6-membered core compounds as modulators of werner syndrome RECQ DNA helicase and uses thereof

Abstract

Disclosed herein are compounds having activity as inhibitors of Werner Syndrome RecQ DNA helicase (WRN), pharmaceutical compositions comprising the compounds, and methods of treating certain disorders, such as cancer, including but not limited to colorectal, endometrial, gastric and ovarian cancer. In particular, the disclosure provides compounds of Formula (I):, and pharmaceutically acceptable salts thereof, wherein the substituents are as described herein.

Description

6-MEMBERED CORE COMPOUNDS AS MODULATORS OF WERNER SYNDROME RECQ DNA HELICASE AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 666,083, filed June 28, 2024. FIELD

[0002] Provided herein are compounds having activity as inhibitors of Werner Syndrome RecQ DNA helicase (WRN). Also provided herein are pharmaceutical compositions comprising such compounds and methods of using such compounds and compositions in treating certain diseases such as cancer, including cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) such as, but not limited to, colorectal, endometrial, gastric, and ovarian cancer. Also provided are methods of making such compounds and intermediates thereof. BACKGROUND

[0003] Loss of DNA mismatch repair (MMR) occurs in 10–30% of colorectal, endometrial, gastric, ovarian, and other cancer types. MMR deficient cancers (MMRd) have a high mutational burden and frequent insertion and / or deletion events in repetitive DNA tracts, which is a phenotype known as high microsatellite instability (MSI-H). Werner syndrome protein (WRN) belongs to the RecQ DNA helicase family and is a 3’ to 5’ DNA-unwinding, DNA-dependent ATPase. WRN has been identified as a synthetic lethal target for, e.g., dMMR / MSI-H cancers. WRN depletion causes DNA double-strand breaks in MSI-H cells, leading to cell cycle arrest and / or apoptosis.

[0004] Mismatch repair-deficient (MMRd) tumors with high levels of microsatellite instability (MSI-H) generally respond well to immunotherapy but are relatively less responsive to conventional chemotherapy. In some cases, the standard of care for MMRd / MSI-H cancers is therapy with immune checkpoint inhibitors. Nevertheless, between 30-50% of patients with MMRd / MSI-H advanced or metastatic tumors do not exhibit a durable response to immune checkpoint inhibitors.SUMMARY

[0005] While there have been advances in cancer treatments, such as immune checkpoint inhibitors, there is a continued unmet need for new treatments and therapies for the treatment of cancer, and in particular cancers characterized as mismatch-repair deficient (MMRd) or microsatellite instability-high (MSI-H), including among them cancers of colorectal, endometrial, gastric and ovarian origin.

[0006] Provided herein are compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, said compounds having activity as inhibitors of Werner Syndrome RecQ DNA Helicase (WRN). Said compounds inhibit the portion of WRN known to be responsible for the DNA unwinding and ATP hydrolysis functions of WRN, and which is comprised of two helicase subdomains termed D1 and D2 followed by three helicase-associated domains called a zinc-binding domain, a Winged-Helix (WH) domain and a helicase and RNase D C-terminal (HRDC) domain.

[0007] One aspect of the disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: X is N or C-Rx, wherein Rxis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl; Y is N or C-Ry, wherein Ryis H, halogen, CN, OH, C1-3alkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Rb)2, wherein each instance of Rbindependently is H or C1- 3alkyl; wherein the C1-3alkyl of each instance of Raand Rbindependently is unsubstituted or substituted with one or more substituents and each substituent independently is OH or C1-3alkoxy; Z is N or C-Rz, wherein Rzis H or halogen; R1is C1-6alkyl, C1-6alkenyl, N(Rc)(Rd), C3-8cycloalkyl, C3-8cycloalkenyl, heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-10 total ring atoms and 1-3 heteroatomsindependently selected from N, O, and S, wherein Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3- 6cycloalkyl, or C3-6cycloalkenyl; wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C0-6alkylene-OH, C0-3alkylene-CN, C1- 4alkyl, C1-4alkenyl, C0-3alkylene-C1-3haloalkyl, C0-6alkylene-C1-3alkoxy, C0-2alkylene- C1-3haloalkoxy, C0-3alkylene-C3-6cycloalkyl, or C0-3alkylene-phenyl; wherein, when R1is C6-10aryl, heteroaryl having 5-10 total ring atoms, C3-8cycloalkyl, or heterocycloalkyl having 3-10 total ring atoms, then two adjacent substituents of R1, together with the atoms to which they are attached, may form C3-6cycloalkyl, C3-6cycloalkenyl, heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-6 total ring atoms and 1-3 heteroatoms independently selected from N, O and S; wherein the cycle formed by the two adjacent substituents of R1can be unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy; wherein, when R1is substituted with C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl, the C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, or C1-3alkoxy; wherein, when R1is substituted with C1-4alkyl or C1-4alkenyl, the C1- 4alkyl or C1-4alkenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, NH2, NH(C1-3alkyl), or N(C1-3alkyl)2; R2is C6-10aryl or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein R2is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, C1- 3haloalkyl, C1-3cycloalkyl, or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; R3is:wherein Q is N or C; wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, D, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0- 2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is D, halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, or C1-3alkoxy.

[0008] Another aspect of the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.

[0009] Yet another aspect of the disclosure provides method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of Formula (I) or a pharmaceutical composition comprising the compound or salt of Formula (I).

[0010] Still another aspect of the disclosure provides a compound or salt of Formula (I) for use as a medicament. Another aspect of the disclosure provides a compound or salt disclosed herein, or the pharmaceutical composition disclosed herein for use in the treatment of cancer.

[0011] Yet another aspect of the disclosure provides a compound or salt of Formula (I), or the pharmaceutical composition comprising a compound or salt of Formula (I), for the manufacture of a medicament for the treatment of cancer. Another aspect of the disclosure provides the use of a compound or salt disclosed herein, or the pharmaceutical composition of the disclosure, wherein the cancer is characterized as microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR), or any combination of the foregoing. In some cases, the cancer is characterized as tumor-agnostic MSI-H / dMMR cancer. In some cases, the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian, urothelial, small bowel, brain, biliary tract, bladder,gastroesophageal, head-and-neck, skin, sarcoma, thoracic, or pancreatic cancer, or any combination of the foregoing.

[0012] Yet another aspect of the disclosure provides a compound of Formula (II):(II), or a salt thereof, wherein RW, X, Y, Z, and R1are as described for Formula (I). In some cases, Rwis H, halogen, C1-3alkyl, or C0-2alkylene-C1- 3alkoxy; X is CH, Y is N, and Z is N; and R1 is as described for Formula (I).

[0013] Yet another aspect of the disclosure provides a compound of Formula (III):(III), or a salt thereof, wherein RW, X, Y, Z, and R1are as described for Formula (I). In some cases, Rwc1is H, C1-3alkyl, C0-2alkylene-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; X is CH, Y is N, and Z is N; and R1is as described for Formula (I).

[0014] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. The description hereafter includes specific cases, embodiments, and examples with the understanding that the disclosure is illustrative and is not intended to limit the embodiments of the present disclosure to the specific cases, embodiments, and examples described herein. DETAILED DESCRIPTION

[0015] Disclosed herein are compounds having activity as modulators (e.g., inhibitors) of WRN, pharmaceutical compositions comprising the compounds, and uses and methods of treating disorders, such as cancer, with the compounds and pharmaceutical composition described herein.

[0016] Without being bound by theory, the disclosed compounds herein inhibit the portion of WRN known to be responsible for DNA unwinding and ATP hydrolysis functions of WRN, and which is comprised of two helicase subdomains termed D1 and D2 followed by three helicase-associated domains called a zinc-binding domain, a Winged-Helix (WH) domain and a helicase and RNase D C-terminal (HRDC) domain.DEFINITIONS

[0017] The following definitions are provided to assist in understanding the scope of this disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0018] The term “alkyl” refers to a saturated straight chain hydrocarbon or saturated branched chain hydrocarbon containing the indicated number of carbon atoms. For example, C3alkyl means an alkyl group that has 3 carbon atoms (e.g., n-propyl or isopropyl). For example, a C1-6alkyl refers to an alkyl group having 1 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C1-6alkyl includes alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges)). A “C1-4alkyl” includes, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, and n-hexyl.

[0019] The term “alkenyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. For example, C3alkenyl means the alkenyl group has 3 carbon atoms (e.g., 1-propenyl or 2- propenyl). For example, a C2-6alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-6alkenyl includes alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). A C2-4alkenyl includes, for example, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or 3-butenyl. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0020] The term “alkynyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds.For example, C3alkynyl means the alkynyl group has 3 carbon atoms. For example, a C2- 6alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-6alkynyl includes any alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). For illustration, C2-4alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl. Nonlimiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0021] The term “carbocyclyl” refers to a monocyclic ring or a polycyclic ring system containing only carbon atoms as ring members. “Carbocyclyl” includes, for example, cycloalkyl, cycloalkenyl, and aryl groups. When a carbocyclyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. The carbocyclyl ring or ring system includes the indicated number of carbon atoms as ring members. For illustration, C6carbocyclyl includes, for example, cyclohexyl, cyclohexenyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.2]pentyl, and phenyl. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C3-6carbocyclyl includes carbocyclyl groups having 3, 4, 5, or 6 carbon atoms in the ring or ring system (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., carbocyclyl groups with 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atom ring members, or any combination of the foregoing ranges). Nonlimiting examples of carbocyclyl rings include cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, spiro[4.4]nonanyl, and naphthalenyl.

[0022] The term “cycloalkyl” refers to a saturated, hydrocarbon monocyclic ring, or a saturated, hydrocarbon polycyclic ring system containing the indicated number of carbon atoms as ring members in the ring or ring system. No ring in a cycloalkyl ring or ring system has s double bond, a heteroatom, or is aromatic. When a cycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example, C5cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring or ring system. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C3-7cycloalkyl includes cycloalkyl groups having 3, 4,5, 6, or 7 carbon atoms in the ring (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 3-4, 3-5, 3-6, 3-7, 4-5, 4-6, 4-7, 5-6, 5-7, or 6-7 carbon atom ring members, or any combination of the foregoing ranges). Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbornyl, decalinyl, and 7,7-dimethylbicyclo[2.2.1]heptanyl.

[0023] The term “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring or ring system containing the indicated number of carbon atoms as ring members and having one or more carbon-carbon double bonds in the ring or ring system. No ring in a cycloalkenyl ring or ring system contains a double bond or is aromatic. When a cycloalkenyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example, C5cycloalkenyl refers to a cycloalkenyl group that has 5 carbon atoms in the ring or ring system. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C5-7cycloalkenyl includes cycloalkenyl groups having 5, 6, or 7 carbon atoms in the ring or ring system (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 5-6, 5-7, or 6-7 carbon atom ring members in the ring or ring system, or combinations of the foregoing ranges). Nonlimiting examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and bicyclo[2.2.1]hept-2-enyl.

[0024] The term “aryl” refers to a monocyclic aromatic, hydrocarbon ring (i.e., phenyl,) or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic hydrocarbon ring system containing the indicated number of carbon atoms. For example, C10aryl refers to an aryl group that has 10 carbon atoms in the ring system (e.g., naphthyl). When an aryl group is a polycyclic ring system, each ring in the ring system is aromatic, and no ring in the ring system contains a heteroatom. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C6-14aryl includes aryl groups having 6-14 (e.g., 6, 10, or 14) carbon atoms in the ring or ring system (or combinations of the foregoing), as well as all subgroups in the indicated range (e.g., 6-10 or 10-14 carbon atom ring members in the ring or ring system, or combinations of the foregoing). Nonlimiting examples of aryl groups include phenyl, naphthyl, and anthracenyl.

[0025] The term “heteroatom,” unless otherwise stated herein, refers to oxygen, sulfur, nitrogen, and phosphorus.

[0026] The term “heteroalkyl” refers to an alkyl group containing one or more heteroatoms (e.g., one or more of N, O, and S) at the heteroalkyl’s point of attachment (e.g., alkoxy), between two carbon atoms (e.g., ether), at the end of the alkyl substituent (e.g., (CH2)4OH, or a combination thereof (e.g., polyether). A heteroalkyl contains the indicated number of total atoms (i.e., the sum of the carbon atoms and heteroatoms in the chain). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroalkyl having 2-6 total atoms and 1, 2, or 3 heteroatoms independently selected from O and S includes heteroalkyl groups having 2, 3, 4, 5, or 6 total atoms in the heteroalkyl chain (or any combination of the foregoing), as well as all subgroups of total atoms in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 total atoms, or any combination of the foregoing ranges), wherein 1, 2, or 3 (or any combination of the foregoing) of the total atoms in the chain are heteroatoms, as well as all subgroups in the indicated range (e.g., 1-2, 1-3, or 2-3 heteroatoms, or any combination of the foregoing). Thus, a heteroalkyl having 5-7 total atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses moieties containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of heteroalkyl groups include - O(CH2)3CH3, —CH2CH2OCH2CH3, —(CH2)4NH2, —O(CH2)3NH2, —NH(CH2)3OH, — (OCH2CH2)2OH, —(OCH2CH2)3OH, —(OCH2CH2)3OCH3, and —(CH2CH2NH)2CH2-CH2NH2.

[0027] The term “heterocyclyl” refers to a ring or ring system containing carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S) in the ring or ring system, and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring or ring system). “Heterocyclyl” groups include, for example, heterocycloalkyl, heterocycloalkenyl, heteroaryl groups, or other ring systems having at least one heteroatom. Where the heterocyclyl is a ring system (e.g., a bicyclic, a tricyclic, or a tetracyclic system), two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For illustration, a heterocyclyl having 6 total ring atoms and 1, 2, or 3 heteroatoms independently selected from N, O, and S includes, for example, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothipyranyl, dithianyl, morpholinyl, thiomorpholinyl,pyridinyl (or pyridyl), pyridazinyl, pyrimidinyl, and triazinyl. A heterocyclyl having 5-7 total ring atoms and 1, 2, or 3 heteroatoms independently selected from N, O, and S refers to a ring or ring system having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom independently is selected from N, O, and S. Thus, a heterocyclyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Examples of heterocyclyl groups include but are not limited to azetidinyl, aziridinyl, 1,3-dioxin-yl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,3- oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, dioxolanyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, maleimidyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, indolinyl, isoindolinyl, 2,3- dihydrobenzofuranyl, oxetanyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, succinimidyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, and 1,4- dihydroquinolinyl.

[0028] The term “heterocycloalkyl” refers to a saturated, monocyclic ring or saturated, polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring). When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. No ring in a heterocycloalkyl ring or ring system contains a double bond or is aromatic. For example, a heterocycloalkyl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independentlyselected from N, O, and S includes rings having 5, 6, or 7 total atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom independently is selected from N, O, and S. Thus, a heterocycloalkyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Nonlimiting examples of heterocycloalkyl groups include but are not limited to aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene-yl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, azepanyl, and 1,4-diazepanyl.

[0029] The term “heterocycloalkenyl” refers to a monocyclic ring or a polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), wherein the ring or ring system has one or more double bonds. In a polycyclic ring system, the one or more heteroatoms may be located in any ring within the system, including in a ring lacking a double bond. When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion, and any ring in the ring system can contain a double bond. No ring in a heterocycloalkenyl ring or ring system is aromatic. For example, a heterocycloalkenyl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to a ring having at least one double bond, 3 carbon atoms, and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkenyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S includes rings having at least one double bond and 5, 6, or 7 total atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatomsand each heteroatom independently is selected from N, O, and S. Thus, heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing at least one double bond and, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Nonlimiting examples of heterocycloalkenyl groups include but are not limited to dihydropyrrolyl, dihydrofuranyl, dihydrothiophene-yl, dihydroisoxazolyl, tetrahydropyridyl, dihydropyranyl, dihydrothiopyranyl, 3a,4,5,6,7,7a-hexahydrobenzofuranyl, 1,3a,3,4,7,7a-hexahydroisobenzofuranyl, and 3a,4,5,6,7,7a-hexahydroindolyl.

[0030] The term “heteroaryl” refers to a monocyclic aromatic ring comprising carbon and one or more heteroatoms, and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic ring system having one or more heteroatoms and the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring system). When a heteroaryl group is a polycyclic ring system, each ring in the ring system is aromatic. For example, a heteroaryl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S refers to an aromatic ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms, or any combination of the foregoing), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. A heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of monocyclicheteroaryl groups include: pyrrolyl, furanyl, thiophene-yl (or thienyl), pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (or pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Nonlimiting examples of bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzimidazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, furopyridinyl (e.g., furo[2,3-b]pyridinyl), imidazopyridinyl (imidazo[4,5-b]pyridinyl), imidazothiazolyl (e.g., imidazo[4,5-d]thiazolyl), indolizinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl (e.g., oxazolo[5,4-b]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (e.g., pyrrolo[2,3-b]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, cinnolinyl, isoquinolyl, pyrazolopyridinyl (e.g., pyrazolo[3,4-b]pyridinyl), and thiazolopyrindinyl (e.g., thiazolo[5,4-b]pyridinyl). Nonlimiting examples of tricyclic heteroaryl groups include carbazolyl, 4,5-benzindolyl, dibenzofuranyl, dibenzothiophene-yl, phenazinyl, and acridinyl.

[0031] The term “alkylene” refers to a divalent saturated, straight or branched hydrocarbon chain diradical containing the indicated number of carbon atoms. For example, C3alkylene means the alkylene group has 3 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, C1-6alkylene means an alkylene group having a 1, 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2- 4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). When the number of carbon atoms in an alkylene group is indicated as “C0,” then the alkylene group is not present and the recited substituent is directly attached to the rest of the compound. For example, the term C0-6alkylene-OH indicates that the OH group can be directly attached to the compound or through a C1-6alkylene linker. Examples of alkylene groups include methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (— CH2CH2CH2—), isopropylene (—CH(CH3)CH2—), 1-butylene (—CH2CH2CH2CH2—), 1- methylbutylene (—CH(CH3)CH2CH2—), 2-methylbutylene (—CH2CH(CH3)CH2—), and 3- methylbutylene (—CH2CH2CH2(CH3)—).

[0032] The term “heteroalkylene” refers to an alkylene group containing one or more heteroatoms (e.g., one or more of N, O, and S) at one or more of the heteroalkylene’s points of attachment (e.g., -OCH2CH2O- or -OCH2CH2-) or between two carbon atoms (e.g., ether), or a combination thereof. A heteroalkylene contains the indicated number of total atoms (i.e.,the sum of the carbon atoms and heteroatoms in the chain). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroalkylene having 2-6 total atoms and 1, 2, or 3 heteroatoms independently selected from O and S includes heteroalkylene groups having 2, 3, 4, 5, or 6 total atoms in the heteroalkylene chain (or any combination of the foregoing), as well as all subgroups of total atoms in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 total atoms, or any combination of the foregoing ranges), wherein 1, 2, or 3 (or any combination of the foregoing) of the total atoms in the chain are heteroatoms, as well as all subgroups in the indicated range (e.g., 1-2, 1-3, or 2-3 heteroatoms, or any combination of the foregoing). Thus, a heteroalkylene having 5-7 total atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses moieties containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of heteroalkylene groups include - O(CH2)2O-.

[0033] The term “alkylene bridge” refers to an alkylene group that forms a bridge on a ring, wherein the bridge has the indicated number of carbon atoms. For example, a C1alkylenebridge ( ) on a cyclohexylene ring can be depicted as, for example,C2alkylene bridge (on a cyclohexylene ring can be depicted as, for example,on a cyclohexylene ring can be depicted as,for example,.

[0034] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0035] The term “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen. The halogen is independently selected at each occurrence. The term includes, for example, monohaloalkyl (e.g., CH2F, CH(CH2F)CH3) dihaloalkyl (e.g., CHF2, CH(CHF2)CH3), trihaloalkyl (e.g., CF3, CH(CF3)CH3), and polyhaloalkyl (e.g., CF(CF3)CH3). A haloalkyl group may or may not be perhalogenated (e.g., perfluorinated, such as CF(CF3)CF3). For example, the term “C1-4haloalkyl” refers to a C1-4alkyl, wherein one or more hydrogen atoms is substituted with a halogen. For illustration, C1-4haloalkyl includes, for example, CH2F, CHF2, CF3, CHFCl, CH2CF3, CFHCF3, CF2CF3, CH(CF3)2, CF(CHF2)2, CH(CH2F)(CF3), CH2Cl, CHCl2, CCl3, CH2CCl3, CClHCCl3, CCl2CCl3, CH(CCl3)2, CCl(CHCl2)2, CH(CH2Cl)CCl3, and CH2CF(CH3)2.

[0036] The term “oxo” refers to a substituent oxygen atom connected to another atom by a double bond example, an oxo substituent on a cyclopentyl ring can be depicted as:

[0037] The term “carbonyl” refers to a divalent C=O radical, such as.

[0038] The terms “hydroxy” and “hydroxyl” are interchangeable and refer to a —OH group.

[0039] The term “thiol” refers to a —SH group.

[0040] The terms “alkoxy” and “alkoxyl” are interchangeable and refer to an —O-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C3alkoxy group means the alkoxy group has 3 carbon atoms (e.g., OCH2CH2CH3). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C1-6alkoxy includes alkoxy groups having 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2- 5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). Nonlimiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, 1- methylethyloxy (iso-propoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0041] The term “thioalkyl” refer to an —S-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C3thioalkyl group means the thioalkyl group has 3 carbon atoms (e.g., SCH2CH2CH3). Where a range is indicated, all members of that range andall subgroups within that range are envisioned. For example, a C1-6thioalkyl includes thioalkyl groups having 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). Nonlimiting examples of thioalkyl groups include methylthiyl, ethylthiyl, n-propylthiyl, isopropylthiyl, n-butylthiyl, isobutylthiyl, sec-butylthiyl, and tert-butylthiyl).

[0042] The terms “haloalkoxy” and “haloalkoxyl” are interchangeable and refer to an alkoxy group in which one or more of the hydrogen atoms is replaced by a halogen. The halogen is independently selected at each occurrence. The term includes monohaloalkoxy (e.g., OCH2F, OCH(CH2F)CH3) dihaloalkoxy (e.g., OCHF2, OCH(CHF2)CH3), trihaloalkoxy (e.g., OCF3, OCH(CF3)CH3), and polyhaloalkoxy (e.g., OCF(CF3)CH3). A haloalkoxy group may or may not be perhalogenated (e.g., perfluorinated, such as OCF(CF3)CF3). For example, the term “C1-4haloalkoxy” refers to a C1-4alkoxy as defined herein, wherein one or more hydrogen atoms is substituted with a halogen. Representative examples of C1-4haloalkoxy include OCH2F, OCHF2, OCF3, OCHFCl, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, OCH(CH2F)(CF3), OCH2Cl, OCHCl2, OCF3, OCHFCl, OCH2CCl3, OCClHCCl3, OCCl2CCl3, OCH(CCl3)2, OCCl(CHCl2)2, OCH(CH2Cl)CCl3, and OCH2CF(CH3)2.

[0043] The term “cyano” refers to a —CN group.

[0044] The term “amino” refers to —NH2.

[0045] The term “alkylamino” refers to a — NHR group in which R is alkyl.

[0046] The term “dialkylamino” refers to a —NR2group in which each R independently is alkyl.

[0047] The term “ether” refers to an oxygen atom bonded to two alkyl or aryl groups (R-O- R). The term “ether bridge” refers to an ether group that forms a bridge on a ring, wherein the O bridge has the indicated number of carbon atoms. For example, a C1ether bridge ( ) O O on a cyclohexylene ring cyclohexylene ring can be depicted as, for example, or .

[0048] The term “thioether” refers to a sulfur atom bonded to two alkyl or aryl groups (R- S-R). The term “thioether bridge” refers to a thioether group that forms a bridge on a ring, wherein the bridge has the indicated number of carbon atoms. For example, a C1thioether bridge () on a cyclohexylene ring cyclohexylene ring can be depicted as, for example,

[0049] The term “solvate” refers to a molecular aggregate comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non- stoichiometric amount of one or more pharmaceutically acceptable solvent molecules.

[0050] The term “hydrate” refers to a solvate in which the solvent is water.

[0051] The term “geminal” refers to substituents that are attached to the same atom. Geminal R groups on a chain and ring can be depicted as:respectively.

[0052] The term “vicinal” refers to substituents that are attached to adjacent atoms along a chain or within a ring. Vicinal R groups along a chain and within a ring can be depicted as, respectively.

[0053] The term “non-neighboring” refers to substituents that are attached to atoms along a chain or within a ring that are not attached to adjacent atoms and that are not geminal. Non- RRneighboring R groups along a chain and within a ring can be depicted asand

[0054] The term “protecting group” refers to a removable moiety that modifies a desired functional group to block the desired functional group from reacting in a subsequent chemical reaction. For example, the term “nitrogen protecting group” refers to a removable moiety that modifies a functional group having a nitrogen atom to block the functional group having a nitrogen atom from reacting in a subsequent chemical reaction (e.g., tert-butyloxycarbonyl). Examples of protecting groups are detailed in Greene, T. W., Wuts, P. G, “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book, such as Wuts, P.G.M. and Greene, T.W. “Greene’s Protective Groups in Organic Synthesis,” Fourth Edition, John Wiley & Sons, Hoboken: 2007).

[0055] As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0056] The term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure or functional group with the radical of a specified substituent. A substituted structure or functional group may have a substituent at any substitutable position of the structure or functional group. When more than one position in a given structure can be substituted with more than one substituent, the substituent may be either the same or different at each position.

[0057] The term “pharmaceutically acceptable” refers to a species or component that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in a subject.

[0058] The term “pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine). Additionally, the salts of the compounds described herein, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules.

[0059] The term “pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound, solvate, or salt disclosed herein to prepare a pharmaceutically acceptable composition or formulation. Excipients include, for example, vehicles (e.g., solvents, dispersion media), coatings, isotonic and absorption delaying agents, diluents, colorants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, and preservatives (e.g., antibacterial and antifungal agents).

[0060] The term “therapeutically effective amount” as used herein refers to that amount of a compound disclosed herein that elicits a desired biological or medical response in a cell, a tissue, a system, or a subject.

[0061] The term “patient” or “subject” refers to humans and other mammals. The term “mammal” as used herein includes, for example, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), and monkeys. Human subjects include neonates, infants, juveniles, adults, and geriatric subjects. COMPOUNDS OF THE DISCLOSURE

[0062] Disclosed herein are compounds of Formula (I):or apharmaceutically acceptable salt thereof. Also disclosed herein are compounds or salts of Formula (I) having a structure of Formula (wherein the variables are as described for Formula (I). Additionally, disclosed herein are compounds or salts of Formula (I) having a structure of Formula (wherein the variables are as described for Formula (I).

[0063] Provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: X is N or C-Rx, wherein Rxis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl; Y is N or C-Ry, wherein Ryis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Rb)2, wherein each instance of Rbindependently is H or C1-3alkyl; wherein the C1-3alkyl of each instance of Raand Rbindependently is unsubstituted or substituted with one or more substituents and each substituent independently is OH, halogen, or C1-3alkoxy; Z is N or C-Rz, wherein Rzis H or halogen; wherein 0, 1, 2, or 3 of X, Y, and Z is N; R1is C1-6alkyl, C1-6alkenyl, N(Rc)(Rd), C3-8cycloalkyl, C3-8cycloalkenyl, heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl; wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C0-6alkylene-OH, C0-3alkylene-CN, C1- 4alkyl, C1-4alkenyl, C0-3alkylene-C1-3haloalkyl, C0-6alkylene-C1-3alkoxy, C0-2alkylene- C1-3haloalkoxy, C0-3alkylene-C3-6cycloalkyl, or C0-3alkylene-phenyl; wherein, when R1is C6-10aryl, heteroaryl having 5-10 total ring atoms, C3- 8cycloalkyl, or heterocycloalkyl having 3-10 total ring atoms, then two adjacent substituents of R1, together with the atoms to which they are attached, may form C3-6cycloalkyl, C3-6cycloalkenyl, heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-6 total ring atoms and 1-3 heteroatoms independently selected from N, O and S; wherein the cycle formed by the two adjacent substituents of R1can be unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy;wherein, when R1is substituted with C0-3alkylene-C3-6cycloalkyl or C0- 3alkylene-phenyl, the C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, or C1- 3alkoxy; wherein, when R1is substituted with C1-4alkyl or C1-4alkenyl, the C1-4alkyl or C1-4alkenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, NH2, N(C1-3alkyl)H, or N(C1-3alkyl)2; R2is C6-10aryl or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein R2is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3cycloalkyl, or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; R3iswherein Q is N or C; wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, D, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0- 2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is D, halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, or C1-3alkoxy. Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein 0, 1, 2, or 3 of X, Y, and Z is N. In some cases, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are provided wherein 0, 1, or 2 of X, Y, and Z is N. In some cases, compounds of Formula (I), or apharmaceutically acceptable salt thereof, are provided wherein 0 or 1 of X, Y, and Z is N. In some cases, X, Y, and Z is C. In some cases, one of X, Y, and Z are N. In some cases, two of X, Y, and Z are N. In some cases, three of X, Y, and Z are N.

[0064] In some cases, the compound of Formula (I) is a neutral form. In some cases, the compound of Formula (I) is a salt. In some cases, the compound of Formula (I) is a pharmaceutically acceptable salt.

[0065] In some cases, the compound of Formula (I) comprises D. In some cases, the compound of Formula (I) does not comprise D.

[0066] In some cases, the compound of Formula (I) has R3that iswherein Q is N or C; wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; and wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, or C1-3alkoxy.

[0067] In some cases, the compound of Formula (I) has R3that iswherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; andwherein R3is unsubstituted or substituted with 1-3 substituents and each substituent

[0068] As used in this disclosure,also may be referred to as the core ring. In some cases, each of X, Y, and Z is independently N or C-Rx. In some cases, at least one of X, Y, and Z is N. In some cases, X, Y, and Z are each N. In some cases, core ring comprises two N in total. In some cases, core ring comprises one N in total. In some cases, one of X, Y, and Z is N. In some cases, two of X, Y, and Z are N. In some cases, both Y and Z are N and X as C-Rx. In some cases, both X and Y are N and Z is C-Rx. In some cases, both X and Z are N and X is C-Rx. In some cases, both X and Z are C-Rxand Y is N. In some cases, both Y and Z are C-Rxand X is N. In some cases, both X and Y are C-Rxand Y is N. In some cases, X, Y,and Z are C-Rx. In some cases, the core ring is. In some cases, the core ring issome cases, the core ring i

[0069] In some cases, X is N. In some cases, X is C-Rx, wherein Rxis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl. In some cases, X is CH. In some cases, X is CHalogen. In some cases, X is CF, CBr, or CCl. In some cases, X is CF. In some cases, X is CBr. In some cases, X is CCl. In some cases, X is CCN or COH. In some cases, X is CCN. In some cases, X is COH. In some cases, X is C-C1-3alkyl. In some cases, X is CCH3. In some cases, X is CCH2CH3. In some cases, X is CCH2CH2CH3. In some cases, X is C-C1-3haloalkyl. In some cases, X is C-CF3, C-CHF2, C-CH2F. In some cases, X is C-C0-3alkylene- C1-3alkoxy. In some cases, X is C-C1-3alkoxy. In some cases, X is C-OCH3. As used herein, a linker that is C0means the terminal group (e.g., C1-3alkoxy) is directly connected without an alkylene linker. In some cases, X is C-C1-3alkylene-C1-3alkoxy. In some cases, X is C-C1- 3alkylene-methoxy. In some cases, X is C-C1-3alkylene-ethoxy. In some cases, X is C-C1-3alkylene-propoxy. In some cases, X is C-CH2-OCH3. In some cases, X is C-N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl. In some cases, X is C-NH2. In some cases, X is C-N(Ra)2, wherein each Ra, together with the atoms to which they are attached, form a heterocycloalkyl with N as the heteroatom and having 4-6 heteroatoms independently selected from N, O, and S. In some cases of X is C-N(Ra)2, each instance of Rais independently C1-3alkyl, wherein each instance of Rbindependently is unsubstituted or substituted with one or more substituents and each substituent independently is OH, halogen, or C1-3alkoxy.

[0070] In some cases, Y is N.In some cases, Y is C-Ry, wherein Ryis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Rb)2, wherein each instance of Rbindependently is H or C1-3alkyl. In some cases, Y is CH. In some cases, Y is CHalogen. In some cases, Y is CF, CBr, or CCl. In some cases, Y is CF. In some cases, Y is CBr. In some cases, Y is CCl. In some cases, Y is CCN or COH. In some cases, Y is CCN. In some cases, Y is COH. In some cases, Y is C-C1-3alkyl. In some cases, Y is CCH3. In some cases, Y is CCH2CH3. In some cases, Y is CCH2CH2CH3. In some cases, Y is C-C1- 3haloalkyl. In some cases, Y is C-CF3, C-CHF2, C-CH2F. In some cases, Y is C-C0-3alkylene- C1-3alkoxy. In some cases, Y is C-C1-3alkoxy. In some cases, Y is C-OCH3. In some cases, Y is C-C1-3alkylene-C1-3alkoxy. In some cases, Y is C-C1-3alkylene-methoxy. In some cases, Y is CC1-3alkylene-ethoxy. In some cases, Y is CC1-3alkylene-propoxy. In some cases, Y is C- CH2-OCH3. In some cases, Y is CN(Rb)2, wherein each instance of Rbindependently is H or C1-3alkyl. In some cases, Y is CNH2.In some cases, Y is N(Rb)2, wherein each Rb, togetherwith the atoms to which they are attached, form a heterocycloalkyl with N as the heteroatom and having 4-6 heteroatoms independently selected from N, O, and S.

