Pyridine derivatives for treating cancer

Abstract

The disclosure provides for compounds, compositions, and methods for modulating CKAP5.

Description

WSGR Docket No. 59792-717.601PYRIDINE DERIVATIVES FOR TREATING CANCERCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 715,063 filed November 1, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Cytoskeleton-associated protein 5 (CKAP5, also known as chTOG or XMAP215) is a plus-end tracking microtubule-associated protein that promotes microtubule polymerization and stability. It localizes to the mitotic spindle apparatus, where it plays a critical role in chromosome alignment and segregation during cell division. Eoss of CKAP5 activity disrupts mitosis, leading to aberrant spindle formation, chromosome misalignment, and ultimately mitotic arrest and cell death.

[0003] Although several mitotic proteins have been successfully targeted in cancer therapy, these agents are often limited by significant adverse events. Notably, recent studies suggest that CKAP5 is preferentially required in chromosomally unstable cells relative to normal cells, raising the possibility that agents targeting CKAP5 could achieve a favorable therapeutic index in cancer patients and identifying CKAP5 as a compelling candidate cancer target.SUMMARY

[0004] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I) as disclosed herein.

[0005] Also disclosed herein is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (la).WSGR Docket No. 59792-717.601

[0006] Also disclosed herein is a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (lb).

[0007] Also disclosed herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Ic).

[0008] Also disclosed herein is a compound of Formula (la-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (la-1).

[0009] Also disclosed herein is a compound of Formula (Ib-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Ib-1).WSGR Docket No. 59792-717.601

[0010] Also disclosed herein is a compound of Formula (Ic-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Ic-1).

[0011] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0012] Also disclosed herein is a method of modulating CKAP5 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0013] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0014] In some embodiments, the disease or disorder is cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A shows WT He La cells expressing GFP -tagged EB3.

[0016] FIG. IB shows He La cells expressing GFP-tagged EB3 transduced with a CKAP5 -targeting CRISPR lentivirus to knockout and deplete CKAP5.

[0017] FIG. 2A shows untreated HeLa cells expressing GFP-tagged EB3.

[0018] FIG. 2B shows HeLa cells expressing GFP-tagged EB3 treated with Compound A.INCORPORATION BY REFERENCE

[0019] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONDefinitions

[0020] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” andWSGR Docket No. 59792-717.601 variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0021] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0022] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0023] ‘ ‘Oxo” refers to =0.

[0024] ‘ ‘Amino” refers to -NH2.

[0025] “Hydroxy” refers to -OH.

[0026] “Carboxyl” refers to -COOH.

[0027] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2-methyl-l- butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3- dimethyl-1 -butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range, such as “Ci-Ce alkyl,” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl, a Ci- C5 alkyl, a C1-C4 alkyl, or a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is independently optionally substituted with halogen.

[0028] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about theWSGR Docket No. 59792-717.601 double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2O7UCH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkenyl,” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is independently optionally substituted with halogen.

[0029] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkynyl,” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is independently optionally substituted with halogen.

[0030] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, - OMe, -NH2, or -NO2. In some embodiments, the alkylene is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is independently optionally substituted with halogen.

[0031] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -WSGR Docket No. 59792-717.601COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is independently optionally substituted with halogen.

[0032] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is independently optionally substituted with halogen.

[0033] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 folly saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 folly saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 folly saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered folly saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclof l. l. l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl,WSGR Docket No. 59792-717.601 cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

[0034] ‘ ‘Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro.

[0035] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.

[0036] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0037] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0038] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0039] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is independently optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -WSGR Docket No. 59792-717.601CFs, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is independently optionally substituted with halogen.

[0040] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 8-membered partially or fully saturated ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 6- membered partially or fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 6- membered fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 folly saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 folly saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 folly saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 folly saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydroforyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzoforan-l-yl, 3-oxo-l,3-WSGR Docket No. 59792-717.601 dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 - to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is independently optionally substituted with halogen.

[0041] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl is a 5 - to 10-membered ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5 - to 6-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may beWSGR Docket No. 59792-717.601 optionally quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is independently optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, - OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is independently optionally substituted with halogen. In some embodiments, the heteroaryl is independently optionally substituted with on oxo to form an N-oxide.

[0042] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc ).

[0043] The term “each alkyl is independently optionally substituted with one or more R” means that any alkyl moiety is independently optionally substituted with one or more R. For example, the alkyl moiety in a deuteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is independently optionally substituted with one or more R.WSGR Docket No. 59792-717.601

[0044] The term “one or more” when referring to an optional substituent means that the subject group is independently optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is independently optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is independently optionally substituted with one, two, or three substituents. In some embodiments, the subject group is independently optionally substituted with one or two substituents. In some embodiments, the subject group is independently optionally substituted with one substituent. In some embodiments, the subject group is independently optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.

[0045] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0046] ‘ ‘Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0047] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0048] As used herein, a “disease or disorder associated with CKAP5” or, alternatively, “a CKAP5 - mediated disease or disorder” means any disease or other deleterious condition in which CKAP5, or a mutant thereof, is known or suspected to play a role.Compounds

[0049] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a disease or disorder associated with CKAP5.

[0050] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heteroaryl;WSGR Docket No. 59792-717.601 each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; and / or two R1on the same atom form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two Rlaon the same atom form an oxo; n is 0, 1, 2, 3, or 4;Ring B is 5 -membered ring; each R2is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4;= is a single or a double bond;U is C or N;T is C or N; provided that not both U and T are N;X is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Y is N or CR4;WSGR Docket No. 59792-717.601R4is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Z is N or CR5;R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;R6is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2- Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;R7is hydrogen or Ci-Cealkyl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andL is absent or Ci-Csalkylene independently optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, - S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci- C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2,WSGR Docket No. 59792-717.601Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-Cshaloalkoxy, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, Ci-Csheteroalkyl, Cs-C. cycloalkyl. or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo.

[0051] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - - L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, SF5, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -NRaC(=N(Ra))Rb, - C(=N(Ra))N(Ra)2, -S(=O)NRcRd, -S(=O)2ORa, -OS(=O)2Ra, -N=S(=O)RcRd, -S(=O)(=NRb)(Rb), Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted; and / or two R1are taken together to form an oxo; n is 0, 1, 2, 3, or 4;Ring B is 5 -membered ring; each R2is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted; m is 0, 1, 2, 3, or 4;= is a single or a double bond;U is C or N;T is C or N; provided that not both U and T are N;X is N or CR3;WSGR Docket No. 59792-717.601R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted;Y is N or CR4;R4is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted;Z is N or CR5;R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted;R6is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2- Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;R7is hydrogen or Ci-Cealkyl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;WSGR Docket No. 59792-717.601 or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andL is absent or Ci-Csalkylene independently optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, - S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci- C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci -Chalky I. Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-CChaloalkoxy. C-CChydroxyalkyl. Ci-Ckaminoalkyl. Ci-CChctcroalkyl. Cs-C. cycloalkyl. or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo.

[0052] In some embodiments of a compound of Formula (I), Ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring B is 5 -membered heteroaryl comprising one, two, three, or 4 heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), Ring B is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), Ring B is 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), Ring B is 5 -membered heteroaryl comprising one or two heteroatoms that are N. In some embodiments of a compound of Formula (I), Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl. In some embodiments of a compound of Formula (I), Ring B is pyrazolyl.

[0053] In some embodiments of a compound of Formula (I), Ring B is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring B is 5 -membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S. In some embodiments of a compound of Formula (I), Ring B is 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), Ring B is 5 -membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (I), Ring B is 5- membered heterocycloalkyl comprising one or two heteroatoms that are O. In some embodiments of a compound of Formula (I), Ring B is tetrahydrofuranyl, 1,3-dioxolanyl, or pyrrolidinyl. In some embodiments of a compound of Formula (I), Ring B is 1,3-dioxolanyl.

[0054] In some embodiments of a compound of Formula (I), each R2is independently halogen, -CN, - OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), each R2is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), each R2is independently halogen or Ci-Cealkyl.

[0055] In some embodiments of a compound of Formula (I), m is 0 or 1. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 0.WSGR Docket No. 59792-717.601

[0056] In some embodiments of a compound of Formula (I), U is C and T is C. In some embodiments of a compound of Formula (I), U is N and T is C. In some embodiments of a compound of Formula (I), U is C and T is N.

[0057] In some embodiments of a compound of Formula (I), the compound is of Formula (la):Formula (la).

[0058] In some embodiments of a compound of Formula (I), the compound is of Formula (lb):Formula (lb).

[0059] In some embodiments of a compound of Formula (I), the compound is of Formula (Ic):Formula (Ic).

[0060] In some embodiments of a compound of Formula (I) or (la)-(Ic), X is CR3. In some embodiments of a compound of Formula (I) or (la)-(Ic), X is N.

[0061] In some embodiments of a compound of Formula (I) or (la)-(Ic), Y is CR4. In some embodiments of a compound of Formula (I) or (la)-(Ic), Y is N.

[0062] In some embodiments of a compound of Formula (I) or (la)-(Ic), Z is CR5. In some embodiments of a compound of Formula (I) or (la)-(Ic), Z is N.

[0063] In some embodiments of a compound of Formula (I) or (la)-(Ic), R6is hydrogen, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R6is hydrogen, Ci-Cealkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R6is hydrogen.

[0064] In some embodiments of a compound of Formula (I) or (la)-(Ic), R7is hydrogen, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of aWSGR Docket No. 59792-717.601 compound of Formula (I) or (la)-(Ic), R7is hydrogen, Ci-Cealkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R7is hydrogen.

[0065] In some embodiments of a compound of Formula (I) or (la)-(Ic),

[0066] In some embodiments of a compound of Formula (I) or (la), the compound is of Formula (la-1) :Formula (la-1).

[0067] In some embodiments of a compound of Formula (I) or (lb), the compound is of Formula (Ib-1):Formula (Ib-1).

[0068] In some embodiments of a compound of Formula (I) or (Ic), the compound is of Formula (Ic-1):Formula (Ic-1).

[0069] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen, halogen, or Ci- Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogenWSGR Docket No. 59792-717.601 or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen.

[0070] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen, halogen, -CN, -OH, -ORa, - NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is halogen.

