1.82 - 1.92 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 112: 4-((*S)-1-(2-Chlorophenyl)-3-oxoisoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000311_0002
[00634] The title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)isoindolin-1-one (Intermediate 20) instead of (S)-2-(2-chlorophenyl)pyrrolidine and XantPhos/Pd2(dba)3 instead of SPhos Pd G4 in Step A. Separation of 4-(1-(2-chlorophenyl)-3- oxoisoindolin-2-yl)benzoic acid (Step B) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% MeOH/CO2; Rt = 8.17 min (second eluting product)) provided an intermediate that was elaborated to the 309 QB\184200.00050\92364964.2 VVID-746PC title compound. MS (ESI): mass calcd. for C26H23ClN2O4S, 494.1; m/z found, 495.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (br d, J = 7.9 Hz, 1H), 7.82 - 8.02 (m, 3H), 7.70 - 7.81 (m, 2H), 7.54 - 7.69 (m, 3H), 7.37 - 7.52 (m, 1H), 7.22 - 7.36 (m, 1H), 7.04 - 7.35 (m, 2H), 6.68 - 6.97 (m, 3H), 4.80 (td, J = 7.2, 3.7 Hz, 1H), 3.00 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 113: 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000312_0001
[00635] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C23H26ClFN2O3S, 464.1; m/z found, 465.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.72 (m, 1H), 7.39 (ddt, J = 7.4, 2.4, 1.1 Hz, 1H), 7.24 – 7.08 (m, 3H), 6.93 (ddd, J = 15.1, 4.6, 1.4 Hz, 1H), 6.62 – 6.44 (m, 3H), 6.38 (ddd, J = 16.7, 6.2, 2.4 Hz, 1H), 5.09 (td, J = 5.8, 3.8 Hz, 1H), 5.05 – 4.92 (m, 1H), 3.74 – 3.57 (m, 2H), 2.94 (s, 3H), 2.18 (dq, J = 12.7, 6.0 Hz, 1H), 2.06 – 1.80 (m, 3H), 1.72 – 1.52 (m, 3H), 1.40 (dd, J = 7.1, 2.1 Hz, 3H). Example 114: 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000312_0002
[00636] The title compound was prepared via separation 4-(2-(2-chlorophenyl)piperidin-1-yl)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 113) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 18% MeOH/CO2; Rt = 3.31 min). MS (ESI): mass calcd. for C23H26ClFN2O3S, 464.1; m/z found, 465.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.79 (m, 1H), 7.40 (dt, J = 7.6, 1.1 Hz, 1H), 7.23 – 7.08 (m, 3H), 6.93 (dd, J = 15.1, 4.5 Hz, 1H), 6.62 – 6.42 (m, 3H), 6.37 (dd, J = 16.7, 2.4 Hz, 1H), 5.09 (t, J = 5.7 Hz, 1H), 5.05 – 4.93 (m, 1H), 3.72 – 3.58 (m, 2H), 2.94 (s, 3H), 2.25 – 2.10 (m, 1H), 2.02 – 1.81 (m, 3H), 1.67 – 1.61 (m, 2H), 1.41 (d, J = 7.1 Hz, 3H). 310 QB\184200.00050\92364964.2 VVID-746PC Example 115: 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide.
Figure imgf000313_0001
[00637] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)piperidin-1-yl)-2-fluoro- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 113) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 18% MeOH/CO2; Rt = 3.95 min). MS (ESI): mass calcd. for C23H26ClFN2O3S, 464.1; m/z found, 465.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 9.7, 8.9 Hz, 1H), 7.39 (dt, J = 7.4, 1.2 Hz, 1H), 7.21 – 7.10 (m, 3H), 6.93 (dd, J = 15.1, 4.6 Hz, 1H), 6.61 – 6.43 (m, 3H), 6.38 (dd, J = 16.7, 2.5 Hz, 1H), 5.10 (t, J = 5.7 Hz, 1H), 5.04 – 4.95 (m, 1H), 3.71 – 3.60 (m, 2H), 2.94 (s, 3H), 2.23 – 2.12 (m, 1H), 2.04 – 1.83 (m, 4H), 1.64 (dt, J = 8.7, 5.6 Hz, 2H), 1.40 (d, J = 7.1 Hz, 3H). Example 116: 4-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000313_0002
[00638] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C22H25ClN2O4S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.51 (m, 2H), 7.37 (dt, J = 7.8, 1.5 Hz, 1H), 7.33 – 7.29 (m, 1H), 7.19 – 7.05 (m, 2H), 6.96 – 6.80 (m, 3H), 6.47 (ddd, J = 15.2, 5.7, 1.7 Hz, 1H), 6.03 (dd, J = 7.9, 2.4 Hz, 1H), 5.09 – 4.84 (m, 2H), 4.16 – 3.92 (m, 3H), 3.78 – 3.60 (m, 2H), 3.35 (ddd, J = 12.0, 8.0, 3.8 Hz, 1H), 2.92 (d, J = 1.6 Hz, 3H), 1.40 (dd, J = 7.1, 2.4 Hz, 3H). Example 117: 4-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide. 311 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000314_0001
[00639] The title compound was prepared in a manner analogous to Example 1 using 2-(2- fluorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C23H27FN2O3S, 430.2; m/z found, 431.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.54 (m, 2H), 7.23 – 6.88 (m, 5H), 6.84 (d, J = 8.5 Hz, 2H), 6.48 (ddd, J = 15.1, 4.0, 1.7 Hz, 1H), 5.92 (d, J = 7.8 Hz, 1H), 5.10 – 4.90 (m, 2H), 3.58 (dd, J = 6.6, 5.4 Hz, 2H), 2.94 (d, J = 1.0 Hz, 3H), 2.19 – 1.81 (m, 4H), 1.66 – 1.59 (m, 2H), 1.41 (dd, J = 7.1, 2.2 Hz, 3H). Example 118: 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-cyano-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000314_0002
[00640] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo- 2-cyanobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C24H26ClN3O3S, 471.1; m/z found, 472.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.9, 1.5 Hz, 1H), 7.37 (dt, J = 7.2, 1.1 Hz, 1H), 7.18 – 7.06 (m, 3H), 7.04 (d, J = 2.7 Hz, 1H), 6.93 – 6.81 (m, 2H), 6.56 (ddd, J = 15.1, 8.1, 1.7 Hz, 1H), 6.25 – 6.13 (m, 1H), 5.04 (td, J = 5.8, 1.5 Hz, 1H), 4.95 (tdd, J = 7.1, 4.8, 1.8 Hz, 1H), 3.70 – 3.49 (m, 2H), 2.93 (s, 3H), 2.25 – 2.07 (m, 1H), 2.06 – 1.80 (m, 3H), 1.72 – 1.50 (m, 2H), 1.41 (dd, J = 7.1, 1.4 Hz, 3H). Example 119: 4-(3-(2-Chlorophenyl)thiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000314_0003
312 QB\184200.00050\92364964.2 VVID-746PC [00641] The title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)thiomorpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4- bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H24ClFN2O3S2, 482.1; m/z found, 483.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.84 (td, J = 9.2, 1.7 Hz, 1H), 7.40 (dt, J = 7.3, 1.8 Hz, 1H), 7.29 (dd, J = 7.1, 2.4 Hz, 1H), 7.25 – 7.15 (m, 2H), 6.90 (ddd, J = 15.1, 4.6, 1.7 Hz, 1H), 6.60 – 6.49 (m, 2H), 6.45 (ddd, J = 15.1, 2.6, 1.7 Hz, 1H), 6.31 (ddd, J = 16.3, 7.6, 2.5 Hz, 1H), 5.22 – 5.14 (m, 1H), 5.02 – 4.91 (m, 1H), 4.11 – 3.80 (m, 2H), 3.20 – 2.92 (m, 4H), 2.90 (d, J = 1.3 Hz, 3H), 1.38 (dd, J = 7.1, 2.1 Hz, 3H). Example 120: 4-(2-(2,5-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000315_0001
[00642] The title compound was prepared in a manner analogous to Example 1 using 2-(2,5- difluorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4- bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H23F3N2O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 9.1 Hz, 1H), 7.11 – 6.99 (m, 1H), 6.97 – 6.83 (m, 2H), 6.67 – 6.51 (m, 2H), 6.47 (dt, J = 15.1, 1.7 Hz, 1H), 6.30 (dd, J = 8.9, 2.3 Hz, 1H), 6.15 – 6.04 (m, 1H), 5.06 – 4.89 (m, 2H), 3.70 (td, J = 8.8, 2.6 Hz, 1H), 3.52 – 3.35 (m, 1H), 2.90 (s, 3H), 2.54 – 2.34 (m, 1H), 2.16 – 1.90 (m, 3H), 1.38 (dd, J = 7.1, 2.2 Hz, 3H). Example 121: 4-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000315_0002
[00643] The title compound was prepared in a manner analogous to Example 1 using 2-(2,6- difluorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4- bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H23F3N2O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.72 (m, 1H), 7.25 313 QB\184200.00050\92364964.2 VVID-746PC – 7.12 (m, 1H), 6.95 – 6.77 (m, 3H), 6.58 – 6.41 (m, 2H), 6.29 (dt, J = 8.9, 2.7 Hz, 1H), 6.10 (ddd, J = 16.3, 3.9, 2.3 Hz, 1H), 5.28 – 5.11 (m, 1H), 5.06 – 4.87 (m, 1H), 3.67 – 3.44 (m, 2H), 2.90 (s, 3H), 2.60 – 2.45 (m, 1H), 2.29 – 2.01 (m, 3H), 1.37 (dd, J = 7.1, 1.8 Hz, 3H). Example 122: 4-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000316_0001
[00644] The title compound was prepared via separation of 4-(2-(2,6-difluorophenyl)pyrrolidin-1-yl)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 121) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 5.26 min (first eluting product)). MS (ESI): mass calcd. for C22H23F3N2O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.75 (m, 1H), 7.19 (tt, J = 8.4, 6.3 Hz, 1H), 6.97 – 6.78 (m, 3H), 6.57 – 6.40 (m, 2H), 6.29 (dd, J = 8.9, 2.4 Hz, 1H), 6.12 (dd, J = 16.2, 2.4 Hz, 1H), 5.22 (dd, J = 7.9, 4.3 Hz, 1H), 5.03 – 4.94 (m, 1H), 3.70 – 3.57 (m, 1H), 3.57 – 3.45 (m, 1H), 2.92 (s, 3H), 2.60 – 2.44 (m, 1H), 2.30 – 2.02 (m, 3H), 1.38 (d, J = 7.1 Hz, 3H). Example 123: 5-(2-(2-Chlorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000316_0002
[00645] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)azepane instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C23H27ClFN3O3S, 479.1; m/z found, 480.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.56 (m, 2H), 7.42 (dt, J = 7.0, 1.9 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.10 (dd, J = 6.9, 2.6 Hz, 1H), 6.92 (dt, J = 15.1, 4.7 Hz, 1H), 6.63 – 6.39 (m, 2H), 4.98 – 4.81 (m, 2H), 3.93 (d, J = 16.0 Hz, 1H), 3.78 (dd, J = 15.5, 11.2 Hz, 1H), 2.91 (d, J = 4.0 Hz, 3H), 2.63 – 2.53 (m, 1H), 2.19 – 1.86 (m, 3H), 1.79 – 1.32 (m, 7H). Example 124: 4-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide. 314 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000317_0001
[00646] The title compound was prepared in a manner analogous to Example 1 using 2-(2,4- dimethylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C24H29FN2O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 9.2 Hz, 1H), 7.03 (s, 1H), 6.98 – 6.81 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 6.60 – 6.41 (m, 2H), 6.23 (d, J = 8.9 Hz, 1H), 6.03 (d, J = 16.1 Hz, 1H), 5.05 – 4.93 (m, 1H), 4.88 (d, J = 8.1 Hz, 1H), 3.72 (td, J = 8.5, 3.6 Hz, 1H), 3.56 – 3.40 (m, 1H), 2.91 (s, 3H), 2.39 (s, 4H), 2.28 (s, 3H), 2.12 – 2.01 (m, 2H), 1.88 (ddd, J = 11.5, 5.6, 2.5 Hz, 1H), 1.38 (dd, J = 7.1, 2.5 Hz, 3H). Example 125: 4-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide.
Figure imgf000317_0002
[00647] The title compound was prepared via separation of 4-(2-(2,4-dimethylphenyl)pyrrolidin-1-yl)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 124) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 2.94 min). MS (ESI): mass calcd. for C24H29FN2O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 9.2 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.98 – 6.82 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 6.59 – 6.40 (m, 2H), 6.29 – 6.16 (m, 1H), 6.03 (d, J = 16.1 Hz, 1H), 5.04 – 4.94 (m, 1H), 4.89 (dd, J = 8.3, 2.1 Hz, 1H), 3.73 (ddd, J = 10.0, 7.2, 3.7 Hz, 1H), 3.55 – 3.42 (m, 1H), 2.92 (s, 3H), 2.39 (s, 4H), 2.28 (s, 3H), 2.15 – 1.99 (m, 2H), 1.95 – 1.81 (m, 1H), 1.38 (d, J = 7.1 Hz, 3H). Example 126: 4-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide. 315 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000318_0001
[00648] The title compound was prepared via separation of 4-(2-(2,4-dimethylphenyl)pyrrolidin-1-yl)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 124) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 3.60 min). MS (ESI): mass calcd. for C24H29FN2O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 9.2 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.98 – 6.82 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 6.62 – 6.42 (m, 2H), 6.30 – 6.15 (m, 1H), 6.03 (d, J = 16.1 Hz, 1H), 5.04 – 4.94 (m, 1H), 4.88 (dd, J = 8.3, 2.0 Hz, 1H), 3.77 – 3.66 (m, 1H), 3.53 – 3.42 (m, 1H), 2.92 (s, 3H), 2.39 (s, 4H), 2.29 (s, 3H), 2.14 – 2.00 (m, 2H), 1.95 – 1.81 (m, 1H), 1.39 (d, J = 7.2 Hz, 3H). Example 127: 4-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000318_0002
[00649] The title compound was prepared in a manner analogous to Example 1 using 2-(2,3- difluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H23F3N2O3S, 452.1; m/z found, 453.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.85 (td, J = 9.1, 2.0 Hz, 1H), 7.13 – 7.00 (m, 1H), 7.00 – 6.86 (m, 2H), 6.76 – 6.67 (m, 1H), 6.62 – 6.40 (m, 2H), 6.35 – 6.24 (m, 1H), 6.16 – 6.05 (m, 1H), 5.08 (d, J = 8.2 Hz, 1H), 5.04 – 4.94 (m, 1H), 3.75 – 3.64 (m, 1H), 3.54 – 3.41 (m, 1H), 2.92 (d, J = 0.8 Hz, 3H), 2.55 – 2.39 (m, 1H), 2.17 – 1.95 (m, 3H), 1.39 (dd, J = 7.1, 2.0 Hz, 3H). Example 128: 4-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide. 316 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000319_0001
[00650] The title compound was prepared via separation of 4-(2-(2,3-difluorophenyl)pyrrolidin-1-yl)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 127) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 3.34 min (second eluting product)). MS (ESI): mass calcd. for C22H23F3N2O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 9.1 Hz, 1H), 7.06 (dtd, J = 9.7, 7.9, 1.7 Hz, 1H), 7.00 – 6.84 (m, 2H), 6.69 (ddt, J = 7.9, 6.3, 1.6 Hz, 1H), 6.61 – 6.41 (m, 2H), 6.30 (dd, J = 8.9, 2.4 Hz, 1H), 6.11 (dd, J = 16.0, 2.3 Hz, 1H), 5.07 (d, J = 8.2 Hz, 1H), 5.04 – 4.90 (m, 1H), 3.76 – 3.61 (m, 1H), 3.48 (td, J = 9.1, 6.7 Hz, 1H), 2.92 (s, 3H), 2.56 – 2.37 (m, 1H), 2.17 – 1.92 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 129: 4-(2-(2,4-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000319_0002
[00651] The title compound was prepared in a manner analogous to Example 1 using 2-(2,4- difluorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 4- bromo-2-fluorobenzoate instead of methyl 4-bromobenzoate in Step A. MS (ESI): mass calcd. for C22H23F3N2O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.76 (m, 1H), 7.00 – 6.80 (m, 3H), 6.79 – 6.67 (m, 1H), 6.61 – 6.41 (m, 2H), 6.30 (dt, J = 8.9, 2.5 Hz, 1H), 6.10 (dt, J = 16.0, 2.7 Hz, 1H), 5.07 – 4.89 (m, 2H), 3.77 – 3.61 (m, 1H), 3.47 (td, J = 9.4, 6.9 Hz, 1H), 2.92 (d, J = 0.9 Hz, 3H), 2.43 (dq, J = 14.4, 7.8 Hz, 1H), 2.16 – 1.90 (m, 3H), 1.39 (dd, J = 7.1, 2.1 Hz, 3H). Example 130: 5-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine- 2-carboxamide. 317 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000320_0001
[00652] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)azepane instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2- carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H27ClN4O3S, 462.2; m/z found, 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.3 Hz, 1H), 8.08 (s, 2H), 7.47 - 7.57 (m, 1H), 7.23 - 7.38 (m, 3H), 6.72 - 6.83 (m, 1H), 6.62 - 6.70 (m, 1H), 4.68 - 4.92 (m, 2H), 4.13 (br dd, J = 15.4, 3.8 Hz, 1H), 3.81 (br dd, J = 15.6, 10.4 Hz, 1H), 2.97 (d, J = 6.4 Hz, 3H), 2.26 - 2.33 (m, 1H), 1.92 - 2.05 (m, 2H), 1.74 - 1.90 (m, 2H), 1.36 - 1.58 (m, 3H), 1.28 (dd, J = 7.0, 4.8 Hz, 3H). Example 131: 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide.
Figure imgf000320_0002
[00653] The title compound was prepared via separation 5-(2-(2-chlorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Example 130) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 4.74 min). MS (ESI): mass calcd. for C22H27ClN4O3S, 462.2; m/z found, 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.5 Hz, 1H), 8.08 (s, 2H), 7.47 - 7.60 (m, 1H), 7.23 - 7.38 (m, 3H), 6.74 - 6.84 (m, 1H), 6.60 - 6.72 (m, 1H) 4.71 - 4.87 (m, 2H), 4.13 (br dd, J = 15.5, 3.8 Hz, 1H), 3.81 (br dd, J = 15.4, 10.5 Hz, 1H), 2.98 (s, 3H), 2.26 - 2.34 (m, 1H), 1.91 - 2.06 (m, 2H), 1.72 - 1.91 (m, 2H), 1.35 - 1.60 (m, 3H), 1.28 (d, J = 7.1 Hz, 3H). Example 132: 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide. 318 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000321_0001
[00654] The title compound was prepared via separation 5-(2-(2-chlorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Example 130) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 7.62 min). MS (ESI): mass calcd. for C22H27ClN4O3S, 462.2; m/z found, 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.6 Hz, 1H), 8.08 (s, 2H), 7.46 - 7.58 (m, 1H), 7.20 - 7.41 (m, 3H), 6.73 - 6.80 (m, 1H), 6.62 - 6.69 (m, 1H) 4.68 - 4.89 (m, 2H), 4.13 (br dd, J = 15.7, 4.1 Hz, 1H), 3.81 (br dd, J = 15.6, 10.5 Hz, 1H), 2.96 (s, 3H), 2.29 - 2.38 (m, 1H), 1.91 - 2.06 (m, 2H), 1.74 - 1.90 (m, 2H), 1.35 - 1.59 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 133: 5-((*R)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2-carboxamide.
Figure imgf000321_0002
[00655] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2- carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 9.92 min) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 8.6 Hz, 1H), 8.23 (s, 2H), 7.46 - 7.53 (m, 1H), 7.19 - 7.29 (m, 3H), 6.74 - 6.82 (m, 1H), 6.64 - 6.71 (m, 1H), 5.12 (t, J = 5.7 Hz, 1H), 4.70 - 4.81 (m, 1H), 3.69 - 3.78 (m, 2H), 2.98 (s, 3H), 2.04 - 2.17 (m, 1H), 1.89 - 2.00 (m, 1H), 1.76 - 1.87 (m, 2H), 1.54 - 1.63 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H). Example 134: 5-((*S)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2-carboxamide. 319 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000322_0001
[00656] The title compound was prepared in a manner analogous to Example 1 using 2-(2- chlorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2- carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 13.2 min) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.5 Hz, 1H), 8.23 (s, 2H), 7.47 - 7.51 (m, 1H), 7.18 - 7.29 (m, 3H), 6.73 - 6.81 (m, 1H), 6.61 - 6.71 (m, 1H), 5.12 (t, J = 5.8 Hz, 1H), 4.68 - 4.80 (m, 1H), 3.67 - 3.78 (m, 2H), 2.97 (s, 3H), 2.06 - 2.16 (m, 1H), 1.89 - 2.01 (m, 1H), 1.74 - 1.87 (m, 2H), 1.51 - 1.64 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H). Example 135: 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000322_0002
[00657] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 25) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*R,2*S,5*S)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.44 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C22H22ClF2N3O3S, 481.1; m/z found, 482.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.5 Hz, 1H), 7.40 - 7.26 (m, 3H), 6.87 - 6.81 (m, 1H), 6.78 - 6.62 (m, 3H), 5.32 (d, J = 5.0 Hz, 1H), 4.79 - 4.65 (m, 1H), 4.01 (d, J = 9.8 Hz, 1H), 3.62 (dd, J = 5.1, 9.6 Hz, 1H), 2.97 (s, 3H), 2.32 - 2.26 (m, 1H), 2.01 - 1.92 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H), 0.67 - 0.57 (m, 1H), 0.39 - 0.29 (m, 1H). 320 QB\184200.00050\92364964.2 VVID-746PC Example 136: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide.
Figure imgf000323_0001
[00658] The title compound was prepared in a manner analogous to Example 1 using methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromobenzoate and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.1; m/z found, 452.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.43 (d, J = 8.6 Hz, 1H), 7.40 - 7.57 (m, 2H), 7.21 - 7.36 (m, 2H), 7.07 (dd, J = 7.6, 1.6 Hz, 1H), 6.73 - 6.82 (m, 1H), 6.60 - 6.72 (m, 2H), 5.12 - 5.25 (m, 1H), 4.67 - 4.80 (m, 1H), 3.82 - 3.90 (m, 1H), 3.45 - 3.58 (m, 1H), 3.34 - 3.41 (m, 1H), 2.98 (s, 3H), 1.81 - 2.08 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 137: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)-2- fluorobenzamide.
Figure imgf000323_0002
[00659] The title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate in Step A and (R,E)-4-(ethylsulfonyl)but-3-en-2-amine hydrochloride (Intermediate 2) instead of (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4- methylbenzenesulfonic acid (Intermediate 1) in Step C. MS (ESI): mass calcd. for C23H26ClFN2O3S, 464.1; m/z found, 465.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.82 (t, J = 9.1 Hz, 1H), 7.42 (dd, J = 7.8, 1.4 Hz, 1H), 7.20 (td, J = 7.6, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.4 Hz, 1H), 6.95 (dd, J = 7.6, 1.8 Hz, 1H), 6.89 (dd, J = 15.2, 4.6 Hz, 1H), 6.54 (dd, J = 14.7, 7.5 Hz, 1H), 6.36 (dd, J = 15.2, 1.7 Hz, 1H), 6.25 (dd, J = 8.9, 2.3 Hz, 1H), 6.06 (dd, J = 16.0, 2.3 Hz, 1H), 5.11 (dd, J = 8.4, 1.7 Hz, 1H), 5.03 – 4.92 (m, 1H), 3.80 – 3.70 (m, 1H), 3.55 – 3.46 (m, 1H), 2.97 (q, J = 7.5 Hz, 2H), 2.54 – 2.41 (m, 1H), 2.13 – 1.95 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H), 1.30 (t, J = 7.4 Hz, 3H). Example 138: 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine- 2-carboxamide. 321 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000324_0001
[00660] The title compound was prepared in a manner analogous to Example 1 using 3-(2- chlorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5- bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C20H23ClN4O4S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 2H), 7.82 (d, J = 8.3 Hz, 1H), 7.41 (ddd, J = 7.9, 4.4, 1.4 Hz, 1H), 7.31 – 7.10 (m, 3H), 6.90 (ddd, J = 15.1, 4.5, 1.1 Hz, 1H), 6.48 (dt, J = 15.1, 1.5 Hz, 1H), 5.10 – 4.88 (m, 2H), 4.26 – 3.95 (m, 3H), 3.89 – 3.72 (m, 2H), 3.54 – 3.41 (m, 1H), 2.91 (s, 3H), 1.43 (d, J = 7.1 Hz, 3H). Example 139: 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000324_0002
[00661] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 27) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H23ClFN3O3S, 463.1; m/z found, 464.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 8.6, 2.3 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.18 - 7.41 (m, 3H), 6.98 (br d, J = 7.6 Hz, 1H), 6.50 - 6.83 (m, 3H), 5.30 (d, J = 4.8 Hz, 1H), 4.64 - 4.84 (m, 1H), 4.01 (d, J = 9.8 Hz, 1H), 3.61 (dd, J = 9.6, 5.0 Hz, 1H), 2.97 (d, J = 2.9 Hz, 3H), 2.17 - 2.38 (m, 1H), 1.86 - 2.04 (m, 1H), 1.25 (dd, J = 7.0, 1.1 Hz, 3H), 0.60 (td, J = 7.9, 5.2 Hz, 1H), 0.35 (q, J = 4.1 Hz, 1H). Example 140: 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide. 322 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000325_0001
[00662] The title compound was prepared via separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 139) by SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 36% MeOH/CO2; Rt = 10.5 min (second eluting product)). MS (ESI): mass calcd. for C22H23ClFN3O3S, 463.1; m/z found, 464.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.20 - 7.39 (m, 3H), 6.98 (br d, J = 7.6 Hz, 1H), 6.56 - 6.83 (m, 3H), 5.30 (d, J = 5.0 Hz, 1H), 4.63 - 4.80 (m, 1H), 4.01 (d, J = 9.8 Hz, 1H), 3.62 (dd, J = 9.7, 5.1 Hz, 1H), 2.98 (s, 3H), 2.21 - 2.35 (m, 1H), 1.87 - 2.02 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H), 0.53 - 0.65 (m, 1H), 0.26 - 0.40 (m, 1H). Example 141: 4-(rac-(2*R,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000325_0002
[00663] The title compound was prepared in a manner analogous to Example 1 using 5-(2-chlorophenyl)- 3-methyl-pyrrolidin-3-ol (Intermediate 18) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step A) via RP-HPLC (35-65% ACN in 10 mM aqueous NH4HCO3 (second eluting product)) provided the cis racemate that was elaborated to the title compound. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 7.95 (br t, J = 8.6 Hz, 1H), 7.37 - 7.53 (m, 2H), 7.13 - 7.29 (m, 3H), 6.62 - 6.85 (m, 2H), 6.00 - 6.20 (m, 2H), 5.00 (dd, J = 9.1, 3.2 Hz, 1H), 4.61 - 4.84 (m, 2H), 3.71 (d, J = 10.0 Hz, 1H), 3.42 (d, J = 10.0 Hz, 1H), 2.99 (s, 3H), 2.53 - 2.60 (m, 1H), 1.99 (dd, J = 12.8, 2.9 Hz, 1H), 1.34 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 142: 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide. 323 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000326_0001
[00664] The title compound was prepared via separation of 4-(rac-(2*R,4*R)-2-(2-chlorophenyl)-4- hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 141) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 6.95 min (second eluting product)). MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, J = 8.0, 3.4 Hz, 1H), 7.41 - 7.50 (m, 2H), 7.18 - 7.29 (m, 3H), 6.63 - 6.83 (m, 2H), 6.02 - 6.20 (m, 2H), 5.00 (dd, J = 9.1, 3.2 Hz, 1H), 4.76 (s, 2H), 3.72 (d, J = 10.0 Hz, 1H), 3.42 (d, J = 10.0 Hz, 1H), 2.99 (s, 3H), 2.53 - 2.62 (m, 1H), 1.99 (dd, J = 12.8, 3.1 Hz, 1H), 1.34 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 143: 4-(rac-(2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000326_0002
[00665] The title compound was prepared in a manner analogous to Example 1 using 5-(2-chlorophenyl)- 3-methyl-pyrrolidin-3-ol (Intermediate 18) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step A) via RP-HPLC (35-65% ACN in 10 mM aqueous NH4HCO3 (first eluting product)) provided the trans racemate that was elaborated to the title compound. MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 7.88 - 7.98 (m, 1H), 7.36 - 7.51 (m, 2H), 7.19 - 7.31 (m, 3H), 6.72 - 6.80 (m, 1H), 6.64 - 6.70 (m, 1H), 6.16 (br t, J = 6.4 Hz, 1H), 6.05 (br dd, J = 14.4, 7.6 Hz, 1H), 5.19 (dd, J = 9.1, 7.4 Hz, 1H), 5.00 (br s, 1H), 4.70 - 4.81 (m, 1H), 3.75 (d, J = 10.4 Hz, 1H), 3.50 (br d, J = 10.3 Hz, 1H), 2.99 (d, J = 2.4 Hz, 3H), 2.55 (br s, 1H), 1.71 - 1.80 (m, 1H), 1.36 (s, 3H), 1.25 (dd, J = 7.0, 3.0 Hz, 3H). 324 QB\184200.00050\92364964.2 VVID-746PC Example 144: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000327_0001
[00666] Step A: Methyl (S)-5-(2-(2-chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylate. (S)-2-(2- chlorophenyl)pyrrolidine (150 mg, 0.653 mmol, 1.0 eq) and methyl 5-chloropyrazine-2-carboxylate (115 mg, 0.653 mmol, 1.0 eq) were taken up in 1,4-dioxane (2.2 mL, 0.30 M). To this was added N,N- diisopropylethylamine (0.24 mL, 1.37 mmol, 2.1 eq) and the reaction was heated to 100°C for 12 h. After cooling to rt, the reaction was quenched with water and brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-50% EtOAc in heptanes) provided methyl (S)-5-(2-(2-chlorophenyl)pyrrolidin-1- yl)pyrazine-2-carboxylate (213 mg, quant. yield). MS (ESI): mass calcd. for C16H16ClN3O2, 317.1; m/z found, 318.0 [M+H]+. [00667] Step B: (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylic acid. Methyl (S)-5-(2-(2- chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylate (213 mg, 0.670 mmol, 1.0 eq) was taken up in methanol (2.7 mL, 0.25 M). To this was added lithium hydroxide (2.7 mL, 5.36 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60°C for 2 hours. After cooling to rt, the reaction was adjusted to pH ~2 with 1N HCl. The precipitate was collected by filtration to provide (S)-5-(2-(2-chlorophenyl)pyrrolidin-1- yl)pyrazine-2-carboxylic acid (188 mg, 92% yield). MS (ESI): mass calcd. for C15H14ClN3O2, 303.1; m/z found, 304.0 [M+H]+. [00668] Step C: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylic acid (188 mg, 0.619 mmol, 1.0 eq) and HATU (272 mg, 0.681 mmol, 1.1 eq) were taken up in DMF (2.1 mL, 0.30 M). To this was added N,N-diisopropylethylamine (0.24 mL, 1.36 mmol, 2.2 eq) and the reaction was stirred at rt for 10 min. Then, (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 209 mg, 0.650 mmol, 1.05 eq) was added and the reaction was stirred at rt for 2 h. The crude material was purified by RP-HPLC (5-95% ACN in 0.1% HCOOH water) to provide 5-((S)-2-(2- chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (224 mg, 83% yield) as a white solid. MS (ESI): mass calcd. for C20H23ClN4O3S, 434.1; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.53 – 7.35 (m, 3H), 7.19 (td, J = 7.6, 1.8 Hz, 1H), 7.13 (td, J = 7.5, 1.4 Hz, 1H), 6.97 – 6.85 (m, 2H), 6.44 (dd, J = 15.1, 1.7 Hz, 1H), 5.46 – 5.29 (m, 1H), 4.97 – 4.83 (m, 1H), 4.04 – 3.92 (m, 1H), 3.84 – 3.71 (m, 1H), 2.89 (s, 3H), 2.60 – 2.45 (m, 1H), 2.13 – 1.98 (m, 3H), 1.36 (d, J = 7.1 Hz, 3H). 325 QB\184200.00050\92364964.2 VVID-746PC Example 145: 5-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide.
Figure imgf000328_0001
[00669] The title compound was prepared in a manner analogous to Example 144 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 5.9, 1.4 Hz, 1H), 7.48 – 7.37 (m, 2H), 7.23 – 7.10 (m, 3H), 6.91 (ddd, J = 15.2, 8.0, 4.5 Hz, 1H), 6.44 (ddd, J = 15.1, 8.6, 1.7 Hz, 1H), 5.43 (q, J = 6.1 Hz, 1H), 4.99 – 4.88 (m, 1H), 4.76 – 4.65 (m, 1H), 3.65 – 3.54 (m, 1H), 2.91 (d, J = 7.8 Hz, 3H), 2.26 – 2.15 (m, 1H), 2.13 – 2.03 (m, 1H), 2.03 – 1.95 (m, 1H), 1.92 – 1.76 (m, 1H), 1.72 – 1.60 (m, 2H), 1.56 (s, 1H), 1.43 – 1.34 (m, 3H). Example 146: 5-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000328_0002
[00670] The title compound was prepared via separation of 5-(2-(2-chlorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 145) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 35% MeOH/CO2 with 0.1% DEA; Rt = 4.97 min). MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.46 – 7.38 (m, 2H), 7.22 – 7.13 (m, 3H), 6.92 (dd, J = 15.1, 4.5 Hz, 1H), 6.45 (dd, J = 15.1, 1.8 Hz, 1H), 5.44 (t, J = 5.7 Hz, 1H), 4.97 – 4.88 (m, 1H), 4.69 (ddd, J = 13.7, 6.1, 3.0 Hz, 1H), 3.60 (ddd, J = 13.7, 11.5, 5.0 Hz, 1H), 2.92 (s, 3H), 2.27 – 2.14 (m, 1H), 2.12 – 1.92 (m, 2H), 1.92 – 1.76 (m, 1H), 1.70 – 1.62 (m, 2H), 1.38 (d, J = 7.1 Hz, 3H). Example 147: 5-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 326 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000329_0001
[00671] The title compound was prepared via separation of 5-(2-(2-chlorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 145) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 35% MeOH/CO2 with 0.1% DEA; Rt = 5.77 min). MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 1.4 Hz, 1H), 7.49 – 7.38 (m, 2H), 7.24 – 7.13 (m, 3H), 6.90 (dd, J = 15.1, 4.5 Hz, 1H), 6.43 (dd, J = 15.1, 1.8 Hz, 1H), 5.42 (t, J = 5.8 Hz, 1H), 4.98 – 4.88 (m, 1H), 4.70 (ddd, J = 13.7, 6.1, 3.0 Hz, 1H), 3.60 (ddd, J = 13.7, 11.5, 5.0 Hz, 1H), 2.90 (s, 3H), 2.26 – 2.15 (m, 1H), 2.12 – 1.94 (m, 2H), 1.90 – 1.76 (m, 1H), 1.70 – 1.60 (m, 2H), 1.39 (d, J = 7.1 Hz, 3H). Example 148: 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000329_0002
[00672] The title compound was prepared in a manner analogous to Example 144 using 2-(2,6- difluorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H22F2N4O3S, 436.1; m/z found, 437.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.60 (d, J = 5.7 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.21 – 7.10 (m, 1H), 6.89 (ddd, J = 15.2, 4.6, 0.8 Hz, 1H), 6.86 – 6.75 (m, 2H), 6.44 (dd, J = 15.1, 1.7 Hz, 1H), 5.42 (d, J = 7.6 Hz, 1H), 4.97 – 4.85 (m, 1H), 3.79 (t, J = 6.9 Hz, 2H), 2.88 (s, 3H), 2.59 – 2.47 (m, 1H), 2.28 – 2.00 (m, 3H), 1.37 (d, J = 7.1 Hz, 3H). Example 149: 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 327 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000330_0001
[00673] The title compound was prepared via separation of 5-(2-(2,6-difluorophenyl)pyrrolidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 148) by SFC (Stationary phase: IC (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 5.73 min). MS (ESI): mass calcd. for C20H22F2N4O3S, 436.1; m/z found, 437.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.63 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.18 (tt, J = 8.4, 6.3 Hz, 1H), 6.92 (dd, J = 15.2, 4.5 Hz, 1H), 6.83 (t, J = 8.5 Hz, 2H), 6.45 (dd, J = 15.1, 1.8 Hz, 1H), 5.45 (s, 1H), 4.99 – 4.88 (m, 1H), 3.81 (t, J = 6.7 Hz, 2H), 2.91 (s, 3H), 2.61 – 2.49 (m, 1H), 2.31 – 2.03 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 150: 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000330_0002
[00674] The title compound was prepared via separation of 5-(2-(2,6-difluorophenyl)pyrrolidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 148) by SFC (Stationary phase: IC (2x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 6.53 min). MS (ESI): mass calcd. for C20H22F2N4O3S, 436.1; m/z found, 437.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.61 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.18 (tt, J = 8.2, 6.2 Hz, 1H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.83 (t, J = 8.5 Hz, 2H), 6.44 (dd, J = 15.1, 1.8 Hz, 1H), 5.50 – 5.36 (m, 1H), 4.98 – 4.87 (m, 1H), 3.89 – 3.75 (m, 2H), 2.90 (s, 3H), 2.61 – 2.48 (m, 1H), 2.31 – 2.02 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 151: 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 328 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000331_0001
[00675] The title compound was prepared in a manner analogous to Example 144 using 2-(2,3- difluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C 20H22F2N4O3S, 436.1; m/z found, 437.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.10 – 6.99 (m, 1H), 7.00 – 6.85 (m, 2H), 6.73 – 6.64 (m, 1H), 6.45 (dt, J = 15.2, 2.0 Hz, 1H), 5.37 (s, 1H), 4.98 – 4.86 (m, 1H), 3.91 (dt, J = 10.8, 5.6 Hz, 1H), 3.74 (q, J = 8.7 Hz, 1H), 2.90 (d, J = 1.9 Hz, 3H), 2.51 (td, J = 11.9, 6.3 Hz, 1H), 2.16 – 1.99 (m, 3H), 1.39 (dd, J = 7.1, 2.0 Hz, 3H). Example 152: 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000331_0002
[00676] The title compound was prepared via separation of 5-(2-(2,3-difluorophenyl)pyrrolidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 151) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 2.79 min (second eluting product)). MS (ESI): mass calcd. for C20H22F2N4O3S, 436.1; m/z found, 437.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 – 8.76 (m, 1H), 7.59 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.12 – 7.01 (m, 1H), 6.99 – 6.87 (m, 2H), 6.70 (ddt, J = 7.8, 6.2, 1.6 Hz, 1H), 6.46 (dd, J = 15.1, 1.8 Hz, 1H), 5.46 – 5.33 (m, 1H), 4.99 – 4.88 (m, 1H), 3.98 – 3.88 (m, 1H), 3.80 - 3.72 (m, 1H), 2.91 (s, 3H), 2.58 – 2.45 (m, 1H), 2.18 – 2.00 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 153: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2- carboxamide. 329 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000332_0001
[00677] The title compound was prepared in a manner analogous to Example 144 using 2-(o- tolyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C21H26N4O3S, 414.2; m/z found, 415.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 – 8.75 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.23 – 7.17 (m, 1H), 7.14 (tdd, J = 7.5, 3.6, 1.4 Hz, 1H), 7.06 (tdd, J = 7.5, 5.4, 1.6 Hz, 1H), 6.92 – 6.81 (m, 2H), 6.43 (ddd, J = 15.1, 8.0, 1.8 Hz, 1H), 5.16 (s, 1H), 4.96 – 4.84 (m, 1H), 4.04 – 3.94 (m, 1H), 3.78 (dt, J = 11.3, 8.0 Hz, 1H), 2.87 (s, 3H), 2.49 (ddd, J = 11.8, 8.8, 3.2 Hz, 1H), 2.43 (d, J = 3.2 Hz, 3H), 2.14 – 2.00 (m, 2H), 2.00 – 1.89 (m, 1H), 1.35 (dd, J = 7.1, 5.2 Hz, 3H). Example 154: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2- carboxamide.
Figure imgf000332_0002
[00678] The title compound was prepared via separation of N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5- (2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide (Example 153) by SFC (Stationary phase: A6 (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 5.95 min (second eluting product)). MS (ESI): mass calcd. for C21H26N4O3S, 414.2; m/z found, 415.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.48 – 7.30 (m, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.16 (td, J = 7.3, 1.4 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.95 – 6.85 (m, 2H), 6.45 (dd, J = 15.1, 1.8 Hz, 1H), 5.18 (s, 1H), 4.98 – 4.87 (m, 1H), 4.01 (ddd, J = 11.3, 6.4, 4.4 Hz, 1H), 3.85 – 3.75 (m, 1H), 2.89 (s, 3H), 2.57 – 2.47 (m, 1H), 2.45 (s, 3H), 2.15 – 2.02 (m, 2H), 2.02 – 1.92 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H). Example 155: 5-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 330 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000333_0001
[00679] The title compound was prepared in a manner analogous to Example 144 using 2-(2,4- dimethylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C22H28N4O3S, 428.2; m/z found, 429.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.83 – 8.74 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.94 – 6.82 (m, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.44 (ddd, J = 15.2, 8.1, 1.8 Hz, 1H), 5.12 (s, 1H), 4.97 – 4.85 (m, 1H), 4.03 – 3.92 (m, 1H), 3.83 – 3.71 (m, 1H), 2.87 (d, J = 1.1 Hz, 3H), 2.54 – 2.40 (m, 1H), 2.39 (d, J = 3.1 Hz, 3H), 2.26 (d, J = 2.7 Hz, 3H), 2.13 – 2.01 (m, 2H), 1.98 – 1.87 (m, 1H), 1.36 (dd, J = 7.1, 5.6 Hz, 3H). Example 156: 5-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000333_0002
[00680] The title compound was prepared via separation of 5-(2-(2,4-dimethylphenyl)pyrrolidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 155) by SFC (Stationary phase: A2S (2x25 cm); Mobile phase: 15% EtOH/CO2 with 0.1% DEA; Rt = 4.87 min). MS (ESI): mass calcd. for C22H28N4O3S, 428.2; m/z found, 429.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.82 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.94 – 6.87 (m, 2H), 6.77 (d, J = 7.9 Hz, 1H), 6.45 (dd, J = 15.1, 1.8 Hz, 1H), 5.14 (s, 1H), 4.98 – 4.88 (m, 1H), 4.00 (ddd, J = 11.2, 7.4, 3.8 Hz, 1H), 3.84 – 3.73 (m, 1H), 2.92 (s, 3H), 2.49 (p, J = 9.2 Hz, 1H), 2.41 (s, 3H), 2.28 (s, 3H), 2.14 – 2.04 (m, 2H), 1.95 (ddt, J = 12.5, 6.4, 3.2 Hz, 1H), 1.37 (d, J = 7.1 Hz, 3H). Example 157: 5-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 331 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000334_0001
[00681] The title compound was prepared via separation of 5-(2-(2,4-dimethylphenyl)pyrrolidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 155) by SFC (Stationary phase: A2S (2x25 cm); Mobile phase: 15% EtOH/CO2 with 0.1% DEA; Rt = 5.50 min). MS (ESI): mass calcd. for C22H28N4O3S, 428.2; m/z found, 429.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.82 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.06 – 7.02 (m, 1H), 6.93 – 6.87 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.43 (dd, J = 15.1, 1.8 Hz, 1H), 5.13 (s, 1H), 4.97 – 4.88 (m, 1H), 4.00 (ddd, J = 11.1, 7.2, 3.6 Hz, 1H), 3.79 (q, J = 9.1 Hz, 1H), 2.90 (s, 3H), 2.48 (p, J = 9.3 Hz, 1H), 2.41 (s, 3H), 2.28 (s, 3H), 2.13 – 2.02 (m, 2H), 1.95 (ddt, J = 12.4, 6.3, 3.2 Hz, 1H), 1.39 (d, J = 7.1 Hz, 3H). Example 158: 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide.
Figure imgf000334_0002
[00682] The title compound was prepared in a manner analogous to Example 144 using 3-(2- chlorophenyl)morpholine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H23ClN4O4S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.86 (t, J = 1.1 Hz, 1H), 7.73 (dd, J = 6.2, 1.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.43 (ddd, J = 7.6, 3.3, 1.6 Hz, 1H), 7.32 (dd, J = 7.4, 2.1 Hz, 1H), 7.27 – 7.15 (m, 3H), 6.91 (ddd, J = 15.1, 6.8, 4.5 Hz, 1H), 6.45 (ddd, J = 15.1, 7.9, 1.8 Hz, 1H), 5.48 – 5.40 (m, 1H), 5.00 – 4.88 (m, 1H), 4.45 – 4.35 (m, 1H), 4.26 – 4.17 (m, 2H), 4.12 – 4.06 (m, 1H), 3.91 – 3.77 (m, 2H), 2.91 (d, J = 6.5 Hz, 3H), 1.40 (dd, J = 7.1, 5.2 Hz, 3H). Example 159: 5-((*S)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 332 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000335_0001
[00683] The title compound was prepared via separation of 5-(3-(2-chlorophenyl)morpholino)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 158) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 20% EtOH/CO2 with 0.1% DEA; Rt = 4.21 min). MS (ESI): mass calcd. for C20H23ClN4O4S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 1.4 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.32 (dd, J = 7.4, 2.1 Hz, 1H), 7.25 – 7.15 (m, 2H), 6.92 (dd, J = 15.1, 4.6 Hz, 1H), 6.46 (dd, J = 15.1, 1.8 Hz, 1H), 5.45 (dd, J = 4.7, 2.6 Hz, 1H), 5.00 – 4.89 (m, 1H), 4.44 – 4.34 (m, 1H), 4.27 – 4.18 (m, 2H), 4.14 – 4.06 (m, 1H), 3.90 – 3.77 (m, 2H), 2.92 (s, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 160: 5-((*R)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000335_0002
[00684] The title compound was prepared via separation of 5-(3-(2-chlorophenyl)morpholino)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 158) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 20% EtOH/CO2 with 0.1% DEA; Rt = 5.19 min). MS (ESI): mass calcd. for C20H23ClN4O4S, 450.1; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 1.4 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.31 (dd, J = 7.4, 2.1 Hz, 1H), 7.26 – 7.16 (m, 2H), 6.89 (dd, J = 15.1, 4.5 Hz, 1H), 6.44 (dd, J = 15.1, 1.8 Hz, 1H), 5.43 (dd, J = 4.6, 2.7 Hz, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.35 (m, 1H), 4.24 – 4.16 (m, 2H), 4.09 (dd, J = 12.1, 4.6 Hz, 1H), 3.90 – 3.77 (m, 2H), 2.90 (s, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 161: 5-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide. 333 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000336_0001
[00685] The title compound was prepared in a manner analogous to Example 144 using 2-(2- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C21H25FN4O3S, 432.2; m/z found, 433.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.81 (dd, J = 1.4, 0.7 Hz, 1H), 7.76 (dd, J = 4.7, 1.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.27 – 7.18 (m, 1H), 7.13 – 6.98 (m, 3H), 6.91 (dt, J = 15.1, 4.8 Hz, 1H), 6.45 (ddd, J = 15.1, 5.0, 1.8 Hz, 1H), 5.61 (td, J = 6.4, 4.2 Hz, 1H), 4.99 – 4.89 (m, 1H), 4.63 – 4.54 (m, 1H), 3.53 – 3.40 (m, 1H), 2.91 (d, J = 4.6 Hz, 3H), 2.26 – 2.07 (m, 2H), 1.98 – 1.88 (m, 1H), 1.84 – 1.54 (m, 3H), 1.40 (dd, J = 7.1, 4.2 Hz, 3H). Example 162: 5-((*R)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000336_0002
[00686] The title compound was prepared via separation of 5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 161) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 20% EtOH/CO2 with 0.1% DEA; Rt = 3.38 min). MS (ESI): mass calcd. for C21H25FN4O3S, 432.2; m/z found, 433.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.82 (d, J = 1.3 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.23 (ddd, J = 8.7, 4.5, 2.0 Hz, 1H), 7.11 – 7.01 (m, 3H), 6.93 (dd, J = 15.1, 4.5 Hz, 1H), 6.46 (dd, J = 15.1, 1.8 Hz, 1H), 5.62 (t, J = 5.2 Hz, 1H), 4.98 – 4.90 (m, 1H), 4.60 (ddd, J = 13.6, 5.7, 2.9 Hz, 1H), 3.47 (ddd, J = 13.6, 11.8, 4.5 Hz, 1H), 2.92 (s, 3H), 2.27 – 2.17 (m, 1H), 2.18 – 2.09 (m, 1H), 1.98 – 1.89 (m, 1H), 1.84 – 1.74 (m, 1H), 1.74 – 1.66 (m, 1H), 1.66 – 1.59 (m, 1H), 1.40 (d, J = 7.1 Hz, 3H). Example 163: 5-((*S)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 334 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000337_0001
[00687] The title compound was prepared via separation of 5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 161) by SFC (Stationary phase: AS-H (2x25 cm); Mobile phase: 20% EtOH/CO2 with 0.1% DEA; Rt = 4.92 min). MS (ESI): mass calcd. for C21H25FN4O3S, 432.2; m/z found, 433.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.82 (d, J = 1.4 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.12 – 7.01 (m, 3H), 6.92 (dd, J = 15.1, 4.5 Hz, 1H), 6.45 (dd, J = 15.1, 1.8 Hz, 1H), 5.63 – 5.58 (m, 1H), 4.99 – 4.90 (m, 1H), 4.61 (ddd, J = 13.6, 5.7, 2.9 Hz, 1H), 3.47 (ddd, J = 13.6, 11.7, 4.5 Hz, 1H), 2.91 (s, 3H), 2.26 – 2.17 (m, 1H), 2.18 – 2.09 (m, 1H), 1.98 – 1.90 (m, 1H), 1.83 – 1.74 (m, 1H), 1.74 – 1.66 (m, 1H), 1.66 – 1.59 (m, 1H), 1.41 (d, J = 7.1 Hz, 3H). Example 164: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethyl)phenyl)pyrrolidin-1- yl)pyrazine-2-carboxamide.
Figure imgf000337_0002
[00688] The title compound was prepared in a manner analogous to Example 144 using 2-(2- trifluoromethylphenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C21H23F3N4O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.83 (t, J = 1.9 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.50 – 7.35 (m, 4H), 7.18 (d, J = 7.7 Hz, 1H), 6.90 (ddd, J = 14.9, 10.2, 4.5 Hz, 1H), 6.43 (ddd, J = 15.3, 13.6, 1.8 Hz, 1H), 5.39 (s, 1H), 4.98 – 4.88 (m, 1H), 4.10 – 4.01 (m, 1H), 3.87 (q, J = 9.5 Hz, 1H), 2.91 (d, J = 9.6 Hz, 3H), 2.67 – 2.56 (m, 1H), 2.19 – 2.07 (m, 2H), 2.03 (s, 1H), 1.38 (dd, J = 8.9, 7.1 Hz, 3H). Example 165: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*R)-2-(2- (trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine-2-carboxamide. 335 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000338_0001
[00689] The title compound was prepared via separation of N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5- (2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine-2-carboxamide (Example 164) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 30% EtOH/CO2 with 0.1% DEA; Rt = 3.06 min). MS (ESI): mass calcd. for C21H23F3N4O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.86 – 8.81 (m, 1H), 7.74 (dt, J = 7.9, 0.9 Hz, 1H), 7.50 – 7.41 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.45 (dd, J = 15.1, 1.8 Hz, 1H), 5.40 (d, J = 8.1 Hz, 1H), 4.97 – 4.88 (m, 1H), 4.06 (ddd, J = 11.5, 7.5, 4.1 Hz, 1H), 3.91 – 3.83 (m, 1H), 2.92 (s, 3H), 2.67 – 2.56 (m, 1H), 2.20 – 2.06 (m, 2H), 2.08 – 2.00 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H). Example 166: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(2-(trifluoromethyl)phenyl)pyrrolidin- 1-yl)pyrazine-2-carboxamide.
Figure imgf000338_0002
[00690] The title compound was prepared via separation of N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5- (2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine-2-carboxamide (Example 164) by SFC (Stationary phase: AD-H (2x25 cm); Mobile phase: 30% EtOH/CO2 with 0.1% DEA; Rt = 3.34 min). MS (ESI): mass calcd. for C21H23F3N4O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.85 – 8.81 (m, 1H), 7.77 – 7.72 (m, 1H), 7.49 – 7.37 (m, 4H), 7.18 (d, J = 7.8 Hz, 1H), 6.89 (dd, J = 15.1, 4.5 Hz, 1H), 6.42 (dd, J = 15.1, 1.8 Hz, 1H), 5.39 (d, J = 8.2 Hz, 1H), 4.98 – 4.89 (m, 1H), 4.06 (ddd, J = 11.6, 7.5, 4.1 Hz, 1H), 3.87 (dt, J = 11.4, 7.8 Hz, 1H), 2.90 (s, 3H), 2.67 – 2.56 (m, 1H), 2.19 – 2.06 (m, 2H), 2.06 – 2.00 (m, 1H), 1.39 (d, J = 7.1 Hz, 3H). Example 167: 5-(2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide. 336 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000339_0001
[00691] The title compound was prepared in a manner analogous to Example 144 using 2- cyclohexylpyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H30N4O3S, 406.2; m/z found, 407.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.82 (t, J = 1.1 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.50 (dd, J = 8.5, 2.4 Hz, 1H), 6.96 (ddd, J = 15.1, 4.5, 1.0 Hz, 1H), 6.49 (ddd, J = 15.1, 4.5, 1.8 Hz, 1H), 5.03 – 4.93 (m, 1H), 4.13 – 4.03 (m, 1H), 3.61 – 3.51 (m, 2H), 2.93 (s, 3H), 2.12 – 1.97 (m, 3H), 1.97 – 1.79 (m, 2H), 1.79 – 1.70 (m, 2H), 1.70 - 1.61 (m, 2H), 1.54 (d, J = 12.2 Hz, 1H), 1.44 (dd, J = 7.1, 0.7 Hz, 3H), 1.29 – 1.18 (m, 1H), 1.19 – 0.99 (m, 4H). Example 168: 5-((*R)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide.
Figure imgf000339_0002
[00692] The title compound was prepared via separation of 5-(2-cyclohexylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 167) by SFC (Stationary phase: ID-H (2x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 2.08 min). MS (ESI): mass calcd. for C20H30N4O3S, 406.2; m/z found, 407.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 15.1, 4.5 Hz, 1H), 6.48 (dd, J = 15.1, 1.8 Hz, 1H), 5.02 – 4.91 (m, 1H), 4.09 (s, 1H), 3.61 – 3.48 (m, 2H), 2.93 (s, 3H), 2.12 – 1.57 (m, 10H), 1.53 (d, J = 11.7 Hz, 1H), 1.43 (d, J = 7.1 Hz, 3H), 1.15 – 0.97 (m, 4H). Example 169: 5-((*S)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide. 337 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000340_0001
[00693] The title compound was prepared via separation of 5-(2-cyclohexylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 167) by SFC (Stationary phase: ID-H (2x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 2.93 min). MS (ESI): mass calcd. for C20H30N4O3S, 406.2; m/z found, 407.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 1.4 Hz, 1H), 7.77 – 7.68 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 15.1, 4.4 Hz, 1H), 6.49 (dd, J = 15.0, 1.8 Hz, 1H), 5.04 – 4.92 (m, 1H), 4.08 (s, 1H), 3.62 – 3.49 (m, 2H), 2.93 (s, 3H), 2.13 – 1.57 (m, 10H), 1.53 (d, J = 11.8 Hz, 1H), 1.43 (d, J = 7.1 Hz, 3H), 1.18 – 0.96 (m, 4H). Example 170: 5-(2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000340_0002
[00694] The title compound was prepared in a manner analogous to Example 144 using 2-(2,3- dichlorophenyl)pyrrolidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H22Cl2N4O3S, 468.1; m/z found, 468.8 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.82 (s, 1H), 7.54 – 7.42 (m, 2H), 7.40 (ddd, J = 8.0, 5.1, 1.5 Hz, 1H), 7.11 (q, J = 7.7 Hz, 1H), 6.92 (ddd, J = 15.1, 5.5, 4.5 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.45 (ddd, J = 15.1, 4.9, 1.8 Hz, 1H), 5.43 (s, 1H), 4.99 – 4.90 (m, 1H), 4.06 – 3.94 (m, 1H), 3.79 (s, 1H), 2.92 (d, J = 4.3 Hz, 3H), 2.61 – 2.50 (m, 1H), 2.15 – 1.96 (m, 3H), 1.40 (dd, J = 7.1, 3.9 Hz, 3H). Example 171: 5-((*S)-2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 338 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000341_0001
[00695] The title compound was prepared via separation of 5-(2-(2,3-dichlorophenyl)pyrrolidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 170) by SFC (Stationary phase: AD-H (3x25 cm); Mobile phase: 40% EtOH/CO 2; Rt = 8.86 min (second eluting product)). MS (ESI): mass calcd. for C20H22Cl2N4O3S, 468.1; m/z found, 468.8 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 8.0, 1.5 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.95 – 6.81 (m, 2H), 6.45 (dd, J = 15.1, 1.7 Hz, 1H), 5.43 (s, 1H), 5.00 – 4.87 (m, 1H), 4.05 – 3.94 (m, 1H), 3.84 – 3.72 (m, 1H), 2.92 (s, 3H), 2.63 – 2.47 (m, 1H), 2.19 – 1.95 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 172: 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide.