[0071] In some cases, X is CNH2, CNHC1-3alkyl, or CN(C1-3alkyl)2. In some cases, X is CNH2. In some cases, X is CNHC1-3alkyl. In some cases, X is CN(C1-3alkyl)2. In some cases, the C1-3alkyl of X is unsubstituted. In some cases, C1-3alkyl of X is substituted with one or more substituents and each substituent independently is OH, halogen, or C1-3alkoxy. In some cases, Y is CNH2, CNHC1-3alkyl, or CN(C1-3alkyl)2. In some cases, Y is CNH2. In some cases, Y is CNHC1-3alkyl. In some cases, Y is CN(C1-3alkyl)2. In some cases of X or Y, such C1-3alkyl of X or Y is unsubstituted. In some cases, C1-3alkyl of X or Y is substituted with one or more substituents and each substituent independently is OH, halogen, or C1-3alkoxy.

[0072] In some cases, Z is N or CH. In some cases, Z is N. In some cases, Z is CH.

[0073] In some cases, R1is C1-6alkyl, C1-6alkenyl, N(Rc)(Rd), C3-8cycloalkyl, C3-8cycloalkenyl, heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl. In some cases, R1is C1-6alkyl. In some cases, R1is C1-6alkenyl. In some cases, R1is N(Rc)(Rd). In some cases, R1is C3-8cycloalkyl. In some cases, R1is C3-8cycloalkenyl. In some cases, R1is heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, R1is C6-10aryl. In some cases, R1is heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, R1is heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl. In some cases, Rcis H and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl. In some cases, Rcis C1-3alkyl and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl.

[0074] In some cases, R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C0-6alkylene-OH, C0-3alkylene-CN, C1-4alkyl, C1- 4alkenyl, C0-3alkylene-C1-3haloalkyl, C0-6alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-3alkylene-C3-6cycloalkyl, or C0-3alkylene-phenyl. In some cases, R1is unsubstituted. In some cases, R1is substituted with one or more substituents. In some cases, each substituent independently is halogen. In some cases, each substituent independently is C0-6alkylene-OH. In some cases, each substituent independently is OH. In some cases, each substituentindependently is C0-3alkylene-CN. In some cases, each substituent independently is CH2CN. In some cases, each substituent independently is CN. In some cases, each substituent independently is C1-4alkyl. In some cases, each substituent independently is C1-4alkenyl. In some cases, each substituent independently is C0-3alkylene-C1-3haloalkyl. In some cases, each substituent independently is C0-6alkylene-C1-3alkoxy. In some cases, each substituent independently is C1-3haloalkoxy. In some cases, each substituent independently is C0-3alkylene-C3-6cycloalkyl. In some cases, each substituent independently is C3-6cycloalkyl. In some cases, each substituent independently is cyclopropyl. In some cases, each substituent independently is C0-3alkylene-phenyl. In some cases, each substituent independently is phenyl. In some cases, R1is substituted with two geminal substituents and with 1-2 additional substituents on R1. In some cases, R1is substituted with one or more of halogen, C1-4alkyl, or C1-3haloalkoxy. In some cases, R1is substituted with one or more of halogen or C1-4alkyl. In some cases, R1is substituted with one or more of C1-3haloalkoxy. In some cases, R1is substituted with one or more of F, Br, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. In some cases, R1is substituted with one or more of F, Br, or Cl. In some cases, R1is substituted with two geminal heteroatoms. In some cases, R1is substituted with two geminal F atoms. In some cases, R1is substituted with two geminal C1-4alkyl. In some cases, R1is substituted with two geminal CH3. In some cases, R1is substituted with one or more of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3. In some cases, R1is substituted with one or more of CH2F, CHF2, or CF3.

[0075] In some cases, when R1a cyclic group described herein, two adjacent substituents of R1, together with the atoms to which they are attached, may form C3-6cycloalkyl, C3-6cycloalkenyl, heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-6 total ring atoms and 1-3 heteroatoms independently selected from N, O and S. In some cases, such resulting fused cyclic group is unsubstituted. In some cases, such resulting fused cyclic group is substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, or C1-3alkoxy. In some cases, each substituent independently is halogen or C1-3alkyl. In some cases, each substituent independently is halogen. In some cases, each substituent independently is C1-3alkyl. In some cases, each substituent independently is CN. In some cases, the cyclic R1is C6-10aryl, heteroaryl having 5-10 total ring atoms, C3-8cycloalkyl, or heterocycloalkyl having 3-10 total ring atoms. In some cases, R1is C6-10aryl.In some cases, R1is heteroaryl having 5-10 total ring atoms. In some cases, R1is C3- 8cycloalkyl. In some cases, R1is heterocycloalkyl having 3-10 total ring atoms.

[0076] In some cases, when R1is substituted with C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl, the C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl substituent on R1is unsubstituted or substituted with one or more substituents. In some cases, when R1is substituted with C1-4alkyl or C1-4alkenyl, the C1-4alkyl or C1-4alkenyl substituent on R1is unsubstituted or substituted with one or more substituents. In some cases, such substituent on R1is not further substituted. In some cases, such substituent on R1is further substituted with 1, 2, 3, or 4 substituents. In some cases, such R1is further substituted with 1, 2, or 3 substituents. In some cases, such substituent on R1is further substituted with 1 or 2 substituents. In some cases, such substituent on R1is further substituted with 1 substituent. In some cases, such substituent on R1is further substituted independently with halogen, OH, CN, C1-3alkyl, or C1-3alkoxy. In some cases, such substituent on R1is further substituted independently with NH2, NH(C1-3alkyl), or N(C1-3alkyl)2. In some cases, such substituent on R1is further substituted independently with halogen. In some cases, such substituent on R1is further substituted independently with F, Br, or Cl. In some cases, such substituent on R1is further substituted independently with C1-3alkyl. In some cases, such substituent on R1is further substituted independently with CH3, CH2CH3, CH2CH2CH3, CH(CH3)2. In some cases, such substituent on R1is further substituted independently with halogen or C1-3alkyl. In some cases, R1is substituted with one or more of F, Br, Cl, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, such substituent on R1is further substituted independently with F or CH3. In some cases, such substituent on R1is further substituted independently with NH2, NHCH3, or N(CH3)2.

[0077] In some cases, R2is C6-10aryl or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, R2is C6-10aryl. In some cases, R2is heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, R2is unsubstituted. In some cases, R2is substituted with one or more substituents. In some cases, R2is substituted with 1 or 2 substituents. In some cases, R2is substituted with 1, 2, or 3 substituents. In some cases, R2is substituted with 1, 2, 3, or 4 substituents. In some cases, each substituent on R2independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3cycloalkyl, or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, each substituent on R2independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.In some cases, each substituent on R2independently is F, Br, Cl, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, or OCH(CH3)2. In some cases, each substituent on R2independently is C1-3cycloalkyl or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0079] In some cases, each of Re, Rz, Rv, Rw, Rwc1and Rwc2of R3independently is H, D, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1- 3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene- heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl. In some cases, each of Re, Rz, Rv, Rw, Rwc1and Rwc2of R3independently is H, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl. In some cases, R3isunsubstituted. In some cases, R3is substituted with 1-3 substituents and each substituent independently is D, halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, or C1-3alkoxy.

[0080] In some cases, each of Re, Rz, Rv, Rw, Rwc1and Rwc2of R3independently is H. In some cases, each of Re, Rz, Rv, and Rwof R3independently is H. In some cases, each of Re, Rz, Rvis H and Rwc1is C1-3alkyl. In some cases, each of Re, Rz, Rvis H and Rwc1is C3-7cycloalkyl. In some cases, each of Rw, Rz, Rv, Rwc1, and Rwc2is H. In some cases, each of Reor Rzis H. In some cases, each of Rwand Rwc1independently is H, halogen, or C1-3alkyl.

[0081] In some cases, each of RZis H, halogen, C1-3alkyl, C1-3haloalkyl, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, or C1-3alkylene-NH2. In some cases, each of RZis H, halogen, C1-3alkyl, C1-3haloalkyl. In some cases, each of RZis H. In some cases, each of RZis halogen. In some cases, each of RZis C1-3alkyl. In some cases, each of RZis C1-3haloalkyl. In some cases, each of RZis C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, or C1-3alkylene-NH2.

[0082] In some cases,some cases, R3is.

[0083] In some cases, Formula (I) has a structure of Formula (II): some casews, R is H, X is CH, Y is N, and Z is N. In some cases, Formula (I) has a structure of Formulasome cases, X is CH, Y is N, and Z is N. In some cases, Rwc1is H, C1-3alkyl. In some cases, Rwc1is C0-2alkylene-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0084] In some cases, for Formula (I), (II), and (III), R1is heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, R1is heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, R1is heterocycloalkyl having 4-7 total ring atoms and 1-2 heteroatoms independently selected from N and O. In some cases, R1is heterocycloalkyl having 7 total ring atoms and 1 heteroatom that is N. In some cases, R1is heterocycloalkyl having 6 total ring atoms and 1 heteroatom that is N. In some cases, R1is heterocycloalkyl having 5 total ring atoms and 1 heteroatom that is N. In some cases, R1is heterocycloalkyl having 4 total ring atoms and 1 heteroatom that is N. In some cases, R1is connected to the core ring through a N of the heterocycle. In some cases, R1is, , ,.

[0086] In some cases, R1is heterocycloalkyl comprising two spiro-connected rings, wherein rings are connected through a shared carbon atom. In some cases, the heterocycloalkyl comprising two spiro-connected rings is unsubstituted. In some cases, the heterocycloalkyl comprising two spiro-connected rings is substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1-3haloalkyl. In some cases, each substituent independently is halogen or C1-,

[0087] In some cases, R1is C3-8cycloalkyl. In some cases, R1is C3-6cycloalkyl. In some cases, R1is C4-6cycloalkyl. In some cases, R1is C3-5cycloalkyl. In some cases, R1is unsubstituted. In some cases, R1is substituted with one or more substituents and each substituent independently is halogen or C1-3alkyl. In some cases,

[0088] Provided herein is a compound as listed in Table A or a pharmaceutically acceptable salt thereof. Table A*Example No. recited with an “-a” refers to the compound as a racemic mixture of that corresponding compound with stereochemistry from that Example No.

[0089] Provided herein is a compound as listed in Table B or a pharmaceutically acceptable salt thereof. Table B*Example No. recited with an “-a” refers to the compound as a racemic mixture of that corresponding compound with stereochemistry from that Example No.

[0090] In some cases, provided herein is a compound as listed in Table A’ or a pharmaceutically acceptable salt thereof. Table A’

[0091] In some cases, provided herein is a compound as listed in Table B’ or a pharmaceutically acceptable salt thereof. Table B’

[0092] In some cases, provided herein is a compound of Formula (I) having a structure ofacceptable salts thereof.

[0093] In some cases, provided herein is a compound of Formula (I) having a structure of

[0094] In some cases, provided herein is a compound of Formula (I) having a structure of, , ,r pharmaceutically acceptable salts thereof.

[0095] In some cases, provided herein is a compound of Formula (I) having a structure ofr pharmaceutically acceptable salts thereof.

[0096] In some cases, provided herein is a compound of Formula (I) having a structure ofr pharmaceutically acceptable salts thereof.

[0097] In some cases, provided herein is a compound of Formula (I) having a structure of, or pharmaceutically acceptable salts thereof.

[0098] In some cases, provided herein is a compound of Formula (I) having a structure ofr pharmaceutically acceptable salts thereof.

[0099] In some cases, provided herein is a compound of Formula (I) having a structure of, or pharmaceutically acceptable salts thereof.

[0100] In some cases, provided herein is a compound of Formula (I) having a structure of, or pharmaceutically acceptable salts thereof.

[0101] In some cases, provided herein is a compound of Formula (I) having a structure of, or pharmaceutically acceptable salts thereof.

[0102] In some cases, provided herein is a compound of Formula (I) having a structure of

[0103] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds.STEREOISOMERS

[0104] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.

[0105] If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of the structure. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted. For example,represents. Similarly, for example, the chemical name (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H- isoindole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole. A bond drawn with a wavy line may be used to indicate that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.

[0106] The term “stereoisomer” or “stereoisomerically pure” compound refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% byweight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0107] This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). TAUTOMERS

[0108] As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula. For example, represents Similarly, for example, thechemical name (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole and (4R,5R)-4-methoxy-5- methyl-4,5,6,7-tetrahydro-2H-indazole. Accordingly, the scope of the present disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein.ISOTOPICALLY-LABELED COMPOUNDS

[0109] In some cases, the scope of the present disclosure includes pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labelled compounds of the compounds disclosed herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances. As such, the term “deuterated” refers to the substitution of one or more hydrogen atoms with one or more deuterium atoms on a particular structure or functional group. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically- labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying GENERAL SYNTHETIC PROCEDURES and EXAMPLES sections using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed. BIOLOGICAL ACTIVITY

[0110] In some cases, the compounds or salts disclosed herein (such as compounds of Formula (I), Formula (II), Formula (III), compounds listed in Table A, Table B, Table A’, Table B’, and pharmaceutically acceptable salt of any of the foregoing), have an IC50value of less than 5 µM, or less than 4 µM, or less than 3 µM, or less than 2 µM, or less than 1 µM, or less than 0.9 µM, or less than 0.7 µM, or less than 0.6 µM, or less than 0.5 µM, or less than 0.4 µM, or less than 0.3 µM, or less than 0.2 µM, or less than 0.1 µM, or less than 0.09 µM, or less than 0.08 µM, or less than 0.07 µM, or less than 0.06 µM, or less than 0.05 µM, orless than 0.04 µM, or less than 0.03 µM, or less than 0.02 µM, or less than 0.01 µM in the WRN DNA unwinding assay, described in “SECTION 3: Biochemical and Cellular Assays.” In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50 value of less than 1 µM. In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50 value of less than 0.5 µM. In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of less than 0.3 µM. In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50 value of less than 0.1 µM. Also provided herein are compounds of the disclosure, and pharmaceutically acceptable salts of the foregoing, having an IC50of less than 5 µM in the cellular viability assay described herein. Further provided herein are compounds of the disclosure, and pharmaceutically acceptable salts of the foregoing, having an IC50 of less than 3, 1, 0.5, 0.1, 0.05, 0.04, 0.03, 0.02, 0.01 µM in the cellular viability assay.

[0111] The foregoing merely summarizes certain aspect of this disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way. FORMULATION AND ROUTE OF ADMINISTRATION

[0112] While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a compound or salt disclosed herein (such as compounds of Formula (I), Formula (I’), Formula (IA), or Formula (IB), or compounds listed in Table A, Table B, Table A’, Table B’, or compounds of Embodiments, or a pharmaceutically acceptable salt of any of the foregoing), in combination with one or more pharmaceutically acceptable excipients and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In some cases, the pharmaceutical composition described herein comprises a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0113] The compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended. The compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0114] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. In some cases, the pharmaceutical composition is made in the form of a dosage unit containing a particular amount of the active ingredient.

[0115] Thus, a further aspect of the disclosure is a pharmaceutical composition comprising one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, for use as a medicament.

[0116] Provided herein as Embodiment 14 is pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 13, and a pharmaceutically acceptable excipient. METHODS OF USE

[0117] In some cases, the compounds described herein can act inhibitors of WRN. Without intending to be bound by any particular theory, the compounds described herein form a covalent bond with WRN. Consequently, the covalent attachment of said compounds to WRN contributes to inhibiting the functions of WRN to unwind DNA and hydrolyze ATP.

[0118] Besides being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.

[0119] In several embodiments, as disclosed elsewhere herein, a method of treating a patient is provided. In several embodiments, the method comprises administering a therapeutic amount of a compound or salt disclosed herein (such as compounds of Formula (I), Formula (I’), Formula (IA), or Formula (IB), or compounds listed in Table A, Table B, Table A’, Table B’, or a pharmaceutically acceptable salt of any of the foregoing) to a patient.

[0120] Another aspect of the disclosure provides methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to cancer such as solid tumor dMMR / MSI-H cancers, from adult onset or hereditary cases (Lynch Syndrome).

[0121] In some cases, the compounds are useful in methods of treating cancer selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian, urothelial, small bowel, brain, biliary tract, bladder, gastroesophageal, head-and-neck, skin, sarcoma, thoracic, or pancreatic cancer, or any combination of the foregoing. In some cases, the compounds are useful in methods of treating cancer selected from endometrial, gastric, esophageal, small bowel, ovarian, and adrenocortical cancer. In some cases, the compounds are useful in methods of treating cancer selected from urothelial, small bowel, brain, biliary tract, bladder, gastroesophageal, head- and-neck, skin, sarcoma, thoracic, and pancreatic cancer. In some cases, the cancer is prostate, cervical, bladder, or brain cancer.

[0122] In some cases, provided herein is a method of treating cancer in a subject, comprising administering a compound of the disclosure, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In some cases, the cancer is characterized as tumor-agnostic MSI-H / dMMR cancer.

[0123] In some cases, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian, urothelial, small bowel, brain, biliary tract, bladder, gastroesophageal, head-and-neck, skin, sarcoma, thoracic, or pancreatic cancer, or any combination of the foregoing.

[0124] In some cases, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and is selected from colorectal, gastric, prostate,endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, and ovarian cancer. In some cases, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and is selected from urothelial, small bowel, brain, biliary tract, bladder, gastroesophageal, head-and-neck, skin, sarcoma, thoracic, and pancreatic cancer.

[0125] In some cases, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric and endometrial cancer.

[0126] In some cases, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from prostate cancer, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma. GENERAL SYNTHETIC PROCEDURES

[0127] The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.

[0128] Generally, the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or other formula provided herein can be synthesized according to the following schemes. Variables used in the following schemes are the variables as defined for Formula (I) elsewhere herein, unless otherwise noted. All starting materials are either commercially available, for example, from A2B Chemicals LLC, AA Blocks, LLC, Advanced ChemBlocks, Inc., Ambeed Inc., Ark Pharm., Inc., Combi-Blocks Inc., Enamine LTD, Oakwood Products, Inc., PharmaBlock Inc., Sigma-Aldrich Inc., Strem Chemicals Inc., Synthonix, Inc., or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting materials may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvent, reaction temperature, and reagents, forthe Schemes discussed in this section, may be found in the examples provided herein. The abbreviation PG refers to a protecting group, as defined herein in the DEFINITIONS AND GENERAL TERMINOLOGY section. In the scheme below, each PG can be the same as or different from another PG in the compound, so long as each protecting group can be selectively removed. For Scheme 1, in some cases, the PG group on oxygen (i.e., OPG) is methyl or ethyl. In some cases, the PG group on oxygen is methyl (i.e., OMe). In some cases, the PG group on oxygen is ethyl (i.e., OEt).

[0129] In general, the compounds of Formula (I) can be synthesized according to Methods A-L as described in the Examples. In general, the compounds of Formula (I) can be synthesized according to Scheme 1. Scheme 1 is a generalized scheme for Method A. In some cases, the compounds of Formula (I) are synthesized by a method comprising Step 1 of Scheme 1. In some cases, the compounds of Formula (I) are synthesized by a method comprising Step 2 of Scheme 1. In some cases, the compounds of Formula (I) are synthesized by a method comprising Step 3 of Scheme 1. In some cases, the compounds of Formula (I) are synthesized by a method comprising Step 4 of Scheme 1. In some cases, the compounds of Formula (I) are synthesized by a method comprising Step 5 of Scheme 1. Compounds of Formula (I), (II), (III), (IV), and (V) can be synthesized similarly to the general procedures described herein for Formula (I). The X, Y, Z, R1, R2, R3, Re, Rz, Rw, and Rvare as described herein elsewhere for Formula (I). In some cases, the boronic acid can be substituted with a pinacol boronic ester or other similar reagents. In some cases, the Suzuki coupling step can be a metal-catalyzed amination or Buchwald-Hartwig amination. Scheme 1:

[0130] Provided herein as Embodiment 210 is a process for preparing the compound or salt of any one of Embodiments 1-199, comprising providing a compound or salt of any one of Tables C, 1-1, 1-2, or 1-3 and converting it into a separate compound or salt of any one of Tables 1A, 1B, 1C, 2-1, 2-2, 2-3, 2-4, 2-5, 2-7, 2-8, A, A’, B, or B’.

[0131] As can be appreciated by the skilled artisan, the above synthetic scheme and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.

[0132] Purification methods for the compounds described herein are known in the art and include, for example, chromatography (e.g., column chromatography using e.g., silica gel), supercritical fluid chromatography (SFC), high performance liquid chromatography (HPLC), liquid-liquid extraction, crystallization, filtration, distillation and trituration. INTERMEDIATES

[0133] The disclosure further encompasses intermediate compounds, including structures produced from the synthetic procedures described, whether isolated or generated in-situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure.

[0134] Provided herein are intermediates found in Table C, nitrogen-protected analogs thereof, racemic mixtures thereof, stereoisomers thereof, and salts thereof of any of the foregoing. Table C

[0135] Another aspect of the disclosure is a process for preparing a compound or salt described herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V); compounds listed in Table A, Table B, Table A’, and Table B’; compounds of Embodiments; and pharmaceutically acceptable salt of any of the foregoing), comprising converting an intermediate described herein, such an intermediate listed in Table C, 1-1, 1-2, or 1-3, or a nitrogen-protected analog thereof, racemic mixtures thereof, stereoisomers thereof, or a salt of any of the foregoing into a compound disclosed herein. In some cases, the intermediate is a compound listed in Table C, a nitrogen-protected analog thereof, racemic mixtures thereof, stereoisomers thereof, or a salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table 1-1, a nitrogen-protected analog thereof, racemic mixtures thereof, stereoisomers thereof, or a salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table 1-2, a nitrogen-protected analog thereof, racemic mixtures thereof, stereoisomers thereof, or a salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table 1-3, a nitrogen-protected analog thereof, racemic mixtures thereof, stereoisomers thereof, or a salt of any of the foregoing.

[0136] In some cases, the intermediate is A-1, or a salt thereof. In some cases, the intermediate is B-1, or a salt thereof. In some cases, the intermediate is B-2, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-3, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-4, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-5, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-6, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-7, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-8, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-9, racemicmixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B- 10, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-11, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-12, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13-1, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13-2, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B- 13.1, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13.2, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13.3, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13.4, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is B-13.5, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is C-1, or a salt thereof. In some cases, the intermediate is C-2, racemic mixture thereof, stereoisomer thereof, or a salt thereof. In some cases, the intermediate is C-3, racemic mixture thereof, stereoisomer thereof, or a salt thereof.

[0137] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well- adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art. ENUMERATED EMBODIMENTS

[0138] Provided herein as Embodiment 1 is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:X is N or C-Rx, wherein Rxis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0- 3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl; Y is N or C-Ry, wherein Ryis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0- 3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Rb)2, wherein each instance of Rbindependently is H or C1-3alkyl; wherein the C1-3alkyl of each instance of Raand Rbindependently is unsubstituted or substituted with one or more substituents and each substituent independently is OH or C1-3alkoxy; Z is N or C-Rz, wherein Rzis H or halogen; wherein 0, 1, 2, or 3 of X, Y, and Z is N, R1is C1-6alkyl, C1-6alkenyl, N(Rc)(Rd), C3-8cycloalkyl, C3-8cycloalkenyl, heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl; wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C0-6alkylene-OH, C0- 3alkylene-CN, C1-4alkyl, C1-4alkenyl, C0-3alkylene-C1-3haloalkyl, C0-6alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-3alkylene-C3-6cycloalkyl, or C0-3alkylene-phenyl; wherein, when R1is C6-10aryl, heteroaryl having 5-10 total ring atoms, C3-8cycloalkyl, or heterocycloalkyl having 3-10 total ring atoms, then two adjacent substituents of R1, together with the atoms to which they are attached, may form C3-6cycloalkyl, C3-6cycloalkenyl, heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-6 total ring atoms and 1-3 heteroatoms independently selected from N, O and S; wherein the cycle formed by the two adjacent substituents of R1can be unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1- 3alkoxy; wherein, when R1is substituted with C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl, the C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, or C1-3alkoxy; wherein, when R1is substituted with C1-4alkyl or C1-4alkenyl, the C1-4alkyl or C1-4alkenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, NH2, NH(C1-3alkyl), or N(C1-3alkyl)2; R2is C6-10aryl or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein R2is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1- 3alkoxy, C1-3haloalkyl, C1-3cycloalkyl, or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; R3is:wherein Q is N or C; wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, D, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene- N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3- 8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is D, halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, or C1-3alkoxy.

[0139] Provided herein as Embodiment 2 is the compound or salt of Embodiment1, wherein

[0140] Provided herein as Embodiment 3 is the compound or salt of Embodiment1 or 2,.

[0141] Provided herein as Embodiment 4 is the compound or salt of Embodiment1 or 2,

[0142] Provided herein as Embodiment 5 is the compound or salt of Embodiment1 or 2, wherein.

[0143] Provided herein as Embodiment 6 is the compound or salt of Embodiment1 or 2, wherein

[0144] Provided herein as Embodiment 7 is the compound or salt of Embodiment1 or 2, wherein.

[0145] Provided herein as Embodiment 8 is the compound or salt of Embodiment1 or 2, wherein.

[0146] Provided herein as Embodiment 9 is the compound or salt of Embodiment1 or 2, wherein.

[0147] Provided herein as Embodiment 10 is the compound or salt of Embodiment1 or 2,

[0148] Provided herein as Embodiment 11 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein

[0149] Provided herein as Embodiment 12 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein

[0150] Provided herein as Embodiment 13 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein

[0151] Provided herein as Embodiment 14 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein

[0152] Provided herein as Embodiment 15 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein

[0153] Provided herein as Embodiment 16 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein.

[0154] Provided herein as Embodiment 17 is the compound or salt of any one ofEmbodiments1, 2, and 10, wherein.

[0155] Provided herein as Embodiment 18 is the compound or salt of any one of Embodiments1, 2, and 10, wherein X is N.

[0156] Provided herein as Embodiment 19 is the compound or salt of any one of Embodiments1, 2, and 10, wherein X is C-Rx.

[0157] Provided herein as Embodiment 20 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis H, halogen, N(Ra)2, C1-3alkyl, or C1-3alkoxy.

[0158] Provided herein as Embodiment 21 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 20, wherein Rxis H, F, Cl, NH2, methyl, or methoxy.

[0159] Provided herein as Embodiment 22 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 20, wherein Rxis H or methyl.

[0160] Provided herein as Embodiment 23 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 20, wherein Rxis OH.

[0161] Provided herein as Embodiment 24 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis C0-3alkylene-C1-3alkoxy.

[0162] Provided herein as Embodiment 25 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis CH2-C1-3alkoxy.

[0163] Provided herein as Embodiment 26 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis methoxy or CH2-methoxy.

[0164] Provided herein as Embodiment 27 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis C1-3haloalkoxy.

[0165] Provided herein as Embodiment 28 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis halogen.

[0166] Provided herein as Embodiment 29 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 28, wherein Rxis F, Cl, or Br.

[0167] Provided herein as Embodiment 30 is the compound or salt of any one of Embodiments1, 2, 10, and 19, wherein Rxis H.

[0168] Provided herein as Embodiment 31 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 20, wherein Rxis methyl.

[0169] Provided herein as Embodiment 32 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 20, wherein Rxis N(Ra)2.

[0170] Provided herein as Embodiment 33 is the compound or salt of any one of Embodiments1, 2, 10, 19, 20, and 32, wherein each Raindependently is H or methyl.

[0171] Provided herein as Embodiment 34 is the compound or salt of any one of Embodiments1, 2, 10, 19, 20, 32, and 33, wherein at least one instance of Rais H.

[0172] Provided herein as Embodiment 35 is the compound or salt of any one of Embodiments1, 2, 10, 19, 20, and 32-34, wherein at least one instance of Rais methyl.

[0173] Provided herein as Embodiment 36 is the compound or salt of any one of Embodiments1, 2, 10, 19, 20, and 32-34, wherein each Rais H.

[0174] Provided herein as Embodiment 37 is the compound or salt of any one of Embodiments1, 2, 10, 19, 20, 32, and 33-35, wherein each Rais methyl.

[0175] Provided herein as Embodiment 38 is the compound or salt of any one of Embodiments1, 2, 10, 19, and 20, wherein Rxis methoxy.

[0176] Provided herein as Embodiment 39 is the compound or salt of any one of Embodiments1-3, wherein Y is N.

[0177] Provided herein as Embodiment 40 is the compound or salt of any one of Embodiments1-3, wherein Y is C-Ry.

[0178] Provided herein as Embodiment 41 is the compound or salt of any one of Embodiments1-3 and 40, wherein Ryis H.

[0179] Provided herein as Embodiment 42 is the compound or salt of any one of Embodiments1-3 and 40, wherein Ryis CN or N(H)2.

[0180] Provided herein as Embodiment 43 is the compound or salt of any one of Embodiments1-3, wherein Z is N.

[0181] Provided herein as Embodiment 44 is the compound or salt of any one of Embodiments1-3, wherein Z is C.

[0182] Provided herein as Embodiment 45 is the compound or salt of any one of Embodiments1-44, wherein R1is C1-4alkyl, C1-4alkenyl, N(Rc)(Rd), C4-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0183] Provided herein as Embodiment 46 is the compound or salt of any one of Embodiments1-45, wherein R1is C1-4alkyl, C1-4alkenyl, or N(Rc)(Rd).

[0184] Provided herein as Embodiment 47 is the compound or salt of any one of Embodiments1-46, wherein R1is C1-4alkyl or C1-4alkenyl.

[0185] Provided herein as Embodiment 48 is the compound or salt of any one of Embodiments1-47, wherein R1is C1-3alkyl or C1-3alkenyl.

[0186] Provided herein as Embodiment 49 is the compound or salt of any one of Embodiments1-46, wherein R1is N(Rc)(Rd).

[0187] Provided herein as Embodiment 50 is the compound or salt of any one of Embodiments1-46 and 49, wherein Rcis H.

[0188] Provided herein as Embodiment 51 is the compound or salt of any one of Embodiments1-46 and 49, wherein Rcis C1-3alkyl.

[0189] Provided herein as Embodiment 52 is the compound or salt of any one of Embodiments1-46, 49, and 51, wherein Rcis methyl.

[0190] Provided herein as Embodiment 53 is the compound or salt of any one of Embodiments1-46 and 49-52, wherein Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl.

[0191] Provided herein as Embodiment 54 is the compound or salt of any one of Embodiments1-46 and 49-53, wherein Rdis C1-6alkyl.

[0192] Provided herein as Embodiment 55 is the compound or salt of any one of Embodiments1-46 and 49-53, wherein Rdis C3-6cycloalkyl or C3-6cycloalkenyl.

[0193] Provided herein as Embodiment 56 is the compound or salt of any one of Embodiments1-46, 49-53, and 55, wherein Rdis C4-6cycloalkyl.

[0194] Provided herein as Embodiment 57 is the compound or salt of any one of Embodiments1-45, wherein R1is C4-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0195] Provided herein as Embodiment 58 is the compound or salt of any one of Embodiments1-45 and 57, wherein R1is heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0196] Provided herein as Embodiment 59 is the compound or salt of any one of Embodiments1-45, 57, and 58, wherein R1is heterocycloalkyl having 4 total ring atoms and one heteroatom independently selected from N, O, and S.

[0197] Provided herein as Embodiment 60 is the compound or salt of any one of Embodiments1-45, 57, and 58, wherein R1is heterocycloalkyl having 5 total ring atoms and one heteroatom independently selected from N, O, and S.

[0198] Provided herein as Embodiment 61 is the compound or salt of any one of Embodiments1-45, 57, and 58, wherein R1is heterocycloalkyl having 6 total ring atoms and one heteroatom independently selected from N, O, and S.

[0199] Provided herein as Embodiment 62 is the compound or salt of any one of Embodiments1-45, 57, and 58, wherein R1is heterocycloalkyl having 7 total ring atoms and one heteroatom independently selected from N, O, and S.

[0200] Provided herein as Embodiment 63 is the compound or salt of any one of Embodiments1-45, 57, 58, and 62, wherein R1is heterocycloalkyl comprising two spiro- connected rings, wherein rings are connected through a shared carbon atom, and the heterocycloalkyl is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1-3haloalkyl.

[0201] Provided herein as Embodiment 64 is the compound or salt of any one of Embodiments1-45, 57, 58, and 62, wherein the two spiro-connected rings comprises two four-membered rings or one four-membered ring and one three-membered ring.

[0202] Provided herein as Embodiment 65 is the compound or salt of any one of Embodiments1-45, and 57-63, wherein R1has one N and one O as ring heteroatoms.

[0203] Provided herein as Embodiment 66 is the compound or salt of any one of Embodiments1-45, and 57-63, wherein R1has one N as a ring heteroatom.

[0204] Provided herein as Embodiment 67 is the compound or salt of any one of Embodiments1-45, and 57-63, wherein R1has one O as a ring heteroatom.

[0205] Provided herein as Embodiment 68 is the compound or salt of any one of Embodiments1-45, and 57-67, wherein R1is C6-10aryl or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0206] Provided herein as Embodiment 69 is the compound or salt of any one of Embodiments1-45, wherein R1is C4-7cycloalkyl or heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0207] Provided herein as Embodiment 70 is the compound or salt of any one of Embodiments1-45 and 69, wherein R1has two adjacent substituents that, together with theatoms to which they are attached, form C3-6cycloalkyl, C3-6cycloalkenyl, or a heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0208] Provided herein as Embodiment 71 is the compound or salt of any one of Embodiments1-70, wherein R1is heterocycloalkyl that comprises spiro-connected rings and the heterocycloalkyl is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1-3haloalkyl.

[0209] Provided herein as Embodiment 72 is the compound or salt of any one of Embodiments1-71, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0210] Provided herein as Embodiment 73 is the compound or salt of any one of Embodiments1-71, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0211] Provided herein as Embodiment 74 is the compound or salt of any one of Embodiments1-70, wherein R1is heterocycloalkyl having 8-10 total ring atoms and two fused rings, further wherein two non-adjacent atoms on a ring join together to form a C1-2alkylene bridge.

[0212] Provided herein as Embodiment 75 is the compound or salt of any one of Embodiments1-70 and 74, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0213] Provided herein as Embodiment 76 is the compound or salt of any one of Embodiments1-70, wherein R1is bridged-heterocycloalkyl having 5 or 6 total ring atoms and two non-adjacent atoms join together to form a C1-2alkylene bridge.

