Ras-PI3k inhibitors for the treatment of cancer and immunological diseases

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-746PCRAS-PI3K INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] 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

[0002] The disclosure relates to compounds and methods for modulating RAS-PI3K. BACKGROUND OF THE DISCLOSURE

[0003] There is a need for improved cancer therapeutics and methods of treatment, particularly for modulation of RAS-PI3K. SUMMARY

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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\92364964.2VVID-746PCmodulation 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.

[0009] 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:wherein: each is a single bond when X8is CH2and is absent when X8is absent; each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; or X1is C, X4is N or C, and X1and X4together 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 X2and X3is independently CR3or N, wherein not more than one of X2and X3is N; R1is C1-C6alkyl or C3-C6cycloalkyl; each R2is independently hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R3is independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)NR4R5, or -O-C1-C6alkyl; each of R4and R5is independently hydrogen or C1-C6alkyl; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or 2 QB\184200.00050\92364964.2VVID-746PCX5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-3 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent; or X5is CH, X6is CH2, X7is N, and X5and X7together with three to four additional atoms, form a fused 5 to 6-membered heterocyclic ring, wherein the fused 5 to 6-membered heterocyclic ring issubstituted with 0-2 R8, and X8is absent; orX5and X6are each CH, X7is CH2or O, and X8is CH2; each R6is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl; or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7cycloalkyl; each R7is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyl or C1-C6haloalkoxyl; y is 0, 1, 2 or 3; and each R8is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; each R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; and each R10is independently C1-C3alkyl.

[0011] The present disclosure also provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:3 QB\184200.00050\92364964.2VVID-746PC(Ia) wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; R1is C1-C6alkyl; R2is hydrogen or C1-C6alkyl; each R3is independently hydrogen, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, -C(O)NR4R5, or -O-C1-C6 alkyl; each of R4and R5is independently hydrogen or C1-C6alkyl; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7cycloalkyl; each R7is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxyl; y is 0, 1, 2 or 3; and each R8is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0012] In some embodiments of Formula (Ia), R1and R2are methyl.

[0013] In some embodiments of Formula (Ia), one of X1and X4is N.

[0014] In some embodiments of Formula (Ia), one of X2and X3is N.

[0015] In some embodiments of Formula (Ia), X1is N.

[0016] In some embodiments of Formula (Ia), X3is N.

[0017] In some embodiments of Formula (Ia), X2and X4are each CR3.

[0018] In some embodiments of Formula (Ia), each of X1, X2, X3and X4is CR3.

[0019] In some embodiments of Formula (Ia), each R3is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy.

[0020] In some embodiments of Formula (Ia), X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2. 4 QB\184200.00050\92364964.2VVID-746PC

[0021] In some embodiments of Formula (Ia), X5and X6are 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 R8is independently chloro or fluoro.

[0023] In some embodiments of Formula (Ia), each R6is independently chloro, fluoro, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, or C1-C3hydroxyalkyl.

[0024] In some embodiments of Formula (Ia), each R7is independently chloro, fluoro or C1-C3alkyl.

[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:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl. 5 QB\184200.00050\92364964.2VVID-746PC

[0027] In some embodiments, the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0028] In some embodiments, the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:6 QB\184200.00050\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0029] In some embodiments, the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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\92364964.2VVID-746PCeach R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0030] In some embodiments, the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or -O-C1-C3 alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0031] In some embodiments, the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof: 8 QB\184200.00050\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0032] In some embodiments, the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; 9 QB\184200.00050\92364964.2VVID-746PCR2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[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\92364964.2VVID-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\92364964.2VVID-746PCsurvival, 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:wherein: each is a single bond when X8is CH2and is absent when X8is absent; each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; or X1is C, X4is N or C, and X1and X4together 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 X2and X3is independently CR3or N, wherein not more than one of X2and X3is N; R1is C1-C6alkyl or C3-C6cycloalkyl; each R2is independently hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; 12 QB\184200.00050\92364964.2VVID-746PCeach R3is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -C(O)NR4R5, or -O-C1-C6alkyl; each of R4and R5is independently hydrogen or C1-C6alkyl; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-3 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent; or X5is CH, X6is CH2, X7is N, and X5and X7together 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 X8is absent; or X5and X6are each CH, X7is CH2or O, and X8is CH2; each R6is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl; or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7cycloalkyl; each R7is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyl or C1-C6haloalkoxyl; y is 0, 1, 2 or 3; and each R8is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; each R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; and each R10is independently C1-C3alkyl.

[0053] In some embodiments of Formula (I), each of R1and R2is independently methyl or cyclopropyl.

[0054] In some embodiments of Formula (I), one of X1and X4is N.

[0055] In some embodiments of Formula (I), one of X2and X3is N.

[0056] In some embodiments of Formula (I), X3is N. 13 QB\184200.00050\92364964.2VVID-746PC

[0057] In some embodiments of Formula (I), X1is N.

[0058] In some embodiments of Formula (I), X4is N.

[0059] In some embodiments of Formula (I), X2and X4are each CR3.

[0060] In some embodiments of Formula (I), each of X1, X2, X3and X4is CR3.

[0061] In some embodiments of Formula (I), X1is C, X4is N or C, X1and X4together 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 X2and X3are each CR3.

[0062] In some embodiments of Formula (I), each R3is independently hydrogen, chloro, fluoro, methyl, methoxy, -CF2, -CF3, or -CN.