Figure imgf000341_0002
[00696] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chlorophenyl)- 4,4-difluoropiperidine (Intermediate 9) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMF instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% MeOH/CO 2; Rt = 5.65 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClF2N4O3S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.30 (br d, J = 8.0 Hz, 1H), 7.94 (br d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.8, 5.13 Hz, 1H), 7.12 (td, J = 8.2, 3.1 Hz, 1H), 6.64 - 6.89 (m, 3H), 6.35 - 6.52 (m, 1H), 5.29 - 5.47 (m, 1H), 4.68 - 4.93 (m, 1H), 3.89 - 4.03 (m, 1H), 3.45 - 3.62 (m, 1H), 2.98 (s, 3H), 2.31 - 2.46 (m, 1H), 1.80 - 2.11 (m, 3H), 1.27 (d, J = 7.1 Hz, 3H). Example 173: 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide. 339 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000342_0001
[00697] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chlorophenyl)- 4,4-difluoropiperidine (Intermediate 9) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMF instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% MeOH/CO2; Rt = 8.13 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClF2N4O3S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.69 (m, 2H), 7.96 (s, 1H), 7.47 - 7.57 (m, 1H), 7.22 - 7.37 (m, 3H), 6.72 - 6.85 (m, 1H), 6.62 - 6.70 (m, 1H), 5.74 (t, J = 6.4 Hz, 1H), 4.63 - 4.86 (m, 2H), 3.90 - 4.01 (m, 1H), 2.98 (s, 3H), 2.58 - 2.77 (m, 2H), 2.29 - 2.44 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H). Example 174: 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000342_0002
[00698] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-3- fluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C20H22ClFN4O4S 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 - 8.68 (m, 2H), 8.12 (dd, J = 8.3, 1.3 Hz, 1H), 7.22 - 7.38 (m, 3H), 6.74 - 6.85 (m, 1H), 6.64 - 6.72 (m, 1H), 5.67 (br s, 1H), 4.75 - 4.86 (m, 1H), 4.18 - 4.27 (m, 1H), 4.10 - 4.17 (m, 2H), 4.02 - 4.08 (m, 1H), 3.70 - 3.81 (m, 2H), 2.98 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 175: 5-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 340 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000343_0001
[00699] The title compound was prepared via separation of 5-(3-(2-chloro-3-fluorophenyl)morpholino)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 174) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO 2 with 0.1% NH4OH; Rt = 6.17 min). MS (ESI): mass calcd. for C20H22ClFN4O4S 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.68 (m, 2H), 8.13 (d, J = 1.1 Hz, 1H), 7.21 - 7.39 (m, 3H), 6.75 - 6.84 (m, 1H), 6.63 - 6.73 (m, 1H), 5.67 (br d, J = 2.4 Hz, 1H), 4.80 (td, J = 6.9, 5.5 Hz, 1H), 4.18 - 4.26 (m, 1H), 4.10 - 4.17 (m, 2H), 4.00 - 4.08 (m, 1H), 3.76 (d, J = 8.0 Hz, 2H), 2.98 (s, 3H), 1.30 (d, J = 6.9 Hz, 3H). Example 176: 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000343_0002
[00700] The title compound was prepared via separation of 5-(3-(2-chloro-3-fluorophenyl)morpholino)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 174) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 8.12 min). MS (ESI): mass calcd. for C20H22ClFN4O4S 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.69 (m, 2H), 8.11 (s, 1H), 7.21 - 7.39 (m, 3H), 6.75 - 6.83 (m, 1H), 6.66 - 6.73 (m, 1H), 5.66 (br d, J = 2.3 Hz, 1H), 4.74 - 4.85 (m, 1H), 4.19 - 4.28 (m, 1H), 4.09 - 4.17 (m, 2H), 4.01 - 4.08 (m, 1H), 3.70 - 3.82 (m, 2H), 2.98 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 177: 5-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 341 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000344_0001
[00701] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-4- fluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(3-(2-chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 5.38 min) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O4S, 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.73 (m, 2H), 8.11 (s, 1H), 7.41 - 7.60 (m, 2H), 7.15 (td, J = 8.5, 2.5 Hz, 1H), 6.76 - 6.83 (m, 1H), 6.64 - 6.74 (m, 1H), 5.61 (br s, 1H), 4.68 - 4.91 (m, 1H), 4.22 (br d, J = 10.3 Hz, 1H), 3.96 - 4.14 (m, 3H), 3.74 (br d, J = 8.1 Hz, 2H), 2.98 (s, 3H), 1.30 (br d, J = 6.9 Hz, 3H). Example 178: 5-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000344_0002
[00702] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-4- fluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(3-(2-chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% MeOH/CO2 with 0.1% NH4OH; Rt = 7.14 min) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O4S, 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 - 8.70 (m, 2H), 8.11 (s, 1H), 7.41 - 7.58 (m, 2H), 7.15 (td, J = 8.5, 2.6 Hz, 1H), 6.76 - 6.86 (m, 1H), 6.63 - 6.73 (m, 1H), 5.61 (br s, 1H), 4.72 - 4.89 (m, 1H), 4.22 (br d, J = 9.9 Hz, 1H), 3.96 - 4.13 (m, 3H), 3.74 (br d, J = 8.1 Hz, 2H), 2.98 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 179: 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 342 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000345_0001
[00703] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-4- fluorophenyl)azepane (Intermediate 13) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 8.30 min) provided the title compound. MS (ESI): mass calcd. for C22H26ClFN4O3S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.65 (m, 2H), 7.55 - 8.04 (m, 1H), 7.48 (br d, J = 6.8 Hz, 1H), 7.24 - 7.32 (m, 1H), 7.10 - 7.21 (m, 1H), 6.74 - 6.84 (m, 1H), 6.61 - 6.72 (m, 1H), 5.04 - 5.47 (m, 1H), 4.73 - 4.84 (m, 1H), 4.42 - 4.72 (m, 1H), 3.58 - 3.75 (m, 1H), 2.98 (s, 3H), 2.29 - 2.39 (m, 1H), 1.92 - 2.04 (m, 2H), 1.74 - 1.89 (m, 2H), 1.34 - 1.53 (m, 3H), 1.26 - 1.32 (m, 3H). Example 180: 5-((*S)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000345_0002
[00704] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-4- fluorophenyl)azepane (Intermediate 13) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 9.97 min) provided the title compound. MS (ESI): mass calcd. for C22H26ClFN4O3S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.66 (m, 2H), 7.54 - 8.05 (m, 1H), 7.43 - 7.53 (m, 1H), 7.25 - 7.32 (m, 1H), 7.16 (dt, J = 2.3, 8.4 Hz, 1H), 6.72 - 6.83 (m, 1H), 6.62 - 6.70 (m, 1H), 5.02 - 5.51 (m, 1H), 4.73 - 4.85 (m, 1H), 4.37 - 4.72 (m, 1H), 3.59 - 3.75 (m, 1H), 2.97 (s, 3H), 2.28 - 2.39 (m, 1H), 1.91 - 2.04 (m, 2H), 1.75 - 1.89 (m, 2H), 1.35 - 1.53 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). 343 QB\184200.00050\92364964.2 VVID-746PC Example 181: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000346_0001
[00705] The title compound was prepared in a manner analogous to Example 144 using (1R,2S,5S)-2-(2- chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 26) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.69 (br s, 1H), 7.17 - 7.34 (m, 2H), 6.74 - 6.83 (m, 2H), 6.61 - 6.71 (m, 1H), 5.55 (d, J = 5.3 Hz, 1H), 4.72 - 4.86 (m, 1H), 4.08 (d, J = 10.3 Hz, 1H), 3.88 (dd, J = 10.3, 5.3 Hz, 1H), 2.98 (s, 3H), 2.27 - 2.37 (m, 1H), 1.92 - 2.06 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.65 (td, J = 7.9, 5.3 Hz, 1H), 0.30 (br d, J = 4.5 Hz, 1H). Example 182: 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000346_0002
[00706] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 25) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2 with 0.1% NH4OH; Rt = 10.0 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.66 (br s, 1H), 7.19 - 7.35 (m, 2H), 6.73 - 6.83 (m, 2H), 6.62 - 6.72 (m, 1H), 5.55 (d, J = 5.1 Hz, 1H), 4.71 - 4.84 (m, 1H), 4.08 (d, J = 10.5 Hz, 1H), 344 QB\184200.00050\92364964.2 VVID-746PC 3.88 (dd, J = 10.4, 5.3 Hz, 1H), 2.98 (s, 3H), 2.26 - 2.37 (m, 1H), 1.92 - 2.06 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.65 (td, J = 7.8, 5.4 Hz, 1H), 0.24 - 0.35 (m, 1H). Example 183: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000347_0001
[00707] The title compound was prepared in a manner analogous to Example 144 using (1R,2S,5S)-2-(2- chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 26) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrimidine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.6 Hz, 1H), 7.87 (s, 2H), 7.22 - 7.43 (m, 2H), 6.85 (br d, J = 7.8 Hz, 1H), 6.75 - 6.81 (m, 1H), 6.64 - 6.71 (m, 1H), 5.34 (d, J = 5.0 Hz, 1H), 4.71 - 4.85 (m, 1H), 4.10 (d, J = 9.5 Hz, 1H), 3.65 (dd, J = 9.5, 5.0 Hz, 1H), 2.98 (s, 3H), 2.24 - 2.36 (m, 1H), 1.93 - 2.05 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.62 (td, J = 8.0, 5.2 Hz, 1H), 0.29 - 0.40 (m, 1H). Example 184: 6-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide.
Figure imgf000347_0002
[00708] The title compound was prepared in a manner analogous to Example 144 using (1R,2S,5S)-2-(2- chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 26) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 6-fluoronicotinate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C22H23ClFN3O3S, 463.1; m/z found, 464.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.90 (dd, J = 2.4, 8.9 Hz, 1H), 7.31 - 7.14 (m, 2H), 6.83 - 6.64 (m, 3H), 6.40 (br d, J = 8.9 Hz, 1H), 5.44 (d, J = 5.1 Hz, 1H), 4.78 (dt, J = 3.5, 7.4 Hz, 1H), 3.98 (d, J = 10.3 Hz, 1H), 3.74 (dd, J = 5.3, 10.1 Hz, 1H), 2.98 345 QB\184200.00050\92364964.2 VVID-746PC (s, 3H), 2.32 - 2.19 (m, 1H), 1.99 - 1.87 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H), 0.69 - 0.55 (m, 1H), 0.28 (br d, J = 4.4 Hz, 1H). Example 185: 5-(rac-(1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000348_0001
[00709] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 28) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H22F2N4O3S, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.62 (m, 2H), 7.76 (br d, J = 8.8 Hz, 1H), 7.22 - 7.34 (m, 1H), 6.99 - 7.11 (m, 1H), 6.61 - 6.84 (m, 3H), 5.53 (d, J = 5.1 Hz, 1H), 4.70 - 4.86 (m, 1H), 4.04 (br d, J = 10.5 Hz, 1H), 3.85 (dd, J = 10.4, 5.2 Hz, 1H), 2.98 (s, 3H), 2.24 (br s, 1H), 1.93 - 2.03 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.60 - 0.72 (m, 1H), 0.26 - 0.34 (m, 1H). Example 186: 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000348_0002
[00710] The title compound was prepared via separation of 5-(rac-(1*S,2*R,5*R)-2-(2,3-difluorophenyl)- 3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 185) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 10.7 min (second eluting product)). MS (ESI): mass calcd. for C21H22F2N4O3S, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.66 (br s, 1H), 7.19 - 7.35 (m, 2H), 6.73 - 6.83 (m, 2H), 6.62 - 6.72 (m, 1H), 5.55 (d, J = 5.1 Hz, 1H), 4.71 - 4.84 (m, 1H), 4.08 (d, J = 10.5 Hz, 1H), 3.88 (dd, J = 10.4, 5.3 Hz, 1H), 2.98 (s, 3H), 2.26 - 2.37 (m, 1H), 1.92 - 2.06 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.65 (td, J = 7.8, 5.4 Hz, 1H), 0.24 - 0.35 (m, 1H). 346 QB\184200.00050\92364964.2 VVID-746PC Example 187: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000349_0001
[00711] The title compound was prepared in a manner analogous to Example 144 using (R,E)-4- (ethylsulfonyl)but-3-en-2-amine hydrochloride (Intermediate 2) instead of (R,E)-4-(methylsulfonyl)but-3- en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1) in Step C. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.52 – 7.37 (m, 3H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.14 (td, J = 7.6, 1.4 Hz, 1H), 6.95 (dd, J = 7.7, 1.7 Hz, 1H), 6.88 (dd, J = 15.1, 4.6 Hz, 1H), 6.34 (dd, J = 15.1, 1.7 Hz, 1H), 5.47 – 5.33 (m, 1H), 4.97 – 4.85 (m, 1H), 4.05 – 3.95 (m, 1H), 3.85 – 3.73 (m, 1H), 2.96 (q, J = 7.4 Hz, 2H), 2.61 – 2.47 (m, 1H), 2.14 – 1.99 (m, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 7.4 Hz, 3H). Example 188: 5-(2-(2-Fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide.
Figure imgf000349_0002
[00712] The title compound was prepared in a manner analogous to Example 144 using 2-(2- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H23FN4O3S, 418.1; m/z found, 419.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.61 – 7.41 (m, 2H), 7.26 – 7.18 (m, 1H), 7.12 – 7.04 (m, 1H), 7.04 – 6.97 (m, 1H), 6.96 – 6.85 (m, 2H), 6.44 (ddd, J = 15.2, 4.1, 1.7 Hz, 1H), 5.34 (s, 1H), 4.97 – 4.86 (m, 1H), 4.00 – 3.88 (m, 1H), 3.81 – 3.68 (m, 1H), 2.89 (d, J = 3.1 Hz, 3H), 2.55 – 2.40 (m, 1H), 2.12 – 2.04 (m, 2H), 1.38 (dd, J = 7.1, 3.4 Hz, 3H). Example 189: 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide. 347 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000350_0001
[00713] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-3- fluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-chloro-3-methyl- pyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4- dioxane in Step A. MS (ESI): mass calcd. for C21H24ClFN4O4S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.0 Hz, 1H), 7.22 - 7.35 (m, 3H), 6.75 - 6.82 (m, 1H), 6.64 - 6.71 (m, 1H), 5.61 (br d, J = 3.5 Hz, 1H), 4.69 - 4.83 (m, 1H), 4.09 - 4.24 (m, 2H), 4.04 (d, J = 3.1 Hz, 2H), 3.77 (br dd, J = 8.2, 3.8 Hz, 2H), 2.98 (s, 3H), 2.57 (d, J = 2.1 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H). Example 190: 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000350_0002
[00714] The title compound was prepared via separation of 5-(3-(2-chloro-3-fluorophenyl)morpholino)-3- methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 189) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 7.96 min (second eluting product)). MS (ESI): mass calcd. for C21H24ClFN4O4S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.54 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.21 - 7.38 (m, 3H), 6.75 - 6.82 (m, 1H), 6.62 - 6.70 (m, 1H), 5.62 (t, J = 3.3 Hz, 1H), 4.70 - 4.82 (m, 1H), 4.08 - 4.22 (m, 2H), 4.04 (d, J = 3.3 Hz, 2H), 3.70 - 3.83 (m, 2H), 2.98 (s, 3H), 2.57 (s, 3H), 1.29 (d, J = 7.1 Hz, 3H). Example 191: 5-(3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 348 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000351_0001
[00715] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-6- fluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C20H22ClFN4O4S, 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.6 Hz, 1H), 8.55 (dd, J = 5.5, 1.3 Hz, 1H), 7.98 (dd, J = 14.8, 1.3 Hz, 1H), 7.30 - 7.44 (m, 2H), 7.09 - 7.20 (m, 1H), 6.64 - 6.82 (m, 2H), 5.57 - 5.64 (m, 1H), 4.72 - 4.86 (m, 1H), 3.75 - 4.17 (m, 6H), 2.97 (d, J = 1.8 Hz, 3H), 1.29 (d, J = 7.1 Hz, 3H). Example 192: 5-((*R)-3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000351_0002
[00716] The title compound was prepared via separation of 5-(3-(2-chloro-6-fluorophenyl)morpholino)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 191) by SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 15.8 min (second eluting product)). MS (ESI): mass calcd. for C20H22ClFN4O4S, 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.27 - 7.43 (m, 2H), 7.14 (ddd, J = 11.3, 8.1, 1.3 Hz, 1H), 6.74 - 6.85 (m, 1H), 6.61 - 6.73 (m, 1H), 5.61 (t, J = 5.1 Hz, 1H), 4.73 - 4.85 (m, 1H), 3.99 - 4.19 (m, 4H), 3.71 - 3.96 (m, 2H), 2.98 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 193: 5-(3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 349 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000352_0001
[00717] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-3,6- difluorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C20H21ClF2N4O4S, 486.1; m/z found, 487.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 8.6 Hz, 1H), 8.53 (dd, J = 4.7, 1.3 Hz, 1H), 8.07 (dd, J = 13.9, 1.3 Hz, 1H), 7.36 - 7.47 (m, 1H), 7.21 (tdd, J = 9.9, 4.7, 2.8 Hz, 1H), 6.64 - 6.83 (m, 2H), 5.61 (td, J = 5.0, 2.0 Hz, 1H), 4.72 - 4.86 (m, 1H), 3.96 - 4.17 (m, 4H), 3.84 - 3.95 (m, 1H), 3.72 - 3.83 (m, 1H), 2.97 (s, 3H), 1.30 (dd, J = 7.0, 1.1 Hz, 3H). Example 194: 5-((*R)-3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000352_0002
[00718] The title compound was prepared via separation of 5-(3-(2-chloro-3,6-difluorophenyl)morpholino)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 193) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.92 min (second eluting product)). MS (ESI): mass calcd. for C20H21ClF2N4O4S, 486.1; m/z found, 487.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.6 Hz, 1H), 8.52 (d, J = 0.8 Hz, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.41 (dt, J = 4.6, 8.7 Hz, 1H), 7.20 (dt, J = 4.6, 9.8 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.71 - 6.63 (m, 1H), 5.61 (t, J = 5.0 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.17 - 4.09 (m, 1H), 4.08 - 3.96 (m, 3H), 3.94 - 3.84 (m, 1H), 3.84 - 3.74 (m, 1H), 3.03 - 2.94 (m, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 195: 5-((*S)-2-(2-Fluoro-3-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide. 350 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000353_0001
[00719] The title compound was prepared in a manner analogous to Example 144 using 2-(2-fluoro-3- methylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-fluoro-3-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 9.22 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H25FN4O3S, 432.2; m/z found, 433.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 - 8.63 (m, 2H), 7.52 - 8.04 (m, 1H), 7.11 - 7.20 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.75 - 6.86 (m, 2H), 6.63 - 6.71 (m, 1H), 5.38 - 5.48 (m, 1H), 4.72 - 4.84 (m, 1H), 3.88 - 3.98 (m, 1H), 3.62 - 3.73 (m, 1H), 2.96 - 3.01 (m, 3H), 2.36 - 2.48 (m, 1H), 2.23 - 2.28 (m, 3H), 2.00 - 2.10 (m, 1H), 1.85 - 1.98 (m, 2H), 1.25 - 1.33 (m, 3H). Example 196: 5-((*R)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000353_0002
[00720] The title compound was prepared in a manner analogous to Example 144 using 2-(3-fluoro-2- methylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(3-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2; Rt = 5.80 min) provided the title compound. MS (ESI): mass calcd. for C21H25FN4O3S, 432.2; m/z found, 433.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (br s, 1H), 8.48 (br d, J = 8.4 Hz, 1H), 7.38 - 7.89 (m, 1H), 6.95 - 7.16 (m, 2H), 6.75 - 6.84 (m, 1H), 6.62 - 6.75(m, 2H), 5.37 (br d, J = 7.3 Hz, 1H), 4.71 - 4.85 (m, 1H), 3.92 - 4.03 (m, 1H), 3.63 - 3.80 (m, 1H), 2.98 (s, 3H), 2.45 (br d, J = 7.6 Hz, 1H), 2.31 (s, 3H), 1.78 -2.10 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). 351 QB\184200.00050\92364964.2 VVID-746PC Example 197: 5-((*S)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000354_0001
[00721] The title compound was prepared in a manner analogous to Example 144 using 2-(3-fluoro-2- methylphenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(3-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2; Rt = 8.66 min) provided the title compound. MS (ESI): mass calcd. for C21H25FN4O3S, 432.2; m/z found, 433.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (br s, 1H), 8.47 (br d, J = 8.4 Hz, 1H), 7.62 (br s, 1H), 6.93 - 7.17 (m, 2H), 6.62 - 6.83 (m, 3H), 5.36 (br d, J = 7.1 Hz, 1H), 4.72 - 4.84 (m, 1H), 3.89 - 4.03 (m, 1H), 3.64 - 3.78 (m, 1H), 2.97 (s, 3H), 2.46 (br d, J = 6.4 Hz, 1H), 2.32 (s, 3H), 1.79 - 2.09 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 198: 5-((*R)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000354_0002
[00722] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-3- fluorophenyl)azepane (Intermediate 14) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 6.75 min) provided the title compound. MS (ESI): mass calcd. for C22H26ClFN4O3S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 - 8.65 (m, 2H), 7.60 - 8.02 (m, 1H), 7.26 - 7.37 (m, 2H), 7.05 - 7.13 (m, 1H), 6.75 - 6.82 (m, 1H), 6.62 - 6.69 (m, 1H), 5.14 - 5.51 (m, 1H), 4.72 - 4.85 (m, 1H), 4.31 - 4.71 (m, 1H), 3.61 - 3.77 (m, 1H), 2.97 (s, 3H), 2.30 - 2.44 (m, 1H), 1.91 - 2.06 (m, 2H), 1.74 - 1.90 (m, 2H), 1.34 - 1.56 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). 352 QB\184200.00050\92364964.2 VVID-746PC Example 199: 5-((*S)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000355_0001
[00723] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-3- fluorophenyl)azepane (Intermediate 14) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 9.57 min) provided the title compound. MS (ESI): mass calcd. for C22H26ClFN4O3S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.65 (m, 2H), 7.59 - 8.02 (m, 1H), 7.23 - 7.40 (m, 2H), 7.05 - 7.16 (m, 1H), 6.72 - 6.83 (m, 1H), 6.63 - 6.71 (m, 1H), 5.13 - 5.55 (m, 1H), 4.73 - 4.85 (m, 1H), 4.40 - 4.71 (m, 1H), 3.60 - 3.78 (m, 1H), 2.96 (s, 3H), 2.31 - 2.43 (m, 1H), 1.91 - 2.06 (m, 2H), 1.74 - 1.90 (m, 2H), 1.34 - 1.56 (m, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 200: 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000355_0002
[00724] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 27) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H23ClN4O3S, 446.1; m/z found, 447.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.49 (m, 2H), 7.62 - 7.47 (m, 2H), 7.31 - 7.25 (m, 1H), 7.23 - 7.16 (m, 1H), 6.92 (br d, J = 7.6 Hz, 1H), 6.83 - 6.73 (m, 1H), 6.71 - 6.62 (m, 1H), 5.54 (d, J = 5.1 Hz, 1H), 4.78 (td, J = 1.6, 3.5 Hz, 1H), 4.07 (d, J = 10.6 Hz, 1H), 3.88 (dd, J = 5.3, 10.6 Hz, 1H), 2.97 (d, J = 1.6 Hz, 3H), 2.37 - 2.26 (m, 1H), 2.01 - 1.91 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.63 (dt, J = 5.3, 7.9 Hz, 1H), 0.31 (br d, J = 4.4 Hz, 1H). 353 QB\184200.00050\92364964.2 VVID-746PC Example 201: 5-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000356_0001
[00725] The title compound was prepared via separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 200) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 3.84 min). MS (ESI): mass calcd. for C21H23ClN4O3S, 446.1; m/z found, 447.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.62 - 8.49 (m, 2H), 7.57 (br s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.28 (dt, J = 1.6, 7.6 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.91 (br d, J = 6.9 Hz, 1H), 6.83 - 6.73 (m, 1H), 6.71 - 6.62 (m, 1H), 5.53 (d, J = 5.1 Hz, 1H), 4.85 - 4.71 (m, 1H), 4.07 (d, J = 10.5 Hz, 1H), 3.88 (dd, J = 5.3, 10.6 Hz, 1H), 2.98 (s, 3H), 2.36 - 2.27 (m, 1H), 2.00 - 1.92 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.63 (dt, J = 5.3, 7.9 Hz, 1H), 0.31 (q, J = 4.2 Hz, 1H). Example 202: 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000356_0002
[00726] The title compound was prepared via separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 200) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 5.89 min). MS (ESI): mass calcd. for C21H23ClN4O3S, 446.1; m/z found, 447.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.64 - 8.46 (m, 2H), 7.61 - 7.46 (m, 2H), 7.31 - 7.24 (m, 1H), 7.24 - 7.16 (m, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.72 - 6.63 (m, 1H), 5.53 (d, J = 5.3 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.07 (d, J = 10.6 Hz, 1H), 3.88 (dd, J = 5.3, 10.6 Hz, 1H), 2.97 (s, 3H), 2.37 - 2.27 (m, 1H), 2.00 - 1.91 (m, 1H), 1.33 - 1.25 (m, 3H), 0.63 (dt, J = 5.3, 7.9 Hz, 1H), 0.31 (q, J = 4.3 Hz, 1H). Example 203: 5-(2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 354 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000357_0001
[00727] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-3- fluorophenyl)-4,4-difluoropiperidine (Intermediate 10) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H22ClF3N4O3S, 502.1; m/z found, 503.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.67 (m, 2H), 8.06 (dd, J = 9.3, 1.2 Hz, 1H), 7.26 - 7.37 (m, 2H), 7.16 (br d, J = 7.4 Hz, 1H), 6.74 - 6.82 (m, 1H), 6.62 - 6.72 (m, 1H), 5.74 - 5.87 (m, 1H), 4.74 - 4.84 (m, 1H), 4.58 - 4.70 (m, 1H), 3.89 - 4.00 (m, 1H), 2.97 (s, 3H), 2.59 - 2.81 (m, 2H), 2.33 - 2.45 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H). Example 204: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000357_0002
[00728] The title compound was prepared via separation of 5-(2-(2-chloro-3-fluorophenyl)-4,4- difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 203) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 7.86 min). MS (ESI): mass calcd. for C21H22ClF3N4O3S, 502.1; m/z found, 503.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.67 (m, 2H), 8.05 (s, 1H), 7.27 - 7.38 (m, 2H), 7.16 (br d, J = 7.3 Hz, 1H), 6.75 - 6.83 (m, 1H), 6.60 - 6.73 (m, 1H), 5.80 (t, J = 6.3 Hz, 1H), 4.73 - 4.86 (m, 1H), 4.58 - 4.69 (m, 1H), 3.89 - 4.00 (m, 1H), 2.97 (s, 3H), 2.59 - 2.83 (m, 2H), 2.31 - 2.45 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H). Example 205: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 355 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000358_0001
[00729] The title compound was prepared via separation of 5-(2-(2-chloro-3-fluorophenyl)-4,4- difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 203) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 10.8 min). MS (ESI): mass calcd. for C21H22ClF3N4O3S, 502.1; m/z found, 503.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.70 (m, 2H), 8.07 (d, J = 1.3 Hz, 1H), 7.25 - 7.38 (m, 2H), 7.16 (d, J = 6.9 Hz, 1H), 6.74 - 6.84 (m, 1H), 6.63 - 6.73 (m, 1H), 5.81 (t, J = 6.4 Hz, 1H), 4.79 (ddd, J = 13.7, 6.9, 1.3 Hz, 1H), 4.63 (dt, J = 13.5, 4.4 Hz, 1H), 3.89 - 4.01 (m, 1H), 2.98 (s, 3H), 2.59 - 2.82 (m, 2H), 2.30 - 2.46 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H). Example 206: 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000358_0002
[00730] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2-chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 29) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H21ClF2N4O3S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J = 8.5, 2.6 Hz, 1H), 8.56 (d, J = 3.9 Hz, 1H), 7.62 - 7.77 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.19 (br t, J = 7.5 Hz, 1H), 6.98 (br d, J = 6.8 Hz, 1H), 6.74 - 6.83 (m, 1H), 6.62 - 6.72 (m, 1H), 5.78 (dd, J = 6.2, 2.2 Hz, 1H), 4.71 - 4.86 (m, 1H), 4.30 (br d, J = 11.8 Hz, 1H), 4.11 - 4.23 (m, 1H), 3.25 (td, J = 11.3, 6.4 Hz, 1H), 2.98 (s, 3H), 2.87 (td, J = 11.1, 6.6 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 207: 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 356 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000359_0001
[00731] The title compound was prepared by separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chlorophenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Example 206) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 10.2 min (second eluting product)). MS (ESI): mass calcd. for C21H21ClF2N4O3S, 482.1; m/z found, 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.5 Hz, 1H), 8.56 (s, 1H), 7.72 (br s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.30 (td, J = 7.7, 1.4 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.94 - 7.03 (m, 1H), 6.74 - 6.84 (m, 1H), 6.62 - 6.73 (m, 1H), 5.78 (dd, J = 6.1, 2.3 Hz, 1H), 4.74 - 4.86 (m, 1H), 4.25 - 4.34 (m, 1H), 4.11 - 4.22 (m, 1H), 3.19 - 3.29 (m, 1H), 2.98 (s, 3H), 2.79 - 2.92 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 208: 5-(rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000359_0002
[00732] The title compound was prepared in a manner analogous to Example 144 using rac-(1*S,2*S,5*R)- 2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 33) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br d, J = 7.9 Hz, 2H), 7.58 - 8.25 (m, 1H), 7.22 - 7.39 (m, 2H), 6.90 (br d, J = 6.8 Hz, 1H), 6.73 - 6.84 (m, 1H), 6.68 (s, 1H), 5.51 (br s, 1H), 4.70 - 4.87 (m, 1H), 4.03 (br s, 2H), 2.98 (s, 3H), 1.87 (br s, 1H), 1.68 (br s, 1H), 1.30 (br d, J = 6.8 Hz, 3H), 0.83 - 1.02 (m, 1H), 0.45 (br s, 1H). Example 209: 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 357 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000360_0001
[00733] The title compound was prepared by separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Example 208) via SFC (Stationary phase: OZ (2.5x25 cm); Mobile phase: 55% iPrOH/CO2; Rt = 5.03 min). MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br d, J = 8.0 Hz, 2H), 7.58 - 8.16 (m, 1H), 7.22 - 7.39 (m, 2H), 6.91 (br d, J = 6.9 Hz, 1H), 6.72 - 6.83 (m, 1H), 6.68 (s, 1H), 5.51 (br s, 1H), 4.73 - 4.83 (m, 1H), 4.03 (br s, 2H), 2.97 (s, 3H), 1.87 (br s, 1H), 1.59 - 1.77 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.92 (td, J = 7.8, 5.1 Hz, 1H), 0.45 (br s, 1H). Example 210: 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000360_0002
[00734] The title compound was prepared by separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Example 208) via SFC (Stationary phase: OZ (2.5x25 cm); Mobile phase: 55% iPrOH/CO2; Rt = 9.37 min). MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br d, J = 8.3 Hz, 2H), 7.22 - 7.37 (m, 2H), 6.90 (br d, J = 7.0 Hz, 1H), 6.74 - 6.84 (m, 1H), 6.62 - 6.70 (m, 1 H), 5.51 (br s, 1H), 4.74 - 4.83 (m, 1H), 4.03 (br s, 2H), 2.98 (s, 3H), 1.87 (br s, 1H), 1.68 (br s, 1H), 1.29 (br d, J = 6.9 Hz, 3H), 0.87 - 0.98 (m, 1H), 0.45 (br d, J = 3.7 Hz, 1H). Example 211: 5-(rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 358 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000361_0001
[00735] The title compound was prepared in a manner analogous to Example 144 using rac-(1*S,2*R,5*R)- 2-(3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane (Intermediate 31) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C20H22ClN5O3S, 447.1; m/z found, 448.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (br d, J = 8.0 Hz, 1H), 8.39 (br s, 1H), 8.31 (br d, J = 4.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.43 - 7.75 (m, 1H), 7.30 (ddd, J = 8.0, 4.7, 1.7 Hz, 1H), 6.73 - 6.84 (m, 1H), 6.59 - 6.71 (m, 1H), 5.72 (d, J = 5.5 Hz, 1H), 4.70 - 4.84 (m, 1H), 3.85 - 4.02 (m, 2H), 2.97 (s, 3H), 2.34 (quin, J = 5.8 Hz, 1H), 1.92 - 2.02 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.59 (t, J = 6.6 Hz, 2H). Example 212: 5-((1*R,2*S,5*S)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000361_0002
[00736] The title compound was prepared by separation of 5-(rac-(1*S,2*R,5*R)-2-(3-chloropyridin-2-yl)- 3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 211) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.94 min (second eluting product)). MS (ESI): mass calcd. for C20H22ClN5O3S, 447.1; m/z found, 448.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J = 4.0 Hz, 1H), 7.91 - 8.00 (m, 1H), 7.50 - 7.76 (m, 1H), 7.30 (dd, J = 8.1, 4.6 Hz, 1H), 6.73 - 6.85 (m, 1H), 6.61 - 6.69 (m, 1H), 5.72 (d, J = 5.4 Hz, 1H), 4.77 (td, J = 6.9, 5.5 Hz, 1H), 3.94 - 4.01 (m, 1H), 3.86 - 3.93 (m, 1H), 2.97 (s, 3H), 2.28 - 2.39 (m, 1H), 1.97 (quin, J = 6.1 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.55 - 0.64 (m, 2H). Example 213: 5-(6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide. 359 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000362_0001
[00737] The title compound was prepared in a manner analogous to Example 144 using 6-(2-chlorophenyl)- 4-oxa-7-azaspiro[2.5]octane (Intermediate 32) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5- fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4- dioxane in Step A. MS (ESI): mass calcd. for C22H25ClN4O4S, 476.1; m/z found, 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.68 (m, 2H), 8.07 (dd, J = 1.1, 7.8 Hz, 1H), 7.47 - 7.54 (m, 2H), 7.27 - 7.36 (m, 2H), 6.75 - 6.85 (m, 1H), 6.66 - 6.73 (m, 1H), 5.73 (t, J = 3.5 Hz, 1H), 4.73 - 4.88 (m, 1H), 4.17 - 4.29 (m, 1H), 4.04 - 4.16 (m, 2H), 3.90 (dd, J = 3.3, 13.6 Hz, 1H), 2.98 (d, J = 3.5 Hz, 3H), 1.28 - 1.35 (m, 3H), 0.89 - 0.98 (m, 1H), 0.75 - 0.88 (m, 2H), 0.62 - 0.71 (m, 1H). Example 214: 5-((*R)-6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000362_0002
[00738] The title compound was prepared by separation of 5-(6-(2-chlorophenyl)-4-oxa-7- azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 213) via SFC (Stationary phase: OZ (2.5x25 cm); Mobile phase: 60% EtOH/CO2; Rt = 8.18 min (second eluting product)). MS (ESI): mass calcd. for C22H25ClN4O4S, 476.1; m/z found, 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 - 8.69 (m, 2H), 8.06 (d, J = 0.8 Hz, 1H), 7.47 - 7.56 (m, 2H), 7.26 - 7.37 (m, 2H), 6.75 - 6.86 (m, 1H), 6.65 - 6.72 (m, 1H), 5.72 (br d, J = 2.6 Hz, 1H), 4.74 - 4.89 (m, 1H), 4.17 - 4.28 (m, 1H), 4.05 - 4.16 (m, 2H), 3.87 - 3.97 (m, 1H), 2.98 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H), 0.89 - 1.01 (m, 1H), 0.76 - 0.88 (m, 2H), 0.63 - 0.72 (m, 1H). Example 215: 5-((*R)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 360 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000363_0001
[00739] The title compound was prepared in a manner analogous to Example 144 using 6-(2-chloro-3- fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane (Intermediate 7) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2-chloro-3-fluorophenyl)-2-oxa-7- azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% EtOH/CO2; Rt = 7.14 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.67 (m, 2H), 7.97 (d, J = 1.0 Hz, 1H), 7.17 - 7.36 (m, 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.72 - 6.87 (m, 1H), 6.61 - 6.70 (m, 1H), 5.65 (t, J = 5.9 Hz, 1H), 4.79 (td, J = 7.0, 5.6 Hz, 1H), 4.38 - 4.51 (m, 2H), 4.30 (t, J = 6.3 Hz, 2H), 3.85 (d, J = 6.0 Hz, 1H), 3.73 - 3.82 (m, 1H), 2.98 (s, 3H), 2.24 - 2.47 (m, 3H), 2.00 - 2.13 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 216: 5-((*S)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000363_0002
[00740] The title compound was prepared in a manner analogous to Example 144 using 6-(2-chloro-3- fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane (Intermediate 7) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2-chloro-3-fluorophenyl)-2-oxa-7- azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% EtOH/CO2; Rt = 10.4 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.64 (m, 2H), 7.94 (d, J = 1.1 Hz, 1H), 7.19 - 7.37 (m, 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.73 - 6.82 (m, 1H), 6.63 - 6.71 (m, 1H), 5.63 (t, J = 5.9 Hz, 1H), 4.78 (td, J = 6.9, 5.7 Hz, 1H), 4.38 - 361 QB\184200.00050\92364964.2 VVID-746PC 4.51 (m, 2H), 4.29 (t, J = 5.9 Hz, 2H), 3.85 (d, J = 6.0 Hz, 1H), 3.76 (ddd, J = 13.9, 11.1, 4.4 Hz, 1H), 2.97 (s, 3H), 2.23 - 2.47 (m, 3H), 2.07 (ddd, J = 13.5, 11.3, 5.8 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 217: 5-(rac-(1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000364_0001
[00741] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 30) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H20ClF3N4O3S, 500.1; m/z found, 501.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (dd, J = 8.6, 2.4 Hz, 1H), 8.51 - 8.57 (m, 1H), 7.82 (br d, J = 14.4 Hz, 1H), 7.28 - 7.36 (m, 1H), 7.18 - 7.26 (m, 1H), 6.75 - 6.88 (m, 2H), 6.62 - 6.73 (m, 1H), 5.80 (dd, J = 6.1, 2.0 Hz, 1H), 4.79 (sext, J = 6.8 Hz, 1H), 4.31 (br d, J = 11.3 Hz, 1H), 4.17 (br dd, J = 10.1, 6.9 Hz, 1H), 3.21 - 3.30 (m, 1H), 2.98 (s, 3H), 2.90 (td, J = 11.0, 6.6 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 218: 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000364_0002
[00742] The title compound was prepared by separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chloro-3- fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Example 217) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.67 min (second eluting product)). MS (ESI): mass calcd. for C21H20ClF3N4O3S, 500.1; m/z found, 501.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 0.6 Hz, 1H), 7.83 (br s, 1H), 7.27 - 7.37 (m, 1H), 7.22 (td, J = 8.0, 5.7 Hz, 1H), 6.62 - 6.86 (m, 3H), 5.80 (dd, J = 362 QB\184200.00050\92364964.2 VVID-746PC 6.1, 1.9 Hz, 1H), 4.71 - 4.86 (m, 1H), 4.31 (d, J = 11.0 Hz, 1H), 4.11 - 4.23 (m, 1H), 3.20 - 3.30 (m, 1H), 2.98 (s, 3H), 2.90 (td, J = 11.1, 6.6 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 219: 5-(5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000365_0001
[00743] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chlorophenyl)- 1,4-oxazepane (Intermediate 5) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4- dioxane in Step A. MS (ESI): mass calcd. for C21H25ClN4O4S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.65 (m, 2H), 7.62 - 7.81 (m, 1H), 7.46 - 7.55 (m, 1H), 7.24 - 7.37 (m, 3H), 6.72 - 6.84 (m, 1H), 6.59 - 6.70 (m, 1H), 5.26 - 5.46 (m, 1H), 4.82 - 4.98 (m, 1H), 4.70 - 4.81 (m, 1H), 4.02 - 4.15 (m, 2H), 3.80 - 3.95 (m, 1H), 3.50 - 3.62 (m, 1H), 3.37 - 3.48 (m, 1H), 2.97 (d, J = 8.9 Hz, 3H), 2.45 (br d, J = 5.8 Hz, 1H), 2.10 - 2.26 (m, 1H), 1.17 - 1.34 (m, 3H). Example 220: 5-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000365_0002
[00744] The title compound was prepared via separation of 5-(5-(2-chlorophenyl)-1,4-oxazepan-4-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 219) by SFC (Stationary phase: OZ (2.5x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 11.2 min (second eluting product)). MS (ESI): mass calcd. for C21H25ClN4O4S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.65 (m, 2H), 7.60 - 7.81 (m, 1H), 7.45 - 7.54 (m, 1H), 7.23 - 7.37 (m, 3H), 6.72 - 6.82 (m, 1H), 6.58 - 6.70 (m, 1H), 5.28 - 5.43 (m, 1H), 4.88 (br d, J = 14.3 Hz, 1H), 4.70 - 4.83 (m, 1H), 3.99 - 4.14 (m, 2H), 3.83 - 3.98 (m, 1H), 3.55 (dd, J = 12.4, 9.4 Hz, 1H), 3.37 - 3.49 (m, 1H), 2.98 (s, 3H), 2.42 - 2.48 (m, 1H), 2.09 - 2.25 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H). 363 QB\184200.00050\92364964.2 VVID-746PC Example 221: 5-(5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000366_0001
[00745] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chloro-3- fluorophenyl)-1,4-oxazepane (Intermediate 15) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H24ClFN4O4S, 482.1; m/z found, 483.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.54 - 8.64 (m, 2H), 7.79 (br s, 1H), 7.29 - 7.39 (m, 2H), 7.14 - 7.22 (m, 1H), 6.73 - 6.85 (m, 1H), 6.61 - 6.69 (m, 1H), 5.42 (br d, J = 6.6 Hz, 1H), 4.73 - 4.91 (m, 2H), 4.01 - 4.13 (m, 2H), 3.90 (br dd, J = 15.6, 9.8 Hz, 1H), 3.51 - 3.62 (m, 1H), 3.43 (br d, J = 9.8 Hz, 1H), 2.97 (d, J = 6.2 Hz, 3H), 2.40 - 2.49 (m, 1H), 2.10 - 2.24 (m, 1H), 1.29 (dd, J = 6.9, 3.9 Hz, 3H). Example 222: 5-((*R)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide.
Figure imgf000366_0002
[00746] The title compound was prepared via separation of 5-(5-(2-chloro-3-fluorophenyl)-1,4-oxazepan- 4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 221) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% EtOH/CO2 with 0.1% NH4OH; Rt = 6.00 min). MS (ESI): mass calcd. for C21H24ClFN4O4S, 482.1; m/z found, 483.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 - 8.66 (m, 2H), 7.78 (br d, J = 6.5 Hz, 1H), 7.28 - 7.42 (m, 2H), 7.17 (br dd, J = 6.1, 2.9 Hz, 1H), 6.75 - 6.82 (m, 1H), 6.62 - 6.69 (m, 1H), 5.42 (br d, J = 7.7 Hz, 1H), 4.72 - 4.88 (m, 2H), 4.03 - 4.13 (m, 2H), 3.90 (br dd, J = 15.7, 9.4 Hz, 1H), 3.56 (br dd, J = 12.4, 9.5 Hz, 1H), 3.41 - 3.49 (m, 1H), 2.98 (s, 3H), 2.41 - 2.49 (m, 1H), 2.08 - 2.25 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 223: 5-((*S)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide. 364 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000367_0001
[00747] The title compound was prepared via separation of 5-(5-(2-chloro-3-fluorophenyl)-1,4-oxazepan- 4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 221) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% EtOH/CO2 with 0.1% NH4OH; Rt = 9.50 min). MS (ESI): mass calcd. for C21H24ClFN4O4S, 482.1; m/z found, 483.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.53 - 8.66 (m, 2H), 7.78 (br s, 1H), 7.28 - 7.39 (m, 2H), 7.17 (dd, J = 6.2, 2.7 Hz, 1H), 6.74 - 6.80 (m, 1H), 6.63 - 6.69 (m, 1H), 5.42 (br d, J = 6.6 Hz, 1H), 4.74 - 4.90 (m, 2H), 4.02 - 4.14 (m, 2H), 3.90 (br dd, J = 15.6, 9.8 Hz, 1H), 3.56 (br dd, J = 12.2, 9.8 Hz, 1H), 3.41 - 3.47 (m, 1H), 2.96 (s, 3H), 2.41 - 2.49 (m, 1H), 2.09 - 2.24 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 224: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide.
Figure imgf000367_0002
[00748] Step A: Methyl (S)-6-(2-(2-chlorophenyl)pyrrolidin-1-yl)nicotinate. Methyl 6-fluoronicotinate (107 mg, 0.676 mmol, 1.0 eq), (S)-2-(2-chlorophenyl)pyrrolidine (135 mg, 0.710 mmol, 1.05 eq), and potassium carbonate (234 mg, 1.69 mmol, 2.5 eq) were taken up in DMF (2.3 mL, 0.30 M). The reaction was heated to 100°C for 20 hours. After cooling to rt, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-15% EtOAc in heptanes) provided methyl (S)-6-(2-(2- chlorophenyl)pyrrolidin-1-yl)nicotinate (176 mg, 82% yield). MS (ESI): mass calcd. for C17H17ClN2O2, 316.1; m/z found, 317.2 [M+H]+. [00749] Step B: (S)-6-(2-(2-Chlorophenyl)pyrrolidin-1-yl)nicotinic acid. Methyl (S)-6-(2-(2- chlorophenyl)pyrrolidin-1-yl)nicotinate (172 mg, 0.543 mmol, 1.0 eq) was taken up in methanol (2.2 mL, 0.25 M). To this was added lithium hydroxide (2.2 mL, 4.34 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60°C for 2 hours. After cooling to rt, the reaction was adjusted to pH ~2 with 1N HCl. The 365 QB\184200.00050\92364964.2 VVID-746PC precipitate was collected by filtration to provide (S)-6-(2-(2-chlorophenyl)pyrrolidin-1-yl)nicotinic acid (136 mg, 82% yield) as a white solid. MS (ESI): mass calcd. for C16H15ClN2O2, 302.1; m/z found, 303.0 [M+H]+. [00750] Step C: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide. (S)-6-(2-(2-Chlorophenyl)pyrrolidin-1-yl)nicotinic acid (136 mg, 0.449 mmol, 1.0 eq) and HATU (198 mg, 0.494 mmol, 1.1 eq) were taken up in DMF (1.5 mL, 0.30 M). To this was added N,N- diisopropylethylamine (0.17 mL, 0.988 mmol, 2.2 eq) and the reaction was stirred at rt for 20 minutes. Finally, (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 152 mg, 0.472 mmol, 1.05 eq) was added and the reaction was stirred at rt for 1 hour. The crude material was filtered through a PTFE filter with MeOH. Purification by RP-HPLC (20-95% ACN in 0.1% HCOOH water) provided 6-((S)-2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide (190 mg, 97% yield) as a white solid. MS (ESI): mass calcd. for C21H24ClN3O3S, 433.1; m/z found, 434.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 7.8, 1.5 Hz, 1H), 7.25 – 7.10 (m, 2H), 6.97 (dd, J = 7.6, 1.8 Hz, 1H), 6.91 (dd, J = 15.1, 4.6 Hz, 1H), 6.49 (dd, J = 15.1, 1.7 Hz, 1H), 6.28 – 6.07 (m, 2H), 5.35 (s, 1H), 5.00 – 4.88 (m, 1H), 3.98 (t, J = 8.9 Hz, 1H), 3.77 (t, J = 9.4 Hz, 1H), 2.93 (s, 3H), 2.58 – 2.44 (m, 1H), 2.14 – 1.95 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 225: 6-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide.
Figure imgf000368_0001
[00751] The title compound was prepared in a manner analogous to Example 224 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C 22H26ClN3O3S, 447.1; m/z found, 448.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 9.1, 2.5 Hz, 1H), 7.37 (dt, J = 7.5, 1.1 Hz, 1H), 7.20 – 7.08 (m, 3H), 6.89 (ddd, J = 15.1, 4.7, 2.0 Hz, 1H), 6.45 (ddd, J = 15.1, 3.2, 1.7 Hz, 1H), 6.28 (d, J = 9.1 Hz, 1H), 6.22 – 6.12 (m, 1H), 5.40 (td, J = 5.8, 2.0 Hz, 1H), 4.99 – 4.89 (m, 1H), 4.66 – 4.55 (m, 1H), 3.58 (ddd, J = 13.5, 11.4, 4.9 Hz, 1H), 2.89 (d, J = 1.5 Hz, 3H), 2.23 – 2.10 (m, 1H), 2.09 – 1.99 (m, 1H), 1.99 – 1.89 (m, 1H), 1.89 – 1.72 (m, 1H), 1.69 – 1.50 (m, 2H), 1.38 (dd, J = 7.2, 1.7 Hz, 3H). Example 226: 6-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide. 366 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000369_0001
[00752] The title compound was prepared via separation of 6-(2-(2-chlorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Example 225) by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 4.69 min). MS (ESI): mass calcd. for C22H26ClN3O3S, 447.1; m/z found, 448.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.37 (dd, J = 7.4, 1.2 Hz, 1H), 7.19 – 7.06 (m, 3H), 6.90 (dd, J = 15.1, 4.7 Hz, 1H), 6.45 (dd, J = 15.1, 1.7 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H), 5.98 (d, J = 7.7 Hz, 1H), 5.40 (t, J = 5.7 Hz, 1H), 5.00 – 4.88 (m, 1H), 4.64 (ddd, J = 13.5, 6.0, 3.1 Hz, 1H), 3.57 (ddd, J = 13.5, 11.4, 4.9 Hz, 1H), 2.91 (s, 3H), 2.22 – 2.10 (m, 1H), 2.10 – 2.00 (m, 1H), 2.00 – 1.90 (m, 1H), 1.89 – 1.73 (m, 1H), 1.68 – 1.52 (m, 3H), 1.38 (d, J = 7.1 Hz, 3H). Example 227: 6-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide.
Figure imgf000369_0002
[00753] The title compound was prepared via separation of 6-(2-(2-chlorophenyl)piperidin-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Example 225) by SFC (Stationary phase: IH (2x25 cm); Mobile phase: 30% MeOH/CO2; Rt = 5.52 min). MS (ESI): mass calcd. for C22H26ClN3O3S, 447.1; m/z found, 448.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.38 (dt, J = 7.4, 1.0 Hz, 1H), 7.19 – 7.06 (m, 3H), 6.89 (dd, J = 15.1, 4.6 Hz, 1H), 6.44 (dd, J = 15.2, 1.7 Hz, 1H), 6.27 (dd, J = 9.2, 0.7 Hz, 1H), 5.98 (d, J = 7.8 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 5.01 – 4.88 (m, 1H), 4.64 (ddd, J = 13.5, 6.0, 3.1 Hz, 1H), 3.57 (ddd, J = 13.4, 11.4, 4.9 Hz, 1H), 2.90 (s, 3H), 2.23 – 2.10 (m, 1H), 2.09 – 2.00 (m, 1H), 2.00 – 1.89 (m, 1H), 1.87 – 1.74 (m, 1H), 1.67 – 1.51 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H). Example 228: 2-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide. 367 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000370_0001
[00754] The title compound was prepared in a manner analogous to Example 224 using 2-(2- chlorophenyl)piperidine hydrochloride instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 2- chloropyrimidine-5-carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 1.1 Hz, 2H), 7.39 – 7.33 (m, 1H), 7.17 – 7.07 (m, 3H), 6.88 (dt, J = 15.1, 4.4 Hz, 1H), 6.44 (ddd, J = 15.1, 6.7, 1.7 Hz, 1H), 6.03 – 5.90 (m, 2H), 5.00 – 4.89 (m, 1H), 4.86 (ddd, J = 13.7, 5.9, 2.4 Hz, 1H), 3.52 (ddd, J = 13.8, 12.0, 4.7 Hz, 1H), 2.90 (d, J = 5.6 Hz, 3H), 2.19 – 2.06 (m, 2H), 1.97 – 1.87 (m, 1H), 1.83 – 1.68 (m, 1H), 1.71 – 1.51 (m, 2H), 1.39 (dd, J = 7.1, 2.9 Hz, 3H). Example 229: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methoxy-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)nicotinamide.
Figure imgf000370_0002
[00755] The title compound was prepared in a manner analogous to Example 224 using methyl 6-chloro-2- methoxypyridine-3-carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C22H26ClN3O4S, 463.1; m/z found, 464.0 [M+H]+. 1H NMR (499 MHz, CDCl3) δ 8.16 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 1.5 Hz, 1H), 7.20 – 7.08 (m, 2H), 6.97 (dd, J = 7.5, 1.9 Hz, 1H), 6.93 (dd, J = 15.1, 4.4 Hz, 1H), 6.44 (dd, J = 15.1, 1.8 Hz, 1H), 6.25 - 5.32 (m, 1H), 4.96 (qt, J = 7.2, 5.4 Hz, 1H), 3.87 (s, 1H), 3.67 (s, 2H), 2.92 (s, 3H), 2.47 (dt, J = 12.4, 8.5 Hz, 1H), 2.06 (s, 2H), 2.01 – 1.93 (m, 1H), 1.60 (s, 3H), 1.36 (d, J = 7.1 Hz, 3H). Example 230: 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide. 368 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000371_0001
[00756] The title compound was prepared in a manner analogous to Example 224 using methyl 5,6- difluoronicotinate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)pyrrolidine instead of (S)-2- (2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2-chlorophenyl)pyrrolidin-1-yl)-5-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 38% EtOH/CO2; Rt = 1.53 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.2; m/z found, 452.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 - 8.43 (m, 2H), 7.75 (dd, J = 14.5, 1.8 Hz, 1H), 7.39 - 7.48 (m, 1H), 7.18 - 7.28 (m, 2H), 7.05 - 7.11 (m, 1H), 6.70 - 6.81 (m, 2H), 5.58 - 5.66 (m, 1H), 4.78 (qd, J = 7.2, 2.5 Hz, 1H), 4.06 - 4.21 (m, 1H), 3.75 - 3.88 (m, 1H), 2.99 (s, 3H), 2.36 - 2.44 (m, 1H), 1.94 - 2.04 (m, 1H), 1.75 - 1.92 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H). Example 231: 6-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000371_0002
[00757] The title compound was prepared in a manner analogous to Example 224 using methyl 2,6- difluoronicotinate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)pyrrolidine instead of (S)-2- (2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2-chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 2.46 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.1; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (dd, J = 2.8, 7.9 Hz, 1H), 7.88 (br s, 1H), 7.49 (dd, J = 1.2, 7.7 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.00 (dd, J = 1.6, 7.5 Hz, 1H), 6.81 - 6.64 (m, 2H), 5.40 - 5.22 (m, 1H), 4.81 - 4.69 (m, 1H), 3.88 (br d, J = 8.9 Hz, 1H), 3.59 (br d, J = 6.6 Hz, 1H), 2.99 (s, 3H), 2.47 - 2.40 (m, 1H), 2.02 (br d, J = 7.5 Hz, 1H), 1.95 - 1.82 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H). 369 QB\184200.00050\92364964.2 VVID-746PC Example 232: 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000372_0001
[00758] The title compound was prepared in a manner analogous to Example 224 using methyl 2,6- difluoronicotinate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)pyrrolidine instead of (S)-2- (2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2-chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 2.87 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.1; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (br d, J = 7.1 Hz, 1H), 7.94 - 7.82 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.04 - 6.96 (m, 1H), 6.81 - 6.64 (m, 2H), 5.42 - 5.21 (m, 1H), 4.82 - 4.66 (m, 1H), 3.95 - 3.81 (m, 1H), 3.66 - 3.50 (m, 1H), 2.99 (s, 3H), 2.46 - 2.39 (m, 1H), 2.07 - 1.96 (m, 1H), 1.96 - 1.80 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H). Example 233: 6-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide.
Figure imgf000372_0002
[00759] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.42 (br d, J = 7.5 Hz, 1H), 8.00 (dd, J = 9.0, 2.1 Hz, 1H), 7.49 (dd, J = 8.8, 2.1 Hz, 1H), 7.04 - 7.15 (m, 2H), 6.70 - 6.82 (m, 2H), 6.48 (br d, J = 5.8 Hz, 1H), 5.37 (br d, J = 7.4 Hz, 1H), 4.79 (td, J = 7.3, 3.4 Hz, 1H), 3.94 (br t, J = 8.3 Hz, 1H), 3.54 - 3.68 (m, 1H), 2.99 (d, J = 2.5 Hz, 3H), 2.38 - 2.47 (m, 1H), 2.01 - 2.10 (m, 1H), 1.83 - 1.96 (m, 2H), 1.28 (dd, J = 7.1, 1.8 Hz, 3H). Example 234: 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide. 370 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000373_0001
[00760] The title compound was prepared via separation of 6-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Example 233) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 9.00 min (second eluting product)). MS (ESI): mass calcd. for C21H23ClFN3O3S, 451; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 8.6, 2.4 Hz, 1H), 7.46 (dd, J = 8.7, 2.5 Hz, 1H), 6.94 - 7.15 (m, 2H), 6.68 - 6.84 (m, 2H), 6.29 - 6.51 (m, 1H), 5.29 - 5.42 (m, 1H), 4.74 - 4.87 (m, 1H), 3.83 - 3.96 (m, 1H), 3.52 - 3.64 (m, 1H), 2.99 (s, 3H), 2.38 - 2.46 (m,1H), 1.98 - 2.11 (m, 1H), 1.80 - 1.96 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H). Example 235: 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000373_0002
[00761] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of methyl 6- (2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)nicotinate (Step A) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 37% MeOH/CO2; Rt = 2.18 min (second eluting product)) provided an intermediate that was elaborated to the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.1; m/z found, 452.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.37 (br d, J = 7.6 Hz, 1H), 7.97 (dd, J = 8.8, 1.9 Hz, 1H), 7.22 - 7.36 (m, 2H), 6.87 (br d, J = 7.2 Hz, 1H), 6.70 - 6.81 (m, 2H), 6.41 - 6.56 (m, 1H), 5.42 (br d, J = 7.6 Hz, 1H), 4.72 - 4.86 (m, 1H), 3.92 (br t, J = 8.0 Hz, 1H), 3.53 - 3.67 (m, 1H), 2.99 (s, 3H), 2.41- 2.49 (m, 1H), 2.01 - 2.12 (m, 1H), 1.84 - 1.98 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H). Example 236: 6-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide. 371 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000374_0001
[00762] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2- chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 6.02 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.30 (br d, J = 8.0 Hz, 1H), 7.94 (br d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.8, 5.13 Hz, 1H), 7.12 (td, J = 8.2, 3.1 Hz, 1H), 6.64 - 6.89 (m, 3H), 6.35 - 6.52 (m, 1H), 5.29 - 5.47 (m, 1H), 4.68 - 4.93 (m, 1H), 3.89 - 4.03 (m, 1H), 3.45 - 3.62 (m, 1H), 2.98 (s, 3H), 2.31 - 2.46 (m, 1H), 1.80 - 2.11 (m, 3H), 1.27 (d, J = 7.1 Hz, 3H). Example 237: 6-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000374_0002
[00763] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2- chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 9.13 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br s, 1H), 8.30 (br d, J = 7.9 Hz, 1H), 7.94 (br d, J = 8.8 Hz, 1H), 7.52 (br dd, J = 8.6, 5.1 Hz, 1H), 7.03 - 7.21 (m, 1H), 6.66 - 6.87 (m, 3H), 6.45 (br s, 1H), 5.36 (br d, J = 6.8 Hz, 1H), 4.65 - 4.98 (m, 1H), 3.94 (br t, J = 8.6 Hz, 1H), 3.48 - 3.63 (m, 1H), 2.99 (s, 3H), 2.37 - 2.48 (m, 1H), 1.81 - 2.09 (m, 3H), 1.27 (br d, J = 7.0 Hz, 3H). Example 238: 5-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide. 372 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000375_0001
[00764] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 5-chloropyrazine-2- carboxylate instead of methyl 6-fluoronicotinate in Step A. Separation of 5-(2-(2-chloro-4- fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 33% EtOH/CO2; Rt = 5.60 min) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br d, J = 8.3 Hz, 2H), 7.57 - 8.08 (m, 1H), 7.49 (br d, J = 8.5 Hz, 1H), 7.06 - 7.17 (m, 2H), 6.75 - 6.85 (m, 1H), 6.61 - 6.72 (m, 1H), 5.41 (br d, J = 7.8 Hz, 1H), 4.74 - 4.84 (m, 1H), 3.95 - 4.06 (m, 1H), 3.61 - 3.74 (m, 1H), 2.98 (s, 3H), 2.45 (br d, J = 6.5 Hz, 1H), 1.99 - 2.11 (m, 1H), 1.83 - 1.98 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H). Example 239: 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000375_0002
[00765] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 5-chloropyrazine-2- carboxylate instead of methyl 6-fluoronicotinate in Step A. Separation of 5-(2-(2-chloro-4- fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 33% EtOH/CO2; Rt = 7.20 min) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br d, J = 8.4 Hz, 2H), 7.58 - 7.98 (m, 1H), 7.50 (br d, J = 8.5 Hz, 1H), 7.07 - 7.17 (m, 2H), 6.76 - 6.84 (m, 1H), 6.66 - 6.72 (m, 1H), 5.41 (br d, J = 7.5 Hz, 1H), 4.73 - 4.87 (m, 1H), 3.94 - 4.08 (m, 1H), 3.69 (br d, J = 8.4 Hz, 1H), 2.99 (s, 3H), 2.45 (br d, J = 7.50 Hz, 1H), 2.02 - 2.12 (m, 1H), 1.85 - 1.97 (m, 2H), 1.31 (d, J = 7.00 Hz, 3H). 373 QB\184200.00050\92364964.2 VVID-746PC Example 240: 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R, E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide.