[0071] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R5is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R5is hydrogen, halogen, or Ci- Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R5is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R5is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R5is hydrogen.

[0072] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5- or 6- membered heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S.

[0073] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 6- membered heteroaryl comprising one or two heteroatoms that are N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is pyridinyl.

[0074] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5- membered heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5 -membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5- membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5- membered heteroaryl comprising one, two, or three heteroatoms that are N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5-membered heteroaryl comprising one or twoWSGR Docket No. 59792-717.601 heteroatoms that are N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, or triazolyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is pyrazolyl or triazolyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (Ia-1)- (Ic-1), Ring A is pyrazolyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic- 1), Ring A is triazolyl.

[0075] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is a fused bicyclic ring. In some embodiments, Ring A is a 5-5 fused bicyclic ring. In some embodiments, Ring A issome embodiments, Ring A is a 5-6 fused bicyclic ring. In some embodiments, Ring A isIn some embodiments,

[0076] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla.

[0077] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0078] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently Ci-Cealkyl independently optionally substituted with one or more Rla.

[0079] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently Ci-Ceaminoalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0080] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently Ci-Ceaminoalkyl.

[0081] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently -L-cycloalkyl or -L-heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0082] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently -L-cycloalkyl or -L-heterocycloalkyl.WSGR Docket No. 59792-717.601

[0083] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0084] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently cycloalkyl or heterocycloalkyl.

[0085] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently cycloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 3- to 6-membered cycloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 3- to 5-membered cycloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 3- to 4- membered cycloalkyl.

[0086] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently heterocycloalkyl independently optionally substituted with one or more Rla.In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently heterocycloalkyl.

[0087] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la- l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N, O, and S and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla.

[0088] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la- l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N, O, and S and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla.

[0089] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N and O and wherein the heterocycloalkyl is independently optionallyWSGR Docket No. 59792-717.601 substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la- l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N and O and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla.

[0090] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N and O and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la- l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N and O and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla.

[0091] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms that is N and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6- membered heterocycloalkyl comprising one or two heteroatoms that is N and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom that is N and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla.

[0092] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms that is N and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5- membered heterocycloalkyl comprising one or two heteroatoms that is N and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom that is N and wherein the heterocycloalkyl is independently optionally substituted with one or more Rla.

[0093] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic),WSGR Docket No. 59792-717.601 or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN, O, and S.

[0094] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN, O, and S.

[0095] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN and O.

[0096] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN and O.

[0097] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms that is O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms that is O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom that is O.

[0098] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms that is O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5 -membered heterocycloalkyl comprising one or two heteroatoms that is O. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom that is O.WSGR Docket No. 59792-717.601

[0099] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms that is N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms that is N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 6-membered heterocycloalkyl comprising one heteroatom that is N.

[0100] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms that is N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms that is N. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently 4- to 5-membered heterocycloalkyl comprising one heteroatom that is N.

[0101] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0102] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0103] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, or Ci-Cehaloalkyl; and / or two Rlaon the same atom form an oxo. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently halogen, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two Rlaon the same atom form an oxo. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently - C(=O)Raor -C(=O)NRcRd; and / or two Rlaon the same atom form an oxo. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently halogen, Ci-Cealkyl, or Ci- Cehaloalkyl; and / or two Rlaon the same atom form an oxo.

[0104] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each Rlais independently -S(=O)2Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd.WSGR Docket No. 59792-717.601

[0105] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1isa compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), eacheach optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I),(la)-(Ic), or (la-l)-(Ic-l), each

[0106] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is

[0107] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la- l)-(Ic-l), each R1is independently

[0108] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R1is independently halogen,WSGR Docket No. 59792-717.601

[0109] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 0, 1, or 2. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 0 or 1. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 0. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 1.

[0110] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l),WSGR Docket No. 59792-717.601

[0111] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l),WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601

[0112] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l),

[0113] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l),

[0114] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l),Formula (II); wherein:W1is N or CR8;R8is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl;R9is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl;R10is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a; each R10ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl,WSGR Docket No. 59792-717.601 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R10aon the same atom form an oxo;W2is N or CR11; andR11is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl.

[0115] In some embodiments of a compound of Formula (II), W1is CR8. In some embodiments of a compound of Formula (II), W1is N.

[0116] In some embodiments of a compound of Formula (II), R8is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R8is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R8is hydrogen or halogen. In some embodiments of a compound of Formula (II), R8is hydrogen.

[0117] In some embodiments of a compound of Formula (II), W2is CR11. In some embodiments of a compound of Formula (II), W2is N.

[0118] In some embodiments of a compound of Formula (II), R11is hydrogen, halogen, or Ci-Cealkyl.

[0119] In some embodiments of a compound of Formula (II), R11is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R11is hydrogen or halogen. In some embodiments of a compound of Formula (II), R11is hydrogen.

[0120] In some embodiments of a compound of Formula (II), R9is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R9is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R9is hydrogen or halogen. In some embodiments of a compound of Formula (II), R9is hydrogen.

[0121] In some embodiments of a compound of Formulaembodiments of a compound of Formulasome embodiments of a compound of Formula

[0122] In some embodiments of a compound of Formula (II), R10is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.

[0123] In some embodiments of a compound of Formula (II), R10is Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein theWSGR Docket No. 59792-717.601 alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R10a.

[0124] In some embodiments of a compound of Formula (II), R10is Ci-Cealkyl independently optionally substituted with one or more R10a.

[0125] In some embodiments of a compound of Formula (II), R10is Ci-Ceaminoalkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R10a.

[0126] In some embodiments of a compound of Formula (II), R10is Ci-Ceaminoalkyl.

[0127] In some embodiments of a compound of Formula (II), R10is -L-cycloalkyl or -L- heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R10a.

[0128] In some embodiments of a compound of Formula (II), R10is -L-cycloalkyl or -L- heterocycloalkyl.

[0129] In some embodiments of a compound of Formula (II), R10is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R10a.

[0130] In some embodiments of a compound of Formula (II), R10is cycloalkyl or heterocycloalkyl.

[0131] In some embodiments of a compound of Formula (II), R10is cycloalkyl. In some embodiments of a compound of Formula (II), R10is cycloalkyl. In some embodiments of a compound of Formula (II), R10is independently 3- to 6-membered cycloalkyl. In some embodiments of a compound of Formula (II), R10is independently 3- to 5-membered cycloalkyl. In some embodiments of a compound of Formula (II), R10is independently 3- to 4-membered cycloalkyl.

[0132] In some embodiments of a compound of Formula (II), R10is heterocycloalkyl independently optionally substituted with one or more R10a.

[0133] In some embodiments of a compound of Formula (II), R10is heterocycloalkyl.

[0134] In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 6- membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N, O, and S and heterocycloalkyl independently optionally substituted with one or more R10a.

[0135] In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN, O, and S and heterocycloalkyl independently optionallyWSGR Docket No. 59792-717.601 substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 5- membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N, O, and S and heterocycloalkyl independently optionally substituted with one or more R10a.

[0136] In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN and O and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N and O and heterocycloalkyl independently optionally substituted with one or more R10a.

[0137] In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN and O and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN and O and heterocycloalkyl independently optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN and O and heterocycloalkyl independently optionally substituted with one or more R10a.

[0138] In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN, O, and S. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN, O, and S.

[0139] In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN, O, and S. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN, O, and S.

[0140] In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting ofN and O.WSGR Docket No. 59792-717.601

[0141] In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting ofN and O. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of N and O.

[0142] In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one, two, or three heteroatoms that is O. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms that is O. In some embodiments of a compound of Formula (II), R10is 4- to 6-membered heterocycloalkyl comprising one heteroatom that is O.

[0143] In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one, two, or three heteroatoms that is O. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms that is O. In some embodiments of a compound of Formula (II), R10is 4- to 5-membered heterocycloalkyl comprising one heteroatom that is O.

[0144] In some embodiments of a compound of Formula (II), each R10ais independently halogen, -CN, - OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0145] In some embodiments of a compound of Formula (II), each R10ais independently halogen, -CN, - OH, -ORa, -S(=O)2Ra, -NRcRd, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0146] In some embodiments of a compound of Formula (II), each R10ais independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, or Ci-C6haloalkyl; and / or two R10aon the same atom form an oxo. In some embodiments of a compound of Formula (II), each R10ais independently halogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two R10aon the same atom form an oxo. In some embodiments of a compound of Formula (II), each R10ais independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two R10aon the same atom form an oxo.WSGR Docket No. 59792-717.601

[0148] In some embodiments of a compound of Formula, each optionally substituted with one or more R10a. In some embodiments of a compound of Formula (II),WSGR Docket No. 59792-717.601

[0150] In some embodiments of a compound of Formulaembodiments of a compound of Formula (II), R10isWSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601

[0153] In some embodiments of a compound of Formula

[0154] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl.

[0155] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl.WSGR Docket No. 59792-717.601

[0156] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2- Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl.

[0157] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0158] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is absent or -CH2-. In some embodiments of a compound disclosed herein, L is Ci-Csalkylene independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2- or -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2-.

[0159] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, - OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, - C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, - NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci- C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, C3-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, or Ci-C3haloalkoxy;WSGR Docket No. 59792-717.601 and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, or Ci-Csalkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen or Ci -Csalkyl; and / or two R on the same atom form an oxo.

[0160] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0161] In some embodiments the compound disclosed herein is selected from a compound found in table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.Table 1WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601* Relative stereochemistry was arbitrarily assigned.WSGR Docket No. 59792-717.601** racemic mixture.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0162] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0163] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes, such as3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for theirWSGR Docket No. 59792-717.601 ease of preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents. In some embodiments, one or more -CH3 in a compound disclosed herein has been replaced by a -CDs.

[0164] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0165] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0166] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0167] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0168] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids, such as hydrochloric acid, hydrobromic acid,WSGR Docket No. 59792-717.601 sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1 -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0169] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI.C4 alkyl)4 hydroxide, and the like.

[0170] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0171] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0172] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.WSGR Docket No. 59792-717.601Tautomers

[0173] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.Method of Treatment

[0174] Disclosed herein is a method of modulating CKAP5 activity in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0175] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is colorectal cancer.

[0176] Also disclosed herein is a method of treating a Wnt / p-catenin driven cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the Wnt / p-catenin driven cancer is colorectal cancer.