[0063] In some embodiments of Formula (I), X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent.

[0064] In some embodiments of Formula (I), X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent.

[0065] In some embodiments of Formula (I), each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent. For example, in some such embodiments, X5and X6are each CH, substituted with 0-1 R6and 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), X5is CH, X6is CH2, X7is N, and X5and X7together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8is absent.

[0067] In some embodiments of Formula (I), X5and X6are each CH, X7is CH2or O, and X8is CH2.

[0068] In some embodiments of Formula (I), each R6is independently fluoro, chloro, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl; or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring.

[0069] In some embodiments of Formula (I), each R7is independently fluoro, chloro, -OCH3, -CF3, -OCF3, or C1-C3alkyl.

[0070] In some embodiments of Formula (I), each R8is independently fluoro, chloro, -CN, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, cyclopropyl, oxetanyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9.

[0071] In some embodiments of Formula (I), ring A is phenyl. 14 QB\184200.00050\92364964.2VVID-746PC

[0072] In some embodiments of Formula (I), ring A is pyridinyl or cyclohexyl.

[0073] In some embodiments of Formula (I), R10is methyl.

[0074] In some embodiments of Formula (I), the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8, and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is independently halogen or C1-C3alkyl.

[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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is independently halogen or C1-C3alkyl.

[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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is independently halogen or C1-C3alkyl.

[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\92364964.2VVID-746PCwherein: R1is C1-C3 alkyl or C3-C6 cycloalkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent; or X5is CH, X6is CH2, X7is N, and X5and X7together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8is absent; or X5and X6are each CH, X7is CH2or O, and X8is CH2; each R6is independently halogen, hydroxyl, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6heterocyclyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, or C1-C3haloalkoxyl; y is 0, 1, 2 or 3; each R8is independently halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; and 18 QB\184200.00050\92364964.2VVID-746PCeach R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl.

[0078] In some embodiments of Formula (V), X5and X6are each CH, substituted with 0-1 R6and 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:wherein: R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6 spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; each R8is independently halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -C1-C3alkylene-O-R9; and R9is C1-C3alkyl. 19 QB\184200.00050\92364964.2VVID-746PC

[0080] In some embodiments of Formula (I), the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1, or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2, or 3; and each R8is 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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1, or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2, or 3; and each R8is independently halogen or C1-C3alkyl.

[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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3 alkyl; X4is C or N; X9is CH or NR10; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and R10is C1-C3alkyl.

[0083] In some embodiments of Formula (I), the compound is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; or 22 QB\184200.00050\92364964.2VVID-746PCX1is C, X4is N or C, and X1and X4together 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 X2and X3is independently CR3or N, wherein not more than one of X2and X3is N; R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl; each R3is independently hydrogen, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; X5and X6are each CH2, substituted with 0-2 R6, or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 R6is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1, or 2; ring A is aryl, 6-membered heteroaryl, or C6cycloalkyl; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, or C1-C3haloalkoxyl; y is 0, 1, 2, or 3; each R8is independently halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; each R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; and R10is C1-C3alkyl.

[0084] In some embodiments of Formula (X), each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N.

[0085] In some embodiments of Formula (X), X5and X6are each CH, substituted with 0-1 R6and 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\92364964.2VVID-746PC

[0087] In some embodiments of Formula (I), the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof:wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen or C1-C3alkyl; each R3is independently hydrogen, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, or X5is CH, X6is CH2, X7is N, and X5and X7together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring; each R6is independently halogen, hydroxyl, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6heterocyclyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; ring A is aryl, w is 0, 1, or 2; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxyl; 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\92364964.2VVID-746PCwherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3is independently hydrogen, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; X5and X6are each CH, X7is CH2or O, and X8is CH2; ring A is aryl; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxyl; 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\92364964.2VVID-746PC2-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\92364964.2VVID-746PC2-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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC4-((*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\92364964.2VVID-746PC4-((*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\92364964.2VVID-746PC4-(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\92364964.2VVID-746PC5-(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\92364964.2VVID-746PCN-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC6-((*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\92364964.2VVID-746PC4-((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\92364964.2VVID-746PC4-(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\92364964.2VVID-746PCN-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC6-((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\92364964.2VVID-746PC5-((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:wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; R1is C1-C6alkyl; R2is hydrogen or C1-C6alkyl; each R3is independently hydrogen, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, -C(O)NR4R5, or -O-C1-C6alkyl; each of R4and R5is independently hydrogen or C1-C6alkyl; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or 50 QB\184200.00050\92364964.2VVID-746PCX5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7cycloalkyl; each R7is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxyl; y is 0, 1, 2 or 3; and each R8is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl.

[0091] In some embodiments of Formula (Ia), R1and R2are methyl.

[0092] In some embodiments of Formula (Ia), one of X1and X4is N.

[0093] In some embodiments of Formula (Ia), one of X2and X3is N.

[0094] In some embodiments of Formula (Ia), X1is N.

[0095] In some embodiments of Formula (Ia), X3is N.

[0096] In some embodiments of Formula (Ia), X2and X4are each CR3.

[0097] In some embodiments of Formula (Ia), each of X1, X2, X3and X4is CR3.

[0098] In some embodiments of Formula (Ia), each R3is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy.

[0099] In some embodiments of Formula (Ia), X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2.