Figure imgf000376_0001
[00766] The title compound was prepared in a manner analogous to Example 224 using methyl 5,6- difluoronicotinate instead of methyl 6-fluoronicotinate and 2-(2-chloro-3-fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1- yl)-5-fluoro-N-((R, E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% EtOH/CO2 with 0.1% NH4OH; Rt = 9.77 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br t, J = 3.7 Hz, 2H), 7.68 - 7.85 (m, 1H), 7.19 - 7.34 (m, 2H), 6.91 - 7.01 (m, 1H), 6.64 - 6.84 (m, 2H), 5.55 - 5.70 (m, 1H), 4.72 - 4.89 (m, 1H), 4.06 -4.21 (m, 1H), 3.71 - 3.91 (m, 1H), 2.94 - 3.08 (m, 3H), 2.35 - 2.46 (m, 1H), 1.75 - 2.07 (m, 3H), 1.18 - 1.35 (m, 3 H). Example 241: 5-((S)-2-(2-chlorophenyl)pyrrolidin-1-yl)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000376_0002
[00767] The title compound was prepared in a manner analogous to Example 224 using 5-chloro-3-methyl- pyrazine-2-carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 8.5 Hz, 1H), 7.49 (br d, J = 7.1 Hz, 2H), 7.20 - 7.33 (m, 2H), 7.07 (dd, J = 7.5, 1.5 Hz, 1H), 6.73 - 6.83 (m, 1H), 6.59 - 6.71 (m, 1H), 5.42 (br d, J = 4.1 Hz, 1H), 4.69 - 4.82 (m, 1H), 3.99 (ddd, J = 10.5, 7.6, 3.2 Hz, 1H), 3.71 (br d, J = 8.8 Hz, 1H), 2.98 (s, 3H), 2.56 (br s, 3H), 2.41 - 2.49 (m, 1H), 1.80 - 2.11 (m, 3H), 1.27 (d, J = 7.0 Hz, 3H). Example 242: 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide. 374 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000377_0001
[00768] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-5- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2- chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 17.0 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.62 (m, 2H), 7.72 - 8.04 (m, 1H), 7.55 (dd, J = 8.8, 5.1 Hz, 1H), 7.15 (td, J = 8.4, 3.3 Hz, 1H), 6.95 (dd, J = 9.5, 3.0 Hz, 1H), 6.76 - 6.84 (m, 1H), 6.65 - 6.72 (m, 1H), 5.40 (br d, J = 7.7 Hz, 1H), 4.71 - 4.86 (m, 1H), 4.01 - 4.15 (m, 1H), 3.59 - 3.73 (m, 1H), 2.98 (s, 3H), 2.41 - 2.47 (m, 1H), 2.06 (br dd, J = 6.6, 2.4 Hz, 1H), 1.84 - 2.00 (m, 2H), 1.31 (d, J = 7.1 Hz, 3H). Example 243: 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000377_0002
[00769] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2- chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 11.4 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br d, J = 8.0 Hz, 2H), 7.51 - 8.10 (m, 1H), 7.19 - 7.39 (m, 2H), 6.92 (d, J = 7.4 Hz, 1H), 6.75 - 6.85 (m, 1H), 6.60 - 6.74 (m, 1H), 5.46 (br d, J = 8.00 Hz, 1H), 4.67 - 4.93 (m, 1H), 4.02 (br t, J = 8.1 Hz, 1H), 3.69 (q, J = 8.3 Hz, 1H), 2.98 (s, 3H), 2.47 (br s, 1H), 2.01 - 2.15 (m, 1H), 1.84 - 2.01 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H). 375 QB\184200.00050\92364964.2 VVID-746PC Example 244: 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000378_0001
[00770] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-6- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2- chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.73 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 - 8.63 (m, 2H), 7.60 - 7.91 (m, 1H), 7.06 - 7.40 (m, 3H), 6.74 - 6.84 (m, 1H), 6.59 - 6.72 (m, 1H), 5.53 (br t, J = 6.8 Hz, 1H), 4.78 (td, J = 6.9, 5.6 Hz, 1H), 3.63 - 3.92 (m, 2H), 2.98 (s, 3H), 2.53 - 2.57 (m, 1H), 1.99 - 2.20 (m, 3H), 1.28 (d, J = 7.0 Hz, 3H). Example 245: 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000378_0002
[00771] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)azepane instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2-chlorophenyl)azepan-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% iPrOH/CO2; Rt = 6.60 min) provided the title compound. MS (ESI): mass calcd. for C22H27ClN4O3S, 462.2; m/z found, 463.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.67 (m, 2H), 8.02 (s, 1H), 7.43 - 7.53 (m, 1H), 7.23 - 7.34 (m, 3H), 6.74 - 6.84 (m, 1H), 6.58 - 6.71 (m, 1H), 5.12 - 5.40 (m, 1H), 4.73 - 4.87 (m, 1H), 4.52 - 4.71 (m, 1H), 3.60 - 3.77 (m, 1H), 2.97 (s, 3H), 2.31 - 2.40 (m, 1H), 1.92 - 2.06 (m, 2H), 1.75 - 1.89 (m, 2H), 1.35 - 1.55 (m, 3H), 1.28 (d, J = 7.0 Hz, 3H). 376 QB\184200.00050\92364964.2 VVID-746PC Example 246: 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000379_0001
[00772] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)azepane instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2-chlorophenyl)azepan-1-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% iPrOH/CO2; Rt = 12.6 min) provided the title compound. MS (ESI): mass calcd. for C22H27ClN4O3S, 462.2; m/z found, 463.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.66 (m, 2H), 7.57 - 7.99 (m, 1H), 7.42 - 7.55 (m, 1H), 7.20 - 7.32 (m, 3H), 6.72 - 6.82 (m, 1H), 6.60 - 6.69 (m, 1H), 5.07 - 5.42 (m, 1H), 4.78 (td, J = 6.8, 5.5 Hz, 1H), 4.41 - 4.71 (m, 1H), 3.59 - 3.75 (m, 1H), 2.96 (s, 3H), 2.30 - 2.41 (m, 1H), 1.92 - 2.05 (m, 2H), 1.76 -1.89 (m, 2H), 1.37 - 1.57 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 247: 5-(2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000379_0002
[00773] The title compound was prepared in a manner analogous to Example 224 using 2-(2-chloro-4- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 5-chloropyrazine-2- carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C21H24ClFN4O3S, 466.1; m/z found, 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.67 (m, 2H), 7.88 (dd, J = 8.4, 0.8 Hz, 1H), 7.49 (dt, J = 8.6, 2.1 Hz, 1H), 7.30 (ddd, J = 8.5, 6.3, 1.9 Hz, 1H), 7.12 (br t, J = 8.4 Hz, 1H), 6.73 - 6.82 (m, 1H), 6.63 - 6.71 (m, 1H), 5.58 (q, J = 5.0 Hz, 1H), 4.72 - 4.84 (m, 1H), 4.39 - 4.50 (m, 1H), 3.56 - 3.68 (m, 1H), 2.97 (d, J = 3.1 Hz, 3H), 2.03 - 2.15 (m, 1H), 1.86 - 2.01 (m, 2H), 1.67 - 1.80 (m, 1H), 1.43 - 1.66 (m, 2H), 1.29 (dd, J = 7.0, 1.8 Hz, 3H). Example 248: 5-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide. 377 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000380_0001
[00774] The title compound was prepared via separation of 5-(2-(2-chloro-4-fluorophenyl)piperidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 247) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% EtOH/CO2; Rt = 4.08 min). MS (ESI): mass calcd. for C21H24ClFN4O3S, 466.1; m/z found, 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.68 (m, 2H), 7.90 (d, J = 1.1 Hz, 1H), 7.48 (dd, J = 8.8, 2.6 Hz, 1H), 7.30 (dd, J = 8.8, 6.1 Hz, 1H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 6.73 - 6.83 (m, 1H), 6.62 - 6.72 (m, 1H), 5.58 (t, J = 5.4 Hz, 1H), 4.79 (td, J = 6.9, 5.6 Hz, 1H), 4.38 - 4.49 (m, 1H), 3.54 - 3.69 (m, 1H), 2.98 (s, 3H), 2.03 - 2.15 (m, 1H), 1.84 - 2.00 (m, 2H), 1.47 - 1.79 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 249: 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000380_0002
[00775] The title compound was prepared via separation of 5-(2-(2-chloro-4-fluorophenyl)piperidin-1-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 247) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% EtOH/CO2; Rt = 5.82 min). MS (ESI): mass calcd. for C21H24ClFN4O3S, 466.1; m/z found, 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.65 (m, 2H), 7.87 (d, J = 1.1 Hz, 1H), 7.49 (dd, J = 8.8, 2.6 Hz, 1H), 7.31 (dd, J = 8.8, 6.1 Hz, 1H), 7.12 (td, J = 8.5, 2.6 Hz, 1H), 6.72 - 6.81 (m, 1H), 6.61 - 6.71 (m, 1H), 5.57 (t, J = 5.4 Hz, 1H), 4.78 (td, J = 7.0, 5.8 Hz, 1H), 4.40 - 4.53 (m, 1H), 3.53 - 3.69 (m, 1H), 2.97 (s, 3H), 2.03 - 2.18 (m, 1H), 1.85 - 2.01 (m, 2H), 1.43 - 1.80 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 250: 5-((*R)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide. 378 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000381_0001
[00776] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-3- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2- chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.29 min) provided the title compound. MS (ESI): mass calcd. for C21H24ClFN4O3S, 466.1; m/z found, 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.62 (m, 2H), 7.92 (d, J = 1.0 Hz, 1H), 7.25 - 7.33 (m, 2H), 7.08 - 7.14 (m, 1H), 6.74 - 6.82 (m, 1H), 6.62 - 6.72 (m, 1H), 5.65 (t, J = 5.5 Hz, 1H), 4.73 - 4.83 (m, 1H), 4.45 (dt, J = 10.7, 3.0 Hz, 1H), 3.56 - 3.71 (m, 1H), 2.97 (s, 3H), 2.06 - 2.19 (m, 1H), 1.89 - 2.03 (m, 2H), 1.68 - 1.80 (m, 1H), 1.45 - 1.65 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H). Example 251: 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000381_0002
[00777] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-3- fluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2- chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 10.6 min) provided the title compound. MS (ESI): mass calcd. for C21H24ClFN4O3S, 466.1; m/z found, 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.61 (m, 2H), 7.94 (d, J = 1.1 Hz, 1H), 7.24 - 7.32 (m, 2H), 7.07 - 7.16 (m, 1H), 6.74 - 6.82 (m, 1H), 6.63 - 6.71 (m, 1H), 5.67 (t, J = 5.5 Hz, 1H), 4.78 (td, J = 6.9, 5.6 Hz, 1H), 4.30 - 4.50 (m, 1H), 3.51 - 3.71 (m, 1H), 2.98 (s, 3H), 2.06 - 2.19 (m, 1H), 1.87 - 2.03 (m, 2H), 1.69 - 1.82 (m, 1H), 1.44 - 1.66 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H). 379 QB\184200.00050\92364964.2 VVID-746PC Example 252: 5-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000382_0001
[00778] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2,3-difluorophenyl)piperidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(2-(2,3-difluorophenyl)piperidin- 1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 12.3 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H24F2N4O3S, 450.2; m/z found, 451.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 - 8.63 (m, 2H), 8.19 (d, J = 1.0 Hz, 1H), 7.25 - 7.38 (m, 1H), 7.07 - 7.17 (m, 1H), 6.95 - 7.03 (m, 1H), 6.75 - 6.85 (m, 1H), 6.63 - 6.72 (m, 1H), 5.87 - 5.94 (m, 1H), 4.75 - 4.85 (m, 1H), 4.43 (br d, J = 11.0 Hz, 1H), 3.37 - 3.46 (m, 1H), 2.98 (s, 3H), 2.00 - 2.17 (m, 2H), 1.81 - 1.91 (m, 1H), 1.60 - 1.74 (m, 2H), 1.41 - 1.53 (m, 1H), 1.31 (d, J = 7.1 Hz, 3H). Example 253: 5-((1*S,2*R,5*R)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000382_0002
[00779] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and rac-(1*R,2*S,5*S)-2-(2-chloro-4- fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 24) instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 2.90 min) provided the title compound. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.64 (br s, 1H), 7.50 (dd, J = 8.7, 2.5 Hz, 1H), 7.07 (td, J = 8.6, 2.2 Hz, 1H), 6.89 - 7.00 (m, 1H), 6.73 - 6.84 (m, 1H), 6.58 - 6.71 (m, 1H), 5.49 (d, J = 5.1 Hz, 1H), 4.69 - 4.86 (m, 1H), 380 QB\184200.00050\92364964.2 VVID-746PC 4.07 (d, J = 10.4 Hz, 1H), 3.86 (dd, J = 10.5, 5.2 Hz, 1H), 2.98 (s, 3H), 2.19 - 2.36 (m, 1H), 1.86 - 2.05 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.56 - 0.71 (m, 1H), 0.29 (q, J = 4.0 Hz, 1H). Example 254: 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000383_0001
[00780] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and rac-(1*R,2*S,5*S)-2-(2-chloro-4- fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 24) instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 4.09 min) provided the title compound. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.52 (s, 1H), 7.62 (br s, 1H), 7.50 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (td, J = 8.4, 2.5 Hz, 1H), 6.92 - 6.99 (m, 1H), 6.74 - 6.81 (m, 1H), 6.64 - 6.71 (m, 1H), 5.50 (d, J = 5.1 Hz, 1H), 4.71 - 4.83 (m, 1H), 4.07 (d, J = 10.5 Hz, 1H), 3.86 (dd, J = 10.5, 5.3 Hz, 1H), 2.98 (s, 3H), 2.30 (td, J = 7.9, 3.9 Hz, 1H), 1.91 - 2.00 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.64 (td, J = 7.9, 5.3 Hz, 1H), 0.26 - 0.33 (m, 1H). Example 255: 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000383_0002
[00781] The title compound was prepared in a manner analogous to Example 224 using methyl 5-chloro-3- methyl-pyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 3-(2-chlorophenyl)morpholine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(3-(2-chlorophenyl)morpholino)- 3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 8.47 min (second eluting product)) provided 381 QB\184200.00050\92364964.2 VVID-746PC the title compound. MS (ESI): mass calcd. for C21H25ClN4O4S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.50 (dd, J = 7.6, 1.3 Hz, 1H), 7.40 (dd, J = 7.3, 1.7 Hz, 1H), 7.21 - 7.33 (m, 2H), 6.73 - 6.83 (m, 1H), 6.63 - 6.71 (m, 1H), 5.57 (br s, 1H), 4.69 - 4.82 (m, 1H), 4.09 - 4.26 (m, 2H), 4.00 - 4.07 (m, 2H), 3.71 - 3.84 (m, 2H), 2.98 (s, 3H), 2.58 (s, 3H), 1.28 (d, J = 7.0 Hz, 3H). Example 256: 5-(rac-(2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000384_0001
[00782] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)-5- methylpyrrolidine (Intermediate 6) instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Only the cis racemate of 2-(2-chlorophenyl)-5-methylpyrrolidine (Intermediate 6) reacted in Step A. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 4.5, 1.0 Hz, 1H), 8.52 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 - 7.56 (m, 2H), 7.26 - 7.33 (m, 2H), 7.13 - 7.22 (m, 1H), 6.73 - 6.82 (m, 1H), 6.63 - 6.70 (m, 1H), 5.29 (t, J = 7.5 Hz, 1H), 4.72 - 4.84 (m, 1H), 4.50 (td, J = 6.6, 3.1 Hz, 1H), 2.97 (d, J = 4.6 Hz, 3H), 2.54 - 2.64 (m, 1H), 2.14 - 2.26 (m, 1H), 1.83 - 1.96 (m, 1H), 1.66 - 1.79 (m, 1H), 1.48 (d, J = 6.3 Hz, 3H), 1.28 (dd, J = 7.0, 2.0 Hz, 3H). Example 257: 5-((2*R,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000384_0002
[00783] The title compound was prepared via separation of 5-(rac-(2*S,5*S)-2-(2-chlorophenyl)-5- methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 256) by SFC (Stationary phase: OZ (2.5x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.15 min). MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 382 QB\184200.00050\92364964.2 VVID-746PC (d, J = 1.1 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 7.46 - 7.55 (m, 2H), 7.27 - 7.33 (m, 2H), 7.15 - 7.22 (m, 1H), 6.73 - 6.81 (m, 1H), 6.61 - 6.68 (m, 1H), 5.29 (t, J = 7.4 Hz, 1H), 4.73 - 4.82 (m, 1H), 4.47 - 4.54 (m, 1H), 2.97 (s, 3H), 2.60 (dtd, J = 12.2, 7.4, 4.5 Hz, 1H), 2.15 - 2.24 (m, 1H), 1.84 - 1.95 (m, 1H), 1.69 - 1.77 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 7.0 Hz, 3H). Example 258: 5-((2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000385_0001
[00784] The title compound was prepared via separation of 5-(rac-(2*S,5*S)-2-(2-chlorophenyl)-5- methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 256) by SFC (Stationary phase: OZ (2.5x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.55 min). MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.1 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 7.47 - 7.57 (m, 2H), 7.25 - 7.33 (m, 2H), 7.15 - 7.21 (m, 1H), 6.75 - 6.82 (m, 1H), 6.61 - 6.70 (m, 1H), 5.29 (t, J = 7.5 Hz, 1H), 4.78 (ddd, J = 13.8, 6.9, 1.3 Hz, 1H), 4.44 - 4.56 (m, 1H), 2.98 (s, 3H), 2.59 (dtd, J = 12.2, 7.3, 4.5 Hz, 1H), 2.20 (ddt, J = 12.1, 9.7, 7.3 Hz, 1H), 1.83 - 1.96 (m, 1H), 1.68 - 1.78 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 7.0 Hz, 3 H). Example 259: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide.
Figure imgf000385_0002
[00785] Step A: (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)pyrimidine-2-carboxylic acid. Methyl 5- bromopyrimidine-2-carboxylate (51 mg, 0.229 mmol, 1.05 eq) was taken up in toluene (1.1 mL, 0.20 M) and placed under N2. To this was added (S)-2-(2-chlorophenyl)pyrrolidine (50 mg, 0.218 mmol, 1.0 eq), cesium carbonate (217 mg, 0.653 mmol, 3.0 eq), and SPhos Pd G4 (17 mg, 0.022 mmol, 0.1 eq). The reaction was heated to 100°C for 24 hours. After cooling to rt, the reaction was quenched with water and extracted with 20% iPrOH in CHCl3. The combined organic extracts were dried over Na2SO4, filtered, and 383 QB\184200.00050\92364964.2 VVID-746PC concentrated under reduced pressure. Purification by RP-HPLC (5-95% ACN in 0.1% HCOOH water) provided (S)-5-(2-(2-chlorophenyl)pyrrolidin-1-yl)pyrimidine-2-carboxylic acid (4.0 mg, 6% yield). MS (ESI): mass calcd. for C15H14ClN3O2, 303.1; m/z found, 304.0 [M+H]+. Step B: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine- 2-carboxamide. 5(S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)pyrimidine-2-carboxylic acid (4.0 mg, 0.013 mmol, 1.0 eq), (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 4.4 mg, 0.014 mmol, 1.05 eq), and HATU (5.8 mg, 0.014 mmol, 1.1 eq) were taken up in DMF (0.13 mL, 0.10 M). To this was added N,N-diisopropylethylamine (5.0 µL, 0.029 mmol, 2.2 eq) and the reaction was stirred at rt for 30 minutes. The crude material was filtered through a PTFE filter with MeOH. Purification by RP-HPLC (20-95% ACN in 0.1% HCOOH water) provided 5-((S)-2-(2- chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (5.7 mg, quant. yield) as a white solid. MS (ESI): mass calcd. for C20H23ClN4O3S, 434.1; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 7.9, 1.4 Hz, 1H), 7.22 (td, J = 7.7, 1.7 Hz, 1H), 7.16 (td, J = 7.5, 1.4 Hz, 1H), 6.96 – 6.87 (m, 2H), 6.47 (dd, J = 15.1, 1.8 Hz, 1H), 5.21 (dd, J = 8.3, 2.4 Hz, 1H), 5.05 – 4.92 (m, 1H), 3.90 – 3.81 (m, 1H), 3.60 (q, J = 8.6 Hz, 1H), 2.91 (s, 3H), 2.63 – 2.50 (m, 1H), 2.20 – 2.02 (m, 3H), 1.41 (d, J = 7.1 Hz, 3H). Example 260: 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000386_0001
[00786] Step A: 2-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoro-5-iodopyridine. To a mixture of 2,4- difluoro-5-iodopyridine (1.0 g, 4.15 mmol, 1.0 eq) in DMF (10 mL, 0.42 M) was added potassium carbonate (1.7 g, 12.4 mmol, 3.0 eq) and 2-(2-chlorophenyl)pyrrolidine (754 mg, 4.15 mmol, 1.0 eq). The reaction mixture was stirred at 80°C for 16 h. After cooling to rt, the mixture was poured into H 2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (55-85% ACN in 10 mM NH4HCO3 water) to give 2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-4-fluoro-5-iodopyridine (400 mg, 24% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.5 Hz, 1H), 7.41 (dd, J = 7.8, 1.1 Hz, 1H), 7.07 - 7.25 (m, 2 H), 7.00 (dd, J = 7.5, 1.5 Hz, 1H), 5.86 (br d, J = 10.8 Hz, 1H), 5.18 (br d, J = 7.8 Hz, 1H), 3.79 - 3.97 (m, 1H), 3.57 - 3.72 (m, 1H), 2.37 - 2.58 (m, 1H), 1.90 - 2.03 (m, 3H). 384 QB\184200.00050\92364964.2 VVID-746PC [00787] Step B: 6-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoronicotinic acid. To a mixture of 2-(2-(2- chlorophenyl)pyrrolidin-1-yl)-4-fluoro-5-iodopyridine (400 mg, 0.990 mmol, 1.0 eq) in THF (5.0 mL, 0.20 M) was added iPrMgCl (0.50 mL, 0.990 mmol, 1.0 eq). The mixture was stirred for 1 h at 0°C under N2 before being poured onto freshly crushed carbon dioxide. The pH of the reaction was adjusted to ~4 by slow addition of dilute HCl. The reaction mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-(2-(2-chlorophenyl)pyrrolidin-1-yl)-4-fluoronicotinic acid (200 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.15 - 13.16 (m, 1H), 8.47 (br s, 1H), 7.48 (br d, J = 7.5 Hz, 1H), 7.10 - 7.35 (m, 2H), 7.00 (br d, J = 6.9 Hz, 1H), 5.75 - 6.82 (m, 1H), 5.02 - 5.73 (m, 1H), 3.87 (s, 1H), 3.56 (br dd, J = 4.7, 2.4 Hz, 1H), 2.42 (br s, 1H), 1.99 - 2.07 (m, 1H), 1.87 (br d, J = 7.9 Hz, 2H). [00788] Step C: 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)nicotinamide. To a mixture of 6-(2-(2-chlorophenyl)pyrrolidin-1-yl)-4-fluoronicotinic acid (120 mg, 0.370 mmol, 1.0 eq) in DMF (3.0 mL, 0.12 M) was added HATU (213 mg, 0.560 mmol, 1.5 eq), DIPEA (0.20 mL, 1.12 mmol, 3.0 eq) and (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 132 mg, 0.410 mmol, 1.1 eq). The reaction mixture was stirred at rt for 2 h before being purified by RP-HPLC (45-75% ACN in 10 mM NH4HCO3 water) to give 6-(2-(2- chlorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (160 mg, 95% yield) as a white solid. Separation via SFC (Stationary phase: OX (3x25 cm); Mobile phase: 65% EtOH/CO2; Rt = 2.24 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN3O3S, 451.1; m/z found, 452.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (br d, J = 11.0 Hz, 1H), 8.21 (br d, J = 7.9 Hz, 1H), 7.47 (dd, J = 7.6, 1.1 Hz, 1H), 7.12 - 7.34 (m, 2H), 6.99 (dd, J = 7.3, 1.7 Hz, 1H), 6.64 - 6.86 (m, 2H), 5.84 - 6.54 (m, 1H), 5.41 (br s, 1H), 4.65 - 4.85 (m, 1H), 3.87 (br t, J = 8.6 Hz, 1H), 3.56 (br d, J = 6.9 Hz, 1H), 3.00 (s, 3H), 2.33 - 2.48 (m, 1H), 1.97 - 2.12 (m, 1H), 1.77 - 1.96 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H). Example 261: 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide.
Figure imgf000387_0001
[00789] The title compound was prepared in a manner analogous to Example 260 using 2-(2-chloro-4- fluorophenyl)pyrrolidine instead of 2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 6-(2-(2-chloro- 4-fluorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide (Step C) via SFC (Stationary phase: OX (3x25 cm); Mobile phase: 60% iPrOH/CO2; Rt = 4.60 min (second eluting 385 QB\184200.00050\92364964.2 VVID-746PC product)) provided the title compound. MS (ESI): mass calcd. for C21H22ClF2N3O3S, 469.1; m/z found, 470.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.35 (m, 1H), 8.23 (br d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 6.98 - 7.17 (m, 2H), 6.68 - 6.82 (m, 2H), 5.98 - 6.51 (m, 1H), 5.28 - 5.44 (m, 1H), 4.69 - 4.81 (m, 1H), 3.86 (br t, J = 8.0 Hz, 1H), 3.45 - 3.61 (m, 1H), 3.00 (s, 3H), 2.36 - 2.46 (m, 1H), 1.97 - 2.08 (m, 1H), 1.78 - 1.95 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H). Example 262: 4-((*R)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000388_0001
[00790] Step A: Methyl 2-fluoro-4-(2-oxopiperidin-1-yl)benzoate. To a solution of piperidin-2-one (2.0 g, 20.6 mmol, 1.2 eq) and methyl 4-bromo-2-fluorobenzoate (4.0 g, 17.2 mmol, 1.0 eq) in toluene (40 mL, 0.43 M) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.0 g, 3.40 mmol, 0.2 eq), cesium carbonate (11.2 g, 34.3 mmol, 2.0 eq) and tris(dibenzylideneacetone)dipalladium(0) (1.6 g, 1.70 mmol, 0.1 eq) under N2. The reaction was stirred at 100°C for 16 h. After cooling to rt, the mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0- 50% EtOAc in PE) to afford methyl 2-fluoro-4-(2-oxopiperidin-1-yl)benzoate (4.3 g, quant. yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (t, J = 8.4 Hz, 1H), 7.14 - 7.22 (m, 2H), 3.93 (s, 3H), 3.69 (t, J = 5.6 Hz, 2H), 2.60 (t, J = 6.4 Hz, 2H), 1.89 - 2.03 (m, 4H). [00791] Step B: Methyl 2-fluoro-4-(6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridin-1(2H)- yl)benzoate. To a solution of methyl 2-fluoro-4-(2-oxopiperidin-1-yl)benzoate (200 mg, 0.800 mmol, 1.0 eq) in DCM (5.0 mL, 0.16 M) was added N,N-diisopropylethylamine (0.28 mL, 1.59 mmol, 2.0 eq) and trifluoromethanesulfonic anhydride (292 mg, 1.03 mmol, 1.3 eq). The mixture was stirred at 0°C for 2 h before being poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give methyl 2-fluoro-4-(6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridin-1(2H)-yl)benzoate (300 mg, 98% yield) as a brown solid. MS (ESI): mass calcd. for C14H13F4NO5S, 383.3; m/z found, 384.0 [M+H]+. [00792] Step C: Methyl 4-(6-(2,3-difluorophenyl)-3,4-dihydropyridin-1(2H)-yl)-2-fluorobenzoate. To a solution of methyl 2-fluoro-4-(6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridin-1(2H)-yl)benzoate (1.2 g, 3.13 mmol, 1.0 eq), (2,3-difluorophenyl)boronic acid (544 mg, 3.44 mmol, 1.1 eq), and potassium 386 QB\184200.00050\92364964.2 VVID-746PC carbonate (865 mg, 6.26 mmol, 2.0 eq) in 1,4-dioxane/H2O (10:1, 16.5 mL, 0.19 M) was added Pd(PPh3)4 (181 mg, 0.160 mmol, 0.05 eq). The reaction was stirred under N2 at 90°C for 16 h. After cooling to rt, the mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-10% EtOAc in PE) to give methyl 4-(6-(2,3-difluorophenyl)-3,4- dihydropyridin-1(2H)-yl)-2-fluorobenzoate (1.0 g, 92% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.67 (t, J = 8.6 Hz, 1H), 6.89 - 7.04 (m, 3H) 6.43 - 6.59 (m, 2H), 5.60 (br s, 1H), 3.84 (s, 3H), 3.76 - 3.81 (m, 2H), 2.37 (br t, J = 6.6 Hz, 2H), 1.85 - 1.91 (m, 2H). [00793] Step D: Methyl 4-(2-(2,3-difluorophenyl)piperidin-1-yl)-2-fluorobenzoate. To a solution of methyl 4-(6-(2,3-difluorophenyl)-3,4-dihydropyridin-1(2H)-yl)-2-fluorobenzoate (560 mg, 1.60 mmol, 1.0 eq) in methanol (40 mL, 0.04 M) was added Pd/C (50% by weight, 600 mg). The reaction was stirred under H2 (15 psi) for 3 h. The solution was filtered and concentrated under reduced pressure to give methyl 4-(2- (2,3-difluorophenyl)piperidin-1-yl)-2-fluorobenzoate (500 mg, 89% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (t, J = 8.9 Hz, 1H), 6.89 - 7.09 (m, 2H), 6.81 (s, 1H), 6.38 - 6.55 (m, 2H), 5.15 (t, J = 5.2 Hz, 1H), 3.85 (s, 3 H), 3.71 (dt, J = 12.7, 5.0 Hz, 1H), 3.44 - 3.54 (m, 1H), 2.06 - 2.20 (m, 2H), 1.77 - 1.98 (m, 2H), 1.56 - 1.73 (m, 2H). [00794] Step E: 4-(2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluorobenzoic acid. To a solution of methyl 4- (2-(2,3-difluorophenyl)piperidin-1-yl)-2-fluorobenzoate (500 mg, 1.43 mmol, 1.0 eq) in THF (4.0 mL, 0.18 M) and methanol (2.0 mL, 0.18 M) was added LiOH·H2O (180 mg, 4.29 mmol, 3.0 eq) in H2O (2.0 mL, 0.18 M). The reaction was stirred at 40°C for 12 h. The crude mixture was concentrated then acidified with 3M HCl to pH ~4. The mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 4-(2-(2,3-difluorophenyl)piperidin-1-yl)-2-fluorobenzoic acid (440 mg, 92% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J = 9.0 Hz, 1H), 7.30 (br d, J = 8.6 Hz, 1H), 7.03 - 7.15 (m, 1H), 6.92 (t, J = 7.3 Hz, 1H), 6.54 - 6.66 (m, 2H), 5.30 (t, J = 4.9 Hz, 1H), 3.80 (dt, J = 12.9, 4.5 Hz, 1H), 3.41 (ddd, J = 12.9, 11.0, 4.5 Hz, 1H), 1.96 - 2.13 (m, 2H), 1.83 (dt, J = 8.8, 4.3 Hz, 1H), 1.65 - 1.76 (m, 1H), 1.54 - 1.61 (m, 1H), 1.35 - 1.45 (m, 1H). [00795] Step F: 4-((*R)-2-(2,3-Difluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide. A solution of (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 173 mg, 0.540 mmol, 1.2 eq), 4-(2-(2,3-difluorophenyl)piperidin-1-yl)-2-fluorobenzoic acid (150 mg, 0.450 mmol, 1.0 eq), HATU (255 mg, 0.670 mmol, 1.5 eq), and N,N-diisopropylethylamine (0.22 mL, 1.34 mmol, 3.0 eq) in DCM (2.0 mL, 0.22 M) was stirred at rt for 12 h. The reaction mixture was poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP- HPLC (40-70% ACN in 0.1% TFA water) to afford 4-(2-(2,3-difluorophenyl)piperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (170 mg, 81% yield) as a pale yellow solid. Separation via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 1.62 min) provided the title 387 QB\184200.00050\92364964.2 VVID-746PC compound. MS (ESI): mass calcd. for C23H25F3N2O3S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 8.1, 2.9 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.27 (br d, J = 8.8 Hz, 1H), 7.08 (br d, J = 5.1 Hz, 1H), 6.93 (br t, J = 7.2 Hz, 1H), 6.73 - 6.80 (m, 1H), 6.59 - 6.72 (m, 3H), 5.22 (t, J = 5.0 Hz, 1H), 4.75 (br d, J = 5.6 Hz, 1H), 3.59 - 3.73 (m, 1H), 3.38 - 3.48 (m, 1H), 2.99 (s, 3H), 2.01 - 2.11 (m, 1H), 1.96 (br s, 1H), 1.84 (br d, J = 4.5 Hz, 1H), 1.72 (br d, J = 4.8 Hz, 1H), 1.53 - 1.63 (m, 1H), 1.43 (br dd, J = 9.6, 4.1 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 263: 4-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000390_0001
[00796] The title compound was prepared via separation of 4-(2-(2,3-difluorophenyl)piperidin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 262, Step F) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 1.77 min). MS (ESI): mass calcd. for C23H25F3N2O3S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 8.1, 2.9 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.27 (br d, J = 8.7 Hz, 1H), 7.08 (br d, J = 5.1 Hz, 1H), 6.93 (br t, J = 7.2 Hz, 1H), 6.73 - 6.80 (m, 1H), 6.59 - 6.72 (m, 3H), 5.22 (t, J = 5.0 Hz, 1H), 4.75 (br d, J = 5.6 Hz, 1H), 3.59 - 3.73 (m, 1H), 3.38 - 3.48 (m, 1H), 2.99 (s, 3H), 2.01 - 2.11 (m, 1H), 1.96 (br s, 1 H), 1.84 (br d, J = 4.5 Hz, 1H), 1.72 (br d, J = 4.7 Hz, 1H), 1.53 - 1.63 (m, 1H), 1.43 (br dd, J = 9.6, 4.1 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 264: 4-((*R)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000390_0002
[00797] The title compound was prepared in a manner analogous to Example 262 using (2,4- difluorophenyl)boronic acid instead of (2,3-difluorophenyl)boronic acid in Step C. Separation of 4-(2-(2,4- difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Step F) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 26% MeOH/CO2; Rt = 1.19 min) provided the title compound. MS (ESI): mass calcd. for C23H25F3N2O3S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 388 QB\184200.00050\92364964.2 VVID-746PC MHz, DMSO-d6) δ 8.06 (dd, J = 7.8, 2.9 Hz, 1H), 7.40 - 7.52 (m, 1H), 7.24 (ddd, J = 11.3, 9.1, 2.6 Hz, 1H), 7.14 (td, J = 8.7, 6.7 Hz, 1H), 6.95 (td, J = 8.5, 2.3 Hz, 1H), 6.56 - 6.83 (m, 4H), 5.11 (t, J = 4.9 Hz, 1H), 4.68 - 4.81 (m, 1H), 3.64 (dt, J = 12.7, 4.9 Hz, 1H), 3.37 - 3.49 (m, 1H), 3.00 (s, 3H), 1.96 - 2.10 (m, 1H), 1.78 - 1.95 (m, 2H), 1.71 (ddt, J = 13.6, 9.1, 4.8, 4.8 Hz, 1H), 1.38 - 1.61 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H). Example 265: 4-((*S)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000391_0001
[00798] The title compound was prepared in a manner analogous to Example 262 using (2,4- difluorophenyl)boronic acid instead of (2,3-difluorophenyl)boronic acid in Step C. Separation of 4-(2-(2,4- difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Step F) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 26% MeOH/CO2; Rt = 1.33 min) provided the title compound. MS (ESI): mass calcd. for C23H25F3N2O3S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 7.9, 2.9 Hz, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.24 (ddd, J = 11.2, 9.2, 2.5 Hz, 1H), 7.09 - 7.18 (m, 1H), 6.95 (td, J = 8.5, 2.2 Hz, 1H), 6.56 - 6.80 (m, 4H), 5.12 (t, J = 4.9 Hz, 1H), 4.70 - 4.81 (m, 1H), 3.65 (dt, J = 12.6, 4.7 Hz, 1H), 3.38 - 3.49 (m, 1H), 2.99 (s, 3H), 1.97 - 2.08 (m, 1H), 1.79 - 1.95 (m, 2H), 1.71 (dtt, J = 13.7, 9.2, 4.8 Hz, 1H), 1.36 - 1.61 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H). Example 266: 3-Fluoro-5-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000391_0002
[00799] The title compound was prepared in a manner analogous to Example 262 using methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromo-2-fluorobenzoate in Step A and (4-fluoro-2- methylphenyl)boronic acid instead of (2,3-difluorophenyl)boronic acid in Step C. Separation of 3-fluoro- 5-(2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Step F) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% MeOH/CO2; Rt = 4.65 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C23H27F2N3O3S, 463.1; m/z found, 389 QB\184200.00050\92364964.2 VVID-746PC 464.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 6.97 - 7.13 (m, 3H), 6.88 (td, J = 8.6, 2.7 Hz, 1H), 6.73 - 6.81 (m, 1H), 6.62 - 6.70 (m, 1H), 5.02 (br t, J = 5.4 Hz, 1H), 4.68 - 4.79 (m, 1H), 3.72 (dt, J = 12.7, 5.0 Hz, 1H), 3.54 - 3.64 (m, 1H), 2.98 (s, 3H), 2.41 (s, 3H), 1.97 - 2.10 (m, 1H), 1.85 - 1.95 (m, 1H), 1.69 - 1.84 (m, 2H), 1.48 - 1.61 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H). Example 267: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-3-(2,3,4- trifluorophenyl)morpholino)benzamide.
Figure imgf000392_0001
[00800] The title compound was prepared in a manner analogous to Example 262 using morpholin-3-one instead of piperidin-2-one in Step A and (2,3,4-trifluorophenyl)boronic acid instead of (2,3- difluorophenyl)boronic acid in Step C. Separation of 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)- 4-(3-(2,3,4-trifluorophenyl)morpholino)benzamide (Step F) via SFC (Stationary phase: IF (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 5.94 min) provided the title compound. MS (ESI): mass calcd. for C22H22F4N2O4S, 486.1; m/z found 487.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (dd, J = 7.8, 2.4 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.05 - 7.31 (m, 2H), 6.62 - 6.88 (m, 4H), 5.16 (br s, 1H), 4.77 (br d, J = 5.0 Hz, 1H), 3.92 - 4.12 (m, 3H), 3.76 (ddd, J = 11.4, 8.4, 5.4 Hz, 1H), 3.44 - 3.61 (m, 2H), 3.00 (s, 3H), 1.27 (d, J = 7.1 Hz, 3H). Example 268: 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-3-(2,3,4- trifluorophenyl)morpholino)benzamide.
Figure imgf000392_0002
[00801] The title compound was prepared in a manner analogous to Example 262 using morpholin-3-one instead of piperidin-2-one in Step A and (2,3,4-trifluorophenyl)boronic acid instead of (2,3- difluorophenyl)boronic acid in Step C. Separation of 2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)- 4-(3-(2,3,4-trifluorophenyl)morpholino)benzamide (Step F) via SFC (Stationary phase: IF (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 8.20 min) provided the title compound. MS (ESI): mass calcd. for 390 QB\184200.00050\92364964.2 VVID-746PC C22H22F4N2O4S, 486.1; m/z found 487.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (dd, J = 7.9, 2.6 Hz, 1H), 7.50 (t, J = 8.7 Hz, 1H), 7.17 - 7.26 (m, 1H), 7.08 - 7.16 (m, 1H), 6.62 - 6.84 (m, 4H), 5.16 (br s, 1H), 4.67 - 4.85 (m, 1H), 3.92 - 4.13 (m, 3H), 3.67 - 3.82 (m, 1H), 3.44 - 3.60 (m, 2H), 3.00 (s, 3H), 1.27 (d, J = 7.0 Hz, 3H). Example 269: 4-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000393_0001
[00802] Step A: Methyl rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3- yl)benzoate. To a solution of rac-(1*R,4*R,5*S)-4-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 21, 48 mg, 0.230 mmol, 1.2 eq) and methyl 4-iodobenzoate (50 mg, 0.190 mmol, 1.0 eq) in toluene (2.0 mL, 0.10 M) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22 mg, 0.400 mmol, 0.2 eq), cesium carbonate (124 mg, 0.380 mmol, 2.0 eq) and tris(dibenzylideneacetone)dipalladium(0) (17.5 mg, 0.020 mmol, 0.1 eq) under N2. The reaction was stirred at 100°C for 16 h. After cooling to rt, the reaction mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 3:1) to give methyl rac-4- ((1*S,2*R,5*R)-2-(2-chlorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (40 mg, 61% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.9 Hz, 2H), 7.16 - 7.21 (m, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.99 (d, J = 6.1 Hz, 1H), 3.86 (s, 3H), 2.60 - 2.68 (m, 1H), 2.24 - 2.34 (m, 1H), 0.99 (td, J = 8.2, 5.4 Hz, 1H), 0.87 - 0.92 (m, 1H). [00803] Step B: Methyl rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-3- yl)benzoate. To a solution of methyl rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-4-oxo-3- azabicyclo[3.1.0]hexan-3-yl)benzoate (170 mg, 0.500 mmol, 1.0 eq) in THF (3.0 mL, 0.17 M) was added BH3·Me2S (0.30 mL, 2.49 mmol, 5.0 eq) at 0°C under N2. The reaction was stirred at rt for 16 h before being quenched with MeOH and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 4:1) to give methyl rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)benzoate (80 mg, 0.240 mmol, 49% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.9 Hz, 2H), 7.44 (dd, J = 7.9, 1.1 Hz, 1H), 7.20 (td, J = 7.6, 1.6 Hz, 1H), 7.12 (td, J = 7.5, 0.8 Hz, 1H), 6.94 (dd, J = 7.7, 1.4 Hz, 1H), 6.35 (d, J = 8.9 Hz, 2H), 5.27 (d, J = 5.0 Hz, 1H), 391 QB\184200.00050\92364964.2 VVID-746PC 3.97 (d, J = 9.4 Hz, 1H), 3.82 (s, 3H), 3.65 (dd, J = 9.4, 5.1 Hz, 1H), 2.33 - 2.43 (m, 1H), 1.81 - 1.92 (m, 1H), 0.58 (td, J = 7.9, 5.4 Hz, 1H), 0.36 (q, J = 4.3 Hz, 1H). [00804] Step C: rac-4-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoic acid. To a solution of methyl rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (80 mg, 0.240 mmol, 1.0 eq) in THF/MeOH/water (3:1:1, 2.5 mL, 0.10 M) was added LiOH·H2O (31 mg, 0.730 mmol, 3.0 eq) under N2. The reaction was stirred at 50°C for 6 h. The mixture was concentrated, then diluted with H2O and neutralized by 1M HCl to pH ~4. After extraction with EtOAc, the organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give rac-4- ((1*S,2*R,5*R)-2-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoic acid (75 mg, 98% yield) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) δ 7.71 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.21 - 7.28 (m, 1H), 7.12 - 7.20 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 8.9 Hz, 2H), 5.24 (d, J = 4.9 Hz, 1H), 4.02 (d, J = 9.7 Hz, 1H), 3.63 (dd, J = 9.2, 4.8 Hz, 1H), 2.33 - 2.43 (m, 1H), 1.84 - 1.97 (m, 1H), 0.52 - 0.63 (m, 1H), 0.33 - 0.41 (m, 1H). [00805] Step D: 4-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide. To a solution of rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)benzoic acid (90 mg, 0.290 mmol, 1.0 eq) in DCM (2.0 mL, 0.14 M) was added DIPEA (0.10 mL, 0.860 mmol, 3.0 eq) and HATU (164 mg, 0.430 mmol, 1.5 eq) under N2. After 5 min, (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 92 mg, 0.290 mmol, 1.0 eq) was added and the reaction was stirred at rt for 2 h. The reaction mixture was poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (30- 65% ACN in 10 mM NH4HCO3 water) to give 4-(rac-(1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (90 mg, 71% yield) as a white solid. Separation via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 55% MeOH/CO2; Rt = 1.55 min) provided the title compound. MS (ESI): mass calcd. for C23H25ClN2O3S, 444.1; found 445.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.52 (dd, J = 7.9, 1.0 Hz, 1H), 7.18 - 7.31 (m, 2H), 6.94 (dd, J = 7.7, 1.1 Hz, 1H), 6.72 - 6.79 (m, 1H), 6.64 - 6.70 (m, 1H), 6.33 (d, J = 8.8 Hz, 2H), 5.13 (d, J = 5.0 Hz, 1H), 4.72 - 4.83 (m, 1H), 4.01 (d, J = 9.5 Hz, 1H), 3.53 (dd, J = 9.4, 5.0 Hz, 1H), 2.98 (s, 3H), 2.20 - 2.30 (m, 1H), 1.85 - 1.94 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H), 0.55 (td, J = 7.9, 4.9 Hz, 1H), 0.31 (q, J = 4.1 Hz, 1H). Example 270: 4-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide. 392 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000395_0001
[00806] The title compound was prepared via separation of 4-(rac-(1*S,2*R,5*R)-2-(2-chlorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 269, Step D) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 55% MeOH/CO2; Rt = 1.77 min). MS (ESI): mass calcd. for C23H25ClN2O3S, 444.1; found 445.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.18 - 7.32 (m, 2H), 6.91 - 6.96 (m, 1H), 6.73 - 6.82 (m, 1H), 6.64 - 6.72 (m, 1H), 6.33 (d, J = 8.8 Hz, 2H), 5.13 (d, J = 4.8 Hz, 1H), 4.72 - 4.83 (m, 1H), 4.01 (d, J = 9.2 Hz, 1H), 3.53 (dd, J = 9.2, 4.9 Hz, 1H), 2.98 (s, 3H), 2.17 - 2.29 (m, 1H), 1.86 - 1.96 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 0.55 (td, J = 8.0, 5.0 Hz, 1H), 0.31 (q, J = 4.0 Hz, 1H). Example 271: 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000395_0002
[00807] The title compound was prepared in a manner analogous to Example 269 using rac-(1*R,4*R,5*S)- 4-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 22) instead of rac- (1*R,4*R,5*S)-4-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 16) and methyl 5-bromo- 3-fluoropicolinate instead of methyl 4-iodobenzoate in Step A. Separation of 5-(rac-(1*R,2*S,5*S)-2-(2- chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide (Step D) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 8.97 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C22H22ClF2N3O3S, 481.1; m/z found, 482.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.7, 2.4 Hz, 1H), 7.34 (s, 1H), 7.14 (td, J = 8.5, 2.4 Hz, 1H), 6.98 - 7.06 (m, 1H), 6.73 - 6.79 (m, 1H), 6.70 (dd, J = 14.1, 2.0 Hz, 1H), 6.62 - 6.67 (m, 1H), 5.27 (d, J = 5.0 Hz, 1H), 4.66 - 4.79 (m, 1H), 4.01 (d, J = 9.8 Hz, 1H), 3.60 (dd, J = 9.8, 5.0 Hz, 1H), 2.98 (s, 3H), 2.19 - 2.31 (m, 1H), 1.91 - 1.99 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H), 0.61 (td, J = 7.8, 5.3 Hz, 1H), 0.33 (br d, J = 3.9 Hz, 1H). 393 QB\184200.00050\92364964.2 VVID-746PC Example 272: 4-(rac-(1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000396_0001
[00808] The title compound was prepared in a manner analogous to Example 269 using rac-(1*R,4*R,5*S)- 4-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 22) instead of rac- (1*R,4*R,5*S)-4-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 16) and methyl 4-bromo- 2-fluorobenzoate instead of methyl 4-iodobenzoate in Step A. MS (ESI): mass calcd. for C23H23ClF2N2O3S, 480.1; m/z found, 481.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (td, J = 7.6, 2.7 Hz, 1H), 7.54 (dd, J = 8.7, 2.6 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.13 (td, J = 8.5, 2.6 Hz, 1H), 6.96 (dd, J = 8.6, 6.4 Hz, 1H), 6.61 - 6.84 (m, 2H), 6.03 - 6.21 (m, 2H), 5.11 (d, J = 5.0 Hz, 1H), 4.65 - 4.88 (m, 1H), 3.97 (d, J = 9.6 Hz, 1H), 3.54 (dd, J = 9.5, 5.0 Hz, 1H), 2.99 (d, J = 0.8 Hz, 3H), 2.17 - 2.30 (m, 1H), 1.91 (td, J = 7.7, 3.9 Hz, 1H), 1.25 (dd, J = 7.1, 2.4 Hz, 3H), 0.57 (td, J = 7.9, 5.0 Hz, 1H), 0.27 (br d, J = 4.0 Hz, 1H). Example 273: 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000396_0002
[00809] The title compound was prepared via separation of 4-(rac-(1*R,2*S,5*S)-2-(2-chloro-4- fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide (Example 272) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.63 min (second eluting product)). MS (ESI): mass calcd. for C23H23ClF2N2O3S, 480.1; m/z found, 481.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (dd, J = 7.9, 2.6 Hz, 1H), 7.54 (dd, J = 8.7, 2.6 Hz, 1H), 7.41 (t, J = 8.6 Hz, 1H), 7.13 (td, J = 8.5, 2.63 Hz, 1H), 6.96 (dd, J = 8.6, 6.4 Hz, 1H), 6.60 - 6.83 (m, 2H), 6.11 (br d, J = 11.3 Hz, 2H), 5.12 (d, J = 5.1 Hz, 1H), 4.66 - 4.82 (m, 1H), 3.97 (d, J = 9.5 Hz, 1H), 3.54 (dd, J = 9.5, 5.0 Hz, 1H), 2.99 (s, 3H), 2.16 - 2.32 (m, 1H), 1.91 (td, J = 7.9, 3.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H), 0.57 (td, J = 7.9, 4.9 Hz, 1H), 0.27 (q, J = 4.1 Hz, 1H). 394 QB\184200.00050\92364964.2 VVID-746PC Example 274: 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000397_0001
[00810] The title compound was prepared in a manner analogous to Example 269 using rac-(1*R,4*R,5*S)- 4-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 22) instead of rac- (1*R,4*R,5*S)-4-(2-chlorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 16) in Step A. Separation of 4-(rac-(1*R,2*S,5*S)-2-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)benzamide (Step D) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% MeOH/CO2 with 0.1% NH4OH; Rt = 8.19 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C23H24ClFN2O3S, 462.1; m/z found, 463.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.0 Hz, 1H), 7.43 - 7.71 (m, 3H), 7.10 (td, J = 8.5, 2.6 Hz, 1H), 6.96 (dd, J = 8.6, 6.4 Hz, 1H), 6.63 - 6.81 (m, 2H), 6.33 (d, J = 8.9 Hz, 2H), 5.10 (d, J = 4.9 Hz, 1H), 4.69 - 4.85 (m, 1H), 4.01 (d, J = 9.5 Hz, 1H), 3.52 (dd, J = 9.3, 4.9 Hz, 1H), 2.99 (s, 3H), 2.19 - 2.28 (m, 1H), 1.84 - 1.96 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H), 0.56 (td, J = 7.9, 4.9 Hz, 1H), 0.29 (q, J = 4.1 Hz, 1H). Example 275: 6-((1*R,2*S,5*S)-2-(2-Chloro-4-fluoro-phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E,1R)- 1-methyl-3-methylsulfonyl-allyl)pyridine-3-carboxamide.
Figure imgf000397_0002
[00811] Step A: Methyl rac-6-((1*R,2*S,5*S)-2-(2-chloro-4-fluorophenyl)-4-oxo-3- azabicyclo[3.1.0]hexan-3-yl)nicotinate. To a solution of rac-(1*R,4*R,5*S)-4-(2-chloro-4-fluorophenyl)- 3-azabicyclo[3.1.0]hexan-2-one (Intermediate 22, 600 mg, 2.66 mmol, 1.0 eq) in DMF (8.0 mL, 0.33 M) was added potassium carbonate (1.1 g, 7.98 mmol, 3.0 eq) and methyl 6-fluoronicotinate (536 mg, 3.46 mmol, 1.3 eq). The reaction was stirred at 120°C for 8 h. After cooling to rt, the reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 1:2) to give methyl rac-6-((1*R,2*S,5*S)-2-(2-chloro-4-fluorophenyl)-4-oxo-3- azabicyclo[3.1.0]hexan-3-yl)nicotinate (500 mg, 52% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 395 QB\184200.00050\92364964.2 VVID-746PC δ 8.73 (dd, J = 2.3, 0.8 Hz, 1H), 8.26 (dd, J = 8.8, 2.3 Hz, 1H), 8.11 (dd, J = 8.8, 0.8 Hz, 1H), 7.18 (dd, J = 8.4, 2.6 Hz, 1H), 6.73 (td, J = 8.3, 2.6 Hz, 1H), 6.55 (dd, J = 8.6, 5.9 Hz, 1H), 6.22 (d, J = 6.3 Hz, 1H), 3.87 - 3.88 (m, 3H), 2.61 - 2.71 (m, 1H), 2.30 (ddd, J = 9.0, 6.0, 3.3 Hz, 1H), 1.03 (ddd, J = 8.8, 7.8, 5.4 Hz, 1H), 0.80 - 0.91 (m, 1H). The title compound was prepared in a manner analogous to Example 290, Steps B-D using methyl rac-6- ((1*R,2*S,5*S)-2-(2-chloro-4-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)nicotinate instead of methyl rac-4-((1*S,2*R,5*R)-2-(2-chlorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)benzoate in Step B. Separation of 6-(rac-(1*R,2*S,5*S)-2-(2-chloro-4-fluoro-phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((E,1R)-1-methyl-3-methylsulfonyl-allyl)pyridine-3-carboxamide (Step D) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 36% MeOH/CO 2; Rt = 7.80 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C22H23ClFN3O3S, 463.1; m/z found, 464.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.1 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 7.89 (dd, J = 8.9, 2.4 Hz, 1H), 7.45 (dd, J = 8.7, 2.6 Hz, 1H), 7.05 (td, J = 8.5, 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 6.4 Hz, 1H), 6.65 - 6.81 (m, 2H), 6.36 (br d, J = 8.8 Hz, 1H), 5.38 (d, J = 5.1 Hz, 1H), 4.78 (td, J = 7.3, 3.5 Hz,1H), 3.98 (d, J = 10.3 Hz, 1H), 3.73 (dd, J = 10.2, 5.2 Hz, 1H), 2.99 (s, 3H), 2.21 - 2.29 (m, 1H), 1.84 - 1.97 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H), 0.60 (td, J = 7.9, 5.1 Hz, 1H), 0.25 (q, J = 4.3 Hz, 1H). Example 276: 4-(2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000398_0001
[00812] Step A: Methyl 4-(4-acetoxy-2-(2-chlorophenyl)pyrrolidin-1-yl)-2-fluorobenzoate. To a solution of 5-(2-chlorophenyl)pyrrolidin-3-yl acetate (Intermediate 17, 2.0 g, 8.34 mmol, 1.0 eq) in toluene (15 mL, 0.55 M) was added methyl 4-bromo-2-fluorobenzoate (2.3 g, 10.0 mmol, 1.2 eq), RuPhos Pd G4 (354 mg, 0.410 mmol, 0.05 eq), and cesium carbonate (5.4 g, 16.7 mmol, 2.0 eq). The mixture was stirred at 100°C for 16 h under N2. After cooling to rt, the reaction was concentrated under vacuum and the residue was purified by FCC on silica (15-25% EtOAc in PE) to afford methyl 4-(4-acetoxy-2-(2- chlorophenyl)pyrrolidin-1-yl)-2-fluorobenzoate (1.3 g, 39% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 - 7.85 (m, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.14 - 7.25 (m, 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.04 - 6.30 (m, 2H), 5.37 - 5.49 (m, 1H), 5.14 - 5.33 (m, 1H), 4.09 - 4.13 (m, 1H), 3.82 - 3.89 (m, 3H), 3.54 - 3.68 (m, 1H), 2.68 - 2.91 (m, 1H), 2.17 - 2.36 (m, 1H), 2.09 - 1.78 (m, 3H). [00813] Step B: 4-(2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluorobenzoate. To a solution of methyl 4-(4-acetoxy-2-(2-chlorophenyl)pyrrolidin-1-yl)-2-fluorobenzoate (1.3 g, 3.32 mmol, 1.0 eq) in 396 QB\184200.00050\92364964.2 VVID-746PC methanol (15 mL, 0.22 M) was added potassium carbonate (458 mg, 3.32 mmol, 1.0 eq). The mixture was stirred at rt for 1 h before being filtered and concentrated under vacuum to give methyl 4-(2-(2- chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluorobenzoate (1.0 g, 86% yield) as a yellow oil. 1H NMR (400 MHz, Methanol-d4) δ 7.61 - 7.75 (m, 1H), 7.38 - 7.51 (m, 1H), 7.07 - 7.29 (m, 3H), 5.98 - 6.26 (m, 2H), 5.10 - 5.36 (m, 1H), 4.50 - 4.68 (m, 1H), 4.01 (dd, J = 10.5, 5.0 Hz, 1H), 3.65 - 3.86 (m, 3H), 3.48 - 3.57 (m, 1H), 2.54 - 2.82 (m, 1H), 1.99 - 2.14 (m, 1H). [00814] Step C: Methyl 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluorobenzoate. To a solution of methyl 4-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluorobenzoate (1.0 g, 2.85 mmol, 1.0 eq) in THF (10 mL, 0.28 M) was added NaH (228 mg, 5.71 mmol, 2.0 eq) at 0°C under N2. Iodomethane (0.53 mL, 8.57 mmol, 3.0 eq) was added and the mixture was stirred at rt for 16 h under N2. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by FCC on silica (PE:EtOAc = 9:1) to afford methyl 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)-2- fluorobenzoate (800 mg, 76% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.64 - 7.80 (m, 1H), 7.33 - 7.43 (m, 1H), 7.11 - 7.23 (m, 2H), 6.93 - 7.03 (m, 1H), 6.06 - 6.22 (m, 2H), 5.06 - 5.27 (m, 1H), 4.13 - 4.19 (m, 1H), 3.96 (dd, J = 10.3, 5.6 Hz, 1H), 3.79 - 3.87 (m, 3H), 3.54 - 3.75 (m, 1H), 3.07 - 3.45 (m, 3H), 2.53 - 2.74 (m, 1H), 2.12 - 2.35 (m, 1H). [00815] Step D: 4-(2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluorobenzoic acid. To a solution of methyl 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluorobenzoate (550 mg, 1.51 mmol, 1.0 eq) in THF/MeOH/water (2:2:1, 7.5 mL, 0.20 M) was added LiOH·H2O (317 mg, 7.55 mmol, 5.0 eq). The mixture was stirred at rt for 24 h. The pH of the reaction was adjusted to ~5 with 2M HCl and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluorobenzoic acid (520 mg, quant. yield) as a yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 7.52 - 7.61 (m, 1H), 7.38 - 7.48 (m, 1H), 7.08 - 7.25 (m, 3H), 5.98 - 6.19 (m, 2H), 5.03 - 5.22 (m, 1H), 4.12 - 4.20 (m, 1H), 3.94 - 4.03 (m, 1H), 3.52 - 3.87 (m, 1H), 3.37 (s, 2H), 3.11 - 3.17 (m, 1H), 2.58 - 2.72 (m, 1H), 2.03 - 2.26 (m, 1H). [00816] Step E: 4-(2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide. To a solution of 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1- yl)-2-fluorobenzoic acid (80 mg, 0.229 mmol, 1.0 eq) in DCM (1.0 mL, 0.22 M) was added DIPEA (59 mg, 0.457 mmol, 2.0 eq) and HATU (130 mg, 0.343 mmol, 1.5 eq). The mixture was stirred at rt for 10 min before addition of (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 73 mg, 0.228 mmol, 1.0 eq). The mixture was stirred at rt for 1 h before being quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by RP-HPLC (25-55% ACN in 10 mM NH4HCO3 water) to afford 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (39 mg, 35% yield) as a white solid. MS (ESI): mass calcd. for 397 QB\184200.00050\92364964.2 VVID-746PC C23H26ClFN2O4S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (br s, 1H), 7.41 - 7.51 (m, 2H), 7.09 - 7.30 (m, 3H), 6.63 - 6.84 (m, 2H), 6.09 - 6.25 (m, 2H), 4.97 - 5.18 (m, 1H), 4.68 - 4.87 (m, 1H), 4.10 - 4.24 (m, 1H), 3.83 - 4.04 (m, 1H), 3.51 - 3.70 (m, 1H), 3.25 - 3.36 (m, 3H), 3.09 (d, J = 1.9 Hz, 1H), 2.99 (d, J = 1.9 Hz, 2H), 2.56 - 2.74 (m, 1H), 1.93 - 2.11 (m, 1H), 1.20 - 1.32 (m, 3H). Example 277: 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000400_0001
[00817] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1- yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 276) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 11.0 min (second eluting product)). MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J = 7.9, 3.3 Hz, 1H), 7.43 - 7.51 (m, 2H), 7.20 - 7.32 (m, 2H), 7.08 - 7.14 (m, 1H), 6.62 - 6.82 (m, 2H), 6.12 - 6.22 (m, 2H), 4.97 - 5.10 (m, 1H), 4.71 - 4.87 (m, 1H), 4.07 - 4.20 (m, 1H), 3.81 - 3.90 (m, 1H), 3.60 - 3.70 (m, 1H), 3.09 (s, 3H), 2.99 (s, 3H), 2.61 - 2.78 (m, 1H), 2.02 - 2.15 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 278: 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000400_0002
[00818] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1- yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 276) by SFC (Stationary phase: AD (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 12.9 min (third eluting product)). MS (ESI): mass calcd. for C23H26ClFN2O4S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J = 8.0, 3.1 Hz, 1H), 7.39 - 7.53 (m, 2H), 7.23 - 7.33 (m, 2H), 7.14 (dd, J = 7.2, 2.2 Hz, 1H), 6.64 - 6.84 (m, 2H), 6.08 - 6.20 (m, 2H), 5.04 - 5.17 (m, 1H), 4.69 - 4.82 (m, 1H), 4.10 - 4.17 (m, 1H), 3.93 - 4.03 398 QB\184200.00050\92364964.2 VVID-746PC (m, 1H), 3.56 (dd, J = 10.8, 2.6 Hz, 1H), 3.24 - 3.30 (m, 3H), 2.99 (s, 3H), 2.54 - 2.63 (m, 1H), 1.91 - 2.05 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H). Example 279: 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000401_0001
[00819] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1- yl)-2-fluorobenzoate (Example 276, Step B) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 7.96 min (third eluting product)). This was reacted under the conditions described in Example 276, Steps D-E to provide the title compound. MS (ESI): mass calcd. for C22H24ClFN2O4S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, J = 7.9, 3.3 Hz, 1H), 7.38 - 7.56 (m, 2H), 7.17 - 7.28 (m, 3H), 6.60 (d, J = 1.5 Hz, 2H), 6.07 - 6.25 (m, 2H), 4.90 - 5.11 (m, 2H), 4.72 - 4.82 (m, 1H), 4.45 - 4.54 (m, 1H), 3.65 (d, J = 3.5 Hz, 2H), 2.99 (s, 3H), 2.64 - 2.74 (m, 1H), 1.88 - 1.99 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 280: 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000401_0002
[00820] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1- yl)-2-fluorobenzoate (Example 276, Step B) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 6.37 min (second eluting product)). This was reacted under the conditions described in Example 276, Steps D-E to provide the title compound. MS (ESI): mass calcd. for C22H24ClFN2O4S, 466.1; m/z found, 467.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J = 7.9, 3.4 Hz, 1H), 7.39 - 7.52 (m, 2H), 7.22 - 7.34 (m, 2H), 7.06 - 7.18 (m, 1H), 6.72 - 6.82 (m, 1H), 6.62 - 6.72 (m, 1H), 6.03 - 6.26 (m, 2H), 5.09 - 5.24 (m, 2H), 4.67 - 4.83 (m, 1H), 4.36 - 4.47 (m, 1H), 3.96 (dd, J = 10.4, 4.9 Hz, 1H), 3.39 (br dd, 399 QB\184200.00050\92364964.2 VVID-746PC J = 10.3, 2.6 Hz, 1H), 2.99 (s, 3H), 2.45 (br d, J = 7.4 Hz, 1H), 1.93 (dt, J = 12.1, 6.0 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 281: 4-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000402_0001
[00821] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1- yl)-2-fluorobenzoate (Example 276, Step B) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 14.3 min (fourth eluting product)). This was reacted under the conditions described in Example 276, Steps D-E to provide the title compound. MS (ESI): mass calcd. for C22H24ClFN2O4S, 466.1; m/z found, 467.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (br dd, J = 7.9, 2.8 Hz, 1H), 7.40 - 7.53 (m, 2H), 7.23 - 7.31 (m, 2H), 7.06 - 7.17 (m, 1H), 6.63 - 6.89 (m, 2H), 6.04 - 6.22 (m, 2H), 5.10 - 5.26 (m, 2H), 4.70 - 4.84 (m, 1H), 4.42 (br d, J = 3.4 Hz, 1H), 3.95 (br dd, J = 10.4, 4.8 Hz, 1H), 3.39 (br dd, J = 10.6, 2.2 Hz, 1H), 2.99 (s, 3H), 2.39 - 2.48 (m, 1H), 1.86 - 2.00 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H). Example 282: 4-(2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide.