[0177] Also disclosed herein is a method of treating a BCL9 driven cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the BCL9 driven cancer is colorectal cancer.

[0178] Disclosed herein is a method of treating a CKAP5 -associated disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0179] As used herein, a “CKAP5 -associated disease or disorder” refers to a disease or disorder known to be associated with altered CKAP5 expression, level, and / or activity. Notably, a “CKAP5 -associated disease or disorder” includes cancer and / or proliferative diseases, conditions, or disorders. Certain exemplary “CKAP5 -associated disease or disorders” include liver cancer (e.g. hepatocellular carcinoma or HCC), lung cancer (e.g., NSCLC), colorectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, cervical cancer, brain cancer (e.g., glioblastoma), renal cancer (e.g., papillary renal carcinoma), stomach cancer, esophageal cancer, medulloblastoma, thyroid carcinoma, rhabdomyosarcoma, osteosarcoma, squamous cell carcinoma (e.g., oral squamous cell carcinoma), melanoma, breast cancer, and hematopoietic disorders (e.g., leukemias and lymphomas, and other immune cell-related disorders). Other hyperproliferative diseases or disorders may also be targeted, including, e.g., bladder, cervical (uterine), endometrial (uterine), head and neck, and oropharyngeal cancers.WSGR Docket No. 59792-717.601

[0180] By “proliferative disease” or “cancer” as used herein is meant, a disease, condition, trait, genotype or phenotype characterized by unregulated cell growth or replication; including hepatocellular carcinoma (HCC), leukemias, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia, AIDS related cancers such as Kaposi's sarcoma; breast cancers; bone cancers such as osteosarcoma, chondrosarcomas, Ewing's sarcoma, fibrosarcomas, Giant cell tumors, adamantinomas, and chordomas; Brain cancers such as meningiomas, glioblastomas, lower-grade astrocytomas, oligodendrocytomas, pituitary tumors, Schwannomas, and Metastatic brain cancers; cancers of the head and neck including various lymphomas such as mantle cell lymphoma, non-Hodgkins lymphoma, adenoma, squamous cell carcinoma, laryngeal carcinoma, gallbladder and bile duct cancers, cancers of the retina such as retinoblastoma, cancers of the esophagus, gastric cancers, multiple myeloma, ovarian cancer, uterine cancer, thyroid cancer, testicular cancer, endometrial cancer, melanoma, colorectal cancer, bladder cancer, prostate cancer (prostate carcinoma), lung cancer (including non-small cell lung carcinoma and small cell lung carcinoma), pancreatic cancer, sarcomas, Wilms' tumor, cervical cancer, head and neck cancer, skin cancers, nasopharyngeal carcinoma, liposarcoma, epithelial carcinoma, renal cell carcinoma, gallbladder adeno carcinoma, parotid adenocarcinoma, endometrial sarcoma, multidrug resistant cancers; and proliferative diseases and conditions, such as neovascularization associated with tumor angiogenesis, macular degeneration (e.g., wet / dry AMD), corneal neovascularization, diabetic retinopathy, neovascular glaucoma, myopic degeneration and other proliferative diseases and conditions such as restenosis and polycystic kidney disease, and other cancer or proliferative disease, condition, trait, genotype or phenotype that can respond to the modulation of disease related gene expression in a cell or tissue.Dosing

[0181] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by any suitable methods.Routes of Administration

[0182] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.WSGR Docket No. 59792-717.601In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.Pharmaceutical Compositions / Formulations

[0183] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0184] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.Combination

[0185] Disclosed herein are methods of treating a disease or disorder associated with CKAP5 using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0186] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.WSGR Docket No. 59792-717.601EXAMPLES

[0187] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0188] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0189] Aminocyanopyridine compounds described herein can be prepared according to General Scheme 1.General Scheme 1.

[0190] Aromatic ketones can be condensed with aldehydes and malononitrile in the presence of weak acids in solvents such as trifluoroethanol to afford di-substituted aminocyanopyridine derivatives.Example 1: 2-amino-6-(benzo[d] [l,3]dioxol-4-yl)-4-(l-cyclopropyl-lH-pyrazol-4-yl)nicotinonitrile

[0191] To a solution of l-(benzo[d][l,3]dioxol-4-yl)ethan-l-one (200 mg, 1.22 mmol, 1.00 eq) and 1- cyclopropylpyrazole-4-carbaldehyde (165 mg, 1.22 mmol, 1.00 eq) in 2,2,2-trifluoroethanol (3 mL) was added ammonium acetate (93.9 mg, 1.22 mmol, 1.00 eq) and propanedinitrile (76.7 pL, 1.22 mmol, 1.00 eq) at 15 °C. The mixture was stirred at 80 °C for 10 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 80 x 30 mm x 3 pm; mobile phase: [H2O (0.1% TFA) - MeCN]; gradient: 30% - 60% B over 8.0 min), followed by prep-HPLC (column: Phenomenex Luna C18 75 x 30 mm x 3 pm; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 25% - 55% B over 8.0 min) and (column: Phenomenex Luna C18 100 x 30 mm x 3 pm; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 35% - 65% B over 8.0 min) to give 2-amino-6- (benzo[d][l,3]dioxol-4-yl)-4-(l-cyclopropyl-lH-pyrazol-4-yl)nicotinonitrile (25.1 mg, 72.7 pmol, 6.0% yield, 100% purity). ’H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.42 (s, 1H), 7.99 (s, 1H), 7.60 (dd, J= 8.0, 1.3 Hz, 1H), 7.44 (s, 1H), 7.03 - 6.94 (m, 4H), 6.14 (s, 2H), 3.90 - 3.84 (m, 1H), 1.13 - 1.10 (m, 2H), 1.04 - 1.01 (m, 2H). LCMS. (ESI+): m / z 346.1 (M+H)+.

[0192] Further elaboration of the condensed aminocyanopyridine compounds like those described in herein are possible as depicted in General Scheme 1.1.WSGR Docket No. 59792-717.601General Scheme 1.1.Example 2: 2-amino-6-(benzo[< / | [l,3]dioxol-4-yl)-4-(l-(2-(2-oxooxazolidin-3-yl)ethyl)-LH-pyrazol-4- yl)nicotinonitrile

[0193] Step 1. A mixture of l-(benzo[d][l,3]dioxol-4-yl)ethan-l-one (200 mg, 1.22 mmol, 1.00 eq), 1H- pyrazole-4-carbaldehyde (117 mg, 1.22 mmol, 1.00 eq), NH4OAc (93.9 mg, 1.22 mmol, 1.00 eq) and propanedinitrile (80.5 mg, 1.22 mmol, 76.7 pL, 1.00 eq) in TFE (2 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 12 h under a N2 atmosphere. The reaction mixture was then cooled to 0 °C, and a saturated solution of NH4CI (10 mL) was then slowly added over 30 min. The mixture was extracted with EtOAc (2x 10 mL). The combined organic layers were washed with brine (3 mL), dried overNa2SC>4, filtered and concentrated to give 2-amino-6-(benzo[d][l,3]dioxol- 4-yl)-4-(lH-pyrazol-4-yl)nicotinonitrile (200 mg, crude) as a white solid, which was used without additional purification.

[0194] Step 2. To the crude product (100 mg, 328 mmol, 1.00 eq) was added 3-(2- chloroethyl)oxazolidin-2-one (49.0 mg, 328 pmol, 1.00 eq) and CS2CO3 (213 mg, 655 pmol, 2.00 eq), followed by DMF (1 mL). The resulting mixture was degassed and purged with N2 3 times, and then stirred at 80 °C for 12 h. Following which, the reaction mixture was poured into H2O (3 mL) at 20 °C slowly, and then extracted with DCM (3x 1 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 pm; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 30% - 60% B over 8.0 min) to give 2-amino-6-(benzo[<7|[l,3]dioxol-4-yl)-4-(l-(2-(2-oxooxazolidin-3-yl)ethyl)- lH-pyrazol-4-yl)nicotinonitrile (15.2 mg, 36.3 pmol, 11% yield, 100% purity). 'HNMR. DMSO-<A, 400 MHz: 5 = ppm 8.47 (s, 1H), 8.07 (s, 1H), 7.63 (d, J= 7.2 Hz, 1H), 7.47 (s, 1H), 7.03 (d, J= 7.2 Hz, 1H), 6.97 (t, J= 7.2 Hz, 1H), 6.92 (s, 2H), 6.16 (s, 2H), 4.41 (t, J= 5.6 Hz, 2H), 4.22 (t, J= 8.0 Hz, 2H), 3.61 (t, J= 5.6 Hz, 2H), 3.44 (t, J= 8.0 Hz, 2H). LCMS. (ESI+): m / z 419.1 (M+H)+.

[0195] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.2.WSGR Docket No. 59792-717.601General Scheme 1.2.Example 3: 4-(l-(l-acetylazetidin-3-yl)-LH-pyrazol-4-yl)-2-amino-6-(6-fluorobenzo[< / | [l,3]dio ol-4- yl)nicotinonitrile

[0196] Step 1. To a solution of 2-amino-6-(6-fliiorobcnzo|t / || 1 ,3 ]dioxol-4-yl)-4-( lH-pyrazol-4- yl)nicotinonitrile (80.0 mg, 247 pmol, 1.00 eq) and tert-butyl 3 -iodoazetidine -1 -carboxylate (56.1 mg, 198 pmol, 0.800 eq) in DMF (2 mL) was added CS2CO3 (161 mg, 495 pmol, 2.00 eq) at 25 °C. The mixture was stirred at 80 °C for 1 h. The reaction was quenched by slow addition of H2O (6 mL), extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d] [ 1 ,3]dioxol-4-yl)pyridin-4-yl)- IH-pyrazol- 1 -yl)azetidine- 1 - carboxylate as a yellow solid (110 mg, 230 pmol, 93% yield). ’H NMR. DMSO-t / e 400 MHz: 5 = ppm 8.51 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 7.37 (dd, J= 11.4, 2.6 Hz, 1H), 7.06 (dd, J= 8.0, 2.8 Hz, 1H), 6.99 (s, 2H), 6.21 (s, 2H), 5.40 - 5.34 (m, 1H), 4.33 (brt, J= 8.4 Hz, 2H), 4.18 (br s, 2H), 1.42 (s, 9H).