[0100] In some embodiments of Formula (Ia), X5and X6are 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.

[0101] In some embodiments of Formula (Ia), each R8is independently chloro or fluoro.

[0102] In some embodiments of Formula (Ia), each R6is independently chloro, fluoro, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, or C1-C3hydroxyalkyl.

[0103] In some embodiments of Formula (Ia), each R7is independently chloro, fluoro or C1-C3alkyl.

[0104] In some embodiments of Formula (Ia), ring A is phenyl.

[0105] In some embodiments, the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: 51 QB\184200.00050\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0106] In some embodiments, the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; 52 QB\184200.00050\92364964.2VVID-746PCR2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0107] In some embodiments, the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; 53 QB\184200.00050\92364964.2VVID-746PCw is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0108] In some embodiments, the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0109] In some embodiments, the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: 54 QB\184200.00050\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0110] In some embodiments, the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; 55 QB\184200.00050\92364964.2VVID-746PCR2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0111] In some embodiments, the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; 56 QB\184200.00050\92364964.2VVID-746PCw is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] In some embodiments, the disease is cancer.

[0116] 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.

[0117] In some embodiments, the disease or condition is an immunological disease or condition.

[0118] In some embodiments, the immunological condition is wound healing deficiency.

[0119] The present disclosure provides for use of a compound of Formula (I) through (XII) or Formula (Ia) through (VIIIa) for the treatment of cancer.

[0120] 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.

[0121] 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.

[0122] In some embodiments, the immunological condition addressed by the use is wound healing deficiency.

[0123] 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\92364964.2VVID-746PCcancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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

[0130] 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\92364964.2VVID-746PCstereoisomers 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.

[0131] 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.

[0132] 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).

[0133] In some embodiments, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0134] 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\92364964.2VVID-746PC

[0135] 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.

[0136] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. 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.

[0137] 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 by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0138] 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 with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I 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.

[0139] In some embodiments of a compound disclosed herein, one or more of R1, R2, R3, R4, R5, R5, R6, R7, R8groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

[0140] 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.

[0141] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R1, R2, R3, R4, R5, R5, R6, R7, R8is 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.

[0142] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H 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.

[0143] 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\92364964.2VVID-746PCTetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0144] 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.

[0145] 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.

[0146] “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.

[0147] 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.

[0148] 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\92364964.2VVID-746PCform 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.

[0149] 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

[0150] 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.

[0151] 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.

[0152] 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\92364964.2VVID-746PCpreservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[0153] 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.

[0154] In some embodiments, the compounds disclosed herein are administered orally.

[0155] 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.

[0156] In another aspect, the compounds disclosed herein are administered by inhalation.

[0157] In another aspect, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0158] In another aspect, the compounds disclosed herein are formulated as eye drops.

[0159] 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.

[0160] 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.

[0161] 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\92364964.2VVID-746PCcompound 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.

[0162] In certain embodiments, the compound disclosed herein is administered in a local rather than systemic manner.

[0163] In some embodiments, the compound disclosed herein is administered topically. In some embodiments, the compound disclosed herein is administered systemically.

[0164] 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.

[0165] 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.

[0166] For administration by inhalation, a compound disclosed herein is formulated for use as an aerosol, a mist or a powder.

[0167] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0168] In some embodiments, compounds disclosed herein are prepared as transdermal dosage forms.

[0169] In one aspect, a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.

[0170] 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.

[0171] 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

[0172] 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\92364964.2VVID-746PCthereof, 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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

[0179] 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\92364964.2VVID-746PCor 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.

[0180] 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.

[0181] 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.

[0182] 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”).

[0183] 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

[0184] In certain instances, it is appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent.

[0185] 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.

[0186] 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.

[0187] 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\92364964.2VVID-746PCDefinitions

[0188] 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.

[0189] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0190] “Oxo” refers to the =O substituent.

[0191] “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-C10alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10alkyl, C1-C9alkyl, C1- C8alkyl, C1-C7alkyl, C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, C1-C2alkyl, C2-C8alkyl, C3-C8alkyl and C4-C8alkyl. 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.

[0192] “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-.

[0193] “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.

[0194] “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\92364964.2VVID-746PC

[0195] “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.

[0196] 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).

[0197] “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.

[0198] “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: ,, ,

[0199] “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\92364964.2VVID-746PCspiro[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.

[0200] “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.

[0201] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

[0202] “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.

[0203] “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.

[0204] “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\92364964.2VVID-746PCinclude, 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.

[0205] “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.

[0206] 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\92364964.2VVID-746PChaloalkyl, 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).

[0207] 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:

[0208] 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.

[0209] 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\92364964.2VVID-746PCor 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).

[0210] 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.

[0211] 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.