[0214] Provided herein as Embodiment 77 is the compound or salt of any one of Embodiments1-45, 58, 69, and 76, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0215] Provided herein as Embodiment 78 is the compound or salt of any one of Embodiments1-45, 58, 69, and 76, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0216] Provided herein as Embodiment 79 is the compound or salt of any one of Embodiments1-45, 57, 58, 66, 69, and 70, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0217] Provided herein as Embodiment 80 is the compound or salt of any one of Embodiments1-45, 57, 58, 66, and 69, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0218] Provided herein as Embodiment 81 is the compound or salt of any one of Embodiments1-45, 57, 58, 66, and 69, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0219] Provided herein as Embodiment 82 is the compound or salt of any one of Embodiments1-45, 57, and 70, wherein R1is aryl with two adjacent substituents that provide a 5-membered heterocyclyl represented bywhich can be unsubstituted or further substituted by replacing one or more ring H atoms with one or more substituents of R1.

[0220] Provided herein as Embodiment 83 is the compound or salt of any one of Embodiments1-82, wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-4alkyl, C1-4alkenyl unsubstituted or substituted with halogen, C0-3alkylene-C1-3haloalkyl, C0-3alkylene-C3-6cycloalkyl, C6-10aryl, or two adjacent substituents that, together with the atoms to which they are attached, form C3-6cycloalkyl group or a heterocycloalkyl having 4-6 total ring atoms and 1-2 heteroatoms independently selected from N or O.

[0221] Provided herein as Embodiment 84 is the compound or salt of any one of Embodiments1-83, wherein each substituent of R1independently is F, methyl, ethyl, =C-F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, cyclopropyl, phenyl.

[0222] Provided herein as Embodiment 85 is the compound or salt of any one of Embodiments1-83, wherein each substituent of R1independently is F, methyl, ethyl, CF3, CHF2, CH2F, or cyclopropyl.

[0223] Provided herein as Embodiment 86 is the compound or salt of any one of Embodiments1-85, wherein R1is substituted with 1, 2, 3, 4, or 5 substituents.

[0224] Provided herein as Embodiment 87 is the compound or salt of any one of Embodiments1-85, wherein R1is substituted with 1, 2, 3, or 4 substituents.

[0225] Provided herein as Embodiment 88 is the compound or salt of any one of Embodiments1-85, wherein R1is substituted with 3 or 4 substituents.

[0226] Provided herein as Embodiment 89 is the compound or salt of any one of Embodiments1-85, wherein R1is substituted with 1, 2, or 3 substituents.

[0227] Provided herein as Embodiment 90 is the compound or salt of any one of Embodiments1-85, wherein R1is substituted with 1 or 2 substituents.

[0228] Provided herein as Embodiment 91 is the compound or salt of any one of Embodiments1-85, wherein R1is substituted with 1 substituent.

[0229] Provided herein as Embodiment 92 is the compound or salt of any one of Embodiments1-91, wherein R1is substituted with C3-6cycloalkyl that is unsubstituted or substituted with one or more halogens.

[0230] Provided herein as Embodiment 93 is the compound or salt of Embodiment92, wherein the C3-6cycloalkyl substituent of R1is unsubstituted.

[0231] Provided herein as Embodiment 94 is the compound or salt of Embodiment92, wherein the C3-6cycloalkyl substituent of R1is substituted with one or more halogens.

[0232] Provided herein as Embodiment 95 is the compound or salt of Embodiment92, wherein the C3-6cycloalkyl substituent of R1is substituted with 1, 2, or 3 halogens.

[0233] Provided herein as Embodiment 96 is the compound or salt of any one of Embodiments1-90, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen, OH, CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C3-4cycloalkyl.

[0234] Provided herein as Embodiment 97 is the compound or salt of any one of Embodiments1-90, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen, C1-3alkyl, C1-3haloalkyl.

[0235] Provided herein as Embodiment 98 is the compound or salt of any one of Embodiments1-91, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen or C1-3alkyl.

[0236] Provided herein as Embodiment 99 is the compound or salt of any one of Embodiments1-91, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen or methyl.

[0237] Provided herein as Embodiment 100 is the compound or salt of any one of Embodiments1-91, wherein R1is substituted with 1, 2, 3, or 4 substituents and each R1substituent independently is halogen or methyl.

[0238] Provided herein as Embodiment 101 is the compound or salt of any one of Embodiments1-97, wherein R1is substituted with one or more substituents and each R1substituent independently is C1-3haloalkyl.

[0239] Provided herein as Embodiment 102 is the compound or salt of any one of Embodiments1-83, wherein R1is unsubstituted.

[0240] Provided herein as Embodiment 103 is the compound or salt of any one of Embodiments1-102, wherein R2is C6-10aryl.

[0241] Provided herein as Embodiment 104 is the compound or salt of any one of Embodiments1-103, wherein R2is phenyl.

[0242] Provided herein as Embodiment 105 is the compound or salt of any one of Embodiments1-102, wherein R2is heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0243] Provided herein as Embodiment 106 is the compound or salt of any one of Embodiments1-102 and 105, wherein R2is pyrimidinyl.

[0244] Provided herein as Embodiment 107 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is OH or CN.

[0245] Provided herein as Embodiment 108 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, or C1-3alkoxy.

[0246] Provided herein as Embodiment 109 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen and CN.

[0247] Provided herein as Embodiment 110 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen and OH.

[0248] Provided herein as Embodiment 111 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen.

[0249] Provided herein as Embodiment 112 is the compound or salt of any one of Embodiments108-111, wherein each halogen substituent of R2independently is F, Cl, or Br.

[0250] Provided herein as Embodiment 113 is the compound or salt of any one of Embodiments108-111, wherein halogen is F.

[0251] Provided herein as Embodiment 114 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is C1-3alkyl.

[0252] Provided herein as Embodiment 115 is the compound or salt of any one of Embodiments1-106, wherein R2is substituted with one or more substituents and each substituent independently is methyl.

[0253] Provided herein as Embodiment 116 is the compound or salt of any one of Embodiments1-115, wherein R2is substituted with 1, 2, 3, or 4 substituents.

[0254] Provided herein as Embodiment 117 is the compound or salt of any one of Embodiments1-115, wherein R2is substituted with 1, 2, or 3 substituents.

[0255] Provided herein as Embodiment 118 is the compound or salt of any one of Embodiments1-115, wherein R2is substituted with 1 or 2 substituents.

[0256] Provided herein as Embodiment 119 is the compound or salt of any one of Embodiments1-115, wherein R2is substituted with 1 substituents.

[0257] Provided herein as Embodiment 120 is the compound or salt of any one of Embodiments1-106, wherein R2is unsubstituted.

[0258] Provided herein as Embodiment 121 is the compound or salt of any one of Embodiments1-120, wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2of R3independently is H, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene- heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is halogen, CN, C1-3alkyl C1-3haloalkyl, OH, or C1-3alkoxy.

[0259]

[0260] Provided herein as Embodiment 122 is the compound or salt of any one of Embodiments1-120, wherein R3is.

[0261]

[0262] Provided herein as Embodiment 123 is the compound or salt of any one of Embodiments1-120, wherein R3is Rvis H.

[0263] Provided herein as Embodiment 124 is the compound or salt of any one of Embodiments1-123, wherein Rwis H or C1-3alkyl.

[0264] Provided herein as Embodiment 125 is the compound or salt of any one of Embodiments1-123, wherein Rwis H.

[0265] Provided herein as Embodiment 126 is the compound or salt of any one of Embodiments1-125, wherein Rwis C1-3alkyl.

[0266] Provided herein as Embodiment 127 is the compound or salt of any one of Embodiments1-125, wherein Rwis methyl.

[0267] Provided herein as Embodiment 128 is the compound or salt of any one of Embodiments1-123, wherein Rwis C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0268] Provided herein as Embodiment 129 is the compound or salt of any one of Embodiments1-123, wherein Rwis CH2-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0269] Provided herein as Embodiment 130 is the compound or salt of any one of Embodiments1-123, wherein Rwis CH2-heterocycloalkyl having 3-5 total ring atoms and 1-2 heteroatoms independently selected from N, O, and S.

[0270] Provided herein as Embodiment 131 is the compound or salt of any one of Embodiments1-123, wherein Rwis CH2-heterocycloalkyl having 3-5 total ring atoms and 1-2 heteroatoms independently selected from N or O.

[0271] Provided herein as Embodiment 132 is the compound or salt of any one of Embodiments1-123, wherein Rwis C0-2alkylene-heterocycloalkyl that is unsubstituted or substituted with one or more substituents and each substituent independently is C1-3alkyl, C1-3alkenyl, halogen, or C1-3haloalkyl.

[0272] Provided herein as Embodiment 133 is the compound or salt of any one of Embodiments1-123, wherein Rwis C0-2alkylene-heterocycloalkyl that is unsubstituted or substituted with 1-2 halogen.

[0273] Provided herein as Embodiment 134 is the compound or salt of any one of Embodiments1-121, wherein R3is.

[0274] Provided herein as Embodiment 135 is the compound or salt of any one of Embodiments 1-121 and 134, wherein each of Rw, Rz, and Rwc1independently is H, halogen, or C1-3alkyl.

[0275] Provided herein as Embodiment 136 is the compound or salt of any one of Embodiments 1-121 and 135, wherein each of Rw, Rz, and Rwc1is H.

[0276] Provided herein as Embodiment 137 is the compound or salt of any one of Embodiments 1-121, 134, and 135, wherein each of Rwand Rzindependently is H.

[0277] Provided herein as Embodiment 138 is the compound or salt of any one of Embodiments1-121, 134, and 135, wherein

[0278] Provided herein as Embodiment 139 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is H.

[0279] Provided herein as Embodiment 140 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is methyl.

[0280] Provided herein as Embodiment 141 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is C3-7cycloalkyl.

[0281] Provided herein as Embodiment 142 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is C4-6cycloalkyl.

[0282] Provided herein as Embodiment 143 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0283] Provided herein as Embodiment 144 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0284] Provided herein as Embodiment 145 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N.

[0285] Provided herein as Embodiment 146 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from O.

[0286] Provided herein as Embodiment 147 is the compound or salt of Embodiment1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from S.

[0287] Provided herein as Embodiment 148 is the compound or salt of any one of Embodiments1-121, 134, 135, and 138-147, wherein Rwc2is H.

[0288] Provided herein as Embodiment 149 is the compound or salt of Embodiment1-121, 134, 135, and 138-147, wherein Rwc2is C1-3alkyl.

[0289] Provided herein as Embodiment 150 is the compound or salt of Embodiment1-121, 134, 135, and 138-147, wherein Rwc2is methyl.

[0290] Provided herein as Embodiment 151 is the compound or salt of any one of Embodiments1-148, wherein

[0291] Provided herein as Embodiment 152 is the compound or salt of any one of Embodiments1-148, wherein Rvis H.

[0292] Provided herein as Embodiment 153 is the compound or salt of any one of Embodiments1-148, wherein RZis H, halogen, C1-3alkyl, C1-3haloalkyl, C0-2alkylene-C1- 3haloalkoxy, C0-2alkylene-CN, or C1-3alkylene-NH2.

[0293] Provided herein as Embodiment 154 is the compound or salt of any one of Embodiments1-121, 134, 135, 138, and 148, wherein R3is

[0294] Provided herein as Embodiment 155 is the compound or salt of any one of Embodiments1-138 and 148, wherein R3is.

[0295] Provided herein as Embodiment 156 is the compound or salt of any one of Embodiments 1-133, wherein Formula (I) has a structure of Formula (II):

[0296] Provided herein as Embodiment 157 is the compound or salt of Embodiment156, wherein Rwis H.

[0297] Provided herein as Embodiment 158 is the compound or salt of Embodiment156 or 157, wherein X is CH, Y is N, and Z is N.

[0298] Provided herein as Embodiment 159 is the compound or salt of any one of Embodiments156-158, wherein R1is heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0299] Provided herein as Embodiment 160 is the compound or salt of any one of Embodiments 1-121, wherein Formula (I) has a structure of Formula (III):

[0300] Provided herein as Embodiment 161 is the compound or salt of Embodiment160, wherein X is CH, Y is N, and Z is N.

[0301] Provided herein as Embodiment 162 is the compound or salt of Embodiment160 or 161, wherein R1is heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0302] Provided herein as Embodiment 163 is the compound or salt of any one of Embodiments160-162, wherein Rwc1is H, C1-3alkyl, C0-2alkylene-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0303] Provided herein as Embodiment 164 is the compound or salt of any one of Embodiments 1-45, 57, 69, 83, 84, 86, 87, and 103-163, wherein R1is.

[0304] Provided herein as Embodiment 165 is the compound or salt of any one of Embodiments 1-45, 57, 58, 66, 69, 71, 73, 83, and 103-163, wherein R1is

[0305] Provided herein as Embodiment 166 is the compound or salt of any one of Embodiments 1-45, 57, 69, 83, and 103-163, wherein R1is

[0306] Provided herein as Embodiment 167 is the compound or salt of any one of Embodiments 1-45, 57, 58, 61, 66, 69, 83, and 103-163, wherein R1is

[0307] Provided herein as Embodiment 168 is the compound or salt of any one of Embodiments 1-45, 57, 70, 83, and 103-163, wherein R1is ,.

[0308] Provided herein as Embodiment 169 is the compound or salt of any one of Embodiments 1-45, 57, and 103-163, wherein R1is.

[0309] Provided herein as Embodiment 170 is the compound or salt of Embodiment 1, wherein the compound is a compound listed in Table A.

[0310] Provided herein as Embodiment 171 is the compound or salt of Embodiment170, wherein the compound is a compound listed in Table B.

[0311] Provided herein as Embodiment 172 is the compound or salt of Embodiment 1, wherein the compound is a compound listed in Table A’.

[0312] Provided herein as Embodiment 173 is the compound or salt of Embodiment172, wherein the compound is a compound listed in Table B’.

[0313] Provided herein as Embodiment 174 is the compound or salt of any one of Embodiments 1-45, 57-59, 66, 69, 80, 81, 83-88, 96, 97, 100, 103, 104, 108-113, 116-119, 121-124, 127, and 156-159, wherein the compound is.

[0314] Provided herein as Embodiment 175 is the compound or salt of Embodiment 1-121, wherein the compound is

[0315] Provided herein as Embodiment 175 is the compound or salt of Embodiment 1-121, wherein the compound is

[0316] Provided herein as Embodiment 177 is the compound or salt of Embodiment 1-121, 134, 135, 138, 148, 154, 155, and 160-162 wherein the compound is

[0317] Provided herein as Embodiment 178 is the compound or salt of Embodiment 1-148, wherein the compound is

[0318] Provided herein as Embodiment 179 is the compound or salt of Embodiment 1-148, wherein the compound is

[0319] Provided herein as Embodiment 180 is the compound or salt of Embodiment 1-148, wherein the compound is , ,

[0320] Provided herein as Embodiment 181 is the compound or salt of Embodiment 1-148, wherein the compound is

[0321] Provided herein as Embodiment 182 is the compound or salt of Embodiment 1-148, wherein the compound is.

[0322] Provided herein as Embodiment 183 is the compound or salt of Embodiment 1-148, wherein the compound is.

[0323] Provided herein as Embodiment 184 is the compound or salt of Embodiment 1-148, wherein the compound is

[0324] Provided herein as Embodiment 185 is the compound or salt of Embodiment 1, wherein the compound is.

[0325] Provided herein as Embodiment 186 is the compound or salt of Embodiment 1, wherein the compound is.

[0326] Provided herein as Embodiment 187 is the compound or salt of Embodiment 1, wherein the compound is.

[0327] Provided herein as Embodiment 188 is the compound or salt of Embodiment 1, wherein the compound is.

[0328] Provided herein as Embodiment 189 is the compound or salt of Embodiment 1, wherein the compound is.

[0329] Provided herein as Embodiment 190 is the compound or salt of Embodiment 1, wherein the compound is.

[0330] Provided herein as Embodiment 191 is the compound or salt of Embodiment 1, wherein the compound is.

[0331] Provided herein as Embodiment 192 is the compound or salt of Embodiment 1, wherein the compound is.

[0332] Provided herein as Embodiment 193 is the compound or salt of Embodiment 1, wherein the compound is

[0333] Provided herein as Embodiment 194 is the compound or salt of Embodiment 1, wherein the compound is.

[0334] Provided herein as Embodiment 195 is the compound or salt of Embodiment 1, wherein the compound is.

[0335] Provided herein as Embodiment 196 is the compound or salt of Embodiment 1, wherein the compound is.

[0336] Provided herein as Embodiment 197 is the compound or salt of Embodiment 1, wherein the compound is.

[0337] Provided herein as Embodiment 198 is the compound of any one of Embodiments 1-197.

[0338] Provided herein as Embodiment 199 is the salt of any one of Embodiments 1-197.

[0339] Provided herein as Embodiment 200 is a pharmaceutical composition comprising the compound or salt of any one of Embodiments1-199 and a pharmaceutically acceptable excipient.

[0340] Provided herein as Embodiment 201 is a method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of Embodiments1-199 or the composition of Embodiment 200.

[0341] Provided herein as Embodiment 202 is the method of Embodiment 201, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0342] Provided herein as Embodiment 203 is the method of embodiment 201 or 202, wherein the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer, or any combination of the foregoing.

[0343] Provided herein as Embodiment 204 is a compound or salt of any one of Embodiments 1-199 or the pharmaceutical composition of Embodiment 200 for use as a medicament.

[0344] Provided herein as Embodiment 205 is a compound or salt of any one of Embodiments 1-199 or the pharmaceutical composition of Embodiment 200 for use in the treatment of cancer.

[0345] Provided herein as Embodiment 206 is the use of the compound or salt of any one of Embodiments 1-199 or the pharmaceutical composition of Embodiment 200 for the manufacture of a medicament for the treatment of cancer.

[0346] Provided herein as Embodiment 207 is the use of the compound of salt of any one of Embodiments 1-199 or the pharmaceutical composition of Embodiment 200, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0347] Provided herein as Embodiment 208 is the use of any one of Embodiments 1-199 or the pharmaceutical composition of Embodiment 200, wherein the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian, urothelial, small bowel, brain, biliary tract, bladder, gastroesophageal, head-and-neck, skin, sarcoma, thoracic, pancreatic cancer, or any combination of the foregoing.

[0348] Provided herein as Embodiment 209 is the use of any one of Embodiments 206-208, wherein the cancer is characterized as tumor-agnostic MSI-H / dMMR cancer.

[0349] Provided herein as Embodiment 210 is the process for preparing the compound or salt of any one of Embodiments 1-199, comprising providing a compound or salt of any one of Tables C, 1-1, 1-2, or 1-3 and converting it into a separate compound or salt of any one of Tables 1A, 1B, 1C, 2-1, 2-2, 2-3, 2-4, 2-5, 2-7, 2-8, A, A’, B, or B’. OTHER ENUMERATED EMBODIMENTS

[0350] Provided herein as Embodiment A1 is compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: X is N or C-Rx, wherein Rxis H, halogen, CN, OH, C1-3alkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl; Y is N or C-Ry, wherein Ryis H, halogen, CN, OH, C1-3alkyl, C0-3alkylene-C1- 3alkoxy, C1-3haloalkoxy, or N(Rb)2, wherein each instance of Rbindependently is H or C1-3alkyl; wherein the C1-3alkyl of each instance of Raand Rbindependently is unsubstituted or substituted with one or more substituents and each substituent independently is OH or C1-3alkoxy; Z is N or C-Rz, wherein Rzis H or halogen; R1is C1-6alkyl, C1-6alkenyl, N(Rc)(Rd), C3-8cycloalkyl, C3-8cycloalkenyl, heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3- 6cycloalkyl, or C3-6cycloalkenyl; wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C0-6alkylene-OH, C0-3alkylene-CN, C1- 4alkyl, C1-4alkenyl, C0-3alkylene-C1-3haloalkyl, C0-6alkylene-C1-3alkoxy, C1- 3haloalkoxy, C0-3alkylene-C3-6cycloalkyl, or C0-3alkylene-phenyl; wherein, when R1is C6-10aryl, heteroaryl having 5-10 total ring atoms, C3-8cycloalkyl, or heterocycloalkyl having 3-10 total ring atoms, then two adjacent substituents of R1, together with the atoms to which they are attached, may form C3-6cycloalkyl, C3-6cycloalkenyl, heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-6 total ring atoms and 1-3 heteroatoms independently selected from N, O and S; wherein the cycle formed by the two adjacent substituents of R1can be unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy;wherein, when R1is substituted with C0-3alkylene-C3-6cycloalkyl or C0- 3alkylene-phenyl, the C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, or C1- 3alkoxy; wherein, when R1is substituted with C1-4alkyl or C1-4alkenyl, the C1-4alkyl or C1-4alkenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, NH2, NH(C1-3alkyl), or N(C1-3alkyl)2; R2is C6-10aryl or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein R2is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3cycloalkyl, or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; R3is:wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, D, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1- 3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is D, halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, C1-3alkoxy.

[0351] Provided herein as Embodiment A2 is the compound or salt of Embodiment A1, wherein

[0352] Provided herein as Embodiment A3 is the compound or salt of Embodiment A1 or.

[0353] Provided herein as Embodiment A4 is the compound or salt of Embodiment A1 or 2, wherein.

[0354] Provided herein as Embodiment A5 is the compound or salt of Embodiment A1 or

[0355] Provided herein as Embodiment A6 is the compound or salt of Embodiment A1 or 2, wherein.

[0356] Provided herein as Embodiment A7 is the compound or salt of Embodiment A1 or

[0357] Provided herein as Embodiment A8 is the compound or salt of Embodiment A1 or A2, wherein

[0358] Provided herein as Embodiment A9 is the compound or salt of Embodiment A1 or A2, wherein

[0359] Provided herein as Embodiment A10 is the compound or salt of Embodiment A1 or

[0360] Provided herein as Embodiment A11 is the compound or salt of any one of Embodiments A1, A2, and A10, wherein

[0361] Provided herein as Embodiment A12 is the compound or salt of any one of Embodiments A1, A2, and A10, wherein

[0362] Provided herein as Embodiment A13 is the compound or salt of any one of Embodiments A1, A2, and A10, wherein

[0363] Provided herein as Embodiment A14 is the compound or salt of any one of Embodiments A1, A2, and A10,, wherein

[0364] Provided herein as Embodiment A15 is the compound or salt of any one of Embodiments A1, A2, and A10,, wherein

[0365] Provided herein as Embodiment A16 is the compound or salt of any one of Embodiments A1, A2, and A10,, wherein.

[0366] Provided herein as Embodiment A17 is the compound or salt of any one of Embodiments A1, A2, and A10,, wherein.

[0367] Provided herein as Embodiment A18 is the compound or salt of any one of Embodiments A1, A2, and A10,, wherein X is N.

[0368] Provided herein as Embodiment A19 is the compound or salt of any one of Embodiments A1, A2, and A10,, wherein X is C-Rx.

[0369] Provided herein as Embodiment A20 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis H, halogen, N(Ra)2, C1-3alkyl, or C1- 3alkoxy.

[0370] Provided herein as Embodiment A21 is the compound or salt of any one of Embodiments A1, A2, A10, A19, and A20, wherein Rxis H, F, Cl, NH2, methyl, or methoxy.

[0371] Provided herein as Embodiment A22 is the compound or salt of any one of Embodiments A1, A2, A10, A19, and A20, wherein Rxis H or methyl.

[0372] Provided herein as Embodiment A23 is the compound or salt of any one of Embodiments A1, A2, A10, A19, and A20, wherein Rxis OH.

[0373] Provided herein as Embodiment A24 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis C0-3alkylene-C1-3alkoxy.

[0374] Provided herein as Embodiment A25 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis CH2-C1-3alkoxy.

[0375] Provided herein as Embodiment A26 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis methoxy or CH2-methoxy.

[0376] Provided herein as Embodiment A27 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis C1-3haloalkoxy.

[0377] Provided herein as Embodiment A28 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis halogen.

[0378] Provided herein as Embodiment A29 is the compound or salt of any one of Embodiments A1, A2, A10, A19, and A28, wherein Rxis F, Cl, or Br.

[0379] Provided herein as Embodiment A30 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis H.

[0380] Provided herein as Embodiment A31 is the compound or salt of any one of Embodiments A1, A2, A10, and A19, wherein Rxis methyl.

[0381] Provided herein as Embodiment A32 is the compound or salt of any one of Embodiments A1, A2, A10, A19, and A20, wherein Rxis N(Ra)2.

[0382] Provided herein as Embodiment A33 is the compound or salt of any one of Embodiments A1, A2, A10, A19, A20, and A32, wherein each Raindependently is H or methyl.

[0383] Provided herein as Embodiment A34 is the compound or salt of any one of Embodiments A1, A2, A10, A19, A20, A32, and A33, wherein at least one instance of Rais H.

[0384] Provided herein as Embodiment A35 is the compound or salt of any one of Embodiments A1, A2, A10, A19, A20, and A32-A34, wherein at least one instance of Rais methyl.

[0385] Provided herein as Embodiment A36 is the compound or salt of any one of Embodiments A1, A2, A10, A19, A20, and A32-34, wherein each Rais H.

[0386] Provided herein as Embodiment A37 is the compound or salt of any one of Embodiments A1, A2, A10, A19, A20, and A32-A35, wherein each Rais methyl.

[0387] Provided herein as Embodiment A38 is the compound or salt of any one of Embodiments A1, A2, A10, A19, and A20, wherein Rxis methoxy.

[0388] Provided herein as Embodiment A39 is the compound or salt of any one of Embodiments A1-A3, wherein Y is N.

[0389] Provided herein as Embodiment A40 is the compound or salt of any one of Embodiments A1-A3, wherein Y is C-Ry.

[0390] Provided herein as Embodiment A41 is the compound or salt of any one of Embodiments A1-A3 and A40, wherein Ryis H.

[0391] Provided herein as Embodiment A42 is the compound or salt of any one of Embodiments A1-A3 and A40, wherein Ryis CN or N(H)2.

[0392] Provided herein as Embodiment A43 is the compound or salt of any one of Embodiments A1-A3, wherein Z is N.

[0393] Provided herein as Embodiment A44 is the compound or salt of any one of Embodiments A1-A3, wherein Z is C.

[0394] Provided herein as Embodiment A45 is the compound or salt of any one of Embodiments A1-A44, wherein R1is C1-4alkyl, C1-4alkenyl, N(Rc)(Rd), C4-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0395] Provided herein as Embodiment A46 is the compound or salt of any one of Embodiments A1-A45, wherein R1is C1-4alkyl, C1-4alkenyl, or N(Rc)(Rd).

[0396] Provided herein as Embodiment A47 is the compound or salt of any one of Embodiments A1-A46, wherein R1is C1-4alkyl or C1-4alkenyl.

[0397] Provided herein as Embodiment A48 is the compound or salt of any one of Embodiments A1-A47, wherein R1is C1-3alkyl or C1-3alkenyl.

[0398] Provided herein as Embodiment A49 is the compound or salt of any one of Embodiments A1-A46, wherein R1is N(Rc)(Rd).

[0399] Provided herein as Embodiment A50 is the compound or salt of any one of Embodiments A1-A46 andA 49, wherein Rcis H.

[0400] Provided herein as Embodiment A51 is the compound or salt of any one of Embodiments A1-A46 and A49, wherein Rcis C1-3alkyl.

[0401] Provided herein as Embodiment A52 is the compound or salt of any one of Embodiments A1-A46, A49, and A51, wherein Rcis methyl.

[0402] Provided herein as Embodiment A53 is the compound or salt of any one of Embodiments A1-A46 and A49-A52, wherein Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl.

[0403] Provided herein as Embodiment A54 is the compound or salt of any one of Embodiments A1-A46 and A49-A53, wherein Rdis C1-6alkyl.

[0404] Provided herein as Embodiment A55 is the compound or salt of any one of Embodiments A1-A46 and A49-A53, wherein Rdis C3-6cycloalkyl or C3-6cycloalkenyl.

[0405] Provided herein as Embodiment 56 is the compound or salt of any one of Embodiments A1-A46, A49-A53, and A55, wherein Rdis C4-6cycloalkyl.

[0406] Provided herein as Embodiment A57 is the compound or salt of any one of Embodiments A1-A45, wherein R1is C4-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0407] Provided herein as Embodiment A58 is the compound or salt of any one of Embodiments A1-A45 and A57, wherein R1is heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0408] Provided herein as Embodiment A59 is the compound or salt of any one of Embodiments A1-A45, A57, and A58, wherein R1is heterocycloalkyl having 4 total ring atoms and one heteroatom independently selected from N, O, and S.

[0409] Provided herein as Embodiment A60 is the compound or salt of any one of Embodiments A1-A45, A57, and A58, wherein R1is heterocycloalkyl having 5 total ring atoms and one heteroatom independently selected from N, O, and S.

[0410] Provided herein as Embodiment A61 is the compound or salt of any one of Embodiments A1-A45,A 57, and A58, wherein R1is heterocycloalkyl having 6 total ring atoms and one heteroatom independently selected from N, O, and S.

[0411] Provided herein as Embodiment A62 is the compound or salt of any one of Embodiments A1-A45, A57, and A58, wherein R1is heterocycloalkyl having 7 total ring atoms and one heteroatom independently selected from N, O, and S.

[0412] Provided herein as Embodiment A63 is the compound or salt of any one of Embodiments A1-A45, A57, A58, and A62, wherein R1is heterocycloalkyl comprising twospiro-connected rings, wherein rings are connected through a shared carbon atom, and the heterocycloalkyl is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1-3haloalkyl.

[0413] Provided herein as Embodiment A64 is the compound or salt of any one of Embodiments A1-A45, A57, A58, and A62, wherein the two spiro-connected rings comprises two four-membered rings or one four-membered ring and one three-membered ring.

[0414] Provided herein as Embodiment A65 is the compound or salt of any one of Embodiments A1-A45, and A57-A63, wherein R1has one N and one O as ring heteroatoms.

[0415] Provided herein as Embodiment A66 is the compound or salt of any one of Embodiments A1-45, and A57-A63, wherein R1has one N as a ring heteroatom.

[0416] Provided herein as Embodiment A67 is the compound or salt of any one of Embodiments A1-A45, and A57-A63, wherein R1has one O as a ring heteroatom.

[0417] Provided herein as Embodiment A68 is the compound or salt of any one of Embodiments A1-A45, and A57-A67, wherein R1is C6-10aryl or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0418] Provided herein as Embodiment A69 is the compound or salt of any one of Embodiments A1-A45, wherein R1is C4-7cycloalkyl or heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0419] Provided herein as Embodiment A70 is the compound or salt of any one of Embodiments A1-A45 andA 69, wherein R1has two adjacent substituents that, together with the atoms to which they are attached, form C3-6cycloalkyl, C3-6cycloalkenyl, or a heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0420] Provided herein as Embodiment A71 is the compound or salt of any one of Embodiments A1-A70, wherein R1is heterocycloalkyl that comprises spiro-connected rings and the heterocycloalkyl is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1- 3haloalkyl.

[0421] Provided herein as Embodiment A72 is the compound or salt of any one of Embodiments A1-A71, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0422] Provided herein as Embodiment A73 is the compound or salt of any one of Embodiments A1-A71, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0423] Provided herein as Embodiment A74 is the compound or salt of any one of Embodiments A1-A70, wherein R1is heterocycloalkyl having 8-10 total ring atoms and two fused rings, further wherein two non-adjacent atoms on a ring join together to form a C1- 2alkylene bridge.

[0424] Provided herein as Embodiment A75 is the compound or salt of any one of Embodiments A1-A70 and A74, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0425] Provided herein as Embodiment A76 is the compound or salt of any one of Embodiments A1-A70, wherein R1is bridged-heterocycloalkyl having 5 or 6 total ring atoms and two non-adjacent atoms join together to form a C1-2alkylene bridge.

[0426] Provided herein as Embodiment A77 is the compound or salt of any one of Embodiments A1-A45, A58, A69, and A76, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0427] Provided herein as Embodiment A78 is the compound or salt of any one of Embodiments A1-A45, A58, A69, and A76, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0428] Provided herein as Embodiment A79 is the compound or salt of any one of Embodiments A1-A45, A57, A58, A66, A69, and A70, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0429] Provided herein as Embodiment A80 is the compound or salt of any one of Embodiments A1-A45, A57, A58, A66, and A69, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0430] Provided herein as Embodiment A81 is the compound or salt of any one of Embodiments A1-45, A57, A58, A66, and A69, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

[0431] Provided herein as Embodiment A82 is the compound or salt of any one of Embodiments A1-A45, A57, and A70, wherein R1is aryl with two adjacent substituents that provide a 5-membered heterocyclyl represented bywhich can be unsubstituted or further substituted by replacing one or more ring H atoms with one or more substituents of R1.

[0432] Provided herein as Embodiment A83 is the compound or salt of any one of Embodiments A1-A82, wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-4alkyl, C1-4alkenyl unsubstituted or substituted with halogen, C0-3alkylene-C1-3haloalkyl, C0-3alkylene-C3-6cycloalkyl, C6-10aryl, or two adjacent substituents that, together with the atoms to which they are attached, form C3-6cycloalkyl group or a heterocycloalkyl having 4-6 total ring atoms and 1-2 heteroatoms independently selected from N or O.

[0433] Provided herein as Embodiment A84 is the compound or salt of any one of Embodiments A1-A83, wherein each substituent of R1independently is F, methyl, ethyl, =C- F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, cyclopropyl, phenyl.

[0434] Provided herein as Embodiment A85 is the compound or salt of any one of Embodiments A1-A83, wherein each substituent of R1independently is F, methyl, ethyl, CF3, CHF2, CH2F, or cyclopropyl.

[0435] Provided herein as Embodiment A86 is the compound or salt of any one of Embodiments A1-A85, wherein R1is substituted with 1, 2, 3, 4, or 5 substituents.

[0436] Provided herein as Embodiment A87 is the compound or salt of any one of Embodiments A1-A85, wherein R1is substituted with 1, 2, 3, or 4 substituents.