Figure imgf000402_0002
[00822] Step A: Methyl 4-(4-acetoxy-2-(2-chlorophenyl)pyrrolidin-1-yl)benzoate. To the solution of 5-(2- chlorophenyl)pyrrolidin-3-yl acetate (Intermediate 17, 2.0 g, 8.34 mmol, 1.0 eq) in toluene (40 mL, 0.21 M) was added methyl 4-bromobenzoate (2.15 g, 10.0 mmol, 1.2 eq), RuPhos Pd G4 (710 mg, 0.834 mmol, 0.1 eq), and Cs2CO3 (5.44 g, 16.7 mmol, 2.0 eq). The mixture was stirred at 100°C for 16 h under N2. After cooling to rt, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to obtain methyl 4-(4-acetoxy-2-(2- chlorophenyl)pyrrolidin-1-yl)benzoate (1.5 g, 48% yield) as a colorless oil. MS (ESI): mass calcd. for 400 QB\184200.00050\92364964.2 VVID-746PC C20H20ClNO4, 373.1; m/z found, 374.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 - 7.89 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 6.98 - 7.24 (m, 2H), 7.04 (dd, J = 7.6, 1.4 Hz, 1H), 6.35 - 6.44 (m, 2H), 5.17 - 5.51 (m, 2H), 4.07 - 4.23 (m, 1H), 3.80 - 3.85 (m, 3H), 3.65 (dd, J = 10.9, 3.6 Hz, 1H), 2.66 - 2.88 (m, 1H), 2.18 - 2.38 (m, 1H), 2.06 - 2.11 (m, 2H), 1.79 (s, 1H). [00823] Step B: Methyl 4-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)benzoate. To a solution of methyl 4-(4-acetoxy-2-(2-chlorophenyl)pyrrolidin-1-yl)benzoate (1.5 g, 4.01 mmol, 1.0 eq) in methanol (15 mL, 0.27 M) was added potassium carbonate (555 mg, 4.01 mmol, 1.0 eq). The reaction was stirred at rt for 1 h before being filtered and concentrated in vacuo. The crude product was purified by FCC on silica (0-33% EtOAc in PE) to give methyl 4-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)benzoate (1.1 g, 83% yield) as a white solid. MS (ESI): mass calcd. for C 18H18ClNO3, 331.1; m/z found, 332.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.68 - 7.81 (m, 2H), 7.35 - 7.50 (m, 1H), 7.03 - 7.31 (m, 3H), 6.41 (br d, J = 6.9 Hz, 2H), 5.08 - 5.38 (m, 1H), 4.51 - 4.65 (m, 1H), 4.05 - 4.15 (m, 1H), 3.77 - 3.84 (m, 3H), 3.46 - 3.59 (m, 1H), 2.50 - 2.82 (m, 1H), 2.03 - 2.13 (m, 1H). [00824] Step C: Methyl 4-(2-(2-chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate. To a solution of oxalyl chloride (884 mg, 6.96 mmol, 2.1 eq) in DCM (20 mL, 0.17 M) was added DMSO (1.09 g, 13.9 mmol, 4.2 eq) dropwise at -78°C under N2. The reaction was stirred at -78°C for 0.5 h before a solution of methyl 4- (2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)benzoate (1.1 g, 3.32 mmol, 1.0 eq) in DCM (15 mL) was added. The mixture was stirred at -78°C for 1 h before TEA (1.7 g, 16.6 mmol, 5.0 eq) was added at -78°C. The reaction was allowed to warm to rt and stirred for 1 h before being diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to obtain methyl 4-(2-(2-chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate (900 mg, 82% yield) as a white solid. MS (ESI): mass calcd. for C18H16ClNO3, 329.1; m/z found, 330.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 9.0 Hz, 2H), 7.45 (dd, J = 7.9, 1.0 Hz, 1H), 7.23 (td, J = 7.7, 1.6 Hz, 1H), 7.15 (td, J = 7.5, 0.9 Hz, 1H), 6.96 (dd, J = 7.7, 1.4 Hz, 1H), 6.50 (d, J = 8.9 Hz, 2H), 5.68 (dd, J = 9.9, 3.0 Hz, 1H), 4.14 (s, 2H), 3.85 (s, 3H), 3.42 (dd, J = 18.9, 9.9 Hz, 1H), 2.64 (dd, J =19.0, 3.1 Hz, 1H). [00825] Step D: Methyl 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate. To a solution of methyl 4-(2-(2-chlorophenyl)-4-oxopyrrolidin-1-yl)benzoate (800 mg, 2.43 mmol, 1.0 eq) in DCM (10 mL, 0.24 M) was added DAST (1.17 g, 7.28 mmol, 3.0 eq) at -78°C under N2. The reaction was stirred at -78°C for 0.5 h then rt for 4 h. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to give methyl 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate (500 mg, 59% yield) as a white solid. MS (ESI): mass calcd. for C18H16ClF2NO2, 351.1; m/z found, 352.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.83 - 7.92 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.09 - 7.26 (m, 3H), 6.37 (d, J = 8.9 Hz, 2H), 5.39 (dd, J = 9.1, 3.8 Hz, 1H), 4.10 - 4.20 (m, 1H), 3.97 (dt, J = 16.5, 11.6 Hz, 1H), 3.84 (s, 3H), 3.01 - 3.18 (m, 1H), 2.42 - 2.57 (m, 1H). 401 QB\184200.00050\92364964.2 VVID-746PC [00826] Step E: 4-(2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoic acid. Methyl 4-(2-(2- chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoate (400 mg, 1.14 mmol, 1.0 eq) was taken up in HBr (70% in water, 5.0 mL). The reaction was stirred at 110°C for 2 h. After cooling to rt, the mixture was concentrated under reduced pressure to give 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoic acid (380 mg, quant. yield) as a brown solid. MS (ESI): mass calcd. for C17H14ClF2NO2, 337.1; m/z found, 338.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.86 - 7.97 (m, 2H), 7.44 (br d, J = 6.9 Hz, 2H), 7.06 - 7.20 (m, 2H), 6.41 (br d, J = 7.6 Hz, 2H), 5.37 - 5.49 (m, 1H), 4.10 - 4.24 (m, 1H), 3.94 - 4.06 (m, 1H), 3.01 - 3.20 (m, 1H), 2.41 - 2.61 (m, 1H). [00827] Step F: 4-(2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide. To a solution of 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1-yl)benzoic acid (300 mg, 0.888 mmol, 1.0 eq) in DCM (6.0 mL, 0.15 M) was added DIPEA (0.46 mL, 2.66 mmol, 3.0 eq) and HATU (507 mg, 1.33 mmol, 1.5 eq). The mixture was stirred at rt for 10 min before (R,E)-4-(methylsulfonyl)but- 3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 328 mg, 1.07 mmol, 1.2 eq) was added. The reaction was stirred at rt for 3 h before being diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 0:1) to obtain 4-(2-(2- chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (250 mg, 60% yield) as a white solid. MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (br d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.22 - 7.39 (m, 2H), 7.16 (br d, J = 7.5 Hz, 1H), 6.64 - 6.81 (m, 2H), 6.42 (d, J = 8.8 Hz, 2H), 5.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.74 - 4.86 (m, 1H), 4.19 - 4.41 (m, 1H), 4.00 (dt, J = 18.6, 11.2 Hz, 1H), 3.16 - 3.30 (m, 1H), 2.99 (d, J = 2.0 Hz, 3H), 2.30 - 2.42 (m, 1H), 1.27 (br d, J = 7.0 Hz, 3H). Example 283: 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000404_0001
[00828] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 282) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 20% EtOH/CO2; Rt = 5.65 min). MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.53 (dd, J = 7.8, 1.0 Hz, 1H), 7.23 - 7.37 (m, 2H), 7.15 (d, J = 7.4 Hz, 1H), 6.65 - 6.83 (m, 2H), 6.42 (d, J = 8.9 Hz, 2H), 5.32 (dd, J = 9.2, 3.2 Hz, 1H), 4.70 - 4.86 (m, 1H), 4.29 (ddd, J =14.0, 11.6, 402 QB\184200.00050\92364964.2 VVID-746PC 7.1 Hz, 1H), 3.94 - 4.09 (m, 1H), 3.19 - 3.31 (m, 1H), 2.99 (s, 3H), 2.30 - 2.45 (m, 1H), 1.27 (d, J = 7.13 Hz, 3H). Example 284: 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000405_0001
[00829] The title compound was prepared via separation of 4-(2-(2-chlorophenyl)-4,4-difluoropyrrolidin-1- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 282) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 20% EtOH/CO2; Rt = 9.45 min). MS (ESI): mass calcd. for C22H23ClF2N2O3S, 468.1; m/z found, 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (br d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.21 - 7.36 (m, 2H), 7.16 (br d, J = 7.6 Hz, 1H), 6.66 - 6.85 (m, 2H), 6.42 (d, J = 8.9 Hz, 2H), 5.32 (dd, J = 9.2, 3.2 Hz, 1H), 4.74 - 4.84 (m, 1H), 4.23 - 4.36 (m, 1H), 4.00 (dt, J = 18.3, 11.7 Hz, 1H), 3.15 - 3.31 (m, 1H), 2.99 (s, 3H), 2.31 - 2.45 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H). Example 285: 5-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000405_0002
[00830] Step A: Methyl 3-chloro-5-(2-(2-chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylate. A solution of 2-(2-chlorophenyl)pyrrolidine (1.0 g, 5.50 mmol, 1.0 eq), methyl 3,5-dichloropyrazine-2-carboxylate (1.3 g, 6.06 mmol, 1.1 eq), and K2CO3 (913 mg, 6.61 mmol, 1.2 eq) in DMF (10 mL, 0.55 M) was stirred at 70°C for 16 h. After cooling to rt, the reaction mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC on silica (0-50% EtOAc in PE) to provide methyl 3-chloro-5-(2-(2-chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylate (1.2 g, 62% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.33 - 7.39 (m, 1H), 7.07 - 7.20 (m, 3H), 5.64 (t, J = 7.4 Hz, 1H), 3.87 - 3.99 (m, 4H), 3.39 (br t, J = 7.2 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.06 - 2.15 (m, 1H), 1.80 - 2.03 (m, 2H). 403 QB\184200.00050\92364964.2 VVID-746PC [00831] Step B: Methyl 5-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluoropyrazine-2-carboxylate. To a solution of methyl 3-chloro-5-(2-(2-chlorophenyl)pyrrolidin-1-yl)pyrazine-2-carboxylate (1.0 g, 2.84 mmol, 1.0 eq) in DMF (10 mL, 0.28 M) was added CsF (1.3 g, 8.51 mmol, 3.0 eq). The reaction was stirred at 80°C for 16 h. After cooling to rt, the mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (PE:EtOAc = 1:1) to provide methyl 5-(2- (2-chlorophenyl)pyrrolidin-1-yl)-3-fluoropyrazine-2-carboxylate (450 mg, 47% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.8 Hz, 1H), 7.32 - 7.38 (m, 1H), 7.06 - 7.20 (m, 3H), 5.62 (t, J = 7.5 Hz, 1H), 3.84 - 4.00 (m, 3H), 3.36 (br s, 1H), 2.57 - 2.72 (m, 1H), 1.77 - 2.16 (m, 4H). [00832] Step C: 5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoropyrazine-2-carboxylic acid. To a solution of methyl 5-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluoropyrazine-2-carboxylate (350 mg, 1.04 mmol, 1.0 eq) in DCE (2.0 mL, 0.52 M) was added Me3SnOH (565 mg, 3.12 mmol, 3.0 eq). The mixture was stirred at 110°C for 2 h. After cooling to rt, the mixture was concentrated in vacuo to provide 5-(2-(2- chlorophenyl)pyrrolidin-1-yl)-3-fluoropyrazine-2-carboxylic acid (330 mg, 98% yield) as a white solid. MS (ESI): mass calcd. for C15H13ClFN3O2, 321.1; m/z found, 322.1 [M+H]+. [00833] Step D: 5-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide. To a solution of 5-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluoropyrazine- 2-carboxylic acid (330 mg, 1.03 mmol, 1.0 eq) in DMF (5.0 mL, 0.21 M) was added (R,E)-4- (methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 330 mg, 1.03 mmol, 1.0 eq), HATU (585 mg, 1.54 mmol, 1.5 eq), and DIPEA (398 mg, 3.08 mmol, 3.0 eq). The mixture was stirred at rt for 16 h before being purified by RP-HPLC (35-65% ACN in 10 mM NH4HCO3 water) to provide 5- (2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (150 mg, 32% yield) as a yellow solid. Separation via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 3.30 min) provided the title compound. MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 - 8.56 (m, 1H), 7.76 - 8.27 (m, 1H), 7.51 (br d, J = 7.6 Hz, 1H), 7.18 - 7.36 (m, 2H), 7.04 - 7.15 (m, 1H), 6.61 - 6.85 (m, 2H), 5.34 - 5.47 (m, 1H), 4.66 - 4.82 (m, 1H), 3.90 - 4.12 (m, 1H), 3.61 - 3.78 (m, 1H), 3.32 (s, 3H), 2.44 (br s, 1H), 1.81 - 2.14 (m, 3H), 1.28 (br d, J = 6.6 Hz, 3H). Example 286: 5-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000406_0001
404 QB\184200.00050\92364964.2 VVID-746PC [00834] The title compound was prepared by separation of 5-(2-(2-chlorophenyl)pyrrolidin-1-yl)-3-fluoro- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 285, Step D) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 5.10 min). MS (ESI): mass calcd. for C20H22ClFN4O3S, 452.1; m/z found, 453.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.38 - 8.54 (m, 1H), 7.45 - 7.58 (m, 1H), 7.51 (br d, J = 7.6 Hz, 1H), 7.19 - 7.37 (m, 2H), 7.10 (br d, J = 6.75 Hz, 1H), 6.58 - 6.83 (m, 2H), 5.37 - 5.46 (m, 1H), 4.67 - 4.82 (m, 1H), 3.91 - 4.09 (m, 1H), 3.61 - 3.79 (m, 1H), 2.98 (s, 3H), 2.44 (br s, 1H), 1.88 - 2.14 (m, 3H), 1.28 (br d, J = 6.88 Hz, 3H). Example 287: 5-(2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide.
Figure imgf000407_0001
[00835] The title compound was prepared in a manner analogous to Example 285 using 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of 2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H21ClF2N4O3S, 470.1; m/z found, 471.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.55 (m, 1H), 7.74 - 8.15 (m, 1H), 7.17 - 7.44 (m, 2H), 6.96 (br d, J = 7.4 Hz, 1H), 6.63 - 6.87 (m, 2H), 5.42 (br d, J = 7.6 Hz, 1H), 4.68 - 4.83 (m, 1H), 4.02 (br d, J = 1.1 Hz, 1H), 3.65 - 3.77 (m, 1H), 2.98 (s, 3H), 2.42 - 2.49 (m, 1H), 2.07 (br s, 1H), 1.84 - 2.01 (m, 2H), 1.29 (br d, J = 7.0 Hz, 3H). Example 288: 5-(2-((*R)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000407_0002
[00836] The title compound was prepared by separation of 5-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)- 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 287) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 2.70 min). MS (ESI): mass calcd. for C20H21ClF2N4O3S, 470.1; m/z found, 471.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (br d, J = 405 QB\184200.00050\92364964.2 VVID-746PC 8.3 Hz, 1H), 7.62 - 8.15 (m, 1H), 7.22 - 7.38 (m, 2H), 6.95 (br d, J = 7.3 Hz, 1H), 6.74 - 6.84 (m, 1H), 6.61 - 6.71 (m, 1H), 5.42 (br d, J = 7.5 Hz, 1H), 4.69 - 4.83 (m, 1H), 3.95 - 4.11 (m, 1H), 3.64 - 3.78 (m, 1H), 2.98 (s, 3H), 2.52 (br s, 1H), 1.84 - 2.16 (m, 3H), 1.24 - 1.34 (m, 3H). Example 289: 5-(2-((*S)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000408_0001
[00837] The title compound was prepared by separation of 5-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)- 3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 287) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 4.50 min). MS (ESI): mass calcd. for C20H21ClF2N4O3S, 470.1; m/z found, 471.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.57 (m, 1H), 7.75 - 8.17 (m, 1H), 7.20 - 7.40 (m, 2H), 6.96 (br d, J = 7.5 Hz, 1H), 6.63 - 6.83 (m, 2H), 5.42 (br d, J = 8.0 Hz, 1H), 4.69 - 4.82 (m, 1H), 3.92 - 4.10 (m, 1H), 3.64 - 3.79 (m, 1H), 2.98 (s, 3H), 2.57 (br s, 1H), 2.07 (br s, 1H), 1.86 - 2.01 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H). Example 290: 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000408_0002
[00838] The title compound was prepared in a manner analogous to Example 285 using 3-(2-chloro-3- fluorophenyl)morpholine instead of 2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C20H21ClF2N4O4S, 486.1; m/z found, 487.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (br d, J = 8.8 Hz, 1H), 8.01 - 8.11 (m, 1H), 7.32 - 7.43 (m, 3H), 6.65 - 6.83 (m, 2H), 5.59 (br d, J = 2.6 Hz, 1H), 4.71 - 4.83 (m, 1H), 4.11 - 4.22 (m, 3H), 4.01 - 4.08 (m, 1H), 3.71 - 3.79 (m, 2H), 2.98 (s, 3H), 1.27 - 1.33 (m, 3H). 406 QB\184200.00050\92364964.2 VVID-746PC Example 291: 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000409_0001
[00839] The title compound was prepared via separation of 5-(3-(2-chloro-3-fluorophenyl)morpholino)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 290) by SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% MeOH/CO 2; Rt = 9.13 min (second eluting product)). MS (ESI): mass calcd. for C20H21ClF2N4O4S, 486.1; m/z found, 487.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.26 - 7.45 (m, 3H), 6.75 - 6.82 (m, 1H), 6.66 - 6.71 (m, 1H), 5.59 (br d, J = 2.5 Hz, 1H), 4.70 - 4.85 (m, 1H), 4.01 - 4.23 (m, 4H), 3.69 - 3.86 (m, 2H), 2.98 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 292: 6-(2-(2-Chlorophenyl)azepan-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide.
Figure imgf000409_0002
[00840] Step A: Methyl 4-fluoro-6-(2-oxoazepan-1-yl)pyridine-3-carboxylate. To the solution of azepan- 2-one (650 mg, 5.74 mmol, 1.0 eq) in toluene (10 mL, 0.57 M) was added methyl 6-bromo-4-fluoro- pyridine-3-carboxylate (1.6 g, 6.89 mmol, 1.2 eq), RuPhos Pd G4 (488 mg, 0.570 mmol, 0.1 eq), and Cs2CO3 (5.6 g, 17.2 mmol, 3.0 eq). The mixture was stirred at 100°C for 16 h under N2. After cooling to rt, the reaction was concentrated then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by FCC on silica (10-17% EtOAc in PE) to give methyl 4-fluoro-6-(2-oxoazepan-1- yl)pyridine-3-carboxylate (1.0 g, 65% yield) as a yellow oil. MS (ESI): mass calcd. for C13H15FN2O3, 266.1; m/z found, 267.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 10.3 Hz, 1H), 7.89 (d, J = 13.2 Hz, 1H), 4.23 (br d, J = 8.1 Hz, 2H), 3.95 (s, 3H), 2.80 (br d, J = 6.7 Hz, 2H), 1.88 - 1.79 (m, 6H). 407 QB\184200.00050\92364964.2 VVID-746PC [00841] Step B: Methyl 6-(7-diphenoxyphosphoryloxy-2,3,4,5-tetrahydroazepin-1-yl)-4-fluoro-pyridine-3- carboxylate. To a solution of methyl 4-fluoro-6-(2-oxoazepan-1-yl)pyridine-3-carboxylate (500 mg, 1.88 mmol, 1.0 eq) in THF (15 mL, 0.13 M) was added KHMDS (2.8 mL, 2.81 mmol, 1.5 eq) at -78°C under N2. The mixture was stirred at -78°C for 1 h before a solution of diphenyl phosphorochloridate (757 mg, 2.82 mmol, 1.5 eq) in THF (5.0 mL) was added. The reaction mixture was stirred at -78°C for 1h before being quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC on silica (15- 25% EtOAc in PE) to give methyl 6-(7-diphenoxyphosphoryloxy-2,3,4,5-tetrahydroazepin-1-yl)-4-fluoro- pyridine-3-carboxylate (700 mg, 75% yield) as a yellow solid. MS (ESI): mass calcd. for C25H24FN2O6P, 498.1; m/z found, 499.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 10.4 Hz, 1H), 7.13 - 7.03 (m, 5H), 6.97 - 6.91 (m, 5H), 6.12 (d, J = 13.1 Hz, 1H), 5.40 (dt, J = 3.1, 6.4 Hz, 1H), 3.90 - 3.64 (m, 5H), 1.93 - 1.80 (m, 2H), 1.63 - 1.50 (m, 2H), 1.40 - 1.27 (m, 2H). [00842] Step C: Methyl 6-(7-(2-chlorophenyl)-2,3,4,5-tetrahydro-1H-azepin-1-yl)-4-fluoronicotinate. To a solution of methyl 6-(7-diphenoxyphosphoryloxy-2,3,4,5-tetrahydroazepin-1-yl)-4-fluoro-pyridine-3- carboxylate (350 mg, 0.702 mmol, 1.0 eq) in 1,4-dioxane/water (10:1, 5.5 mL, 0.13 M) was added 2- chlorophenylboronic acid (165 mg, 1.05 mmol, 1.5 eq), Na2CO3 (223 mg, 2.10 mmol, 3.0 eq), and Pd(dppf)Cl2 (501 mg, 0.070 mmol, 0.1 eq). The mixture was stirred at 100°C for 2 h under N2. After cooling to rt, the solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-15% EtOAc in PE) to provide methyl 6-(7-(2- chlorophenyl)-2,3,4,5-tetrahydro-1H-azepin-1-yl)-4-fluoronicotinate (62 mg, 24% yield) as a yellow oil. MS (ESI): mass calcd. for C19H18ClFN2O2, 360.1; m/z found, 361.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 10.6 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.27 - 7.23 (m, 1H), 7.16 - 7.08 (m, 2H), 5.99 (t, J = 6.1 Hz, 1H), 5.83 (br d, J = 13.9 Hz, 1H), 4.41 - 3.93 (m, 2H), 3.76 (s, 3H), 2.35 - 2.26 (m, 2H), 1.85 (q, J = 5.8 Hz, 2H), 1.62 - 1.53 (m, 2H). [00843] Step D: Methyl 6-(2-(2-chlorophenyl)azepan-1-yl)-4-fluoronicotinate. To a solution of methyl 6- (7-(2-chlorophenyl)-2,3,4,5-tetrahydro-1H-azepin-1-yl)-4-fluoronicotinate (60 mg, 0.166 mmol, 1.0 eq) in THF (5.0 mL, 0.03 M) was added PtO2 (10 mg). The reaction was stirred at rt for 12 h under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give methyl 6-(2-(2- chlorophenyl)azepan-1-yl)-4-fluoronicotinate (28 mg, 46% yield). This was used directly in the next step without purificaiton. MS (ESI): mass calcd. for C19H20ClFN2O2, 362.1; m/z found, 363.0 [M+H]+. [00844] Step E: 6-(2-(2-Chlorophenyl)azepan-1-yl)-4-fluoronicotinic acid. To a solution of methyl 6-(2- (2-chlorophenyl)azepan-1-yl)-4-fluoronicotinate (28 mg, 0.077 mmol, 1.0 eq) in THF/water (3:1, 0.80 mL, 0.1 M) was added LiOH·H2O (10 mg, 0.232 mmol, 3.0 eq). The reaction was stirred at 50°C for 12 h. After cooling to rt, the solution was concentrated under vacuum to give 6-(2-(2-chlorophenyl)azepan-1-yl)-4- fluoronicotinic acid (26 mg, 97% yield) as a white solid. This was used in the next step directly. MS (ESI): mass calcd. for C18H18ClFN2O2, 348.1; m/z found, 349.1 [M+H]+. 408 QB\184200.00050\92364964.2 VVID-746PC [00845] Step F: 6-(2-(2-Chlorophenyl)azepan-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide. To a solution of 6-(2-(2-chlorophenyl)azepan-1-yl)-4-fluoronicotinic acid (26 mg, 0.074 mmol, 1.0 eq) and (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 26 mg, 0.082 mmol, 1.1 eq) in DMF (2.0 mL, 0.04 M) was added HATU (34 mg, 0.089 mmol, 1.2 eq) and DIPEA (29 mg, 0.224 mmol, 3.0 eq). The reaction was stirred at rt for 3 h before being quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by RP-HPLC (50-80% ACN in 10 mM NH4HCO3 water) to give 6-(2-(2-chlorophenyl)azepan-1-yl)-4-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide (2.4 mg, 6% yield) as a yellow solid. MS (ESI): mass calcd. for C 23H27ClFN3O3S, 479.1; m/z found, 480.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.31 (m, 1H), 8.25 - 8.14 (m, 1H), 7.49 - 7.40 (m, 1H), 7.31 - 7.14 (m, 4H), 6.86 - 6.64 (m, 2H), 4.81 - 4.69 (m, 1H), 3.72 - 3.56 (m, 1H), 3.30 - 3.21 (m, 2H), 3.04 - 2.94 (m, 3H), 2.45 - 2.34 (m, 2H), 2.01 - 1.88 (m, 2H), 1.82 - 1.69 (m, 2H), 1.49 - 1.38 (m, 2H), 1.28 - 1.20 (m, 3H). Example 293: 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide.
Figure imgf000411_0001
[00846] Step A: Methyl 4-(3-(2-chlorophenyl)thiomorpholino)-2-fluorobenzoate. Methyl 4-bromo-2- fluorobenzoate (150 mg, 0.630 mmol, 1.0 eq) was taken up in toluene (2.5 mL, 0.25 M) and placed under N2. To this was added 3-(2-chlorophenyl)thiomorpholine (142 mg, 0.660 mmol, 1.05 eq), cesium carbonate (629 mg, 1.90 mmol, 3.0 eq), and SPhos Pd G4 (49 mg, 0.063 mmol, 0.1 eq). The reaction was heated to 100°C for 20 hours. After cooling to rt, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-15% EtOAc in heptanes) provided methyl 4-(3-(2- chlorophenyl)thiomorpholino)-2-fluorobenzoate (147 mg, 64% yield) as a tan solid. MS (ESI): mass calcd. for C18H17ClFNO2S, 365.1; m/z found, 366.0 [M+H]+. [00847] Step B: Methyl 4-(3-(2-chlorophenyl)-1-oxidothiomorpholino)-2-fluorobenzoate. Methyl 4-(3-(2- chlorophenyl)thiomorpholino)-2-fluorobenzoate (15 mg, 0.041 mmol, 1.0 eq) was taken up in acetonitrile (0.20 mL, 0.20 M). To this was added Selectfluor® (15 mg, 0.041 mmol, 1.0 eq) and water (1.5 µL, 0.082 mmol, 2.0 eq). The reaction was stirred at rt for 10 min before being quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under 409 QB\184200.00050\92364964.2 VVID-746PC reduced pressure. The crude product was used directly in the next step without purification. MS (ESI): mass calcd. for C18H17ClFNO3S, 381.1; m/z found, 382.0 [M+H]+. [00848] Step C: 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluorobenzoic acid. Methyl 4-(3-(2- chlorophenyl)-1-oxidothiomorpholino)-2-fluorobenzoate (52 mg, 0.140 mmol, 1.0 eq) was taken up in methanol (0.54 mL, 0.25 M). To this was added lithium hydroxide (0.54 mL, 1.10 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60°C for 2 hours. After cooling to rt, the reaction was adjusted to pH ~2 with 1N HCl. The resulting precipitate was collected by filtration to provide 4-(3-(2-chlorophenyl)-1- oxidothiomorpholino)-2-fluorobenzoic acid (41 mg, 82% yield). MS (ESI): mass calcd. for C17H15ClFNO3S, 367.0; m/z found, 368.0 [M+H]+. [00849] Step D: 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide. 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluorobenzoic acid (20 mg, 0.054 mmol, 1.0 eq) and HATU (25 mg, 0.065 mmol, 1.2 eq) were taken up in DMF (0.35 mL, 0.16 M). N,N- Diisopropylethylamine (28 µL, 0.160 mmol, 3.0 eq) was added and the reaction was stirred for 5 minutes. (R,E)-4-(Methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 17 mg, 0.054 mmol, 1.0 eq) was added and the reaction was stirred for 30 min at rt. Purification via RP-HPLC (20-95% ACN in 0.1% HCOOH water) provided 4-(3-(2-chlorophenyl)-1-oxidothiomorpholino)-2-fluoro-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)benzamide (23 mg, 86% yield). MS (ESI): mass calcd. for C22H24ClFN2O4S2, 498.1; m/z found, 499.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.12 (tt, J = 9.0, 2.6 Hz, 1H), 6.70 – 6.56 (m, 2H), 6.50 – 6.35 (m, 2H), 6.22 – 6.09 (m, 1H), 6.07 – 5.63 (m, 4H), 4.91 – 4.28 (m, 1H), 4.27 – 4.13 (m, 1H), 3.51 – 3.28 (m, 1H), 3.08 – 1.99 (m, 8H), 0.65 (dd, J = 7.1, 1.9 Hz, 3H). Example 294: 4-((*R)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000412_0001
[00850] Step A: Methyl 4-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-2,5-difluorobenzoate. To a mixture of 2-(2-chloro-3-fluorophenyl)pyrrolidine (500 mg, 2.50 mmol, 1.0 eq) in toluene (10 mL, 0.25 M) was added methyl 4-bromo-2,5-difluorobenzoate (754 mg, 3.00 mmol, 1.2 eq), XantPhos (87 mg, 0.150 mmol, 0.06 eq), Pd2(dba)3 (69 mg, 0.075 mmol, 0.03 eq), and cesium carbonate (2.4 g, 7.51 mmol, 3.0 eq). The reaction mixture was placed under N2 and stirred at 100°C for 16 h. After cooling to rt, the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, 410 QB\184200.00050\92364964.2 VVID-746PC dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-15% EtOAc in PE) to give methyl 4-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-2,5- difluorobenzoate (620 mg, 67% yield) as a pale yellow solid. MS (ESI): mass calcd. for C18H15ClF3NO2, 369.1; m/z found, 370.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 14.5, 6.9 Hz, 1H), 7.10 - 7.17 (m, 1H), 7.01 - 7.09 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.11 (dd, J = 13.3, 7.2 Hz, 1H), 5.34 (br d, J = 8.0 Hz, 1H), 3.93 - 4.00 (m, 1H), 3.84 (s, 3H), 3.65 - 3.74 (m, 1H), 2.41 - 2.54 (m, 1H), 1.90 - 2.10 (m, 3H). [00851] Step B: Methyl 4-(2-(2-chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluorobenzoate. To a solution of NaIO4 (222 mg, 1.03 mmol, 3.8 eq) in H2O (2.0 mL, 0.067 M) was added RuCl3 (2.8 mg, 0.013 mmol, 0.05 eq). The mixture was stirred for 5 min before a solution of methyl 4-(2-(2-chloro-3- fluorophenyl)pyrrolidin-1-yl)-2,5-difluorobenzoate (100 mg, 0.270 mmol, 1.0 eq) in ethyl acetate (2.0 mL, 0.067 M) was added. The mixture was stirred at rt for 16 h before being poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 1:1) to give methyl 4-(2-(2-chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluorobenzoate (70 mg, 67% yield) as a colorless oil. MS (ESI): mass calcd. for C18H13ClF3NO3, 383.1; m/z found, 384.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 11.1, 6.3 Hz, 1H), 7.30 (dd, J = 10.9, 5.9 Hz, 1H), 7.19 (td, J = 8.0, 5.3 Hz, 1H), 7.03 - 7.10 (m, 1H), 6.99 (d, J = 7.8 Hz, 1H), 5.84 (br t, J = 6.7 Hz, 1H), 3.90 (s, 3H), 2.68 - 2.84 (m, 3H), 2.05 (s, 1H). [00852] Step C: 4-(2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluorobenzoic acid. To a solution of methyl 4-(2-(2-chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluorobenzoate (360 mg, 0.938 mmol, 1.0 eq) in THF (4.0 mL, 0.16 M) and H2O (1.6 mL, 0.16 M) was added LiOH·H2O (118 mg, 2.81 mmol, 3.0 eq). The reaction was stirred at rt for 16 h before being poured into 1M HCl and extracted with EtOAc. The combined organic layers were concentrated under vacuum to give 4-(2-(2-chloro-3- fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluorobenzoic acid (280 mg, 80% yield) as a white solid, which was used directly in the next step. [00853] Step D: 4-((*R)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide. To a solution of 4-(2-(2-chloro-3-fluorophenyl)-5- oxopyrrolidin-1-yl)-2,5-difluorobenzoic acid (200 mg, 0.541 mmol, 1.0 eq) and (R,E)-4- (methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 191 mg, 0.595 mmol, 1.1 eq) in DCM (2.0 mL, 0.27 M) was added DIPEA (209 mg, 1.62 mmol, 3.0 eq) and HATU (308 mg, 0.811 mmol, 1.5 eq). The mixture was stirred at rt for 6 h before being diluted with H2O and extracted with DCM. The combined organic layers were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 0:1) to give 4-(2-(2-chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (240 mg, 88% yield) as a white solid. Separation via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 55% iPrOH/CO2; Rt = 11.2 min) provided the title compound. MS (ESI): mass calcd. for C22H20ClF3N2O4S, 500.1; m/z found, 501.1 [M+H]+. 1H NMR 411 QB\184200.00050\92364964.2 VVID-746PC (400 MHz, DMSO-d6) δ 8.68 (br d, J = 7.9 Hz, 1H), 7.52 (dd, J = 10.4, 6.1 Hz, 2H), 7.19 - 7.43 (m, 3H), 6.75 (s, 2H), 5.85 (br t, J = 7.0 Hz, 1H), 4.73 (br t, J = 7.0 Hz, 1H), 3.00 (s, 3H), 2.62 - 2.75 (m, 3H), 1.81 - 2.03 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H). Example 295: 4-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000414_0001
[00854] The title compound was prepared via separation of 4-(2-(2-chloro-3-fluorophenyl)-5- oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide (Example 294, Step D) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 55% iPrOH/CO2; Rt = 14.5 min). MS (ESI): mass calcd. for C22H20ClF3N2O4S, 500.1; m/z found, 501.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br d, J = 7.9 Hz, 1H), 7.52 (dd, J = 10.4, 6.1 Hz, 2H), 7.18 - 7.41 (m, 3H), 6.74 (s, 2H), 5.84 (br t, J = 6.9 Hz, 1H), 4.73 (br t, J = 7.1 Hz, 1H), 3.00 (s, 3H), 2.62 - 2.75 (m, 3H), 1.84 - 2.03 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H). Example 296: 5-(2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000414_0002
[00855] The title compound was prepared in a manner analogous to Example 294 using methyl 5-bromo-3- fluoropicolinate instead of methyl 4-bromo-2,5-difluorobenzoate in Step A. MS (ESI): mass calcd. for C21H20ClF2N3O4S, 483.1; m/z found, 484.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (dd, J = 8.4, 2.7 Hz, 1H), 8.35 (d, J = 9.9 Hz, 1H), 8.11 (td, J = 12.7, 1.9 Hz, 1H), 7.29 - 7.40 (m, 2H), 7.11 (br d, J = 5.8 Hz, 1H), 6.73 - 6.81 (m, 1H), 6.66 - 6.73 (m, 1H), 5.88 - 5.98 (m, 1H), 4.70 - 4.82 (m, 1H), 2.99 (d, J = 3.6 Hz, 3H), 2.65 - 2.76 (m, 3H), 1.91 - 2.01 (m, 1H), 1.28 (dd, J = 7.0, 2.5 Hz, 3H). 412 QB\184200.00050\92364964.2 VVID-746PC Example 297: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000415_0001
[00856] The title compound was prepared by separation of 5-(2-(2-chloro-3-fluorophenyl)-5-oxopyrrolidin- 1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Example 296) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 15.1 min (second eluting product)). MS (ESI): mass calcd. for C21H20ClF2N3O4S, 483.1; m/z found, 484.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.3 Hz, 1H), 8.36 (s, 1H), 8.10 (dd, J = 12.9, 1.9 Hz, 1H), 7.29 - 7.40 (m, 2H), 7.11 (br d, J = 6.8 Hz, 1H), 6.66 - 6.82 (m, 2H), 5.92 (br d, J = 8.3 Hz, 1H), 4.68 - 4.82 (m, 1H), 2.99 (s, 3H), 2.65 - 2.75 (m, 3H), 1.90 - 2.01 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 298: 4-(2-(2-Chlorophenyl)-4-oxopiperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide.
Figure imgf000415_0002
[00857] Step A: tert-Butyl 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate. To a solution of tert-butyl 2-(2-chlorophenyl)-4-oxopiperidine-1-carboxylate (Intermediate 8, 2.2 g, 7.10 mmol, 1.0 eq) in toluene (30 mL, 0.24 M) was added ethylene glycol (1.3 g, 21.3 mmol, 3.0 eq) and 4- methylbenzenesulfonic acid (61 mg, 0.355 mmol, 0.05 eq). The mixture was stirred at 120°C for 16 h. After cooling to rt, the solution was concentrated under reduced pressure. Purification by FCC on silica (0- 25% EtOAc in PE) afforded tert-butyl 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (1.0 g, 40% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.27 - 7.33 (m, 2H), 7.12 - 7.24 (m, 2H), 5.38 (dd, J = 7.8, 6.5 Hz, 1H), 4.22 - 4.29 (m, 1H), 3.92 - 4.02 (m, 2H), 3.85 - 3.91 (m, 1H), 3.75 - 3.82 (m, 1H), 3.55 (ddd, J = 13.6, 11.6, 4.6 Hz, 1H), 2.19 (dd, J = 14.0, 6.3 Hz, 1H), 1.96 - 2.07 (m, 3H), 1.22 (s, 9H). 413 QB\184200.00050\92364964.2 VVID-746PC [00858] Step B: 7-(2-Chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane. tert-Butyl 7-(2-chlorophenyl)-1,4- dioxa-8-azaspiro[4.5]decane-8-carboxylate (1.0 g, 2.83 mmol, 1.0 eq) was taken up in DCM/TFA (5:1, 12 mL, 0.24 M). The mixture was stirred at rt for 1 h before being poured into sat. aq. NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (700 mg, 98% yield). MS (ESI): mass calcd. for C13H16ClNO2, 253.1; m/z found, 254.1 [M+H]+. [00859] Step C: Methyl 4-(7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-fluorobenzoate. 7- (2-Chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (700 mg, 2.76 mmol, 1.0 eq) was taken up in toluene (7.0 mL, 0.39 M) and placed under N2. Methyl 4-bromo-2-fluorobenzoate (964 mg, 4.14 mmol, 1.5 eq), cesium carbonate (1.8 g, 5.52 mmol, 2.0 eq), and RuPhos Pd G4 (117 mg, 0.138 mmol, 0.05 eq) were added. The mixture was stirred at 100°C for 16 h. After cooling to rt, the solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-50% EtOAc in PE) to give methyl 4-(7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-fluorobenzoate (650 mg, 58% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.69 (t, J = 8.8 Hz, 1H), 7.32 - 7.37 (m, 1H), 7.18 - 7.25 (m, 1H), 7.05 - 7.16 (m, 2H), 6.36 - 6.54 (m, 2H), 5.03 (dd, J = 9.3, 5.0 Hz, 1H), 3.88 - 4.05 (m, 4H), 3.83 (s, 3H), 3.70 - 3.81 (m, 1H), 3.58 - 3.69 (m, 1H), 2.30 (ddd, J = 13.9, 5.0, 1.4 Hz, 1H), 2.11 - 2.20 (m, 1H), 2.01 (dd, J = 13.9, 9.3 Hz, 2H). [00860] Step D: Methyl 4-(2-(2-chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoate. To a solution of methyl 4-(7-(2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-fluorobenzoate (650 mg, 1.60 mmol, 1.0 eq) in THF (7.0 mL, 0.25 M) was added 10% H2SO4 (7.0 mL). The mixture was stirred at rt for 96 h before being poured into sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (30-60% ACN in 10 mM NH4HCO3 water) to give methyl 4-(2-(2- chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoate (150 mg, 24% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (t, J = 8.8 Hz, 1H), 7.44 (br d, J = 7.8 Hz, 1H), 7.29 (br s, 1H), 7.19 - 7.27 (m, 2H), 6.29 - 6.48 (m, 2H), 5.41 (br t, J = 5.6 Hz, 1H), 4.02 (br t, J = 6.2 Hz, 2H), 3.86 (s, 3H), 3.11 - 3.20 (m, 1H), 3.00 - 3.09 (m, 1H), 2.66 - 2.89 (m, 2H). [00861] Step E: 4-(2-(2-Chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoic acid. A solution of methyl 4- (2-(2-chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoate (150 mg, 0.414 mmol, 1.0 eq) and SnMe3OH (750 mg, 4.15 mmol, 10 eq) in DCE (3.0 mL, 0.14 M) was stirred at 110°C for 72 h. After cooling to rt, the mixture was concentrated in vacuo to give 4-(2-(2-chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoic acid (140 mg, 97% yield) as a red solid, which was used directly in the next step without purification. MS (ESI): mass calcd. for C18H15ClFNO3, 347.1; m/z found, 348.1 [M+H]+. [00862] Step F: 4-(2-(2-Chlorophenyl)-4-oxopiperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide. To a solution of 4-(2-(2-chlorophenyl)-4-oxopiperidin-1-yl)-2-fluorobenzoic acid (150 414 QB\184200.00050\92364964.2 VVID-746PC mg, 0.431 mmol, 1.0 eq) in DCM (2.0 mL, 0.31 M) was added HATU (246 mg, 0.647 mmol, 1.5 eq) and DIPEA (0.30 mL, 1.73 mmol, 4.0 eq). The mixture was stirred at rt for 5 min before (R,E)-4- (methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 180 mg, 0.561 mmol, 1.3 eq) was added. The mixture was stirred at rt for 1 h before being diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (25-55% ACN in 10 mM NH4HCO3 water) to give 4-(2-(2-chlorophenyl)-4-oxopiperidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (26 mg, 12% yield) as a white solid. MS (ESI): mass calcd. for C23H24ClFN2O4S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 8.09 (m, 1H), 7.46 - 7.56 (m, 2H), 7.38 - 7.44 (m, 1H), 7.28 - 7.37 (m, 2H), 6.73 - 6.84 (m, 1H), 6.66 - 6.73 (m, 1H), 6.41 - 6.51 (m, 2H), 5.34 (t, J = 5.9 Hz, 1H), 4.71 - 4.82 (m, 1H), 4.05 (br t, J = 6.1 Hz, 2H), 3.24 (dd, J = 15.6, 6.6 Hz, 1H), 3.00 (s, 3H), 2.82 (dd, J = 15.5, 5.3 Hz, 1H), 2.57 - 2.73 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H). Example 299: 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000417_0001
[00863] Step A: Methyl rac-5-((1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-4-oxo-3- azabicyclo[3.1.0]hexan-3-yl)-3-fluoropicolinate. To a solution of rac-(1*S,4*S,5*R)-4-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 23, 150 mg, 0.665 mmol, 1.0 eq) in toluene (5.0 mL, 0.13 M) was added XantPhos (77 mg, 0.130 mmol, 0.2 eq), Cs2CO3 (650 mg, 1.99 mmol, 3.0 eq), and methyl 5-bromo-3-fluoropicolinate (187 mg, 0.800 mmol, 1.2 eq). The mixture was stirred at 100°C for 12 h under N2. After cooling to rt, the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to provide methyl rac-5-((1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3- fluoropicolinate (150 mg, 60% yield) as a yellow solid. MS (ESI): mass calcd. for C18H13ClF2N2O3, 378.1; m/z found, 379.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 8.00 (dd, J = 2.0, 12.4 Hz, 1H), 7.07- 7.15 (m, 2H), 6.44 - 6.50 (m, 1H), 5.97 (d, J = 6.1 Hz, 1H), 3.94 - 3.98 (m, 3H), 2.65 - 2.77 (m, 1H), 2.35 (ddd, J = 3.4, 5.9, 8.9 Hz, 1H), 1.09 (dt, J = 5.6, 8.3 Hz, 1H), 0.90 - 1.01 (m, 1H). 415 QB\184200.00050\92364964.2 VVID-746PC [00864] Step B: rac-5-(((*S)-((1*R,2*S)-2-Carboxycyclopropyl)(2-chloro-3-fluorophenyl)methyl)amino)- 3-fluoropicolinic acid. To a solution of methyl rac-5-((1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-4-oxo- 3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoropicolinate (200 mg, 0.530 mmol, 1.0 eq) in THF/MeOH/water (2:1:1, 8.0 mL, 0.07 M) was added LiOH·H2O (66 mg, 1.58 mmol, 3.0 eq). The mixture was stirred at rt for 2 h before the solvent was concentrated under reduced pressure. The crude material was acidified with 1N HCl to pH ~5. The precipitate was collected by filtration to give rac-5-(((*S)-((1*R,2*S)-2- carboxycyclopropyl)(2-chloro-3-fluorophenyl)methyl)amino)-3-fluoropicolinic acid (150 mg, 74% yield) as a yellow solid. MS (ESI): mass calcd. for C17H13ClF2N2O4, 382.1; m/z found, 383.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.21 - 12.56 (m, 1H), 7.91 (br s, 1H), 7.71 (br d, J = 7.1 Hz, 1H), 7.51 - 7.57 (m, 1H), 7.45 (dt, J = 5.6, 8.0 Hz, 1H), 7.29 - 7.40 (m, 1H), 6.64 (dd, J = 2.0, 13.8 Hz, 1H), 4.95 (br t, J = 8.8 Hz, 1H), 1.88 - 2.03 (m, 1H), 1.81 (dt, J = 5.7, 8.1 Hz, 1H), 1.12 - 1.37 (m, 2H). [00865] Step C: rac-5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)- 3-fluoropicolinic acid. To a solution of rac-5-(((*S)-((1*R,2*S)-2-carboxycyclopropyl)(2-chloro-3- fluorophenyl)methyl)amino)-3-fluoropicolinic acid (130 mg, 0.340 mmol, 1.0 eq) in DCM (2.0 mL, 0.17 M) was added HATU (130 mg, 0.340 mmol, 1.0 eq) and DIPEA (0.12 mL, 0.680 mmol, 2.0 eq). The mixture was stirred at rt for 2 h before being concentrated under vacuum to provide the title compound (123 mg, quant. yield) which was used in the next step as is. MS (ESI): mass calcd. for C17H11ClF2N2O3, 364.0; m/z found, 365.1 [M+H]+. [00866] Step D: 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3- fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide. To a mixture of rac-5-((1*R,2*S,5*S)-2- (2-chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoropicolinic acid (123 mg, 0.337 mmol, 1.0 eq) and DIPEA (0.12 mL, 0.675 mmol, 2.0 eq) in DCM (5.0 mL, 0.067 M) was added HATU (154 mg, 0.405 mmol, 1.2 eq) and (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 108 mg, 0.337 mmol, 1.0 eq). The mixture was stirred at rt for 2 h. Purification by RP-HPLC (20-50% ACN in 10 mM NH4HCO3 water) provided 5-(rac-(1*R,2*S,5*S)-2-(2-chloro-3- fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide (80 mg, 48% yield). Separation via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 12.6 min (second eluting product)) provided the title compound. MS (ESI): mass calcd. for C22H20ClF2N3O4S, 495.1; m/z found, 496.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.81 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.81 (dd, J = 2.0, 12.8 Hz, 1H), 7.29 - 7.41 (m, 1H), 7.22 (dt, J = 5.6, 8.0 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.75 - 6.82 (m, 1H), 6.67 - 6.74 (m, 1H), 6.16 (d, J = 6.1 Hz, 1H), 4.75 (br d, J = 4.9 Hz, 1H), 2.99 (s, 3H), 2.61 - 2.72 (m, 1H), 2.31 (ddd, J = 3.3, 5.9, 8.8 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.89 - 1.07 (m, 2H). Example 300: 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 416 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000419_0001
[00867] Step A: Methyl rac-5-((1*S,2*R,5*R)-2-(2-chloro-3-fluorophenyl)-4-oxo-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate. To a solution of rac-(1*S,4*S,5*R)-4-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 23, 180 mg, 0.798 mmol, 1.0 eq) and methyl 5-bromopyrazine-2-carboxylate (260 mg, 1.20 mmol, 1.5 eq) in toluene (5.0 mL, 0.16 M) was added cesium carbonate (780 mg, 2.39 mmol, 3.0 eq). RuPhos Pd G4 (68 mg, 0.080 mmol, 0.1 eq) was added and the reaction was degassed and purged with N2. The mixture was stirred at 100°C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-35% EtOAc in PE) to give methyl rac-5-((1*S,2*R,5*R)-2-(2-chloro-3- fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (210 mg, 73% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 1.4 Hz, 1H), 8.80 (d, J = 1.4 Hz, 1H), 7.00 - 7.06 (m, 2H), 6.39 (d, J = 7.4 Hz, 1H), 6.18 (d, J = 6.3 Hz, 1H), 3.98 (s, 3H), 2.75 (dtd, J = 7.7, 6.1, 4.4 Hz, 1H), 2.35 (ddd, J = 9.0, 5.9, 3.4 Hz, 1H), 1.08 - 1.14 (m, 1H), 0.97 - 1.01 (m, 1H). [00868] Step B: rac-5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3- azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylic acid. To a solution of methyl rac-5-((1*S,2*R,5*R)-2- (2-chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (200 mg, 0.553 mmol, 1.0 eq) in DCE (10 mL, 0.055 M) was added Me3SnOH (500 mg, 2.76 mmol, 5.0 eq). The reaction was degassed, purged with N2, and stirred at 110°C for 16 h. After cooling to rt, the mixture was filtered and concentrated under reduced pressure to give rac-5-((1*S,2*R,5*R)-2-(2-chloro-3-fluorophenyl)-4-oxo- 3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylic acid (190 mg, 99% yield) as a brown oil, which was used in the next step without purification. MS (ESI): mass calcd. for C16H11ClFN3O3, 347.1; m/z found, 348.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.45 (br s, 1H), 8.73 - 8.95 (m, 1H), 6.99 - 7.10 (m, 2H), 6.33 - 6.48 (m, 1H), 6.18 (br d, J = 5.9 Hz, 1H), 2.69 - 2.79 (m, 1H), 2.33 (br s, 1H) 1.08 (br d, J = 5.6 Hz, 1H), 0.96 (br s, 1H). [00869] Step C: 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. To a solution of rac-5-((1*S,2*R,5*R)- 2-(2-chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylic acid (190 mg, 0.546 mmol, 1.0 eq) and DIPEA (0.3 mL, 1.64 mmol, 3.0 eq) in DCM (5.0 mL, 0.11 M) was added HATU (312 mg, 0.820 mmol, 1.5 eq) and (R,E)-4-(methylsulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (Intermediate 1, 211 mg, 0.656 mmol, 1.2 eq). The reaction was stirred at 25°C for 2 h before being 417 QB\184200.00050\92364964.2 VVID-746PC poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP- HPLC (15-65% ACN in 10 mM aqueous NH4HCO3) to give 5-(rac-(1*S,2*R,5*R)-2-(2-chloro-3- fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide (180 mg, 69% yield) as a light yellow solid. Separation via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 5.15 min) provided the title compound. MS (ESI): mass calcd. for C21H20ClFN4O4S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.68 (s, 1H), 7.23 - 7.31 (m, 1H), 7.10 - 7.18 (m, 1H), 6.67 - 6.84 (m, 3H), 6.09 (d, J = 6.1 Hz, 1H), 4.76 - 4.86 (m, 1H), 2.98 (s, 3H), 2.66 - 2.70 (m, 1H), 2.32 - 2.35 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H), 1.08 (td, J = 8.0, 5.3 Hz, 1H), 0.96 - 1.02 (m, 1H). Example 301: 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000420_0001
[00870] The title compound was prepared via separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chloro-3- fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide (Example 300, Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 6.87 min). MS (ESI): mass calcd. for C21H20ClFN4O4S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 1.4 Hz, 1H), 9.02 (d, J = 8.6 Hz, 1H), 8.68 (d, J = 1.3 Hz, 1H), 7.22 - 7.32 (m, 1H), 7.14 (td, J = 8.0, 5.6 Hz, 1H), 6.66 - 6.91 (m, 3H), 6.09 (d, J = 6.0 Hz, 1H), 4.75 - 4.88 (m, 1H), 2.99 (s, 3H), 2.62 - 2.72 (m, 1H), 2.34 (ddd, J = 8.8, 5.9, 3.3 Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.08 (br dd, J = 8.2, 3.2 Hz, 1H), 0.95 - 1.03 (m, 1H). Example 302: 4-((*R)-2-(2-Chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide.