[0212] 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\92364964.2VVID-746PC73 QB\184200.00050\92364964.2VVID-746PC74 QB\184200.00050\92364964.2VVID-746PC75 QB\184200.00050\92364964.2VVID-746PC76 QB\184200.00050\92364964.2VVID-746PC77 QB\184200.00050\92364964.2VVID-746PC78 QB\184200.00050\92364964.2VVID-746PC79 QB\184200.00050\92364964.2VVID-746PC80 QB\184200.00050\92364964.2VVID-746PC81 QB\184200.00050\92364964.2VVID-746PC82 QB\184200.00050\92364964.2VVID-746PC83 QB\184200.00050\92364964.2VVID-746PC84 QB\184200.00050\92364964.2VVID-746PC85 QB\184200.00050\92364964.2VVID-746PC86 QB\184200.00050\92364964.2VVID-746PC87 QB\184200.00050\92364964.2VVID-746PC88 QB\184200.00050\92364964.2VVID-746PC89 QB\184200.00050\92364964.2VVID-746PC90 QB\184200.00050\92364964.2VVID-746PC91 QB\184200.00050\92364964.2VVID-746PC92 QB\184200.00050\92364964.2VVID-746PC93 QB\184200.00050\92364964.2VVID-746PC94 QB\184200.00050\92364964.2VVID-746PC95 QB\184200.00050\92364964.2VVID-746PC96 QB\184200.00050\92364964.2VVID-746PC97 QB\184200.00050\92364964.2VVID-746PC98 QB\184200.00050\92364964.2VVID-746PC99 QB\184200.00050\92364964.2VVID-746PC100 QB\184200.00050\92364964.2VVID-746PC101 QB\184200.00050\92364964.2VVID-746PC102 QB\184200.00050\92364964.2VVID-746PC103 QB\184200.00050\92364964.2VVID-746PC104 QB\184200.00050\92364964.2VVID-746PC105 QB\184200.00050\92364964.2VVID-746PC106 QB\184200.00050\92364964.2VVID-746PC107 QB\184200.00050\92364964.2VVID-746PC108 QB\184200.00050\92364964.2VVID-746PC109 QB\184200.00050\92364964.2VVID-746PC110 QB\184200.00050\92364964.2VVID-746PC111 QB\184200.00050\92364964.2VVID-746PC112 QB\184200.00050\92364964.2VVID-746PC113 QB\184200.00050\92364964.2VVID-746PC114 QB\184200.00050\92364964.2VVID-746PC115 QB\184200.00050\92364964.2VVID-746PC116 QB\184200.00050\92364964.2VVID-746PC117 QB\184200.00050\92364964.2VVID-746PC118 QB\184200.00050\92364964.2VVID-746PC119 QB\184200.00050\92364964.2VVID-746PC120 QB\184200.00050\92364964.2VVID-746PC121 QB\184200.00050\92364964.2VVID-746PC122 QB\184200.00050\92364964.2VVID-746PC123 QB\184200.00050\92364964.2VVID-746PC124 QB\184200.00050\92364964.2VVID-746PC125 QB\184200.00050\92364964.2VVID-746PC126 QB\184200.00050\92364964.2VVID-746PC127 QB\184200.00050\92364964.2VVID-746PC128 QB\184200.00050\92364964.2VVID-746PC129 QB\184200.00050\92364964.2VVID-746PC130 QB\184200.00050\92364964.2VVID-746PC131 QB\184200.00050\92364964.2VVID-746PC132 QB\184200.00050\92364964.2VVID-746PC133 QB\184200.00050\92364964.2VVID-746PC134 QB\184200.00050\92364964.2VVID-746PC135 QB\184200.00050\92364964.2VVID-746PC136 QB\184200.00050\92364964.2VVID-746PC137 QB\184200.00050\92364964.2VVID-746PC138 QB\184200.00050\92364964.2VVID-746PC139 QB\184200.00050\92364964.2VVID-746PC140 QB\184200.00050\92364964.2VVID-746PC141 QB\184200.00050\92364964.2VVID-746PC142 QB\184200.00050\92364964.2VVID-746PC143 QB\184200.00050\92364964.2VVID-746PC144 QB\184200.00050\92364964.2VVID-746PC145 QB\184200.00050\92364964.2VVID-746PC146 QB\184200.00050\92364964.2VVID-746PC147 QB\184200.00050\92364964.2VVID-746PC148 QB\184200.00050\92364964.2VVID-746PCEXAMPLES

[0213] 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.

[0214] 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.

[0215] 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\92364964.2VVID-746PC

[0216] 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 X4are 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 X1and X2are CH and X3and X4are N, a compound of formula (V) may be obtained directly.

[0217] 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 X4are 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).

[0218] 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\92364964.2VVID-746PCAlternatively, 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.

[0219] 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 R2is hydrogen, C1-C6-alkyl, or C3-C6-cycloalkyl and R1is 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

[0220] 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 R2is cyclopropyl. A compound of formula (VII), wherein R2and R1are independently C1-C6alkyl or C3-C6cycloalkyl, 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 R2and R1are independently C1-C6alkyl or C3-C6cycloalkyl. Scheme 3151 QB\184200.00050\92364964.2VVID-746PC

[0221] According to Scheme 3, a compound of formula (V) can be formed from a compound of formula (VIII). A compound of formula (VIII), wherein R7is 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 CO2and acidified with HCl to provide a compound of formula (V), where X1and X3are CH, X4is CF, X2is N, X5and X6are CH2, X7and X8are absent, and ring A is a substituted phenyl. Scheme 4

[0222] According to Scheme 4, a compound of formula (X), wherein X1and X3are independently N or CH and R3and R7are 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

[0223] According to Scheme 5, a compound of formula (XII), wherein R7is H or F, X5and X6are CH2, X7is O or is absent, and X8is 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 6152 QB\184200.00050\92364964.2VVID-746PC

[0224] According to Scheme 6, a compound of formula (XIV), wherein X3is CH or N and R3is H or F, can be formed from a compound of formula (XIII) in the presence of NaIO4and RuCl3in 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

[0225] 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 X2is CH, X3is N or CH, X8is absent, X5and X6are CH2and X7is CH2or 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 Rais SO2CF3. Alternatively, a compound of formula (XVII), wherein X2is N, X3is CH, X8is absent, X5and X6are CH2 and X7is - 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 Rais PO(OPh)2.