[0437] Provided herein as Embodiment A88 is the compound or salt of any one of Embodiments A1-A85, wherein R1is substituted with 3 or 4 substituents.

[0438] Provided herein as Embodiment A89 is the compound or salt of any one of Embodiments A1-A85, wherein R1is substituted with 1, 2, or 3 substituents.

[0439] Provided herein as Embodiment A90 is the compound or salt of any one of Embodiments A1-A85, wherein R1is substituted with 1 or 2 substituents.

[0440] Provided herein as Embodiment A91 is the compound or salt of any one of Embodiments A1-A85, wherein R1is substituted with 1 substituent.

[0441] Provided herein as Embodiment A92 is the compound or salt of any one of Embodiments A1-A91, wherein R1is substituted with C3-6cycloalkyl that is unsubstituted or substituted with one or more halogens.

[0442] Provided herein as Embodiment A93 is the compound or salt of Embodiment A92, wherein the C3-6cycloalkyl substituent of R1is unsubstituted.

[0443] Provided herein as Embodiment A94 is the compound or salt of Embodiment A92, wherein the C3-6cycloalkyl substituent of R1is substituted with one or more halogens.

[0444] Provided herein as Embodiment A95 is the compound or salt of Embodiment A92, wherein the C3-6cycloalkyl substituent of R1is substituted with 1, 2, or 3 halogens.

[0445] Provided herein as Embodiment A96 is the compound or salt of any one of Embodiments A1-A90, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen, OH, CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C3-4cycloalkyl.

[0446] Provided herein as Embodiment A97 is the compound or salt of any one of Embodiments A1-A90, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen, C1-3alkyl, C1-3haloalkyl.

[0447] Provided herein as Embodiment A98 is the compound or salt of any one of Embodiments A1-A91, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen or C1-3alkyl.

[0448] Provided herein as Embodiment A99 is the compound or salt of any one of Embodiments A1-A91, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen or methyl.

[0449] Provided herein as Embodiment A100 is the compound or salt of any one of Embodiments A1-A91, wherein R1is substituted with 1, 2, 3, or 4 substituents and each R1substituent independently is halogen or methyl.

[0450] Provided herein as Embodiment A101 is the compound or salt of any one of Embodiments A1-A97, wherein R1is substituted with one or more substituents and each R1substituent independently is C1-3haloalkyl.

[0451] Provided herein as Embodiment A102 is the compound or salt of any one of Embodiments A1-A83, wherein R1is unsubstituted.

[0452] Provided herein as Embodiment A103 is the compound or salt of any one of Embodiments A1-A102, wherein R2is C6-10aryl.

[0453] Provided herein as Embodiment A104 is the compound or salt of any one of Embodiments A1-A103, wherein R2is phenyl.

[0454] Provided herein as Embodiment A105 is the compound or salt of any one of Embodiments A1-102, wherein R2is heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0455] Provided herein as Embodiment A106 is the compound or salt of any one of Embodiments A1-A102 and A105, wherein R2is pyrimidinyl.

[0456] Provided herein as Embodiment A107 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is OH or CN.

[0457] Provided herein as Embodiment A108 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, or C1-3alkoxy.

[0458] Provided herein as Embodiment A109 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is halogen and CN.

[0459] Provided herein as Embodiment A110 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is halogen and OH.

[0460] Provided herein as Embodiment A111 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is halogen.

[0461] Provided herein as Embodiment A112 is the compound or salt of any one of Embodiments A108-A111, wherein each halogen substituent of R2independently is F, Cl, or Br.

[0462] Provided herein as Embodiment A113 is the compound or salt of any one of Embodiments A108-A111, wherein halogen is F.

[0463] Provided herein as Embodiment A114 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is C1-3alkyl.

[0464] Provided herein as Embodiment A115 is the compound or salt of any one of Embodiments A1-A106, wherein R2is substituted with one or more substituents and each substituent independently is methyl.

[0465] Provided herein as Embodiment A116 is the compound or salt of any one of Embodiments A1-A115, wherein R2is substituted with 1, 2, 3, or 4 substituents.

[0466] Provided herein as Embodiment A117 is the compound or salt of any one of Embodiments A1-A115, wherein R2is substituted with 1, 2, or 3 substituents.

[0467] Provided herein as Embodiment A118 is the compound or salt of any one of Embodiments A1-A115, wherein R2is substituted with 1 or 2 substituents.

[0468] Provided herein as Embodiment A119 is the compound or salt of any one of Embodiments A1-A115, wherein R2is substituted with 1 substituents.

[0469] Provided herein as Embodiment A120 is the compound or salt of any one of Embodiments A1-A106, wherein R2is unsubstituted.

[0470] Provided herein as Embodiment A121 is the compound or salt of any one of Embodiments A1-A120, wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2of R3independently is H, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0- 2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is halogen, CN, C1-3alkyl C1-3haloalkyl, OH, C1-3alkoxy; and

[0471] Provided herein as Embodiment A122 is the compound or salt of any one of Embodiments A1-A120, wherein R3is.

[0472] Provided herein as Embodiment A123 is the compound or salt of any one of Embodiments A1-A120, wherein R3is Rvis H.

[0473] Provided herein as Embodiment A124 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis H or C1-3alkyl.

[0474] Provided herein as Embodiment A125 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis H.

[0475] Provided herein as Embodiment A126 is the compound or salt of any one of Embodiments A1-A125, wherein Rwis C1-3alkyl.

[0476] Provided herein as Embodiment A127 is the compound or salt of any one of Embodiments A1-125, wherein Rwis methyl.

[0477] Provided herein as Embodiment A128 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0478] Provided herein as Embodiment A129 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis CH2-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0479] Provided herein as Embodiment A130 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis CH2-heterocycloalkyl having 3-5 total ring atoms and 1-2 heteroatoms independently selected from N, O, and S.

[0480] Provided herein as Embodiment A131 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis CH2-heterocycloalkyl having 3-5 total ring atoms and 1-2 heteroatoms independently selected from N or O.

[0481] Provided herein as Embodiment A132 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis C0-2alkylene-heterocycloalkyl that is unsubstituted or substituted with one or more substituents and each substituent independently is C1-3alkyl, C1-3alkenyl, halogen, or C1-3haloalkyl.

[0482] Provided herein as Embodiment A133 is the compound or salt of any one of Embodiments A1-A123, wherein Rwis C0-2alkylene-heterocycloalkyl that is unsubstituted or substituted with 1-2 halogen.

[0483] Provided herein as Embodiment A134 is the compound or salt of any one of Embodiments A1-A121, wherein R3is.

[0484] Provided herein as Embodiment A135 is the compound or salt of any one of Embodiments A1-A121 and A134, wherein each of Rw, Rz, and Rwc1independently is H, halogen, or C1-3alkyl.

[0485] Provided herein as Embodiment A136 is the compound or salt of any one of Embodiments A1-A121 and A135, wherein each of Rw, Rz, and Rwc1is H.

[0486] Provided herein as Embodiment A137 is the compound or salt of any one of Embodiments A1-A121, A134, and A135, wherein each of Rwand Rzindependently is H.

[0487] Provided herein as Embodiment A138 is the compound or salt of any one of Embodiments A1-A121, A134, and A135, wherein.

[0488] Provided herein as Embodiment A139 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is H.

[0489] Provided herein as Embodiment A140 is the compound or salt of Embodiment A1- 121, 134, 135, and 138, wherein Rwc1is methyl.

[0490] Provided herein as Embodiment A141 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is C3-7cycloalkyl.

[0491] Provided herein as Embodiment A142 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is C4-6cycloalkyl.

[0492] Provided herein as Embodiment A143 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0493] Provided herein as Embodiment A144 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0494] Provided herein as Embodiment A145 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N.

[0495] Provided herein as Embodiment A146 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from O.

[0496] Provided herein as Embodiment A147 is the compound or salt of Embodiment A1- A121, A134, A135, and A138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from S.

[0497] Provided herein as Embodiment A148 is the compound or salt of any one of Embodiments A1-A121, A134, A135, and A138-A147, wherein Rwc2is H.

[0498] Provided herein as Embodiment A149 is the compound or salt of Embodiment A 1- A121, A134, A135, and A138-A147, wherein Rwc2is C1-3alkyl.

[0499] Provided herein as Embodiment A150 is the compound or salt of Embodiment A 1- A121, A134, A135, and A138-A147, wherein Rwc2is methyl.

[0500] Provided herein as Embodiment A151 is the compound or salt of any one of Embodiments A1-A148, wherein.

[0501] Provided herein as Embodiment A152 is the compound or salt of any one of Embodiments A1-A148, wherein Rvis H.

[0502] Provided herein as Embodiment A153 is the compound or salt of any one of Embodiments A1-A148, wherein RZis H, halogen, C1-3alkyl, C1-3haloalkyl, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, or C1-3alkylene-NH2.

[0503] Provided herein as Embodiment A154 is the compound or salt of any one of Embodiments A1-121, A134, A135, A138, and A148, wherein R3is

[0504] Provided herein as Embodiment A155 is the compound or salt of any one of Embodiments A1-A138 and 1A48, wherein R3is.

[0505] Provided herein as Embodiment A156 is the compound or salt of any one of Embodiments A1-A133, wherein Formula (I) has a structure of Formula (II):

[0506] Provided herein as Embodiment A157 is the compound or salt of Embodiment 156, wherein Rwis H.

[0507] Provided herein as Embodiment A158 is the compound or salt of Embodiment A156 or A157, wherein X is CH, Y is N, and Z is N.

[0508] Provided herein as Embodiment A159 is the compound or salt of any one of Embodiments A156-A158, wherein R1is heterocycloalkyl having 4-7 total ring atoms and 1- 3 heteroatoms independently selected from N, O, and S.

[0509] Provided herein as Embodiment A160 is the compound or salt of any one of Embodiments A1-A121, wherein Formula (I) has a structure of Formula (III):

[0510] Provided herein as Embodiment A161 is the compound or salt of Embodiment A160, wherein X is CH, Y is N, and Z is N.

[0511] Provided herein as Embodiment A162 is the compound or salt of Embodiment A160 or A161, wherein R1is heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0512] Provided herein as Embodiment A163 is the compound or salt of any one of Embodiments A160-A162, wherein Rwc1is H, C1-3alkyl, C0-2alkylene-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0513] Provided herein as Embodiment A164 is the compound or salt of any one of Embodiments A1-A45, A57, A69, A83, A84, A86, A87, and A103-A163, wherein R1is ,

[0514] Provided herein as Embodiment A165 is the compound or salt of any one of Embodiments A1-A45, A57, A58, A66, A69, A71, A73, A83, and A103-A163, wherein R1is.

[0515] Provided herein as Embodiment A166 is the compound or salt of any one of Embodiments A1-A45, A57, A69, A83, and A103-A163, wherein R1is

[0516] Provided herein as Embodiment A167 is the compound or salt of any one of Embodiments A1-45, A57, A58, A61, A66, A69, A83, and A103-A163, wherein R1is

[0517] Provided herein as Embodiment A168 is the compound or salt of any one of Embodiments A1-A45, A57, A70, A83, and A103-A163, wherein R1is.

[0518] Provided herein as Embodiment A169 is the compound or salt of any one of Embodiments A1-A45, A57, and A103-A163, wherein R1is

[0519] Provided herein as Embodiment A170 is the compound or salt of Embodiment A 1, wherein the compound is a compound listed in Table A.

[0520] Provided herein as Embodiment A171 is the compound or salt of Embodiment A 170, wherein the compound is a compound listed in Table B.

[0521] Provided herein as Embodiment A172 is the compound or salt of Embodiment A 1, wherein the compound is a compound listed in Table A’.

[0522] Provided herein as Embodiment A173 is the compound or salt of Embodiment A 172, wherein the compound is a compound listed in Table B’.

[0523] Provided herein as Embodiment A174 is the compound or salt of any one of Embodiments A1-A45, A57-A59, A66, A69, A80, A81, A83-A88, A96, A97, A100, A103, A104, A108-A113, A116-A119, A121-A124, A127, and A156-A159, wherein the compound is.

[0524] Provided herein as Embodiment A175 is the compound or salt of Embodiment A1- A121, wherein the compound is.

[0525] Provided herein as Embodiment A176 is the compound or salt of Embodiment A1- A121, wherein the compound is

[0526] Provided herein as Embodiment A177 is the compound or salt of Embodiment A1- A121, A134, A135, A138, A148, AA154A, 155, and 160-A162 wherein the compound is

[0527] Provided herein as Embodiment A178 is the compound or salt of Embodiment A1- A148, wherein the compound is

[0528] Provided herein as Embodiment A179 is the compound or salt of Embodiment A1- A148, wherein the compound is

[0529] Provided herein as Embodiment A180 is the compound or salt of Embodiment A1- A148, wherein the compound is

[0530] Provided herein as Embodiment A181 is the compound or salt of Embodiment A1- A148, wherein the compound is

[0531] Provided herein as Embodiment A182 is the compound or salt of Embodiment A1- A148, wherein the compound is

[0532] Provided herein as Embodiment A183 is the compound or salt of Embodiment A1, wherein the compound is.

[0533] Provided herein as Embodiment A184 is the compound or salt of Embodiment A1, wherein the compound is.

[0534] Provided herein as Embodiment A185 is the compound or salt of Embodiment A1, wherein the compound is.

[0535] Provided herein as Embodiment A186 is the compound or salt of Embodiment A1, wherein the compound is.

[0536] Provided herein as Embodiment A187 is the compound or salt of Embodiment A1, wherein the compound is.

[0537] Provided herein as Embodiment A188 is the compound or salt of Embodiment A1, wherein the compound is.

[0538] Provided herein as Embodiment A189 is the compound or salt of Embodiment A1, wherein the compound is.

[0539] Provided herein as Embodiment A190 is the compound of any one of Embodiments A1-A189.

[0540] Provided herein as Embodiment A191 is the salt of any one of Embodiments A1- A189.

[0541] Provided herein as Embodiment A192 is a pharmaceutical composition comprising the compound or salt of any one of Embodiments A1-A191 and a pharmaceutically acceptable excipient.

[0542] Provided herein as Embodiment A193 is a method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of Embodiments A1-A191, or the composition of Embodiment A192.

[0543] Provided herein as Embodiment A194 is method of Embodiment A193, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0544] Provided herein as Embodiment A195 is method of Embodiment A193 or A194, wherein the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer, or any combination of the foregoing.

[0545] Provided herein as Embodiment A196 is a compound or salt of any one of Embodiments A1-A191, or the pharmaceutical composition of Embodiment A192 for use as a medicament.

[0546] Provided herein as Embodiment A197 is a compound or salt of any one of Embodiments A1-A191, or the pharmaceutical composition of Embodiment A192 for use in the treatment of cancer.

[0547] The use of Provided herein as Embodiment A198 is the compound or salt of any one of Embodiments A1-A191, or the pharmaceutical composition of Embodiment 192, for the manufacture of a medicament for the treatment of cancer.

[0548] The use of the compound of salt of any one of Embodiments A1-A191 or the pharmaceutical composition of Embodiment A192, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0549] The use of any one of Embodiments A1-A191 or the pharmaceutical composition of Embodiment A192, wherein the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer, or any combination of the foregoing, or any combination of the foregoing. EXAMPLES

[0550] This section provides specific examples of compounds of Formula (I) and methods of making the same. List of Abbreviations

[0551] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.

[0552] Chromatography: Unless otherwise indicated, product-containing residues were purified by passing the material or concentrate through either a Biotage or ISCO brand silica gel column pre-packed with flash silica and eluting the product off the column with a solvent gradient as indicated. Alternatively, product-containing residues were purified by reverse phase MPLC using Flashpure C18 columns.

[0553] Preparative HPLC Method: Where indicated, the compounds described herein were purified via reverse phase HPLC using a Waters FractionLynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 × 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 × 30 mm). A typical run through the instrument included: eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% ACN (0.1% formic acid) in H2O (0.1% formic acid) over 10 min. Conditions can be varied to achieve optimal separations.

[0554] Proton NMR Spectra: Unless otherwise indicated, all1H NMR spectra were collected on a Bruker NMR instrument at 400 MHz or 500 MHz. All observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some1H signals may be missing due to exchange with D from CD3OD, or due to signal suppression.

[0555] Fluorine-19 NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 376 MHz or 471 MHz.

[0556] Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary compounds are reported as mass / charge (m / z), having an [M+H]+ molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a UPLC / MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art. SECTION 1: Synthesis of Intermediates Intermediate A-1: Methyl 5-bromo-6-(4-fluorophenyl)pyrazine-2-carboxylateIntermediate A-1

[0557] Step 1: Methyl 5-amino-6-(4-fluorophenyl)pyrazine-2-carboxylate. To a stirred solution of methyl 5-amino-6-bromopyrazine-2-carboxylate (50 g, 215 mmol) in dioxane (250 mL) and water (62 mL), were added (4-fluorophenyl)boronic acid (45.2 g, 323 mmol) and K3PO4(114 g, 539 mmol) at 27 °C. The reaction mixture was degassed and purged with N2 for 10 min. Pd(dppf)Cl2 (7.88 g, 10.77 mmol) was added to the reaction mixture and purged with N2 for another 5 min. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3 × 250 mL). The combined organic extracts were washed with satd. NaCl solution (250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography eluting with 0% to 25% EtOAc in hexanes to afford methyl 5-amino-6- (4-fluorophenyl)pyrazine-2-carboxylate (40.0 g, 162 mmol, 75% yield). m / z (ESI): 248.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.72 - 7.69 (m, 2H), 7.36 - 7.32 (m, 2H), 7.10 (br s, 2H), 3.82 (s, 3H).

[0558] Step 2: Methyl 5-bromo-6-(4-fluorophenyl)pyrazine-2-carboxylate, Intermediate A1. To a stirred solution of methyl 5-amino-6-(4-fluorophenyl)pyrazine-2-carboxylate (42 g, 170 mmol) in dibromomethane (420 mL) was added isoamyl nitrite (59.7 g, 510 mmol) at 0oC. The reaction mixture was stirred at rt for 1 h. Bromotrimethylsilane (156 g, 1019 mmol) was added to the reaction mixture at 0oC and stirred at rt for 2 h. The reaction mixture wasquenched with aqueous 10% NaHCO3 (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with satd NaCl (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography eluting with 0% to 20% EtOAc in hexanes to afford Intermediate A-1 (22 g, 70.7 mmol, 42% yield). m / z (ESI): 311.0 / 313.0 (1:1) (M+H)+.1H NMR (400 MHz, DMSO- d6) δ 9.00 (s, 1H), 7.82 - 7.79 (m, 2H), 7.42- 7.38 (m, 2H), 3.94 (s, 3H). Intermediate B-1: Methyl 3-amino-6-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazine-2- carboxylate

[0559] To a stirred solution of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (6.0 g, 27 mmol, BLD Pharma. Ltd.) and 4,4-difluoropiperidine hydrochloride (4.26 g, 27.0 mmol, BLD Pharma Ltd.) in DMSO (48.0 mL) was added DIPEA (14.2 mL, 81 mmol, Sonia Industries Ltd.). The reaction mixture was stirred at 130 °C for 4 h under microwave radiation. Then, the reaction mixture was cooled to rt, quenched with ice cold water (100 mL). The resulting precipitate was collected by filtration, washed with H2O (2 × 50 mL) and dried to provide Intermediate B-1 (7.5 g, 25 mmol, 90% yield). m / z (ESI): 307.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.34 (s, 2H), 3.79 (s, 3H), 3.68 (t, J = 5.7 Hz, 4H), 2.12 (tt, J = 14.2, 5.7 Hz, 4H). Intermediate B-2: Methyl 3-bromo-4-(4,4-difluoropiperidin-1-yl)benzoate

[0560] To a stirred solution of methyl 3-bromo-4-fluorobenzoate (2.0 g, 8.6 mmol, BLD Pharma. Ltd.) and 4,4-difluoropiperidine hydrochloride (6.76 g, 42.9 mmol, BLD Pharma. Ltd.) in DMSO (20 mL) was added DIPEA (10.8 mL, 60 mmol, Sonia Industries Ltd.) at rt under N2atmosphere. The reaction mixture was stirred at 130 °C for 16 h in sealed tube. Then, the mixture was diluted with pet. ether (100 mL) and washed with ice cold water (2 ×30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0% to 5% EtOAc in hexanes to afford Intermediate B-2 (0.90 g, 2.7 mmol, 32% yield). m / z (ESI): 336.0 (M+2H)+.1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.19 (t, J = 5.5 Hz, 4H), 2.15 (tt, J = 14.1, 5.5 Hz, 4H). Intermediate B-3: 6-Chloro-5-(4,4-difluoropiperidin-1-yl)picolinic acid

[0561] To a stirred solution of 6-chloro-5-fluoropicolinic acid (500 mg, 2.9 mmol, Angene Ltd.), and 4,4-difluoropiperidine hydrochloride (2.25 g, 14.2 mmol, BLD Pharma. Ltd.) in DMSO (10 mL) was added DIPEA (2.5 mL, 14.2 mmol, Sonia Industries Ltd.). The reaction mixture was stirred and heated at 140 °C for 2 h under microwave radiation. Then, the reaction mixture was diluted with ice-cold water, and acidified with aq. HCl (1 N) to pH ~5. The solid suspension was stirred for another 30 min. The resulting precipitated solid was collected by filtration, washed with H2O (20 mL), and triturated with pet. ether (25 mL). The pet ether layer was decanted, and material was dried to get semi solid crude. The crude material was purified by reverse phase column chromatography (C18) with ACN / water (0- 60%) to afford Intermediate B-3 (300 mg, 3.0 mmol, 60% yield). m / z (ESI): 277.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 3.25 (t, J = 5.6 Hz, 4H), 2.16 (tt, J = 14.0, 5.6 Hz, 4H). Intermediate B-4: Methyl 5-bromo-6-(4,4-difluoropiperidin-1-yl)-2-methylnicotinate

[0562] To a stirred solution of methyl 5-bromo-6-chloro-2-methylnicotinate (2 g, 7.56 mmol, BLD Pharma Ltd.) and 4,4-difluoropiperidine hydrochloride (3.57 g, 22.7 mmol, BLD Pharma Ltd.) in DMSO (20 mL) was added DIPEA (6.6 mL, 38.8 mmol, Avra Pvt. Ltd) at rt under N2atmosphere. The reaction mixture was stirred at 130 °C for 2 h under microwaveradiation. Then, the reaction mixture was diluted with EtOAc (100 mL), washed with ice cold water (3 × 30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0% to 5% EtOAc in pet. ether to provide Intermediate B-4 (1.75 g, 5 mmol, 66% yield). m / z (ESI): 348.9 / 351.0 (1:1) (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 3.82 (s, 3H), 3.56 (t, J = 5.6 Hz, 4H), 2.62 (s, 3H), 2.15-2.05 (m, 4H). Intermediate B-5: Methyl 6-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carboxylate

[0563] To a stirred solution of methyl 5,6-dichloropyrazine-2-carboxylate (9.0 g, 43.5 mmol, Suzhou Sibian Chemical Technology) in DMF (135 mL) was added Cs2CO3 (42.5 g, 130 mmol, BLD Pharma. Ltd.) followed by 4,4-difluoropiperidine hydrochloride (8.22 g, 52 mmol, BLD Pharma. Ltd.) at rt. The reaction mixture was stirred at 50 °C for 3 h. Then, the reaction mixture was diluted with ice cold water (500 mL) and extracted with EtOAc (2 × 150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0% to 15% EtOAc in pet. ether, to provide Intermediate B-5 (11.9 g, 41 mmol, 94% yield). m / z (ESI): 292.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 3.87 (s, 3H), 3.77 – 3.73 (m, 4H), 2.14 (ddd, J = 14.2, 8.4, 5.9 Hz, 4H). Intermediate B-6: Methyl 6-chloro-5-(4,4-difluoropiperidin-1-yl)picolinate

[0564] To a stirred solution of methyl 6-chloro-5-fluoropicolinate (8.0 g, 42 mmol, BLD Pharma Ltd.) and 4,4-difluoropiperidine hydrochloride (9.98 g, 63 mmol, BLD Pharma Ltd.) in DMSO (80 mL) was added DIPEA (22.1 mL, 127 mmol, Sonia Industries Ltd.) at rt under N2 atmosphere. The reaction mixture was stirred at 90 °C for 16 h. Then, the reaction mixturewas cooled to 0 °C, and quenched with 1.5 N HCl. The resulting precipitated solid was collected by filtration,, washed with H2O (150 mL), and dried under vacuum to provide Intermediate B-6 (11.0 g, 38 mmol, 90% yield). m / z (ESI): 291.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 3.86 (s, 3H), 3.32-3.24 (m, 4H), 2.21-2.11 (m, 4H).

[0565] Intermediate compounds in Table 1-1 were prepared following a procedure described above for Intermediates B-1 – B-6, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 1-1Intermediate B-11: Methyl 6-bromo-5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine-2- carboxylate

[0566] Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine-2-carboxylate. To a stirred solution of methyl 5-chloro-3-methylpyrazine-2-carboxylate (4.0 g, 21 mmol, BLD Pharma. Ltd.) in DMSO (40 mL) was added 4,4-difluoropiperidine hydrochloride (10.1 g, 64.3 mmol, BLD Pharma. Ltd.) and DIPEA (18.7 mL g, 129 mmol, Avra Ltd.) at rt under N2 atmosphere. The reaction mixture was stirred at 130 °C for 3 h under microwave radiation. Then, the reaction mixture was diluted with EtOAc (100 mL) and washed with ice cold water (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0% to 6% EtOAc in hexanes, to provide methyl 5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine-2-carboxylate (4.9 g, 18 mmol, 84% yield). m / z (ESI): 272.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 3.87 (t, J = 5.8 Hz, 4H), 3.79 (s, 3H), 2.60 (s, 3H), 2.06 (tt, J = 14.1, 5.8 Hz, 4H).

[0567] Step 2: Methyl 6-bromo-5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine-2- carboxylate, Intermediate B-7. To a stirred solution of methyl 5-(4,4-difluoropiperidin-1-yl)- 3-methylpyrazine-2-carboxylate (6 g, 22 mmol) in DCM (60 mL) at 0 °C was added NBS (4.72 g, 26.5 mmol, Symax Pvt. Ltd.) under N2 atmosphere. The reaction mixture was warmed to rt and stirred for 4 h. Then, the reaction mixture was diluted with DCM (100 mL) and washed with H2O (60 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0% to 5% EtOAc in hexanes, to provide Intermediate B-11 (5.0 g, 14 mmol, 65% yield). m / z (ESI): 350.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 3.70 (dd, J = 6.8, 4.6 Hz, 4H), 2.62 (s, 3H), 2.14 (tt, J = 14.1, 5.7 Hz, 4H).

[0568] Intermediate compounds in Table 1-2 were prepared following a similar procedure described above for Intermediate B-11, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 1-2Intermediate B-13: Methyl 5-((2R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate Intermediate B-13-1: Methyl 5-((2R,3R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate Intermediate B-13-2: Methyl 5-((2R,3S)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate10% Pd / C H ,Intermediate B-13-1 Intermediate B-13-2Step 1: Benzyl (2R,3R)-3-hydroxy-2,3-dimethylazetidine-1-carboxylate, Intermediate B-13.1. To a stirred solution of benzyl (R)-2-methyl-3-oxoazetidine-1-carboxylate (20 g, 91 mmol) in THF (300 mL), was added methyl magnesium bromide (1M solution in THF, 137 mL, 137 mmol) at 0 °C, and stirred at 25 °C for 2 h. The reaction mixture was quenched with satd. aq. NH4Cl aq. (250 mL), extracted with EtOAc (3x 200 mL) and washed with water (100 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by chromatography eluting with a gradient of 5% to 15% EtOAc in hexanes to give benzyl (2R,3R)-3-hydroxy-2,3-dimethylazetidine-1- carboxylate, Intermediate B-13.1 (18 g, 77 mmol, 84% yield). m / z (ESI): 236.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.44 – 7.27 (m, 5H), 5.30 (s, 1H), 5.02 (s, 2H), 3.97 (q, J = 6.5 Hz, 1H), 3.70 (s, 2H), 1.32 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H).Step 2: (2R,3R)-2,3-Dimethylazetidin-3-ol, Intermediate B-13.2. To a solution of Intermediate B-13.1 (5 g, 21.25 mmol) in MeOH (50 mL) was added Pd / C (10%, 4.52 g) and stirred under hydrogen (1 atm) at 25 °C for 16 h. The reaction mixture was filtered through a celite bed and washed with MeOH (2x 50 mL). The filtrate was concentrated under reduced pressure to give (2R,3R)-2,3-dimethylazetidin-3-ol, Intermediate B-13.2 (2 g, 19.77 mmol, 93% yield). The compound was used for the next step without column purification. Step 3: Methyl 6-chloro-5-((2R,3R)-3-hydroxy-2,3-dimethylazetidin-1-yl)pyrazine-2- carboxylate, Intermediate B-13.3. To a stirred solution of methyl 5,6-dichloropyrazine-2- carboxylate (20.0 g, 97 mmol) in DMSO (200 mL) were added DIPEA (50.6 mL, 290 mmol) Intermediate B-13.2 (11.83 g, 117 mmol) at 25oC, and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with ice cold water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with brine solution (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0 to 30% EtOAc in hexanes) to give Intermediate B-13.3 (16 g, 58.9 mmol, 61% yield). m / z (ESI): 272.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 5.47 (s, 1H), 4.40 (d, J = 6.7 Hz, 1H), 4.27 (d, J = 10.3 Hz, 2H), 3.82 (s, 3H), 1.39 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H). Step 4: Methyl 6-(4-fluorophenyl)-5-((2R,3R)-3-hydroxy-2,3-dimethylazetidin-1- yl)pyrazine-2-carboxylate, Intermediate B-13.4. To a stirred solution of Intermediate B-13.3 (17 g, 62.6 mmol) in 1,4-dioxane (135 mL) and water (35 mL) were added (4- fluorophenyl)boronic acid (10.5 g, 75 mmol) and K3PO4 (21.8 g, 125 mmol) at rt. The reaction mixture was degassed and purged with nitrogen gas for 10 min. PdCl2(dppf)·CH2Cl2(5.11 g, 6.26 mmol) was added and the reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was cooled to rt and filtered through a celite bed. The filtrate was quenched with water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine solution (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0 to 30% EtOAc in hexanes) to Intermediate B-13.4 (17 g, 51.3 mmol, 82% yield). m / z (ESI): 332.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.67 – 7.57 (m, 2H), 7.39 – 7.29 (m, 2H), 5.30 (s, 1H), 3.83 (s, 3H), 3.56 (d, J = 9.4 Hz, 1H), 3.32 (d, J = 9.4 Hz, 2H), 1.22 – 1.10 (m, 6H). Step 5: Methyl 5-((2R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate B-13.5. To a stirred solution of Intermediate B-13.4 (17 g, 51.3 mmol) in DCM (200 mL) was added DAST (10.2 mL, 77mmol) at 0 °C, and reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with cold saturated aqueous ammonium chloride solution (100 mL) and extracted with DCM (2 × 200 mL). The combined organic layer was washed with brine solution (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0 to 15% EtOAc in hexanes) to give Intermediate B-13.5 (15.1 g, 45.3 mmol, 88% yield). m / z (ESI): 334.2 (M+H)+. Step 6: Methyl 5-((2R,3R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate B-13-1 and Methyl 5-((2R,3S)-3-fluoro- 2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylate, Intermediate B-13-2. Methyl 5-((2R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylate, Intermediate B-13.5 (15.1 g, 45.3 mmol) was purified by SFC using a Chiralpak IG (250 × 50) mm, column with a mobile phase of liquid CO2: [ACN:MeOH(1:1)] (60:40) and flow rate of 180 mL / min to give peak-1(Intermediate B-13-1, 8.8 g, 26.4 mmol, 58% yield) and peak-2 (Intermediate B-13-2, 2.3 g, 6.90 mmol, 15% yield). Methyl 5-((2R,3R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylate, Intermediate B-13-1. m / z (ESI): 334.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.68 – 7.60 (m, 2H), 7.41 – 7.31 (m, 2H), 4.38 – 4.26 (m, 1H), 3.85 (s, 3H), 3.73 – 3.60 (m, 1H), 3.50 (dd, J = 19.5, 10.4 Hz, 1H), 1.39 (d, J = 6.6 Hz, 3H), 1.28 (dd, J =

[0569] To a solution of but-3-en-2-amine hydrochloride (500 mg, 4.65 mmol, Enamine) and DIPEA (3.25 mL, 18.6 mmol, Sigma-Aldrich Inc.) in DCE (15 mL) was added 2- phenylethenesulfonyl chloride (942 mg, 4.65 mmol, Ark Pharm, Inc.), and the reaction wasstirred at rt for 20 h. The reaction was concentrated and purified by chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane, to provide Intermediate C-1 (905 mg, 3.8 mmol, 82% yield). m / z (ESI): 260.1 (M+Na)+.

[0570] Intermediate compounds in Table 1-3 were prepared following the procedure described for Intermediate C-1, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 1-3SECTION 2: Synthesis of Example Compounds METHOD A Example 1-001: N-(Ethenylsulfonyl)-5-((2R,3S)-3-fluoro-2-methyl-1-azetidinyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamideIntermediate 1-001.2Compound 1-001

[0571] Step 1: Methyl 5-((2R,3S)-3-fluoro-2-methylazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-001.1. To a solution of Intermediate A- 1 (200 mg, 0.64 mmol) and DIPEA (0.34 mL, 1.93 mmol, Sigma-Aldrich Inc.) in DMSO (3.2 mL) was added (2R,3S)-3-fluoro-2-methylazetidine hydrochloride (89 mg, 0.71 mmol, AA Blocks LLC), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc and quenched with sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine (1×). The combined organic extracts were dried over a plug of silica gel and Na2SO4and concentrated under vacuum to provide Intermediate 1-001.1, which was used directly for the next step. m / z (ESI): 320.2 (M+H)+.