[0197] Step 2. The solution of tert-butyl 3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-lH-pyrazol-l-yl)azetidine-l -carboxylate (110 mg, 230 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 2.20 mL, 19.1 eq) was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give 2-amino-4-( l-(azctidin-3-yl)-l / / -pyrazol-4-yl)-6-(6-fliiorobcnzo|t / || l.3|dioxol-4- yl)nicotinonitrile as a yellow solid (110 mg, crude, HC1), which was carried on to the next step without further purification.

[0198] Step 3. To a solution of 2-amino-4-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-6-(6- fluorobenzo[<7][l,3]dioxol-4-yl)nicotinonitrile (110 mg, 265 pmol, 1.00 eq, HC1) in DCM (2 mL) were added TEA ((80.5 mg, 796 pmol, 111 pL, 3.00 eq) and acetyl chloride (25.0 mg, 318 pmol, 22.6 pL, 1.20 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was then quenched by slow addition of H2O (2 mL) and extracted with DCM (2 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD02 - Waters Xbridge BEH C18 150 x 25 x 10 um; mobile phase:WSGR Docket No. 59792-717.601[water (NH4HCO3) - MeCN]; gradient: 20% - 50% B over 10 min) to give 4-(l-(l-acetylazetidin-3-yl)- l / / -pyrazol-4-yl)-2-amino-6-(6-fluorobcnzoft / || l,3]dioxol-4-yl)nicotinonitrile (21.2 mg, 49.1 pmol. 16.9% yield, 97.3% purity). ’H NMR. DMS0-< 400 MHz: 5 = ppm 8.54 (d, J = 0.8 Hz, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 7.37 (dd, J= 11.4, 2.8 Hz, 1H), 7.07 (dd, J= 8.0, 2.8 Hz, 1H), 7.01 (s, 2H), 6.21 (s, 2H), 5.44 - 5.39 (m, 1H), 4.60 (t, J= 8.4 Hz, 1H), 4.44 (dd, J= 8.8, 5.2 Hz, 1H), 4.32 (t, J= 8.8 Hz, 1H), 4.15 (dd, J= 10.0, 5.2 Hz, 1H), 1.83 (s, 3H). LCMS. (ESI+): m / z 421.2 (M+H)+.Example 4: 2-amino-4-(l-(2-aminoethyl)-LH-pyrazol-4-yl)-6-(benzo[< / | [l,3]dioxol-4- yl)nicotinonitrile

[0199] Step 1. To a solution of l-(benzo[d][l,3]dioxol-4-yl)ethan-l-one (100 mg, 609 pmol, 1.00 eq), tert-butyl (2-(4-formyl- IH-pyrazol- l -yl)cthyl)carbamatc (146 mg, 609 pmol, 1.00 eq), propanedinitrile (40.2 mg, 609 pmol, 1.00 eq) in TFE (3 mL) was added NFLOAc (47.0 mg, 609 pmol, 1.00 eq). The mixture was stirred at 80 °C for 12 h. Subsequently, water (5 mL) was added, and the resulting aqueous mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SC>4, and fdtered. The fdtrate was concentrated under reduced pressure to give tertbutyl (2-(4-(2-amino-6-(benzo \d\ [ 1 ,3] dioxol-4-yl)-3 -cyanopyridin-4-yl)- 1 H-py razol - 1 - yl)ethyl)carbamate as a yellow solid (550 mg), which was used without further purification.

[0200] Step 2. The crude mixture (510 mg, 1.14 mmol, 1.00 eq) was dissolved in EtOAc (3 mL) to which HCl / EtOAc (4.00 M, 3.00 mL) was added. The mixture was stirred at 20 °C for 1 h. Following which, the mixture was filtered, and the filter cake was dried under reduced pressure. The crude product was triturated in MeOH (10 mL) at 20 °C for 20 min (two times). The solid was filtered and the filter cake dried to give 2-amino-4-( l -(2-aminocthyl)- IH-pyrazol-4-yl)-6-(bcnzoft / || l,3]dioxol-4- yl)nicotinonitrile (81.6 mg, 212 pmol, 18.6% yield, 99.1% purity, HC1 salt). 'H NMR. CD3OD 400 MHz: 5 = ppm 8.66 (s, 1H), 8.38 (s, 1H), 7.65 (s, 1H), 7.51 (dd, J= 6.0, 3.2 Hz, 1H), 7.02 - 7.08 (m, 2H), 6.18 (s, 2H), 4.60 (t, J= 5.6 Hz, 2 H), 3.52 (t, J= 5.6 Hz, 2H). LCMS. (ESI+): m / z 349.1 (M+H)+.

[0201] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.3.General Scheme 1.3.Example 5: 6-(benzo[< / | [l,3]dioxol-4-yl)-2-(methylamino)-4-(l-(oxetan-3-yl)-LH-pyrazol-4- yl)nicotinonitrile

[0202] To a solution of 2-amino-6-(bcnzoft / || l .3 |dioxol-4-yl)-4-( l -(oxctan-3-yl)- IH-pyrazol-4- yl)nicotinonitrile (100 mg, 277 pmol, 1.00 eq) in THF (2 mL) was added NaH (22.1 mg, 553 pmol, 60.0% purity, 2.00 eq) at 0 °C under N2. 0.5 h later, Mel (31.4 mg, 221 pmol, 13.8 pL, 0.800 eq) was added to the mixture at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. After which, the reaction mixture was diluted with H2O (5 mL) at 0 °C and extracted with EtOAc (5 mL x 3). TheWSGR Docket No. 59792-717.601 combined organic layers were washed with brine (5 mL x 3), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 35% - 65% B over 8.0 min) to give 6-(bcnzo|t / || 1,3 ]dioxol-4-yl)-2-(methylamino)-4-( l-(oxetan-3-yl)-lH-pyrazol-4- yl)nicotinonitrile (16.7 mg, 44.1 pmol, 15.9% yield, 99.1% purity). 'H NMR. DMSO-t / e 400 MHz: 5 = ppm 8.50 (s, 1H), 8.18 (s, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.47 (s, 1H), 7.11 (br d, J= 4.4 Hz, 1H), 7.03 (d, J= 7.2 Hz, 1H), 6.98 (t, J= 8.0 Hz, 1H), 6.15 (s, 2H), 5.73 (quin, J= 6.8 Hz, 1H), 4.97 - 4.92 (m, 4H), 2.98 (d, J= 4.4 Hz, 3H). LCMS. (ESI+): m / z 376.1 (M+H)+.

[0203] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.4.General Scheme 1.4.Example 6: 2-((2-aminoethyl)amino)-6-(benzo[< / ] [l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-LH-pyrazol-4- yl)nicotinonitrile

[0204] Step 1. To a solution of 2-amino-6-(bcnzoft / || 1 ,3 ]dioxol-4-yl)-4-( 1 -(oxetan-3-yl)- lH-pyrazol-4- yl)nicotinonitrile (250 mg, 692 pmol, 1.00 eq) in DMF (5 mL), NaH (69.2 mg, 1.73 mmol, 60.0% purity, 2.50 eq) was added at 0 °C under N2. After 0.5 h, tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (185 mg, 830 pmol, 1.20 eq) was added to the reaction mixture at 0 °C under N2, which was then stirred at 25 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4CI solution (5 mL) at 0 °C and extracted with EtOAc (3x 10 mL). The combined organic layers were washed with brine (3x 10 mL), dried over ISfeSCh, filtered, and concentrated under reduced pressure to give a yellow solid (250 mg).

[0205] Step 2. The resulting solid was dissolved in DCM (5 mL) to which TFA (2.5 mL) was added.The mixture was stirred at 25 °C for 0.5 h. Following which, the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 15% - 40% B over 8.0 min) to give 2- ((2-aminocthyl)amino)-6-(bcnzoft / | [ 1 ,3]dioxol-4-yl)-4-( 1 -(oxetan-3-yl)- lH-pyrazol-4-yl)nicotinonitrile (20.4 mg, 46.5 pmol, 9.39% yield, 99.6% purity, 0.7FA).1H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.53 (s, 1H), 8.39 (br s, 0.7H), 8.20 (s, 1H), 7.71 (dd, J= 8.0, 1.0 Hz, 1H), 7.51 (s, 1H), 7.20 (br t, J= 5.4 Hz, 1H), 7.05 (dd, J= 7.6, 1.2 Hz, 1H), 6.98 (t, J= 8.0 Hz, 1H), 6.16 (s, 2H), 5.74 (quin, J = 6.8 Hz, 1H), 4.98 - 4.92 (m, 4H), 3.66 - 3.63 (m, 2H), 2.99 (br t, J= 6.0 Hz, 2H). LCMS. (ESI+): m / z 405.1 (M+H)+.WSGR Docket No. 59792-717.601

[0206] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.5.General Scheme 1.5.Example 37: 2-amino-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(2H-tetrazol-5-yl)pyrazol-4- yl] pyridine-3-carbonitrile

[0207] Step 1. To a solution of p-tolylsulfonylformonitrile (1.90 g, 10.5 mmol, 1.00 eq) and 1- (azidomethyl)-4-methoxy-benzene (1.88 g, 11.5 mmol, 1.10 eq) in DCM (20 m ) was added dicuprous; toluene; trifluoromethanesulfonate (542 mg, 1.05 mmol, 0.100 eq) at -30 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by 5% ISfeCOs solution (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to give 2-[(4-methoxyphenyl)methyl]- 5-(p-tolylsulfonyl)tetrazole (1.10 g, 3.19 mmol, 31% yield) as a pale yellow solid.

[0208] Step 2. To a solution of 2-amino-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-(lH-pyrazol-4-yl)pyridine- 3 -carbonitrile (220 mg, 680 pmol, 1.00 eq) in DMF (4 mL) were added K2CO3 (282 mg, 2.04 mmol, 3.00 eq) and 2-[(4-methoxyphenyl)methyl]-5-(p-tolylsulfonyl)tetrazole (234 mg, 681 pmol, 1.00 eq) at 25 °C. The mixture was stirred at 60 °C for 4 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to give 2-amino-6-(6-fluoro- l,3-benzodioxol-4-yl)-4-[l-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]pyrazol-4-yl]pyridine-3- carbonitrile (56.0 mg).