[0226] In a second step, a compound of formula (XX), wherein X2and X3are independently N or CH, X8is absent, X5and X6are CH2, and X7is 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\92364964.2VVID-746PC

[0227] 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 X1is CH, X4is CF, X2and X3are independently N or CH, X8is absent, X5and X6are CH2, X7is CH2, O, or - CH2CH2-, and A is a substituted aromatic ring. Scheme 8(XXII)

[0228] According to Scheme 8, a compound of formula (XXII), wherein each R7is 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(XXIII)154 QB\184200.00050\92364964.2VVID-746PC

[0229] 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.

[0230] 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 PPh3and 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

[0231] 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\92364964.2VVID-746PCa 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 Rais SO2CF3or 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).

[0232] 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)4in 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\92364964.2VVID-746PC

[0233] 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

[0234] According to Scheme 13, a compound of formula (XXXVII) can be synthesized from a compound of formula (XXVIII), wherein R3is F or H, X1and X3are dependently CH or N, and Rbis 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 R3is F and X1and X3are CH, a compound of formula (XXXVII) is formed wherein Rbis CH3. In the case where R3is H and X1and X3are N, a compound of formula (XXXVII) is formed wherein Rbis H. 157 QB\184200.00050\92364964.2VVID-746PCScheme 14

[0235] 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 R3is H and X1and X3are 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 X4are CH, X7and X8are absent, X5is CF2, X6is CH2, and A is 2-chlorophenyl. Scheme 15

[0236] 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 R7is 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\92364964.2VVID-746PCagent 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 X8is absent, X5and X6are CH2, X7is CF2and A is a substituted aromatic ring.

[0237] 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 R7is H. In a first step, a compound of formula (XXXI), wherein R7is 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% H2SO4in 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

[0238] 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\92364964.2VVID-746PCreducing 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

[0239] 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 X8is absent, X5and X6are CH2, X7is -CH2O-, and A is 2-chlorophenyl. Scheme 19 160 QB\184200.00050\92364964.2VVID-746PC

[0240] 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

[0241] 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(XXIII)

[0242] 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\92364964.2VVID-746PC(XVI) (XXXVIII)

[0243] 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

[0244] 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

[0245] According to Scheme 24, a compound of formula (III) can be synthesized in two steps from a compound of formula (XXXIX), wherein R7is 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 R7is 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\92364964.2VVID-746PCcompound of formula (III), where X5and X6are CH and form a fused 3-membered saturated ring with another CH that is substituted with CF3, and X7and X8are absent. Scheme 25

[0246] According to Scheme 25, a compound of formula (III) can be prepared in four steps from a compound of formula (XLI), wherein R7is 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 R6is CH3. Finally, a compound of formula (XLIV), wherein R6is C1-C6alkyl or C3-C6cycloalkyl and R7is F or H, can be Boc deprotected as previously described in Scheme 2 to provide a compound of formula (III), where X5, X6and X7together are C(O)NR6CH2and X8is absent. Scheme 26

[0247] 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\92364964.2VVID-746PC(cyclopropylamino)-2-oxoethyl)carbamate. tert-Butyl (1-(2-chloro-3-fluorophenyl)-2- (cyclopropylamino)-2-oxoethyl)carbamate is reduced using LiAlH4in 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 R6is cyclopropyl and R7is F. Scheme 27

[0248] 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 X7and X8are absent, X5and X6are CH2, R6is CH3, and A is 2-chlorophenyl. Scheme 28

[0249] 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\92364964.2VVID-746PCazabicyclo[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 K2CO3in 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 X5and X6are CH and form a fused 3-membered saturated ring with another CH that is substituted with OCH3, and X7and X8are absent. Scheme 29

[0250] 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 MgSO4in 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\92364964.2VVID-746PCprovide 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 NaBH4in 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 I2in 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

[0251] 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 K2CO3and Pd(dppf)Cl2in 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

[0252] 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\92364964.2VVID-746PCScheme 32

[0253] 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

[0254] 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-d3to provide a compound of formula (XV), where R9is CH3or 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

[0255] 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\92364964.2VVID-746PC

[0256] 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

[0257] 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 LiAlH4in 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

[0258] 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 38168 QB\184200.00050\92364964.2VVID-746PC

[0259] 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

[0260] 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

[0261] According to Scheme 40, 2-chloro-5-fluoro-4-methyl-pyrimidine is treated with TEA and Pd(dppf)Cl2in DMF / MeOH under CO at 80 ℃ for a period of 16 h to provide a compound of formula (II), where X3and X4are N, X1is CH, X2is CCH3, and Y is F. Scheme 41

[0262] 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\92364964.2VVID-746PC

[0263] 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

[0264] 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

[0265] 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\92364964.2VVID-746PC6-(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

[0266] 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 CaCl2and NaBH4in MeOH at rt for 2 h to give (5-(2-chloro-3-fluorophenyl)pyrazin-2-yl)methanol. Treatment with PtO2in MeOH under H2at 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\92364964.2VVID-746PCScheme 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(XLVI) (V)