[0572] Step 2: 5-((2R,3S)-3-Fluoro-2-methylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-001.2. To a solution of Intermediate 1-001.1 (203 mg, 0.636 mmol) in MeOH (4.0 mL) and H2O (0.2 mL) was added LiOH∙H2O (133 mg, 3.18 mmol, Combi-Blocks Inc.), and the reaction mixture was stirred at 50 °C for 30 min. Then, the reaction mixture was concentrated, dissolved in EtOAc, and quenched with 2N HCl. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with brine, dried over Na2SO4and concentrated to provide Intermediate 1-001.2, which was used directly for the next step. m / z (ESI): 306.1 (M+H)+.

[0573] Step 3: N-(Ethenylsulfonyl)-5-((2R,3S)-3-fluoro-2-methyl-1-azetidinyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide, Compound 1-001. To a solution of Intermediate 1- 001.2 (192 mg, 0.63 mmol), DIPEA (0.33 mL, 1.89 mmol, Sigma-Aldrich Inc.), T3P®(50 wt% in EtOAc) (1.12 mL, 1.89 mmol, Sigma-Aldrich Inc.), and DMAP (15 mg, 0.13 mmol,Sigma-Aldrich Inc.) in EtOAc (4.2 mL) was added ethenesulfonamide (74 mg, 0.69 mmol, Ambeed, Inc.) and stirred at 50 °C for 15 min. Then, the reaction mixture was quenched with satd. NH4Cl, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0%-50% EtOAc in heptane, to provide Compound 1-001 (123 mg, 0.31 mmol, 50% yield). m / z (ESI): 395.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.72 (br d, J = 4.6 Hz, 1H), 8.71 (s, 1H), 7.94 – 7.77 (m, 2H), 7.37 (t, J = 8.9 Hz, 2H), 7.08 (dd, J = 16.5, 9.8 Hz, 1H), 6.38 (d, J = 16.5 Hz, 1H), 6.26 (d, J = 10.0 Hz, 1H), 5.16 – 4.87 (m, 1H), 4.48 – 4.25 (m, 1H), 4.16 – 3.93 (m, 1H), 3.60 – 3.40 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -111.84 (s, 1F), -178.22 (s, 1F).

[0574] Example 1-002: N-(Ethenylsulfonyl)-5-((4R,6S)-6-fluoro-1-azaspiro[3.3]heptan-1- yl)-6-(4-fluorophenyl)-2-pyrazinecarboxamide.Intermediate 1-002.2 Compound 1-002

[0575] Step 1: Methyl 5-(6-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)pyrazine- 2-carboxylate, Intermediate 1-002.1. Intermediate A-1 (500 mg, 1.61 mmol), 6-fluoro-1- azaspiro[3.3]heptane hydrochloride (244 mg, 1.61 mmol, Enamine), DIPEA (0.84 mL, 4.82 mmol, Sigma-Aldrich Inc.), and DMSO (8 mL) were stirred at 80 °C for 1 h. The reaction mixture was diluted with EtOAc, and quenched with sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc (3 ×) and the combined organic extracts were washed with brine (1×), dried over a short plug of silica and Na2SO4, and concentrated. The crude material waspurified by chromatography, eluting with a gradient of 0%-50% EtOAc in heptane, to provide Intermediate 1-002.1 (490 mg, 1.42 mmol, 88% yield). m / z (ESI): 346.1 (M+H)+.

[0576] Step 2: 5-(6-Fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-002.2. To a solution of Intermediate 1-002.1 (490 mg, 1.42 mmol), MeOH (1.35 mL) and H2O (0.7 mL) was added LiOH∙H2O (298 mg, 7.09 mmol, Combi-Blocks Inc.), and the reaction mixture was stirred at 50 °C for 30 min. Then, the reaction mixture was concentrated, dissolved in EtOAc, and quenched with 2M HCl. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with sat. aq. NaHCO3and brine, then dried over Na2SO4and concentrated to provide Intermediate 1- 002.2, which was used directly for the next step. m / z (ESI): 332.2 (M+H)+.

[0577] Step 3: N-(Ethenylsulfonyl)-5-(6-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide, Compound 1-002-a. To a solution of Intermediate 1- 002.2 (268 mg, 0.81 mmol), DIPEA (0.43 mL, 2.4 mmol, TCI America), T3P®(50 wt% in EtOAc) (1.54 mL, 2.4 mmol, Sigma-Aldrich Inc.), and DMAP (20 mg, 0.16 mmol, Sigma- Aldrich Inc.) in EtOAc (5.4 mL) was added ethenesulfonamide (95 mg, 0.89 mmol, Ambeed, Inc.), and the reaction mixture was stirred at 50 °C for 15 min. Then, the reaction mixture was quenched with satd. NH4Cl, and the aqueous layer was extracted with EtOAc (2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0%-40% EtOAc in heptane, followed by reverse phase chromatography, eluting with a gradient of 0%- 100% ACN (0.1% TFA) in H2O (0.1% TFA). This was further purified by chromatography on a ISCO Redi-Sep 24 g column, eluting with a gradient of 0-50% EtOAc in heptane, to obtain Compound 1-002 (42 mg, 0.10 mmol, 7% yield). m / z (ESI): 421.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.51 (br s, 1H), 8.65 (s, 1H), 7.79 – 7.59 (m, 2H), 7.31 (t, J = 8.9 Hz, 2H), 7.07 (dd, J = 16.5, 10.0 Hz, 1H), 6.35 (d, J = 16.5 Hz, 1H), 6.24 (d, J = 10.0 Hz, 1H), 5.67 – 5.41 (m, 1H), 3.43 – 3.30 (m, 4H), 2.45 – 2.28 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -112.54 (s, 1F), -171.87 (s, 1F). Stereochemistry confirmed by X-Ray crystallography. Example 1-003: 5-(2,3-Dimethyl-1-azetidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-2- pyrazinecarboxamide; Example 1-003-1: 5-((2R,3S)-2,3-Dimethyl-1-azetidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamideIntermediate 1-003.2 Compound 1-003 Peak 3 Compound 1-003-1

[0578] Step 1: Methyl 5-(2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylate, Intermediate 1-003.1. To a solution of Intermediate A-1 (500 mg, 1.61 mmol) and DIPEA (0.84 mL, 4.82 mmol, Sigma-Aldrich Inc.) in DMSO (8 mL) was added 2,3- dimethylazetidine hydrochloride (210 mg, 1.73 mmol, Enamine), and the mixture was stirred at 80 °C for 1 h. Then, the reaction mixture was diluted with EtOAc, quenched with sat. aq. NH4Cl, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over a short plug of silica and Na2SO4, and concentrated to provide Intermediate 1-003.1, which was used directly for the next step. m / z (ESI): 316.2 (M+H)+.

[0579] Step 2: 5-(2,3-Dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylic acid, Intermediate 1-003.2. To a solution of Intermediate 1-003.1 (500 mg, 1.6 mmol) in MeOH (15 mL) and H2O (0.8 mL) was added LiOH∙H2O (333 mg, 7.93 mmol, Combi-Blocks Inc.), and the reaction mixture was stirred at 50 °C for 30 min. Then, the reaction mixture was concentrated, diluted in EtOAc, and quenched with 2N HCl. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with sat. aq. NaHCO3, brine, dried over Na2SO4 and concentrated to provide Intermediate 1-003.2, which was used directly for the next step. m / z (ESI): 302.4 (M+H)+.

[0580] Step 3: 5-(2,3-Dimethyl-1-azetidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-2- pyrazinecarboxamide, Compound 1-003. To a solution of Intermediate 1-003.2 (478 mg, 1.586 mmol), DMAP (39 mg, 0.32 mmol, Sigma-Aldrich Inc.), DIPEA (0.83 mL, 4.8 mmol, Sigma-Aldrich Inc.), and T3P®(50 wt% in EtOAc) (2.83 mL, 4.76 mmol, Sigma-Aldrich Inc.) in EtOAc (10 mL) was added ethenesulfonamide (187 mg, 1.75 mmol, Ambeed, Inc.).The reaction mixture was allowed to stir at 50 °C for 20 min. Then, the reaction mixture was cooled to rt, quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-50% EtOAc in heptane, to provide Compound 1-003 (424 mg, 1.09 mmol, 69% yield). m / z (ESI): 391.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.76 – 11.39 (m, 1H), 8.68 – 8.61 (m, 1H), 7.90 – 7.78 (m, 2H), 7.35 (t, J = 8.9 Hz, 2H), 7.08 (dd, J = 16.5, 10.0 Hz, 1H), 6.37 (d, J =16.5 Hz, 1H), 6.25 (d, J = 9.8 Hz, 1H), 3.93 (quin, J = 6.1 Hz, 1H), 3.82 (t, J = 8.8 Hz, 1H), 2.96 (dd, J = 8.9, 6.2 Hz, 1H), 2.30 – 2.15 (m, 1H), 1.30 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.26 (s, 1F).

[0581] Compound 1-003 was purified by SFC. The first SFC purification was performed using a Chiralcel OX, 2 × 25 cm, 5 µm column with a mobile phase of 25% iPrOH using a flowrate of 80 mL / min to generate (1) a 1steluting isomer, (2) a mixture of a 2ndeluting isomer and a 3rdeluting isomer, and (3) a 4theluting isomer. The mixture of the 2ndeluting isomer and 3rdeluting isomer was purified by SFC using a ChiralPak IE, 2 × 25 cm, 5 um column with a mobile phase of 45% iPrOH using a flowrate of 80 mL / min. to generate the 2ndeluting isomer and the 3rdeluting isomer. The stereochemistry of the 3rdeluting isomer was assigned arbitrarily to be 5-((2R,3S)-2,3-dimethyl-1-azetidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide (Compound 1-003-1) (123 mg, 0.32 mmol, 29% yield). m / z (ESI): 391.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.64 (br s, 1H), 8.66 (s, 1H), 7.93 – 7.77 (m, 2H), 7.35 (t, J = 9.0 Hz, 2H), 7.08 (dd, J = 16.5, 9.8 Hz, 1H), 6.36 (d, J = 16.5 Hz, 1H), 6.25 (d, J = 9.8 Hz, 1H), 3.97 – 3.76 (m, 2H), 2.96 (dd, J = 8.8, 6.3 Hz, 1H), 2.29 – 2.16 (m, 1H), 1.30 (d, J = 6.1 Hz, 3H), 1.10 – 1.04 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.26 (s, 1F). Example 1-004: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-2- pyrazinecarboxamideIntermediate A-1 Intermediate 1-004.1Intermediate 1-004.2 Compound 1-004

[0582] Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylate, Intermediate 1-004.1. To a solution of Intermediate A-1 (37 g, 119 mmol) and DIPEA (104 mL, 595 mmol) in DMSO (370 mL) was added 4,4-difluoropiperidine hydrochloride (28.1 g, 178 mmol), and the reaction mixture was stirred at rt for 16 h. Then, the reaction mixture was diluted with ice cold water (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with brine (3 × 500 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 20-30% EtOAc in hexanes, to provide Intermediate 1-004.1 (38 g, 108 mmol, 91% yield). m / z (ESI): 352.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.91 - 7.87 (m, J = 8.4 Hz, 2H), 7.38 - 7.34 (t, J = 9.2 Hz, 2H), 3.87 (s, 3H), 3.66 - 3.41 (m, 4H), 2.04 - 1.94 (m, 4H).

[0583] Step 2: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylic acid, Intermediate 1-004.2. To a stirred solution of Intermediate 1-004.1 (59 g, 170 mmol) in THF (590 mL) and H2O (295 mL) was added LiOH∙H2O (35.2 g, 840 mmol), and the reaction mixture was stirred at 25 °C for 1 h. Then, the reaction mixture was concentrated, diluted with ice cold water, quenched with 1.5 N HCl solution. The resulting solids were collected by filtration, and dried under vacuum to provide Intermediate 1-004.2 (54 g, 160 mmol, 95% yield). m / z (ESI): 338.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 8.70 (s, 1H), 7.8 – 8.0 (m, 2H), 7.36 (t, J=8.9 Hz, 2H), 3.38 (dd, J=6.9, 4.5 Hz, 4H), 2.00 (td, J=13.6, 6.5 Hz, 4H).

[0584] Step 3: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-2- pyrazinecarboxamide, Compound 1-004. To a solution of Intermediate 1-004.2 (400 mg, 1.19 mmol), T3P®(50 wt.% in EtOAc) (2.11 mL, 3.56 mmol, Sigma-Aldrich Inc.), DIPEA (0.62 mL, 3.56 mmol, Sigma-Aldrich Inc.), and DMAP (29 mg, 0.24 mmol, Sigma-Aldrich Inc.) in EtOAc (8 mL) was added ethenesulfonamide (0.125 mL, 1.54 mmol, Ambeed, Inc.), and the reaction was stirred at 50 °C for 10 min. The reaction mixture was concentrated and purified by chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane, to provide Compound 1-004 (386 mg, 0.91 mmol, 76% yield). m / z (ESI): 427.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.88 (br s, 1H), 8.69 (s, 1H), 8.19 – 8.08 (m, 2H), 7.42 – 7.31 (m, 2H), 7.09 (dd, J = 16.5, 10.0 Hz, 1H), 6.38 (d, J = 16.5 Hz, 1H), 6.27 (d, J = 9.8 Hz, 1H), 3.47 – 3.37 (m, 4H), 2.09 – 1.87 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -95.42 (br s, 2F), -111.63 (s, 1F). Example 1-005: N-(Ethenylsulfonyl)-6-(4-fluorophenyl)-5-(methyl(1- methylcyclobutyl)amino)-2-pyrazinecarboxamideIntermediate A-1 Intermediate 1-005.1Intermediate 1-005.2 Compound 1-005

[0585] Step 1: Methyl 6-(4-fluorophenyl)-5-(methyl(1-methylcyclobutyl)amino)pyrazine- 2-carboxylate, Intermediate 1-005.1. To a stirred mixture of Intermediate A-1 (300 mg, 0.96 mmol) and N,1-dimethylcyclobutan-1-amine hydrochloride (170 mg 1.25 mmol, Enamine) in DMA (2 mL) at rt under N2atmosphere was added DIPEA (0.5 mL, 2.86 mmol, Sigma- Aldrich Inc.), and the resulting mixture was stirred at 85 °C for 18 h. Then, the mixture was purified by chromatography, eluting with a gradient of 0-40% EtOAc in heptane, to provide Intermediate 1-005.1 (105 mg, 0.319 mmol, 33% yield). m / z (ESI): 330.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.73 (dd, J = 9.0, 5.4 Hz, 2H), 7.16 (t, J = 8.7 Hz, 2H),3.96 (s, 3H), 2.41 (s, 3H), 2.30 – 2.13 (m, 4H), 1.95 – 1.74 (m, 2H), 1.54 (s, 3H).19F NMR (376 MHz, CDCl3) δ -111.85 – -114.35 (m, 1F).

[0586] Step 2: Lithium 6-(4-fluorophenyl)-5-(methyl(1-methylcyclobutyl)amino)pyrazine- 2-carboxylate, Intermediate 1-005.2. To a stirred mixture of Intermediate 1-005.1 (100 mg, 0.3 mmol) in MeOH (3 mL) at rt was added LiOH (1 N in H2O) (0.7 mL, 0.7 mmol, Sigma- Aldrich Inc.). The resulting mixture was stirred at rt for 22 h, then concentrated to provide Intermediate 1-005.2, which was used directly for the next step. m / z (ESI): 316.0 (M+H)+.

[0587] Step 3: N-(Ethenylsulfonyl)-6-(4-fluorophenyl)-5-(methyl(1- methylcyclobutyl)amino)-2-pyrazinecarboxamide, Compound 1-005. To a stirred mixture of Intermediate 1-005.2 (50 mg, 0.16 mmol), DMAP (3 mg, 0.03 mmol, Sigma-Aldrich Inc.) and DIPEA (0.10 mL, 0.57 mmol, Sigma-Aldrich Inc.) at rt was added ethenesulfonamide (0.5 M in EtOAc) (0.4 mL, 0.20 mmol, Ambeed, Inc.) and T3P®(50 wt% in EtOAc) (0.30 mL, 0.51 mmol, Sigma-Aldrich Inc.). The resulting mixture was stirred at 55 °C for 1 h. The reaction mixture was quenched with sat. aq. solution of NH4Cl (3 mL) and extracted with EtOAc (3 × 2 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-70% acetone in heptane, to provide Compound 1-005 (39 mg, 0.096 mmol, 62% yield). m / z (ESI): 405.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.75 (s, 1H), 7.64 (dd, J = 8.8, 5.2 Hz, 2H), 7.21 (t, J = 8.6 Hz, 2H), 6.95 (dd, J = 16.5, 9.8 Hz, 1H), 6.60 (d, J = 16.7 Hz, 1H), 6.17 (d, J = 10.0 Hz, 1H), 2.43 (s, 3H), 2.30 – 2.15 (m, 4H), 1.95 – 1.76 (m, 2H), 1.53 (s, 3H).19F NMR (376 MHz, CDCl3) δ -111.27 – -112.04 (m, 1F). Example 1-006: N-(Ethenylsulfonyl)-6-(4-fluorophenyl)-5-((1-methylcyclopentyl)amino)-2- pyrazinecarboxamideIntermediate A-1 Intermediate 1-006.1Intermediate 1-006.2 Compound 1-006

[0588] Step 1: Methyl 6-(4-fluorophenyl)-5-((1-methylcyclopentyl)amino)pyrazine-2- carboxylate, Intermediate 1-006.1. To a stirred mixture of Intermediate A-1 (300 mg, 0.96 mmol) and 1-methylcyclopentan-1-amine hydrochloride (170 mg, 1.25 mmol, ChemBridge) in DMA (4 mL) under N2 atmosphere was added DIPEA (0.51 mL, 2.9 mmol, Sigma-Aldrich Inc.) at rt. The reaction mixture was stirred at 80 °C for 72 h. The reaction was quenched by sat. aq. NH4Cl solution (4 mL), and diluted with EtOAc (15 mL). The mixture was washed with H2O (2 × 3 mL), and the combined aqueous phase was extracted using EtOAc (3 mL). The combined organic extracts were washed with brine, dried using Na2SO4, and concentrated. The residue was purified by chromatography, eluting with a gradient of 5-60% EtOAc in heptane, to provide Intermediate 1-006.1 (80 mg, 25% yield). m / z (ESI): 330.2 (M+H)+.

[0589] Step 2: Lithium 6-(4-fluorophenyl)-5-((1-methylcyclopentyl)amino)pyrazine-2- carboxylate, Intermediate 1-006.2. To a stirred mixture of Intermediate 1-006.1 (80 mg, 0.24 mmol) in MeOH (3 mL) and THF (1 mL) at rt was added LiOH (1 N aq. solution) (0.5 mL, 0.5 mmol, Sigma-Aldrich Inc.), and the resulting mixture was stirred at rt for 16 h. The mixture was concentrated to provide Intermediate 1-006.2, which was used directly for the next step. m / z (ESI): 316.0 (M+H)+.

[0590] Step 3: N-(Ethenylsulfonyl)-6-(4-fluorophenyl)-5-((1-methylcyclopentyl)amino)-2- pyrazinecarboxamide, Compound 1-006. To a stirred mixture of Intermediate 1-006.2 (70 mg, 0.22 mmol) and DMAP (27 mg, 0.22 mmol, Sigma-Aldrich Inc.) at rt was added ethenesulfonamide (0.5 M in EtOAc) (0.5 mL, 0.3 mmol, Ambeed, Inc.), DIPEA (0.15 mL, 0.859 mmol, Sigma-Aldrich Inc.), and T3P®(50 wt% in EtOAc) (0.45 mL, 0.76 mmol,Sigma-Aldrich Inc.). The resulting mixture was stirred at 55 °C for 2 h. Then, the reaction mixture was diluted with sat. aq. NH4Cl solution (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 5- 60% acetone in heptane, to provide Compound 1-006 (4 mg, 5% yield). m / z (ESI): 405.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.82 – 9.48 (m, 1H), 8.87 – 8.75 (m, 1H), 7.60 (dd, J = 8.6, 5.2 Hz, 2H), 7.32 – 7.23 (m, 2H), 6.95 (dd, J = 16.6, 9.9 Hz, 1H), 6.59 (d, J = 16.5 Hz, 1H), 6.17 (d, J = 10.0 Hz, 1H), 5.43 (s, 1H), 2.04 – 1.68 (m, 8H), 1.54 (s, 3H).19F NMR (376 MHz, CDCl3) δ -103.86 – -111.76 (m, 1F). Example 1-089-1: (R)-5-(2-((Difluoromethoxy)methyl)-3,3-difluoroazetidin-1-yl)-6-(4- fluorophenyl)-N-(vinylsulfonyl)pyrazine-2-carboxamideIntermediate 1-089.2 Intermediate 1-089.3Peak 1 Compound 1-089 Compound 1-089-1Step 1: Methyl 5-(3,3-difluoro-2-(hydroxymethyl)azetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-089.1. To a solution of Intermediate A- 1 (1.4 g, 4.5 mmol) and DIPEA (1.57 mL, 9.0 mmol) in DMSO (6 mL) was added (3,3- difluoroazetidin-2-yl)methanol TFA (0.66 g, 5.40 mmol, PharmaBlock, Inc.). The reaction mixture was stirred at 40 °C for 24 h. The crude material was purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, to provide Intermediate 1-089.1 (1.1 g, 3.11 mmol, 69% yield). m / z (ESI): 354.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.70 – 7.61 (m, 2H), 7.25 – 7.18 (m, 2H), 4.90 – 4.79 (m, 1H), 4.04 (br d, J = 5.6 Hz, 2H), 4.00 (s, 3H), 3.95 (dd, J = 10.9, 1.7 Hz, 1H), 3.82 – 3.77 (m, 1H), 3.65 (dt, J = 12.9, 11.4 Hz, 1H). Step 2: Methyl 5-(2-((difluoromethoxy)methyl)-3,3-difluoroazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-089.2. To a stirred mixture of Intermediate 1-089.1 (0.56 g, 1.58 mmol) in DCM (1 mL) and water (1 mL) at rt was added potassium bifluoride (0.49 g, 6.34 mmol) and trimethyl(bromoditrifluoromethyl)silane (0.74 mL, 4.76 mmol). The resulting mixture was stirred at rt for 24 h. The reaction mixture was diluted with brine and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of 0-100% EtOAc in heptane, to provide Intermediate 1-089.1 (0.37 g, 0.92 mmol, 58% yield). m / z (ESI): 404.1 (M+H)+.1H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H), 7.68 (dd, J = 8.8, 5.3 Hz, 2H), 7.23 – 7.19 (m, 2H), 6.28 (s, 1H), 4.96 – 4.84 (m, 1H), 4.34 – 4.21 (m, 2H), 4.00 (s, 3H), 3.99 – 3.93 (m, 1H), 3.64 (s, 1H). Step 3: 5-(2-((Difluoromethoxy)methyl)-3,3-difluoroazetidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylic acid, Intermediate 1-089.3. To a solution of Intermediate 1-089.2 (0.37 g, 0.92 mmol) in THF (6 mL) and H2O (2 mL) at rt was added LiOH∙H2O (192 mg, 4.59 mmol), and the resulting mixture stirred at 40 °C for 3 h. Then, the reaction mixture was concentrated and purified by chromatography on silica gel, eluting with a gradient of 0- 100% EtOAc in heptane, to provide Intermediate 1-089.3 (0.35 g, 0.90 mmol, 98% yield). m / z (ESI): 390.1 (M+H)+. Step 4: 5-(2-((Difluoromethoxy)methyl)-3,3-difluoroazetidin-1-yl)-6-(4- fluorophenyl)-N-(vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-089. To a stirred mixture of Intermediate 1-089.3 (130 mg, 0.33 mmol) and DIPEA (0.29 mL, 1.67 mmol, Sigma-Aldrich Inc.) in EtOAc (3 mL) at rt was added T3P®(50 wt% in EtOAc) (0.60 mL,1.00 mmol, Sigma-Aldrich Inc.) and the mixture was stirred at rt for 30 min. Then ethenesulfonamide (71 mg.0.67 mmol) was added. The resulting mixture was stirred at rt for 2 h. Then, the reaction mixture was diluted with sat. aq. NH4Cl solution (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, to provide Compound 1-089 (70 mg, 0.15 mmol. 44% yield). m / z (ESI): 479.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.99 (br s, 1H), 8.77 – 8.69 (m, 1H), 7.79 (br t, J = 6.2 Hz, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.05 (dd, J = 16.7, 10.0 Hz, 1H), 6.76 (t, J = 74.8 Hz, 1H), 6.27 – 5.79 (m, 2H), 4.92 – 4.79 (m, 1H), 4.30 – 4.10 (m, 2H), 3.97 – 3.82 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -81.93 – -85.02 (m, 2F), - 95.31 – -99.90 (m, 1F), -110.03 – -114.07 (m, 2F). Compound 1-089 was purified by SFC using a ChromegaChiral OX, 2 × 25 cm, 5 µm column with a mobile phase of 40% MeOH using a flowrate of 100 mL / min to generate (1) a 1steluting isomer, (2) a mixture of a 2ndeluting isomer. The stereochemistry of the 1steluting isomer was assigned arbitrarily to be (R)-5-(2-((difluoromethoxy)methyl)-3,3- difluoroazetidin-1-yl)-6-(4-fluorophenyl)-N-(vinylsulfonyl)pyrazine-2-carboxamide (Compound 1-089-1) (22 mg, 0.05 mmol, 40% yield). m / z (ESI): 479.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.98 (br s, 1H), 8.76 (s, 1H), 7.89 (dd, J = 8.7, 5.5 Hz, 2H), 7.39 (t, J = 8.9 Hz, 2H), 7.09 (dd, J = 16.5, 10.0 Hz, 1H), 6.76 (t, J = 74.8 Hz, 1H), 6.43 – 6.16 (m, 2H), 5.01 – 4.79 (m, 1H), 4.33 – 4.25 (m, 1H), 4.17 (dd, J = 11.1, 7.7 Hz, 1H), 4.02 – 3.87 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -83.17 – -84.25 (m, 2F), -97.55 (br d, J = 200.3 Hz, 1F), -110.06 – -112.34 (m, 2F).

[0591] Compounds in Table 2-1 were prepared following the procedure described in Method A, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-11 11Method B Example 1-041: (5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazin-2-yl)(3-methyl- 1,1-dioxidoisothiazol-2(3H)-yl)methanone; Example 1-041-1: (R)-(5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazin-2-yl)(3- methyl-1,1-dioxidoisothiazol-2(3H)-yl)methanoneIntermediate 1-041.1Peak 2 Compound 1-041 Compound 1-041-1

[0592] Step 1: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carbonyl chloride, Intermediate 1-041.1. To a mixture of Intermediate 1-004.2 (1 g, 3 mmol) in DCE (10 mL) was added oxalyl chloride (2M in DCM) (7.41 mL, 14.8 mmol, Sigma-Aldrich Inc.) followed by a couple drops of DMF, and stirred for 5 min at rt. Then, the reaction was heated to 80 °C and stirred for 18 h. The reaction was concentrated and purified by chromatography,eluting with a gradient of 0-100% EtOAc in heptane, to provide Intermediate 1-041.1 (860 mg, 2.42 mmol, 82% yield). m / z (ESI): 355.9 (M+H)+.1H NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H) 7.88 (t, J = 6.49 Hz, 1H) 7.22 (t, J = 7.96 Hz, 1H) 3.64 - 3.56 (m, 2H) 2.06 - 1.94 (m, 2H).

[0593] Step 2: (E)-N-(But-3-en-2-yl)-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-N- (styrylsulfonyl)pyrazine-2-carboxamide, Intermediate 1-041.2. To a solution of Intermediate C-1 (61 mg, 0.26 mmol) in THF (2.6 mL) at 0 °C was added NaH (15.3 mg, 0.38 mmol, Sigma-Aldrich Inc.60% in mineral oil), and the reaction mixture was stirred at rt for 30 min. Then, Intermediate 1-041.1 (100 mg, 0.28 mmol) was added, and the reaction was stirred at rt for 2 h. The reaction was quenched with sat. NaHCO3(5 mL), diluted with brine (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, to provide Intermediate 1-041.2. m / z (ESI): 556.9 (M+H)+.1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 7.83 – 7.77 (m, 2H), 7.57 – 7.51 (m, 1H), 7.50 – 7.41 (m, 2H), 7.40 – 7.35 (m, 2H), 7.25 – 7.12 (m, 4H), 6.21 (ddd, J = 17.2, 10.4, 5.6 Hz, 1H), 5.29 (d, J = 17.3 Hz, 1H), 5.19 (dd, J = 10.3, 1.1 Hz, 1H), 4.72 (dd, J = 6.9, 5.6 Hz, 1H), 3.46 – 3.40 (m, 4H), 2.02 – 1.92 (m, 4H), 1.73 (d, J = 6.9 Hz, 3H).

[0594] Step 3: (5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazin-2-yl)(3-methyl- 1,1-dioxidoisothiazol-2(3H)-yl)methanone, Compound 1-041. To a solution of Intermediate 1-041.2 (140 mg, 0.25 mmol) in trifluorotoluene (8.4 mL) was added Grubbs Catalyst M 202 (48 mg, 0.05 mmol, Strem Chemicals, Inc.), and the mixture was heated to 90 °C for 18 h. The reaction mixture was concentrated and purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, to provide Compound 1-041 (71 mg, 0.16 mmol, 63% yield). m / z (ESI): 453.0 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 8.67 (s, 1H), 8.07 – 7.98 (m, 2H), 7.38 – 7.28 (m, 3H), 7.21 (dd, J = 7.1, 2.9 Hz, 1H), 5.60 – 5.52 (m, 1H), 3.48 – 3.35 (m, 4H), 2.07 – 1.93 (m, 4H), 1.33 (d, J = 6.7 Hz, 3H).19F NMR (DMSO-d6, 376 MHz) δ - 95.44 (br s, 2F), -111.64 (s, 1F).

[0595] Compound 1-041 was purified by SFC using a ChiralPak IB, 2 × 25 cm 5 µm column with a mobile phase of 20% iPrOH using a flowrate of 80 mL / min to generate to obtain a 1steluting isomer and a 2ndeluting isomer. The stereochemistry of the 2ndeluting isomer was assigned arbitrarily to be (R)-(5-(4,4-difluoropiperidin-1-yl)-6-(4- fluorophenyl)pyrazin-2-yl)(3-methyl-1,1-dioxidoisothiazol-2(3H)-yl)methanone (Compound 1-041-1) (29 mg, 0.06 mmol, 44% yield). m / z (ESI): 453.0 (M+H)+.1H NMR (400 MHz,DMSO-d6) δ 8.68 (s, 1H), 8.07 – 7.99 (m, 2H), 7.39 – 7.30 (m, 3H), 7.22 (dd, J = 7.1, 2.9 Hz, 1H), 5.57 (br d, J = 6.5 Hz, 1H), 3.51 – 3.36 (m, 4H), 2.13 – 1.92 (m, 4H), 1.34 (d, J = 6.7 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -95.43 (br s, 2F), -111.64 (s, 1F).

[0596] Compounds in Table 2-2 were prepared following the procedure described in Method B, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-2Method C Example 1-046: (1,1-Dioxido-1,2-thiazol-2(3H)-yl)(4-(4-fluorophenyl)-5-(2-thiophenyl)-2- pyrimidinyl)methanoneStep 9

[0597] Step 1: 1-(4-Fluorophenyl)-2-(thiophen-2-yl)ethan-1-one, Intermediate 1-046.1. To the solution of 2-(thiophen-2-yl)acetic acid (9 g, 63.3 mmol) and methyl 4-fluorobenzoate (9.76 g, 63.3 mmol) in DMF (25 mL) was added LiHMDS (1 M in THF, 253 mL, 253 mmol) at -10 °C under N2 atmosphere and stirred for 3 h at same temperature. The reaction mixture was quenched with satd. aq. solution of NH4Cl (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with chilled water (2 × 150 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography eluting with a gradient of 0% to 10% EtOAc in hexanes, to provide Intermediate 1-046.1 (8 g, 36.3 mmol, 57% yield). m / z (ESI): no ionization.1H NMR (400 MHz, DMSO-d6) δ 8.16 – 8.13 (m, 2H), 7.42 – 7.36 (m, 3H), 6.98 (m, 2H), 4.65 (s, 2H).

[0598] Step 2: (E)-3-(Dimethylamino)-1-(4-fluorophenyl)-2-(thiophen-2-yl)prop-2-en-1- one, Intermediate 1-046.2. To the solution of Intermediate 1-046.1 and 1,1-dimethoxy-N,N-dimethylmethanamine (48.3 mL, 363 mmol) in toluene (160 mL) was added p-toluene sulfonic acid monohydrate (0.691 g, 3.63 mmol) at rt under N2 atmosphere and stirred for 3 h at 100 °C. The reaction mixture was concentrated directly under vacuum and residue was quenched with 10% NaHCO3 solution (25 mL) and extracted with EtOAc (2 × 150 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography eluting with a gradient of 15% to 40% EtOAc in hexanes, to give Intermediate 1-046.2 (8 g, 29.1 mmol, 80% yield). m / z (ESI): 276.2 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 7.47 – 7.38 (m, 4H), 7.18 – 7.10 (m, 2H), 6.98 (dd, J = 5.2, 3.5 Hz, 1H), 6.78 (dd, J = 3.5, 1.2 Hz, 1H), 2.80 (s, 6H).

[0599] Step 3: 4-(4-Fluorophenyl)-2-(methylthio)-5-(thiophen-2-yl)pyrimidine, Intermediate 1-046.3. To the solution of Intermediate 1-046.2 (6.8 g, 24.70 mmol) and thiourea (2.82 g, 37.0 mmol) in EtOH (136 mL) was added potassium tert-butoxide (5.54 g, 49.4 mmol) at rt under N2 atmosphere and stirred for 1 h at 80 °C. The reaction mixture was cooled to 0 °C and methyl iodide (2.32 mL, 37.0 mmol) in DCM (5 mL) was added dropwise, then stirred for 1 h at 0 °C. The reaction mixture was diluted with sat. NH4Cl solution (25 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography eluting with a gradient of 0% to 10% EtOAc in hexanes, to provide Intermediate 1-046.3 (6 g, 19.8 mmol, 80% yield). m / z (ESI): 303.0 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 8.77 (s, 1H), 7.62 (dd, J = 5.1, 1.2 Hz, 1H), 7.58 – 7.50 (m, 2H), 7.33 – 7.21 (m, 2H), 7.15 (dd, J = 3.5, 1.3 Hz, 1H), 7.09 (dd, J = 5.1, 3.6 Hz, 1H), 2.59 (s, 3H).