Figure imgf000420_0002
418 QB\184200.00050\92364964.2 VVID-746PC [00871] The title compound was prepared in a manner analogous to Example 1 using methyl 4-bromo-2- fluorobenzoate instead of methyl 4-bromobenzoate, 5-(2-chlorophenyl)-1-methylpiperazin-2-one (Intermediate 121) instead of (S)-2-(2-chlorophenyl)pyrrolidine, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 4-(2-(2-chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 10.2 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H25ClFN3O4S, 493.1; m/z found, 494.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 7.9, 2.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.49 (t, J = 8.7 Hz, 1H), 7.35 (td, J = 7.6, 1.3 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.04 - 6.96 (m, 1H), 6.82 - 6.73 (m, 1H), 6.71 - 6.63 (m, 1H), 6.41 - 6.31 (m, 2H), 5.22 (br s, 1H), 4.83 - 4.70 (m, 1H), 4.32 - 4.19 (m, 2H), 4.14 (dd, J = 13.6, 4.0 Hz, 1H), 3.54 (dd, J = 13.6, 2.9 Hz, 1H), 2.99 (s, 3H), 2.70 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H). Example 303: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-3- (trifluoromethyl)picolinamide.
Figure imgf000421_0001
[00872] The title compound was prepared in a manner analogous to Example 1 using methyl 5-bromo-3- (trifluoromethyl)picolinate instead of methyl 4-bromobenzoate and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C22H23ClF3N3O3S, 501.1; m/z found, 502.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.55 (m, 2H), 7.37 (dd, J = 7.9, 1.3 Hz, 1H), 7.18 – 7.00 (m, 3H), 6.89 – 6.76 (m, 2H), 6.39 (dd, J = 15.1, 1.7 Hz, 1H), 5.21 – 5.10 (m, 1H), 4.91 – 4.77 (m, 1H), 3.83 – 3.70 (m, 1H), 3.56 – 3.45 (m, 1H), 2.83 (s, 3H), 2.54 – 2.39 (m, 1H), 2.15 – 1.95 (m, 3H), 1.31 (d, J = 7.1 Hz, 3H). Example 304: 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000421_0002
[00873] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 28) instead of (S)-2-(2- 419 QB\184200.00050\92364964.2 VVID-746PC chlorophenyl)pyrrolidine, methyl 5-bromo-3-fluoropicolinate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.34 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H22F3N3O3S, 465.1; m/z found, 466.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.36 (q, J = 8.3 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.82 - 6.72 (m, 3H), 6.71 - 6.60 (m, 1H), 5.33 (d, J = 5.1 Hz, 1H), 4.82 - 4.67 (m, 1H), 3.98 (d, J = 9.8 Hz, 1H), 3.62 (dd, J = 9.7, 5.1 Hz, 1H), 2.99 (s, 3H), 2.30 - 2.20 (m, 1H), 2.02 - 1.91 (m, 1H), 1.27 (d, J = 7.1 Hz, 3H), 0.64 (td, J = 7.8, 5.1 Hz, 1H), 0.30 (q, J = 4.4 Hz, 1H). Example 305: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000422_0001
[00874] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 30) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-2-(2-chloro-3- fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% EtOH/CO2 with 0.1% NH4OH; Rt = 5.20 min, first eluting product) provided the title compound. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C21H20ClF3N4O3S, 500.1; m/z found, 501.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 8.5 Hz, 1H), 7.93 (s, 2H), 7.45 - 7.35 (m, 1H), 7.29 (td, J = 8.0, 5.6 Hz, 1H), 6.95 - 6.84 (m, 1H), 6.83 - 6.74 (m, 1H), 6.73 - 6.63 (m, 1H), 5.61 (dd, J = 5.8, 2.4 Hz, 1H), 4.84 - 4.69 (m, 1H), 4.36 (d, J = 10.1 Hz, 1H), 3.98 - 3.87 (m, 1H), 3.29 - 3.21 (m, 1H), 2.98 (s, 3H), 2.92 (td, J = 11.3, 6.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 306: 8-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)imidazo[1,2-a]pyridine-5-carboxamide. 420 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000423_0001
[00875] The title compound was prepared in a manner analogous to Example 1 using methyl 8- bromoimidazo[1,2-a]pyridine-5-carboxylate instead of methyl 4-bromobenzoate and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. MS (ESI): mass calcd. for C23H25ClN4O3S, 472.1; m/z found, 473.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 7.8, 1.3 Hz, 1H), 7.23 – 7.08 (m, 4H), 6.93 (dd, J = 15.1, 4.6 Hz, 1H), 6.54 (dd, J = 15.1, 1.7 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 5.80 (d, J = 8.4 Hz, 1H), 5.41 (dd, J = 7.8, 4.7 Hz, 1H), 5.00 – 4.90 (m, 1H), 4.80 – 4.72 (m, 1H), 4.34 (dt, J = 10.7, 7.1 Hz, 1H), 2.92 (s, 3H), 2.57 (dq, J = 12.3, 7.5 Hz, 1H), 2.19 – 2.03 (m, 2H), 1.97 (ddd, J = 12.4, 10.8, 5.9 Hz, 1H), 1.41 (d, J = 7.1 Hz, 3H). Example 307: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000423_0002
[00876] The title compound was prepared in a manner analogous to Example 1 using methyl 5-bromo-2- pyrimidinecarboxylate instead of methyl 4-bromobenzoate, rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3- fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 91) instead of (S)-2-(2- chlorophenyl)pyrrolidine, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.37 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N4O3S, 496.1; m/z found, 497.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.6 Hz, 1H), 7.87 (s, 2H), 7.43 - 7.27 (m, 2H), 6.90 (d, J = 7.4 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.71 - 6.63 (m, 1H), 5.37 (br d, J = 3.1 Hz, 1H), 4.84 - 4.67 (m, 1H), 4.35 - 4.03 (m, 3H), 3.68 (ddd, J = 7.1, 4.9, 2.4 Hz, 1H), 2.98 (s, 3H), 2.42 - 2.34 (m, 1H), 2.08 (td, J = 7.6, 3.8 Hz, 1H), 1.33 - 1.18 (m, 4H). Example 308: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide. 421 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000424_0001
[00877] The title compound was prepared in a manner analogous to Example 1 using methyl 5-bromo-2- pyrimidinecarboxylate instead of methyl 4-bromobenzoate, rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3- fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 91) instead of (S)-2-(2- chlorophenyl)pyrrolidine, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 10.1 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N4O3S, 496.1; m/z found, 497.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.5 Hz, 1H), 7.87 (s, 2H), 7.43 - 7.26 (m, 2H), 6.90 (d, J = 7.8 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.71 - 6.63 (m, 1H), 5.38 (br d, J = 3.5 Hz, 1H), 4.83 - 4.69 (m, 1H), 4.35 - 4.02 (m, 3H), 3.67 (ddd, J = 7.1, 4.9, 2.3 Hz, 1H), 2.97 (s, 3H), 2.38 (td, J = 7.8, 3.9 Hz, 1H), 2.16 - 2.03 (m, 1H), 1.33 - 1.18 (m, 4H). Example 309: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000424_0002
[00878] The title compound was prepared in a manner analogous to Example 1 using rac- ((1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 50) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 70% MeOH/CO2; Rt = 2.66 min) provided the title compound. MS (ESI): mass calcd. for C22H21ClFN5O3S, 489.1; m/z found, 490.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 8.4 Hz, 1H), 7.89 (s, 2H), 7.55 - 7.21 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.82 - 6.63 (m, 2H), 5.44 (d, J = 4.5 Hz, 1H), 4.82 - 4.67 (m, 1H), 4.26 (d, J = 10.1 Hz, 1H), 3.67 (dd, J = 10.0, 4.6 Hz, 1H), 3.03 (td, J = 7.8, 4.0 Hz, 1H), 2.97 (s, 3H), 2.79 (td, J = 7.7, 3.9 Hz, 1H), 1.88 (t, J = 3.4 Hz, 1H), 1.28 (d, J = 6.9 Hz, 3H). 422 QB\184200.00050\92364964.2 VVID-746PC Example 310: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000425_0001
[00879] The title compound was prepared in a manner analogous to Example 1 using rac- ((1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 50) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 70% MeOH/CO2; Rt = 5.12 min) provided the title compound. MS (ESI): mass calcd. for C22H21ClFN5O3S, 489.1; m/z found, 490.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 8.6 Hz, 1H), 7.89 (s, 2H), 7.51 - 7.28 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.86 - 6.62 (m, 2H), 5.44 (d, J = 4.5 Hz, 1H), 4.76 (dt, J = 6.9, 5.7 Hz, 1H), 4.26 (d, J = 10.1 Hz, 1H), 3.67 (dd, J = 10.1, 4.6 Hz, 1H), 3.03 (td, J = 7.9, 3.9 Hz, 1H), 2.98 (s, 3H), 2.79 (td, J = 7.7, 4.0 Hz, 1H), 1.88 (t, J = 3.6 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 311: N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*S,2*R,5*R)-2-(2,3-difluorophenyl)- 6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide.
Figure imgf000425_0002
[00880] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 103) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A and using (R,E)-4-(cyclopropylsulfonyl)but-3-en-2- amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2-amine in Step C. Separation of N- ((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)-5-(rac-(1*S,2*R,5*R)-2-(2,3-difluorophenyl)-6,6-difluoro- 3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 423 QB\184200.00050\92364964.2 VVID-746PC cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 5.69 min) provided the title compound. MS (ESI): mass calcd. for C23H22F4N4O3S, 510.1; m/z found, 511.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.5 Hz, 1H), 8.05 (s, 2H), 7.45 - 7.34 (m, 1H), 7.18 - 7.03 (m, 1H), 6.85 - 6.56 (m, 3H), 5.66 (br d, J = 4.0 Hz, 1H), 4.93 - 4.70 (m, 1H), 4.30 (br d, J = 10.3 Hz, 1H), 4.05 - 3.86 (m, 1H), 3.28 - 3.15 (m, 1H), 3.01 - 2.83 (m, 1H), 2.70 - 2.53 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.02 - 0.82 (m, 4H). Example 312: N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*R,2*S,5*S)-2-(2,3-difluorophenyl)- 6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide.
Figure imgf000426_0001
[00881] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 103) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A and using (R,E)-4-(cyclopropylsulfonyl)but-3-en-2- amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2-amine in Step C. Separation of N- ((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)-5-(rac-(1*S,2*R,5*R)-2-(2,3-difluorophenyl)-6,6-difluoro- 3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 8.07 min) provided the title compound. MS (ESI): mass calcd. for C23H22F4N4O3S, 510.1; m/z found, 511.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (br d, J = 7.9 Hz, 1H), 8.04 (s, 2H), 7.51 - 7.33 (m, 1H), 7.20 - 6.99 (m, 1H), 6.86 - 6.57 (m, 3H), 5.83 - 5.52 (m, 1H), 4.90 - 4.63 (m, 1H), 4.41 - 4.22 (m, 1H), 4.02 - 3.85 (m, 1H), 3.26 - 3.16 (m, 1H), 2.96 - 2.85 (m, 1H), 2.64 - 2.58 (m, 1H), 1.30 (br d, J = 6.6 Hz, 3H), 1.07 - 0.91 (m, 4H). Example 313: 5-((1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000426_0002
424 QB\184200.00050\92364964.2 VVID-746PC [00882] The title compound was prepared in a manner analogous to Example 1 using rac- (1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 94) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK- O1 (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 7.57 min) provided the title compound. MS (ESI): mass calcd. for C22H22F4N4O3S, 498.1; m/z found, 499.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 8.5 Hz, 1H), 7.99 (s, 2H), 7.39 (br d, J = 9.5 Hz, 1H), 7.13 (br d, J = 5.3 Hz, 1H), 6.92 - 6.50 (m, 3H), 6.10 - 5.58 (m, 1H), 5.43 (br d, J = 4.5 Hz, 1H), 4.90 - 4.63 (m, 1H), 4.16 (d, J = 9.8 Hz, 1H), 3.67 (br dd, J = 9.4, 4.6 Hz, 1H), 2.98 (s, 3H), 2.53 (br s, 1H), 2.30 (td, J = 7.6, 4.1 Hz, 1H), 1.44 - 1.16 (m, 4H). Example 314: 5-((1*R,2*R,5*S,6*R)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000427_0001
[00883] The title compound was prepared in a manner analogous to Example 1 using rac- (1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 94) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK- O1 (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 15.4 min) provided the title compound. MS (ESI): mass calcd. for C22H22F4N4O3S, 498.1; m/z found, 499.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 8.5 Hz, 1H), 7.99 (s, 2H), 7.58 - 7.27 (m, 1H), 7.13 (br d, J = 5.1 Hz, 1H), 6.95 - 6.62 (m, 3H), 6.04 - 5.55 (m, 1H), 5.42 (br d, J = 4.9 Hz, 1H), 4.77 (br dd, J = 6.7, 1.4 Hz, 1H), 4.16 (d, J = 9.8 Hz, 1H), 3.67 (br dd, J = 9.6, 4.8 Hz, 1H), 2.98 (s, 3H), 2.58 - 2.53 (m, 1H), 2.30 (td, J = 7.7, 4.0 Hz, 1H), 1.47 - 1.22 (m, 4H). Example 315: N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*S,2*R,5*R)-2-(3-fluoro-2- methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide. 425 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000428_0001
[00884] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (3-fluoro-2-methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 105) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A and using (R,E)-4-(cyclopropylsulfonyl)but-3-en-2- amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2-amine in Step C. Separation of N- ((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)-5-(rac-(1*S,2*R,5*R)-2-(3-fluoro-2-methylphenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 3.86 min) provided the title compound. MS (ESI): mass calcd. for C24H25F3N4O3S, 506.2; m/z found, 507.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 8.6 Hz, 1H), 7.93 (s, 2H), 7.09 (br dd, J = 8.1, 4.1 Hz, 2H), 6.87 - 6.58 (m, 3H), 5.62 - 5.40 (m, 1H), 4.90 - 4.63 (m, 1H), 4.34 (br d, J = 10.3 Hz, 1H), 4.01 - 3.76 (m, 1H), 3.30 - 3.21 (m, 1H), 2.86 (dt, J = 11.0, 6.6 Hz, 1H), 2.65 - 2.55 (m, 1H), 2.42 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H), 1.04 - 0.85 (m, 4H). Example 316: N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*R,2*S,5*S)-2-(3-fluoro-2- methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide.
Figure imgf000428_0002
[00885] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (3-fluoro-2-methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 105) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A and using (R,E)-4-(cyclopropylsulfonyl)but-3-en-2- amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2-amine in Step C. Separation of N- ((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)-5-(rac-(1*S,2*R,5*R)-2-(3-fluoro-2-methylphenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% EtOH/CO2; Rt = 5.71 min) provided the title compound. MS (ESI): mass calcd. for C24H25F3N4O3S, 506.2; m/z found, 507.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 426 QB\184200.00050\92364964.2 VVID-746PC 8.5 Hz, 1H), 8.01 - 7.84 (m, 2H), 7.17 - 7.04 (m, 2H), 6.89 - 6.61 (m, 3H), 5.51 (dd, J = 5.6, 2.6 Hz, 1H), 4.85 - 4.69 (m, 1H), 4.34 (d, J = 10.4 Hz, 1H), 3.98 - 3.80 (m, 1H), 3.31 - 3.22 (m, 1H), 2.86 (dt, J = 11.1, 6.4 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.42 (d, J = 1.5 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H), 1.08 - 0.83 (m, 4H). Example 317: 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000429_0001
[00886] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (3-fluoro-2-methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 105) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-6,6-difluoro-2- (3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 5.23 min) provided the title compound. MS (ESI): mass calcd. for C22H23F3N4O3S, 480.1; m/z found, 481.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 8.5 Hz, 1H), 7.92 (s, 2H), 7.16 - 6.95 (m, 2H), 6.86 - 6.74 (m, 2H), 6.72 - 6.62 (m, 1H), 5.51 (dd, J = 5.7, 2.8 Hz, 1H), 4.86 - 4.64 (m, 1H), 4.34 (d, J = 10.4 Hz, 1H), 3.88 (br dd, J = 9.5, 6.0 Hz, 1H), 3.29 - 3.19 (m, 1H), 2.98 (s, 3H), 2.92 - 2.76 (m, 1H), 2.42 (d, J = 1.6 Hz, 3H), 1.28 (d, J = 6.9 Hz, 3H). Example 318: 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000429_0002
[00887] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (3-fluoro-2-methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 105) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-6,6-difluoro-2- (3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- 427 QB\184200.00050\92364964.2 VVID-746PC yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 7.82 min) provided the title compound. MS (ESI): mass calcd. for C22H23F3N4O3S, 480.1; m/z found, 481.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.6 Hz, 1H), 7.92 (s, 2H), 7.21 - 7.03 (m, 2H), 6.89 - 6.60 (m, 3H), 5.51 (br d, J = 2.9 Hz, 1H), 4.76 (br d, J = 6.3 Hz, 1H), 4.34 (d, J = 10.1 Hz, 1H), 3.90 (br d, J = 8.0 Hz, 1H), 3.28 - 3.20 (m, 1H), 2.97 (s, 3H), 2.86 (dt, J = 11.0, 6.4 Hz, 1H), 2.42 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 319: 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000430_0001
[00888] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2-chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 29) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-2-(2- chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 7.49 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C21H21ClF2N4O3S, 482.1; m/z found, 483.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 8.6 Hz, 1H), 7.91 (s, 2H), 7.59 (dd, J = 8.0, 1.0 Hz, 1H), 7.36 (dt, J = 7.7, 1.6 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.10 - 6.99 (m, 1H), 6.82 - 6.75 (m, 1H), 6.72 - 6.63 (m, 1H), 5.59 (dd, J = 5.8, 2.7 Hz, 1H), 4.77 (ddd, J = 13.7, 6.9, 1.3 Hz, 1H), 4.36 (d, J = 10.1 Hz, 1H), 4.01 - 3.84 (m, 1H), 3.22 (ddd, J = 12.2, 10.2, 6.0 Hz, 1H), 2.98 (s, 3H), 2.89 (dt, J = 11.1, 6.4 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 320: 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000430_0002
428 QB\184200.00050\92364964.2 VVID-746PC [00889] The title compound was prepared in a manner analogous to Example 1 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 97) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 6.86 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.2 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.70 (d, J = 8.5 Hz, 1H), 7.84 (s, 2H), 7.40 - 7.33 (m, 1H), 7.32 - 7.25 (m, 1H), 6.84 (br d, J = 7.5 Hz, 1H), 6.81 - 6.74 (m, 1H), 6.70 - 6.64 (m, 1H), 5.31 (d, J = 5.1 Hz, 1H), 4.81 - 4.71 (m, 1H), 4.08 (d, J = 9.6 Hz, 1H), 3.64 (dd, J = 9.5, 5.3 Hz, 1H), 2.98 (s, 3H), 2.07 - 2.01 (m, 1H), 1.78 - 1.72 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.0 Hz, 3H), 0.80 - 0.72 (m, 1H). Example 321: 5-((1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000431_0001
[00890] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 103) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-2-(2,3- difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 4.57 min) provided the title compound. MS (ESI): mass calcd. for C21H20F4N4O3S, 484.1; m/z found, 485.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.5 Hz, 1H), 8.04 (s, 2H), 7.39 (q, J = 8.3 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.84 - 6.73 (m, 2H), 6.72 - 6.65 (m, 1H), 5.66 (br d, J = 4.0 Hz, 1H), 4.83 - 4.72 (m, 1H), 4.30 (d, J = 10.4 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.23 (dt, J = 10.7, 6.2 Hz, 1H), 2.99 (s, 3H), 2.90 (dt, J = 11.3, 6.1 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 322: 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide. 429 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000432_0001
[00891] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 103) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-2-(2,3- difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 6.88 min) provided the title compound. MS (ESI): mass calcd. for C21H20F4N4O3S, 484.1; m/z found, 485.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.6 Hz, 1H), 8.04 (s, 2H), 7.43 - 7.34 (m, 1H), 7.14 - 7.05 (m, 1H), 6.82 - 6.74 (m, 2H), 6.73 - 6.66 (m, 1H), 5.66 (br d, J = 4.3 Hz, 1H), 4.82 - 4.72 (m, 1H), 4.30 (d, J = 10.4 Hz, 1H), 3.96 - 3.85 (m, 1H), 3.23 (dt, J = 10.6, 6.1 Hz, 1H), 2.98 (s, 3H), 2.95 - 2.86 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 323: 5-((1*S,2*S,5*R)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000432_0002
[00892] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2,3-difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane (Intermediate 45) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2,3- difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IM (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 7.02 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H26F2N4O3S, 476.2; m/z found, 477.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 8.5 Hz, 1H), 8.01 (s, 2H), 7.40 - 7.25 (m, 1H), 7.10 - 6.98 (m, 1H), 6.87 - 6.59 (m, 3H), 5.33 (br d, J = 5.8 Hz, 1H), 4.84 - 4.68 (m, 1H), 3.92 (br d, J = 10.3 Hz, 1H), 3.66 (br dd, J = 10.3, 6.2 Hz, 1H), 2.98 (s, 3H), 2.18 - 2.10 (m, 1H), 1.74 - 1.66 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 0.97 (s, 3H), 0.80 (s, 3H). 430 QB\184200.00050\92364964.2 VVID-746PC Example 324: 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000433_0001
[00893] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2-chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane (Intermediate 46) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro-3- fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 3.44 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O3S, 492.1; m/z found, 493.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.6 Hz, 1H), 7.90 (s, 2H), 7.38 - 7.29 (m, 1H), 7.23 (dt, J = 8.0, 5.7 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.83 - 6.75 (m, 1H), 6.71 - 6.65 (m, 1H), 5.27 (d, J = 5.8 Hz, 1H), 4.84 - 4.71 (m, 1H), 3.99 (d, J = 10.3 Hz, 1H), 3.69 (dd, J = 10.3, 6.2 Hz, 1H), 2.98 (s, 3H), 2.28 (dd, J = 8.0, 5.9 Hz, 1H), 1.77 - 1.69 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.96 (s, 3H), 0.89 (s, 3H). Example 325: 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000433_0002
[00894] The title compound was prepared in a manner analogous to Example 1 using rac-(1*R,2*S,5*S)-2- (2-chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane (Intermediate 46) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-bromopyrimidine-2-carboxylate instead of methyl 4-bromobenzoate, and RuPhos Pd G4 instead of SPhos Pd G4 in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro-3- fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% 431 QB\184200.00050\92364964.2 VVID-746PC MeOH/CO2; Rt = 5.37 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O3S, 492.1; m/z found, 493.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.5 Hz, 1H), 7.90 (s, 2H), 7.38 - 7.29 (m, 1H), 7.23 (dt, J = 8.0, 5.7 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.82 - 6.74 (m, 1H), 6.73 - 6.65 (m, 1H), 5.27 (d, J = 5.8 Hz, 1H), 4.84 - 4.71 (m, 1H), 3.99 (d, J = 10.3 Hz, 1H), 3.69 (dd, J = 10.3, 6.2 Hz, 1H), 2.98 (s, 3H), 2.28 (dd, J = 8.0, 5.9 Hz, 1H), 1.77 - 1.68 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.96 (s, 3H), 0.88 (s, 3H). Example 326: 7-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)-2H-indazole-4-carboxamide.
Figure imgf000434_0001
[00895] Methyl 7-fluoro-2-methyl-indazole-4-carboxylate (Intermediate 126, 50 mg, 0.240 mmol, 1.0 eq) and (S)-2-(2-chlorophenyl)pyrrolidine (55 mg, 0.288 mmol, 1.2 eq) were taken up in DMSO (1.2 mL, 0.2M). To this was added pyridine (47 µL, 0.600 mmol, 2.5 eq) and the reaction was heated under microwave irradiation to 160 °C for 4 h. After cooling to rt, the reaction was quenched with water and brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (0-50% EtOAc in heptanes) provided methyl (S)-7-(2-(2-chlorophenyl)pyrrolidin-1-yl)-2-methyl-2H-indazole-4-carboxylate (60 mg, 68% yield). MS (ESI): mass calcd. for C20H20ClN3O2, 369.1; m/z found, 370.0 [M+H]+. [00896] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl (S)-7-(2-(2-chlorophenyl)pyrrolidin-1-yl)-2-methyl-2H-indazole-4-carboxylate in Step B. MS (ESI): mass calcd. for C24H27ClN4O3S, 486.1; m/z found, 487.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.37 (dd, J = 7.8, 1.3 Hz, 1H), 7.25 – 7.17 (m, 1H), 7.15 – 7.01 (m, 3H), 6.95 (dd, J = 15.1, 4.5 Hz, 1H), 6.49 (dd, J = 15.1, 1.7 Hz, 1H), 5.96 (d, J = 7.6 Hz, 1H), 5.85 (s, 2H), 4.98 (q, J = 6.7 Hz, 1H), 4.44 (s, 1H), 4.11 (s, 3H), 2.90 (s, 3H), 2.58 – 2.44 (m, 1H), 2.13 – 1.96 (m, 3H), 1.70 (s, 1H), 1.39 (d, J = 7.1 Hz, 3H). Example 327: 5-((3a*S,4*S,6a*R)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 432 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000435_0001
[00897] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- (rac-(3a*S,4*S,6a*R)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrazine-2- carboxylate (Intermediate 129) in Step B. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.47 (m, 2H), 7.83 (br s, 1H), 7.45 - 7.19 (m, 2H), 6.93 (d, J = 6.9 Hz, 1H), 6.86 - 6.74 (m, 1H), 6.72 - 6.62 (m, 1H), 5.44 (d, J = 1.4 Hz, 1H), 4.79 (br dd, J = 6.7, 1.3 Hz, 1H), 4.21 (dd, J = 11.4, 8.8 Hz, 1H), 4.05 (t, J = 8.4 Hz, 1H), 3.93 - 3.70 (m, 4H), 3.21 - 3.07 (m,1H), 2.98 (s, 3H), 2.90 (br d, J = 7.6 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 328: 5-((3a*R,4*R,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000435_0002
[00898] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- (rac-(3a*R,4*R,6a*S)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrazine-2- carboxylate (Intermediate 130) in Step B. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.46 (m, 2H), 7.85 (br s, 1H), 7.48 - 7.17 (m, 2H), 6.92 (d, J = 6.9 Hz, 1H), 6.85 - 6.74 (m, 1H), 6.71 - 6.61 (m, 1H), 5.44 (d, J = 1.0 Hz, 1H), 4.80 (br dd, J = 6.9, 1.5 Hz, 1H), 4.21 (dd, J = 11.3, 8.8 Hz, 1H), 4.05 (t, J = 8.4 Hz, 1H), 3.93 - 3.72 (m, 4H), 3.22 - 3.08 (m, 1H), 2.98 (s, 3H), 2.95 - 2.81 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 329: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 433 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000436_0001
[00899] Methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate (Intermediate 132 as free base, 55 mg, 0.150 mmol, 1.0 eq) was taken up in MeOH (0.73 mL, 0.2M). To this was added (1-ethoxycyclopropoxy)trimethylsilane (44 µL, 0.220 mmol, 1.5 eq) and acetic acid (25 µL, 0.440 mmol, 3.0 eq) and the reaction was stirred at 60 ºC for 16 h. Upon cooling to rt, the mixture was concentrated under reduced pressure to provide methyl 5-((1*S,3a*R,6a*S)- 1-(2-chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2- carboxylate. MS (ESI): mass calcd. for C21H22ClFN4O2, 416.1; m/z found, 417.0 [M+H]+. [00900] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate in Step B. MS (ESI): mass calcd. for C25H29ClFN5O3S, 533.2; m/z found, 534.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 1.4 Hz, 1H), 7.46 – 7.33 (m, 2H), 7.12 – 7.01 (m, 2H), 6.91 (dd, J = 15.1, 4.5 Hz, 1H), 6.76 – 6.70 (m, 1H), 6.44 (dd, J = 15.1, 1.8 Hz, 1H), 5.59 (d, J = 9.6 Hz, 1H), 4.99 – 4.86 (m, 1H), 4.42 (dd, J = 11.5, 9.5 Hz, 1H), 3.60 – 3.42 (m, 2H), 3.16 – 3.03 (m, 1H), 2.92 (s, 3H), 2.80 (dd, J = 9.5, 2.0 Hz, 1H), 2.65 (dd, J = 9.4, 6.5 Hz, 1H), 2.29 (dd, J = 10.2, 7.5 Hz, 1H), 2.10 (dd, J = 10.2, 3.3 Hz, 1H), 1.38 (d, J = 7.2 Hz, 4H), 0.35 – 0.25 (m, 1H), 0.24 – 0.12 (m, 2H), -0.20 – -0.30 (m, 1H). Example 330: 5-(2-(2-Chlorophenyl)-4-cyclopropylpiperazin-1-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide.
Figure imgf000436_0002
[00901] The title compound was prepared in a manner analogous to Example 329 using methyl 5-(2-(2- chlorophenyl)piperazin-1-yl)-3-fluoropicolinate (Intermediate 133) in the first step. MS (ESI): mass calcd. for C24H28ClFN4O3S, 506.2; m/z found, 507.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.4 Hz, 1H), 7.64 (dd, J = 8.5, 3.3 Hz, 1H), 7.39 (ddd, J = 7.9, 3.1, 1.4 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (tt, J = 7.8, 1.9 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.90 (ddd, J = 15.1, 4.6, 1.9 Hz, 1H), 6.79 (dd, J = 14.1, 6.2 Hz, 1H), 6.47 (ddd, J = 15.1, 1.8, 1.1 Hz, 1H), 5.12 (s, 1H), 4.90 (tt, J = 7.1, 3.5 Hz, 1H), 3.77 – 3.65 (m, 1H), 434 QB\184200.00050\92364964.2 VVID-746PC 3.60 – 3.44 (m, 1H), 3.27 – 2.97 (m, 2H), 2.91 (s, 3H), 2.89 - 2.84 (m, 1H), 1.90 - 1.60 (m, 4H), 1.42 – 1.34 (m, 3H), 0.60 – 0.46 (m, 2H). Example 331: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000437_0001
[00902] The title compound was prepared in a manner analogous to Example 329 using methyl 5-(2-(2- chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (Intermediate 134) in the first step. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 6.08 min) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O3S, 507.2; m/z found, 508.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.56 (m, 2H), 8.17 (d, J = 1.1 Hz, 1H), 7.32 - 7.24 (m, 3H), 6.85 - 6.75 (m, 1H), 6.73 - 6.62 (m, 1H), 5.82 (br d, J = 2.9 Hz, 1H), 4.85 - 4.75 (m, 1H), 4.30 (br d, J = 12.1 Hz, 1H), 3.55 - 3.44 (m, 1H), 3.23 (br d, J = 12.3 Hz, 1H), 3.10 (br d, J = 11.0 Hz, 1H), 2.98 (s, 3H), 2.88 (dd, J = 12.0, 5.0 Hz, 1H), 2.55 (br d, J = 3.8 Hz, 1H), 1.70 (tt, J = 6.4, 3.4 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H), 0.50 - 0.33 (m, 3H), 0.07 (br dd, J = 8.6, 3.3 Hz, 1H). Example 332: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000437_0002
[00903] The title compound was prepared in a manner analogous to Example 329 using methyl 5-(2-(2- chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (Intermediate 134) in the first step. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 8.85 min) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O3S, 507.2; m/z found, 508.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.56 (m, 2H), 8.15 (d, J = 1.1 Hz, 1H), 7.33 - 7.22 (m, 3H), 6.83 - 6.75 (m, 1H), 6.73 - 6.65 (m, 1H), 5.81 (br d, J = 3.1 435 QB\184200.00050\92364964.2 VVID-746PC Hz, 1H), 4.87 - 4.72 (m, 1H), 4.31 (br d, J = 12.5 Hz, 1H), 3.55 - 3.42 (m, 1H), 3.22 (br d, J = 12.0 Hz, 1H), 3.11 (br d, J = 11.1 Hz, 1H), 2.98 (s, 3H), 2.88 (dd, J = 12.0, 5.0 Hz, 1H), 2.56 - 2.52 (m, 1H), 1.70 (tt, J = 6.4, 3.4 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H), 0.50 - 0.32 (m, 3H), 0.13 - 0.01 (m, 1H). Example 333: 5-((1*S,3a*S,6a*S)-5-Acetyl-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000438_0001
[00904] Methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate hydrochloride (Intermediate 132, 99 mg, 0.240 mmol, 1.0 eq) was taken up in DCM (2.6 mL, 0.1M). To this was added TEA (104 µL, 0.720 mmol, 3.0 eq) and the mixture was stirred for 5 min. Acetyl chloride (20 µL, 0.290 mmol, 1.2 eq) was added and the reaction was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to provide methyl 5-((1*S,3a*S,6a*S)-5-acetyl-1-(2- chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate. MS (ESI): mass calcd. for C20H20ClFN4O3, 418.1; m/z found, 419.0 [M+H]+. [00905] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- ((1*S,3a*S,6a*S)-5-acetyl-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine- 2-carboxylate in Step B. MS (ESI): mass calcd. for C24H27ClFN5O4S, 535.1; m/z found, 536.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.82 (dd, J = 9.2, 1.4 Hz, 1H), 7.53 – 7.31 (m, 2H), 7.23 – 7.05 (m, 2H), 6.95 – 6.72 (m, 2H), 6.44 (dd, J = 15.1, 1.7 Hz, 1H), 5.57 (dd, J = 14.4, 8.0 Hz, 1H), 4.98 – 4.86 (m, 1H), 4.48 – 4.16 (m, 1H), 3.91 – 3.62 (m, 3H), 3.62 – 3.49 (m, 1H), 3.47 – 3.32 (m, 1H), 3.29 – 3.16 (m, 1H), 3.17 – 3.05 (m, 1H), 2.91 (s, 3H), 2.00 – 1.64 (m, 3H), 1.39 (dd, J = 7.1, 1.8 Hz, 3H). Example 334: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2- difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000438_0002
436 QB\184200.00050\92364964.2 VVID-746PC [00906] Methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate hydrochloride (Intermediate 132, 55 mg, 0.130 mmol, 1.0 eq) was taken up in DCM (1.4 mL, 0.1M). To this was added TEA (49 µL, 0.400 mmol, 3.0 eq) and 2,2-difluoroethyl 1,1,1- trifluoromethanesulfonate (21 µL, 0.160 mmol, 1.2 eq) and the reaction was stirred at 40 ºC for 3 h. Upon cooling to rt, the mixture was quenched with water and extracted with 20% iPrOH in CHCl3. The combined organic layers were concentrated under reduced pressure to provide methyl 5-((1*S,3a*R,6a*S)-1-(2- chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2- carboxylate. MS (ESI): mass calcd. for C20H20ClF3N4O2, 440.1; m/z found, 441.0 [M+H]+. [00907] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate in Step B. MS (ESI): mass calcd. for C24H27ClF3N5O3S, 557.1; m/z found, 558.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 1.4 Hz, 1H), 7.43 – 7.29 (m, 2H), 7.10 – 6.95 (m, 2H), 6.84 (dd, J = 15.1, 4.5 Hz, 1H), 6.74 (dt, J = 7.0, 1.2 Hz, 1H), 6.37 (dd, J = 15.1, 1.8 Hz, 1H), 5.58 – 5.47 (m, 1H), 5.31 (dt, J = 56.1, 4.4 Hz, 1H), 4.92 – 4.78 (m, 1H), 4.38 (dd, J = 11.5, 9.5 Hz, 1H), 3.58 (dd, J = 11.5, 7.1 Hz, 1H), 3.53 – 3.40 (m, 1H), 3.07 (p, J = 8.3 Hz, 1H), 2.89 – 2.39 (m, 7H), 2.21 – 2.04 (m, 2H), 1.31 (d, J = 7.1 Hz, 3H). Example 335: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2- methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000439_0001
[00908] Methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate hydrochloride (Intermediate 132, 90 mg, 0.220 mmol, 1.0 eq) was taken up in ACN (1.2 mL, 0.2M). To this was added potassium carbonate (90 mg, 0.650 mmol, 3.0 eq) and the mixture was stirred for 5 min at rt. 2-Bromoethyl methyl ether (25 µL, 0.260 mmol, 1.2 eq) was added and the reaction was stirred at 80 ºC for 16 h. After cooling to rt, the mixture was concentrated then quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via RP-HPLC (20-80% ACN in 0.1% aq. HCOOH) provided methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2- methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate (76 mg, 80 % yield). MS (ESI): mass calcd.for C21H24ClFN4O3, 434.1; m/z found, 435.0 [M+H]+. 437 QB\184200.00050\92364964.2 VVID-746PC [00909] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2-methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate in Step B. MS (ESI): mass calcd. for C25H31ClFN5O4S, 551.2; m/z found, 552.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 1.4 Hz, 1H), 7.50 – 7.33 (m, 2H), 7.15 – 7.00 (m, 2H), 6.90 (dd, J = 15.1, 4.5 Hz, 1H), 6.85 – 6.77 (m, 1H), 6.44 (dd, J = 15.1, 1.8 Hz, 1H), 5.59 (d, J = 9.4 Hz, 1H), 4.98 – 4.84 (m, 1H), 4.41 (dd, J = 11.4, 9.5 Hz, 1H), 3.69 – 3.48 (m, 2H), 3.31 – 3.05 (m, 6H), 2.90 (s, 3H), 2.74 – 2.50 (m, 3H), 2.40 – 2.29 (m, 1H), 2.17 (dd, J = 10.0, 7.6 Hz, 1H), 2.10 – 1.99 (m, 1H), 1.38 (d, J = 7.1 Hz, 3H). Example 336: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000440_0001
[00910] The title compound was prepared in a manner analogous to Example 335 using methyl 5-(2-(2- chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (Intermediate 134) instead of Intermediate 132 and iodomethane instead of 2-bromoethyl methyl ether in Step A. Separation of 5-(2-(2-chloro-3- fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 5.57 min) provided the title compound. MS (ESI): mass calcd. for C21H25ClFN5O3S, 481.1; m/z found, 482.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.54 (m, 2H), 8.14 (d, J = 0.9 Hz, 1H), 7.39 - 7.23 (m, 3H), 6.87 - 6.74 (m, 1H), 6.72 - 6.64 (m, 1H), 5.81 (br d, J = 3.8 Hz, 1H), 4.88 - 4.72 (m, 1H), 4.30 (br d, J = 11.7 Hz, 1H), 3.69 - 3.55 (m, 1H), 3.08 (br d, J = 11.9 Hz, 1H), 2.98 (s, 4H), 2.54 (dd, J = 12.1, 5.1 Hz, 1H), 2.20 (s, 4H), 1.30 (d, J = 7.0 Hz, 3H). Example 337: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000440_0002
438 QB\184200.00050\92364964.2 VVID-746PC [00911] The title compound was prepared in a manner analogous to Example 335 using methyl 5-(2-(2- chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (Intermediate 134) instead of Intermediate 132 and iodomethane instead of 2-bromoethyl methyl ether in Step A. Separation of 5-(2-(2-chloro-3- fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 8.10 min) provided the title compound. MS (ESI): mass calcd. for C21H25ClFN5O3S, 481.1; m/z found, 482.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.57 (m, 2H), 8.12 (d, J = 1.3 Hz, 1H), 7.40 - 7.23 (m, 3H), 6.83 - 6.74 (m, 1H), 6.72 - 6.63 (m, 1H), 5.80 (br d, J = 3.8 Hz, 1H), 4.79 (dt, J = 7.2, 6.0 Hz, 1H), 4.31 (br d, J = 12.2 Hz, 1H), 3.67 - 3.53 (m, 1H), 3.08 (br d, J = 12.0 Hz, 1H), 2.98 (s, 4H), 2.55 (dd, J = 12.1, 5.1 Hz, 1H), 2.24 - 2.13 (m, 4H), 1.30 (d, J = 7.0 Hz, 3H). Example 338: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000441_0001
[00912] Methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate hydrochloride (Intermediate 132, 75 mg, 0.181 mmol, 1.0 eq) and formaldehyde (67 µL, 0.907 mmol, 5.0 eq) were taken up in MeOH (0.9 mL, 0.2M). To this was added sodium triacetoxyborohydride (121 mg, 0.544 mmol, 3.0 eq) and the reaction was stirred at rt for 1.5 h. The reaction was quenched with sat. aq. NaHCO3 and extracted with 20% iPrOH in CHCl3. The combined organic extracts were concentrated under reduced pressure to provide methyl 5-((1*S,3a*R,6a*S)-1-(2-chloro-3- fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxylate, which was carried on without purification. MS (ESI): mass calcd. for C19H20ClFN4O2, 390.1; m/z found, 391.0 [M+H]+. [00913] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- ((1*S,3a*R,6a*S)-1-(2-chloro-3-fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrazine-2-carboxylate in Step B. MS (ESI): mass calcd. for C23H27ClFN5O3S, 507.2; m/z found, 508.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.5 Hz, 1H), 8.51 (s, 1H), 7.75 (br s, 1H), 7.32 - 7.17 (m, 2H), 6.84 (d, J = 7.5 Hz, 1H), 6.82 - 6.75 (m, 1H), 6.70 - 6.63 (m, 1H), 5.65 (d, J = 9.5 Hz, 1H), 4.85 - 4.73 (m, 1H), 4.33 (t, J = 10.3 Hz, 1H), 3.60 (dd, J = 10.9, 7.8 Hz, 1H), 3.48 (dq, J = 9.0, 3.8 Hz, 1H), 3.19 - 3.08 (m, 1H), 2.98 (s, 3H), 2.63 (br d, J = 8.5 Hz, 1H), 2.37 (dd, J = 9.0, 6.4 Hz, 1H), 2.02 (s, 4H), 1.85 (dd, J = 9.6, 3.6 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). 439 QB\184200.00050\92364964.2 VVID-746PC Example 339: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000442_0001
[00914] The title compound was prepared in a manner analogous to Example 338 using methyl 5-(2-(2- chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (Intermediate 134) instead of Intermediate 132 and oxetan-3-one instead of formaldehyde in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4- (oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 42% MeOH/CO2; Rt = 5.40 min) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O4S, 523.2; m/z found, 524.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.57 (m, 2H), 8.16 (d, J = 1.1 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.36 - 7.28 (m, 2H), 6.84 - 6.76 (m, 1H), 6.72 - 6.64 (m, 1H), 5.84 (br d, J = 3.0 Hz, 1H), 4.87 - 4.74 (m, 1H), 4.54 (td, J = 9.2, 6.6 Hz, 2H), 4.44 (t, J = 6.1 Hz, 1H), 4.34 (br d, J = 11.9 Hz, 1H), 4.19 (t, J = 6.0 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.48 (quin, J = 6.2 Hz, 1H), 3.03 - 2.93 (m, 5H), 2.57 (br dd, J = 12.0, 4.9 Hz, 1H), 2.23 (dt, J = 11.2, 3.8 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 340: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000442_0002
[00915] The title compound was prepared in a manner analogous to Example 338 using methyl 5-(2-(2- chloro-3-fluorophenyl)piperazin-1-yl)pyrazine-2-carboxylate (Intermediate 134) instead of Intermediate 132 and oxetan-3-one instead of formaldehyde in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4- (oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 42% MeOH/CO2; Rt = 6.22 min) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O4S, 523.2; m/z found, 524.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.57 (m, 2H), 8.14 (s, 1H), 7.46 - 7.39 (m, 1H), 7.37 - 7.29 (m, 2H), 6.83 - 6.74 (m, 1H), 6.73 - 6.65 (m, 1H), 5.83 (br d, J = 3.2 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.58 - 4.50 (m, 2H), 4.44 440 QB\184200.00050\92364964.2 VVID-746PC (t, J = 6.1 Hz, 1H), 4.39 - 4.32 (m, 1H), 4.19 (t, J = 6.0 Hz, 1H), 3.70 - 3.58 (m, 1H), 3.48 (quin, J = 6.0 Hz, 1H), 3.03 - 2.94 (m, 5H), 2.57 (br dd, J = 12.1, 5.0 Hz, 1H), 2.28 - 2.17 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). Example 341: tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate.
Figure imgf000443_0001
[00916] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using tert-butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (Intermediate 131) in Step B. MS (ESI): mass calcd. for C27H33ClFN5O5S, 593.2; m/z found, 538.0 [M+2H-Boc]+. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 7.4 Hz, 1H), 7.53 – 7.34 (m, 2H), 7.10 (d, J = 12.3 Hz, 2H), 6.96 – 6.74 (m, 2H), 6.44 (dt, J = 15.1, 2.2 Hz, 1H), 5.52 (d, J = 8.0 Hz, 1H), 4.97 – 4.86 (m, 1H), 4.27 (d, J = 50.9 Hz, 1H), 3.90 – 3.49 (m, 3H), 3.40 (dt, J = 11.6, 4.2 Hz, 1H), 3.30 – 2.95 (m, 3H), 2.90 (d, J = 5.6 Hz, 3H), 1.48 – 1.17 (m, 12H). Example 342: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000443_0002
[00917] tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Example 341, 20 mg, 0.034 mmol, 1.0 eq) was taken up in MeOH (0.17 mL, 0.2M). To this was added hydrochloric acid (42 µL, 0.168 mmol, 5.0 eq, 4N in 1,4-dioxane) and the reaction was heated to 40 °C for 1.5 hours. The mixture was concentrated under reduced pressure to provide the title compound (16 mg, 90% yield) as a yellow solid. MS (ESI): mass calcd. for C22H25ClFN5O3S, 493.1; m/z found, 494.0 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.59 (s, 1H), 8.00 (s, 1H), 7.34 – 7.21 (m, 2H), 7.11 – 7.04 (m, 1H), 6.89 (dd, J = 15.2, 4.9 Hz, 1H), 6.67 (dt, J = 15.3, 1.2 Hz, 1H), 5.89 (d, J = 8.0 Hz, 1H), 4.93 – 4.82 (m, 1H), 4.45 (t, J = 9.9 Hz, 1H), 441 QB\184200.00050\92364964.2 VVID-746PC 4.04 – 3.89 (m, 2H), 3.70 – 3.60 (m, 1H), 3.52 – 3.44 (m, 2H), 3.19 – 3.08 (m, 1H), 2.96 (s, 3H), 2.86 (dd, J = 12.3, 9.4 Hz, 1H), 1.41 (d, J = 7.1 Hz, 3H). Example 343: 5-((1*S,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(dimethylamino)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000444_0001
[00918] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- (rac-(1*S,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3- yl)pyrazine-2-carboxylate (Intermediate 135) in Step B. Separation of 5-(rac-(1*S,2*S,5*S,6*S)-2-(2- chloro-3-fluorophenyl)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 5.23 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O3S, 507.2; m/z found, 508.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.76 (br s, 1H), 7.34 - 7.19 (m, 2H), 6.84 - 6.64 (m, 3H), 5.54 (d, J = 5.8 Hz, 1H), 4.79 (br d, J = 5.9 Hz, 1H), 4.08 - 3.87 (m, 2H), 2.99 (s, 3H), 2.33 (br t, J = 5.9 Hz, 1H), 2.07 (br t, J = 6.1 Hz, 1H), 1.97 (s, 6H), 1.40 - 1.27 (m, 4H). Example 344: 5-((7*S,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000444_0002
[00919] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- (rac-(7*R,9a*S)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2- carboxylate (Intermediate 138) in Step B. Separation of 5-(rac-(7*S,9a*R)-7-(2-chloro-3- fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 6.22 min) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O4S, 523.1; m/z found, 524.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 2H), 8.13 (br s, 1H), 442 QB\184200.00050\92364964.2 VVID-746PC 7.38 - 7.24 (m, 3H), 6.83 - 6.75 (m, 1H), 6.72 - 6.64 (m, 1H), 5.92 - 5.82 (m, 1H), 4.88 - 4.72 (m, 1H), 4.37 - 4.23 (m, 1H), 3.87 (dd, J = 10.8, 2.6 Hz, 1H), 3.80 - 3.73 (m, 1H), 3.51 (br t, J = 10.4 Hz, 1H), 3.25 (t, J = 10.5 Hz, 1H), 3.19 - 3.08 (m, 2H), 2.98 (s, 3H), 2.74 (dd, J = 12.2, 5.0 Hz, 1H), 2.65 (br d, J = 11.5 Hz, 1H), 2.34 (br t, J = 10.3 Hz, 1H), 2.16 (dt, J = 11.6, 3.2 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 345: 5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000445_0001
[00920] The title compound was prepared in a manner analogous to Example 1, Steps B-C, using methyl 5- (rac-(7*R,9a*S)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyrazine-2- carboxylate (Intermediate 138) in Step B. Separation of 5-(rac-(7*S,9a*R)-7-(2-chloro-3- fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 8.94 min) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O4S, 523.1; m/z found, 524.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.59 (m, 2H), 8.11 (br s, 1H), 7.40 - 7.26 (m, 3H), 6.83 - 6.75 (m, 1H), 6.73 - 6.65 (m, 1H), 5.85 (br d, J = 3.1 Hz, 1H), 4.85 - 4.74 (m, 1H), 4.35 - 4.26 (m, 1H), 3.87 (dd, J = 10.9, 2.7 Hz, 1H), 3.76 (br d, J = 10.0 Hz, 1H), 3.51 (br t, J = 10.4 Hz, 1H), 3.25 (s, 1H), 3.15 - 3.08 (m, 2H), 2.98 (s, 3H), 2.74 (dd, J = 12.2, 4.9 Hz, 1H), 2.65 (br d, J = 11.7 Hz, 1H), 2.38 - 2.29 (m, 1H), 2.21 - 2.12 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 346: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-6-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000445_0002
[00921] The title compound was prepared in a manner analogous to Example 144 using methyl 5-chloro-6- methylpyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate in Step A. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.39 – 7.30 (m, 1H), 7.13 (dtd, J = 12.3, 7.3, 1.9 Hz, 2H), 7.04 (dd, J = 7.3, 2.2 Hz, 1H), 6.92 (dd, J = 15.1, 4.4 Hz, 1H), 6.45 (dd, J = 15.2, 1.8 Hz, 1H), 5.72 (dd, J = 7.5, 5.0 Hz, 1H), 443 QB\184200.00050\92364964.2 VVID-746PC 5.03 – 4.82 (m, 1H), 4.10 (dt, J = 10.7, 6.6 Hz, 1H), 3.82 (dt, J = 10.8, 6.8 Hz, 1H), 2.90 (s, 3H), 2.51 (s, 4H), 2.06 – 1.87 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H). Example 347: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000446_0001
[00922] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (Intermediate 65) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 25% EtOH/CO2; Rt = 9.29 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H24FN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.68 (br s, 1H), 7.33 - 7.19 (m, 2H), 6.82 - 6.74 (m, 2H), 6.71 - 6.63 (m, 1H), 5.55 (d, J = 5.4 Hz, 1H), 4.85 - 4.73 (m, 1H), 4.57 - 4.41 (m, 1H), 4.08 (d, J = 10.5 Hz, 1H), 3.90 (dd, J = 10.5, 5.5 Hz, 1H), 3.22 (dd, J = 11.4, 5.6 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.98 (s, 3H), 2.22 (ddd, J = 7.5, 5.3, 3.6 Hz, 1H), 1.94 - 1.87 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.93 (br s, 1H). Example 348: 5-((*R)-4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000446_0002
[00923] The title compound was prepared in a manner analogous to Example 144 using 4-(2-chloro-3- fluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 39) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(4-(2-chloro-3-fluorophenyl)-5- azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 4.0 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 444 QB\184200.00050\92364964.2 VVID-746PC MHz, DMSO-d6) δ 8.60 - 8.48 (m, 2H), 7.90 - 7.53 (m, 1H), 7.36 - 7.28 (m, 2H), 7.16 - 7.07 (m, 1H), 6.83 - 6.75 (m, 1H), 6.70 - 6.62 (m, 1H), 5.16 (s, 1H), 4.86 - 4.70 (m, 1H), 4.17 (br t, J = 8.4 Hz, 1H), 3.83 (td, J = 9.9, 7.4 Hz, 1H), 2.97 (s, 3H), 2.46 - 2.40 (m, 1H), 1.73 (dt, J = 7.4, 5.2 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.94 - 0.86 (m, 1H), 0.77 (dt, J = 9.6, 4.8 Hz, 1H), 0.65 - 0.56 (m, 1H), 0.49 (dt, J = 9.6, 5.6 Hz, 1H). Example 349: 5-((*S)-4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000447_0001
[00924] The title compound was prepared in a manner analogous to Example 144 using 4-(2-chloro-3- fluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 39) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(4-(2-chloro-3-fluorophenyl)-5- azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 5.0 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br d, J = 8.1 Hz, 2H), 7.89 - 7.46 (m, 1H), 7.32 (br dd, J = 7.7, 4.1 Hz, 2H), 7.12 (br t, J = 4.6 Hz, 1H), 6.80 - 6.73 (m, 1H), 6.69 - 6.63 (m, 1H), 5.15 (s, 1H), 4.71 - 4.87 (m, 1H), 4.17 (br t, J = 8.8 Hz, 1H), 3.92 - 3.77 (m, 1H), 2.97 (s, 3H), 2.45 - 2.39 (m, 1H), 1.72 (dt, J = 7.5, 5.8 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.95 - 0.85 (m, 1H), 0.81 - 0.72 (m, 1H), 0.66 - 0.55 (m, 1H), 0.52 - 0.43 (m, 1H). Example 350: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000447_0002
[00925] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 67) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) 445 QB\184200.00050\92364964.2 VVID-746PC via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.92 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.48 (m, 2H), 7.66 (br s, 1H), 7.36 - 7.16 (m, 2H), 6.87 - 6.61 (m, 3H), 5.56 (d, J = 5.4 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.90 (dd, J = 10.6, 5.4 Hz, 1H), 3.24 (dd, J = 10.8, 6.3 Hz, 1H), 3.03 - 2.94 (m, 7H), 2.30 - 2.22 (m, 1H), 1.98 - 1.85 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.03 - 0.94 (m, 1H). Example 351: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000448_0001
[00926] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 67) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 11.0 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.48 (m, 2H), 7.69 (br s, 1H), 7.34 - 7.20 (m, 2H), 6.83 - 6.75 (m, 2H), 6.71 - 6.62 (m, 1H), 5.56 (d, J = 5.3 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.10 (d, J = 10.6 Hz, 1 H), 3.90 (dd, J = 10.5, 5.4 Hz, 1H), 3.24 (dd, J = 10.9, 6.4 Hz, 1H), 3.04 - 2.95 (m, 7H), 2.30 - 2.23 (m, 1H), 1.96 - 1.88 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.99 (br s, 1H). Example 352: (1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide.
Figure imgf000448_0002
[00927] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 446 QB\184200.00050\92364964.2 VVID-746PC (Intermediate 87) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of rac-(1*R,2*R,5*S,6*R)-2-(2-chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 7.17 min) provided the title compound. MS (ESI): mass calcd. for C24H27ClFN5O4S, 535.2; m/z found, 536.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.6 Hz, 1H), 8.52 (s, 1H), 7.73 (br s, 1H), 7.37 - 7.23 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.84 - 6.74 (m, 1H), 6.73 - 6.60 (m, 1H), 5.64 (d, J = 5.0 Hz, 1H), 4.86 - 4.72 (m, 1H), 4.22 (d, J = 10.6 Hz, 1H), 3.95 (dd, J = 10.7, 5.1 Hz, 1H), 2.98 (s, 3H), 2.71 (s, 3H), 2.62 (s, 3H), 2.57 - 2.53 (m, 1H), 2.44 - 2.34 (m, 1H), 1.88 (t, J = 3.3 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 353: (1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide.
Figure imgf000449_0001
[00928] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (Intermediate 87) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of rac-(1*R,2*R,5*S,6*R)-2-(2-chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 10.1 min) provided the title compound. MS (ESI): mass calcd. for C24H27ClFN5O4S, 535.2; m/z found, 536.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.6 Hz, 1H), 8.52 (s, 1H), 7.70 (br s, 1H), 7.39 - 7.22 (m, 2H), 6.95 (br d, J = 7.8 Hz, 1H), 6.84 - 6.74 (m, 1H), 6.72 - 6.62 (m, 1H), 5.64 (d, J = 4.9 Hz, 1H), 4.84 - 4.70 (m, 1H), 4.22 (d, J = 10.8 Hz, 1H), 3.95 (dd, J = 10.6, 5.1 Hz, 1H), 2.98 (s, 3H), 2.71 (s, 3H), 2.62 (s, 3H), 2.58 - 2.53 (m, 1H), 2.43 - 2.36 (m, 1H), 1.88 (t, J = 3.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 354: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. 447 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000450_0001
[00929] The title compound was prepared in a manner analogous to Example 144 using (R,E)-4- (cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (R,E)-4-(methylsulfonyl)but-3-en-2- amine in Step C. MS (ESI): mass calcd. for C22H25ClN4O3S, 460.1; m/z found, 461.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.85 – 8.79 (m, 1H), 7.52 – 7.38 (m, 3H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.15 (td, J = 7.5, 1.4 Hz, 1H), 6.95 (dd, J = 7.7, 1.8 Hz, 1H), 6.84 (dd, J = 15.2, 4.5 Hz, 1H), 6.42 (dd, J = 15.2, 1.7 Hz, 1H), 5.39 (d, J = 7.7 Hz, 1H), 5.00 – 4.89 (m, 1H), 4.05 – 3.95 (m, 1H), 3.85 – 3.74 (m, 1H), 2.60 – 2.47 (m, 1H), 2.32 (tt, J = 7.9, 4.8 Hz, 1H), 2.13 – 2.01 (m, 3H), 1.37 (d, J = 7.1 Hz, 3H), 1.23 – 1.16 (m, 2H), 1.05 – 0.95 (m, 2H). Example 355: N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethoxy)phenyl)pyrrolidin-1- yl)pyrazine-2-carboxamide.