[0267] 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 R3is CH3or 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 X1is CH, X3and X4are N, and X2is CR3where R3is CH3or OCH3. Scheme 47fluorophenyl)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\92364964.2VVID-746PC2(1H)-yl)pyrazine-2-carboxylate. Similarly, a compound of formula (XLVII), where R7and R3are independently H or F and X1is CH or N, can be subjected to the same conditions to provide a compound of formula (XLVIII). Scheme 48

[0269] 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

[0270] 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 K2CO3in 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\92364964.2VVID-746PC

[0271] 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

[0272] 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

[0273] 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\92364964.2VVID-746PCyl)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).175 QB\184200.00050\92364964.2VVID-746PC

[0274] 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.

[0275] 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.

[0276] 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\92364964.2VVID-746PC

[0277] 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.

[0278] 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 C10H13F2NO3, 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.

[0279] 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\92364964.2VVID-746PC

[0280] 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).

[0281] 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 N2was 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).

[0282] 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 N2was 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).

[0283] 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\92364964.2VVID-746PC

[0284] 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 N2was 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.

[0285] 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.

[0286] 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\92364964.2VVID-746PC

[0287] 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 N2was 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. NaHCO3and 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).

[0288] 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. NaHCO3and 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.

[0289] 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\92364964.2VVID-746PC4,4-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]+.

[0290] 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.

[0291] 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.

[0292] 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 N2was 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).

[0293] 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 N2and 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\92364964.2VVID-746PCwas 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).

[0294] 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, 1.0eq) in 1,4-dioxane / water (3:1 v / v, 12 mL, 0.20 M) at 20°C under N2 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).

[0295] 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).

[0296] 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\92364964.2VVID-746PC

[0297] 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).

[0298] 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.

[0299] 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).

[0300] 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\92364964.2VVID-746PC

[0301] 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.

[0302] 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).

[0303] 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\92364964.2VVID-746PC1H), 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).

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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\92364964.2VVID-746PCmass 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.

[0308] 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.

[0309] 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.

[0310] 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).

[0311] 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\92364964.2VVID-746PC0.15 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.

[0312] 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).

[0313] 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 N2was 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).

[0314] 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. NaHCO3and 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\92364964.2VVID-746PC

[0315] 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. NaHCO3and 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).

[0316] 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.

[0317] 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.

[0318] 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\92364964.2VVID-746PC5.43 (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).

[0319] 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).

[0320] 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]+.

[0321] 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.

[0322] 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\92364964.2VVID-746PCwarm 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.

[0323] 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.

[0324] 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.190 QB\184200.00050\92364964.2VVID-746PC

[0325] 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.

[0326] 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.

[0327] 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).

[0328] 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\92364964.2VVID-746PCbeing 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).

[0329] 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. NaHCO3and 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.

[0330] 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.

[0331] 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 / CO2with 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\92364964.2VVID-746PCIntermediate 27: rac-(1*R,2*S,5*S)-2-(2-Chlorophenyl)-3-azabicyclo[3.1.0]hexane.

[0332] 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.

[0333] 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.

[0334] 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\92364964.2VVID-746PCIntermediate 30: rac-(1*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane.

[0335] 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.

[0336] 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).

[0337] 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\92364964.2VVID-746PC

[0338] 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).

[0339] 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.

[0340] 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\92364964.2VVID-746PC

[0341] 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).

[0342] 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.

[0343] 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).

[0344] 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\92364964.2VVID-746PCeq) 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.

[0345] 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.

[0346] 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.

[0347] To a solution of tert-butyl1-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 N2before 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).

[0348] 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\92364964.2VVID-746PCJ = 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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\92364964.2VVID-746PC1H), 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.

[0353] 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.

[0354] 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.

[0355] 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\92364964.2VVID-746PC3.59 (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.

[0356] 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.

[0357] 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.

[0358] 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\92364964.2VVID-746PCThe 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.

[0359] 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]+.

[0360] 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. NaHCO3and 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.

[0361] 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 ZnBr2instead 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\92364964.2VVID-746PC

[0362] 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

[0363] 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.

[0364] 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.202 QB\184200.00050\92364964.2VVID-746PC

[0365] 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 N2and 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]+.

[0366] 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]+.

[0367] 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. NaHCO3and 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.203 QB\184200.00050\92364964.2VVID-746PC

[0368] 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.

[0369] 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.

[0370] 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.

[0371] 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 N2was 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\92364964.2VVID-746PCcompletely, 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 N2for 12 h before being quenched with sat. aq. NaHCO3and 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).

[0372] 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.

[0373] 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.

[0374] 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\92364964.2VVID-746PC

[0375] 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.

[0376] 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.

[0377] 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.

[0378] 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\92364964.2VVID-746PCfound, 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. BocO

[0379] 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.

[0380] 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).

[0381] 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\92364964.2VVID-746PC

[0382] 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 N2and 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).

[0383] 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.

[0384] 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.208 QB\184200.00050\92364964.2VVID-746PC

[0385] 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...