[0600] Step 4: 4-(4-Fluorophenyl)-2-(methylsulfonyl)-5-(thiophen-2-yl)pyrimidine, Intermediate 1-046.4. To the solution of Intermediate 1-046.3 (4 g, 13.23 mmol) in DCM (80 mL) at 0 °C was added m-CPBA (6.85 g, 39.7 mmol) and allow to stir at 0 °C to rt for 16 h. The reaction mixture was diluted with water (50mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed with 10% NaOH solution (50 mL) followed by sat. sodium sulphite solution (50 mL), brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by chromatography eluting with a gradient of 0% to 35% EtOAc in hexanes, to provide Intermediate 1-046.4 (3.5 g, 10.47 mmol, 79% yield). m / z (ESI): 335.2 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 9.23 (s, 1H), 7.75 (dd, J = 5.1, 1.2 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.41 – 7.28 (m, 3H), 7.17 (dd, J = 5.1, 3.6 Hz, 1H), 3.48 (s, 3H).

[0601] Step 5: 4-(4-Fluorophenyl)-5-(thiophen-2-yl)pyrimidin-2-ol, Intermediate 1-046.5. To a solution of Intermediate 1-046.4 (4 g, 11.96 mmol) in THF (80 mL) and water (40 mL) at 0 °C was added KOH (3.36 g, 59.8 mmol) and allowed to stir at 25 °C for 4 h. The reaction mixture was diluted with water (15 mL) and the pH was adjusted to 2 with 1.5 N HCl (10 mL). The solution was extracted with DCM: MeOH (90:10) (3 × 25 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide Intermediate 1-046.5 (3.0 g, 11.02 mmol, 92% yield). m / z (ESI): 273.0 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 12.35 (br s, 1H), 8.31 (s, 1H), 7.56 – 7.42 (m, 3H), 7.31 – 7.16 (m, 2H), 7.00 (dd, J = 5.1, 3.5 Hz, 1H), 6.96 (dd, J = 3.5, 1.3 Hz, 1H).

[0602] Step 6: 2-Bromo-4-(4-fluorophenyl)-5-(thiophen-2-yl)pyrimidine, Intermediate 1- 046.6 To a stirred solution of Intermediate 1-046.5 (3 g, 11.02 mmol) in toluene (60.0 mL) was added phosphorus oxybromide (12.63 g, 44.1 mmol) and the reaction mixture was stirred at 100 °C for 16 h. After cooling down to rt, the mixture was diluted with sat. NaHCO3 solution (25 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with satd NaCl (25 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography eluting with a gradient of 0% to 10% EtOAc in hexanes, to provide Intermediate 1-046.6 (3.0 g, 8.95 mmol, 81% yield). m / z (ESI): 336.0 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 8.86 (s, 1H), 7.68 (dd, J = 5.1, 1.2 Hz, 1H), 7.57 – 7.46 (m, 2H), 7.34 – 7.22 (m, 3H), 7.12 (dd, J = 5.1, 3.6 Hz, 1H).

[0603] Step 7: Methyl 4-(4-fluorophenyl)-5-(thiophen-2-yl)pyrimidine-2-carboxylate, Intermediate 1-046.7. A small autoclave was charged with Intermediate 1-046.6 (3.0 g, 8.95 mmol), DMA (30 mL), MeOH (60 mL), dppf (0.744 g, 1.34 mmol), NaOAc (1.47 g, 17.90 mmol), and Pd(OAc)2(0.301 g, 1.34 mmol). The mixture was flushed with N2 gas twice and stirred under CO gas atmosphere (50 psi) at 90 °C for 16 h. The reaction mixture was filtered through a celite bed, washed with MeOH (2 × 20 mL), and concentrated in vacuo. The crude material purified by chromatography eluting with a gradient of 0% to 30% EtOAc in hexanes, to provide Intermediate 1-046.7 (1.8 g, 5.73 mmol, 64% yield). m / z (ESI): 315.2 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 9.16 (s, 1H), 7.72 (dd, J = 5.1, 1.2 Hz, 1H), 7.61 – 7.50 (m, 2H), 7.37 – 7.26 (m, 3H), 7.14 (dd, J = 5.1, 3.7 Hz, 1H), 3.94 (s, 3H).

[0604] Step 8: 4-(4-Fluorophenyl)-5-(thiophen-2-yl)pyrimidine-2-carboxylic acid, Intermediate 1-046.8. To a solution of Intermediate 1-046.7 (1.8 g, 5.73 mmol) in THF (18mL), EtOH (9 mL), and water (9 mL) was added lithium hydroxide hydrate (1.20 g, 28.6 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated directly under vacuum and diluted with 1.5 N HCl (pH ~3) to get precipitation. The solid was filtered, washed with 10 mL chilled water, then dried under vacuum to obtain a solid which was then triturated with pentane and dried again under vacuum to provide Intermediate 1-046.8 (1.2 g, 4.00 mmol, 70% yield). m / z (ESI): 301.2 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 13.70 (br s, 1H), 9.12 (s, 1H), 7.71 (dd, J = 5.0, 1.2 Hz, 1H), 7.64 – 7.46 (m, 2H), 7.39 – 7.26 (m, 3H), 7.14 (dd, J = 5.1, 3.6 Hz, 1H).

[0605] Step 9: (1,1-Dioxidoisothiazol-2(3H)-yl)(4-(4-fluorophenyl)-5-(thiophen-2- yl)pyrimidin-2-yl)methanone, Compound 1-046. To a solution of Intermediate 1-046.8 (100 mg, 0.33 mmol) in DCM (1 mL) at 0 °C was added oxalyl chloride (2 M in DCM) (0.50 mL, 1.0 mmol, Sigma-Aldrich Inc.). The reaction mixture was stirred for 1 h and concentrated under vacuum. A mixture of 2,3-dihydroisothiazole 1,1-dioxide (79 mg, 0.67 mmol, Enamine) and Cs2CO3 (434 mg, 1.33 mmol, Ambeed, Inc.) in ACN (1 mL) was added, and the reaction mixture was stirred for 1 h at 60 °C. Then, the reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified with prep HPLC, eluting with a gradient of 0-100% ACN in H2O (with 0.1% TFA). The combined product fractions were basified with sat. NaHCO3, filtered, and concentrated to provide Compound 1-046 (12 mg, 0.03 mmol, 9% yield). m / z (ESI): 401.9 (M+H)+.1H NMR (CDCl3, 400 MHz) δ 9.00 (s, 1H), 7.7 - 7.8 (m, 2H), 7.46 (dd, J = 1.7, 4.6 Hz, 1H), 7.0 - 7.1 (m, 4H), 6.98 (td, J = 2.5, 7.3 Hz, 1H), 6.78 (td, J = 2.2, 7.3 Hz, 1H), 4.89 (t, J = 2.4 Hz, 2H).19F NMR (CDCl3, 376 MHz) δ -109.68 (br s, 1F). Method D Example 1-047: 5-(3,3-Difluoro-2,2-dimethyl-1-azetidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide

[0606] Step 1: 5-(3,3-Difluoro-2,2-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-047.1. A mixture of Intermediate A-1 (210 mg, 0.675 mmol), 3,3-difluoro-2,2-dimethylazetidine hydrochloride (160 mg, 1.01 mmol, Enamine), and DIPEA (0.35 mL, 2.03 mmol, Sigma-Aldrich Inc.) in THF (2 mL) was stirred at 50 °C for 16 h. Then, LiOH∙H2O (142 mg, 3.4 mmol, Sigma-Aldrich Inc.) and H2O (0.5 mL) were added, and the resulting mixture was stirred at rt for 16 h. The mixture was quenched with HCl aq. (1N) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over MgSO4, concentrated to provide Intermediate 1-047.1 that was taken to the next step. m / z (ESI): 338.0 (M+H)+.

[0607] Step 2: 5-(3,3-Difluoro-2,2-dimethyl-1-azetidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide, Compound 1-047. A mixture of Intermediate 1-047.1 (228 mg, 0.68 mmol), DMAP (8 mg, 0.07 mmol, Sigma-Aldrich Inc.), T3P®(50% wt. in EtOAc) (1.21 mL, 2.03 mmol, Sigma-Aldrich Inc.), ethenesulfonamide (109 mg, 1.01 mmol, Enamine), and DIPEA (0.35 mL, 2.03 mmol, Sigma-Aldrich Inc.) in EtOAc (2 mL) was stirred at 60 °C for 1 h. The mixture was cooled to rt, diluted with sat. NH4Cl (15 mL), and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over MgSO4and concentrated. The residue was purified by chromatography, eluting with a gradient of 0- 100% EtOAc in heptane, to provide Compound 1-047 (55 mg, 0.13 mmol, 19% yield). m / z (ESI): 427.0 (M+H)+.1H NMR (500 MHz, DMSO-d6) δ 11.60 - 11.75 (m, 1H), 8.66 (s, 1H), 7.72 (dd, J= 8.6, 5.5 Hz, 2H), 7.36 (t, J = 8.9 Hz, 2H), 7.07 (dd, J = 16.5, 10.0 Hz, 1H), 6.35 (br d, J = 16.9 Hz, 1H), 6.20 - 6.26 (m, 1H), 3.84 (t, J = 12.1 Hz, 2H), 1.57 (s, 6H).19F NMR (471 MHz, DMSO-d6) δ -111.80 (s, 2F), -111.97 (s, 1F). Example 1-048: N-(Ethenylsulfonyl)-6-(4-fluorophenyl)-5-(2,2,3-trimethyl-1-azetidinyl)-2- pyrazinecarboxamideIntermediate 1-048.2Compound 1-048

[0608] Step 1: Methyl 6-(4-fluorophenyl)-5-(2,2,3-trimethylazetidin-1-yl)pyrazine-2- carboxylate, Intermediate 1-048.1. To a solution of Intermediate A-1 (500 mg, 1.61 mmol) and DIPEA (1.0 mL, 5.74 mmol, Sigma-Aldrich Inc.) in DMSO (10 mL) was added a solution of 2,2,3-trimethylazetidine hydrochloride (218 mg, 1.607 mmol, Enamine) in DMSO. The mixture was stirred at 50 °C for 18 h. Then, the reaction was diluted with EtOAc and H2O, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated and purified by chromatography, eluting with a gradient of 0-50% EtOAc in heptane, to provide Intermediate 1-048.1 (361 mg, 1.1 mmol, 68% yield). m / z (ESI): 330.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.79 – 8.70 (m, 1H), 7.54 – 7.43 (m, 2H), 7.18 – 7.08 (m, 2H), 3.94 (s, 3H), 3.47 – 3.38 (m, 1H), 2.97 – 2.87 (m, 1H), 2.40 – 2.25 (m, 1H), 1.60 (s, 3H), 1.49 (s, 3H), 1.03 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, CDCl3) δ -112.50 – -112.93 (m, 1F).

[0609] Step 2: 6-(4-Fluorophenyl)-5-(2,2,3-trimethylazetidin-1-yl)pyrazine-2-carboxylic acid, Intermediate 1-048.2. To a solution of Intermediate 1-048.1 (361 mg, 0.943 mmol) in THF (5 mL) was added aqueous 1M LiOH (2 mL), and the solution was stirred at rt for 4 d. Then, the reaction was diluted with H2O, quenched with 2N HCl, and the aqueous solution was extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated to provide Intermediate 1-048.2 (345 mg, 1.09 mmol, quantitative), which was used directly for the next step. m / z (ESI): 316.1 (M+H)+.

[0610] Step 3: N-(Ethenylsulfonyl)-6-(4-fluorophenyl)-5-(2,2,3-trimethyl-1-azetidinyl)-2- pyrazinecarboxamide, Compound 1-048. To a solution of Intermediate 1-048.2 (345 mg,0.93 mmol) and ethenesulfonamide (164 mg, 1.53 mmol, Enamine) in THF (10 mL) was added 4-methylmorpholine (0.31 mL, 2.82 mmol, Sigma-Aldrich Inc.) then diphenyl phosphorochloridate (0.25 mL, 1.21 mmol, Sigma-Aldrich Inc.), and the solution was stirred at rt for 16 h. Then, the reaction was diluted with EtOAc and H2O, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated and purified by chromatography, eluting with 0-50% EtOAc in heptane, to provide a residue. The residue was repurified by reverse-phase chromatography, eluting with a gradient of 10-100% MeCN (0.1% formic acid) in H2O (0.1% formic acid) over 20 min to provide the over- acylated product. The material was dissolved in THF and aqueous 1M LiOH (1 mL) was added. The reaction mixture was stirred at rt for 16 h. The mixture was quenched with aqueous 2N HCl and the aqueous layer extracted with EtOAc (2 × 10 mL). The combined organic extracts were concentrated and purified by chromatography, eluting with 0-50% EtOAc in heptane, to provide Compound 1-048 (21 mg, 0.05 mmol, 6% yield). m / z (ESI): 405.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.76 (s, 1H), 7.46 – 7.40 (m, 2H), 7.18 (t, J = 8.2 Hz, 2H), 6.95 (dd, J = 16.6, 9.9 Hz, 1H), 6.58 (d, J = 16.5 Hz, 1H), 6.15 (d, J = 9.8 Hz, 1H), 3.46 (t, J = 9.1 Hz, 1H), 2.96 (dd, J = 9.4, 6.5 Hz, 1H), 2.40 – 2.30 (m, 1H), 1.61 (s, 3H), 1.50 (s, 3H), 1.04 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, CDCl3) δ -111.38 – -111.65 (m, 1F).

[0611] Compounds in Table 2-3 were prepared following the procedure described in Method D, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-3Method E Example 1-057: 3-Amino-5-(4,4-difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamideIntermediate B-1 Intermediate 1-057.1Intermediate 1-057.2 Compound 1-057

[0612] Step 1: Methyl 3-amino-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine- 2-carboxylate, Intermediate 1-057.1. To a stirred solution of Intermediate B-1 (7.5 g, 24.5 mmol) in 1,4-dioxane (60 mL) and H2O (15 mL) was added (4-fluorophenyl)boronic acid (3.76 g, 26.9 mmol, BLD Pharma Ltd.) and K2CO3(6.76 g, 48.9 mmol), and the reaction mixture was purged under N2atmosphere for 10 min. Then, PdCl2(dppf)DCM (1.99 g, 2.45 mmol, Hindustan Platinum) was added, and the reaction mixture was stirred at 90 °C for 4 h in a sealed tube. Next, the solution was filtered and concentrated in vacuum to give the crude material. The crude material was purified by chromatography, eluting with a gradient of 5- 10% EtOAc in hexanes, to provide Intermediate 1-057.1 (8.0 g, 21.8 mmol, 89% yield). m / z(ESI): 367.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.73 – 7.70 (m, 2H), 7.30 – 7.25 (m, 4H), 3.79 (s, 3H), 3.31 (s, 4H), 2.00 – 1.94 (m, 4H).

[0613] Step 2: 3-Amino-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-057.2. To stirred solution of Intermediate 1-057.1 (8.0 g, 21.8 mmol) in MeOH (20 mL), THF (40 mL) and H2O (20 mL) was added LiOH∙H2O (2.61 g, 109 mmol, Sigma-Aldrich Inc.), and the reaction mixture was stirred at rt for 4 h. Then, the reaction mixture was concentrated, diluted with H2O (10 mL), and pH adjusted to 4-6 with 1.5N HCl. The resulting solid was collected by filtration to provide Intermediate 1-057.2 (7.5 g, 21.3 mmol, 97% yield). m / z (ESI): 353.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.80 (dd, J = 8.6, 5.7 Hz, 2H), 7.24 (t, J = 8.7 Hz, 4H), 3.27 (t, J = 5.5 Hz, 4H), 2.00 – 1.93 (m, 4H).

[0614] Step 3: 3-Amino-5-(4,4-difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide, Compound 1-057. To a stirred solution of Intermediate 1-057.2 (150 mg, 0.43 mmol) and ethenesulfonamide (54.7 mg, 0.51 mmol, Suzhou Sibian Chemical Technology) in THF (5 mL) was added DIPEA (223 µL, 1.28 mmol, Sonia Industries Ltd.), DMAP (5 mg, 0.04 mmol, TCI Ltd.) and T3P®(50% in EtOAc) (760 µL, 1.28 mmol, Allessya) at rt under N2atmosphere. The reaction mixture was stirred at rt for 2 h. Then, the reaction mixture was quenched with ice cold water (5 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-70% EtOAc in hexanes, to provide Compound 1-057. m / z (ESI): 442.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (br s, 1H), 8.01 – 7.91 (m, 2H), 7.46 – 7.41 (m, 2H), 7.34 – 7.24 (m, 2H), 7.08 (dd, J = 16.5, 10.0 Hz, 1H), 6.35 (d, J = 16.5 Hz, 1H), 6.24 (d, J = 9.9 Hz, 1H), 3.35 (d, J = 5.3 Hz, 4H), 2.05 - 1.92 (m, 4H). Example 1-058: 6-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-4'-fluoro[biphenyl]-3- carboxamideIntermediate B-2Intermediate 1-058.1Intermediate 1-058.2 Compound 1-058

[0615] Step 1: Methyl 6-(4,4-difluoropiperidin-1-yl)-4'-fluoro-[1,1'-biphenyl]-3- carboxylate, Intermediate 1-058.1. To a stirred solution of Intermediate B-2 (900 mg, 2.7 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was added (4-fluorophenyl)boronic acid (1.2 g, 8.08 mmol, BLD Pharma Ltd.) and Na2CO3 (856 mg, 8.08 mmol, Avra Ltd.). The reaction mixture was purged with N2atmosphere for 5 min, then PdCl2(dppf)DCM (440 mg, 0.54 mmol, Hindustan Platinum) was added, and the mixture was purged under N2 atmosphere for 5 min. The reaction mixture was stirred at 100 °C for 16 h in sealed tube. Then, the reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (2 × 30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0-5% EtOAc in hexanes, to afford Intermediate 1- 058.1 (700 mg, 2.00 mmol, 74% yield). m / z (ESI): 350.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.89 (dd, J = 8.4, 2.2 Hz, 1H), 7.76 – 7.65 (m, 3H), 7.48 – 7.28 (m, 2H), 7.21 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 2.97 (t, J = 5.5 Hz, 4H), 1.89 (tt, J = 13.2, 5.4 Hz, 4H).

[0616] Step 2: Methyl 6-(4,4-difluoropiperidin-1-yl)-4'-fluoro-[1,1'-biphenyl]-3-carboxylic acid, Intermediate 1-058.2. To a stirred solution of Intermediate 1-058.1 (700 mg, 2.00 mmol) in THF (4.9 mL), MeOH (2.1 mL) and H2O (2.1 mL) was added LiOH∙H2O (420 mg, 10 mmol, Sigma-Aldrich Inc.) at rt and stirred for 6 h. The reaction mixture was quenched with 1N HCl (5 mL) and the resulting precipitate was collected by filtration and dried to provide Intermediate 1-058.2 (550 mg, 1.64 mmol, 82% yield). m / z (ESI): 336.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.90 – 7.74 (m, 2H), 7.66 (ddd, J = 8.8, 5.5, 2.6 Hz, 2H), 7.26(t, J = 8.9 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 2.88 (t, J = 5.7 Hz, 4H), 1.87 (tt, J = 13.9, 5.4 Hz, 4H). One exchangeable proton was not observed.

[0617] Step 3: 6-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-4'-fluoro[biphenyl]-3- carboxamide, Compound 1-058. To a stirred solution of Intermediate 1-058.2 (200 mg, 0.60 mmol) and ethenesulfonamide (77 mg, 0.72 mmol, Suzhou Sibian Chemical Technology) in THF (5 mL) was added DIPEA (313 µL, 1.79 mmol, Sonia Industries), DMAP (7 mg, 0.06 mmol, TCI Ltd.) and T3P®(50% in EtOAc) (1.05 mL, 1.79 mmol, Allessya) at rt under N2atmosphere. The reaction mixture was stirred at rt for 2 h. Then, the reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (2 × 30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography, eluting with a mobile phase of ACN in H2O (with 0.1% formic acid) and a flow rate 15 mL / min, to afford Compound 1-058 (16 mg, 0.038 mmol, 6% yield). m / z (ESI): 425.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.14 (br s, 1H), 8.04 – 7.74 (m, 2H), 7.76 – 7.68 (m, 2H), 7.48 – 7.18 (m, 2H), 7.24 – 6.97 (m, 2H), 6.19 (d, J = 16.6 Hz, 1H), 6.01 (br s, 1H) 3.08 – 2.84 (m, 4H), 1.95 - 1.82 (m, 4H). Example 1-059: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-2- pyridinecarboxamideIntermediate B-3 Intermediate 1-059.1Compound 1-059

[0618] Step 1: 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)picolinic acid, Intermediate 1-059.1. To a stirred solution of Intermediate B-3 (350 mg, 1.26 mmol) in 1,4-dioxane (2.8 mL) and H2O (0.7 mL) was added (4-fluorophenyl)boronic acid (354 mg, 2.53 mmol, BLD Pharma Ltd.) and K3PO4(806 mg, 3.8 mmol, Sigma-Aldrich Inc.). The reaction mixture was purged with N2 for 10 min. Then, PdCl2(dppf)DCM (103 mg, 0.13 mmol, Hindustan Platinum Ltd.) was added, and the reaction mixture was purged with N2 for a further 5 min. The reaction mixture was heated at 100 °C for 16 h. Then, the reaction mixture was filtered through a pad of celite, washed with EtOAc, acidified with aq. NaHSO4, and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by MPLC (Flashpure C18 column,Grace) eluting with ACN / water 0- 80% to provide Intermediate 1-059.1 (230 mg, 0.68 mmol, 54% yield). m / z (ESI): 337.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.02 (dd, J = 8.5, 5.7 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.32 (t, J = 8.9 Hz, 2H), 2.99 (t, J = 5.4 Hz, 4H), 2.04 – 1.91 (m, 4H).

[0619] Step 2: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-2- pyridinecarboxamide, Compound 1-059. To a stirred solution of Intermediate 1-059.1 (40 mg, 0.12 mmol) and ethenesulfonamide (15.3 mg, 0.14 mmol, Enamine Ltd.) in EtOAc (3 mL) was added T3P®(50% in EtOAc) (0.21 mL, 0.36 mmol, Sigma-Aldrich Inc.), DMAP (2 mg, 0.012 mmol, TCI Ltd.) and DIPEA (62 µL, 0.36 mmol, Sonia Industries Ltd.) and stired at rt for 2 h. Then, the reaction mixture was quenched with ice cold water (10 mL) and extracted with EtOAc (2 × 15 mL). The organic extract was washed with 1.5 N HCl (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to afford Compound 1-059 (46 mg, 0.11 mmol, 91% yield). m / z (ESI): 426.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.66 (br s, 1H), 8.28 – 8.18 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.09 (dd, J = 16.5, 9.9 Hz, 1H), 6.38 (d, J = 16.5 Hz, 1H), 6.27 (d, J = 9.9 Hz, 1H), 3.06 – 2.99 (m, 4H), 2.10-1.95 (m, 4H).19F NMR (DMSO-d6, 376 MHz) δ -96.09 (br s, 2F), - 112.46 (s, 1F). Example 1-060: 6-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-5-(4-fluorophenyl)-2- methyl-3-pyridinecarboxamideIntermediate B-4 Step 1 Intermediate 1-060.1 Step 2Intermediate 1-060.2 Compound 1-060

[0620] Step 1: Methyl 6-(4,4-difluoropiperidin-1-yl)-5-(4-fluorophenyl)-2- methylnicotinate, Intermediate 1-060.1. To a stirred solution of Intermediate B-4 (1.75 g,5.01 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was added (4-fluorophenyl) boronic acid (2.10 g, 15.04 mmol, BLD Pharma Ltd.) and Na2CO3 (1.60 g, 15.0 mmol) at rt. The reaction mixture was purged with N2for 5 min. Then, PdCl2(dppf)DCM (0.82 g, 1.0 mmol, Hindustan Platinum Ltd.) was added, and the mixture was purged with N2 for a further 5 min. The reaction mixture was stirred at 100 °C for 3 h under microwave radiation. Then, the reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a mobile phase of 5% EtOAc in hexanes, to provide Intermediate 1-060.1 (1.5 g, 4.1 mmol, 82% yield). m / z (ESI): 365.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.62 (dd, J = 8.6, 5.6 Hz, 2H), 7.32 (d, J = 17.6 Hz, 2H), 3.80 (s, 3H), 3.28 (t, J = 5.8 Hz, 4H), 2.67 (s, 3H), 2.02-1.83 (m, 4H).

[0621] Step 2: 6-(4,4-Difluoropiperidin-1-yl)-5-(4-fluorophenyl)-2-methylnicotinic acid, Intermediate 1-060.2. To a stirred solution of Intermediate 1-060.1 (1.6 g, 4.4 mmol) in THF (8 mL), MeOH (8 mL) and H2O (4 mL) was added LiOH (0.270 g, 6.59 mmol) at 0 °C. The resulting mixture was stirred at rt for 3 h. Then, the reaction mixture was quenched with 1N HCl and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC, eluting with a mobile phase of 45% ACN in H2O, to provide Intermediate 1-060.2 (1.45 g, 4.14 mmol, 94% yield). m / z (ESI): 351.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.89 (s, 1H), 7.67-7.57 (m, 2H), 7.31 (t, J = 8.8 Hz, 2H), 3.26 (t, J = 5.5 Hz, 4H), 2.67 (s, 3H), 1.95-1.88 (m, 4H).

[0622] Step 3: 6-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-5-(4-fluorophenyl)-2- methyl-3-pyridinecarboxamide, Compound 1-060. To a stirred solution of Intermediate 1- 060.2 (100 mg, 0.29 mmol) and ethenesulfonamide (36.7 mg, 0.34 mmol, Enamine Ltd.) in THF (2 mL) was added DMAP (3.5 mg, 0.03 mmol, TCI Ltd.), DIPEA (150 µL, 0.86 mmol, Avra Pvt. Ltd.) and T3P®(50% in EtOAc) (0.51 mL, 0.856 mmol, Sigma-Aldrich Inc.) at rt under N2 atmosphere. The reaction mixture was stirred at rt for 2 h Then, the reaction was quenched with ice cold water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase column chromatography, eluting with a mobile phase of 60% ACN in H2O. Then, the residue was purified by SFC, using a Chiralcel OD-H 250x30 mm column, using a mobile phase of liquid CO2: (Methanol / ACN, 1:1) (55:45) with a flow rate of 100 mL / min, to get Compound 1-060 (40 mg, 0.09 mmol,32% yield). m / z (ESI): 440.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.09 (br s, 1H), 7.78 (s, 1H), 7.69-7.65 (m, 2H), 7.32 (t, J = 9.2 Hz, 2H), 7.12 -7.05 (m, 1H), 6.23 (d, J = 16.8 Hz, 1H), 6.09 (d, J = 9.2 Hz, 1H), 3.29-3.21 (m, 4H), 2.55 (s, 3H), 1.99-1.89 (m, 4H).

[0623] Compounds in Table 2-4 were prepared following the procedure described in Method E, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-4Method F Example 1-066: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-methylphenyl)-2- pyrazinecarboxamide OH

[0624] Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(p-tolyl)pyrazine-2-carboxylate, Intermediate 1-066.1. To a solution of Intermediate B-5 (261 mg, 0.90 mmol), K3PO4 (687 mg, 3.2 mmol, Sigma-Aldrich Inc.), and (4-fluorophenyl)boronic acid (247 mg, 1.82 mmol, Sigma-Aldrich Inc.) in 2-methyltetrahydrofuran (5 mL) and H2O (0.5 mL) was added SPhos Pd G3 (52 mg, 0.06 mmol, Sigma-Aldrich Inc.). The reaction mixture was stirred at 60 °C for 18 h. Then, the reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over MgSO4, and filtered through celite before concentrating. The crude material was purified by chromatography, eluting with 0-50% EtOAc in heptane, to provide Intermediate 1-066.1 (200 mg, 0.57 mmol, 64% yield). m / z (ESI): 348.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.32 – 7.21 (m, 1H), 7.32 – 7.21 (m, 2H), 3.99 (s, 3H), 3.53 – 3.45 (m, 4H), 2.42 (s, 3H), 2.03 – 1.91 (m, 4H).19F NMR (376 MHz, CDCl3) δ -97.34 (br s, 2F).

[0625] Step 2: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-methylphenyl)-2- pyrazinecarboxamide, Intermediate 1-066.2. To a solution of Intermediate 1-066.1 (195 mg, 0.51 mmol) in 2-methyltetrahydrofuran (5 mL) and MeOH (2 mL) was added aqueous 1M LiOH (2 mL). The reaction mixture was stirred at rt for 3 h. Then, the reaction wasconcentrated to provide Intermediate 1-066.2 (168 mg, 0.50 mmol, 100% yield), which was used directly for the next step. m / z (ESI): 334.2 (M+H)+.

[0626] Step 3: 5-(4,4-Difluoropiperidin-1-yl)-6-(p-tolyl)-N-(vinylsulfonyl)pyrazine-2- carboxamide, Compound 1-066. To a solution of Intermediate 1-066.2 (129 mg, 0.39 mmol) in DMF (2 mL) was added DIPEA (0.20 mL, 1.16 mmol, Sigma-Aldrich Inc.) and T3P®(50 wt% in EtOAc) (0.69 mL, 1.16 mmol, Strem Chemicals Inc.). The reaction was stirred for 5 min at rt, then ethenesulfonamide (62 mg, 0.58 mmol, Enamine) was added, and the reaction was stirred at 50 °C for 5 d. The reaction mixture was diluted with EtOAc and H2O, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated and purified by chromatography, eluting with 0%-50% EtOAc in heptane, to provide Compound 1-066 (40 mg, 0.09 mmol, 24% yield). m / z (ESI): 423.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.84 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 6.95 (dd, J = 16.5, 9.8 Hz, 1H), 6.62 (d, J = 16.5 Hz, 1H), 6.19 (d, J = 9.8 Hz, 1H), 3.57 – 3.49 (m, 4H), 2.47 (s, 3H), 2.05 – 1.92 (m, 4H).19F NMR (376 MHz, CDCl3) δ - 97.52 (br d, J = 9.5 Hz, 2F).

[0627] Compounds in Table 2-5 were prepared following the procedure described in Method F, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-5Method H Example 1-075: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-3- methyl-2-pyrazinecarboxamideIntermediate B-11Intermediate 1-075.1Intermediate 1-075.2 Compound 1-075

[0628] Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-methylpyrazine- 2-carboxylate, Intermediate 1-075.1. To a stirred solution of Intermediate B-11 (6.0 g, 17.1 mmol) in 1,4-dioxane (48 mL) and H2O (12 mL) was added (4-fluorophenyl)boronic acid (6.0 g, 17.13 mmol, BLD Pharma Ltd.) and K3PO4(8.95 g, 51.4 mmol, Avra Ltd.). The reaction mixture was purged with N2 for 5 min and PdCl2(dppf)DCM (1.399 g, 1.71 mmol, Angene Pvt. Ltd.) was added, and the reaction mixture was purged with N2 for additional 5 min. The reaction mixture was stirred at 90 °C for 8 h. Then, the reaction mixture was diluted with EtOAc (250 mL) and filtered through celite. The filtrate was washed with 1.5 N HCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0%-30% EtOAc in hexanes, to provide Intermediate 1-075.1 (5 g, 14 mmol, 80% yield). m / z (ESI): 366.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.90 – 7.82 (m, 2H), 7.34 (t, J = 8.9 Hz, 2H), 4.04 (q, J = 7.1 Hz, 4H), 3.84 (s, 3H), 3.38 (t, J = 5.8 Hz, 3H), 2.66 (q, J = 7.1 Hz, 4H).

[0629] Step 2: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-methylpyrazine-2- carboxylic acid, Intermediate 1-075.2. To a stirred solution of Intermediate 1-075.1 (5 g, 14mmol) in MeOH (20 mL), THF (20 mL) and H2O (10 mL) was added LiOH (0.33 g, 13.7 mmol, Avra Ltd.). The reaction mixture was stirred at rt for 6 h. Then, the reaction mixture was concentrated and acidified with 1.5 N HCl to adjust pH to ~5. The resulting solid was collected by filtration, washed with H2O (30 mL), and dried to provide Intermediate 1-075.2 (4.5 g, 12.8 mmol, 94% yield). m / z (ESI): 352.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.87 (m, 2H), 7.28 (t, J = 8.9 Hz, 2H), 3.20 – 3.13 (m, 4H), 2.57 (s, 3H), 2.03 – 1.89 (m, 4H). One exchangeable proton was not observed.