Figure imgf000450_0002
[00930] The title compound was prepared in a manner analogous to Example 144 using 2-(2- (trifluoromethoxy)phenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. MS (ESI): mass calcd. for C21H23F3N4O4S, 484.1; m/z found, 485.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.83 – 8.77 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.34 – 7.27 (m, 2H), 7.21 – 7.13 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.90 (ddd, J = 15.1, 5.5, 4.5 Hz, 1H), 6.44 (ddd, J = 15.1, 5.7, 1.8 Hz, 1H), 5.40 – 5.27 (m, 1H), 4.98 – 4.86 (m, 1H), 4.02 – 3.93 (m, 1H), 3.79 (q, J = 9.0 Hz, 1H), 2.90 (d, J = 4.0 Hz, 3H), 2.60 – 2.45 (m, 1H), 2.14 – 1.99 (m, 3H), 1.38 (dd, J = 7.1, 4.4 Hz, 3H). Example 356: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 448 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000451_0001
[00931] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.1]heptane (Intermediate 59) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 1.37 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br d, J = 8.6 Hz, 2H), 8.19 - 7.52 (m, 1H), 7.34 - 7.18 (m, 2H), 6.98 (br d, J = 7.0 Hz, 1H), 6.83 - 6.72 (m, 1H), 6.71 - 6.61 (m, 1H), 5.67 (br s, 1H), 4.88 - 4.68 (m, 1H), 4.05 (br s, 2H), 2.98 (s, 3H), 2.71 (br t, J = 5.6 Hz, 2H), 2.30 (dt, J = 9.2, 6.0 Hz, 1H), 1.97 (dt, J = 9.7, 6.3 Hz, 1H), 1.61 (br t, J = 8.6 Hz, 1H), 1.54 - 1.43 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 357: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000451_0002
[00932] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chloro-3- fluorophenyl)-3-azabicyclo[3.1.1]heptane (Intermediate 59) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-3- azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 1.55 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br d, J = 8.5 Hz, 2H), 8.21 - 7.50 (m, 1H), 7.36 - 7.19 (m, 2H), 6.99 (br d, J = 7.3 Hz, 1H), 6.85 - 6.73 (m, 1H), 6.71 - 6.62 (m, 1H), 5.67 (br s, 1H), 4.86 - 4.66 (m, 1H), 4.05 (br s, 2H), 2.97 (s, 3H), 2.72 (br t, J = 5.6 Hz, 2H), 2.30 (dt, J = 9.3, 5.9 Hz, 1H), 1.97 (dt, J = 9.8, 6.3 Hz, 1H), 1.61 (br t, J = 8.5 Hz, 1H), 1.45 - 1.54 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). 449 QB\184200.00050\92364964.2 VVID-746PC Example 358: 5-((*S)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000452_0001
[00933] The title compound was prepared in a manner analogous to Example 144 using 6-(2-chloro-3- fluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 108) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2-chloro-3-fluorophenyl)-5- azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 14.7 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.49 (m, 2H), 8.00 - 7.55 (m, 1H), 7.36 - 7.23 (m, 2H), 7.08 (br d, J = 6.8 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.72 - 6.63 (m, 1H), 5.57 (br d, J = 8.0 Hz, 1H), 4.87 - 4.72 (m, 1H), 3.87 (d, J = 10.4 Hz, 1H), 3.72 (d, J = 10.4 Hz, 1H), 2.98 (s, 3H), 2.77 (dd, J = 12.4, 8.4 Hz, 1H), 1.60 (br d, J = 12.5 Hz, 1H), 1.30 (d, J = 6.9 Hz, 3H), 0.74 - 0.64 (m, 2H), 0.63 - 0.54 (m, 1H), 0.27 (br d, J = 7.9 Hz, 1H). Example 359: 5-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000452_0002
[00934] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 117) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.72 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.42 (m, 2H), 7.41 - 7.18 (m, 2H), 6.89 (br d, J = 7.5 Hz, 1H), 6.84 - 6.74 (m, 450 QB\184200.00050\92364964.2 VVID-746PC 1H), 6.72 - 6.60 (m, 1H), 5.55 (br s, 1H), 4.88 - 4.72 (m, 1H), 4.04 (br s, 2H), 3.31 - 3.28 (m, 2H), 3.26 (s, 3H), 2.98 (s, 3H), 1.88 - 1.78 (m, 2H), 1.64 (br s, 1H), 1.30 - 1.23 (m, 3H), 1.15 (br d, J = 2.5 Hz, 1H). Example 360: 5-((1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000453_0001
[00935] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 117) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 12.8 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.44 (m, 2H), 7.38 - 7.17 (m, 2H), 6.90 (br d, J = 6.9 Hz, 1H), 6.83 - 6.73 (m, 1H), 6.71 - 6.62 (m, 1H), 5.54 (br s, 1H), 4.87 - 4.70 (m, 1H), 4.04 (br s, 2H), 3.29 (br s, 2H), 3.26 (s, 3H), 2.97 (s, 3H), 1.87 - 1.79 (m, 2H), 1.68 - 1.60 (m, 1H), 1.30 - 1.23 (m, 3H), 1.19 - 1.10 (m, 1H). Example 361: (1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide.
Figure imgf000453_0002
[00936] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (Intermediate 118) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of rac-(1*R,2*S,5*S,6*R)-2-(2-chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4- (methylsulfonyl)but-3-en-2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 5.36 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C24H27ClFN5O4S, 535.2; m/z found, 536.2 451 QB\184200.00050\92364964.2 VVID-746PC [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.34 (m, 2H), 8.21 - 7.68 (m, 1H), 7.42 - 7.17 (m, 2H), 6.92 (br d, J = 7.3 Hz, 1H), 6.85 - 6.75 (m, 1H), 6.72 - 6.59 (m, 1H), 5.63 (s, 1H), 4.87 - 4.70 (m, 1H), 4.22 - 4.03 (m, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.83 (s, 3H), 2.20 (br d, J = 3.5 Hz, 2H), 2.05 - 1.92 (m, 1H), 1.29 (br d, J = 6.9 Hz, 3H). Example 362: 5-((1*S,2*R,5*R)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000454_0001
[00937] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 106) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% EtOH/CO2; Rt = 4.65 min) provided the title compound. MS (ESI): mass calcd. for C22H25FN4O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.44 (m, 2H), 7.44 (br s, 1H), 7.14 - 6.95 (m, 2H), 6.84 - 6.71 (m, 1H), 6.70 - 6.55 (m, 2H), 5.47 (d, J = 5.1 Hz, 1H), 4.86 - 4.68 (m, 1H), 4.03 (d, J = 11.0 Hz, 1H), 3.87 (dd, J = 11.1, 5.3 Hz, 1H), 2.97 (s, 3H), 2.41 (s, 3H), 2.35 - 2.24 (m, 1H), 2.03 - 1.84 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H), 0.71 - 0.48 (m, 1H), 0.42 - 0.18 (m, 1H). Example 363: 5-((1*R,2*S,5*S)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000454_0002
[00938] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 106) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); 452 QB\184200.00050\92364964.2 VVID-746PC Mobile phase: 35% EtOH/CO2; Rt = 6.42 min) provided the title compound. MS (ESI): mass calcd. for C22H25FN4O3S, 444.2; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.43 (m, 2H), 7.41 (br s, 1H), 7.16 - 6.99 (m, 2H), 6.81 - 6.70 (m, 1H), 6.70 - 6.56 (m, 2H), 5.48 (d, J = 5.1 Hz, 1H), 4.86 - 4.67 (m, 1H), 4.03 (d, J = 11.0 Hz, 1H), 3.87 (dd, J = 11.1, 5.2 Hz, 1H), 2.97 (s, 3H), 2.41 (s, 3H), 2.35 - 2.22 (m, 1H), 2.01 - 1.87 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H), 0.66 - 0.55 (m, 1H), 0.33 (q, J = 4.3 Hz, 1H). Example 364: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide.
Figure imgf000455_0001
[00939] The title compound was prepared in a manner analogous to Example 144 using methyl 5- fluoropyrimidine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate and DMSO instead of 1,4-dioxane in Step A and using (R,E)-4-(cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (R,E)-4-(methylsulfonyl)but-3-en-2-amine in Step C. MS (ESI): mass calcd. for C 22H25ClN4O3S, 460.1; m/z found, 461.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 7.9, 1.3 Hz, 1H), 7.21 (td, J = 7.7, 1.7 Hz, 1H), 7.14 (td, J = 7.5, 1.3 Hz, 1H), 6.92 (dd, J = 7.6, 1.7 Hz, 1H), 6.83 (dd, J = 15.2, 4.4 Hz, 1H), 6.43 (dd, J = 15.2, 1.7 Hz, 1H), 5.19 (dd, J = 8.3, 2.3 Hz, 1H), 5.04 – 4.92 (m, 1H), 3.88 – 3.80 (m, 1H), 3.62 – 3.53 (m, 1H), 2.60 – 2.48 (m, 1H), 2.31 (tt, J = 8.0, 4.8 Hz, 1H), 2.19 – 2.01 (m, 3H), 1.39 (d, J = 7.1 Hz, 3H), 1.21 – 1.15 (m, 2H), 1.02 – 0.94 (m, 2H). Example 365: 5-((3a*S,4*R,6a*R)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000455_0002
[00940] The title compound was prepared in a manner analogous to Example 144 using rac- (3a*R,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 41) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (3a*S,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); 453 QB\184200.00050\92364964.2 VVID-746PC Mobile phase: 38% EtOH/CO2 with 0.1% NH4OH; Rt = 4.14 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.6 Hz, 1H), 8.52 (d, J = 0.8 Hz, 1H), 7.75 (br s, 1H), 7.34 - 7.20 (m, 2H), 6.88 (d, J = 7.8 Hz, 1H), 6.82 - 6.75 (m, 1H), 6.72 - 6.61 (m, 1H), 5.67 (d, J = 9.1 Hz, 1H), 4.85 - 4.70 (m, 1H), 4.27 (dd, J = 11.1, 9.1 Hz, 1H), 3.83 - 3.67 (m, 3H), 3.64 - 3.53 (m, 1H), 3.40 (dd, J = 9.6, 7.3 Hz, 1H), 3.29 (td, J = 6.0, 3.3 Hz, 1H), 3.08 (dd, J = 9.5, 3.9 Hz, 1H), 2.98 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 366: 5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000456_0001
[00941] The title compound was prepared in a manner analogous to Example 144 using rac- (3a*R,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 41) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (3a*S,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 38% EtOH/CO2 with 0.1% NH4OH; Rt = 6.13 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.47 (m, 2H), 7.72 (br s, 1H), 7.37 - 7.18 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.82 - 6.75 (m, 1H), 6.71 - 6.65 (m, 1H), 5.66 (d, J = 9.1 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.27 (dd, J = 11.1, 9.1 Hz, 1H), 3.80 - 3.75 (m, 1H), 3.74 - 3.66 (m, 2H), 3.65 - 3.55 (m, 1H), 3.40 (dd, J = 9.4, 7.3 Hz, 1H), 3.28 (td, J = 6.1, 3.1 Hz, 1H), 3.08 (dd, J = 9.5, 3.8 Hz, 1H), 2.98 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 367: 5-((1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000456_0002
[00942] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 103) instead of (S)-2-(2- 454 QB\184200.00050\92364964.2 VVID-746PC chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 5.26 min) provided the title compound. MS (ESI): mass calcd. for C21H20F4N4O3S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 8.6 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 7.90 (s, 1H), 7.32 (q, J = 8.6 Hz, 1H), 7.12 - 6.99 (m, 1H), 6.88 - 6.62 (m, 3H), 5.81 (br d, J = 4.8 Hz, 1H), 4.90 - 4.72 (m, 1H), 4.31 - 4.20 (m, 1H), 4.17 - 4.09 (m, 1H), 3.28 - 3.17 (m, 1H), 2.98 (s, 3H), 2.89 (td, J = 11.0, 6.6 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 368: 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000457_0001
[00943] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 103) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(2,3-difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 7.83 min) provided the title compound. MS (ESI): mass calcd. for C21H20F4N4O3S, 484.1; m/z found, 485.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 1.1 Hz, 1H), 7.87 (s, 1H), 7.33 (q, J = 8.4 Hz, 1H), 7.11 - 6.98 (m, 1H), 6.86 - 6.65 (m, 3H), 5.81 (br d, J = 4.8 Hz, 1H), 4.88 - 4.72 (m, 1H), 4.31 - 4.20 (m, 1H), 4.19 - 4.07 (m, 1H), 3.29 - 3.17 (m, 1H), 2.98 (s, 3H), 2.89 (td, J = 11.1, 6.3 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 369: 5-((1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000457_0002
455 QB\184200.00050\92364964.2 VVID-746PC [00944] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,4*S,5*R)- 4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile (Intermediate 57) instead of (S)-2- (2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,4*S,5*R)-4-(2-chloro-3-fluorophenyl)-1-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 4.88 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H21ClFN5O3S, 489.1; m/z found, 490.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 8.6 Hz, 1H), 8.51 (d, J = 1.1 Hz, 1H), 7.74 (s, 1H), 7.37 - 7.30 (m, 1H), 7.25 (td, J = 8.0, 5.8 Hz, 1H), 6.88 (br d, J = 7.5 Hz, 1H), 6.82 - 6.74 (m, 1H), 6.64 - 6.71 (m, 1H), 5.72 (d, J = 5.0 Hz, 1H), 4.85 - 4.71 (m, 1H), 4.43 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 10.1 Hz, 1H), 3.10 (dt, J = 8.8, 5.3 Hz, 1H), 2.98 (s, 3H), 1.49 (dd, J = 8.6, 5.8 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.18 (t, J = 5.6 Hz, 1H). Example 370: 5-((1*S,2*R,5*R)-2-(2,6-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000458_0001
[00945] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 107) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 6.48 min) provided the title compound. MS (ESI): mass calcd. for C21H22F2N4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br d, J = 8.5 Hz, 1H), 8.44 (s, 1H), 7.80 (s, 1H), 7.46 - 7.27 (m, 1H), 7.22 - 7.11 (m, 1H), 7.00 - 6.84 (m, 1H), 6.83 - 6.74 (m, 1H), 6.72 - 6.57 (m, 1H), 5.61 (br s, 1H), 4.83 - 4.74 (m, 1H), 3.87 (br s, 2H), 2.98 (s, 3H), 2.24 (br d, J = 4.1 Hz, 1H), 2.02 (br s, 1H), 1.29 (d, J = 6.9 Hz, 3H), 0.86 - 0.72 (m, 1H), 0.48 (br d, J = 4.6 Hz, 1H). Example 371: 5-((1*R,2*S,5*S)-2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 456 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000459_0001
[00946] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 107) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 8.89 min) provided the title compound. MS (ESI): mass calcd. for C21H22F2N4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.8 Hz, 1H), 8.45 (s, 1H), 7.78 (s, 1H), 7.39 - 7.28 (m, 1H), 7.24 - 7.08 (m, 1H), 6.99 - 6.86 (m, 1H), 6.83 - 6.63 (m, 2H), 5.62 (d, J = 5.4 Hz, 1H), 4.86 - 4.73 (m, 1H), 3.90 - 3.80 (m, 2H), 2.98 (s, 3H), 2.30 - 2.17 (m, 1H), 2.02 (br s, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.86 - 0.69 (m, 1H), 0.48 (q, J = 4.2 Hz, 1H). Example 372: 5-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000459_0002
[00947] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (Intermediate 119) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 2.43 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.54 (m, 1H), 8.51 - 7.82 (m, 1H), 7.39 - 7.21 (m, 2H), 6.96 - 6.85 (m, 1H), 6.83 - 6.75 (m, 1H), 6.70 - 6.62 (m, 1H), 5.60 - 5.45 (m, 1H), 4.84 - 4.72 (m, 1H), 4.03 (br s, 2H), 3.90 - 3.71 (m, 2H), 3.47 - 3.39 (m, 1H), 3.37 - 3.29 (m, 1H), 3.02 - 2.93 (m, 3H), 1.86 - 1.77 (m, 1H), 1.66 - 1.52 (m, 1H), 1.37 - 1.24 (m, 3H), 1.05 (br s, 1H). 457 QB\184200.00050\92364964.2 VVID-746PC Example 373: 5-((1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000460_0001
[00948] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (Intermediate 119) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*R,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 4.31 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br d, J = 8.0 Hz, 1H), 8.54 - 7.91 (m, 1H), 7.33 (br d, J = 8.0 Hz, 2H), 6.92 (br d, J = 7.1 Hz, 1H), 6.85 - 6.75 (m, 1H), 6.72 - 6.65 (m, 1H), 5.54 (br s, 1H), 4.87 - 4.74 (m, 2H), 4.73 - 4.64 (m, 1H), 4.04 (br s, 2H), 3.49 - 3.41 (m, 1H), 3.39 - 3.32 (m, 1H), 2.99 (s, 3H), 1.89 - 1.78 (m, 1H), 1.62 (br s, 1H), 1.35 - 1.27 (m, 3H), 1.07 (br d, J = 1.0 Hz, 1H). Example 374: 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000460_0002
[00949] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 6,6-difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 104) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-6,6-difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 4.43 min) provided the title compound. MS (ESI): mass calcd. for C21H21F3N4O3S, 466.1; m/z found, 467.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 - 8.49 (m, 2H), 7.79 (s, 1H), 7.35 - 7.20 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.95 - 6.86 (m, 1H), 6.84 - 6.75 (m, 1H), 6.72 - 458 QB\184200.00050\92364964.2 VVID-746PC 6.64 (m, 1H), 5.79 (br d, J = 4.5 Hz, 1H), 4.87 - 4.72 (m, 1H), 4.33 - 4.21 (m, 1H), 4.19 - 4.09 (m, 1H), 3.24 - 3.09 (m, 1H), 2.98 (s, 3H), 2.86 (td, J = 11.1, 6.5 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 375: 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000461_0001
[00950] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 6,6-difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 104) instead of (S)-2-(2- chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-6,6-difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 7.35 min) provided the title compound. MS (ESI): mass calcd. for C21H21F3N4O3S, 466.1; m/z found, 467.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 - 8.52 (m, 2H), 7.76 (s, 1H), 7.36 - 7.22 (m, 2H), 7.07 - 7.01 (m, 1H), 6.95 - 6.86 (m, 1H), 6.82 - 6.75 (m, 1H), 6.72 - 6.65 (m, 1H), 5.83 - 5.76 (m, 1H), 4.79 (td, J = 7.0, 5.8 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.19 - 4.09 (m, 1H), 3.18 (td, J = 10.4, 6.5 Hz, 1H), 2.98 (s, 3H), 2.85 (td, J = 11.1, 6.4 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 376: 5-((*R)-2-(2-Chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000461_0002
[00951] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chlorophenyl)- 1-methylpiperazin-2-one (Intermediate 121) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 7.57 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C21H24ClN5O4S, 477.1; m/z found, 478.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.52 (m, 2H), 7.91 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.38 - 7.22 (m, 2H), 7.11 (d, J = 7.3 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.71 - 6.63 (m, 1H), 5.81 - 5.69 (m, 1H), 4.89 - 4.72 (m, 1H), 4.65 - 459 QB\184200.00050\92364964.2 VVID-746PC 4.48 (m, 2H), 4.12 (dd, J = 13.7, 4.2 Hz, 1H), 3.63 (dd, J = 13.8, 3.4 Hz, 1H), 2.98 (s, 3H), 2.74 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 377: 5-((1S,2S,5R,6S)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000462_0001
[00952] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 90) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5- (rac-(1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2 with 0.1% NH4OH; Rt = 6.31 min, first eluting product) provided the title compound. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C22H23F3N4O3S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.66 - 8.43 (m, 2H), 7.78 (s, 1H), 7.31 (q, J = 8.7 Hz, 1H), 7.11 - 7.02 (m, 1H), 6.84 - 6.73 (m, 2H), 6.73 - 6.63 (m, 1H), 5.56 (br d, J = 4.9 Hz, 1H), 4.89 - 4.70 (m, 1H), 4.39 - 4.01 (m, 3H), 3.96 - 3.84 (m, 1H), 2.98 (s, 3H), 2.33 (br d, J = 1.8 Hz, 1H), 2.14 - 1.98 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.20 (dt, J = 7.1, 3.5 Hz, 1H). Example 378: 5-((1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000462_0002
[00953] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 94) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: 460 QB\184200.00050\92364964.2 VVID-746PC WHELK-O1 (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 10.1 min) provided the title compound. MS (ESI): mass calcd. for C22H22F4N4O3S, 498.1; m/z found, 499.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.7 Hz, 1H), 8.53 (d, J = 1.1 Hz, 1H), 7.78 (s, 1H), 7.33 (q, J = 8.4 Hz, 1H), 7.13 - 7.02 (m, 1H), 6.84 - 6.74 (m, 2H), 6.73 - 6.64 (m, 1H), 5.94 - 5.55 (m, 2H), 4.85 - 4.71 (m, 1H), 4.14 (d, J = 10.7 Hz, 1H), 3.90 (br dd, J = 10.5, 5.1 Hz, 1H), 2.98 (s, 3H), 2.57 - 2.52 (m, 1H), 2.34 - 2.26 (m, 1H), 1.38 - 1.27 (m, 4H). Example 379: 5-((1*R,2*R,5*S,6*R)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000463_0001
[00954] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 94) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-6-(difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 12.0 min) provided the title compound. MS (ESI): mass calcd. for C22H22F4N4O3S, 498.1; m/z found, 499.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 1.0 Hz, 1H), 7.80 (s, 1H), 7.32 (q, J = 8.4 Hz, 1H), 7.12 - 7.03 (m, 1H), 6.79 (dd, J = 15.2, 5.2 Hz, 2H), 6.72 - 6.63 (m, 1H), 5.96 - 5.55 (m, 2H), 4.86 - 4.73 (m, 1H), 4.14 (d, J = 10.5 Hz, 1H), 3.90 (br dd, J = 10.2, 5.1 Hz, 1H), 2.98 (s, 3H), 2.53 (br d, J = 3.9 Hz, 1H), 2.34 - 2.26 (m, 1H), 1.39 - 1.27 (m, 4H). Example 380: 5-((1*S,3*S,5*S)-3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000463_0002
[00955] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-3- fluorophenyl)-2-azabicyclo[3.1.0]hexane (Intermediate 111) instead of (S)-2-(2-chlorophenyl)pyrrolidine 461 QB\184200.00050\92364964.2 VVID-746PC and DMSO instead of 1,4-dioxane in Step A. Separation of methyl 5-(3-(2-chloro-3-fluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazine-2-carboxylate (Step A) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 10.6 min, fourth eluting product) provided the pure diastereomer that was elaborated to the title compound analogous to Example 144, Steps B-C. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.43 (m, 2H), 8.33 - 7.77 (m, 1H), 7.31 - 7.17 (m, 2H), 6.86 - 6.76 (m, 1H), 6.73 - 6.65 (m, 2H), 5.79 (dd, J = 10.8, 3.6 Hz, 1H), 4.86 - 4.74 (m, 1H), 4.24 - 4.14 (m, 1H), 3.12 - 3.04 (m, 1H), 2.99 (s, 3H), 1.95 (dd, J = 13.4, 3.8 Hz, 1H), 1.83 - 1.75 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 1.04 - 0.96 (m, 1H), 0.71 (dt, J = 5.2, 2.6 Hz, 1H). Example 381: 5-((1*S,3*R,5*S)-3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000464_0001
[00956] The title compound was prepared in a manner analogous to Example 144 using 3-(2-chloro-3- fluorophenyl)-2-azabicyclo[3.1.0]hexane (Intermediate 111) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of methyl 5-(3-(2-chloro-3-fluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazine-2-carboxylate (Step A) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 7.77 min, third eluting product) provided the pure diastereomer that was elaborated to the title compound analogous to Example 144, Steps B-C. MS (ESI): mass calcd. for C21H22ClFN4O3S, 464.1; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.6 Hz, 1H), 8.51 (d, J = 1.1 Hz, 1H), 8.18 (br s, 1H), 7.34 - 7.25 (m, 2H), 7.20 - 7.13 (m, 1H), 6.86 - 6.77 (m, 1H), 6.72 - 6.63 (m, 1H), 5.36 (dd, J = 8.8, 4.1 Hz, 1H), 4.87 - 4.74 (m, 1H), 4.00 - 3.87 (m, 1H), 2.99 (s, 3H), 2.67 (dd, J = 13.0, 9.5 Hz, 1H), 2.09 (ddd, J = 13.2, 7.0, 4.3 Hz, 1H), 1.92 - 1.80 (m, 1H), 1.32 (d, J = 7.1 Hz, 3H), 1.08 (td, J = 8.8, 5.1 Hz, 1H), 0.63 (dt, J = 4.8, 2.4 Hz, 1H). Example 382: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 462 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000465_0001
[00957] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3-azabicyclo[3.1.0]hexane (Intermediate 70) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 5.14 min) provided the title compound. MS (ESI): mass calcd. for C23H23[2H3]ClFN4O4S, 511.1; m/z found, 512.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.46 (m, 2H), 7.66 (br s, 1H), 7.37 - 7.16 (m, 2H), 6.84 - 6.73 (m, 2H), 6.71 - 6.60 (m, 1H), 5.56 (d, J = 5.4 Hz, 1H), 4.83 - 4.69 (m, 1H), 4.09 (d, J = 10.6 Hz, 1H), 3.89 (dd, J = 10.5, 5.4 Hz, 1H), 3.23 (dd, J = 10.9, 6.4 Hz, 1H), 3.03 - 2.94 (m, 4H), 2.31 - 2.22 (m, 1H), 1.96 - 1.87 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.98 (td, J = 6.3, 3.2 Hz, 1H). Example 383: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000465_0002
[00958] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3-azabicyclo[3.1.0]hexane (Intermediate 70) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.95 min) provided the title compound. MS (ESI): mass calcd. for C23H23[2H3]ClFN4O4S, 511.1; m/z found, 512.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.39 (m, 2H), 7.69 (br s, 1H), 7.35 - 7.18 (m, 2H), 6.84 - 6.74 (m, 2H), 6.71 - 6.58 (m, 1H), 5.56 (d, J = 5.3 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.10 (d, J = 10.5 Hz, 1H), 3.89 (dd, J = 10.6, 5.4 Hz, 1H), 3.23 (dd, J = 10.9, 6.3 Hz, 1H), 3.03 - 2.94 (m, 4H), 2.26 (ddd, J = 7.5, 5.3, 3.6 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.03 - 0.92 (m, 1H). 463 QB\184200.00050\92364964.2 VVID-746PC Example 384: 5-((*S)-2-(2-Chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000466_0001
[00959] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chlorophenyl)- 2-methylpyrrolidine (Intermediate 124) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5- fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4- dioxane in Step A. Separation of 5-(2-(2-chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 7.17 min) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.18 (m, 2H), 7.95 - 7.08 (m, 5H), 6.82 - 6.59 (m, 2H), 4.83 - 4.66 (m, 1H), 4.01 - 3.71 (m, 2H), 2.97 (s, 3H), 2.60 - 2.51 (m, 1H), 2.28 - 2.16 (m, 1H), 2.15 - 2.01 (m, 2H), 1.94 (s, 3H), 1.27 (br d, J = 6.9 Hz, 3H). Example 385: 5-((*R)-2-(2-Chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide.
Figure imgf000466_0002
[00960] The title compound was prepared in a manner analogous to Example 144 using 2-(2-chlorophenyl)- 2-methylpyrrolidine (Intermediate 124) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5- fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4- dioxane in Step A. Separation of 5-(2-(2-chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 8.53 min) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 - 8.10 (m, 2H), 7.95 - 7.10 (m, 5H), 6.81 - 6.72 (m, 1H), 6.69 - 6.61 (m, 1H), 4.83 - 4.69 (m, 1H), 3.97 - 3.72 (m, 2H), 2.97 (s, 3H), 2.57 - 2.51 (m, 1H), 2.27 - 2.15 (m, 1H), 2.13 - 1.99 (m, 2H), 1.94 (br s, 3H), 1.33 - 1.18 (m, 3H). 464 QB\184200.00050\92364964.2 VVID-746PC Example 386: 5-((*R)-6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000467_0001
[00961] The title compound was prepared in a manner analogous to Example 144 using 6-(2,3- difluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 109) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2,3-difluorophenyl)-5- azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 3.02 min) provided the title compound. MS (ESI): mass calcd. for C22H24F2N4O3S, 462.1; m/z found, 463.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.49 (m, 2H), 7.82 (br s, 1H), 7.30 (q, J = 8.4 Hz, 1H), 7.13 - 7.05 (m, 1H), 7.04 - 6.97 (m, 1H), 6.84 - 6.76 (m, 1H), 6.71 - 6.64 (m, 1H), 5.58 (br d, J = 7.5 Hz, 1H), 4.86 - 4.74 (m, 1H), 3.83 (d, J = 10.5 Hz, 1H), 3.68 (d, J = 10.5 Hz, 1H), 2.98 (s, 3H), 2.73 (dd, J = 12.4, 8.3 Hz, 1H), 1.67 (br d, J = 12.1 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.74 - 0.56 (m, 3H), 0.37 - 0.28 (m, 1H). Example 387: 5-((*S)-6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000467_0002
[00962] The title compound was prepared in a manner analogous to Example 144 using 6-(2,3- difluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 109) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2,3-difluorophenyl)-5- azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 5.17 min) provided the title compound. MS (ESI): mass calcd. for C22H24F2N4O3S, 462.1; m/z found, 463.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.46 (m, 2H), 7.81 (br s, 1H), 7.36 - 7.26 (m, 1H), 7.14 - 7.06 (m, 1H), 7.04 - 6.96 (m, 1H), 6.83 - 6.75 (m, 1H), 6.73 - 6.64 (m, 1H), 5.58 (br d, J = 7.4 Hz, 1H), 4.79 (qd, J = 13.2, 6.6 Hz, 465 QB\184200.00050\92364964.2 VVID-746PC 1H), 3.83 (d, J = 10.5 Hz, 1H), 3.68 (d, J = 10.5 Hz, 1H), 2.98 (s, 3H), 2.73 (br dd, J = 12.2, 8.3 Hz, 1H), 1.67 (br d, J = 12.1 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.73 - 0.56 (m, 3H), 0.38 - 0.26 (m, 1H). Example 388: 5-((3a*S,4*R,6a*R)-4-(2,3-Difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000468_0001
[00963] The title compound was prepared in a manner analogous to Example 144 using rac- (3a*R,4*S,6a*S)-4-(2,3-difluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 43) instead of (S)- 2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (3a*S,4*R,6a*R)-4-(2,3-difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% EtOH/CO2 with 0.1% NH4OH; Rt = 4.48 min) provided the title compound. MS (ESI): mass calcd. for C22H24F2N4O4S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.43 (m, 2H), 7.83 (s, 1H), 7.44 - 7.23 (m, 1H), 7.15 - 7.02 (m, 1H), 6.88 - 6.60 (m, 3H), 5.67 (d, J = 9.0 Hz, 1H), 4.87 - 4.70 (m, 1H), 4.36 - 4.17 (m, 1H), 3.86 - 3.61 (m, 3H), 3.58 - 3.39 (m, 2H), 3.29 - 3.24 (m, 1H), 3.20 (br dd, J = 9.6, 3.6 Hz, 1H), 2.98 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 389: 5-((3a*R,4*S,6a*S)-4-(2,3-Difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000468_0002
[00964] The title compound was prepared in a manner analogous to Example 144 using rac- (3a*R,4*S,6a*S)-4-(2,3-difluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 43) instead of (S)- 2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (3a*S,4*R,6a*R)-4-(2,3-difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% EtOH/CO2 with 0.1% NH4OH; Rt = 6.57 min) provided the title compound. MS (ESI): 466 QB\184200.00050\92364964.2 VVID-746PC mass calcd. for C22H24F2N4O4S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.47 (m, 2H), 7.80 (s, 1H), 7.31 (q, J = 8.4 Hz, 1H), 7.08 (br d, J = 5.1 Hz, 1H), 6.94 - 6.63 (m, 3H), 5.67 (d, J = 9.0 Hz, 1H), 4.78 (dt, J = 7.0, 5.6 Hz, 1H), 4.24 (dd, J = 11.2, 9.1 Hz, 1H), 3.87 - 3.61 (m, 3H), 3.58 - 3.40 (m, 2H), 3.30 - 3.15 (m, 2H), 2.98 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 390: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000469_0001
[00965] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 79) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 3.40 min) provided the title compound. MS (ESI): mass calcd. for C25H28ClFN4O4S, 534.2; m/z found, 535.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.66 (br s, 1H), 7.34 - 7.20 (m, 2H), 6.83 - 6.74 (m, 2H), 6.71 - 6.64 (m, 1H), 5.56 (d, J = 5.4 Hz, 1H), 4.77 (td, J = 6.9, 5.8 Hz, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.89 (dd, J = 10.6, 5.4 Hz, 1H), 3.30 (dd, J = 11.2, 6.6 Hz, 1H), 3.08 (dd, J = 11.1, 7.1 Hz, 1H), 2.98 (s, 3H), 2.95 - 2.89 (m, 1H), 2.31 - 2.24 (m, 1H), 1.95 - 1.88 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.05 - 0.97 (m, 1H), 0.28 - 0.22 (m, 4H). Example 391: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000469_0002
[00966] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexane 467 QB\184200.00050\92364964.2 VVID-746PC (Intermediate 79) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% iPrOH/CO2; Rt = 6.80 min) provided the title compound. MS (ESI): mass calcd. for C25H28ClFN4O4S, 534.2; m/z found, 535.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.69 (br s, 1H), 7.34 - 7.19 (m, 2H), 6.85 - 6.74 (m, 2H), 6.71 - 6.62 (m, 1H), 5.56 (d, J = 5.3 Hz, 1H), 4.78 (td, J = 6.9, 5.6 Hz, 1H), 4.10 (d, J = 10.4 Hz, 1H), 3.89 (dd, J = 10.6, 5.44 Hz, 1H), 3.30 (dd, J = 11.1, 6.6 Hz, 1H), 3.08 (dd, J = 11.1, 7.1 Hz, 1H), 2.98 (s, 3H), 2.96 - 2.88 (m, 1H), 2.30 - 2.23 (m, 1H), 1.96 - 1.89 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.06 - 0.96 (m, 1H), 0.29 - 0.21 (m, 4H). Example 392: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrimidine-2-carboxamide.
Figure imgf000470_0001
[00967] The title compound was prepared in a manner analogous to Example 144 using methyl 5-fluoro-4- methylpyrimidine-2-carboxylate (Intermediate 127) instead of methyl 5-chloropyrazine-2-carboxylate and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 7.51 - 7.42 (m, 1H), 7.37 - 7.31 (m, 1H), 7.29 - 7.21 (m, 2H), 6.83 - 6.72 (m, 1H), 6.71 - 6.61 (m, 1H), 5.24 (t, J = 7.3 Hz, 1H), 4.75 (br dd, J = 3.7, 2.2 Hz, 1H), 4.10 (q, J = 7.8 Hz, 1H), 3.52 (dt, J = 8.4, 3.9 Hz, 1H), 2.97 (d, J = 4.4 Hz, 3H), 2.62 (s, 3H), 2.55 - 2.45 (m, 1H), 2.12 - 1.91 (m, 2H), 1.84 - 1.69 (m, 1H), 1.28 (dd, J = 7.0, 2.4 Hz, 3H). Example 393: 5-((1*R,3a*S,6a*R)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000470_0002
468 QB\184200.00050\92364964.2 VVID-746PC [00968] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,3a*S,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 112) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 4.04 min) provided the title compound. MS (ESI): mass calcd. for C25H29ClFN5O4S, 549.2; m/z found, 550.2 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.68 - 8.46 (m, 2H), 7.75 (br s, 1H), 7.36 - 7.21 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.84 - 6.74 (m, 1H), 6.72 - 6.63 (m, 1H), 5.69 (d, J = 9.6 Hz, 1H), 4.78 (dt, J = 6.8, 5.6 Hz, 1H), 4.43 (t, J = 6.4 Hz, 1H), 4.39 - 4.28 (m, 2H), 4.24 (t, J = 5.9 Hz, 1H), 3.78 (t, J = 5.8 Hz, 1H), 3.67 (dd, J = 11.1, 7.1 Hz, 1H), 3.51 - 3.41 (m, 1H), 3.37 - 3.33 (m, 1H), 3.22 - 3.11 (m, 1H), 2.98 (s, 3H), 2.70 (br d, J = 8.8 Hz, 1H), 2.29 (dd, J = 8.9, 6.5 Hz, 1H), 2.02 - 1.91 (m, 1H), 1.89 - 1.81 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 394: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000471_0001
[00969] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,3a*S,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 112) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 6.66 min) provided the title compound. MS (ESI): mass calcd. for C25H29ClFN5O4S, 549.2; m/z found, 550.2 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.66 - 8.46 (m, 2H), 7.72 (br s, 1H), 7.38 - 7.20 (m, 2H), 6.94 (d, J = 7.4 Hz, 1H), 6.84 - 6.74 (m, 1H), 6.71 - 6.64 (m, 1H), 5.68 (d, J = 9.5 Hz, 1H), 4.85 - 4.70 (m, 1H), 4.43 (t, J = 6.4 Hz, 1H), 4.39 - 4.28 (m, 2H), 4.24 (t, J = 5.9 Hz, 1H), 3.78 (t, J = 5.8 Hz, 1H), 3.66 (dd, J = 11.1, 7.1 Hz, 1H), 3.53 - 3.42 (m, 1H), 3.36 - 3.33 (m, 1H), 3.22 - 3.09 (m, 1H), 2.98 (s, 3H), 2.76 - 2.65 (m, 1H), 2.39 - 2.23 (m, 1H), 2.00 - 1.91 (m, 1H), 1.90 - 1.81 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). 469 QB\184200.00050\92364964.2 VVID-746PC Example 395: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000472_0001
[00970] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 67) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.12 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.5 Hz, 1H), 7.86 (s, 2H), 7.42 - 7.25 (m, 2H), 6.88 (br d, J = 7.5 Hz, 1H), 6.82 - 6.73 (m, 1H), 6.71 - 6.62 (m, 1H), 5.35 (d, J = 5.0 Hz, 1H), 4.83 - 4.69 (m, 1H), 4.12 (d, J = 9.5 Hz, 1H), 3.66 (dd, J = 9.7, 5.1 Hz, 1H), 3.23 (dd, J = 10.9, 6.5 Hz, 1H), 2.98 (d, J = 2.0 Hz, 6H), 2.29 - 2.21 (m, 1H), 1.96 - 1.89 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.09 - 0.99 (m, 1H). Example 396: 5-((1*R,3a*S,6a*R)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2- trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000472_0002
[00971] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,3a*S,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 113) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 3.39 min) provided the title 470 QB\184200.00050\92364964.2 VVID-746PC compound. MS (ESI): mass calcd. for C24H26ClF4N5O3S, 575.1; m/z found, 576.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.46 (m, 2H), 7.76 (br s, 1H), 7.34 - 7.14 (m, 2H), 6.87 - 6.74 (m, 2H), 6.71 - 6.63 (m, 1H), 5.67 (d, J = 9.5 Hz, 1H), 4.78 (dt, J = 6.9, 5.7 Hz, 1H), 4.34 (t, J = 10.2 Hz, 1H), 3.61 (dd, J = 11.1, 7.4 Hz, 1H), 3.49 (br dd, J = 7.6, 3.2 Hz, 1H), 3.24 - 3.09 (m, 2H), 3.02 - 2.94 (m, 4H), 2.86 (br d, J = 8.0 Hz, 1H), 2.71 (dd, J = 9.0, 6.8 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.16 (dd, J = 9.8, 3.5 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 397: 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2- trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000473_0001
[00972] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,3a*S,6a*S)-1-(2-chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 113) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*R,3a*S,6a*R)-1-(2-chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH/CO2; Rt = 4.57 min) provided the title compound. MS (ESI): mass calcd. for C24H26ClF4N5O3S, 575.1; m/z found, 576.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.45 (m, 2H), 7.72 (br s, 1H), 7.33 - 7.16 (m, 2H), 6.87 - 6.73 (m, 2H), 6.72 - 6.61 (m, 1H), 5.66 (d, J = 9.5 Hz, 1H), 4.84 - 4.70 (m, 1H), 4.35 (br t, J = 10.3 Hz, 1H), 3.61 (dd, J = 11.2, 7.3 Hz, 1H), 3.53 - 3.44 (m, 1H), 3.24 - 3.07 (m, 2H), 3.03 - 2.91 (m, 4H), 2.86 (br d, J = 8.3 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.35 - 2.26 (m, 1H), 2.16 (dd, J = 9.8, 3.3 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 398: 5-((*R)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000473_0002
471 QB\184200.00050\92364964.2 VVID-746PC [00973] The title compound was prepared in a manner analogous to Example 144 using 6-(2-chloro-3- fluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 108) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2-chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 5.64 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.6 Hz, 1H), 7.91 (s, 2H), 7.43 - 7.24 (m, 2H), 7.11 (d, J = 6.6 Hz, 1H), 6.85 - 6.75 (m, 1H), 6.73 - 6.60 (m, 1H), 5.40 - 5.27 (m, 1H), 4.77 (dt, J = 6.9, 5.7 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.68 - 3.57 (m, 1H), 2.98 (s, 3H), 2.78 (dd, J = 12.6, 8.4 Hz, 1H), 1.65 (dd, J = 12.5, 1.9 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.75 - 0.64 (m, 2H), 0.64 - 0.57 (m, 1H), 0.37 - 0.28 (m, 1H). Example 399: 5-((*S)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000474_0001
[00974] The title compound was prepared in a manner analogous to Example 144 using 6-(2-chloro-3- fluorophenyl)-5-azaspiro[2.4]heptane (Intermediate 108) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(6-(2-chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 7.87 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.5 Hz, 1H), 7.91 (s, 2H), 7.42 - 7.23 (m, 2H), 7.11 (d, J = 6.9 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.72 - 6.59 (m, 1H), 5.33 (dd, J = 8.2, 1.7 Hz, 1H), 4.77 (dt, J = 6.9, 5.8 Hz, 1H), 3.78 - 3.70 (m, 1H), 3.67 - 3.58 (m, 1H), 2.98 (s, 3H), 2.78 (dd, J = 12.4, 8.4 Hz, 1H), 1.64 (dd, J = 12.4, 1.9 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.76 - 0.66 (m, 2H), 0.64 - 0.56 (m, 1H), 0.40 - 0.25 (m, 1H). Example 400: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 472 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000475_0001
[00975] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3-azabicyclo[3.1.0]hexane (Intermediate 76) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 4.75 min) provided the title compound. MS (ESI): mass calcd. for C23H24ClF3N4O4S, 544.1; m/z found, 545.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.47 (m, 2H), 7.67 (br s, 1H), 7.33 - 7.20 (m, 2H), 6.78 (dd, J = 15.3, 5.4 Hz, 2H), 6.71 - 6.27 (m, 2H), 5.57 (d, J = 5.4 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.11 (d, J = 10.6 Hz, 1H), 3.91 (dd, J = 10.6, 5.4 Hz, 1H), 3.70 (dd, J = 11.3, 7.1 Hz, 1H), 3.55 (dd, J = 11.3, 7.4 Hz, 1H), 2.98 (s, 3H), 2.42 - 2.34 (m, 1H), 2.08 - 1.99 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.14 - 1.04 (m, 1H). Example 401: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000475_0002
[00976] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3-azabicyclo[3.1.0]hexane (Intermediate 76) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% iPrOH/CO2; Rt = 9.58 min) provided the title compound. MS (ESI): mass calcd. for C23H24ClF3N4O4S, 544.1; m/z found, 545.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.46 (m, 2H), 7.70 (br s, 1H), 7.34 - 7.18 (m, 2H), 6.85 - 6.73 (m, 2H), 6.71 - 6.25 (m, 2H), 5.57 (d, J = 5.3 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.12 (d, J = 10.6 Hz, 1H), 3.91 (dd, J = 10.6, 473 QB\184200.00050\92364964.2 VVID-746PC 5.4 Hz, 1H), 3.70 (dd, J = 11.3, 7.1 Hz, 1H), 3.55 (dd, J = 11.3, 7.4 Hz, 1H), 2.98 (s, 3H), 2.41 - 2.35 (m, 1H), 2.08 - 2.00 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.09 (td, J = 6.7, 3.5 Hz, 1H). Example 402: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000476_0001
[00977] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 50) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 3.14 min) provided the title compound. MS (ESI): mass calcd. for C22H21ClFN5O3S, 489.1; m/z found, 490.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (br d, J = 8.4 Hz, 1H), 8.55 - 8.46 (m, 1H), 7.68 (br s, 1H), 7.48 - 7.32 (m, 1H), 7.32 - 7.22 (m, 1H), 6.96 - 6.60 (m, 3H), 5.62 (br d, J = 4.5 Hz, 1H), 4.98 - 4.68 (m, 1H), 4.25 (br d, J = 11.0 Hz, 1H), 3.90 (br dd, J = 10.8, 4.7 Hz, 1H), 3.09 - 2.95 (m, 4H), 2.83 - 2.72 (m, 1H), 1.81 (br s, 1H), 1.29 (br d, J = 6.8 Hz, 3H). Example 403: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000476_0002
[00978] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 50) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); 474 QB\184200.00050\92364964.2 VVID-746PC Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 7.71 min) provided the title compound. MS (ESI): mass calcd. for C22H21ClFN5O3S, 489.1; m/z found, 490.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.46 (m, 2H), 7.71 (s, 1H), 7.47 - 7.06 (m, 2H), 6.99 - 6.53 (m, 3H), 5.62 (d, J = 4.8 Hz, 1H), 4.96 - 4.69 (m, 1H), 4.25 (d, J = 10.9 Hz, 1H), 3.90 (dd, J = 10.9, 5.0 Hz, 1H), 3.11 - 2.95 (m, 4H), 2.85 - 2.72 (m, 1H), 1.81 (t, J = 3.4 Hz, 1H), 1.29 (d, J = 7.1 Hz, 3H). Example 404: 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000477_0001
[00979] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*R,5*S)- 2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (Intermediate 120) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro- 3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 60% MeOH/CO2; Rt = 3.39 min) provided the title compound. MS (ESI): mass calcd. for C21H22ClFN4O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.78 - 8.47 (m, 2H), 8.38 - 8.06 (m, 1H), 7.37 - 7.18 (m, 2H), 7.04 (br d, J = 7.0 Hz, 1H), 6.84 - 6.73 (m, 1H), 6.70 - 6.61 (m, 1H), 5.64 (br s, 1H), 4.90 (br s, 1H), 4.84 - 4.73 (m, 1H), 4.62 (br s, 1H), 4.30 - 3.99 (m, 2H), 3.31 - 3.25 (m, 1H), 2.98 (s, 3H), 2.18 - 2.07 (m, 1H), 1.29 (br d, J = 4.6 Hz, 3H). Example 405: 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000477_0002
[00980] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*R,5*S)- 2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (Intermediate 120) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate instead of methyl 5-chloropyrazine-2- 475 QB\184200.00050\92364964.2 VVID-746PC carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro- 3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 60% MeOH/CO2; Rt = 5.74 min) provided the title compound. MS (ESI): mass calcd. for C21H22ClFN4O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.75 - 8.49 (m, 2H), 8.40 - 8.10 (m, 1H), 7.37 - 7.17 (m, 2H), 7.04 (br d, J = 7.3 Hz, 1H), 6.83 - 6.72 (m, 1H), 6.71 - 6.64 (m, 1H), 5.64 (br s, 1H), 4.90 (br d, J = 3.3 Hz, 1H), 4.84 - 4.73 (m, 1H), 4.63 (br d, J = 2.5 Hz, 1H), 4.31 - 3.94 (m, 2H), 3.31 - 3.24 (m, 1H), 2.97 (s, 3H), 2.13 (br d, J = 7.2 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H). Example 406: 5-((rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000478_0001
[00981] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (Intermediate 61) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H22ClFN4O4S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 1H), 8.56 (br d, J = 2.9 Hz, 1H), 7.97 - 7.76 (m, 1H), 7.38 - 7.25 (m, 2H), 7.24 - 7.16 (m, 1H), 6.83 - 6.75 (m, 1H), 6.73 - 6.62 (m, 1H), 5.66 (d, J = 3.5 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.84 - 4.69 (m, 2H), 4.18 (br d, J = 10.8 Hz, 1H), 3.98 (dd, J = 12.1, 3.0 Hz, 1H), 3.05 - 2.94 (m, 4H), 2.01 (d, J = 9.4 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 407: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000478_0002
[00982] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 67) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrimidinecarboxylate 476 QB\184200.00050\92364964.2 VVID-746PC instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A and (R,E)- 4-(cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2- amine in Step C. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6- (methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 35% EtOH/CO2; Rt = 5.80 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C25H28ClFN4O4S, 534.1; m/z found, 535.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.7 Hz, 1H), 7.87 (s, 2H), 7.43 - 7.25 (m, 2H), 6.89 (br d, J = 7.8 Hz, 1H), 6.81 - 6.71 (m, 1H), 6.69 - 6.61 (m, 1H), 5.36 (d, J = 5.1 Hz, 1H), 4.85 - 4.71 (m, 1H), 4.13 (d, J = 9.7 Hz, 1H), 3.67 (dd, J = 9.6, 5.0 Hz, 1H), 3.24 (dd, J = 10.9, 6.3 Hz, 1H), 3.05 - 2.95 (m, 4H), 2.64 - 2.58 (m, 1H), 2.30 - 2.21 (m, 1H), 1.93 (td, J = 7.9, 4.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.09 - 0.94 (m, 5H). Example 408: 5-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000479_0001
[00983] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 68) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 5.50 min) provided the title compound. MS (ESI): mass calcd. for C23H26F2N4O4S, 492.2; m/z found, 493.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.47 (m, 2H), 7.74 (s, 1H), 7.38 - 7.26 (m, 1H), 7.13 - 7.01 (m, 1H), 6.84 - 6.64 (m, 3H), 5.55 (d, J = 5.4 Hz, 1H), 4.86 - 4.67 (m, 1H), 4.06 (d, J = 10.6 Hz, 1H), 3.87 (dd, J = 10.6, 5.3 Hz, 1H), 3.23 (dd, J = 10.8, 6.4 Hz, 1H), 2.99 (d, J = 7.9 Hz, 7H), 2.20 (br t, J = 7.8 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.99 (td, J = 6.6, 3.3 Hz, 1H). Example 409: 5-((1*R,2*R,5*S,6*R)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 477 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000480_0001
[00984] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 68) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 9.15 min) provided the title compound. MS (ESI): mass calcd. for C23H26F2N4O4S, 492.2; m/z found, 493.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.44 (m, 2H), 7.77 (s, 1H), 7.30 (q, J = 8.6 Hz, 1H), 7.14 - 6.98 (m, 1H), 6.86 - 6.62 (m, 3H), 5.55 (d, J = 5.4 Hz, 1H), 4.88 - 4.71 (m, 1H), 4.06 (d, J = 10.5 Hz, 1H), 3.87 (dd, J = 10.6, 5.4 Hz, 1H), 3.23 (dd, J = 10.8, 6.4 Hz, 1H), 2.99 (d, J = 7.3 Hz, 7H), 2.19 (br t, J = 7.8 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.99 (tt, J = 6.7, 3.5 Hz, 1H). Example 410: 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000480_0002
[00985] The title compound was prepared in a manner analogous to Example 144 using 2-(rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetonitrile (Intermediate 55) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 5.63 min) provided the title compound. MS (ESI): mass calcd. for C23H23ClFN5O3S, 503.1; m/z found, 504.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.6 Hz, 1H), 8.53 (s, 1H), 7.70 (br s, 1H), 7.38 - 7.20 (m, 2H), 6.80 (dd, J = 15.3, 5.3 Hz, 2H), 6.74 - 6.64 (m, 1H), 5.58 (d, J = 5.4 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.13 (d, J = 10.6 Hz, 1H), 3.92 (dd, J = 10.7, 5.4 Hz, 478 QB\184200.00050\92364964.2 VVID-746PC 1H), 2.99 (s, 3H), 2.61 - 2.55 (m, 1H), 2.48 - 2.41 (m, 1H), 2.40 - 2.32 (m, 1H), 2.09 - 1.99 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 1.02 (td, J = 6.7, 3.4 Hz, 1H). Example 411: 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000481_0001
[00986] The title compound was prepared in a manner analogous to Example 144 using 2-(rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetonitrile (Intermediate 55) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.72 min) provided the title compound. MS (ESI): mass calcd. for C23H23ClFN5O3S, 503.1; m/z found, 504.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.6 Hz, 1H), 8.52 (d, J = 1.1 Hz, 1H), 7.73 (br s, 1H), 7.38 - 7.19 (m, 2H), 6.86 - 6.75 (m, 2H), 6.74 - 6.63 (m, 1H), 5.59 (d, J = 5.4 Hz, 1H), 4.88 - 4.73 (m, 1H), 4.14 (d, J = 10.5 Hz, 1H), 3.93 (dd, J = 10.7, 5.4 Hz, 1H), 3.00 (s, 3H), 2.61 - 2.55 (m, 1H), 2.49 - 2.42 (m, 1H), 2.40 - 2.32 (m, 1H), 2.10 - 2.00 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 1.07 - 0.97 (m, 1H). Example 412: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000481_0002
[00987] The title compound was prepared in a manner analogous to Example 144 using 2-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)propan-2-ol (Intermediate 63) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: 479 QB\184200.00050\92364964.2 VVID-746PC AD (3x25 cm); Mobile phase: 33% iPrOH/CO2; Rt = 5.80 min) provided the title compound. MS (ESI): mass calcd. for C24H28ClFN4O4S, 522.2; m/z found, 523.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.72 (br s, 1H), 7.34 - 7.17 (m, 2H), 6.83 - 6.74 (m, 1H), 6.74 - 6.63 (m, 2H), 5.54 (d, J = 5.6 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.12 (s, 1H), 4.05 - 3.97 (m, 1H), 3.96 - 3.89 (m, 1H), 2.98 (s, 3H), 2.37 - 2.30 (m, 1H), 2.07 - 1.97 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.03 (s, 3H), 0.68 (s, 3H), 0.64 (t, J = 3.8 Hz, 1H). Example 413: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000482_0001
[00988] The title compound was prepared in a manner analogous to Example 144 using 2-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)propan-2-ol (Intermediate 63) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 33% iPrOH/CO2; Rt = 9.60 min) provided the title compound. MS (ESI): mass calcd. for C24H28ClFN4O4S, 522.2; m/z found, 523.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.75 (br s, 1H), 7.32 - 7.17 (m, 2H), 6.85 - 6.74 (m, 1H), 6.73 - 6.62 (m, 2H), 5.54 (d, J = 5.5 Hz, 1H), 4.79 (qd, J = 13.6, 6.9 Hz, 1H), 4.12 (s, 1H), 4.05 - 3.98 (m, 1H), 3.96 - 3.87 (m, 1H), 2.98 (s, 3H), 2.38 - 2.29 (m, 1H), 2.06 - 1.99 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.03 (s, 3H), 0.68 (s, 3H), 0.64 (br t, J = 3.4 Hz, 1H). Example 414: 5-((1*S,2*S,5*R,6*S)-6-Cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000482_0002
480 QB\184200.00050\92364964.2 VVID-746PC [00989] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 51) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 4.45 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H21F2N5O3S, 473.1; m/z found, 474.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 1.0 Hz, 1H), 7.79 (s, 1H), 7.44 - 7.30 (m, 1H), 7.14 - 7.02 (m, 1H), 6.86 - 6.75 (m, 2H), 6.70 - 6.62 (m, 1H), 5.59 (d, J = 4.9 Hz, 1H), 4.85 - 4.74 (m, 1H), 4.22 (d, J = 11.0 Hz, 1H), 3.87 (dd, J = 10.9, 4.9 Hz, 1H), 3.05 - 3.00 (m, 1H), 2.98 (s, 3H), 2.77 (td, J = 7.7, 4.0 Hz, 1H), 1.82 (t, J = 3.5 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H). Example 415: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000483_0001
[00990] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chloro-3- fluorophenyl)-1-methylpiperazin-2-one (Intermediate 122) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A and using (R,E)-4-(cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2-amine in Step C. Separation of 5-(2-(2-chloro-3- fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% iPrOH/CO2 with 0.1% NH4OH; Rt = 11.0 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H25ClFN5O4S, 521.1; m/z found, 522.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.5 Hz, 1H), 8.60 (d, J = 1.1 Hz, 1H), 7.98 (s, 1H), 7.44 - 7.27 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.81 - 6.72 (m, 1H), 6.68 - 6.59 (m, 1H), 5.80 (t, J = 3.5 Hz, 1H), 4.81 (dt, J = 7.0, 5.8 Hz, 1H), 4.65 - 4.56 (m, 1H), 4.55 - 4.47 (m, 1H), 4.15 (dd, J = 13.8, 4.3 Hz, 1H), 3.63 (dd, J = 13.8, 3.2 Hz, 1H), 2.74 (s, 3H), 2.66 - 2.56 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.03 - 0.91 (m, 4H). Example 416: 5-((1R,2S,5S,6S)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 481 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000484_0001
[00991] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 96) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 13.0 min, second eluting product) provided the title compound. Absolute stereochemistry determined by single crystal x-ray structure. MS (ESI): mass calcd. for C22H24F2N4O3S, 462.2; m/z found, 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 1.0 Hz, 1H), 7.74 (s, 1H), 7.30 (q, J = 8.4 Hz, 1H), 7.09 - 7.00 (m, 1H), 6.82 - 6.75 (m, 1H), 6.74 - 6.64 (m, 2H), 5.51 (d, J = 5.5 Hz, 1H), 4.78 (dt, J = 7.0, 5.6 Hz, 1H), 4.02 (d, J = 10.5 Hz, 1H), 3.85 (dd, J = 10.6, 5.5 Hz, 1H), 2.98 (s, 3H), 1.99 (br t, J = 7.7 Hz, 1H), 1.78 - 1.69 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.0 Hz, 3H), 0.69 (td, J = 6.1, 3.3 Hz, 1H). Example 417: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000484_0002
[00992] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 91) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2; Rt = 4.90 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N4O3S, 496.1; m/z found, 497.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (br d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.70 (br s, 1H), 7.37 - 7.19 (m, 2H), 6.87 - 6.75 (m, 2H), 6.71 - 6.59 (m, 482 QB\184200.00050\92364964.2 VVID-746PC 1H), 5.58 (br d, J = 5.1 Hz, 1H), 4.79 (qd, J = 13.6, 6.6 Hz, 1H), 4.35 - 4.05 (m, 3H), 3.91 (dt, J = 5.2, 3.1 Hz, 1H), 2.98 (s, 3H), 2.44 - 2.37 (m, 1H), 2.14 - 2.03 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.20 (br d, J = 3.3 Hz, 1H). Example 418: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000485_0001
[00993] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 91) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2; Rt = 6.60 min) provided the title compound. MS (ESI): mass calcd. for C22H23ClF2N4O3S, 496.1; m/z found, 497.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.67 (br s, 1H), 7.37 - 7.19 (m, 2H), 6.87 - 6.74 (m, 2H), 6.73 - 6.61 (m, 1H), 5.58 (br d, J = 3.8 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.37 - 4.00 (m, 3H), 3.91 (ddd, J = 7.9, 5.3, 2.8 Hz, 1H), 2.98 (s, 3H), 2.40 - 2.35 (m, 1H), 2.11 - 2.04 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.23 - 1.13 (m, 1H). Example 419: 5-((1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000485_0002
[00994] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,4*S,5*R)- 4-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 72) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- 483 QB\184200.00050\92364964.2 VVID-746PC (1*R,4*S,5*R)-4-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 3.53 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.7 Hz, 1H), 8.50 (s, 1H), 7.72 (br s, 1H), 7.33 - 7.19 (m, 2H), 6.78 (dd, J = 15.2, 5.2 Hz, 2H), 6.71 - 6.64 (m, 1H), 5.58 (d, J = 5.1 Hz, 1H), 4.83 - 4.73 (m, 1H), 4.15 (d, J = 10.2 Hz, 1H), 3.85 (d, J = 10.2 Hz, 1H), 3.61 - 3.55 (m, 1H), 3.47 (d, J = 10.4 Hz, 1H), 3.31 (s, 3H), 2.98 (s, 3H), 2.26 - 2.19 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.75 (dd, J = 8.1, 5.2 Hz, 1H), 0.58 (t, J = 4.5 Hz, 1H). Example 420: 5-((1*S,4*R,5*S)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000486_0001
[00995] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,4*S,5*R)- 4-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 72) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,4*S,5*R)-4-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 6.41 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 8.49 (s, 1H), 7.75 (br s, 1H), 7.33 - 7.18 (m, 2H), 6.84 - 6.74 (m, 2H), 6.70 - 6.63 (m, 1H), 5.58 (d, J = 5.1 Hz, 1H), 4.84 - 4.73 (m, 1H), 4.16 (d, J = 10.1 Hz, 1H), 3.85 (d, J = 10.1 Hz, 1H), 3.61 - 3.56 (m, 1H), 3.50 - 3.45 (m, 1H), 3.31 (s, 3H), 2.98 (s, 3H), 2.27 - 2.18 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.79 - 0.72 (m, 1H), 0.58 (br t, J = 4.3 Hz, 1H). Example 421: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 484 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000487_0001
[00996] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chloro-3- fluorophenyl)-1-cyclopropylpiperazin-2-one (Intermediate 123) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4- cyclopropyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 8.52 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H25ClFN5O4S, 521.1; m/z found, 522.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.6 Hz, 1H), 8.58 (s, 1H), 7.96 (br s, 1H), 7.43 - 7.35 (m, 1H), 7.29 (dt, J = 8.0, 5.6 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.83 - 6.75 (m, 1H), 6.71 - 6.62 (m, 1H), 5.71 (br s, 1H), 4.79 (dt, J = 6.9, 5.8 Hz, 1H), 4.66 (d, J = 16.6 Hz, 1H), 4.44 (d, J = 16.5 Hz, 1H), 4.14 (dd, J = 13.8, 3.8 Hz, 1H), 3.54 (dd, J = 13.8, 3.0 Hz, 1H), 2.97 (s, 3H), 2.57 - 2.52 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 0.73 - 0.58 (m, 1H), 0.54 - 0.41 (m, 1H), 0.27 - 0.12 (m, 1H), -0.45 (qd, J = 10.4, 5.2 Hz, 1H). Example 422: 5-((1*S,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000487_0002
[00997] The title compound was prepared in a manner analogous to Example 144 using rac-(1*S,2*S,5*S)- 2-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 74) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 3.68 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.5 Hz, 1H), 8.50 (s, 1H), 7.51 (s, 1H), 7.35 - 7.29 (m, 1H), 7.28 - 7.21 (m, 1H), 6.97 (br d, J = 7.6 Hz, 1H), 485 QB\184200.00050\92364964.2 VVID-746PC 6.80 - 6.72 (m, 1H), 6.69 - 6.62 (m, 1H), 5.72 (s, 1H), 4.82 - 4.70 (m, 1H), 4.09 (d, J = 10.6 Hz, 1H), 3.88 (dd, J = 10.6, 5.3 Hz, 1H), 3.75 (d, J = 10.6 Hz, 1H), 3.28 (s, 3H), 3.19 (d, J = 10.5 Hz, 1H), 2.97 (s, 3H), 1.98 - 1.90 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.86 (br t, J = 4.8 Hz, 1H), 0.72 (dd, J = 7.9, 5.6 Hz, 1H). Example 423: 5-((1*R,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000488_0001
[00998] The title compound was prepared in a manner analogous to Example 144 using rac-(1*S,2*S,5*S)- 2-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 74) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 7.18 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O4S, 508.1; m/z found, 509.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H), 7.55 (s, 1H), 7.34 - 7.28 (m, 1H), 7.28 - 7.21 (m, 1H), 6.97 (br d, J = 7.8 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.69 - 6.62 (m, 1H), 5.72 (s, 1H), 4.77 (dt, J = 6.9, 5.8 Hz, 1H), 4.09 (d, J = 10.5 Hz, 1H), 3.88 (dd, J = 10.6, 5.3 Hz, 1H), 3.76 (d, J = 10.6 Hz, 1H), 3.28 (s, 3H), 3.19 (d, J = 10.6 Hz, 1H), 2.97 (s, 3H), 1.94 (td, J = 8.6, 4.6 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H), 0.85 (br t, J = 4.7 Hz, 1H), 0.72 (dd, J = 8.2, 5.6 Hz, 1H). Example 424: 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000488_0002
[00999] The title compound was prepared in a manner analogous to Example 144 using rac-(1*R,2*S,5*S)- 2-(3-fluoro-2-methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 105) instead of (S)-2- 486 QB\184200.00050\92364964.2 VVID-746PC (2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*R,5*R)-6,6- difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 33% iPrOH/CO2; Rt = 5.73 min) provided the title compound. MS (ESI): mass calcd. for C22H23F3N4O3S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.55 (m, 2H), 7.54 (br s, 1H), 7.11 - 6.99 (m, 2H), 6.83 - 6.62 (m, 3H), 5.73 (dd, J = 6.1, 2.3 Hz, 1H), 4.87 - 4.69 (m, 1H), 4.33 - 4.22 (m, 1H), 4.15 (br dd, J = 10.5, 6.8 Hz, 1H), 3.31 - 3.23 (m, 1H), 2.98 (s, 3H), 2.84 (dt, J = 11.0, 6.4 Hz, 1H), 2.39 (d, J = 1.3 Hz, 3H), 1.28 (d, J = 7.0 Hz, 3H). Example 425: 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000489_0001
[001000] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S)-2-(3-fluoro-2-methylphenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 105) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*R,5*R)-6,6-difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 33% iPrOH/CO2; Rt = 7.98 min) provided the title compound. MS (ESI): mass calcd. for C22H23F3N4O3S, 480.1; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.53 (m, 2H), 7.50 (br s, 1H), 7.12 - 6.99 (m, 2H), 6.82 - 6.63 (m, 3H), 5.73 (dd, J = 6.1, 2.4 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.29 - 4.21 (m, 1H), 4.19 - 4.08 (m, 1H), 3.30 - 3.24 (m, 1H), 2.97 (s, 3H), 2.83 (dt, J = 11.1, 6.4 Hz, 1H), 2.40 (d, J = 1.3 Hz, 3H), 1.28 (d, J = 7.0 Hz, 3H). Example 426: 5-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 487 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000490_0001
[001001] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 92) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 8.32 min) provided the title compound. MS (ESI): mass calcd. for C23H26F2N4O3S, 476.2; m/z found, 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.1 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.43 (br s, 1H), 7.16 - 6.99 (m, 2H), 6.81 - 6.73 (m, 1H), 6.70 - 6.64 (m, 2H), 5.58 - 5.43 (m, 1H), 4.82 - 4.72 (m, 1H), 4.32 - 4.01 (m, 3H), 3.92 (ddd, J = 11.2, 5.3, 2.0 Hz, 1H), 2.97 (s, 3H), 2.43 - 2.36 (m, 4H), 2.08 - 1.98 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.22 (br dd, J = 7.6, 3.4 Hz, 1H). Example 427: 5-((1*R,2*R,5*S,6*R)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000490_0002
[001002] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 92) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.63 min) provided the title compound. MS (ESI): mass calcd. for C23H26F2N4O3S, 476.2; m/z found, 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.52 (m, 2H), 7.46 (br s, 1H), 7.15 - 7.00 (m, 2H), 6.84 - 6.72 (m, 1H), 6.70 - 6.60 (m, 2H), 5.53 488 QB\184200.00050\92364964.2 VVID-746PC (br d, J = 3.9 Hz, 1H), 4.78 (br d, J = 6.9 Hz, 1H), 4.31 - 4.00 (m, 3H), 3.92 (dt, J = 5.6, 3.4 Hz, 1H), 2.98 (s, 3H), 2.40 (s, 4H), 2.04 (br t, J = 7.9 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.21 (br dd, J = 7.1, 3.2 Hz, 1H). Example 428: 5-((1*S,2*S,5*R,6*S)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000491_0001
[001003] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 52) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 5.19 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H24FN5O3S, 469.2; m/z found, 470.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.51 (m, 2H), 7.42 (s, 1H), 7.17 - 7.03 (m, 2H), 6.83 - 6.72 (m, 2H), 6.71 - 6.59 (m, 1H), 5.54 (d, J = 4.9 Hz, 1H), 4.86 - 4.69 (m, 1H), 4.22 (d, J = 11.4 Hz, 1H), 3.87 (dd, J = 11.4, 4.9 Hz, 1H), 3.11 (td, J = 7.8, 4.1 Hz, 1H), 2.97 (s, 3H), 2.72 (td, J = 7.6, 4.1 Hz, 1H), 2.44 (s, 3H), 1.81 (t, J = 3.5 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). Example 429: 5-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000491_0002
[001004] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-6-((difluoromethoxy)methyl)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 77) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation 489 QB\184200.00050\92364964.2 VVID-746PC of 5-(rac-(1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 9.02 min) provided the title compound. MS (ESI): mass calcd. for C24H27F3N4O4S, 524.2; m/z found, 525.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 1.3 Hz, 1H), 8.52 (d, J = 8.6 Hz, 1H), 7.43 (br s, 1H), 7.12 - 6.99 (m, 2H), 6.80 - 6.72 (m, 1H), 6.69 - 6.62 (m, 2H), 6.51 - 6.27 (m, 1H), 5.52 (d, J = 5.4 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.10 - 4.01 (m, 1H), 3.97 - 3.88 (m, 1H), 3.69 - 3.61 (m, 1H), 3.58 - 3.51 (m, 1H), 2.97 (s, 3H), 2.43 - 2.34 (m, 4H), 2.04 - 1.95 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.09 (tt, J = 7.1, 3.4 Hz, 1H). Example 430: 5-((1*R,2*R,5*S,6*R)-2-(3-Fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000492_0001
[001005] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-6-((difluoromethoxy)methyl)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 77) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 45% EtOH/CO2; Rt = 10.6 min) provided the title compound. MS (ESI): mass calcd. for C24H27F3N4O4S, 524.2; m/z found, 525.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 1.0 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 7.46 (br s, 1H), 7.13 - 6.94 (m, 2H), 6.83 - 6.73 (m, 1H), 6.70 - 6.59 (m, 2H), 6.52 - 6.26 (m, 1H), 5.52 (d, J = 5.5 Hz, 1H), 4.83 - 4.71 (m, 1H), 4.05 (d, J = 11.1 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.69 - 3.60 (m, 1H), 3.59 - 3.51 (m, 1H), 2.97 (s, 3H), 2.41 - 2.34 (m, 4H), 2.07 - 1.95 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.09 (qd, J = 7.0, 3.4 Hz, 1H). Example 431: 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 490 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000493_0001
[001006] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 97) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 11.9 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (br d, J = 8.5 Hz, 1H), 8.50 (s, 1H), 7.63 (br s, 1H), 7.35 - 7.17 (m, 2H), 6.83 - 6.73 (m, 2H), 6.71 - 6.62 (m, 1H), 5.53 (d, J = 5.4 Hz, 1H), 4.86 - 4.71 (m, 1H), 4.05 (br d, J = 10.6 Hz, 1H), 3.87 (dd, J = 10.6, 5.5 Hz, 1H), 2.97 (s, 3H), 2.10 - 2.04 (m, 1H), 1.74 (br t, J = 7.9 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.0 Hz, 3H), 0.69 (br d, J = 5.5 Hz, 1H). Example 432: 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000493_0002
[001007] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 97) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 14.7 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.66 (br s, 1H), 7.36 - 7.20 (m, 2H), 6.83 - 6.72 (m, 2H), 6.69 - 6.58 (m, 1H), 5.53 (d, J 491 QB\184200.00050\92364964.2 VVID-746PC = 5.4 Hz, 1H), 4.78 (br dd, J = 6.8, 1.3 Hz, 1H), 4.06 (d, J = 10.5 Hz, 1H), 3.97 - 3.80 (m, 1H), 2.98 (s, 3H), 2.07 (ddd, J = 7.4, 5.4, 3.5 Hz, 1H), 1.80 - 1.67 (m, 1H), 1.29 (d, J = 7.1 Hz, 3H), 0.87 (d, J = 6.0 Hz, 3H), 0.70 (br d, J = 5.5 Hz, 1H). Example 433: 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000494_0001
[001008] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexane (Intermediate 83) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrazinecarboxylate instead of methyl 5- chloro-2-pyrazinecarboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 5.23 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.68 (br s, 1H), 7.38 - 7.28 (m, 1H), 7.25 (br d, J = 5.5 Hz, 1H), 6.83 - 6.72 (m, 2H), 6.71 - 6.62 (m, 1H), 5.58 (d, J = 5.8 Hz, 1H), 4.89 - 4.70 (m, 1H), 4.14 - 4.02 (m, 1H), 4.02 - 3.87 (m, 1H), 3.01 (s, 3H), 2.97 (s, 3H), 2.94 (s, 1H), 2.44 (br d, J = 7.4 Hz, 1H), 2.22 - 2.18 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 434: 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000494_0002
[001009] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexane (Intermediate 83) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoro-2-pyrazinecarboxylate instead of methyl 5- chloro-2-pyrazinecarboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- 492 QB\184200.00050\92364964.2 VVID-746PC (1*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 9.28 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O4S, 494.1; m/z found, 495.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.6 Hz, 1H), 8.50 (d, J = 0.9 Hz, 1H), 7.72 (br s, 1H), 7.37 - 7.29 (m, 1H), 7.25 (br d, J = 5.5 Hz, 1H), 6.83 - 6.73 (m, 2H), 6.71 - 6.63 (m, 1H), 5.58 (d, J = 5.9 Hz, 1H), 4.84 - 4.73 (m, 1H), 4.14 - 4.04 (m, 1H), 4.00 - 3.91 (m, 1H), 3.02 (s, 3H), 2.98 (s, 3H), 2.94 (s, 1H), 2.46 - 2.42 (m, 1H), 2.25 - 2.18 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 435: 5-((1*R,2*S,5*S,6*S)-2-(3-Fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000495_0001
[001010] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 98) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. Separation of 5- (rac-(1*R,2*S,5*S,6*S)-2-(3-fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 4.94 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H27FN4O3S, 458.2; m/z found, 459.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 0.9 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 7.41 (br s, 1H), 7.11 - 6.99 (m, 2H), 6.82 - 6.73 (m, 1H), 6.70 - 6.56 (m, 2H), 5.46 (d, J = 5.5 Hz, 1H), 4.83 - 4.71 (m, 1H), 4.03 - 3.97 (m, 1H), 3.91 - 3.84 (m, 1H), 2.97 (s, 3H), 2.40 (s, 3H), 2.10 - 2.00 (m, 1H), 1.75 - 1.64 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.0 Hz, 3H), 0.75 - 0.65 (m, 1H). Example 436: 5-((1*S,2*S,5*R)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000495_0002
493 QB\184200.00050\92364964.2 VVID-746PC [001011] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S)-2-(2,3-difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane (Intermediate 45) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R)-2-(2,3-difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 12.9 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H26F2N4O3S, 476.2; m/z found, 477.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.6 Hz, 1H), 8.56 (s, 1H), 7.87 (br s, 1H), 7.27 (q, J = 8.3 Hz, 1H), 7.06 - 6.91 (m, 1H), 6.86 - 6.76 (m, 1H), 6.73 - 6.58 (m, 2H), 5.51 (d, J = 6.0 Hz, 1H), 4.81 (dt, J = 6.9, 5.8 Hz, 1H), 3.94 - 3.80 (m, 2H), 2.99 (s, 3H), 2.21 - 2.05 (m, 1H), 1.78 - 1.61 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 0.97 (s, 3H), 0.77 (s, 3H). Example 437: 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000496_0001
[001012] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptane (Intermediate 48) instead of (S)-2- (2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro- 3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 4.88 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.49 (m, 2H), 7.80 (s, 1H), 7.35 - 7.24 (m, 2H), 7.04 (br dd, J = 5.7, 3.3 Hz, 1H), 6.88 - 6.75 (m, 1H), 6.72 - 6.62 (m, 1H), 5.50 (d, J = 8.6 Hz, 1H), 4.79 (dt, J = 6.9, 5.6 Hz, 1H), 4.15 - 4.03 (m, 1H), 3.94 (dd, J = 11.4, 3.9 Hz, 1H), 3.60 - 3.52 (m, 1H), 3.25 - 3.17 (m, 1H), 2.98 (s, 3H), 2.21 - 2.07 (m, 1H), 1.87 - 1.75 (m, 1H), 1.69 - 1.58 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.22 (td, J = 8.7, 6.0 Hz, 1H). Example 438: 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 494 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000497_0001
[001013] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptane (Intermediate 48) instead of (S)-2- (2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R)-2-(2-chloro- 3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2 with 0.1% NH4OH; Rt = 8.05 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.47 (m, 2H), 7.77 (br s, 1H), 7.36 - 7.22 (m, 2H), 7.05 (br dd, J = 5.6, 3.1 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.73 - 6.62 (m, 1H), 5.50 (d, J = 8.8 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.13 - 4.03 (m, 1H), 3.93 (br dd, J = 11.4, 3.8 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.21 (br d, J = 3.3 Hz, 1H), 2.98 (s, 3H), 2.22 - 2.07 (m, 1H), 1.88 - 1.76 (m, 1H), 1.71 - 1.58 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.25 - 1.15 (m, 1H). Example 439: 5-((*R)-1-(2,3-Difluorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000497_0002
[001014] The title compound was prepared in a manner analogous to Example 144 using 1-(2,3- difluorophenyl)isoindoline (Intermediate 110) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5- fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4- dioxane in Step A. Separation of 5-(1-(2,3-difluorophenyl)isoindolin-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% EtOH/CO2 with 0.1% NH4OH; Rt = 4.52 min) provided the title compound. MS (ESI): mass calcd. for C24H22F2N4O3S, 484.1; m/z found, 485.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (br d, J = 8.2 Hz, 2H), 8.07 - 7.93 (m, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.42 - 7.28 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 7.20 - 7.09 (m, 2H), 6.83 - 6.75 (m, 1H), 6.73 - 6.64 (m, 2H), 5.29 - 5.18 (m, 1H), 5.16 - 5.07 (m, 1H), 4.85 - 4.76 (m, 1H), 2.98 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H). 495 QB\184200.00050\92364964.2 VVID-746PC Example 440: 5-((*S)-1-(2,3-Difluorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide.