Claims

VVID-746PCCLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein: each is a single bond when X8is CH2and is absent when X8is absent; each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; or X1is C, X4is N or C, and X1and X4together 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 X2and X3is independently CR3or N, wherein not more than one of X2and X3is N; R1is C1-C6alkyl or C3-C6cycloalkyl; each R2is independently hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R3is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -C(O)NR4R5, or -O-C1-C6alkyl; each of R4and R5is independently hydrogen or C1-C6alkyl; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-3 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent; or 561 QB\184200.00050\92364964.2VVID-746PCX5is CH, X6is CH2, X7is N, and X5and X7together 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 X8is absent; or X5and X6are each CH, X7is CH2or O, and X8is CH2; each R6is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl; or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7cycloalkyl; each R7is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyl or C1-C6haloalkoxyl; y is 0, 1, 2 or 3; and each R8is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; each R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; and each R10is independently C1-C3alkyl.

2. The compound of claim 1, wherein each of R1and R2is independently methyl or cyclopropyl.

3. The compound of any one of claims 1-2, wherein one of X1and X4is N.

4. The compound of any one of claims 1-3, wherein one of X2and X3is N.

5. The compound of any one of claims 1-4, wherein X3is N.

6. The compound of any one of claims 1-5, wherein X1is N.

7. The compound of any one of claims 1-5, wherein X4is N.

8. The compound of any one of claims 1-6, wherein X2and X4are each CR3.

9. The compound of any one of claims 1-2, wherein each of X1, X2, X3and X4is CR3.

10. The compound of any one of claims 1-2, wherein X1is C, X4is N or C, X1and X4together 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 X2and X3are each CR3. 562 QB\184200.00050\92364964.2VVID-746PC11. The compound of any one of claims 1-10, wherein each R3is independently hydrogen, chloro, fluoro, methyl, methoxy, -CF2, -CF3, or -CN.

12. The compound of any one of claims 1-11, wherein X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent.

13. The compound of any one of claims 1-11, wherein X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent.

14. The compound of any one of claims 1-11, wherein each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent.

15. The compound of claim 14, wherein X5and X6are each CH, substituted with 0-1 R6and 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 X5is CH, X6is CH2, X7is N, and X5and X7together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8is absent.

17. The compound of any one of claims 1-11, wherein X5and X6are each CH, X7is CH2or O, and X8is CH2.

18. The compound of any one of claims 1-17, wherein each R6is independently fluoro, chloro, oxo, - CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl; or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring.

19. The compound of any one of claims 1-18, wherein each R7is independently fluoro, chloro, - OCH3, -CF3, -OCF3, or C1-C3alkyl.

20. The compound of any one of claims 1-11 or 14-19, wherein each R8is independently fluoro, chloro, -CN, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, cyclopropyl, oxetanyl, -N(R9)2, -C(O)N(R9)2, - C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-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 R10is methyl. 563 QB\184200.00050\92364964.2VVID-746PC24. The compound of claim 1, wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8, and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is independently halogen or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -O-C1-C3 alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is independently halogen or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is independently halogen or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 X7and X8are each absent; or X5is CH, X6is CH2, X7is N, and X5and X7together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring, and X8is absent; or X5and X6are each CH, X7is CH2or O, and X8is CH2; each R6is independently halogen, hydroxyl, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6heterocyclyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, or C1-C3haloalkoxyl; y is 0, 1, 2 or 3; each R8is independently halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; and 567 QB\184200.00050\92364964.2VVID-746PCeach R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl.

28. The compound of claim 27, wherein X5and X6are each CH, substituted with 0-1 R6and 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:wherein: R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; each R8is independently halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -C1-C3alkylene-O-R9; and R9is C1-C3alkyl. 568 QB\184200.00050\92364964.2VVID-746PC30. The compound of claim 1, wherein the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1, or 2; each R7is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl;y is 0, 1, 2, or 3; and each R8is independently halogen or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; z is 0, 1, or 2; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; or X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, and X8is absent; or X5and X6are each CH, substituted with 0-1 R6and together with one additional carbon atom form a fused cyclopropyl ring, wherein the fused cyclopropyl ring is substituted with 0-2 R8; and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1, or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2, or 3; and each R8is independently halogen or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3 alkyl; X4is C or N; X9is CH or NR10; X5and X6are each CH2, substituted with 0-2 R6, and X7and X8are each absent; each R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; y is 0, 1, 2 or 3; and R10is C1-C3alkyl.

33. The compound of claim 1, wherein the compound is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; or 571 QB\184200.00050\92364964.2VVID-746PCX1is C, X4is N or C, and X1and X4together 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 X2and X3is independently CR3or N, wherein not more than one of X2and X3is N; R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl; each R3is independently hydrogen, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; X5and X6are each CH2, substituted with 0-2 R6, or each X5and X6is independently CH or C, substituted with 0-1 R6and 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 R6is independently halogen, hydroxyl, oxo, -CN, -N(R2)2, -C(O)N(R2)2, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, or C3-C6heterocyclyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; or R6together with X5and the methylene carbon adjacent to X5form a fused cyclopropyl ring, and X8is absent; w is 0, 1, or 2; ring A is aryl, 6-membered heteroaryl, or C6cycloalkyl; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, or C1-C3haloalkoxyl; y is 0, 1, 2, or 3; each R8is independently halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyl, C3-C6cycloalkyl, C3-C6heterocyclyl, -N(R9)2, -C(O)N(R9)2, -C(O)R9, -C(O)OR9, -C1-C3alkylene-R9, or -C1-C3alkylene-O-R9; each R9is independently hydrogen, -CN, -CD3, C1-C4alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; and R10is C1-C3alkyl.