[0630] Step 3: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-methyl-N- (vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-075. To a stirred solution of Intermediate 1-075.2 (150 mg, 0.43 mmol) and ethenesulfonamide (55 mg, 0.51 mmol, Enamine Ltd.) in THF (2 mL) were added DMAP (5 mg, 0.04 mmol, Avra Pvt. Ltd. ), DIPEA (224 µL, 1.28 mmol, Avra Ltd.) and T3P®(50% in EtOAc) (0.76 mL, 1.28 mmol, Sigma-Aldrich Inc.) at rt. The reaction mixture was stirred at rt for 2 h. Then, the reaction mixture was quenched with ice-cold H2O (25 mL) and stirred for 5 min. The resulting solid was collected by filtration, washed with H2O (2 × 30 mL), pet. ether (2 × 30 mL), and dried. The residue was then purified by chromatography, eluting with a mobile phase of 40% EtOAc in pet. ether, to obtain Compound 1-075 (102 mg, 0.21 mmol, 48% yield). m / z (ESI): 439.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.57 (br s, 1H), 8.11 – 8.02 (m, 2H), 7.36 (t, J = 8.9 Hz, 2H), 7.09 (dd, J = 16.5, 10.0 Hz, 1H), 6.37 (d, J = 16.5 Hz, 1H), 6.26 (d, J = 9.9 Hz, 1H), 3.39 (t, J = 5.8 Hz, 4H), 2.65 (s, 3H), 2.10-1.95 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -95.37 (br s, 2F), -112.07 (s, 1F)

[0631] The compound in Table 2-7 was prepared following the procedure described in Method H, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-7Method I Example 1-077: 4-Cyano-5-(4,4-difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyridinecarboxamiden erme a e -Intermediate 1-077.5 Intermediate 1-077.6Compound 1-077

[0632] Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)picolinate, Intermediate 1-077.1. To a stirred solution of Intermediate B-6 (11.0 g, 37.8 mmol) in 1,4-dioxane (200 mL) and H2O (50 mL) was added (4-fluorophenyl)boronic acid (6.88 g, 49.2 mmol, BLD Pharma Ltd.), and K2CO3 (10.46 g, 76 mmol) at rt. The reaction mixture was purged with N2for 5 min, then PdCl2(dppf)DCM (2.77 g, 3.78 mmol, BLD Pharma Ltd.) was added, and the reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was quenched with 1.5 N HCl (50 mL), extracted with EtOAc (2 × 500 mL), and the combined organic extracts were concentrated. The residue was purified by chromatography, eluting with a gradient of 0-20% EtOAc in pet. ether, to provide Intermediate 1-077.1 (12.0 g, 34.3 mmol, 91% yield). m / z (ESI): 351.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.00-7.95 (m, 3H), 7.64 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 8.9 Hz, 2H), 3.86 (s, 3H), 3.02 (t, J = 5.5 Hz, 4H), 2.03-1.93 (m, 4H).

[0633] Step 2: Ethyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)picolinate, Intermediate 1-077.2. To a stirred solution of Intermediate 1-077.1 (6.0 g, 17 mmol) in EtOH (240 mL) was added NaOEt (2.33 g, 34.3 mmol, Sigma-Aldrich Inc.) at 0 °C under N2atmosphere. The reaction mixture was stirred at rt for 2 h. Then, the reaction mixture was quenched with 1.5 N HCl (200 mL) and extracted with EtOAc (2 × 400 mL). The combined organic extracts were washed with H2O (2 × 250 mL) and satd. NaCl solution (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-20% EtOAc in pet. ether, to provide Intermediate 1-077.2 (4 g, 11 mmol, 64% yield). m / z (ESI): 365.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.00-7.95 (m, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 4.31 (q, J = 6.8 Hz, 2H), 3.02-2.99 (m, 4H), 1.99-1.94 (m, 4H), 1.31 (t, J = 6.8 Hz, 3H).

[0634] Step 3: 3-(4,4-Difluoropiperidin-1-yl)-6-(ethoxycarbonyl)-2-(4- fluorophenyl)pyridine 1-oxide, Intermediate 1-077.3. To a stirred solution of Intermediate 1- 077.2 (4 g, 11 mmol) in DCM (160 mL) was added UHP (5.16 g, 54.9 mmol, Oakwood Labs) and TFAA (7.63 mL, 54.9 mmol, Avra Ltd.) at 0 °C under N2 atmosphere. The reaction mixture was stirred at rt for 2 h. Then, the reaction mixture was quenched with satd. Na2S2O3 (50 mL) and extracted with DCM (2 × 50 mL). The combined organic extracts were washed with satd. Na2S2O3 (100 mL) and brine (100 mL). The solution was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-50% EtOAc in pet. ether, to afford Intermediate 1-077.3 (2.1 g, 5.5 mmol, 50% yield). m / z (ESI): 381.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.59 (m, 3H), 7.35 - 7.31 (m, 2H), 7.21 (d, J= 8.8 Hz, 1H), 4.29 (q, J= 7.1 Hz, 2H), 2.93 - 2.90 (m, 4H), 1.78 - 1.71(m, 4H), 1.27 (t, J= 6.8 Hz, 3H).

[0635] Step 4: Ethyl 4-chloro-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)picolinate, Intermediate 1-077.4. A solution of the Intermediate 1-077.3 (2.5 g, 6.6 mmol) in POCl3 (10 mL) was heated at 125 °C for 2 h. Then, the reaction mixture was concentrated, diluted with EtOAc (100 mL), washed with H2O (3 × 30 mL), satd. NaHCO3 (30 mL), and brine(30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-8% EtOAc in pet. ether, to afford Intermediate 1-077.4 (1.3 g, 3.3 mmol, 50% yield). m / z (ESI): 399.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.56 - 7.52 (m, 2H), 7.38 - 7.34 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 2.98 - 2.89 (m, 4H), 1.99 - 1.85 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H).

[0636] Step 5: Ethyl 4-cyano-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)picolinate, Intermediate 1-077.5. To a stirred solution of Intermediate 1-077.4 (1.0 g, 2.5 mmol) in DMF (10 mL) was added Zn(CN)2(38 mg, 3.3 mmol, Lobo Chemicals), and the reaction mixture was purged with N2for 5 min. Then, Pd2(dba)3(0.26 mg, 0.3 mmol, Manchester Organics) and dppf (0.28 g, 0.50 mmol, Combi-Blocks) were added, and the mixture was stirred at 120 °C for 16 h. The reaction mixture was quenched with aq. NaOCl (10 mL) at 0 °C, then with H2O (30 mL), and extracted with EtOAc (100 mL). The organic extract was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-10% EtOAc in pet. ether, to afford Intermediate 1-077.5 (400 mg, 37% yield). m / z (ESI): 390.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.64 - 7.61 (m, 2H), 7.40 - 7.36 (m, 2H), 4.35 (q, J = 6.8Hz, 2H), 3.17 - 3.14 (m, 4H), 2.00 - 1.93 (m, 4H), 1.31 (t, J = 6.8 Hz, 3H).

[0637] Step 6: 4-Cyano-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)picolinic acid, Intermediate 1-077.6. To a stirred solution of Intermediate 1-077.5 (350 mg, 0.9 mmol) in THF (10 mL), EtOH (3 mL) and H2O (3 mL) was added LiOH∙H2O (147 mg, 3.60 mmol) at rt. The reaction mixture was stirred at rt for 2 h. Then, the reaction was quenched with 1.5 N HCl at 0 °C and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with H2O (2 × 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford Intermediate 1-077.6 (300 mg, 0.83 mmol, 92% yield). m / z (ESI): 362.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 13.57 (br s, 1H), 8.22 (s, 1H), 7.65 - 7.61 (m, 2H), 7.39 - 7.35 (m, 2H), 3.19 - 3.11 (m, 4H), 2.02 - 1.93 (m, 4H).

[0638] Step 7: 4-Cyano-5-(4,4-difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyridinecarboxamide, Compound 1-077. To a stirred solution of Intermediate 1-077.6 (130 mg, 0.36 mmol) and ethenesulfonamide (42 mg, 0.40 mmol, ArborLtd.) in THF (5 mL) was added DIPEA (189 µL, 1.1 mmol), DMAP (4 mg, 0.036 mmol, Avra Pvt. Ltd.) and T3P®(50% in EtOAc) (0.64 mL, 1.08 mmol, Sigma-Aldrich Inc.) at 0 °C under N2atmosphere. The reaction mixture was stirred at rt for 3 h. Then, the reaction was quenched with H2O at 0 °C (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-60% EtOAc in pet. ether. Then, the material was dissolved in EtOAc (20 mL), 1.5 N aq HCl (10 mL) was added, and the solution was stirred for 30 min at rt. The organic layer was separated, washed with 1.5 NH4Cl (4 × 10 mL), and H2O (2 × 10 mL). The organic layer was concentrated and dried over Na2SO4to provide Compound 1-077 (78 mg, 0.17 mmol, 48% yield). m / z (ESI): 451.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.01 (br s, 1H), 8.23 (s, 1H), 7.80 - 7.77 (m, 2H), 7.41 - 7.37 (m, 2H), 7.07 (dd, J = 16.4, 9.6 Hz, 1H), 6.33 (d, J = 16.4 Hz, 1H), 6.20 (d, J = 10.0 Hz, 1H), 3.16-3.14 (m, 4H), 2.02-1.95 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -95.51 (s), -112.24 (s) Method J Example 1-078: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-3- methoxy-2-pyrazinecarboxamide

[0639] Step 1: Methyl 3-amino-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine- 2-carboxylate, Intermediate 1-078.1. To a solution of Intermediate 1-057.2 (1 g, 2.8 mmol) in toluene (4 mL) and MeOH (4 mL) at 0 °C was added TMS-diazomethane (2 M in hexanes) (5.68 mL, 11.4 mmol) slowly. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material waspurified by chromatography, eluting with a gradient of 15-30% EtOAc in hexanes, to provide Intermediate 1-078.1 (0.8 g, 2.2 mmol, 77% yield). m / z (ESI): 367.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.67 (m, 2H), 7.33 – 7.25 (m, 4H), 3.79 (s, 3H), 3.32 (d, J = 10.8 Hz, 4H), 2.00 – 1.90 (m, 4H).

[0640] Step 2: Methyl 3-chloro-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine- 2-carboxylate, Intermediate 1-078.2. To a stirred solution of isoamyl nitrite (4.41 mL, 32.8 mmol) in DCM (5 mL) at 0 °C was added trimethylchlorosilane (4.2 mL, 32.8 mmol), and the resulting mixture was stirred for 5 min. Then, Intermediate 1-078.1 (1.2 g, 3.28 mmol) in DCM (5 mL) was added at 0 °C, and the reaction mixture was stirred for 3 h at 0 °C. The reaction mixture was diluted with H2O (5 mL), extracted with DCM (3 × 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography, eluting with a gradient of 5-10% EtOAc in hexanes, to provide Intermediate 1-078.2 (0.75 g, 1.9 mmol, 59% yield) m / z (ESI): 386.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.88 – 7.73 (m, 2H), 7.41 – 7.27 (m, 2H), 3.86 (s, 3H), 3.40 (dd, J = 6.8, 4.8 Hz, 4H), 2.11 – 1.93 (m, 4H).

[0641] Step 3: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3- methoxypyrazine-2-carboxylate, Intermediate 1-078.3. To a solution of Intermediate 1-078.2 (0.3 g, 0.78 mmol) in MeOH (7 mL) was added K2CO3(0.32 g, 2.33 mmol), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered, and concentrated to provide Intermediate 1-078.3 (0.28 g, 0.73 mmol, 94% yield), which was used directly in the next step. m / z (ESI): 382.2 (M+H)+.

[0642] Step 4: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-methoxypyrazine-2- carboxylic acid, Intermediate 1-078.4. To a solution of Intermediate 1-078.3 (0.28 g, 0.734 mmol) in THF (4 mL), MeOH (1 mL), and H2O (1 mL) was added LiOH∙H2O (88 mg, 3.67 mmol), and the resulting mixture stirred for 2 h. Then, the reaction mixture was concentrated, and acidified with aq. citric acid., The resulting solid was collected by filtration and dried to provide Intermediate 1-078.4 (0.29 g), which was used directly in the next step. m / z (ESI): 368.1 (M+H)+.

[0643] Step 5: 5-(4,4-Difluoro-1-piperidinyl)-N-(ethenylsulfonyl)-6-(4-fluorophenyl)-3- methoxy-2-pyrazinecarboxamide, Compound 1-078. To a stirred solution of Intermediate 1- 078.4 (0.15 g, 0.41 mmol) and ethenesulfonamide (44 mg, 0.41 mmol) in DMF (3 mL) was added T3P®(50% in DMF) (0.42 mL, 1.23 mmol), DIPEA (0.21 mL, 1.23 mmol) and DMAP (5 mg, 0.041 mmol) at rt. The reaction mixture was stirred at rt for 2 h. Then, the reactionwas quenched with ice cold water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 10-30% of EtOAc in hexanes, to provide Compound 1-078 (29 mg, 0.06 mmol, 16% yield). m / z (ESI): 457.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 7.97 – 7.88 (m, 2H), 7.38 – 7.28 (m, 2H), 7.05 (dd, J = 16.5, 9.9 Hz, 1H), 6.31 (d, J = 16.6 Hz, 1H), 6.20 (d, J = 10.0 Hz, 1H), 3.97 (s, 3H), 3.42 (t, J = 5.7 Hz, 4H), 2.08 – 1.96 (m, 4H).19F NMR (376 MHz, DMSO-d6): δ -95.36 (s, 2 F), -113.11 (s, 1 F).

[0644] Example 1-084: 3-(Difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-6-(4- fluorophenyl)-N-(vinylsulfonyl)pyrazine-2-carboxamideStep 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-vinylpyrazine-2- carboxylate, Intermediate 1-084.1. To a stirred solution of Intermediate 1-078.2 (1.2 g, 3.11 mmol) in dioxane (12 mL) and water (2.4 mL) were added K2CO3 (1.29 g, 9.33 mmol) and potassium trifluoro(vinyl)borate (0.833 g, 6.22 mmol) at rt. The reaction mixture was purged with N2for 5 min before the addition of PdCl2(dppf)-CH2Cl2adduct (0.381 g, 0.467 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture quenched with water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layer waswashed with water (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0% to 100% EtOAc in hexanes) to give Intermediate 1-084.1 (0.4 g, 1.060 mmol, 34% yield). m / z (ESI): 378.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.87 (m, 2H), 7.50 (dd, J = 16.9, 10.6 Hz, 1H), 7.36 (t, J = 8.9 Hz, 2H), 6.52 (dd, J = 17.0, 2.4 Hz, 1H), 5.68 (dd, J = 10.5, 2.3 Hz, 1H), 3.86 (s, 3H), 3.43 (t, J = 5.8 Hz, 4H), 2.10 – 1.96 (m, 4H). Step 2: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-formylpyrazine-2- carboxylate, Intermediate 1-084.2. To a stirred solution of methyl 5-(4,4-difluoropiperidin-1- yl)-6-(4-fluorophenyl)-3-vinylpyrazine-2-carboxylate, Intermediate 1-084.1 (0.23 g, 0.61 mmol) in acetone (1.6 mL) and water (0.7 mL) were added osmium tetroxide (4% in water, 0.048 mL, 6.09 µmol) and sodium periodate (0.391 g, 1.83 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layer was washed with water (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude Intermediate 1-084.2 (0.2 g), which was used directly for the next step. m / z (ESI): 380.0 (M+H)+. Step 3: Methyl 3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-084.3. To a stirred solution of methyl 5- (4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-formylpyrazine-2-carboxylate, Intermediate 1-084.2 (0.2 g, 0.527 mmol) in DCM (1.4 mL) was added DAST (0.104 mL, 0.791 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture quenched with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (3 × 100 mL). The combined organic layer was washed with water (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0% to 100% EtOAc in hexanes) to give Intermediate 1-084.3. (0.15 g, 0.374 mmol, 71% yield). m / z (ESI): 402.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.88 (m, 2H), 7.46 – 7.34 (m, 3H), 3.89 (s, 3H), 3.47 - 3.44 (m, 4H), 2.07 – 1.96 (m, 4H). Step 4: 3-(Difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine- 2-carboxylic acid, Intermediate 1-084.4. To a stirred solution of methyl 3-(difluoromethyl)-5- (4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-084.3. (0.150 g, 0.374 mmol) in THF (1.5 mL) and H2O (0.5 mL) was added LiOH.H2O (0.063 g, 1.49 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to get the residue. The residue was acidified with 1.5 N HCl (pH ~3), and solid precipitate was filtered through a Büchner funnel and dried underreduced pressure to give crude Intermediate 1-084.4 (0.12 g, 0.310 mmol, 83% yield), which was used directly for the next step. m / z (ESI): 388.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.99 – 7.95 (m, 2H), 7.58 (t, J =54.5 Hz, 1H), 7.38 – 7.34 (m, 2H), 3.38 – 3.32 (m, 4H), 2.04 – 1.95 (m, 4H). Note: Exchangeable proton was not observed in1H-NMR spectrum. Step 5: 3-(Difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-084. To a stirred solution of 3- (difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylic acid, Intermediate 1-084.4. (80 mg, 0.207 mmol) in THF (1.6 mL) were added DMAP (2.52 mg, 0.021 mmol), DIPEA (0.108 mL, 0.62 mmol), ethenesulfonamide (33 mg, 0.310 mmol) and T3P®(50% in EtOAc, 0.36 mL, 0.62 mmol) at rt. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with ice cold water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 10% to 30% EtOAc in hexanes) to give Compound 1- 084 (0.049 g, 0.103 mmol, 50% yield). m / z (ESI): 477.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 8.18 – 8.08 (m, 2H), 7.43 – 7.37 (m, 3H), 7.10 (dd, J = 16.5, 9.9 Hz, 1H), 6.38 (d, J = 16.5 Hz, 1H), 6.27 (d, J = 9.9 Hz, 1H), 3.47 – 3.44 (m, 4H), 2.08 – 1.98 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -95.46 (2F), -110.94 (1F), -118.40 (2F). Example 1-085: 5-(4,4-Difluoropiperidin-1-yl)-3-fluoro-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamideIntermediate 1-057.1 Intermediate 1-085.1Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-(4-fluorophenyl)pyrazine-2- carboxylate, Intermediate 1-085.1. To a stirred solution of methyl 3-amino-5-(4,4- difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-057.1 (0.7 g, 1.911 mmol) in HF-pyridine (2.58 mL, 28.7 mmol) was added NaNO2 (0.171 g, 2.48 mmol) at -10 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 × 50 mL). The combined organic layer was washed with water (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 20% to 40% EtOAc in hexanes) to give Intermediate 1-085.1 (0.5 g, 1.35 mmol, 71% yield). m / z (ESI): 370.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.83 – 7.73 (m, 2H), 7.41 – 7.31 (m, 2H), 3.85 (s, 3H), 3.45 – 3.37 (m, 4H), 2.01 (tt, J = 13.5, 5.7 Hz, 4H). Step 2: 5-(4,4-Difluoropiperidin-1-yl)-3-fluoro-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-085.2. To a stirred solution of methyl 5-(4,4- difluoropiperidin-1-yl)-3-fluoro-6-(4-fluorophenyl)pyrazine-2-carboxylate, Intermediate 1- 085.1. (0.2 g, 0.54 mmol) in THF (4.0 mL) and H2O (0.5 mL) was added LiOH.H2O (0.11 g, 2.71 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous citric acid solution (pH ~3) and extracted with EtOAc (3 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude Intermediate 1-085.2 (0.22 g), which was used directly for the next step. m / z (ESI): 357.0 (M+H)+. Step 3: 5-(4,4-Difluoropiperidin-1-yl)-3-fluoro-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-085. To a stirred solution of 5-(4,4- difluoropiperidin-1-yl)-3-fluoro-6-(4-fluorophenyl)pyrazine-2-carboxylic acid, Intermediate 1-085.2. (130 mg, 0.37 mmol) in THF (5.0 mL) were added DMAP (4.46 mg, 0.037 mmol), DIPEA (192 µL, 1.1 mmol), ethenesulfonamide (47 mg, 0.44 mmol) and T3P®(50% in EtOAc, 0.65 mL, 1.1 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with ice cold water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 15% to 30% EtOAc in hexanes) to give Compound 1-085 (31 mg, 0.070 mmol, 19% yield). m / z (ESI): 445.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.03 – 7.93 (m, 2H), 7.42 – 7.31 (m, 2H), 7.08 (dd, J = 16.5, 9.9 Hz, 1H), 6.34 (d, J = 16.5 Hz, 1H), 6.23 (d, J = 10.0 Hz, 1H), 3.41 (t, J = 5.7 Hz, 4H), 2.01 (td, J = 13.9,13.4, 6.8 Hz, 4H).19F NMR (376 MHz, DMSO-d6) δ -77.55 (s), -95.66 (s), -111.92 (d, J = 8.8 Hz).

[0645] The compound in Table 2-8 was prepared following the procedure described above, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-8Example 1-086: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-(methoxymethyl)-N- (vinylsulfonyl)pyrazine-2-carboxamideIntermediate 1-086.2 Compound 1-086 Step 1: Methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-(methoxymethyl) pyrazine-2-carboxylate, Intermediate 1-086.1. To a stirred solution of methyl 3-chloro-5-(4,4- difluoropiperidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-078.2 (0.7 g, 1.815 mmol) in DMF (7.0 mL) were added triphenylphosphine (0.048 g, 0.181 mmol), zinc chloride (0.247 g, 1.815 mmol) and tributyl(methoxymethyl)stannane (0.730 g, 2.18 mmol) at rt. The reaction mixture was purged with N2 for 5 min before Pd2(dba)3.CHCl3 (0.166 g, 0.18 mmol) was added. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0% to 20% EtOAc in hexanes) to give Intermediate 1-086.1 (0.2 g, 0.506 mmol, 28 % yield). m / z (ESI): 396.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.94 – 7.85 (m, 2H), 7.41 – 7.30 (m, 2H), 4.73 (s, 2H), 3.84 (s, 3H), 3.40 (m, 4H), 3.36 (s, 3H), 1.99 (m, 4H). Step 2: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3- (methoxymethyl)pyrazine-2-carboxylic acid, Intermediate 1-086.2. To a stirred solution of methyl 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-(methoxymethyl) pyrazine-2- carboxylate, Intermediate 1-086.1 (0.2 g, 0.506 mmol) in THF (1.6 mL) and H2O (0.4 mL) was added LiOH.H2O (0.106 g, 2.53 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1.5 N HCl (pH ~3). The solid precipitate was filtered through a Büchner funneland dried under reduced pressure to give crude Intermediate 1-086.2 (0.15 g, 0.393 mmol, 78% yield), which was used directly for the next step. m / z (ESI): 382.8 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.96 (br s, 1H), 7.96 – 7.93 (m, 2H), 7.37 – 7.32 (m, 2H), 4.75 (s, 2H), 3.37 - 3.25 (m, 7H), 2.03 – 1.97 (m, 4H). Step 3: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-(methoxymethyl)-N- (vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-086. To a stirred solution of 5-(4,4- difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-(methoxymethyl)pyrazine-2-carboxylic acid, Intermediate 1-086.2. (0.08 g, 0.210 mmol) in DMF (3.0 mL) were added DMAP (3 mg, 0.021 mmol), DIPEA (0.110 mL, 0.629 mmol), ethenesulfonamide (27 mg, 0.25 mmol) and T3P®(50% in EtOAc, 0.21 mL, 0.63 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture quenched with ice cold water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 10% to 30% EtOAc in hexanes) to give Compound 1- 086 (0.051 g, 0.108 mmol, 52% yield). m / z (ESI): 471.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.76 (br s, 1H), 8.04 (dd, J = 8.5, 5.5 Hz, 2H), 7.36 (t, J = 8.9 Hz, 2H), 7.05 (dd, J = 16.6, 10.0 Hz, 1H), 6.21 (d, J = 17.0 Hz, 1H), 6.06 (bs, 1H), 4.70 (s, 2H), 3.35 (br s, 7H), 2.05-1.90 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -95.29 (s, 2F), -112.078 (s, 1F). Example 1-087: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-hydroxy-N- (vinylsulfonyl)pyrazine-2-carboxamideCompound 1-087Step 1: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-hydroxypyrazine-2- carboxylic acid, Intermediate 1-087.1. A mixture of methyl 5-(4,4-difluoropiperidin-1-yl)-3- fluoro-6-(4-fluorophenyl) pyrazine-2-carboxylate, Intermediate 1-085.1 (1.35 g, 3.66 mmol) and 10% aqueous NaOH solution (7 mL, 3.66 mmol) was stirred at 60 °C for 6 h. The reaction mixture was concentrated under reduced pressure and acidified with 1.0 N HCl (pH= ~2). The precipitated solid was filtered, washed with water (2 × 10 mL), and dried under reduced pressure. The crude material was purified by reverse phase MPLC (C18, 0-60% ACN / H2O) to give 5-(4,4-difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-hydroxypyrazine-2- carboxylic acid, Intermediate 1-087.1 (0.45 g, 1.27 mmol, 35% yield). m / z (ESI): 354.1 (M+H)+. Step 2: 5-(4,4-Difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-hydroxy-N- (vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-087. To a stirred solution of 5-(4,4- difluoropiperidin-1-yl)-6-(4-fluorophenyl)-3-hydroxypyrazine-2-carboxylic acid, Intermediate 1-087.1 (300 mg, 0.85 mmol) in EtOAc (4.0 mL) were added DMAP (10 mg, 0.085 mmol), DIPEA (445 µL, 2.55 mmol), ethenesulfonamide (100 mg, 0.93 mmol) and T3P®(50% in EtOAc, 0.76 mL, 1.27 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with ice cold water (5 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase prep HPLC using column: Kromasil C18 (250 × 21.2) mm 5.0 µm; mobile phase: A: - 10 mM ammonium acetate in water, B: - ACN) to give 5-(4,4-difluoropiperidin-1- yl)-6-(4-fluorophenyl)-3-hydroxy-N-(vinylsulfonyl)pyrazine-2-carboxamide, Compound 1- 087 (12 mg, 0.027 mmol, 3% yield). m / z (ESI): 443.1 (M+H)+.1H NMR (400 MHz, DMSO- d6) δ 7.83 – 7.80 (m, 2H), 7.28 (t, J = 8.8 Hz, 2H), 7.02 – 6.96 (m, 1H), 6.05 (d, J = 16.4 Hz, 1H), 5.84 (br s, 1H), 3.32 – 3.28 (m, 4H), 2.00 – 1.91 (m, 4H). Exchangeable protons were not observed in1H-NMR.19F-NMR (377 MHz, DMSO-d6): δ -95.16 (s, 2F), -114.27 (s, 1F). Example 1-088: 5-((2R,3R)-3-Fluoro-2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamideIntermediate B-13-1 Intermediate 1-088.1Step 2 Compound 1-088 Step 1: 5-((2R,3R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-088.1. To a stirred solution of Intermediate B-13-1 (8.8 g, 26.4 mmol) in THF (40 mL), MeOH (40 mL) and water (20 mL) was added LiOH.H2O (1.264 g, 52.8 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 6 h. The volatile solvents (MeOH, THF) were removed under reduced pressure and the reaction mass was quenched with aqueous 1.5 N HCl solution (pH ~3). The precipitated solid was filtered, washed with cold water (100 mL), triturated with hexanes (~100 mL) and dried under vacuum to give Intermediate 1-088.1 (7.9 g, 24.74 mmol, 94% yield). m / z (ESI): 320.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.93 (br s, 1H), 8.71 (s, 1H), 7.67 – 7.64 (m, 2H), 7.38 –7.33 (m, 2H), 4.33 – 4.28 (m, 1H), 3.69 – 3.62 (m, 1H), 3.51 – 3.42 (m, 1H), 1.42 (d, J= 23 Hz, 3H), 1.30 – 1.28 (dd, J= 6.8 Hz, 2.0 Hz, 3H). Step 2: 5-((2R,3R)-3-Fluoro-2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamide, Compound 1-088. To a stirred solution of 5- ((2R,3R)-3-fluoro-2,3-dimethylazetidin-1-yl)-6-(4-fluorophenyl)pyrazine-2-carboxylic acid, Intermediate 1-088.1 (0.17 g, 0.532 mmol) in THF (4.0 mL) were added DIPEA (0.279 mL, 1.60 mmol), DMAP (6.50 mg, 0.053 mmol), ethenesulfonamide (68 mg, 0.64 mmol) and T3P®(50% in EtOAc, 0.93 mL, 1.59 mmol) at rt. The reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (elution: 0 to 40% EtOAc in hexanes) to give Compound 1-088 (160 mg, 0.392 mmol, 74% yield). m / z (ESI): 409.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.77 (br s, 1H), 8.69 (s, 1H), 7.87 – 7.83 (m, 2H), 7.40 – 7.35 (m, 2H), 7.11 – 7.05 (m, 1H), 6.37(d, J = 16.5 Hz, 1H), 6.26 (d, J = 9.9 Hz, 1H), 4.35 – 4.30 (m, 1H), 3.78 – 3.71 (m, 1H), 3.48 (dd, J =19.3, 10.5 Hz, 1H), 1.43 (d, J = 22.4 Hz, 3H), 1.29 (dd, J = 6.6, 2.2 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -112.18 – -112.25 (1F), -154.68 – -154.88 (1F). Method K Example 1-079: N-(Ethenylsulfonyl)-5-(3-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide Example 1-079-1: (S)-5-(3-Fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamide Example 1-079-2: (R)-5-(3-Fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamidePeak 1 Peak 2 Compound 1-079-1 Compound 1-079-2

[0646] Step 1: Methyl 6-(4-fluorophenyl)-5-(3-hydroxy-1-azaspiro[3.3]heptan-1- yl)pyrazine-2-carboxylate, Intermediate 1-079.1. To a solution of Intermediate A-1 (500 mg, 1.6 mmol) in DMSO (8 mL) was added 1-azaspiro[3.3]heptan-3-ol hydrochloride, (182 mg, 1.61 mmol, Enamine) and DIPEA (0.85 mL, 4.87 mmol, Sigma-Aldrich Inc.). The reactionmixture was stirred at 80 °C for 2 h. Then, the reaction mixture was diluted with EtOAc, quenched with sat. aq. NH4Cl, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over a plug of silica and Na2SO4, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0- 100% EtOAc in heptane, to provide Intermediate 1-079.1 (328 mg, 0.96 mmol, 59% yield). m / z (ESI): 344.1 (M+H)+.

[0647] Step 2: Methyl 5-(3-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)pyrazine- 2-carboxylate, Intermediate 1-079.2. To a solution of Intermediate 1-079.1 (328 mg, 0.955 mmol) in DCM (6 mL) at 0 °C was added dropwise DAST (2.5 M in DCM) (0.57 mL, 1.43 mmol, AstaTech, Inc). The mixture was stirred at 0°C for 30 min, then stirred at rt for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with DCM. The combined organic extracts were dried over Na2SO4 and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0-30% EtOAc in heptane, to provide Intermediate 1-079.2 (258 mg, 0.75 mmol, 78% yield). m / z (ESI): 346.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.60 – 7.44 (m, 2H), 7.38 – 7.22 (m, 2H), 5.30 – 5.01 (m, 1H), 3.83 (s, 3H), 3.72 – 3.53 (m, 1H), 3.36 – 3.30 (m, 1H), 3.16 (qd, J = 10.2, 3.6 Hz, 1H), 2.96 – 2.83 (m, 1H), 2.36 – 2.23 (m, 1H), 2.10 – 2.00 (m, 1H), 1.91 (qt, J = 10.3, 3.0 Hz, 1H), 1.74 – 1.56 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -112.44 (s, 1F), -185.10 (s, 1F).

[0648] Step 3: 5-(3-Fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-079.3. Intermediate 1-079.2 (258 mg, 0.75 mmol), LiOH∙H2O (157 mg, 3.74 mmol, Combi-Blocks Inc.), MeOH (7.0 mL) and H2O (350 µL) were stirred at 50 °C for 30 min. Then, the reaction mixture was concentrated, dissolved in EtOAc, and quenched with 2N HCl. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with sat. aq. NaHCO3, and brine. Then, the material was dried over Na2SO4,filtered, and concentrated to provide Intermediate 1-079.3, which was used directly for the next step. m / z (ESI): 332.2 (M+H)+.

[0649] Step 4: N-(Ethenylsulfonyl)-5-(3-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide, Compound 1-079. To a solution of Intermediate 1- 079.3 (248 mg, 0.75 mmol), DIPEA (0.4 mL, 2.3 mmol, Sigma-Aldrich Inc.), T3P®(50 wt% in EtOAc) (1.5 mL, 2.4 mmol, Sigma-Aldrich Inc.), DMAP (18.3 mg, 0.15 mmol, Sigma- Aldrich Inc.) in EtOAc (5 mL) was added ethenesulfonamide (0.067 mL, 0.82 mmol, Ambeed, Inc.). This mixture was allowed to stir at 50 °C for 20 min. Then, the reactionmixture was quenched with sat. aq. NH4Cl, and the aqueous layer was extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-50% EtOAc in heptane, to provide Compound 1-079 (191 mg, 0.45 mmol, 61% yield). m / z (ESI): 421.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.61 (br s, 1H), 8.68 (s, 1H), 7.75 – 7.56 (m, 2H), 7.39 – 7.30 (m, 2H), 7.07 (dd, J = 16.6, 9.9 Hz, 1H), 6.36 (d, J = 16.5 Hz, 1H), 6.25 (d, J = 10.0 Hz, 1H), 5.35 – 4.98 (m, 1H), 3.77 – 3.56 (m, 1H), 3.41 – 3.33 (m, 1H), 3.25 – 3.09 (m, 1H), 2.97 – 2.80 (m, 1H), 2.37 – 2.22 (m, 1H), 2.10 – 1.96 (m, 1H), 1.97 – 1.84 (m, 1H), 1.76 – 1.55 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -112.25 (s, 1F), -184.96 (s, 1F). Step 5: Compound 1-079 was purified by SFC using a ChiralPak IE, 2 × 25 cm 5 µm column with a mobile phase of 55% iPrOH using a flowrate of 80 mL / min. to generate a 1steluting isomer and a 2ndeluting isomer. The stereochemistry of the 1steluting isomer was assigned arbitrarily to (S)-5-(3-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4-fluorophenyl)-N- (vinylsulfonyl)pyrazine-2-carboxamide (Compound 1-079-1) (75 mg, 0.18 mmol, 40% yield). m / z (ESI): 421.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.62 (br d, J = 2.9 Hz, 1H), 8.68 (s, 1H), 7.73 – 7.63 (m, 2H), 7.40 – 7.29 (m, 2H), 7.07 (dd, J = 16.5, 9.8 Hz, 1H), 6.35 (d, J = 16.5 Hz, 1H), 6.24 (d, J = 10.0 Hz, 1H), 5.28 – 5.04 (m, 1H), 3.75 – 3.57 (m, 1H), 3.40 – 3.36 (m, 1H), 3.17 (qd, J = 10.2, 3.4 Hz, 1H), 2.96 – 2.83 (m, 1H), 2.30 (tt, J = 7.6, 3.8 Hz, 1H), 2.08 – 1.98 (m, 1H), 1.97 – 1.86 (m, 1H), 1.73 – 1.56 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -112.26 (s, 1F), -184.96 (s, 1F). The stereochemistry of the 2ndeluting isomer was assigned arbitrarily to (R)-5-(3-fluoro-1-azaspiro[3.3]heptan-1-yl)-6-(4- fluorophenyl)-N-(vinylsulfonyl)pyrazine-2-carboxamide (Compound 1-079-2) (69 mg, 0.16 mmol, 37% yield). m / z (ESI): 421.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.60 (br s, 1H), 8.68 (s, 1H), 7.73 – 7.63 (m, 2H), 7.38 – 7.27 (m, 2H), 7.07 (dd, J = 16.5, 10.0 Hz, 1H), 6.35 (d, J = 16.7 Hz, 1H), 6.24 (d, J = 10.0 Hz, 1H), 5.30 – 5.03 (m, 1H), 3.73 – 3.57 (m, 1H), 3.42 – 3.36 (m, 1H), 3.17 (qd, J = 10.2, 3.3 Hz, 1H), 2.97 – 2.82 (m, 1H), 2.36 – 2.24 (m, 1H), 2.07 – 1.98 (m, 1H), 1.97 – 1.84 (m, 1H), 1.73 – 1.56 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -112.27 (s, 1F), -184.96 (s, 1F). Method L Example 1-080: 5-(6,6-Difluoro-4-azaspiro[2.3]hexan-4-yl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamideIntermediate 1-080.2 Intermediate 1-080.3Intermediate 1-080.4 Compound 1-080

[0650] Step 1: Methyl 5-(6-benzhydryl-3,3-difluoro-1,6-diazaspiro[3.3]heptan-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-080.1. A mixture of Intermediate A-1 (250 mg, 0.80 mmol), 6-benzhydryl-3,3-difluoro-1,6-diazaspiro[3.3]heptane (265 mg, 0.88 mmol, PharmaBlock, Inc.), DIPEA (0.7 mL, 4 mmol, Sigma-Aldrich Inc.), and DMSO (5 mL) were stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc, quenched with sat. aq. NH4Cl, and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over a plug of silica gel and Na2SO4, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-40% EtOAc in heptane, to provide Intermediate 1-080.1 (76 mg, 0.14 mmol, 18% yield). m / z (ESI): 531.1 (M+H)+.