[0209] Step 3. A solution of 2-amino-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-[2-[(4- methoxyphenyl)methyl]tetrazol-5-yl]pyrazol-4-yl]pyridine-3-carbonitrile (45.0 mg, 88.0 pmol, 1.00 eq) in TFA (2 mL) was stirred at 70 °C for 12 h. The reaction mixture was concentrated under N2 stream to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 30% - 60% B over 8.0 min) to give 2-amino-6-WSGR Docket No. 59792-717.601(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(2H-tetrazol-5-yl)pyrazol-4-yl]pyridine-3-carbonitrile (9.40 mg, 22.9 pmol, 26% yield, 95.3% purity). 'H NMR. DMSO-t / 6400 MHz: 5 = ppm 9.02 (s, 1H), 8.45 (s, 1H), 7.57 (s, 1H), 7.41 (dd, J= 11.6, 2.8 Hz, 1H), 7.10 - 7.09 (m, 2H), 7.08 - 7.07 (m, 1H), 6.23 (s, 2H). LCMS. (ESI+): m / z 392.0 (M+H)

[0210] Alternatively, compounds described herein can be synthesized as described in General Scheme1.6.General Scheme 1.6.Example 38: 6-(6-fluoro-l,3-benzodioxol-4-yl)-2-[2-(methylamino)ethylamino]-4-[l-(oxetan-3- yl)pyrazol-4-yl]pyridine-3-carbonitrile

[0211] Step 1. To a solution of 2-amino-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4- yl] pyridine -3 -carbonitrile (400 mg, 1.05 mmol, 1.00 eq) in DMF (4 m ) were added isopentyl nitrite (74.0 mg, 6.33 mmol, 852 pL, 6.00 eq) and Q1Q2 (851 mg, 6.33 mmol, 6.00 eq) at 25 °C. The mixture was stirred at 40 °C for 2 h. The crude product was triturated with H2O (10 m ) at 25 °C for 10 min. The reaction mixture was fdtered and the cake was washed by H2O (5mL x 5) and dried in vacuum to give 2- chloro-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4-yl]pyridine-3-carbonitrile (450 mg, crude).

[0212] Step 2. To a solution of 2-chloro-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4- yl] pyridine -3 -carbonitrile (450 mg, 1.13 mmol, 1.00 eq) in NMP (4 mb) were added tert-butyl N-(2- aminoethyl)-N-methyl-carbamate (492 mg, 2.82 mmol, 504 pL, 2.50 eq), KF (131 mg, 2.26 mmol, 2.00 eq) and DIPEA (438 mg, 3.39 mmol, 590 pL, 3.00 eq) at 25 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with H2O (20 mb) and extracted with EtOAc (10 mb x 3). The combined organic layers were washed by brine (5 mb x 3), dried over ISfeSCE, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 2) to give tert-butyl N-[2-[[3-cyano-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l- (oxetan-3-yl)pyrazol-4-yl]-2-pyridyl]amino]ethyl]-N-methyl-carbamate (160 mg).

[0213] Step 3. To a solution of tert-butyl N-[2-[[3-cyano-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l- (oxetan-3-yl)pyrazol-4-yl]-2-pyridyl]amino]ethyl]-N-methyl-carbamate (160 mg, 298 pmol, 1.00 eq) in DCM (2 mL) was added TFA (768 mg, 6.73 mmol, 0.500 mL, 22.6 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. To the reaction mixture was added ISfeCCE to adjust to pH = 7-8 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 40% - 75% B over 8.0 min) and the crude product was triturated with EtOH (5 mL) at 25 °C for 10 min to give 6-(6-fluoro-l,3-benzodioxol-4-yl)-2-[2-(methylamino)ethylamino]-4-[l-(oxetan-3-WSGR Docket No. 59792-717.601 yl)pyrazol-4-yl]pyridine-3-carbonitrile (78.3 mg, 175 pmol, 59% yield, 97.5% purity). ’H NMR. DMSO- t / 6400 MHz: 5 = ppm 8.54 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.47 - 7.44 (m, 2H), 7.07 - 7.04 (m, 1H), 6.21 (s, 2H), 5.73 (t, J= 7.0 Hz, 1H), 4.97 - 4.95 (m, 2H), 4.93 -4.92 (m, 2H), 3.49 (br d, J= 2.8 Hz, 2H), 3.44 (br d, J= 4.4 Hz, 2H), 2.81 (s, 3H). LCMS. (ESI+): m / z 437.1 (M+H)+.

[0214] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.7.General Scheme 1.7.Example 39: 2-[2-(dimethylamino)ethylamino]-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3- yl)pyrazol-4-yl]pyridine-3-carbonitrile

[0215] Step 1. To a solution of 2-amino-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4- yl] pyridine -3 -carbonitrile (400 mg, 1.05 mmol, 1.00 eq) in DMF (5 m ) were added Q1Q2 (851 mg, 6.33 mmol, 6.00 eq) and isopentyl nitrite (741 mg, 6.33 mmol, 852 pL, 6.00 eq) at 25 °C. The mixture was stirred at 40 °C for 12 h under N2. The reaction mixture was diluted with H2O (5 m ), fdtered, and the filter cake was dried in vacuum. The crude product was triturated with H2O (5 mb) at 25 °C for 5 min to give 2-chloro-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4-yl]pyridine-3-carbonitrile (480 mg).

[0216] Step 2. To a solution of 2-chloro-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4- yl] pyridine -3 -carbonitrile (450 mg, 1.13 mmol, 1.00 eq) and N',N'-dimethylethane-l,2-diamine (99.5 mg, 1.13 mmol, 123 pL, 1.00 eq) in DMSO (3 mb) were added KF (131 mg, 2.26 mmol, 2.00 eq) and DIPEA (175 mg, 1.35 mmol, 236 pL, 1.20 eq) at 25 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: WePure Biotech XPt C181 50 x 40 x 7um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 25% - 75% B over 8.0 min) to give 2-[2-(dimethylamino)ethylamino]-6-(6-fluoro-l,3- benzodioxol-4-yl)-4-[l-(oxetan-3-yl)pyrazol-4-yl]pyridine-3-carbonitrile (61.1 mg, 133 pmol, 12% yield, 98.2% purity).1H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.53 (s, 1H), 8.20 (s, 1H), 7.49 (s, 1H), 7.44 (dd, J= 11.4, 2.8 Hz, 1H), 7.09 (dd, J= 8.0, 2.4 Hz, 1H), 6.98 (t, J= 5.6 Hz, 1H), 6.23 (s, 2H), 5.75 (t, J= 7.0 Hz, 1H), 4.99 - 4.95 (m, 4H), 3.59 (q, J= 6.5 Hz, 2H), 2.50 - 2.49 (m, 2H), 2.23 (s, 6H). LCMS. (ESI+): m / z 451.2 (M+H)WSGR Docket No. 59792-717.601

[0217] Alternatively, compounds described herein can be synthesized as described in General Scheme1.8.General Scheme 1.8.Example 45: 2-amino-6-(6-fluoro-7-methylbenzo[d] [l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)nicotinonitrile

[0218] Step 1. To a solution of l-(oxetan-3-yl)pyrazole-4-carbaldehyde (2.00 g, 13.1 mmol, 1.00 eq) and propanedinitrile (868 mg, 13.1 mmol, 828 pL, 1.00 eq) in EtOH (20 m ) was added N,N- diethylethanamine (1.33 g, 13.1 mmol, 1.83 m , 1.00 eq) at 20 °C. The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (20 mb), placed in ice water, fdtered, and retain the fdter cake to give 2-[[l-(oxetan-3-yl)pyrazol-4-yl]methylene]propanedinitrile (1.65 g).

[0219] Step 2. The reaction was set up in two parallel batches. To a solution of 2-bromo-4-fluoro-phenol (5.00 g, 26.2 mmol, 1.00 eq) in TFA (40 mb) was added HMTA (7.34 g, 52.4 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 95 °C for 12 h. Two batches were combined. The reaction mixture was cooled to 25 °C, then water (40 mb) and sulfuric acid (20 mb, 50 %) were added to the mixture. The mixture was stirred for 3 h at 25 °C, filtered and the filter cake was dried under reduced pressure to give 3-bromo-5 -fluoro-2 -hydroxy-benzaldehyde as a pale yellow solid (9.45 g, crude).

[0220] Step 3. Solution 1: 3 -bromo-5 -fluoro-2 -hydroxy-benzaldehyde (8.45 g, 38.6 mmol, 1.00 eq) in dioxane (100 mb). Solution 2: H2O2 (17.5 g, 154 mmol, 14.8 mb, 30.0% purity, 4.00 eq), NaOH (3.09 g, 77.2 mmol, 2.00 eq). The solution 1 was pumped by Pump 1 {SI, Pl, 6.559 mb / min} to flow reactor 1 {PERI, PFA, Dynamic mixer, 6.350(1 / 4") mm, 1 mb, 60 °C}. {FERI, PFA, Coils reactor, 3.175(1 / 8") mm, 64.193 mb, 60 °C} . The solution 2 was pumped by Pump 2 {S2, P2, 6.479 mb / min} to flow reactor 1 {FERI, PFA, Dynamic mixer, 6.350(1 / 4") mm, 1 mb, 60 °C} . {FERI, PFA, Coils reactor, 3.175(1 / 8") mm, 64.193mb, 60 °C}. The residence time of flow reactor 1 was {FERI, 5 min}. The mixture was collected with a bottle was stirred at (100 mb of 1 M ice ISfeSOs). The Pump 1 and Pump 2 were started at the same time. The reaction mixture was collected after running FERI, 5 min. Take a sample for analysis after 5 mins. The reaction mixture was extracted with EtOAc (100 mb * 3). The combinedWSGR Docket No. 59792-717.601 organic layers were washed with brine (100 mL), dried over ISfeSC , filtered, and concentrated under reduced pressure to give 3-bromo-5-fluoro-benzene-l,2-diol (9.00 g, crude).

[0221] Step 4. This reaction was set up in two parallel batches. To a solution of 3 -bromo-5 -fluoro- benzene- 1,2-diol (5.00 g, 24.2 mmol, 1.00 eq) and diiodomethane (6.47 g, 24.2 mmol, 1.95 mL, 1.00 eq) in DMF (15 mL) was added K2CO3 (5.01 g, 36.2 mmol, 1.5 eq) at 25 °C. The mixture was stirred at 110 °C for 1 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 20 / 1) to give 4-bromo-6-fluoro- 1,3 -benzodioxole (2.80 g, 12.8 mmol, 27% yield) as a white solid. ’H NMR. DMSO-t / 6400 MHz: 5 = ppm 7.00 (ddd, J= 10.2, 9.0, 2.4 Hz, 2H), 6.15 (s, 2H).