Figure imgf000498_0001
[001015] The title compound was prepared in a manner analogous to Example 144 using 1-(2,3- difluorophenyl)isoindoline (Intermediate 110) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5- fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4- dioxane in Step A. Separation of 5-(1-(2,3-difluorophenyl)isoindolin-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% EtOH/CO2 with 0.1% NH4OH; Rt = 9.46 min) provided the title compound. MS (ESI): mass calcd. for C24H22F2N4O3S, 484.1; m/z found, 485.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (br d, J = 8.4 Hz, 2H), 8.11 - 7.92 (m, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.43 - 7.28 (m, 3H), 7.22 (d, J = 7.3 Hz, 1H), 7.19 - 7.05 (m, 2H), 6.84 - 6.77 (m, 1H), 6.74 - 6.60 (m, 2H), 5.33 - 5.19 (m, 1H), 5.17 - 5.04 (m, 1H), 4.87 - 4.74 (m, 1H), 2.98 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H). Example 441: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000498_0002
[001016] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chloro- 3-fluorophenyl)-1-methylpiperazin-2-one (Intermediate 122) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin- 1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 5.13 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN5O4S, 495.1; m/z found, 496.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 1.0 Hz, 1H), 7.98 (s, 1H), 7.41 - 7.27 (m, 2H), 6.96 (d, J = 7.7 Hz, 1H), 6.83 - 6.75 (m, 1H), 6.71 - 6.63 (m, 1H), 5.79 (t, J = 3.4 Hz, 1H), 4.85 - 4.74 (m, 1H), 4.65 - 4.57 (m, 496 QB\184200.00050\92364964.2 VVID-746PC 1H), 4.56 - 4.47 (m, 1H), 4.15 (dd, J = 13.8, 4.3 Hz, 1H), 3.63 (dd, J = 13.8, 3.2 Hz, 1H), 2.98 (s, 3H), 2.74 (s, 3H), 1.30 (d, J = 7.1 Hz, 3H). Example 442: 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000499_0001
[001017] The title compound was prepared in a manner analogous to Example 144 using 5-(2-chloro- 3-fluorophenyl)-1-methylpiperazin-2-one (Intermediate 122) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin- 1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 7.27 min) provided the title compound. MS (ESI): mass calcd. for C21H23ClFN5O4S, 495.1; m/z found, 496.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 1.1 Hz, 1H), 7.95 (s, 1H), 7.42 - 7.27 (m, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.85 - 6.73 (m, 1H), 6.72 - 6.63 (m, 1H), 5.78 (t, J = 3.5 Hz, 1H), 4.79 (dt, J = 6.9, 5.7 Hz, 1H), 4.66 - 4.56 (m, 1H), 4.56 - 4.46 (m, 1H), 4.14 (dd, J = 13.8, 4.2 Hz, 1H), 3.63 (dd, J = 13.8, 3.4 Hz, 1H), 2.98 (s, 3H), 2.74 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H). Example 443: 4-(Difluoromethyl)-5-((1*R,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000499_0002
[001018] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 96) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-(difluoromethyl)-5-fluoropyrimidine-2-carboxylate (Intermediate 128) instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 4-(difluoromethyl)-5-(rac-(1*R,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step 497 QB\184200.00050\92364964.2 VVID-746PC C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% MeOH/CO2 with 0.1% NH4OH; Rt = 2.98 min) provided the title compound. MS (ESI): mass calcd. for C23H24F4N4O3S, 512.2; m/z found, 513.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 7.51 - 7.16 (m, 2H), 7.08 (br d, J = 5.8 Hz, 1H), 6.89 (br t, J = 6.9 Hz, 1H), 6.82 - 6.61 (m, 2H), 5.54 (d, J = 4.6 Hz, 1H), 4.77 (br d, J = 4.8 Hz, 1H), 3.99 (d, J = 9.0 Hz, 1H), 3.49 (dd, J = 8.8, 4.1 Hz, 1H), 2.97 (s, 3H), 1.94 - 1.79 (m, 1H), 1.64 (td, J = 7.2, 3.8 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.10 (td, J = 6.0, 3.1 Hz, 1H), 0.90 (d, J = 6.0 Hz, 3H). Example 444: 4-(Difluoromethyl)-5-((1*S,2*R,5*R,6*R)-2-(2,3-difluorophenyl)-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000500_0001
[001019] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 96) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 4-(difluoromethyl)-5-fluoropyrimidine-2-carboxylate (Intermediate 128) instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 4-(difluoromethyl)-5-(rac-(1*R,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 50% MeOH/CO2 with 0.1% NH4OH; Rt = 7.45 min) provided the title compound. MS (ESI): mass calcd. for C23H24F4N4O3S, 512.2; m/z found, 513.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (br d, J = 8.6 Hz, 1H), 8.24 (s, 1H), 7.51 - 7.16 (m, 2H), 7.13 - 7.04 (m, 1H), 6.89 (br t, J = 6.8 Hz, 1H), 6.82 - 6.64 (m, 2H), 5.54 (br d, J = 4.5 Hz, 1H), 4.84 - 4.68 (m, 1H), 4.00 (br d, J = 9.0 Hz, 1H), 3.49 (br dd, J = 8.6, 4.3 Hz, 1H), 2.98 (s, 3H), 1.86 (br dd, J = 6.8, 3.3 Hz, 1H), 1.70 - 1.60 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.09 (br d, J = 3.3 Hz, 1H), 0.91 (br d, J = 6.0 Hz, 3H). Example 445: 5-((1*R,2*S,5*S,6*R)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 498 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000501_0001
[001020] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S,6*R)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 101) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*R)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 7.04 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H24F2N4O3S, 462.2; m/z found, 463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.7 Hz, 1H), 8.56 (s, 1H), 7.89 (br s, 1H), 7.27 (q, J = 8.4 Hz, 1H), 7.06 - 6.94 (m, 1H), 6.86 - 6.77 (m, 1H), 6.73 - 6.61 (m, 2H), 5.53 (d, J = 5.8 Hz, 1H), 4.89 - 4.74 (m, 1H), 3.98 - 3.88 (m, 2H), 2.99 (s, 3H), 2.38 - 2.29 (m, 1H), 1.98 - 1.88 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.10 - 0.98 (m, 1H), 0.73 (d, J = 6.7 Hz, 3H). Example 446: 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000501_0002
[001021] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 84) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 4.59 min) provided the title compound. MS (ESI): mass calcd. for C22H21ClF4N4O3S, 532.1; m/z found, 533.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 8.52 (s, 1H), 7.72 (s, 1H), 7.41 - 7.21 (m, 2H), 6.93 (br d, J = 7.2 Hz, 1H), 6.83 - 6.74 499 QB\184200.00050\92364964.2 VVID-746PC (m, 1H), 6.72 - 6.62 (m, 1H), 5.65 (br d, J = 4.5 Hz, 1H), 4.78 (br d, J = 7.7 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.94 (br dd, J = 10.8, 5.3 Hz, 1H), 2.98 (s, 3H), 2.76 - 2.69 (m, 1H), 2.53 (br d, J = 3.3 Hz, 1H), 1.85 (br d, J = 3.8 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H). Example 447: 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000502_0001
[001022] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 84) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-(1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% EtOH/CO2; Rt = 9.94 min) provided the title compound. MS (ESI): mass calcd. for C22H21ClF4N4O3S, 532.1; m/z found, 533.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 8.51 (d, J = 1.0 Hz, 1H), 7.75 (s, 1H), 7.50 - 7.19 (m, 2H), 6.92 (br d, J = 7.7 Hz, 1H), 6.85 - 6.62 (m, 2H), 5.65 (d, J = 5.3 Hz, 1H), 4.78 (br d, J = 5.3 Hz, 1H), 4.26 (d, J = 10.7 Hz, 1H), 3.94 (br dd, J = 10.9, 5.1 Hz, 1H), 2.98 (s, 3H), 2.75 - 2.69 (m, 1H), 2.53 - 2.51 (m, 1H), 1.85 (br dd, J = 7.0, 3.3 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 448: 5-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000502_0002
[001023] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 85) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 500 QB\184200.00050\92364964.2 VVID-746PC 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 10.8 min) provided the title compound. MS (ESI): mass calcd. for C22H21F5N4O3S, 516.1; m/z found, 517.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 0.9 Hz, 1H), 7.80 (s, 1H), 7.41 - 7.29 (m, 1H), 7.17 - 7.05 (m, 1H), 6.87 (br t, J = 7.1 Hz, 1H), 6.82 - 6.75 (m, 1H), 6.71 - 6.64 (m, 1H), 5.63 (br d, J = 4.9 Hz, 1H), 4.84 - 4.73 (m, 1H), 4.22 (d, J = 10.8 Hz, 1H), 3.91 (br dd, J = 10.6, 5.3 Hz, 1H), 2.98 (s, 3H), 2.73 - 2.66 (m, 1H), 2.53 - 2.52 (m, 1H), 1.85 (td, J = 7.1, 3.5 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 449: 5-((1*R,2*R,5*S,6*R)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000503_0001
[001024] The title compound was prepared in a manner analogous to Example 144 using rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 85) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 13.0 min) provided the title compound. MS (ESI): mass calcd. for C22H21F5N4O3S, 516.1; m/z found, 517.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 1.3 Hz, 1H), 7.82 (s, 1H), 7.35 (q, J = 9.0 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.87 (br t, J = 7.1 Hz, 1H), 6.83 - 6.75 (m, 1H), 6.72 - 6.64 (m, 1H), 5.62 (d, J = 5.3 Hz, 1H), 4.88 - 4.71 (m, 1H), 4.22 (d, J = 10.7 Hz, 1H), 3.91 (br dd, J = 10.1, 5.5 Hz, 1H), 2.98 (s, 3H), 2.69 (td, J = 8.0, 4.2 Hz, 1H), 2.53 (br s, 1H), 1.93 - 1.76 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). Example 450: 5-((1*R,2*S,5*S,6*S)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 501 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000504_0001
[001025] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S,6*S)-2-(3-chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 99) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(3-chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 45% MeOH/CO2; Rt = 7.50 min) provided the title compound. MS (ESI): mass calcd. for C21H24ClN5O3S, 461.1; m/z found, 462.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.7 Hz, 1H), 8.39 (br s, 1H), 8.33 - 8.29 (m, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.68 - 7.48 (m, 1H), 7.30 (dd, J = 8.1, 4.7 Hz, 1H), 6.81 - 6.74 (m, 1H), 6.69 - 6.63 (m, 1H), 5.71 (d, J = 5.6 Hz, 1H), 4.81 - 4.72 (m, 1H), 3.96 - 3.86 (m, 2H), 2.97 (s, 3H), 2.13 - 2.06 (m, 1H), 1.77 - 1.70 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.01 - 0.92 (m, 1H), 0.85 (d, J = 6.0 Hz, 3H). Example 451: 5-((1*S,2*R,5*R,6*R)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000504_0002
[001026] The title compound was prepared in a manner analogous to Example 144 using rac- (1*R,2*S,5*S,6*S)-2-(3-chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 99) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*R,2*S,5*S,6*S)-2-(3-chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 45% MeOH/CO2; Rt = 8.76 min) provided the title compound. MS (ESI): mass calcd. for C21H24ClN5O3S, 461.1; m/z found, 462.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.7 Hz, 1H), 8.38 (br s, 1H), 8.30 (d, J = 4.0 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.71 - 7.49 (m, 1H), 7.29 (dd, J = 8.0, 4.6 Hz, 1H), 6.82 - 6.73 (m, 1H), 6.69 - 6.62 (m, 1H), 5.70 (d, J = 5.6 Hz, 1H), 4.81 - 4.71 (m, 1H), 502 QB\184200.00050\92364964.2 VVID-746PC 3.97 - 3.85 (m, 2H), 2.97 (s, 3H), 2.12 - 2.05 (m, 1H), 1.77 - 1.70 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.01 - 0.93 (m, 1H), 0.85 (d, J = 6.0 Hz, 3H). Example 452: 5-((1*S,2*S,5*R,6*S)-2-(3-Chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000505_0001
[001027] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 53) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(3-chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% iPrOH/CO 2; Rt = 4.58 min) provided the title compound. MS (ESI): mass calcd. for C21H21ClN6O3S, 472.1; m/z found, 473.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 8.5 Hz, 1H), 8.42 - 8.33 (m, 2H), 8.04 (dd, J = 8.1, 1.3 Hz, 1H), 7.65 (br s, 1H), 7.38 (dd, J = 8.0, 4.6 Hz, 1H), 6.82 - 6.73 (m, 1H), 6.70 - 6.60 (m, 1H), 5.80 (d, J = 4.9 Hz, 1H), 4.83 - 4.70 (m, 1H), 4.19 (d, J = 11.0 Hz, 1H), 3.92 (dd, J = 10.9, 4.9 Hz, 1H), 3.11 - 3.03 (m, 1H), 2.97 (s, 3H), 2.84 - 2.74 (m, 1H), 2.04 (t, J = 3.6 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 453: 5-((1*R,2*R,5*S,6*R)-2-(3-Chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000505_0002
[001028] The title compound was prepared in a manner analogous to Example 144 using rac- ((1*S,2*S,5*R,6*S)-2-(3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 53) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5- chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac- (1*S,2*S,5*R,6*S)-2-(3-chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); 503 QB\184200.00050\92364964.2 VVID-746PC Mobile phase: 40% iPrOH/CO2; Rt = 9.18 min) provided the title compound. MS (ESI): mass calcd. for C21H21ClN6O3S, 472.1; m/z found, 473.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.5 Hz, 1H), 8.36 (dd, J = 4.6, 1.3 Hz, 2H), 8.03 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (br s, 1H), 7.37 (dd, J = 8.0, 4.6 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.68 - 6.62 (m, 1H), 5.80 (d, J = 5.0 Hz, 1H), 4.80 - 4.72 (m, 1H), 4.19 (d, J = 11.0 Hz, 1H), 3.92 (dd, J = 11.1, 5.1 Hz, 1H), 3.06 (ddd, J = 7.8, 4.7, 3.6 Hz, 1H), 2.97 (s, 3H), 2.78 (td, J = 7.8, 4.1 Hz, 1H), 2.05 (t, J = 3.6 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 454: 5-((7*R,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000506_0001
[001029] The title compound was prepared in a manner analogous to Example 144 using 7-(2-chloro- 3-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine (Intermediate 125) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. Only the trans racemate was isolated from Step A. Separation of 5-(rac-(7*R,9a*R)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IC (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 11.4 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H27ClFN5O4S, 523.2; m/z found, 524.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.5 Hz, 1H), 8.53 (d, J = 1.3 Hz, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.33 - 7.14 (m, 3H), 6.81 - 6.62 (m, 2H), 5.08 (dd, J = 10.6, 4.7 Hz, 1H), 4.86 - 4.72 (m, 1H), 4.29 (dd, J = 12.1, 3.8 Hz, 1H), 3.91 - 3.76 (m, 2H), 3.62 - 3.52 (m, 1H), 3.23 (t, J = 10.3 Hz, 1H), 3.09 (dd, J = 11.9, 4.8 Hz, 1H), 2.98 (s, 3H), 2.93 (d, J = 12.0 Hz, 1H), 2.78 (br d, J = 11.7 Hz, 1H), 2.60 - 2.55 (m, 1H), 2.27 - 2.12 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H). Example 455: 5-((2*R,4*R)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000506_0002
504 QB\184200.00050\92364964.2 VVID-746PC [001030] The title compound was prepared in a manner analogous to Example 144 using 2-(2,3- difluorophenyl)-4-(trifluoromethyl)pyrrolidine (Intermediate 102) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. The cis (second eluting product) and trans (first eluting product) isomers were separated after Step A (FCC: 10-25% EtOAc in PE). Separation of 5-(rac- (2*R,4*R)-2-(2,3-difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 20% EtOH/CO2; Rt = 6.71 min) provided the title compound. MS (ESI): mass calcd. for C21H21F5N4O3S, 504.1; m/z found, 505.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.48 (m, 2H), 7.93 (s, 1H), 7.47 - 7.23 (m, 1H), 7.17 - 7.01 (m, 2H), 6.93 - 6.52 (m, 2H), 5.48 (t, J = 8.0 Hz, 1H), 4.79 (dq, J = 6.9, 1.3 Hz, 1H), 4.30 (dd, J = 10.8, 8.6 Hz, 1H), 3.89 (t, J = 10.1 Hz, 1H), 3.58 (br dd, J = 17.6, 8.9 Hz, 1H), 3.09 - 2.85 (m, 4H), 2.21 - 1.95 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 456: 5-((2*S,4*S)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000507_0001
[001031] The title compound was prepared in a manner analogous to Example 144 using 2-(2,3- difluorophenyl)-4-(trifluoromethyl)pyrrolidine (Intermediate 102) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. The cis (second eluting product) and trans (first eluting product) isomers were separated after Step A (FCC: 10-25% EtOAc in PE). Separation of 5-(rac- (2*R,4*R)-2-(2,3-difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 20% EtOH/CO2; Rt = 9.23 min) provided the title compound. MS (ESI): mass calcd. for C21H21F5N4O3S, 504.1; m/z found, 505.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.50 (m, 2H), 7.90 (s, 1H), 7.33 (br d, J = 8.3 Hz, 1H), 7.21 - 7.01 (m, 2H), 6.83 - 6.57 (m, 2H), 5.48 (t, J = 8.1 Hz, 1H), 4.78 (dt, J = 6.9, 5.8 Hz, 1H), 4.30 (dd, J = 10.7, 8.6 Hz, 1H), 3.88 (t, J = 10.1 Hz, 1H), 3.57 (br d, J = 8.9 Hz, 1H), 3.03 - 2.88 (m, 4H), 2.11 - 1.95 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 457: 5-((2*S,4*R)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 505 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000508_0001
[001032] The title compound was prepared in a manner analogous to Example 144 using 2-(2,3- difluorophenyl)-4-(trifluoromethyl)pyrrolidine (Intermediate 102) instead of (S)-2-(2- chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2- carboxylate, and DMSO instead of 1,4-dioxane in Step A. The cis (second eluting product) and trans (first eluting product) isomers were separated after Step A (FCC: 10-25% EtOAc in PE). Separation of 5-(rac- (2*S,4*R)-2-(2,3-difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% iPrOH/CO2; Rt = 3.98 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C21H21F5N4O3S, 504.1; m/z found, 505.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.48 (m, 2H), 7.96 (br s, 1H), 7.35 (br d, J = 8.5 Hz, 1H), 7.11 (br d, J = 4.8 Hz, 1H), 7.04 - 6.92 (m, 1H), 6.85 - 6.59 (m, 2H), 5.64 (br d, J = 6.6 Hz, 1H), 4.93 - 4.70 (m, 1H), 4.24 (dd, J = 10.9, 8.4 Hz, 1H), 3.87 (dd, J = 11.1, 8.0 Hz, 1H), 3.61 - 3.42 (m, 1H), 2.98 (s, 3H), 2.76 - 2.62 (m, 1H), 2.26 (br dd, J = 10.6, 7.4 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H). Example 458: 5-((*S)-2-(3-Fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide.
Figure imgf000508_0002
[001033] The title compound was prepared in a manner analogous to Example 224 using 2-(3-fluoro- 2-methoxyphenyl)pyrrolidine (Intermediate 88) instead of (S)-2-(2-chlorophenyl)pyrrolidine and methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate in Step A. Separation of 5-(2-(3-fluoro- 2-methoxyphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 10.5 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C21H25FN4O4S, 448.2; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 - 8.41 (m, 2H), 7.99 - 7.54 (m, 1H), 7.23 - 7.07 (m, 1H), 7.03 - 6.92 (m, 1H), 6.86 - 6.73 (m, 2H), 6.72 - 6.61 (m, 1H), 5.41 (br d, J = 6.9 Hz, 1H), 4.87 - 4.68 506 QB\184200.00050\92364964.2 VVID-746PC (m, 1H), 4.07 - 3.87 (m, 4H), 3.70 (br d, J = 10.1 Hz, 1H), 2.98 (s, 3H), 2.49 - 2.36 (m, 1H), 2.18 - 1.77 (m, 3H), 1.29 (d, J = 6.9 Hz, 3H). Example 459: 5-((2*S,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000509_0001
[001034] The title compound was prepared in a manner analogous to Example 224 using methyl 5- fluoropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chlorophenyl)-5- methylpyrrolidine (Intermediate 6) instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A. Separation of 5-(rac-2-(2-chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide (Step C) via RP-HPLC (40-60% ACN in 10 mM aq. NH4HCO3) provided the trans racemate, 5-(rac-(2*S,5*R)-2-(2-chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide. Separation of the trans racemate via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 50% EtOH/CO2; Rt = 6.15 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O3S, 448.1; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.06 (m, 2H), 7.58 - 7.42 (m, 1H), 7.32 - 7.14 (m, 3H), 6.97 - 6.87 (m, 1H), 6.82 - 6.74 (m, 1H), 6.73 - 6.61 (m,1H), 5.62 - 5.40 (m, 1H), 4.83 - 4.63 (m, 2H), 2.98 (s, 3H), 2.76 - 2.57 (m, 1H), 2.19 - 2.03 (m, 1H), 1.89 - 1.67 (m, 2H), 1.36 - 1.20 (m, 6H). Example 460: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4- (trifluoromethyl)nicotinamide.
Figure imgf000509_0002
[001035] The title compound was prepared in a manner analogous to Example 224 using methyl 6- chloro-4-(trifluoromethyl)nicotinate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C22H23ClF3N3O3S, 501.1; m/z found, 502.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 – 7.07 (m, 2H), 6.98 – 6.79 (m, 2H), 6.50 (dd, J = 15.1, 1.7 Hz, 2H), 6.16 (d, J = 7.9 Hz, 1H), 5.43 (s, 1H), 4.97 – 4.79 (m, 1H), 3.93 (s, 1H), 3.72 (s, 1H), 2.89 (s, 3H), 2.53 (q, J = 11.0 Hz, 1H), 2.17 – 1.81 (m, 3H), 1.38 (d, J = 7.1 Hz, 3H). 507 QB\184200.00050\92364964.2 VVID-746PC Example 461: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000510_0001
[001036] The title compound was prepared in a manner analogous to Example 224 using methyl 6- chloro-4-methylpyridine-3-carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C22H26ClN3O3S, 447.1; m/z found, 448.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.39 (dd, J = 7.8, 1.4 Hz, 1H), 7.15 (dtd, J = 22.4, 7.4, 1.6 Hz, 2H), 6.99 – 6.82 (m, 2H), 6.49 (dd, J = 15.2, 1.7 Hz, 1H), 5.98 (s, 2H), 5.33 (d, J = 8.1 Hz, 1H), 4.94 – 4.82 (m, 1H), 3.98 – 3.85 (m, 1H), 3.73 – 3.60 (m, 1H), 2.91 (s, 3H), 2.52 – 2.39 (m, 1H), 2.32 (s, 3H), 2.08 – 1.93 (m, 3H), 1.38 (d, J = 7.1 Hz, 3H). Example 462: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)nicotinamide.
Figure imgf000510_0002
[001037] The title compound was prepared in a manner analogous to Example 224 using methyl 6- chloro-2-methylpyridine-3-carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C22H26ClN3O3S, 447.1; m/z found, 448.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 7.8, 1.4 Hz, 2H), 7.21 – 7.07 (m, 2H), 7.00 (dd, J = 7.7, 1.8 Hz, 1H), 6.89 (dd, J = 15.1, 4.9 Hz, 1H), 6.47 (dd, J = 15.1, 1.7 Hz, 1H), 5.90 (d, J = 8.7 Hz, 1H), 5.67 (d, J = 7.6 Hz, 1H), 5.31 – 5.20 (m, 1H), 4.89 (q, J = 6.4 Hz, 1H), 3.97 (s, 1H), 3.78 (q, J = 8.7 Hz, 1H), 2.92 (s, 3H), 2.62 – 2.41 (m, 4H), 2.05 – 1.90 (m, 3H), 1.38 (d, J = 7.0 Hz, 3H). Example 463: 5-((1*S,2*R,5*R)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 508 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000511_0001
[001038] The title compound was prepared in a manner analogous to Example 224 using rac- (1*R,2*S,5*S)-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 116) instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 5-chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate in Step A. Separation of 5-(2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 4.75 min) provided the title compound. MS (ESI): mass calcd. for C21H23FN4O3S, 430.1; m/z found, 431.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.48 (m, 2H), 7.66 (s, 1H), 7.34 - 7.19 (m, 2H), 7.10 - 7.01 (m, 1H), 6.89 (br t, J = 7.5 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.70 - 6.59 (m, 1H), 5.51 (d, J = 5.2 Hz, 1H), 4.78 (td, J = 7.0, 5.7 Hz, 1H), 4.04 (d, J = 10.8 Hz, 1H), 3.85 (dd, J = 10.8, 5.3 Hz, 1H), 2.98 (s, 3H), 2.32 - 2.13 (m, 1H), 2.02 - 1.86 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 0.65 (td, J = 7.9, 5.2 Hz, 1H), 0.30 (q, J = 4.2 Hz, 1H). Example 464: 5-((1*R,2*S,5*S)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000511_0002
[001039] The title compound was prepared in a manner analogous to Example 224 using rac- (1*R,2*S,5*S)-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 116) instead of (S)-2-(2- chlorophenyl)pyrrolidine and methyl 5-chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate in Step A. Separation of 5-(2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 45% iPrOH/CO2; Rt = 7.50 min) provided the title compound. MS (ESI): mass calcd. for C21H23FN4O3S, 430.1; m/z found, 431.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.50 (m, 2H), 7.63 (s, 1H), 7.36 - 7.20 (m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 6.90 (br t, J = 7.3 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.71 - 6.62 (m, 1H), 5.51 (d, J = 5.2 Hz, 1H), 4.88 - 4.63 (m, 1H), 4.03 (d, J = 10.6 Hz, 1H), 3.85 (dd, J = 10.6, 5.2 Hz, 1H), 2.97 (s, 3H), 2.33 - 2.17 (m, 1H), 1.96 (td, J = 7.8, 3.8 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.65 (td, J = 7.8, 5.2 Hz, 1H), 0.30 (q, J = 4.2 Hz, 1H). 509 QB\184200.00050\92364964.2 VVID-746PC Example 465: 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)nicotinamide.
Figure imgf000512_0001
[001040] The title compound was prepared in a manner analogous to Example 224 using methyl 6- chloro-4-methoxypyridine-3-carboxylate instead of methyl 6-fluoronicotinate in Step A. MS (ESI): mass calcd. for C22H26ClN3O4S, 463.1; m/z found, 464.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.44 – 7.33 (m, 2H), 7.25 – 7.15 (m, 2H), 7.05 (dd, J = 7.0, 2.5 Hz, 1H), 6.91 – 6.83 (m, 2H), 6.47 (dd, J = 15.1, 1.7 Hz, 1H), 5.33 (s, 1H), 4.96 – 4.84 (m, 1H), 4.08 – 3.97 (m, 1H), 3.94 – 3.81 (m, 1H), 3.75 (s, 3H), 2.93 (s, 3H), 2.63 – 2.48 (m, 1H), 2.14 – 2.00 (m, 3H), 1.35 (d, J = 7.1 Hz, 3H). Example 466: 5-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000512_0002
[001041] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A and using (R,E)-4- (cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2- amine in Step C. Separation of 5-(rac-2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% MeOH/CO2 with 0.1% NH4OH; Rt = 4.87 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.46 (m, 2H), 8.05 - 7.58 (m, 1H), 7.37 - 7.19 (m, 2H), 6.92 (d, J = 7.4 Hz, 1H), 6.83 - 6.73 (m, 1H), 6.71 - 6.57 (m, 1H), 5.47 (br d, J = 8.0 Hz, 1H), 4.86 - 4.72 (m, 1H), 4.02 (br t, J = 8.3 Hz, 1H), 3.79 - 3.59 (m, 1H), 2.65 - 2.58 (m, 1H), 2.46 (br s, 1H), 2.16 - 2.02 (m, 1H), 1.99 - 1.81 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H), 1.04 - 0.86 (m, 4H). 510 QB\184200.00050\92364964.2 VVID-746PC Example 467: 5-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000513_0001
[001042] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and 2-(2-chloro-3- fluorophenyl)pyrrolidine instead of (S)-2-(2-chlorophenyl)pyrrolidine in Step A and using (R,E)-4- (cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (R,E)-4-methylsulfonylbut-3-en-2- amine in Step C. Separation of 5-(rac-2-(2-chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) by SFC (Stationary phase: IH (3x25 cm); Mobile phase: 40% MeOH/CO2 with 0.1% NH4OH; Rt = 6.89 min) provided the title compound. MS (ESI): mass calcd. for C22H24ClFN4O3S, 478.1; m/z found, 479.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.46 (m, 2H), 8.01 - 7.53 (m, 1H), 7.37 - 7.21 (m, 2H), 6.93 (br d, J = 7.4 Hz, 1H), 6.81 - 6.74 (m, 1H), 6.71 - 6.62 (m, 1H), 5.47 (br d, J = 8.0 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.10 - 3.97 (m, 1H), 3.79 - 3.63 (m, 1H), 2.69 - 2.57 (m, 1H), 2.47 (br s, 1H), 2.15 - 2.00 (m, 1H), 1.97 - 1.80 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H), 1.02 - 0.88 (m, 4H). Example 468: 5-((3a*S,4*R,6a*R)-4-(2-Chlorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000513_0002
[001043] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and rac-(3a*R,4*S,6a*S)-4-(2- chlorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 42) instead of (S)-2-(2- chlorophenyl)pyrrolidine in Step A. Separation of 5-(rac-(3a*S,4*R,6a*R)-4-(2-chlorophenyl)tetrahydro- 1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 5.61 min) provided the title compound. MS (ESI): mass calcd. for C22H25ClN4O4S, 476.1; m/z found, 477.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.51 (m, 2H), 7.65 (br d, J = 14.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.29 (t, 511 QB\184200.00050\92364964.2 VVID-746PC J = 7.6 Hz, 1H), 7.21 (br t, J = 7.5 Hz,1H), 7.01 (d, J = 7.8 Hz, 1H), 6.82 - 6.74 (m, 1H), 6.71 - 6.62 (m, 1H), 5.65 (d, J = 9.2 Hz, 1H), 4.78 (br d, J = 6.3 Hz, 1H), 4.34 - 4.23 (m, 1H), 3.81 - 3.75 (m, 1H), 3.74 - 3.65 (m, 2H), 3.64 - 3.55 (m, 1H), 3.38 (dd, J = 9.2, 7.5 Hz, 1H), 3.31 - 3.22 (m, 1H), 3.08 (dd, J = 9.5, 3.8 Hz, 1H), 2.98 (d, J = 2.4 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H). Example 469: 5-((3a*R,4*S,6a*S)-4-(2-Chlorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000514_0001
[001044] The title compound was prepared in a manner analogous to Example 224 using methyl 5- chloropyrazine-2-carboxylate instead of methyl 6-fluoronicotinate and rac-(3a*R,4*S,6a*S)-4-(2- chlorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 42) instead of (S)-2-(2- chlorophenyl)pyrrolidine in Step A. Separation of 5-(rac-(3a*S,4*R,6a*R)-4-(2-chlorophenyl)tetrahydro- 1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 50% iPrOH/CO2; Rt = 12.6 min) provided the title compound. MS (ESI): mass calcd. for C22H25ClN4O4S, 476.1; m/z found, 477.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.53 (m, 2H), 7.63 (br s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.29 (dt, J = 7.6, 1.4 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.70 - 6.63 (m, 1H), 5.64 (d, J = 9.2 Hz, 1H), 4.84 - 4.71 (m, 1H), 4.29 (dd, J = 11.3, 9.1 Hz, 1H), 3.80 - 3.75 (m, 1H), 3.73 - 3.65 (m, 2H), 3.64 - 3.55 (m, 1H), 3.38 (dd, J = 9.3, 7.4 Hz, 1H), 3.32 - 3.21 (m, 1H), 3.08 (dd, J = 9.4, 3.7 Hz, 1H), 2.97 (s, 3H), 1.29 (d, J = 6.9 Hz, 3H). Example 470: 5-((2*R,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000514_0002
[001045] To a solution of 5-(2-chlorophenyl)pyrrolidin-3-yl acetate (Intermediate 17, 2.0 g, 8.34 mmol, 1.0 eq) in DMSO (20 mL, 0.4M) was added methyl 5-chloropyrazine-2-carboxylate (1.7 g, 10.0 mmol, 1.2 eq) and TEA (1.7 mL, 12.5 mmol, 1.5 eq). The reaction was stirred at 100 ℃ for 10 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic layers 512 QB\184200.00050\92364964.2 VVID-746PC were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC (20-50% EtOAc in PE) to provide methyl 5-(2-(2-chlorophenyl)-4-methoxypyrrolidin- 1-yl)pyrazine-2-carboxylate (1.4 g, 45% yield) as a pale yellow oil. [001046] Methyl 5-(2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)pyrazine-2-carboxylate was elaborated in a manner analogous to Example 276, Steps B-E. Separation of 5-2-(2-chlorophenyl)-4- methoxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Step E) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 60% MeOH/CO2; Rt = 7.02 min, third eluting product) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O4S, 464.1; m/z found, 465.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br d, J = 8.3 Hz, 2H), 7.79 - 7.55 (m, 1H), 7.52 - 7.44 (m, 1H), 7.33 - 7.16 (m, 3H), 6.83 - 6.74 (m, 1H), 6.71 - 6.62 (m, 1H), 5.41 (br t, J = 7.3 Hz, 1H), 4.85 - 4.71 (m, 1H), 4.19 - 4.13 (m, 1H), 4.11 - 4.02 (m, 1H), 4.02 - 3.91 (m, 1H), 3.29 (s, 3H), 2.98 (s, 3H), 2.69 - 2.59 (m, 1H), 2.11 - 2.01 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H). Example 471: 5-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000515_0001
[001047] Separation of 5-2-(2-chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide (Example 469, Step E) via SFC (Stationary phase: OZ (3x25 cm); Mobile phase: 60% MeOH/CO2; Rt = 10.4 min, fourth eluting product) provided the title compound. MS (ESI): mass calcd. for C21H25ClN4O4S, 464.1; m/z found, 465.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.49 (m, 2H), 7.83 - 7.61 (m, 1H), 7.50 - 7.41 (m, 1H), 7.26 - 7.08 (m, 3H), 6.84 - 6.75 (m, 1H), 6.72 - 6.64 (m, 1H), 5.48 - 5.38 (m, 1H), 4.79 (dt, J = 6.9, 5.7 Hz, 1H), 4.25 - 4.15 (m, 1H), 4.10 - 4.00 (m, 1H), 3.96 - 3.87 (m, 1H), 3.11 (s, 3H), 2.98 (s, 3H), 2.75 - 2.63 (m, 1H), 2.13 (br d, J = 13.0 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). Example 472: 5-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000515_0002
513 QB\184200.00050\92364964.2 VVID-746PC [001048] The title compound was prepared in a manner analogous to Example 1, Steps B-C, from methyl 5-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazine-2-carboxylate (Example 469, Step B). Separation of 5-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 42% EtOH/CO2; Rt = 8.75 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C20H23ClN4O4S, 450.1; m/z found, 451.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br d, J = 8.8 Hz, 2H), 7.83 - 7.56 (m, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.27 - 7.16 (m, 3H), 6.85 - 6.74 (m, 1H), 6.71 - 6.63 (m, 1H), 5.39 (br dd, J = 2.8, 9.0 Hz, 1H), 5.01 (s, 1H), 4.86 - 4.73 (m, 1H), 4.52 (br s, 1H), 3.97 - 3.90 (m, 1H), 3.87 - 3.80 (m, 1H), 2.98 (s, 3H), 2.75 - 2.61 (m, 1H), 1.98 (br d, J = 13.0 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H). Example 473: 5-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide.
Figure imgf000516_0001
[001049] The title compound was prepared in a manner analogous to Example 1, Steps B-C, from methyl 5-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazine-2-carboxylate (Example 469, Step B). Separation of 5-(2-(2-chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH/CO2; Rt = 9.12 min, fourth eluting product) provided the title compound. MS (ESI): mass calcd. for C20H23ClN4O4S, 450.1; m/z found, 451.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br d, J = 8.5 Hz, 2H), 7.80 - 7.52 (m, 1H), 7.50 - 7.44 (m, 1H), 7.31 - 7.16 (m, 3H), 6.84 - 6.74 (m, 1H), 6.70 - 6.61 (m, 1H), 5.46 (br t, J = 7.3 Hz, 1H), 5.25 (d, J = 3.9 Hz, 1H), 4.78 (dt, J = 7.0, 5.8 Hz, 1H), 4.53 - 4.39 (m, 1H), 4.03 (br dd, J = 11.1, 4.1 Hz, 1H), 3.82 (br s, 1H), 2.98 (s, 3H), 2.53 (br s, 1H), 2.04 - 1.92 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H). Example 474: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000516_0002
514 QB\184200.00050\92364964.2 VVID-746PC [001050] Step A: (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxypyrimidine-2-carbonitrile. 5-Bromo-4-methoxy-2-pyrimidinecarbonitrile (100 mg, 0.444 mmol, 1.0 eq), (S)-2-(2- chlorophenyl)pyrrolidine (89 mg, 0.466 mmol, 1.05 eq), RuPhos Pd G4 (38 mg, 0.044 mmol, 0.1 eq), and cesium carbonate (443 mg, 1.33 mmol, 3.0 eq) were taken up in toluene (2.2 mL, 0.2M). The reaction was placed under N2 and heated to 100 °C for 18 hours. After cooling to rt, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (0-70% EtOAc in heptanes) provided (S)-5-(2- (2-chlorophenyl)pyrrolidin-1-yl)-4-methoxypyrimidine-2-carbonitrile (25 mg, 18% yield). MS (ESI): mass calcd. for C16H15ClN4O, 314.1; m/z found, 315.2 [M+H]+. [001051] Step B: (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxypyrimidine-2-carboxylic acid. (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxypyrimidine-2-carbonitrile (25 mg, 0.079 mmol, 1.0 eq) was taken up in 10% aq. NaOH (1 mL) and stirred at 100 °C for 10 h. After cooling to rt, the reaction was diluted with water and adjusted to pH ~4 with 1N HCl. The product was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was carried on without further purification. MS (ESI): mass calcd. for C16H16ClN3O3, 333.1; m/z found, 334.0 [M+H]+. [001052] Step C: 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide. (S)-5-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-4- methoxypyrimidine-2-carboxylic acid (18 mg, 0.054 mmol, 1.0 eq), (R,E)-4-methylsulfonylbut-3-en-2- amine (Intermediate 1, 18 mg, 0.057 mmol, 1.05 eq), and HATU (24 mg, 0.059 mmol, 1.1 eq) were taken up in DMF (0.5 mL, 0.1M). To this was added DIPEA (21 µL, 0.119 mmol, 2.2 eq) and the reaction was stirred at rt for 1 hour. Purification by RP-HPLC (10-95% ACN in 0.1% HCOOH water) provided 5-((S)- 2-(2-chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide (10 mg, 40% yield) as a white solid. MS (ESI): mass calcd. for C21H25ClN4O4S, 464.1; m/z found, 465.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.40 – 7.33 (m, 1H), 7.18 – 7.08 (m, 2H), 6.97 (dd, J = 7.2, 2.2 Hz, 1H), 6.90 (dd, J = 15.1, 4.6 Hz, 1H), 6.48 (dd, J = 15.1, 1.8 Hz, 1H), 5.51 (dd, J = 7.7, 4.7 Hz, 1H), 4.98 – 4.88 (m, 1H), 4.02 (dt, J = 10.2, 6.4 Hz, 1H), 3.90 (s, 3H), 3.65 (dt, J = 10.1, 7.1 Hz, 1H), 2.91 (s, 3H), 2.49 (dq, J = 12.4, 7.5 Hz, 1H), 2.09 – 1.98 (m, 2H), 1.93 – 1.83 (m, 1H), 1.41 (d, J = 7.1 Hz, 3H). Example 475: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4- methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000517_0001
515 QB\184200.00050\92364964.2 VVID-746PC [001053] The title compound was prepared in a manner analogous to Example 474 using (1R,2S,5S)- 2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 114) instead of (S)-2-(2- chlorophenyl)pyrrolidine and 5-bromo-4-methyl-2-pyrimidinecarbonitrile instead of 5-bromo-4-methoxy- 2-pyrimidinecarbonitrile in Step A. MS (ESI): mass calcd. for C22H22ClF3N4O3S, 514.1; m/z found, 515.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.41 - 7.20 (m, 2H), 7.04 (br d, J = 7.3 Hz, 1H), 6.85 - 6.64 (m, 2H), 5.82 (br t, J = 4.1 Hz, 1H), 4.84 - 4.70 (m, 1H), 4.35 - 4.21 (m, 1H), 3.50 - 3.41 (m, 1H), 3.02 - 2.93 (m, 4H), 2.82 - 2.70 (m, 1H), 2.63 (s, 3H), 1.28 (d, J = 7.0 Hz, 3H). Example 476: 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4- methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000518_0001
[001054] The title compound was prepare in a manner analogous to Example 474 using (1S,2R,5R)- 2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 115) instead of (S)-2-(2- chlorophenyl)pyrrolidine and 5-bromo-4-methyl-2-pyrimidinecarbonitrile instead of 5-bromo-4-methoxy- 2-pyrimidinecarbonitrile in Step A. MS (ESI): mass calcd. for C22H22ClF3N4O3S, 514.1; m/z found, 515.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.20 (m, 2H), 7.04 (br d, J = 7.8 Hz, 1H), 6.82 - 6.63 (m, 2H), 5.82 (br s, 1H), 4.82 - 4.69 (m, 1H), 4.29 (br d, J = 9.9 Hz, 1H), 3.43 (td, J = 9.2, 4.4 Hz, 1H), 3.04 - 2.93 (m, 4H), 2.82 - 2.71 (m, 1H), 2.63 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H). Example 477: 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000518_0002
[001055] The title compound was prepared in a manner analogous to Example 474 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 97) instead of (S)-2-(2-chlorophenyl)pyrrolidine and 5-bromo-4-methyl-2-pyrimidinecarbonitrile instead of 5- 516 QB\184200.00050\92364964.2 VVID-746PC bromo-4-methoxy-2-pyrimidinecarbonitrile in Step A. Separation of 5-(rac-(1*R,2*S,5*S,6*S)-2-(2- chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 4.75 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O3S, 492.1; m/z found, 493.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.37 - 7.16 (m, 2H), 6.98 (d, J = 7.4 Hz, 1H), 6.82 - 6.63 (m, 2H), 5.40 (d, J = 4.3 Hz, 1H), 4.82 - 4.61 (m, 1H), 4.07 (d, J = 9.0 Hz, 1H), 3.11 (dd, J = 9.1, 3.9 Hz, 1H), 2.97 (s, 3H), 2.61 (s, 3H), 1.82 (td, J = 7.2, 3.6 Hz, 1H), 1.62 - 1.51 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H), 1.22 (td, J = 6.2, 3.2 Hz, 1H), 0.90 (d, J = 6.0 Hz, 3H). Example 478: 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000519_0001
[001056] The title compound was prepared in a manner analogous to Example 474 using rac- (1*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 97) instead of (S)-2-(2-chlorophenyl)pyrrolidine and 5-bromo-4-methyl-2-pyrimidinecarbonitrile instead of 5- bromo-4-methoxy-2-pyrimidinecarbonitrile in Step A. Separation of 5-(rac-(1*R,2*S,5*S,6*S)-2-(2- chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-O1 (3x25 cm); Mobile phase: 35% MeOH/CO2; Rt = 10.7 min) provided the title compound. MS (ESI): mass calcd. for C23H26ClFN4O3S, 492.1; m/z found, 493.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.33 - 7.16 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.71 - 6.63 (m, 1H), 5.40 (d, J = 4.4 Hz, 1H), 4.85 - 4.62 (m, 1H), 4.07 (d, J = 9.0 Hz, 1H), 3.11 (dd, J = 9.1, 4.1 Hz, 1H), 2.98 (s, 3H), 2.61 (s, 3H), 1.82 (td, J = 7.3, 3.6 Hz, 1H), 1.57 (td, J = 7.1, 3.6 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.22 (td, J = 6.2, 3.2 Hz, 1H), 0.90 (d, J = 6.1 Hz, 3H). Example 479: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((E)-4-(methylsulfonyl)allyl)pyrimidine-2-carboxamide. 517 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000520_0001
[001057] 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)pyrimidine-2-carboxylic acid (Intermediate 136, 25 mg, 0.068 mmol, 1.0 eq) was taken up in DMF (0.17 mL, 0.2M). To this was added HATU (41 mg, 0.101 mmol, 1.5 eq), (2E)-3-(methylsulfonyl)-2-propen-1- amine (10 mg, 0.074 mmol, 1.1 eq), and DIPEA (94 µL, 0.541 mmol, 8.0 eq). The reaction was stirred for 1 h at rt then filtered through a PTFE filter and purified by RP-HPLC (10-100% ACN in 0.1% HCOOH water). This provided 5-((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((E)-4-(methylsulfonyl)allyl)pyrimidine-2-carboxamide (14 mg, 43% yield) as a white solid. MS (ESI): mass calcd. for C20H18ClF3N4O3S, 486.1; m/z found, 487.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.05 – 7.96 (m, 1H), 7.92 (s, 2H), 7.20 – 7.10 (m, 2H), 6.97 (dt, J = 15.1, 4.2 Hz, 1H), 6.88 (td, J = 5.6, 3.6 Hz, 1H), 6.48 (dt, J = 15.1, 2.0 Hz, 1H), 5.56 (dd, J = 6.0, 2.9 Hz, 1H), 4.40 – 4.23 (m, 3H), 3.98 – 3.88 (m, 1H), 3.14 – 3.04 (m, 1H), 2.91 (s, 3H), 2.67 – 2.56 (m, 1H). Example 480: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)pent-1-en-3-yl)pyrimidine-2-carboxamide.