34. The compound of claim 33, wherein each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N.

35. The compound of any one of claims 33-34, wherein X5and X6are each CH, substituted with 0-1 R6and 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\92364964.2VVID-746PC37. The compound of claim 1, wherein the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof:wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4isN and not more than one of X2and X3is N; R1is C1-C3alkyl or C3-C6cycloalkyl; R2is hydrogen or C1-C3alkyl; each R3is independently hydrogen, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; X5, X6and X7together are CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2, substituted with 0-2 R6, CH2NR6CH2, or C(O)NR6CH2, or X5is CH, X6is CH2, X7is N, and X5and X7together with four additional atoms selected from carbon and oxygen, form a fused 6-membered heterocyclic ring; each R6is independently halogen, hydroxyl, oxo, -CN, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6heterocyclyl, or two R6together with a ring atom form a C3-C6spirocyclic ring or a C3-C6spiroheterocyclic ring; ring A is aryl, w is 0, 1, or 2; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxyl; 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\92364964.2VVID-746PCwherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3is independently hydrogen, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl, or -O-C1-C3alkyl; X5and X6are each CH, X7is CH2or O, and X8is CH2; ring A is aryl; each R7is independently halogen, C1-C3alkyl, C1-C3haloalkyl, or C1-C3alkoxyl; 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\92364964.2VVID-746PC4-((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\92364964.2VVID-746PC2-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\92364964.2VVID-746PC4-(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\92364964.2VVID-746PC4-(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\92364964.2VVID-746PC4-((*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\92364964.2VVID-746PC4-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PCN-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC6-((*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\92364964.2VVID-746PC4-((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\92364964.2VVID-746PC4-(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\92364964.2VVID-746PCN-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC6-((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\92364964.2VVID-746PC5-((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:wherein: each of X1, X2, X3and X4is independently CR3or N, wherein not more than one of X1and X4is N and not more than one of X2and X3is N; R1is C1-C6alkyl; R2is hydrogen or C1-C6alkyl; each R3is independently hydrogen, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, -C(O)NR4R5, or -O-C1-C6alkyl; each of R4and R5is independently hydrogen or C1-C6alkyl; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2 or CH2S(O)CH2; or 599 QB\184200.00050\92364964.2VVID-746PCX5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1, 2 or 3; ring A is aryl, heteroaryl or C3-C7cycloalkyl; each R7is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxyl; y is 0, 1, 2 or 3; and each R8is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl.

41. The compound of claim 40, wherein R1and R2are methyl.

42. The compound of claim 40, wherein one of X1and X4is N.

43. The compound of claim 40, wherein one of X2and X3is N.

44. The compound of claim 40, wherein X1is N.

45. The compound of any one of claims 40-44, wherein X3is N.

46. The compound of any one of claims 40-45, wherein X2and X4are each CR3.

47. The compound of claim 40, wherein each of X1, X2, X3and X4is CR3.

48. The compound of any one of claims 40-47, wherein each R3is independently hydrogen, chloro, fluoro, cyano, methyl or methoxy.

49. The compound of claim 40, wherein X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2.

50. The compound of claim 40, wherein X5and X6are 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 R8is independently chloro or fluoro.

52. The compound of claim 40, wherein each R6is independently chloro, fluoro, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, or C1-C3hydroxyalkyl.

53. The compound of claim 40, wherein each R7is independently chloro, fluoro or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

56. The compound of claim 40, wherein the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; 601 QB\184200.00050\92364964.2VVID-746PCR2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

57. The compound of claim 40, wherein the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; 602 QB\184200.00050\92364964.2VVID-746PCw is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

58. The compound of claim 40, wherein the compound is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

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\92364964.2VVID-746PCwherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

60. The compound of claim 40, wherein the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; 604 QB\184200.00050\92364964.2VVID-746PCR2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 spirocyclyl or C3-C6 spiroheterocyclyl; w is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

61. The compound of claim 40, wherein the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1is C1-C3alkyl; R2is hydrogen or C1-C3alkyl; each R3ais independently halogen, C1-C3alkyl, C1-C3haloalkyl or -O-C1-C3alkyl; z is 0, 1, or 2; X5is CH2, wherein X5and X6together are CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2OCH2CH2, CH2CH2OCH2, CH2SCH2, CH2SCH2CH2, CH2CH2SCH2, CH2C(O)CH2or CH2S(O)CH2; or X5and X6are 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 R6is independently halogen, hydroxyl, oxo, C1-C3alkyl, C1-C3alkoxyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C3-C6cycloalkyl, C3-C6spirocyclyl or C3-C6spiroheterocyclyl; 605 QB\184200.00050\92364964.2VVID-746PCw is 0, 1 or 2; each R7is independently halogen, C1-C3alkyl or C1-C3haloalkyl; y is 0, 1, 2 or 3; and each R8is halogen or C1-C3alkyl.

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\92364964.2VVID-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\92364964.2VVID-746PC5-(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\92364964.2VVID-746PC4-((*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\92364964.2VVID-746PC4-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((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\92364964.2VVID-746PC5-(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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC6-((*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\92364964.2VVID-746PC5-((*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\92364964.2VVID-746PC4-((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\92364964.2VVID-746PC6-(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\92364964.2VVID-746PC70. 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

Images