[0222] Step 5. To a solution of 4-bromo-6-fluoro- 1,3 -benzodioxole (200 mg, 913 pmol, 1.00 eq) in THF (5 mL) was added LDA (2.00 M, 685 pL, 1.50 eq) at -78 °C. 0.5 h later, Mel (194 mg, 1.37 mmol, 85.3 pL, 1.50 eq) was added to the mixture at -78 °C. The mixture was stirred at 15 °C for 1 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 20 / 1) to give 7-bromo-5-fluoro- 4-methyl-l,3-benzodioxole (145 mg, 622 pmol, 68% yield) as a white solid. 'H NMR. DMSO-t / e OO MHz: 5 = ppm 6.95 (d, J= 9.8 Hz, 1H), 6. 14 (s, 2H), 2.05 (s, 3H).

[0223] Step 6. To a solution of 7-bromo-5-fluoro-4-methyl- 1,3 -benzodioxole (145 mg, 622 pmol, 1.00 eq) in THF (3 mL) was added w-BuLi (2.50 M, 498 pL, 2.00 eq) at -78 °C. 0.5 h later, N-methoxy-N- methyl-acetamide (96.3 mg, 933 pmol, 99.2 pL, 1.50 eq) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by ice water (3 mL) at 0 °C, diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 40% - 75% B over 8.0 min) to give l-(6-fluoro-7-methyl-l,3- benzodioxol-4-yl)ethanone (30.0 mg, 153 pmol, 25% yield) as a white solid. 'H NMR. DMSO-t / e 400 MHz: 5 = ppm 6.96 (d, J= 11.0 Hz, 1H), 6.23 (s, 2H), 2.51 (br s, 3H), 2.14 (s, 3H)

[0224] Step 7. To a solution of l-(6-fluoro-7-methyl-l,3-benzodioxol-4-yl)ethanone (25.0 mg, 127 pmol, 1.00 eq) and 2-[[l-(oxetan-3-yl)pyrazol-4-yl]methylene]propanedinitrile (51.0 mg, 255 pmol, 2.00 eq) in TFE (1 mL) was added NFLOAc (9.82 mg, 127 pmol, 1.00 eq) at 15 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 35% - 65% B over 8.0 min) to give 2-amino-6-(6-fluoro-7- methylbenzo[d][l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)nicotinonitrile (13.8 mg, 35.0 pmol, 27% yield, 99.7% purity). 'H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.49 (s, 1H), 8.16 (s, 1H), 7.45 (s, 1H),WSGR Docket No. 59792-717.6017.39 (d, J= 12.0 Hz, 1H), 6.96 (s, 2H), 6.21 (s, 2H), 5.73 (t, J = 7.0 Hz, 1H), 4.94 (dd, J = 7.2, 1.8 Hz, 4H), 2.15 (s, 3H). LCMS. (ESI+): m / z 394.1 (M+H)+.

[0225] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.9.General Scheme 1.9.Example 44: 2-amino-6-(6-fluorobenzo[d] [l,3]dioxol-4-yl)-4-(lH-tetrazol-5-yl)nicotinonitrile

[0226] Step 1. To a solution of (4-methoxyphenyl)methanamine (10.0 g, 72.9 mmol, 9.46 m , 1.00 eq) and diethoxymethoxyethane (16.2 g, 109 mmol, 18.2 m , 1.50 eq) in AcOH (20 mb) was added NaNs (5.68 g, 87.4 mmol, 1.20 eq) at 25 °C. The mixture was stirred at 80 °C for 8 h. The reaction mixture was quenched by 5% Na2COs solution (200 mb) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to give l-[(4-methoxyphenyl)methyl]tetrazole (6.45 g, crude) as a yellow solid.1H NMR. DMSO-d6400 MHz: 5 = ppm 9.48 (s, 1H), 7.34 (d, J= 8.8 Hz, 2H), 6.94 (d, J= 8.8 Hz, 2H), 5.62 (s, 2H), 3.74 (s, 3H).

[0227] Step 2. To a solution of l-[(4-methoxyphenyl)methyl]tetrazole (2.00 g, 10.5 mmol, 1.00 eq) and TMEDA (8.10 g, 69.7 mmol, 10.5 mL, 6.63 eq) in THF (20 mL) was added w-BuLi (2.50 M, 4.63 mL, 1. 10 eq) at -78 °C under N2. The mixture was stirred at -78 °C under N2 for 5 min. Then ethyl formate (9.66 g, 130 mmol, 10.5 mL, 12.4 eq) was added at -78 °C under N2. The mixture was stirred at -78 °C under N2 for 30 min, then warmed to 25 °C slowly. The reaction was quenched by adding saturated NH4CI (40 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The organic extracts were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, PE / EtOAc = 1 / 1) to give l-(4-methoxybenzyl)-lH-tetrazole-5-carbaldehyde (650 mg, 2.98 mmol, 28% yield).

[0228] Step 3. To a solution of l-(4-methoxybenzyl)-lH-tetrazole-5-carbaldehyde (650 mg, 2.98 mmol, 1.00 eq) and l-(6-fluoro-l,3-benzodioxol-4-yl)ethanone (163 mg, 894 pmol, 0.300 eq), propanedinitrile (197 mg, 2.98 mmol, 188 pL, 1.00 eq) in TFE (3 mL) was added NFLOAc (230 mg, 2.98 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 100 x 30 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 35% - 65% B over 8.0 min) to give 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(l-(4-methoxybenzyl)-lH-tetrazol-5- yl)nicotinonitrile (65.0 mg, crude) as a yellow solid.WSGR Docket No. 59792-717.601

[0229] Step 4. A solution of 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(l-(4-methoxybenzyl)-lH- tetrazol-5-yl)nicotinonitrile (65.0 mg, 146 pmol, 1.00 eq) in TFA (5 mb) was stirred at 70 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 X 40 mm X 5 um; mobile phase: [column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA) - MeCN]; gradient: 15% - 55% B over 8.0 min) to give 2-amino-6-(6-fluoro-l,3-benzodioxol-4-yl)-4-(lH-tetrazol-5-yl)pyridine-3- carbonitrile (13.0 mg, 40.9 pmol, 28% yield, 100% purity). 'H NMR. DMSO-t / e 400 MHz: 5 = ppm 7.90 (s, 1H), 7.44 (dd, J= 11.4, 2.8 Hz, 1H), 7.28 (br s, 2H), 7.12 - 7.09 (m, 1H), 6.26 (s, 2H). LCMS. (ESI+): m / z 326.1 (M+H)+.

[0230] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.11.General Scheme 1.11.Example 46: 2-amino-6-(5-methylbenzo[d] [l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4- yl)nicotinonitrile

[0231] Step 1. To a solution of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (5.00 g, 21.6 mmol, 1.00 eq) in DCM (100 mL) were added Aids (14.4 g, 108 mmol, 5.90 mL, 4.99 eq) and Py (34.2 g, 432 mmol, 34.9 mL, 20.0 eq) at 25 °C. The mixture was stirred at 45 °C for 12 h. The mixture was adjusted to pH = 1 with 6.00 M of HC1 at 0 °C and concentrated under reduced pressure to remove organic layer. The residue was extracted with THF / EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over ISfeSCL, fdtered, and concentrated under reduced pressure to give 2- bromo-3,4-dihydroxybenzaldehyde (4.90 g, crude). 'H NMR. DMSO-tL 400 MHz: 5 = ppm 11.09 (br s, 1H), 10.05 (s, 1H), 9.62 (br s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H).

[0232] Step 2. To a solution of 2-bromo-3,4-dihydroxybenzaldehyde (4.90 g, 22.6 mmol, 1.00 eq) in DMA (100 mL) was added KF (6.56 g, 113 mmol, 5.00 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. Dibromomethane (4.32 g, 24.8 mmol, 1.74 mL, 1.10 eq) was added to the mixture. The mixture was stirred at 115 °C for 2 h. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give 4-bromobenzo[d][l,3]dioxole-5-carbaldehyde (2.50 g,WSGR Docket No. 59792-717.60110.9 mmol, 48% yield) as a white solid.1H NMR. DMSO-t / 6400 MHz: 5 = ppm 9.99 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 6.28 (s, 2H).

[0233] Step 3. To a solution of 4-bromobenzo[d][l,3]dioxole-5-carbaldehyde (2.50 g, 10.9 mmol, 1.00 eq) in MeOH (10 mb) and THF (10 mb) was added NaBFL (800 mg, 21.2 mmol, 1.94 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was quenched by saturated aqueous NH4CI solution (10 mb) at 0 °C and extracted with EtOAc (3 mb x 3). The combined organic layers were washed with brine (10 mb), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL, PE / EtOAc = 3 / 1) to give (4-bromobenzo[d][l,3]dioxol-5-yl)methanol (1.30 g, 5.63 mmol, 52% yield) as a white solid.1H NMR. DMSO-t / 6400 MHz: 5 = ppm 6.97 (d, J= 8.0 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 6.10 (s, 2H), 4.43 (d, J= 5.6 Hz, 2H).

[0234] Step 4. To a solution of (4-bromobenzo[d][l,3]dioxol-5-yl)methanol (1.30 g, 5.63 mmol, 1.00 eq) in DCM (20 mb) was added TFA (5.13 g, 45.0 mmol, 3.34 mb, 8.00 eq) and EtsSiH (1.31 g, 11.3 mmol, 1.80 mL, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h under N2. The mixture was diluted with H2O (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give 4-bromo-5-methylbenzo[d][l,3]dioxole (500 mg, 2.33 mmol, 41% yield). 'HNMR. DMSO-t / e 400 MHz: 5 = ppm 6.82 (s, 2H), 6.08 (s, 2H), 2.26 (s, 3H).