[0651] Step 2: Methyl 5-(3,3-difluoro-1,6-diazaspiro[3.3]heptan-1-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-080.2. Intermediate 1-080.1 (76 mg, 0.14 mmol), Pd / C (10 wt%) (40 mg, 0.04 mmol, Sigma-Aldrich Inc.), ammonium formate (30 mg, 0.48 mmol, Fisher Scientific) and EtOH (3 mL) were stirred at 60 °C for 2 h. Then,the reaction mixture was filtered over celite, eluting with EtOAc, and concentrated. The material was then dissolved in DCM and filtered over a cotton plug to provide Intermediate 1-080.2 (46 mg, 0.126 mmol, 88% yield). m / z (ESI): 365.2 (M+H)+.

[0652] Step 3: Methyl 5-(6,6-difluoro-4- azaspiro[2.3]hexan-4-yl)-6-(4- fluorophenyl)pyrazine-2-carboxylate, Intermediate 1-080.3. To a solution of N-(benzyloxy)- 1-[4-(trifluoromethyl)phenyl]formamido 2,2-dimethylpropanoate (153 mg, 0.39 mmol, Enamine) in degassed THF (2 mL) was added Intermediate 1-080.2 (94 mg, 0.258 mmol) and the reaction mixture was stirred at 45 °C for 1 h. The reaction mixture was quenched with sat. aq. NaHCO3and extracted with EtOAc. The organic extracts were washed with brine, dried over a plug of silica and Na2SO4, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-20% EtOAc in heptane, to provide Intermediate 1-080.3 (30 mg, 0.09 mmol, 33% yield). m / z (ESI): 350.2 (M+H)+.

[0653] Step 4: 5-(6,6-Difluoro- 4-azaspiro[2.3]hexan-4-yl)-6-(4-fluorophenyl)pyrazine-2- carboxylic acid, Intermediate 1-080.4. To a solution of Intermediate 1-080.3 (30 mg, 0.086 mmol) in MeOH (1 mL) and H2O (0.05 mL) was added LiOH∙H2O (18 mg, 0.43 mmol, Combi-Blocks Inc.). The reaction mixture was allowed to stir at 50 °C for 30 min. Then, the reaction mixture was concentrated, dissolved in EtOAc, quenched with HCl (2M), and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over a short plug of silica and Na2SO4and concentrated to provide Intermediate 1-080.4, which was used directly for the next step. m / z (ESI): 336.2 (M+H)+.

[0654] Step 5: 5-(6,6-Difluoro-4-azaspiro[2.3]hexan-4-yl)-N-(ethenylsulfonyl)-6-(4- fluorophenyl)-2-pyrazinecarboxamide, Compound 1-080. To a solution of Intermediate 1- 080.4 (28 mg, 0.08 mmol), DIPEA (50 µL, 0.29 mmol, Sigma-Aldrich Inc.), T3P®(50 wt% in EtOAc) (0.20 mL, 0.31 mmol, Sigma-Aldrich Inc.), and DMAP (2 mg, 0.02 mmol, Sigma- Aldrich Inc.) in EtOAc (1 mL), was added ethenesulfonamide (10 µL, 0.123 mmol, Ambeed, Inc.). The mixture was stirred at 50 °C for 20 min. Then, the reaction mixture was quenched with satd. NH4Cl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography, eluting with a gradient of 0%-40% EtOAc in heptane, to provide Compound 1-080 (12 mg, 0.03 mmol, 34% yield). m / z (ESI): 425.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.64 (br s, 1H), 8.58 (s, 1H), 7.84 – 7.65 (m, 2H), 7.36 (t, J = 9.0 Hz, 2H), 7.06 (dd, J = 16.5, 10.0 Hz, 1H), 6.35 (d, J = 16.5 Hz, 1H), 6.24 (d, J = 10.0 Hz, 1H), 3.99 (t, J = 11.6 Hz, 2H), 2.01(br d, J = 1.5 Hz, 2H), 1.08 – 0.98 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -104.95 (s, 2F), -111.86 (s, 1F). SECTION 3: Biochemical and Cellular Assays

[0655] Provided in this section is the biological evaluation of the specific examples provided herein. Example A. Helicase Assay for WRN Inhibition

[0656] Effects of compounds on WRN helicase activity were assessed with the helicase assay for WRN unwinding assay. The helicase DNA unwinding assay was adapted from a published protocol (see Sommers, J. A. et al. A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PLoS One 14, e0210525 (2019)).

[0657] Human WRN construct (Helicase Core w /  HRDC (hWRN517–1239)) was preincubated with compound in DMSO stock to final concentrations ranging from 0-200 uM (twofold serial dilutions, final DMSO at 2%) in 2 µL of assay buffer containing 30 mM Tris- HCl pH 7.5, 2 mM MgCl2, 50 mM NaCl, 0.1% Pluronic F-127, 0.02% bovine serum albumin (BSA). After 2 hours incubation at room temperature, unwinding reaction was initiated by adding 2 µL assay buffer containing ATP and pre-annealed dsDNA substrate. OLIGO A: TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC- BHQ2 OLIGO B: TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGCATGGGCTACACAAGCAAG- Cy5

[0658] In a total of 4 µL reaction, WRN was at a final concentration of 0.5 nM, ATP at 2 mM, and dsDNA at 75 nM. Reaction proceeded for 30 minutes at room temperature and stopped by 2 µL of 30 mM EDTA in assay buffer prior to fluorescence measurement at ex. / em.620 / 680 nm on EnVision (Revvity)). Activity was normalized to no-enzyme negative controls (0%) and to no-compound (DMSO only) positive controls and further analyzed for IC50 determination. Example B. Cell Viability Assay

[0659] The effects of compound on cellular viability were determined using the CellTiter-Glo® 2.0 Luminescent Cell Viability Assay (Promega, Madison, WI). The CellTiter-Glo® 2.0 Luminescent Cell Viability Assay is a homogenous method ofdetermining the number of viable cells in culture based on quanitation of the ATP present, an indicator of metabollically active cells. The assay system contains a propriatary thermostable luciferase and a beetle luciferin substrate, in a cell lysis buffer that also contains inhibitors of endogenous enzymes that are released during cell lysis (e.g, ATPases). Upon cell lysis, the luciferin substrate is mono-oxygenated by the lucioferase in the process of Mg2+, ATP and molecular oxygen, generating a stable “glow-type” luminescent signal that is proprtional to the amount of ATP present.

[0660] The cell line HCT116 (a microsatellite instable-high (MSI-H) cell line isolated from the colon of a male colorectal cancer patient) and SW480 cell line (a microsatellite stable (MSS) cell line isolated from the large intestine of a male Dukes C colorectal cancer patient) were used to determine cell viability after treatment with test compounds.

[0661] Assay ready plates were prepared the day before cell seeding with 200 nL of test compounds at 10 mM concentration diluted 2-fold for 18 points in 384-well black walled clear bottom tissue culture plate (Greiner, Kremsmunster, Austria). HCT116 cells were seeded in columns 3-12 and 14-22 with test compounds at 200 cells per well in RPMI 1640 Medium with 10% heat-inactivated fetal bovine serum (FBS HI) and 1X Penicillin- Streptomycin- Glutamine (PSG). SW480 cells were seeded in columns 3-12 and 14-22 at 2000 cells per well in RPMI 1640 Medium with 10% heat-inactivated fetal bovine serum (FBS HI) and 1X Penicillin-Streptomycin-Glutamine (PSG). Both cell lines were seeded in a volume of 40 µL medium per well. Columns 1-2, 13, and 23-24 were filled with 40 µL cell culture medium only. After 72 hours at 37°C in 5% CO2 baseline cell viability was measured by adding 20 µL of CellTiter-Glo® 2.0 reagent to all wells. Cell plates were then gently mixed on a plate shaker for 2 minutes at 500 rpm to lyse cells following a 15 minute room temperature incubation period and then reading the plate on a EnVision (Perkin Elmer, Waltham, MA) plate reader in luminescence mode. The baseline cell viability was substracted from the luminescence value of each well, and cell viability (% of DMSO) was plotted as a function of log compound concentration. The IC50 was then calculated for each compound with a Rout Fit Model in Genedata Screener (Basel, Switzerland).

[0662] The following data (Table Z) categorizes the IC50of each compound for helicase DNA unwinding activity and for inhibiting enzymatic activity of WRN in the indicated cells (HCT116, SW480) Table Z.

[0663] The results presented in Table Z have been generated with the in vitro assays described above. These assays may be used to test any of the compounds described herein to assess and characterize a compound’s biological activity. In view of the disclosure provided herein, compounds not specifically tested would be expected to have similar results.

Claims

What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: X is N or C-Rx, wherein Rxis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Ra)2, wherein each instance of Raindependently is H or C1-3alkyl; Y is N or C-Ry, wherein Ryis H, halogen, CN, OH, C1-3alkyl, C1-3haloalkyl, C0-3alkylene-C1-3alkoxy, C1-3haloalkoxy, or N(Rb)2, wherein each instance of Rbindependently is H or C1-3alkyl; wherein the C1-3alkyl of each instance of Raand Rbindependently is unsubstituted or substituted with one or more substituents and each substituent independently is OH or C1-3alkoxy; Z is N or C-Rz, wherein Rzis H or halogen; wherein 0, 1, 2, or 3 of X, Y, and Z is N, R1is C1-6alkyl, C1-6alkenyl, N(Rc)(Rd), C3-8cycloalkyl, C3-8cycloalkenyl, heterocycloalkyl having 3-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein Rcis H or C1-3alkyl and Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl; wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C0-6alkylene-OH, C0-3alkylene-CN, C1- 4alkyl, C1-4alkenyl, C0-3alkylene-C1-3haloalkyl, C0-6alkylene-C1-3alkoxy, C0-2alkylene- C1-3haloalkoxy, C0-3alkylene-C3-6cycloalkyl, or C0-3alkylene-phenyl; wherein, when R1is C6-10aryl, heteroaryl having 5-10 total ring atoms, C3- 8cycloalkyl, or heterocycloalkyl having 3-10 total ring atoms, then two adjacent substituents of R1, together with the atoms to which they are attached, may form C3-6cycloalkyl, C3-6cycloalkenyl, heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-6 total ring atoms and 1-3 heteroatoms independently selected from N, O and S;wherein the cycle formed by the two adjacent substituents of R1can be unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy; wherein, when R1is substituted with C0-3alkylene-C3-6cycloalkyl or C0- 3alkylene-phenyl, the C0-3alkylene-C3-6cycloalkyl or C0-3alkylene-phenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, or C1-3alkoxy; wherein, when R1is substituted with C1-4alkyl or C1-4alkenyl, the C1-4alkyl or C1-4alkenyl substituent on R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, NH2, NH(C1-3alkyl), or N(C1-3alkyl)2; R2is C6-10aryl or heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein R2is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, OH, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3cycloalkyl, or heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; R3is:wherein Q is N or C; wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2independently is H, D, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1- 3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is D, halogen, CN, C1-3alkyl, C1-3haloalkyl, OH, or C1- 3alkoxy.

3. The compound or salt of claim 1 or 2, wherein. 4 The compound or salt of claim 1 or 2, wherein5. The compound or salt of claim 1 or 2, wherein6 The compound or salt of claim 1 or 2, wherein7. The compound or salt of claim 1 or 2, wherein8. The compound or salt of claim 19. The compound or salt of claim 1 or 2, wherein10. The compound or salt of claim 1 or 2, wherein,.

11. The compound or salt of any one of claims 1, 2, and 10, whereini12. The compound or salt of any one of claims 1, 2, and 10, whereini13. The compound or salt of any one of claims 1, 2, and 10, whereini.The compound or salt of any one of claims 1, 2, and 10, wherein.The compound or salt of any one of claims 1, 2, and 10, wherein.The compound or salt of any one of claims 1, 2, and 10, wherein. The compound or salt of any one of claims 1, 2, and 10, wherein18. The compound or salt of any one of claims 1, 2, and 10, wherein X is N.

19. The compound or salt of any one of claims 1, 2, and 10, wherein X is C-Rx.

20. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis H, halogen, N(Ra)2, C1-3alkyl, or C1-3alkoxy.

21. The compound or salt of any one of claims 1, 2, 10, 19, and 20, wherein Rxis H, F, Cl, NH2, methyl, or methoxy.

22. The compound or salt of any one of claims 1, 2, 10, 19, and 20, wherein Rxis H or methyl.

23. The compound or salt of any one of claims 1, 2, 10, 19, and 20, wherein Rxis OH.

24. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis C0-3alkylene-C1-3alkoxy.

25. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis CH2-C1-3alkoxy.

26. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis methoxy or CH2-methoxy.

27. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis C1-3haloalkoxy.

28. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis halogen.

29. The compound or salt of any one of claims 1, 2, 10, 19, and 28, wherein Rxis F, Cl, or Br.

30. The compound or salt of any one of claims 1, 2, 10, and 19, wherein Rxis H.

31. The compound or salt of any one of claims 1, 2, 10, 19, and 20, wherein Rxis methyl.

32. The compound or salt of any one of claims 1, 2, 10, 19, and 20, wherein Rxis N(Ra)2.

33. The compound or salt of any one of claims 1, 2, 10, 19, 20, and 32, wherein each Raindependently is H or methyl.

34. The compound or salt of any one of claims 1, 2, 10, 19, 20, 32, and 33, wherein at least one instance of Rais H.

35. The compound or salt of any one of claims 1, 2, 10, 19, 20, and 32-34, wherein at least one instance of Rais methyl.

36. The compound or salt of any one of claims 1, 2, 10, 19, 20, and 32-34, wherein each Rais H.

37. The compound or salt of any one of claims 1, 2, 10, 19, 20, 32, and 33-35, wherein each Rais methyl.

38. The compound or salt of any one of claims 1, 2, 10, 19, and 20, wherein Rxis methoxy.

39. The compound or salt of any one of claims 1-3, wherein Y is N.

40. The compound or salt of any one of claims 1-3, wherein Y is C-Ry.

41. The compound or salt of any one of claims 1-3 and 40, wherein Ryis H.

42. The compound or salt of any one of claims 1-3 and 40, wherein Ryis CN or N(H)2.

43. The compound or salt of any one of claims 1-3, wherein Z is N.

44. The compound or salt of any one of claims 1-3, wherein Z is C.

45. The compound or salt of any one of claims 1-44, wherein R1is C1-4alkyl, C1- 4alkenyl, N(Rc)(Rd), C4-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

46. The compound or salt of any one of claims 1-45, wherein R1is C1-4alkyl, C1-4alkenyl, or N(Rc)(Rd).

47. The compound or salt of any one of claims 1-46, wherein R1is C1-4alkyl or C1-4alkenyl.

48. The compound or salt of any one of claims 1-47, wherein R1is C1-3alkyl or C1-3alkenyl.

49. The compound or salt of any one of claims 1-46, wherein R1is N(Rc)(Rd).

50. The compound or salt of any one of claims 1-46 and 49, wherein Rcis H.

51. The compound or salt of any one of claims 1-46 and 49, wherein Rcis C1-3alkyl.

52. The compound or salt of any one of claims 1-46, 49, and 51, wherein Rcis methyl.

53. The compound or salt of any one of claims 1-46 and 49-52, wherein Rdis C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkenyl.

54. The compound or salt of any one of claims 1-46 and 49-53, wherein Rdis C1-6alkyl.

55. The compound or salt of any one of claims 1-46 and 49-53, wherein Rdis C3-6cycloalkyl or C3-6cycloalkenyl.

56. The compound or salt of any one of claims 1-46, 49-53, and 55, wherein Rdis C4-6cycloalkyl.

57. The compound or salt of any one of claims 1-45, wherein R1is C4-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

58. The compound or salt of any one of claims 1-45 and 57, wherein R1is heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

59. The compound or salt of any one of claims 1-45, 57, and 58, wherein R1is heterocycloalkyl having 4 total ring atoms and one heteroatom independently selected from N, O, and S.

60. The compound or salt of any one of claims 1-45, 57, and 58, wherein R1is heterocycloalkyl having 5 total ring atoms and one heteroatom independently selected from N, O, and S.

61. The compound or salt of any one of claims 1-45, 57, and 58, wherein R1is heterocycloalkyl having 6 total ring atoms and one heteroatom independently selected from N, O, and S.

62. The compound or salt of any one of claims 1-45, 57, and 58, wherein R1is heterocycloalkyl having 7 total ring atoms and one heteroatom independently selected from N, O, and S.

63. The compound or salt of any one of claims 1-45, 57, 58, and 62, wherein R1is heterocycloalkyl comprising two spiro-connected rings, wherein rings are connected through a shared carbon atom, and the heterocycloalkyl is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1-3haloalkyl.

64. The compound or salt of any one of claims 1-45, 57, 58, and 62, wherein the two spiro-connected rings comprises two four-membered rings or one four-membered ring and one three-membered ring.

65. The compound or salt of any one of claims 1-45, and 57-63, wherein R1has one N and one O as ring heteroatoms.

66. The compound or salt of any one of claims 1-45, and 57-63, wherein R1has one N as a ring heteroatom.

67. The compound or salt of any one of claims 1-45, and 57-63, wherein R1has one O as a ring heteroatom.

68. The compound or salt of any one of claims 1-45, and 57-67, wherein R1is C6-10aryl or heteroaryl having 5-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

69. The compound or salt of any one of claims 1-45, wherein R1is C4-7cycloalkyl or heterocycloalkyl having 4-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

70. The compound or salt of any one of claims 1-45 and 69, wherein R1has two adjacent substituents that, together with the atoms to which they are attached, formC3-6cycloalkyl, C3-6cycloalkenyl, or a heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

71. The compound or salt of any one of claims 1-70, wherein R1is heterocycloalkyl that comprises spiro-connected rings and the heterocycloalkyl is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, C3-4cycloalkyl, or C0-3alkylene-C1-3haloalkyl.

72. The compound or salt of any one of claims 1-71, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

73. The compound or salt of any one of claims 1-71, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

74. The compound or salt of any one of claims 1-70, wherein R1is heterocycloalkyl having 8-10 total ring atoms and two fused rings, further wherein two non-adjacent atoms on a ring join together to form a C1-2alkylene bridge.

75. The compound or salt of any one of claims 1-70 and 74, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

76. The compound or salt of any one of claims 1-70, wherein R1is bridged- heterocycloalkyl having 5 or 6 total ring atoms and two non-adjacent atoms join together to form a C1-2alkylene bridge.

77. The compound or salt of any one of claims 1-45, 58, 69, and 76, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

78. The compound or salt of any one of claims 1-45, 58, 69, and 76, wherein R1isR1 is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

79. The compound or salt of any one of claims 1-45, 57, 58, 66, 69, and 70, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

80. The compound or salt of any one of claims 1-45, 57, 58, 66, and 69, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

81. The compound or salt of any one of claims 1-45, 57, 58, 66, and 69, wherein R1isR1is unsubstituted or substituted by replacing one or more ring H atoms with one or more substituents.

82. The compound or salt of any one of claims 1-45, 57, and 70, wherein R1is aryl with two adjacent substituents that provide a 5-membered heterocyclyl represented bywhich can be unsubstituted or further substituted by replacing one or more ring H atoms with one or more substituents of R1.

83. The compound or salt of any one of claims 1-82, wherein R1is unsubstituted or substituted with one or more substituents and each substituent independently is halogen, C1-4alkyl, C1-4alkenyl unsubstituted or substituted with halogen, C0- 3alkylene-C1-3haloalkyl, C0-3alkylene-C3-6cycloalkyl, C6-10aryl, or two adjacent substituents that, together with the atoms to which they are attached, form C3-6cycloalkyl group or a heterocycloalkyl having 4-6 total ring atoms and 1-2 heteroatoms independently selected from N or O.

84. The compound or salt of any one of claims 1-83, wherein each substituent of R1independently is F, methyl, ethyl, =C-F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, cyclopropyl, phenyl.

85. The compound or salt of any one of claims 1-83, wherein each substituent of R1independently is F, methyl, ethyl, CF3, CHF2, CH2F, or cyclopropyl.

86. The compound or salt of any one of claims 1-85, wherein R1is substituted with 1, 2, 3, 4, or 5 substituents.

87. The compound or salt of any one of claims 1-85, wherein R1is substituted with 1, 2, 3, or 4 substituents.

88. The compound or salt of any one of claims 1-85, wherein R1is substituted with 3 or 4 substituents.

89. The compound or salt of any one of claims 1-85, wherein R1is substituted with 1, 2, or 3 substituents.

90. The compound or salt of any one of claims 1-85, wherein R1is substituted with 1 or 2 substituents.

91. The compound or salt of any one of claims 1-85, wherein R1is substituted with 1 substituent.

92. The compound or salt of any one of claims 1-91, wherein R1is substituted with C3-6cycloalkyl that is unsubstituted or substituted with one or more halogens.

93. The compound or salt of claim 92, wherein the C3-6cycloalkyl substituent of R1is unsubstituted.

94. The compound or salt of claim 92, wherein the C3-6cycloalkyl substituent of R1is substituted with one or more halogens.

95. The compound or salt of claim 92, wherein the C3-6cycloalkyl substituent of R1is substituted with 1, 2, or 3 halogens.

96. The compound or salt of any one of claims 1-90, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen, OH, CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C3-4cycloalkyl.

97. The compound or salt of any one of claims 1-90, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen, C1-3alkyl, C1-3haloalkyl.

98. The compound or salt of any one of claims 1-91, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen or C1-3alkyl.

99. The compound or salt of any one of claims 1-91, wherein R1is substituted with one or more substituents and each R1substituent independently is halogen or methyl.

100. The compound or salt of any one of claims 1-91, wherein R1is substituted with 1, 2, 3, or 4 substituents and each R1substituent independently is halogen or methyl.

101. The compound or salt of any one of claims 1-97, wherein R1is substituted with one or more substituents and each R1substituent independently is C1-3haloalkyl.

102. The compound or salt of any one of claims 1-83, wherein R1is unsubstituted.

103. The compound or salt of any one of claims 1-102, wherein R2is C6-10aryl.

104. The compound or salt of any one of claims 1-103, wherein R2is phenyl.

105. The compound or salt of any one of claims 1-102, wherein R2is heteroaryl having 5-10 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

106. The compound or salt of any one of claims 1-102 and 105, wherein R2is pyrimidinyl.

107. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is OH or CN.

108. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen, C1-3alkyl, or C1-3alkoxy.

109. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen and CN.

110. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen and OH.

111. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is halogen.

112. The compound or salt of any one of claims 108-111, wherein each halogen substituent of R2independently is F, Cl, or Br.

113. The compound or salt of any one of claims 108-111, wherein halogen is F.

114. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is C1-3alkyl.

115. The compound or salt of any one of claims 1-106, wherein R2is substituted with one or more substituents and each substituent independently is methyl.

116. The compound or salt of any one of claims 1-115, wherein R2is substituted with 1, 2, 3, or 4 substituents.

117. The compound or salt of any one of claims 1-115, wherein R2is substituted with 1, 2, or 3 substituents.

118. The compound or salt of any one of claims 1-115, wherein R2is substituted with 1 or 2 substituents.

119. The compound or salt of any one of claims 1-115, wherein R2is substituted with 1 substituents.

120. The compound or salt of any one of claims 1-106, wherein R2is unsubstituted.

121. The compound or salt of any one of claims 1-120, wherein each of Re, Rz, Rv, Rw, Rwc1and Rwc2of R3independently is H, halogen, C1-3alkyl, C1-3haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-3alkoxy, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RW1)(RW2), C3-7cycloalkyl, or C0-2alkylene-heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the RW1and RW2independently is H or C1-4alkyl; wherein R3is unsubstituted or substituted with 1-3 substituents and each substituent independently is halogen, CN, C1-3alkyl C1-3haloalkyl, OH, or C1-3alkoxy.

122. The compound or salt of any one of claims 1-120, wherein R3is.

123. The compound or salt of any one of claims 1-120, wherein R3is Rvis H.

124. The compound or salt of any one of claims 1-123, wherein Rwis H or C1-3alkyl.

125. The compound or salt of any one of claims 1-123, wherein Rwis H.

126. The compound or salt of any one of claims 1-125, wherein Rwis C1-3alkyl.

127. The compound or salt of any one of claims 1-125, wherein Rwis methyl.

128. The compound or salt of any one of claims 1-123, wherein Rwis C0-2alkylene- heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

129. The compound or salt of any one of claims 1-123, wherein Rwis CH2- heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

130. The compound or salt of any one of claims 1-123, wherein Rwis CH2- heterocycloalkyl having 3-5 total ring atoms and 1-2 heteroatoms independently selected from N, O, and S.

131. The compound or salt of any one of claims 1-123, wherein Rwis CH2- heterocycloalkyl having 3-5 total ring atoms and 1-2 heteroatoms independently selected from N or O.

132. The compound or salt of any one of claims 1-123, wherein Rwis C0-2alkylene- heterocycloalkyl that is unsubstituted or substituted with one or more substituents and each substituent independently is C1-3alkyl, C1-3alkenyl, halogen, or C1-3haloalkyl.

133. The compound or salt of any one of claims 1-123, wherein Rwis C0-2alkylene- heterocycloalkyl that is unsubstituted or substituted with 1-2 halogen.

134. The compound or salt of any one of claims 1-121, wherein R3is.

135. The compound or salt of any one of claims 1-121 and 134, wherein each of Rw, Rz, and Rwc1independently is H, halogen, or C1-3alkyl.

136. The compound or salt of any one of claims 1-121 and 135, wherein each of Rw, Rz, and Rwc1is H.

137. The compound or salt of any one of claims 1-121, 134, and 135, wherein each of Rwand Rzindependently is H.

138. The compound or salt of any one of claims 1-121, 134, and 135, wherein R3is.

139. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is H.

140. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is methyl.

141. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is C3-7cycloalkyl.

142. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is C4-6cycloalkyl.

143. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 3-8 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

144. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

145. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from N.

146. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from O.

147. The compound or salt of claim 1-121, 134, 135, and 138, wherein Rwc1is heterocycloalkyl having 4-6 total ring atoms and 1-3 heteroatoms independently selected from S.

148. The compound or salt of any one of claims 1-121, 134, 135, and 138-147, wherein Rwc2is H.

149. The compound or salt of claim 1-121, 134, 135, and 138-147, wherein Rwc2is C1-3alkyl.

150. The compound or salt of claim 1-121, 134, 135, and 138-147, wherein Rwc2is methyl.

151. The compound or salt of any one of claims 1-148, wherein R3is.

152. The compound or salt of any one of claims 1-148, wherein Rvis H.

153. The compound or salt of any one of claims 1-148, wherein RZis H, halogen, C1-3alkyl, C1-3haloalkyl, C0-2alkylene-C1-3haloalkoxy, C0-2alkylene-CN, or C1-3alkylene-NH2.

154. The compound or salt of any one of claims 1-121, 134, 135, 138, and 148, wherein R3is155. The compound or salt of any one of claims 1-138 and 148, wherein R3is156. The compound or salt of any one of claims 1-133, wherein Formula (I) has a structure of Formula (II):

157. The compound or salt of claim 156, wherein Rwis H.

158. The compound or salt of claim 156 or 157, wherein X is CH, Y is N, and Z is N.

159. The compound or salt of any one of claims 156-158, wherein R1is heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

160. The compound or salt of any one of claims 1-121, wherein Formula (I) has a structure of Formula (III):

161. The compound or salt of claim 160, wherein X is CH, Y is N, and Z is N.

162. The compound or salt of claim 160 or 161, wherein R1is heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

163. The compound or salt of any one of claims 160-162, wherein Rwc1is H, C1- 3alkyl, C0-2alkylene-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

164. The compound or salt of any one of claims 1-45, 57, 69, 83, 84, 86, 87, and 103-163, wherein R1is , ,, , , , , ,165. The compound or salt of any one of claims 1-45, 57, 58, 66, 69, 71, 73, 83, and 103-163, wherein R1is ,166. The compound or salt of any one of claims 1-45, 57, 69, 83, and 103-163, wherein R1is167. The compound or salt of any one of claims 1-45, 57, 58, 61, 66, 69, 83, and 103-163, wherein R1is168. The compound or salt of any one of claims 1-45, 57, 70, 83, and 103-163, wherein R1is.

169. The compound or salt of any one of claims 1-45, 57, and 103-163, wherein R1is.

170. The compound or salt of claim 1, wherein the compound is a compound listed in Table A.

171. The compound or salt of claim 170, wherein the compound is a compound listed in Table B.

172. The compound or salt of claim 1, wherein the compound is a compound listed in Table A’.

173. The compound or salt of claim 172, wherein the compound is a compound listed in Table B’.

174. The compound or salt of any one of claims 1-45, 57-59, 66, 69, 80, 81, 83-88, 96, 97, 100, 103, 104, 108-113, 116-119, 121-124, 127, and 156-159, wherein the compound is.

175. The compound or salt of claim 1-121, wherein the compound is177. The compound or salt of claim 1-121, 134, 135, 138, 148, 154, 155, and 160- 162 wherein the compound is.

178. The compound or salt of claim 1-148, wherein the compound is179. The compound or salt of claim 1-148, wherein the compound is180. The compound or salt of claim 1-148, wherein the compound is , ,181. The compound or salt of claim 1-148, wherein the compound is182. The compound or salt of claim 1-148, wherein the compound is183. The compound or salt of claim 1-148, wherein the compound is.

184. The compound or salt of claim 1-148, wherein the compound is185. The compound or salt of claim 1, wherein the compound is.

186. The compound or salt of claim 1, wherein the compound is.

187. The compound or salt of claim 1, wherein the compound is.

188. The compound or salt of claim 1, wherein the compound is.

189. The compound or salt of claim 1, wherein the compound is r salt of claim 1, wherein the compound is.

191. The compound or salt of claim 1, wherein the compound is.

193. The compound or salt of claim 1, wherein the compound is.

195. The compound or salt of claim 1, wherein the compound is.

197. The compound or salt of claim 1, wherein the compound is.

198. The compound of any one of claims 1-197.

199. The salt of any one of claims 1-197.

200. A pharmaceutical composition comprising the compound or salt of any one of claims 1-199 and a pharmaceutically acceptable excipient.

201. A method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of claims 1-199 or the composition of claim 200.

202. The method of claim 201, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

203. The method of claim 201 or 202, wherein the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer, or any combination of the foregoing.

204. A compound or salt of any one of claims 1-199 or the pharmaceutical composition of claim 200 for use as a medicament.

205. A compound or salt of any one of claims 1-199 or the pharmaceutical composition of claim 200 for use in the treatment of cancer.

206. The use of the compound or salt of any one of claims 1-199 or the pharmaceutical composition of claim 200 for the manufacture of a medicament for the treatment of cancer.

207. The use of the compound of salt of any one of claims 1-199 or the pharmaceutical composition of claim 200, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

208. The use of any one of claims 1-199 or the pharmaceutical composition of claim 200, wherein the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian, urothelial, small bowel, brain, biliary tract, bladder, gastroesophageal, head-and-neck, skin, sarcoma, thoracic, pancreatic cancer, or any combination of the foregoing.

209. The use of any one of claims 206-208, wherein the cancer is characterized as tumor-agnostic MSI-H / dMMR cancer.

210. A process for preparing the compound or salt of any one of claims 1-199, comprising providing a compound or salt of any one of Tables C, 1-1, 1-2, or 1-3 and converting it into a separate compound or salt of any one of Tables 1A, 1B, 1C, 2-1, 2-2, 2-3, 2-4, 2-5, 2-7, 2-8, A, A’, B, or B’.

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