Figure imgf000520_0002
[001058] The title compound was prepared in a manner analogous to Example 479 using (R,E)-1- (methylsulfonyl)pent-1-en-3-amine (Intermediate 35) instead of (2E)-3-(methylsulfonyl)-2-propen-1- amine. MS (ESI): mass calcd. for C22H22ClF3N4O3S, 514.1; m/z found, 515.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.19 – 7.08 (m, 2H), 6.93 – 6.81 (m, 2H), 6.46 (dd, J = 15.1, 1.7 Hz, 1H), 5.54 (dd, J = 6.0, 2.9 Hz, 1H), 4.85 – 4.74 (m, 1H), 4.32 (d, J = 9.8 Hz, 1H), 3.96 – 3.84 (m, 1H), 3.14 – 3.03 (m, 1H), 2.88 (s, 3H), 2.66 – 2.55 (m, 1H), 1.86 – 1.72 (m, 1H), 1.72 – 1.60 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H). Example 481: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide. 518 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000521_0001
[001059] The title compound was prepared in a manner analogous to Example 479 using (S,E)-4- methylsulfonylbut-3-en-2-amine (Intermediate 34) instead of (2E)-3-(methylsulfonyl)-2-propen-1-amine. MS (ESI): mass calcd. for C21H20ClF3N4O3S, 500.1; m/z found, 501.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.20 – 7.09 (m, 2H), 6.94 – 6.82 (m, 2H), 6.46 (dd, J = 15.1, 1.7 Hz, 1H), 5.55 (dd, J = 6.0, 2.9 Hz, 1H), 5.03 – 4.90 (m, 1H), 4.33 (d, J = 9.9 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.15 – 3.03 (m, 1H), 2.91 (s, 3H), 2.67 – 2.56 (m, 1H), 1.41 (d, J = 7.1 Hz, 3H). Example 482: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- -1-cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-2-carboxamide.
Figure imgf000521_0002
[001060] The title compound was prepared in a manner analogous to Example 479 using (R,E)-1- cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (Intermediate 36) instead of (2E)-3-(methylsulfonyl)-2- propen-1-amine. MS (ESI): mass calcd. for C23H22ClF3N4O3S, 526.1; m/z found, 527.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.92 (m, 3H), 7.22 – 7.08 (m, 2H), 6.99 (dd, J = 15.2, 4.4 Hz, 1H), 6.90 (td, J = 5.8, 3.3 Hz, 1H), 6.52 (dd, J = 15.1, 1.8 Hz, 1H), 5.57 (dd, J = 6.0, 2.9 Hz, 1H), 4.35 (d, J = 9.9 Hz, 1H), 4.22 – 4.12 (m, 1H), 3.98 – 3.87 (m, 1H), 3.16 – 3.05 (m, 1H), 2.92 (s, 3H), 2.69 – 2.57 (m, 1H), 1.09 – 0.97 (m, 1H), 0.75 – 0.67 (m, 1H), 0.67 – 0.56 (m, 1H), 0.52 – 0.37 (m, 2H). Example 483: 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide. 519 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000522_0001
[001061] The title compound was prepared in a manner analogous to Example 479 using
Figure imgf000522_0002
(cyclopropylsulfonyl)but-3-en-2-amine (Intermediate 37) instead of (2E)-3-(methylsulfonyl)-2-propen-1- amine. MS (ESI): mass calcd. for C23H22ClF3N4O3S, 526.1; m/z found, 527.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.6 Hz, 1H), 7.93 (s, 2H), 7.45 - 7.35 (m, 1H), 7.29 (dt, J = 8.0, 5.6 Hz, 1H), 6.97 - 6.86 (m, 1H), 6.82 - 6.74 (m, 1H), 6.70 - 6.60 (m, 1H), 5.62 (dd, J = 5.8, 2.4 Hz, 1H), 4.78 (dt, J = 7.0, 5.7 Hz, 1H), 4.36 (d, J = 10.3 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.26 (ddd, J = 11.9, 10.5, 6.1 Hz, 1H), 2.92 (dt, J = 11.1, 6.6 Hz, 1H), 2.66 - 2.55 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.06 - 0.91 (m, 4H). Example 484: 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.
Figure imgf000522_0003
[001062] The title compound was prepared in a manner analogous to Example 479 using 5- ((1S,2R,5R)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2- carboxylic acid (Intermediate 137) instead of 5-((1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylic acid and (R,E)-4-(cyclopropylsulfonyl)but-3-en-2- amine (Intermediate 37) instead of (2E)-3-(methylsulfonyl)-2-propen-1-amine. MS (ESI): mass calcd. for C23H22ClF3N4O3S, 526.1; m/z found, 527.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.4 Hz, 1H), 7.93 (s, 2H), 7.46 - 7.36 (m, 1H), 7.29 (dt, J = 8.1, 5.6 Hz, 1H), 6.96 - 6.87 (m, 1H), 6.81 - 6.71 (m, 1H), 6.70 - 6.61 (m, 1H), 5.61 (dd, J = 5.9, 2.5 Hz, 1H), 4.77 (dt, J = 6.9, 5.8 Hz, 1H), 4.35 (d, J = 10.3 Hz, 1H), 4.02 - 3.87 (m, 1H), 3.30 - 3.20 (m, 1H), 2.92 (dt, J = 11.2, 6.2 Hz, 1H), 2.65 - 2.57 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.04 - 0.91 (m, 4H). In vitro ELISA Target Engagement Assay for PIK3CA [001063] Engagement of compounds on PIK3CA were assessed in Jurkat cellular lysate via a sandwich ELISA. 520 QB\184200.00050\92364964.2 VVID-746PC Synthesis of PIK3CA Biotin Probe (R,Z)-4-((4-(1,3-Dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-amine
Figure imgf000523_0001
[001064] Step A: tert-Butyl (R)-(4-((4-(1,3-dioxolan-2-yl)butyl)thio)but-3-yn-2-yl)carbamate. To a solution of tert-butyl (R)-but-3-yn-2-ylcarbamate (0.90 g, 5.32 mmol, 1.0 eq) in THF (50 mL, 0.09 M) under nitrogen at -70°C was slowly added 2.5M n-butyllithium (4.7 mL, 11.7 mmol, 2.2 eq). The mixture was stirred for 1 h before sulfur (171 mg, 0.660 mmol, 0.12 eq) was added, causing the solution to become red. The reaction mixture was stirred 30 min at -70°C then 30 min at 0°C until consumption of sulfur was complete (dark red solution). 2-(4-Bromobutyl)-1,3-dioxolane (1.1 g, 5.32 mmol, 1.0 eq) in THF (10 mL) was added and the reaction mixture was stirred at 0°C for 2 h. Sat. aq. ammonium chloride was added and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column to give tert-butyl (R)-(4-((4-(1,3-dioxolan-2-yl)butyl)thio)but-3-yn-2-yl)carbamate (1.0 g, 57% yield). [001065] Step B: tert-Butyl (R)-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-yn-2-yl)carbamate. To a solution of tert-butyl (R)-(4-((4-(1,3-dioxolan-2-yl)butyl)thio)but-3-yn-2-yl)carbamate (200 mg, 0.610 mmol, 1.0 eq) in ethyl acetate (2.0 mL, 0.3 M) was added 3-chloroperbenzoic acid (262 mg, 1.52 mmol, 2.5 eq) at 0 ˚C. The mixture was allowed to warm to rt and stirred 16 hours. The mixture was poured into sat. aq. Na 2SO3 and extracted with ethyl acetate. The combined organic layers were washed with sat. aq. sodium bicarbonate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product tert- butyl (R)-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-yn-2-yl)carbamate (250 mg, quant. yield) was used the next step directly without further purification. [001066] Step C: tert-Butyl (R,Z)-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-yl)carbamate. To a solution of tert-butyl (R)-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-yn-2-yl)carbamate (250 mg, 0.690 mmol, 1.0 eq) in THF (3.0 mL, 0.23 M) was added Pd/C (250 mg) and the reaction was stirred at rt for 30 min under H2 (50 psi). The solution was filtered to get the crude product which was purified by FCC (0-25% EtOAc in PE) to provide tert-butyl (R,Z)-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-en-2- yl)carbamate (130 mg, 52% yield) as a white solid. [001067] Step D: (R,Z)-4-((4-(1,3-Dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-amine. To a solution of tert-butyl (R,Z)-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-yl)carbamate (130 mg, 0.358 mmol, 521 QB\184200.00050\92364964.2 VVID-746PC 1.0 eq) in acetonitrile (2.0 mL, 0.18 M) was added p-toluenesulfonic acid monohydrate (82 mg, 0.430 mmol, 1.2 eq) and the reaction was stirred at 50℃ for 2 h. The crude solution was evaporated to get the 4- methylbenzenesulfonic acid salt of (R,Z)-4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-amine (160 mg, quant. yield). 1-((5-Bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((5-(4-(2-(2-(2-(5- ((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4- yl)pentanamido)ethoxy)ethoxy)acetyl)piperazin-1-yl)pentyl)sulfonyl)but-3-en-2-yl)piperidine-4- carboxamide (PIK3CA Biotin Probe)
Figure imgf000524_0001
[001068] Step 1: 4-Bromo-2-iodo-benzenesulfonyl chloride. To a solution of 4-bromo-2-iodo- aniline (1.0 g, 3.36 mmol, 1.0 eq) in concentrated HCl (15 mL) and acetic acid (5 mL, 0.088 M) was added NaNO2 (254 mg, 1.1 eq) at 0℃. This mixture 1 was stirred at 0℃ for 1 hour. In a separate flask, SO2 was bubbled through acetic acid (33 mL, 0.088 M) for about 10 min at 0℃ before CuCl (99 mg, 0.3 eq) was added. SO2 was bubbled through mixture 2 for about 10 min. Mixture 1 was added to the mixture 2 at 0℃. The resulting mixture was stirred at 0-20℃ for 1 hour. The reaction mixture was quenched with water 522 QB\184200.00050\92364964.2 VVID-746PC and extracted with methyl tert-butyl ether. The combined organic layers were washed with sat. aq. sodium bicarbonate and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC (PE:EtOAc 50:1) to give 4-bromo-2-iodo-benzenesulfonyl chloride (4.0 g, 62% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 8.6, 1.9 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H). [001069] Step 2: Ethyl 1-(4-bromo-2-iodo-phenyl)sulfonyl-4-fluoro-piperidine-4-carboxylate. To a solution of 4-bromo-2-iodo-benzenesulfonyl chloride (3.6 g, 9.44 mmol, 1.0 eq) and ethyl 4- fluoropiperidine-4-carboxylate hydrochloride (2.0 g, 9.44 mmol, 1.0 eq) in dichloromethane (10 mL, 0.94 M) was added triethylamine (2.86 g, 28.3 mmol, 3.0 eq) dropwise at 0°C. The reaction was stirred at rt for 1 hour before being quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC to give ethyl 1-(4-bromo-2-iodo-phenyl)sulfonyl-4-fluoro-piperidine-4- carboxylate (4.3 g, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 8.4, 1.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.75 (dt, J = 13.0, 2.6 Hz, 2H), 3.18 (td, J = 12.8, 2.7 Hz, 2H), 2.12 - 2.31 (m, 2H), 1.99 - 2.08 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). [001070] Step 3: Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-piperidine-4- carboxylate. To a solution of ethyl 1-(4-bromo-2-iodo-phenyl)sulfonyl-4-fluoro-piperidine-4-carboxylate (878 mg, 1.69 mmol, 1.0 eq) in 1,4-dioxane (9.0 mL, 0.19 M) and 1 M aq. K3PO4 (2.7 mL) was added 2- chlorophenylboronic acid (290 mg, 1.86 mmol, 1.1 eq) and tetrakis(triphenylphosphine) (195 mg, 0.169 mmol, 0.1 eq). The mixture was stirred at 80°C under nitrogen for 16 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc 3:1) to give ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro- piperidine-4-carboxylate (400 mg, 47% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 1.9, 8.5 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.43 - 7.27 (m, 3H), 4.22 (q, J = 7.0 Hz, 2H), 3.24 (br d, J = 13.4 Hz, 1H), 3.07 (br d, J = 13.3 Hz, 1H), 2.98 - 2.85 (m, 1H), 2.72 - 2.58 (m, 1H), 2.04 - 1.79 (m, 4H), 1.34 - 1.27 (m, 3H). [001071] Step 4: 1-[4-Bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-piperidine-4-carboxylic acid. Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-piperidine-4-carboxylate (460 mg, 0.911 mmol, 1.0 eq) and lithium hydroxide monohydrate (115 mg, 2.73 mmol, 3.0 eq) were taken up in THF/water (3:1, 8 mL, 0.11 M). The mixture was stirred at rt for 2 h before being concentrated and acidified with 6M HCl to adjust to pH 2-4. The resulting precipitate was collection by filtration to afford 1-[4-bromo- 2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-piperidine-4-carboxylic acid (400 mg, 92% yield) as a white solid. [001072] Step 5: (R,Z)-N-(4-((4-(1,3-Dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-yl)-1-((5-bromo-2'- chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide. To a solution of (R,Z)-4-((4-(1,3- 523 QB\184200.00050\92364964.2 VVID-746PC dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-amine, 4-methylbenzenesulfonic acid (153 mg, 0.352 mmol, 1.2 eq) in DCM (5.0 mL, 0.06 M) was added HATU (167 mg, 0.440 mmol, 1.5 eq) and N,N- diisopropylethylamine (0.13 mL, 0.734 mmol, 2.5 eq). After 5 mins, 1-[4-bromo-2-(2- chlorophenyl)phenyl]sulfonyl-4-fluoro-piperidine-4-carboxylic acid (140 mg, 0.294 mmol, 1.0 eq) was added and the reaction was stirred at rt for 2 h. The reaction was quenched with sat. aq. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give (R,Z)-N-(4-((4-(1,3-dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'- biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide (210 mg, quant. yield). [001073] Step 6: (R,Z)-1-((5-Bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-((5- oxopentyl)sulfonyl)but-3-en-2-yl)piperidine-4-carboxamide. To a solution of (R,Z)-N-(4-((4-(1,3- dioxolan-2-yl)butyl)sulfonyl)but-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4- fluoropiperidine-4-carboxamide (210 mg, 0.290 mmol, 1.0 eq) in trifluoroacetic acid (3.0 mL, 0.02 M) was added concentrated HCl (0.6 mL) under nitrogen. The reaction was stirred at rt for 2 h before being filtered and the filtrate concentrated to provide (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4- fluoro-N-(4-((5-oxopentyl)sulfonyl)but-3-en-2-yl)piperidine-4-carboxamide (200 mg, 96% yield). [001074] Step 7: tert-Butyl (R,Z)-4-(5-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4- fluoropiperidine-4-carboxamido)but-1-en-1-yl)sulfonyl)pentyl)piperazine-1-carboxylate. To a solution of (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-((5-oxopentyl)sulfonyl)but-3- en-2-yl)piperidine-4-carboxamide (200 mg, 0.300 mmol, 1.0 eq) in THF/DCE (1:1, 4.0 mL, 0.07 M) was added tert-butyl piperazine-1-carboxylate (66 mg, 0.354 mmol, 1.2 eq). DIPEA was added until pH ~5 and the mixture was stirred for 5 min at rt. NaBH(OAc)3 (248 mg, 4.0 eq) was added and the mixture was stirred at rt for 1 hour. The reaction was quenched with the water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by prep-HPLC to give tert-butyl (R,Z)-4-(5-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2- yl)sulfonyl)-4-fluoropiperidine-4-carboxamido)but-1-en-1-yl)sulfonyl)pentyl)piperazine-1-carboxylate (160 mg, 64% yield). [001075] Step 8: (R,Z)-1-((5-Bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-((5- (piperazin-1-yl)pentyl)sulfonyl)but-3-en-2-yl)piperidine-4-carboxamide. To a solution of tert-butyl (R,Z)- 4-(5-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamido)but-1- en-1-yl)sulfonyl)pentyl)piperazine-1-carboxylate (160 mg, 0.190 mmol, 1.0 eq) in acetonitrile (2.0 mL, 0.09 M) was added 4-methylbenzenesulfonic acid (39 mg, 0.230 mmol, 1.2 eq). The reaction was stirred at 50℃ for 30 min before the solution was evaporated to provide (R,Z)-1-((5-bromo-2'-chloro-[1,1'- biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-((5-(piperazin-1-yl)pentyl)sulfonyl)but-3-en-2-yl)piperidine-4- carboxamide (150 mg, quant. yield), which was used in the next step without further purification. 524 QB\184200.00050\92364964.2 VVID-746PC [001076] Step 9: tert-Butyl (R,Z)-(2-(2-(2-(4-(5-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2- yl)sulfonyl)-4-fluoropiperidine-4-carboxamido)but-1-en-1-yl)sulfonyl)pentyl)piperazin-1-yl)-2- oxoethoxy)ethoxy)ethyl)carbamate. To a solution of (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2- yl)sulfonyl)-4-fluoro-N-(4-((5-(piperazin-1-yl)pentyl)sulfonyl)but-3-en-2-yl)piperidine-4-carboxamide (142 mg, 0.190 mmol, 1 eq) in DCM (5.0 mL, 0.04 M) was added HATU (108 mg, 0.280 mmol, 1.5 eq) and N,N-diisopropylethylamine (83 µL, 0.470 mmol, 2.5 eq). After 5 min, 2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]acetic acid (50 mg, 0.190 mmol, 1 eq) was added and the reaction mixture was stirred at rt for 2 h. The reaction was quenched with sat. aq. NH4Cl extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by prep-TLC to give tert-butyl (R,Z)-(2-(2-(2-(4-(5-((3-(1-((5- bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamido)but-1-en-1- yl)sulfonyl)pentyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)carbamate (110 mg, 58% yield). [001077] Step 10: (R,Z)-N-(4-((5-(4-(2-(2-(2-Aminoethoxy)ethoxy)acetyl)piperazin-1- yl)pentyl)sulfonyl)but-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine- 4-carboxamide. To a solution of tert-butyl (R,Z)-(2-(2-(2-(4-(5-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]- 2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamido)but-1-en-1-yl)sulfonyl)pentyl)piperazin-1-yl)-2- oxoethoxy)ethoxy)ethyl)carbamate (110 mg, 0.110 mmol, 1.0 eq) in MeCN (20 mL, 0.006 M) was added 4-methylbenzenesulfonic acid (23 mg, 0.130 mmol, 1.2 eq). The reaction was stirred at 50℃ for 2 h before the solvent was evaporated to provide (R,Z)-N-(4-((5-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazin-1- yl)pentyl)sulfonyl)but-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine- 4-carboxamide (90 mg, 91% yield), which was used in the next step without further purification. [001078] Step 11: 1-((5-Bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((5-(4- (2-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4- yl)pentanamido)ethoxy)ethoxy)acetyl)piperazin-1-yl)pentyl)sulfonyl)but-3-en-2-yl)piperidine-4- carboxamide. To a solution of (R,Z)-N-(4-((5-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazin-1- yl)pentyl)sulfonyl)but-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine- 4-carboxamide (88 mg, 0.098 mmol, 1.2 eq) in DCM (5.0 mL, 0.02 M) was added HATU (47 mg, 0.120 mmol, 1.5 eq) and N,N-diisopropylethylamine (36 µL, 0.200 mmol, 2.5 eq). After 5 min, D-Biotin (20 mg, 0.082 mmol, 1.0 eq) was added and the reaction was stirred at er for 2 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers wre washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by prep-TLC to give 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((5-(4-(2-(2-(2-(5- ((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4- yl)pentanamido)ethoxy)ethoxy)acetyl)piperazin-1-yl)pentyl)sulfonyl)but-3-en-2-yl)piperidine-4- carboxamide (PIK3CA Biotin Probe) (10.9 mg, 12% yield). MS (ESI): mass calcd. for C47H66BrClFN7O10S3, 1119; m/z found, 1120 [M+H]+. 525 QB\184200.00050\92364964.2 VVID-746PC Biochemical Assay [001079] A solution of PIK3CA Biotin Probe was generated at 10 mM and used in the biological testing.
Figure imgf000528_0001
[001080] Treatment Protocol: Jurkat cellular lysate was generated from frozen cell pellets. Cells were thawed on ice and resuspended in cold Dulbecco’s phosphate buffered saline (DPBS) (12 mL/300e6 cells) then lysed by probe sonication (12x 3 second pulses). Jurkat lysate was plated (50 µl/well) in Armadillo 96 well PCR plates (Thermo Fisher catalog number AB2396). The lysate was treated with serial dilutions of test compounds up to 200 µM and incubated for 1 hour at room temperature. Following compound incubation, PIK3CA Biotin Probe was added to a final concentration of 500 nM, and lysate was mixed by pipetting gently and incubated for an additional 1 hour at room temperature. The mixture was then diluted in 75 µL Dilution buffer. The mixture was centrifuged for 5 minutes at 4122 g and stored at - 80ºC until ELISA TE detection. [001081] ELISA TE Detection: Quantification of PIK3CA TE was initiated by coating of the ELISA plate (Thermo Scientific White 384-Well Immuno plates; Thermo Fisher catalog number 460372). The capture antibody was diluted in plating buffer (1:83) and added to the ELISA plate, 20 µl/well, overnight at 4°C. The plate was then washed twice with PBST, 100 µl/well, and blocked with addition of blocking buffer (100 µl/well, 1 hour at room temperature). During block, treated and probe labeled lysate was thawed. After Block, the block buffer was removed and the thawed lysate was added to the ELISA plate, 30 µl/well, for 1.5 hours at room temperature. Following lysate incubation, the assay plate was washed 3 times with PBST, 100 µl/well. The Neutravidin-HRP was then diluted (1:500 in dilution buffer) and added for 1 hour at room temperature, 20 µl/well. Following incubation, the assay plate was washed 4 times with PBST, 100 µl/well, 526 QB\184200.00050\92364964.2 VVID-746PC HRP substrate was added to plate, 20 µl/well and luminescence signal was read (Clariostar Plate Reader). For each compound the potency of target engagement (TE50) was determined using Graphpad Prism. [001082] Representative Elisa target engagement is presented in Table 2.
Figure imgf000529_0001
527 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000530_0001
528 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000531_0001
529 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000532_0001
530 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000533_0001
531 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000534_0001
532 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000535_0001
533 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000536_0001
534 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000537_0001
535 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000538_0001
536 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000539_0001
537 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000540_0001
538 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000541_0001
539 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000542_0001
540 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000543_0001
541 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000544_0001
542 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000545_0001
543 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000546_0001
544 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000547_0001
545 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000548_0001
546 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000549_0001
547 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000550_0001
In vitro Phospho-AKT(S473) Analysis [001083] Functional activity of the compounds to inhibit pAKT were assessed in H358 cell lines as indicated below. Materials Complete Media FBS, Corning catalog #35-010-CV 548 QB\184200.00050\92364964.2 VVID-746PC Anti-Anti, Gibco catalog #15240-062 96 well plate, Corning catalog #3610 TrypLE, Gibco catalog #12604013 Phospho-AKT(S473) HTRF kit, Cisbio catalog #64AKSPET [001084] Cells were detached from the tissue culture flask with TrypLE. The cells were pelleted at 500 xg for 5 min, TrypLe was removed and then resuspended in the necessary volume of media + 1% FBS to give the appropriate cell density (17,500 cells/mL for FaDu; 20,000 cells/mL for H358). 100 µL of cell suspension/well was dispensed into the 96-well plate while keeping the outer wells of the plate free of cells and filled with PBS to prevent evaporation of interior wells. The plate was incubated at 37°C and allowed to adhere overnight. The cells were treated with a dose response of compound and incubated at 37°C for 30 minutes. The cells were then processed and pAKT(S473) levels were assessed following the specifications of the Cisbio HTRF kit. [001085] 1-[4-Bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-N-[(Z,1R)-1-methyl-3- methylsulfonyl-allyl]piperidine-4-carboxamide was used as an internal standard for the assay to normalize Imax and the absolute inhibition of pAKT for 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-N- [(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide varied from 40-89% for the H358 cell line. Synthesis of 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-N-[(Z,1R)-1-methyl-3- methylsulfonyl-allyl]piperidine-4-carboxamide
Figure imgf000551_0001
[001086] Step 1: tert-Butyl N-[(R)-1-methyl-3-methylsulfanyl-prop-2-ynyl]carbamate. n- Butyllithium solution (40 mL, 99.3 mmol, 2.1 eq) was added dropwise to a solution of tert-butyl N-[(1R)- 1-methylprop-2-ynyl]carbamate (8.0 g, 47.3 mmol, 1.0 eq) and N,N,N,N-tetramethylethylenediamine (5.5 g, 47.3 mmol, 1.0 eq) in anhydrous THF (30 mL, 0.24 M) at 0°C under N 2. After 30 minutes, 1-methyl-4- methylsulfanylsulfonyl-benzene (10 g, 49.6 mmol, 1.1 eq) in THF (80 mL, 0.60 M) was added and the 549 QB\184200.00050\92364964.2 VVID-746PC mixture was stirred at 0°C for 2 h. The reaction was quenched by addition of sat. aq. NH4Cl at 0°C then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by FCC on silica (PE:EtOAc = 5:1) to afford tert-butyl N-[(R)-1-methyl-3-methylsulfanyl-prop-2-ynyl]carbamate (9.0 g, 88% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.65 - 4.76 (m, 1H) 4.50 - 4.63 (m, 1H) 2.37 (s, 3H) 1.46 (s, 9H) 1.39 (d, J = 6.9 Hz, 3H). [001087] Step 2: tert-Butyl N-[(Z,R)-1-methyl-3-methylsulfanyl-allyl]carbamate. tert-Butyl N-[(R)- 1-methyl-3-methylsulfanyl-prop-2-ynyl]carbamate (3.0 g, 13.9 mmol, 1.0 eq), Lindlar catalyst (900 mg), and hexene (6 mL) were taken up in methanol (30 mL, 0.46 M). The mixture was stirred under H2 (30 psi) at 25°C for 3 h before being filtered. The filtrate was concentrated under vacuum and purified by FCC on silica (PE:EtOAc = 3:1) to afford tert-butyl N-[(Z,R)-1-methyl-3-methylsulfanyl-allyl]carbamate (2.6 g, 86% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 5.96 (d, J = 9.6 Hz, 1H), 5.43 (dd, J = 8.0, 9.5 Hz, 1H), 4.63 - 4.34 (m, 2H), 2.28 (s, 3H), 1.45 (s, 9H), 1.22 (d, J = 6.4 Hz, 3H). [001088] Step 3: tert-Butyl N-[(Z,R)-1-methyl-3-methylsulfonyl-allyl]carbamate. To a solution of tert-butyl N-[(Z,R)-1-methyl-3-methylsulfanyl-allyl]carbamate (2.6 g, 12.0 mmol, 1.0 eq) in DCM (10 mL, 1.2 M) was added 3-chloroperbenzoic acid (6.2 g, 35.9 mmol, 3.0 eq) in portions over 5 min. The mixture was stirred at 25°C for 2 h before being diluted with sat. aq. Na2SO3 and extracted with DCM. The combined extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (PE:EtOAc = 1:1) to afford tert-butyl N-[(Z,R)-1-methyl-3-methylsulfonyl-allyl]carbamate (2.4 g, 79% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.31 - 6.22 (m, 1H), 6.21 - 6.11 (m, 1H), 4.63 (s, 1H), 3.19 (s, 3H), 1.42 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). [001089] Step 4: (R,Z)-4-(Methylsulfonyl)but-3-en-2-amine. tert-Butyl N-[(Z,R)-1-methyl-3- methylsulfonyl-allyl]carbamate (2.4 g, 9.47 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (1.8 g, 9.47 mmol, 1.0 eq) were taken up in ACN (30 mL, 0.32 M). The mixture was stirred at 40°C for 16 h. After cooling to rt, the reaction was concentrated under vacuum to afford (R,Z)-4-(methylsulfonyl)but-3- en-2-amine (3.0 g, 99% yield) as a white solid, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.13 (br s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 11.2 Hz, 1H), 6.37 (dd, J = 9.6, 11.2 Hz, 1H), 5.09 (br s, 2H), 4.95 - 4.75 (m, 1H), 3.12 (s, 3H), 2.29 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). [001090] Step 5: 1-[4-Bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-N-[(Z,1R)-1-methyl-3- methylsulfonyl-allyl]piperidine-4-carboxamide. 1-[4-Bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro- piperidine-4-carboxylic acid (500 mg, 1.05 mmol, 1.0 eq), (R,Z)-4-(methylsulfonyl)but-3-en-2-amine (438 mg, 1.36 mmol, 1.3 eq), T3P® (1.67 g, 2.62 mmol, 2.5 eq), and N,N-diisopropylethylamine (407 mg, 3.15 mmol, 3.0 eq) were combined in DCM (5.0 mL, 0.21 M). The mixture was stirred at 25°C for 2 h before being diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, 550 QB\184200.00050\92364964.2 VVID-746PC dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-50% EtOAc in PE) to afford 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro- N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide (428 mg, 66% yield) as a white solid. MS (ESI): mass calcd. for C23H25BrClFN2O5S2, 606; m/z found, 607 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 8.37 (br d, J = 6.0 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.92 - 7.86 (m, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.49 - 7.41 (m, 1H), 7.39 (d, J = 4.1 Hz, 2H), 6.45 (d, J = 11.3 Hz, 1H), 6.28 (dd, J = 9.5, 11.1 Hz, 1H), 5.44 - 5.27 (m, 1H), 3.21 - 3.05 (m, 5H), 2.79 - 2.69 (m, 1H), 2.65 - 2.56 (m, 1H), 2.02 - 1.61 (m, 4H), 1.20 (d, J = 6.9 Hz, 3H). [001091] Representative biochemical data for inhibition of pAKT is presented in Table 3.
Figure imgf000553_0001
551 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000554_0001
552 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000555_0001
553 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000556_0001
554 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000557_0001
555 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000558_0001
556 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000559_0001
557 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000560_0001
558 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000561_0001
[001092] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended 559 QB\184200.00050\92364964.2 VVID-746PC claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. 560 QB\184200.00050\92364964.2

Claims

VVID-746PC CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000563_0001
wherein: each is a single bond when X8 is CH2 and is absent when X8 is absent; each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; or X1 is C, X4 is N or C, and X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-3 R10, and each of X2 and X3 is independently CR3 or N, wherein not more than one of X2 and X3 is N; R1 is C1-C6 alkyl or C3-C6 cycloalkyl; each R2 is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R3 is independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4 and R5 is independently hydrogen or C1-C6 alkyl; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-3 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8, and X7 and X8 are each absent; or 561 QB\184200.00050\92364964.2 VVID-746PC X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with three to four additional atoms, form a fused 5 to 6-membered heterocyclic ring, wherein the fused 5 to 6-membered heterocyclic ring is substituted with 0-2 R8, and X8 is absent; or X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; each R6 is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl; or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7 cycloalkyl; each R7 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl or C1-C6 haloalkoxyl; y is 0, 1, 2 or 3; and each R8 is independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; and each R10 is independently C1-C3 alkyl. 2. The compound of claim 1, wherein each of R1 and R2 is independently methyl or cyclopropyl. 3. The compound of any one of claims 1-2, wherein one of X1 and X4 is N. 4. The compound of any one of claims 1-3, wherein one of X2 and X3 is N. 5. The compound of any one of claims 1-4, wherein X3 is N. 6. The compound of any one of claims 1-5, wherein X1 is N. 7. The compound of any one of claims 1-5, wherein X4 is N. 8. The compound of any one of claims 1-6, wherein X2 and X4 are each CR3. 9. The compound of any one of claims 1-2, wherein each of X1, X2, X3 and X4 is CR3. 10. The compound of any one of claims 1-2, wherein X1 is C, X4 is N or C, X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring, wherein the fused 5-membered aromatic ring is substituted with 0-1 R10, and X2 and X3 are each CR3. 562 QB\184200.00050\92364964.2 VVID-746PC 11. The compound of any one of claims 1-10, wherein each R3 is independently hydrogen, chloro, fluoro, methyl, methoxy, -CF2, -CF3, or -CN. 12. The compound of any one of claims 1-11, wherein X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent. 13. The compound of any one of claims 1-11, wherein X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent. 14. The compound of any one of claims 1-11, wherein each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8, and X7 and X8 are each absent. 15. The compound of claim 14, wherein X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8. 16. The compound of any one of claims 1-11, wherein X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8 is absent. 17. The compound of any one of claims 1-11, wherein X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2. 18. The compound of any one of claims 1-17, wherein each R6 is independently fluoro, chloro, oxo, - CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl; or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring. 19. The compound of any one of claims 1-18, wherein each R7 is independently fluoro, chloro, - OCH3, -CF3, -OCF3, or C1-C3 alkyl. 20. The compound of any one of claims 1-11 or 14-19, wherein each R8 is independently fluoro, chloro, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, cyclopropyl, oxetanyl, -N(R9)2, -C(O)N(R9)2, - C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9. 21. The compound of any one of claims 1-20, wherein ring A is phenyl. 22. The compound of any one of claims 1-20, wherein ring A is pyridinyl or cyclohexyl. 23. The compound of any one of claims 1-22, wherein R10 is methyl. 563 QB\184200.00050\92364964.2 VVID-746PC 24. The compound of claim 1, wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000566_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8, and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is independently halogen or C1-C3 alkyl. 25. The compound of claim 1, wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: 564 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000567_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is independently halogen or C1-C3 alkyl. 26. The compound of claim 1, wherein the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof: 565 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000568_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is independently halogen or C1-C3 alkyl. 27. The compound of claim 1, wherein the compound is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: 566 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000569_0001
wherein: R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8, and X7 and X8 are each absent; or X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8 is absent; or X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; each R6 is independently halogen, hydroxyl, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, or C1-C3 haloalkoxyl; y is 0, 1, 2 or 3; each R8 is independently halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; and 567 QB\184200.00050\92364964.2 VVID-746PC each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. 28. The compound of claim 27, wherein X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8. 29. The compound of claim 1, wherein the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000570_0001
wherein: R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; each R8 is independently halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -C1-C3 alkylene-O-R9; and R9 is C1-C3 alkyl. 568 QB\184200.00050\92364964.2 VVID-746PC 30. The compound of claim 1, wherein the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000571_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1, or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2, or 3; and each R8 is independently halogen or C1-C3 alkyl. 31. The compound of claim 1, wherein the compound is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof: 569 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000572_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; or X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8 is absent; or X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1, or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2, or 3; and each R8 is independently halogen or C1-C3 alkyl. 32. The compound of claim 1, wherein the compound is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof: 570 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000573_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; X4 is C or N; X9 is CH or NR10; X5 and X6 are each CH2, substituted with 0-2 R6, and X7 and X8 are each absent; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and R10 is C1-C3 alkyl. 33. The compound of claim 1, wherein the compound is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000573_0002
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; or 571 QB\184200.00050\92364964.2 VVID-746PC X1 is C, X4 is N or C, and X1 and X4 together with three additional atoms independently selected from carbon and nitrogen form a fused 5-membered aromatic ring; wherein the fused 5-membered aromatic ring is substituted with 0-1 R10, and each of X2 and X3 is independently CR3 or N, wherein not more than one of X2 and X3 is N; R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; each R3 is independently hydrogen, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; X5 and X6 are each CH2, substituted with 0-2 R6, or each X5 and X6 is independently CH or C, substituted with 0-1 R6 and together with one to four additional atoms selected from carbon, nitrogen and oxygen, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; or R6 together with X5 and the methylene carbon adjacent to X5 form a fused cyclopropyl ring, and X8 is absent; w is 0, 1, or 2; ring A is aryl, 6-membered heteroaryl, or C6 cycloalkyl; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, or C1-C3 haloalkoxyl; y is 0, 1, 2, or 3; each R8 is independently halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3 alkylene-R9, or -C1-C3 alkylene-O-R9; each R9 is independently hydrogen, -CN, -CD3, C1-C4 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; and R10 is C1-C3 alkyl. 34. The compound of claim 33, wherein each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N. 35. The compound of any one of claims 33-34, wherein X5 and X6 are each CH, substituted with 0-1 R6 and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8. 36. The compound of any one of claims 33-35, wherein ring A is phenyl. 572 QB\184200.00050\92364964.2 VVID-746PC 37. The compound of claim 1, wherein the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000575_0001
wherein: each of X1 , X 2 , X 3 and X 4 is independently CR 3 or N, wherein not more than one of X 1 and X 4 is N and not more than one of X2 and X3 is N; R1 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is hydrogen or C1-C3 alkyl; each R3 is independently hydrogen, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; X5, X6 and X7 together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, or X5 is CH, X6 is CH2, X7 is N, and X5 and X7 together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring; each R6 is independently halogen, hydroxyl, oxo, -CN, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or two R6 together with a ring atom form a C3-C6 spirocyclic ring or a C3-C6 spiroheterocyclic ring; ring A is aryl, w is 0, 1, or 2; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxyl; and y is 0, 1, 2, or 3. 38. The compound of claim 1, wherein the compound is a compound of Formula (XII), or a pharmaceutically acceptable salt or solvate thereof: 573 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000576_0001
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3 is independently hydrogen, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; X5 and X6 are each CH, X7 is CH2 or O, and X8 is CH2; ring A is aryl; each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxyl; and y is 0, 1, 2 or 3. 39. The compound of claim 1, wherein the compound is selected from the group of: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; (E)-4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-(3-(methylsulfonyl)allyl)benzamide; 4-(3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 574 QB\184200.00050\92364964.2 VVID-746PC 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2,6-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-4-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*S)-2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)pyrrolidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)pyrrolidin-1-yl)benzamide; 2-Fluoro-4-(3-(2-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-(2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((S)-2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; (S,E)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-(3-(methylsulfonyl)allyl)benzamide; 3-Fluoro-5-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 3-Fluoro-5-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-5-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 2-Fluoro-4-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((2*R,4*S)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 575 QB\184200.00050\92364964.2 VVID-746PC 2-Fluoro-4-((2*R,4*S)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((2*S,4*R)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 2-Fluoro-4-((2*S,4*R)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)piperidin-1-yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)piperidin-1-yl)picolinamide; 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)picolinamide; 5-(3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((*S)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 576 QB\184200.00050\92364964.2 VVID-746PC 4-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(3-Chloropyridin-2-yl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 577 QB\184200.00050\92364964.2 VVID-746PC 4-(2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*S)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 578 QB\184200.00050\92364964.2 VVID-746PC 4-((*R)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 6-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-(2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-1-(2-Chlorophenyl)-3-oxoisoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-cyano-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(3-(2-Chlorophenyl)thiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2,5-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chlorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 579 QB\184200.00050\92364964.2 VVID-746PC 4-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2,4-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 5-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((*R)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2- carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)-2-fluorobenzamide; 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(rac-(2*R,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-(rac-(2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 580 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide; 5-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*R)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1- yl)pyrazine-2-carboxamide; 581 QB\184200.00050\92364964.2 VVID-746PC N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1- yl)pyrazine-2-carboxamide; 5-(2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 6-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide; 5-(rac-(1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 582 QB\184200.00050\92364964.2 VVID-746PC 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamid;e 5-((*S)-2-(2-Fluoro-3-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-(2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 583 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 584 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 2-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5- carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R, E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((S)-2-(2-chlorophenyl)pyrrolidin-1-yl)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 585 QB\184200.00050\92364964.2 VVID-746PC 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(rac-(2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*R,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 586 QB\184200.00050\92364964.2 VVID-746PC 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 4-((*R)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 3-Fluoro-5-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-3-(2,3,4- trifluorophenyl)morpholino)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-3-(2,3,4- trifluorophenyl)morpholino)benzamide; 4-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(rac-(1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 6-((1*R,2*S,5*S)-2-(2-Chloro-4-fluoro-phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E,1R)-1-methyl-3- methylsulfonyl-allyl)pyridine-3-carboxamide; 4-(2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 587 QB\184200.00050\92364964.2 VVID-746PC 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-(2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(2-((*R)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(2-((*S)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 6-(2-(2-Chlorophenyl)azepan-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide; 4-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide; 5-(2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)picolinamide; 588 QB\184200.00050\92364964.2 VVID-746PC 4-(2-(2-Chlorophenyl)-4-oxopiperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 4-((*R)-2-(2-Chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-3- (trifluoromethyl)picolinamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 8-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)imidazo[1,2- a]pyridine-5-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*S,2*R,5*R)-2-(2,3-difluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*R,2*S,5*S)-2-(2,3-difluorophenyl)-6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*S,2*R,5*R)-2-(3-fluoro-2-methylphenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; 589 QB\184200.00050\92364964.2 VVID-746PC N-((R,E)-4-(Cyclopropylsulfonyl)but-3-en-2-yl)-5-((1*R,2*S,5*S)-2-(3-fluoro-2-methylphenyl)-6,6- difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide; 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide 5-((1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 7-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-2H- indazole-4-carboxamide; 5-((3a*S,4*S,6a*R)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*R,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(2-(2-Chlorophenyl)-4-cyclopropylpiperazin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*S,6a*S)-5-Acetyl-1-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 590 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2-methoxyethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methylpiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; tert-Butyl (3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(((R,E)-4-(methylsulfonyl)but-3-en-2- yl)carbamoyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((7*S,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-6-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-4-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 591 QB\184200.00050\92364964.2 VVID-746PC (1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethoxy)phenyl)pyrrolidin-1-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((*S)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; (1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-N,N-dimethyl-3-(5-(((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 5-((1*S,2*R,5*R)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(3-Fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((3a*S,4*R,6a*R)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 592 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,2*R,5*R)-2-(2,6-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((1S,2S,5R,6S)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-6-(Difluoromethyl)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3*S,5*S)-3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3*R,5*S)-3-(2-Chloro-3-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((methoxy-d3)methyl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)-2-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-6-(2,3-Difluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 593 QB\184200.00050\92364964.2 VVID-746PC 5-((3a*S,4*R,6a*R)-4-(2,3-Difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*S,6a*S)-4-(2,3-Difluorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyclopropoxymethyl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((1*R,3a*S,6a*R)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,3a*S,6a*R)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,3a*R,6a*S)-1-(2-Chloro-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((*S)-6-(2-Chloro-3-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 594 QB\184200.00050\92364964.2 VVID-746PC 5-((rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2,3-Difluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan- 3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-Cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1R,2S,5S,6S)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,4*R,5*S)-4-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropyl-5-oxopiperazin-1-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 595 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,2*R,5*R)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-6,6-Difluoro-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(3-Fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(3-Fluoro-2-methylphenyl)-6-((difluoromethoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(3-Fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2,3-Difluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-1-(2,3-Difluorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-1-(2,3-Difluorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 596 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 4-(Difluoromethyl)-5-((1*R,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 4-(Difluoromethyl)-5-((1*S,2*R,5*R,6*R)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3- yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S,6*R)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(2,3-Difluorophenyl)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R,6*R)-2-(3-Chloropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R,6*S)-2-(3-Chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S,6*R)-2-(3-Chloropyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((7*R,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((2*R,4*R)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((2*S,4*S)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((2*S,4*R)-2-(2,3-Difluorophenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-(3-Fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 597 QB\184200.00050\92364964.2 VVID-746PC 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4- (trifluoromethyl)nicotinamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((1*S,2*R,5*R)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(cyclopropylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((3a*S,4*R,6a*R)-4-(2-Chlorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((3a*R,4*S,6a*S)-4-(2-Chlorophenyl)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((2*R,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-N- ((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 598 QB\184200.00050\92364964.2 VVID-746PC 5-((1*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E)-4- (methylsulfonyl)allyl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)pent-1-en-3-yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((S,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-1- cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; and 5-((1S,2R,5R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (cyclopropylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 40. A compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000601_0001
wherein: each of X1, X2, X3 and X4 is independently CR3 or N, wherein not more than one of X1 and X4 is N and not more than one of X2 and X3 is N; R1 is C1-C6 alkyl; R2 is hydrogen or C1-C6 alkyl; each R3 is independently hydrogen, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4 and R5 is independently hydrogen or C1-C6 alkyl; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or 599 QB\184200.00050\92364964.2 VVID-746PC X5 and X6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7 cycloalkyl; each R7 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; y is 0, 1, 2 or 3; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl. 41. The compound of claim 40, wherein R1 and R2 are methyl. 42. The compound of claim 40, wherein one of X1 and X4 is N. 43. The compound of claim 40, wherein one of X2 and X3 is N. 44. The compound of claim 40, wherein X1 is N. 45. The compound of any one of claims 40-44, wherein X3 is N. 46. The compound of any one of claims 40-45, wherein X2 and X4 are each CR3. 47. The compound of claim 40, wherein each of X1, X2, X3 and X4 is CR3. 48. The compound of any one of claims 40-47, wherein each R3 is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy. 49. The compound of claim 40, wherein X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2. 50. The compound of claim 40, wherein X5 and X6 are each CH or C, and together with one to four additional carbon atoms, form a fused 3 to 6-membered saturated or aromatic ring, wherein the fused 3 to 6-membered saturated or aromatic ring is substituted with 0-2 R8. 51. The compound of claim 50, wherein each R8 is independently chloro or fluoro. 52. The compound of claim 40, wherein each R6 is independently chloro, fluoro, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl. 53. The compound of claim 40, wherein each R7 is independently chloro, fluoro or C1-C3 alkyl. 54. The compound of claim 40, wherein ring A is phenyl. 55. The compound of claim 40, wherein the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: 600 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000603_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 56. The compound of claim 40, wherein the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000603_0002
wherein: R1 is C1-C3 alkyl; 601 QB\184200.00050\92364964.2 VVID-746PC R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 57. The compound of claim 40, wherein the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000604_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; 602 QB\184200.00050\92364964.2 VVID-746PC w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 58. The compound of claim 40, wherein the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000605_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 59. The compound of claim 40, wherein the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: 603 QB\184200.00050\92364964.2 VVID-746PC
Figure imgf000606_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is optionally substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 60. The compound of claim 40, wherein the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000606_0002
wherein: R1 is C1-C3 alkyl; 604 QB\184200.00050\92364964.2 VVID-746PC R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 61. The compound of claim 40, wherein the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000607_0001
wherein: R1 is C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; each R3a is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5 is CH2, wherein X5 and X6 together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5 and X6 are each CH and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; each R6 is independently halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; 605 QB\184200.00050\92364964.2 VVID-746PC w is 0, 1 or 2; each R7 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; y is 0, 1, 2 or 3; and each R8 is halogen or C1-C3 alkyl. 62. The compound of claim 40, wherein the compound is selected from the group of: 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; (E)-4-(2-(2-Chlorophenyl)piperidin-1-yl)-N-(3-(methylsulfonyl)allyl)benzamide; 4-(3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((R)-3-(2-Chlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-4-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2,6-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)piperidin-1-yl)benzamide; 2-Fluoro-4-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 2-Fluoro-4-((*S)-2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(2-(o-tolyl)pyrrolidin-1-yl)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-2-(o-tolyl)pyrrolidin-1-yl)benzamide; 2-Fluoro-4-(3-(2-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-(2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((S)-2-(2-Chlorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 606 QB\184200.00050\92364964.2 VVID-746PC (S,E)-4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-(3-(methylsulfonyl)allyl)benzamide; 3-Fluoro-5-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-5-(2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 3-Fluoro-5-((*R)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-5-((*S)-2-(2-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 2-Fluoro-4-(2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((2*R,4*S)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide; 2-Fluoro-4-((2*R,4*S)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((2*S,4*R)-2-(2-fluorophenyl)-4-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)benzamide; 2-Fluoro-4-((2*S,4*R)-4-methyl-2-phenylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)piperidin-1-yl)picolinamide; 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)picolinamide; 3-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)picolinamide; 607 QB\184200.00050\92364964.2 VVID-746PC 5-(3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((*S)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 608 QB\184200.00050\92364964.2 VVID-746PC 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(3-Chloropyridin-2-yl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-dimethylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 609 QB\184200.00050\92364964.2 VVID-746PC 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*R)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 2-Fluoro-4-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2-Chlorophenyl)morpholino)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*S)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-3-(2,4-Dichlorophenyl)morpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-1-(2-Chlorophenyl)isoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 6-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-(2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 610 QB\184200.00050\92364964.2 VVID-746PC 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((*R)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-5-oxopyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-1-(2-Chlorophenyl)-3-oxoisoindolin-2-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)piperidin-1-yl)-2-cyano-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(3-(2-Chlorophenyl)thiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2,5-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-(2-(2-Chlorophenyl)azepan-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-(2-(2,4-Difluorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 5-(2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 5-((*R)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl) piperidin-1-yl)-N-((R, E)-4-(methylsulfonyl) but-3-en-2-yl) pyrimidine-2- carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 611 QB\184200.00050\92364964.2 VVID-746PC 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 4-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)-2-fluorobenzamide; 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(rac-(2*R,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-(rac-(2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxy-4-methylpyrrolidin-1-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,6-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Difluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(o-tolyl)pyrrolidin-1-yl)pyrazine-2-carboxamide; 5-(2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,4-Dimethylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 612 QB\184200.00050\92364964.2 VVID-746PC 5-(3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chlorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-(2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine-2- carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*R)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine- 2-carboxamide; N-((R,E)-4-(Methylsulfonyl)but-3-en-2-yl)-5-((*S)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazine- 2-carboxamide; 5-(2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*R)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((*S)-2-Cyclohexylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Dichlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-4-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 613 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide; 6-((1R,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)nicotinamide; 5-(rac-(1*S,2*R,5*R)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2,3-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(ethylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-6-fluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-3-(2-Chloro-3,6-difluorophenyl)morpholino)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Fluoro-3-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(3-Fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 614 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-(2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4,4-difluoropiperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(3-Chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*R)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 615 QB\184200.00050\92364964.2 VVID-746PC 5-((*S)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)pyrazine-2-carboxamide; 5-(rac-(1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-(5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-5-(2-Chlorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((*S)-5-(2-Chloro-3-fluorophenyl)-1,4-oxazepan-4-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*R)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 2-(2-(2-Chlorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5- carboxamide; 6-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-methoxy-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-(2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*R)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 616 QB\184200.00050\92364964.2 VVID-746PC 6-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 6-((*S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-5-fluoro-N-((R, E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 5-((S)-2-(2-chlorophenyl)pyrrolidin-1-yl)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-5-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((S)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-6-fluorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chlorophenyl)azepan-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-4-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*R)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; 617 QB\184200.00050\92364964.2 VVID-746PC 5-((*R)-3-(2-Chlorophenyl)morpholino)-3-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 5-(rac-(2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*R,5*R)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((2*S,5*S)-2-(2-Chlorophenyl)-5-methylpyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-((S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2- carboxamide; 6-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 6-((*S)-2-(2-Chloro-4-fluorophenyl)pyrrolidin-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; 4-((*R)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,3-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2,4-Difluorophenyl)piperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 3-Fluoro-5-((*S)-2-(4-fluoro-2-methylphenyl)piperidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*S)-3-(2,3,4- trifluorophenyl)morpholino)benzamide; 2-Fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-((*R)-3-(2,3,4- trifluorophenyl)morpholino)benzamide; 4-((1*S,2*R,5*R)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)picolinamide; 4-(rac-(1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 618 QB\184200.00050\92364964.2 VVID-746PC 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-fluoro-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 4-((1*R,2*S,5*S)-2-(2-Chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)benzamide; 6-((1*R,2*S,5*S)-2-(2-Chloro-4-fluoro-phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E,1R)-1-methyl-3- methylsulfonyl-allyl)pyridine-3-carboxamide; 4-(2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-methoxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*S,4*R)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-((2*R,4*S)-2-(2-Chlorophenyl)-4-hydroxypyrrolidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3- en-2-yl)benzamide; 4-(2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)benzamide; 4-((*R)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*S)-2-(2-Chlorophenyl)-4,4-difluoropyrrolidin-1-yl)-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((*R)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*S)-2-(2-Chlorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-(2-(2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(2-((*R)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(2-((*S)-2-Chloro-3-fluorophenyl)pyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 5-(3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; 5-((*R)-3-(2-Chloro-3-fluorophenyl)morpholino)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)pyrazine-2-carboxamide; 619 QB\184200.00050\92364964.2 VVID-746PC 6-(2-(2-Chlorophenyl)azepan-1-yl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; 4-(3-(2-Chlorophenyl)-1-oxidothiomorpholino)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 4-((*R)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide; 4-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-2,5-difluoro-N-((R,E)-4-(methylsulfonyl)but- 3-en-2-yl)benzamide; 5-(2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)picolinamide; 5-((*S)-2-(2-Chloro-3-fluorophenyl)-5-oxopyrrolidin-1-yl)-3-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en- 2-yl)picolinamide; 4-(2-(2-Chlorophenyl)-4-oxopiperidin-1-yl)-2-fluoro-N-((R,E)-4-(methylsulfonyl)but-3-en-2- yl)benzamide; 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-N-((R,E)- 4-(methylsulfonyl)but-3-en-2-yl)picolinamide; 5-((1*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide; and 5-((1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R,E)-4- (methylsulfonyl)but-3-en-2-yl)pyrazine-2-carboxamide. 63. A pharmaceutical composition comprising a compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 64. A method of inhibiting RAS-PI3K in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-62, or a pharmaceutically salt, solvate, or stereoisomer thereof. 65. A method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-62 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 66. The method of claim 65, wherein the disease is cancer. 67. The method of claim 66, wherein the cancer is selected from the group of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. 68. The method of claim 65, wherein the disease or condition is an immunological disease or condition. 69. The method of claim 68, wherein the immunological condition is wound healing deficiency. 620 QB\184200.00050\92364964.2 VVID-746PC 70. Use of a compound according to any one of claims 1-62 for the treatment of cancer. 71. The use according to claim 70, wherein the cancer is selected from the group of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. 72. Use of a compound according to any one of claims 1-62 for the treatment of an immunological disease or condition. 73. The use according to claim 72, wherein the immunological condition is wound healing deficiency. 621 QB\184200.00050\92364964.2
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2021204159A1 (en) * 2020-04-08 2021-10-14 Agios Pharmaceuticals, Inc. Menin inhibitors and methods of use for treating cancer
WO2024010782A1 (en) * 2022-07-06 2024-01-11 Vividion Therapeutics, Inc. Pharmaceutical compositions comprising wrn helicase inhibitors
WO2024182404A1 (en) * 2023-02-28 2024-09-06 Vividion Therapeutics, Inc 1-(([1, 1',-biphenyl]-2-yl)sulfonyl)-4-fluoro-n-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide derivatives as ras-pi3k modulators for the treatment of e.g. cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2021204159A1 (en) * 2020-04-08 2021-10-14 Agios Pharmaceuticals, Inc. Menin inhibitors and methods of use for treating cancer
WO2024010782A1 (en) * 2022-07-06 2024-01-11 Vividion Therapeutics, Inc. Pharmaceutical compositions comprising wrn helicase inhibitors
WO2024182404A1 (en) * 2023-02-28 2024-09-06 Vividion Therapeutics, Inc 1-(([1, 1',-biphenyl]-2-yl)sulfonyl)-4-fluoro-n-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide derivatives as ras-pi3k modulators for the treatment of e.g. cancer

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Curr., Pharm. Des.", vol. 6, 2000, article "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development.", pages: 110
"Fieser and Fieser's Reagents for Organic Synthesis", vol. 1-40, 1991, JOHN WILEY AND SONS
"Larock's Comprehensive Organic Transformations", vol. 1-5, 1989, ELSEVIER SCIENCE PUBLISHERS
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT, WILLIAMS & WILKINS
AESOP CHO: "Recent Advances in Oral Prodrug Discovery", ANNUAL REPORTS IN MEDICINAL CHEMISTRY, vol. 41, 2006, pages 395 - 407, XP009184520
CAREYSUNDBERG: "Advanced Organic Chemistry", 2000, PLENUM
EVANS, E. ANTHONY: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM., vol. 64, no. 1-2, 1981, pages 9 - 32
GEORGE W.VARMA, RAJENDER S.: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21
GREENWUTS: "Protective Groups in Organic Synthesis", 1999, WILEY
HOOVER, JOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
KUMAR, S. ET AL.: "Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer", BIOMEDICINE & PHARMACOTHERAPY, vol. 109, 2019, pages 1462 - 1477, XP085552009, ISSN: 0753-3322, DOI: 10.1016/J.BIOPHA.2018.10.182 *
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992, pages 352 - 401
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
NOGRADY: "Medicinal Chemistry A Biochemical Approach", 1985, OXFORD UNIVERSITY PRESS, pages: 388 - 392
PICKAR, DOSAGE CALCULATIONS, 1999
ROOSEBOOM ET AL., PHARMACOLOGICAL REVIEWS, vol. 56, 2004, pages 53 - 102
T. HIGUCHIV. STELLA: "Pro-drugs as Novel Delivery Systems", A.C.S. SYMPOSIUM SERIES, vol. 14

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