[0235] Step 5. To a solution of 4-bromo-5-methylbenzo[d][l,3]dioxole (500 mg, 2.33 mmol, 1.00 eq) in THF (5 mL) was added w-BuLi (2.50 M, 1.86 mL, 2.00 eq) at -70 °C. The mixture was stirred at -70 °C for 0.5 h under N2. N-methoxy-N-methyl-acetamide (599 mg, 5.81 mmol, 618 pL, 2.50 eq) was added to the mixture at -70 °C. The mixture was stirred at 25 °C for 1.5 h under N2. The mixture was diluted with H2O (20 mL) at 0 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE / EtOAc = 5 / 1) to give l-(5-methylbenzo[d][l,3]dioxol-4-yl)ethanone (90.0 mg, 505 pmol, 22% yield). 'H NMR. CDCh 400 MHz: 5 = ppm 6.80 (d, J= 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H), 2.58 (s, 3H), 2.39 (s, 3H).

[0236] Step 6. To a solution of l-(5-methylbenzo[d][l,3]dioxol-4-yl)ethanone (80.0 mg, 449 pmol, 1.00 eq) and 2-[[l-(oxetan-3-yl)pyrazol-4-yl]methylene]propanedinitrile (180 mg, 899 pmol, 2.00 eq) in TFE (4 mL) was added NFLOAc (69.2 mg, 898 pmol, 2.00 eq) at 25 °C. The mixture was stirred at 80 °C for 12 h. The mixture was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 30 mm x 5um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 15% - 45% B over 8.0 min) to give 2-amino-6-(5- methylbenzo[d][l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)nicotinonitrile (8.20 mg, 21.0 pmol, 5% yield, 96.0% purity). 'H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.59 (s, 1H), 8.25 (s, 1H), 7.01 (s, 1H),6.93 (s, 2H), 6.86 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 8.0 Hz, 1H), 5.96 (s, 2H), 5.68 (quin, J= 6.9 Hz, 1H),4.93 (quin, J= 6.6 Hz, 4H), 2.18 (s, 3H). LCMS. (ESI+): m / z 376.1 (M+H)+.WSGR Docket No. 59792-717.601

[0237] Alternatively, compounds described herein can be synthesized as described in General Scheme1.12.General Scheme 1.12.Example 48: 5-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d] [l,3]dioxol-4-yl)pyridin-4-yl)-lH-pyrazol- l-yl)-N-methylpentanamide

[0238] Step 1. To a solution of 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(lH-pyrazol-4- yl)nicotinonitrile (100 mg, 309 pmol, 1.00 eq) and methyl 5-bromopentanoate (66.4 mg, 340 pmol, 48.7 pL, 1.10 eq) in DMF (2 m ) was added CS2CO3 (302 mg, 928 pmol, 3.00 eq) at 15 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with H2O (10 m ) and extracted with EtOAc (10 mb x 2). The combined organic layers were washed with brine (10 mb), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure to give methyl 5-(4-(2-amino-3-cyano-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4-yl)-lH-pyrazol-l-yl)pentanoate (100 mg, crude).

[0239] Step 2. To a solution of methyl 5-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-lH-pyrazol-l-yl)pentanoate (100 mg, 229 pmol, 1.00 eq) in THF (1 mb), H2O (1 mb) and MeOH (2 mb) was added NaOH (27.4 mg, 686 pmol, 3.00 eq) at 15 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (10 mb) and extracted with EtOAc (5 mL x 2). The aqueous layer was adjusted to pH = 4~5 with 1 M of HC1 and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure to give 5-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4-yl)-lH- pyrazol-l-yl)pentanoic acid (38.0 mg, crude).

[0240] Step 3. To a solution of 5-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4- yl)-lH-pyrazol-l-yl)pentanoic acid (38.0 mg, 89.8 pmol, 1.00 eq) and methanamine;hydrochloride (7.27 mg, 108 pmol, 1.20 eq) in DMF (1 mL) were added DIPEA (34.8 mg, 269 pmol, 46.9 pL, 3.00 eq) and HATU (68.3 mg, 180 pmol, 2.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 30% - 60% B over 8.0 min) to give 5-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-WSGR Docket No. 59792-717.601 yl)pyridin-4-yl)-lH-pyrazol-l-yl)-N-methylpentanamide (13.1 mg, 29.2 pmol, 33% yield, 97.4% purity). 'H NMR. DMSO-d6400 MHz: 5 = ppm 8.40 (s, 1H), 8.04 (s, 1H), 7.72 (br d, J= 3.8 Hz, 1H), 7.48 (s, lH), 7.38 (dd, J= 11.4, 2.8 Hz, 1H), 7.07 (dd, J= 8.0, 2.8 Hz, 1H), 6.97 (br s, 2H), 6.23 (s, 2H), 4.21 (t, J= 7.0 Hz, 2H), 2.55 (d, J = 4.6 Hz, 3H), 2.10 (t, J= 7.4 Hz, 2H), 1.81 - 1.77 (m, 2H), 1.52 - 1.46 (m, 2H). LCMS. (ESI+): m / z 437.1 (M+H)+.Alternatively, compounds described herein can be synthesized as described in General Scheme 1.13.General Scheme 1.13.Example 55: 2-amino-6-(6-fluorobenzo[d] [l,3]dioxol-4-yl)-4-(2-(l-(6-methoxyhexanoyl)azetidin-3- yl)-2H-l,2,3-triazol-4-yl)nicotinonitrile

[0241] To a solution of 2-amino-4-(2-(azetidin-3-yl)-2H-l,2,3-triazol-4-yl)-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (100 mg, 264 pmol, 1.00 eq) in Py (2 m ) were added 6- methoxyhexanoic acid (38.5 mg, 264 pmol, 1.00 eq) and EDCI (75.8 mg, 395 pmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 4 h. The mixture was fdtered, and the fdtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (CD04 - Welch Ultimate C18 (150 x 25 mm, 7 um); flow rate: 25 mL / min; gradient: 37% - 67%, B over 10 min; mobile phase A: H2O (0.225% FA), mobile phase B: MeCN) to give 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(2-(l-(6- methoxyhexanoyl)azetidin-3-yl)-2H-l,2,3-triazol-4-yl)nicotinonitrile (45.7 mg, 86.5 pmol, 33% yield, 96.1% purity). ’H NMR. DMS0-< 400 MHz: 5 = ppm 8.50 (s, 1H), 7.72 (s, 1H), 7.41 (dd, J= 11.4, 2.6 Hz, 1H), 7.18 (s, 2H), 7.09 (dd, J= 7.8, 2.8 Hz, 1H), 6.23 (s, 2H), 5.69 - 5.64 (m, 1H), 4.72 (t, J= 8.6 Hz, 1H), 4.52 (dd, J = 9.2, 4.8 Hz, 1H), 4.44 (t, J= 9.0 Hz, 1H), 4.26 (dd, J= 10.2, 5.0 Hz, 1H), 3.29 (t, J = 6.4 Hz, 2H), 3.20 (s, 3H), 2.12 (t, J= 7.4 Hz, 2H), 1.51 (sxt, J= 7.2 Hz, 4H), 1.33 - 1.28 (m, 2H). LCMS. (ESI+): m / z 508.1 (M+H)+.WSGR Docket No. 59792-717.601

[0242] Alternatively, compounds described herein can be synthesized as described in General Scheme1.14.General Scheme 1.14.Example 56: 5-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d] [l,3]dioxol-4-yl)pyridin-4-yl)-2H-l,2,3- triazol-2-yl)azetidin-l-yl)-N-methyl-5-oxopentanamide

[0243] Step 1. To a solution of 2-amino-4-(2-(azetidin-3-yl)-2H-l,2,3-triazol-4-yl)-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (450 mg, 1.08 mmol, 1.00 eq, HC1 salt) in DMF (6 m ) were added 5-methoxy-5-oxo-pentanoic acid (158 mg, 1.08 mmol, 136 ph, 1.00 eq), HATU (370 mg, 974 pmol, 0.900 eq) and DIEA (420 mg, 3.25 mmol, 566 ph, 3.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (30 m ) and extracted with EtOAc (10 mb x 3). The combined organic layers were washed with brine (10 mb x 3), dried over ISfeSCh, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Commercial hexanes / Ethyl acetate = 0 / 1) to give methyl 5-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4-yl)-2H- l,2,3-triazol-2-yl)azetidin-l-yl)-5-oxopentanoate (700 mg).

[0244] Step 2. To a solution of methyl 5-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-2H-l,2,3-triazol-2-yl)azetidin-l-yl)-5-oxopentanoate (100 mg, 197 pmol, 1.00 eq) in H2O (0.2 mb), MeOH (1 mb) and THF (2 mb) was added bi OH (14.2 mg, 591 pmol, 3.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (3 mb), acidified to pH = 1-2 by 1.00 M of HC1, and extracted with DCM (3 mb x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-2H-l,2,3-triazol-2-yl)azetidin-l-yl)-5-oxopentanoic acid (93.0 mg, crude).

[0245] Step 3. To a solution of 5-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin- 4-yl)-2H-l,2,3-triazol-2-yl)azetidin-l-yl)-5-oxopentanoic acid (93.0 mg, 188 pmol, 1.00 eq) in DMF (1 mb) were added methanamine;hydrochloride (25.5 mg, 377 pmol, 2.00 eq), HATU (64.5 mg, 170 pmol, 0.900 eq) and DIPEA (73.1 mg, 565 pmol, 98.5 ph, 3.00 eq) at 15 °C. The mixture was stirred at 15 °C for 2 h. The reaction mixture was filtered to give filtrate. The filtrate was purified by prep-HPLCWSGR Docket No. 59792-717.601(column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 20% - 60% B over 8.0 min) to give 5-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol- 4-yl)pyridin-4-yl)-2H-l,2,3-triazol-2-yl)azetidin-l-yl)-N-methyl-5-oxopentanamide (14.4 mg, 28.4 pmol, 15% yield, 100% purity).1H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.50 (s, 1H), 7.73 (s, 1H), 7.70 (br s, 1H), 7.43 - 7.40 (m, 1H), 7.18 (br s, 2H), 7.11 - 7.08 (m, 1H), 6.24 (s, 2H), 5.69 - 5.64 (m, 1H), 4.70 - 4.68 (m, 1H), 4.52 - 4.49 (m, 1H), 4.44 - 4.41 (m, 1H), 4.31 - 4.27 (m, 1H), 2.55 (d, J= 4.4 Hz, 3H), 2.14 - 2.07 (m, 4H), 1.77 - 1.68 (m, 2H). LCMS. (ESI+): m / z 507.3 (M+H)+.

[0246] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.15.Example 61: 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(2-(l-(methylsulfonyl)azetidin-3-yl)- 2H-l,2,3-triazol-4-yl)nicotinonitrile

[0247] To a solution of 2-amino-4-(2-(azetidin-3-yl)-2H-l,2,3-triazol-4-yl)-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (200 mg, 527 pmol, 1.00 eq) in H2O (1 m ), THF (4 m ) were added ISfeCOs (112 mg, 1.05 mmol, 2.00 eq) and MsCl (220 mg, 1.92 mmol, 149 pL, 3.64 eq) at 0 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched by H2O (5 mb) at 0 °C, filtered and the filter cake was dried in a vacuum. The crude product was triturated with THF (5 mb) at 15 °C, filtered and the filter cake was dried in a vacuum to give 2-amino-6-(6-fluorobenzo[d][l,3]dioxol- 4-yl)-4-(2-(l-(methylsulfonyl)azetidin-3-yl)-2H-l,2,3-triazol-4-yl)nicotinonitrile (156.9 mg, 339 pmol, 64% yield, 99.0% purity). 'H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.52 (s, 1H), 7.76 (s, 1H), 7.41 (dd, J = 11.4, 2.4 Hz, 1H), 7.20 (br s, 2H), 7.10 (dd, J= 8.0, 2.4 Hz, 1H), 6.24 (s, 2H), 5.72 (quin, J= 6.8 Hz, 1H), 4.53 - 4.39 (m, 5H), 3.19 (s, 3H). LCMS. (ESI+): m / z 458.2 (M+H)+.

[0248] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.16.General Scheme 1.16.Example 64: 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(2-(l-(2-hydroxyacetyl)azetidin-3-yl)-2H-l,2,3-triazol-4-yl)nicotinonitrileWSGR Docket No. 59792-717.601

[0249] Step 1: To a solution of 2-amino-4-(2-(azetidin-3-yl)-2H-l,2,3-triazol-4-yl)-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (300 mg, 721 pmol, 1.00 eq, HC1 salt) in DMF (5 mL) were added 2-acetoxyacetic acid (85.2 mg, 721 pmol, 1.00 eq), DIPEA (373 mg, 2.89 mmol, 503 pL, 4.00 eq) and HATU (412 mg, 1.08 mmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (15 mL x 2), brine (20 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Commercial hexanes / Ethyl acetate, from 100 / 0 to 35 / 65) to give 2-(3- (4-(2-amino-3 -cyano-6-(6-fluorobenzo [d] [ 1 ,3]dioxol-4-yl)pyridin-4-yl)-2H- 1 ,2,3 -triazol-2-yl)azetidin- 1 - yl)-2 -oxoethyl acetate (220 mg, 459 pmol, 64% yield) as a yellow solid. ’H NMR. DMSO-t / e 400 MHz: 5 = ppm 8.51 (s, 1H), 7.74 (s, 1H), 7.41 (dd, J= 11.4, 2.8 Hz, 1H), 7.18 (s, 2H), 7.09 (dd, J= 7.8, 2.8 Hz, 1H), 6.24 (s, 2H), 5.75 - 5.70 (m, 1H), 4.82 - 4.76 (m, 1H), 4.61 (s, 3H), 4.52 (br t, J = 9.0 Hz, 1H), 4.35 (br dd, J= 10.2, 4.8 Hz, 1H), 2.09 (s, 3H).

[0250] Step 2: To a solution of 2-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin- 4-yl)-2H-l,2,3-triazol-2-yl)azetidin-l-yl)-2-oxoethyl acetate (210 mg, 438 pmol, 1.00 eq) in THF (3 mL) and H2O (1 mL) was added LiOH.H2O (27.6 mg, 657 pmol, 1.50 eq) at 25°C. The mixture was stirred at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC: (CD03-Welch Xtimate C18 (150 x 25 mm, 5 um); flow rate: 25 mL / min; gradient: 22% - 52%, B over 10 min; mobile phase A: H2O (0.225% FA), mobile phase B: MeCN) to give 2-amino-6-(6-fluorobenzo[d] [ l,3]dioxol-4-yl)-4-(2-( l-(2-hydroxyacetyl)azetidin-3-yl)- 2H-l,2,3-triazol-4-yl)nicotinonitrile (48.5 mg, 106 pmol, 24% yield, 95.5% purity). 'HNMR. DMSO-t / e 400 MHz: 5 = ppm 8.50 (s, 1H), 7.74 (s, 1H), 7.41 (dd, J= 11.4, 2.6 Hz, 1H), 7.17 (br s, 2H), 7.09 (dd, J = 7.8, 2.8 Hz, 1H), 6.24 (s, 2H), 5.72 - 5.69 (m, 1H), 5.11 (t, J= 6.0 Hz, 1H), 4.80 (br t, J= 8.8 Hz, 1H), 4.62 (br dd, J= 9.2, 4.6 Hz, 1H), 4.49 (br t, J= 9.4 Hz, 1H), 4.32 (br dd, J= 10.4, 4.8 Hz, 1H), 3.99 (d, J = 6.0 Hz, 2H). LCMS. (ESI+): m / z 438.0 (M+H)+.

[0251] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.17.Example 70: 4-(l-(l-acryloylazetidin-3-yl)-lH-pyrazol-4-yl)-2-amino-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile

[0252] Step 1 : To a solution of 2-amino-4-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-6-(6- fhrorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (400 mg, 964 pmol, 1.00 eq, HC1 salt) and 3- acetoxypropanoic acid (127 mg, 964 pmol, 1.00 eq) in THF (5 mL) were added DIPEA (374 mg, 2.89WSGR Docket No. 59792-717.601 mmol, 504 pL, 3.00 eq) and HATU (733 mg, 1.93 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiCE, Commercial hexanes / THF = 1 / 5) to give 3-(3-(4-(2-amino-3-cyano-6- (6-fluorobenzo[d] [ 1 ,3]dioxol-4-yl)pyridin-4-yl)- IH-pyrazol- 1 -yl)azetidin- 1 -yl) -3 -oxopropyl acetate (230 mg, 467 pmol, 48% yield) as a white solid.

[0253] Step 2: To a solution of 3-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin- 4-yl)-lH-pyrazol-l-yl)azetidin-l-yl)-3-oxopropyl acetate (220 mg, 447 pmol, 1.00 eq) in THF (4 mb) and H2O (0.5 mb) was added LiOH (32.1 mg, 1.34 mmol, 3.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 urn; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 20% - 50% B over 8.0 min) to give 4-(l-(l-acryloylazetidin-3-yl)- lH-pyrazol-4-yl)-2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (20.6 mg, 47.6 pmol, 11% yield, 100% purity). ’H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.56 (s, 1H), 8.18 (s, 1H), 7.48 (s, 1H), 7.38 (dd, J= 11.4, 2.6 Hz, 1H), 7.07 (dd, J= 8.0, 2.6 Hz, 1H), 7.00 (br s, 2H), 6.38 (dd, J= 17.0, 10.4 Hz, 1H), 6.22 (s, 2H), 6.16 (dd, J= 17.0, 2.0 Hz, 1H), 5.73 (dd, J= 10.4, 2.0 Hz, 1H), 5.52 - 5.42 (m, 1H), 4.73 (br t, J= 8.6 Hz, 1H), 4.54 (br dd, J= 9.0, 5.2 Hz, 1H), 4.44 (br t, J= 9.4 Hz, 1H), 4.26 (br dd, J = 10.4, 5.2 Hz, 1H). LCMS. (ESI+): m / z 433.2 (M+H)+.

[0254] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.18.General Scheme 1.18.Example 71: 2-hydroxyethyl 3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d] [l,3]dioxol-4-yl)pyridin-4- yl)-2H-l,2,3-triazol-2-yl)azetidine-l-carboxylate

[0255] Step 1 : To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (1.00 g, 5.67 mmol, 1.00 eq) in DCM (20 mb) was added TEA (1.72 g, 17.0 mmol, 2.37 mL, 3.00 eq) at 15 °C. Then bis(trichloromethyl) carbonate (860 mg, 2.90 mmol, 5.1 le-1 eq) was added at 0 °C and stirred for 0.5 h. The mixture was stirred for 2 h at 15 °C. 2-((tert-butyldimethylsilyl)oxy)ethyl carbonochloridate (600 mg, crude) in DCM (20 mL) was used into the next step directly.WSGR Docket No. 59792-717.601Step 2: To a solution of 2-amino-4-(2-(azetidin-3-yl)-2H-l,2,3-triazol-4-yl)-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (200 mg, 527 pmol, 1.00 eq) in DCM (6 mL) were added TEA (107 mg, 1.05 mmol, 147 pL, 2.00 eq) and 2-((tert-butyldimethylsilyl)oxy)ethyl carbonochloridate (252 mg, 1.05 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched by slow addition of H2O (6 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give 2-((tert-butyldimethylsilyl)oxy)ethyl 3-(4-(2-amino-3-cyano-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4-yl)-2H-l,2,3-triazol-2-yl)azetidine-l-carboxylate (60.0 mg, crude) as a light yellow solid.1H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.49 (s, 1H), 7.72 (s, 1H), 7.41 (dd, J= 11.4, 2.8 Hz, 1H), 7.18 (s, 2H), 7.09 (dd, J= 8.0, 2.6 Hz, 1H), 6.23 (s, 2H), 5.71 - 5.65 (m, 1H), 4.52 (br s, 2H), 4.33 - 4.28 (m, 2H), 4.06 - 4.02 (m, 2H), 3.76 (t, J= 4.8 Hz, 2H), 0.84 (s, 9H), 0.04 (s, 6H).

[0256] Step 3: A solution of 2-((tert-butyldimethylsilyl)oxy)ethyl 3-(4-(2-amino-3-cyano-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4-yl)-2H-l,2,3-triazol-2-yl)azetidine-l-carboxylate (200 mg, 344 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 6.00 mL, 34.9 eq) at 15 °C and stirred for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD01- Phenomenex luna C18 150 x 25 x 10 um; mobile phase: [H2O (0.225% PA) - MeCN]; gradient: 28% - 58% B over 10.0 min) to give 2-hydroxyethyl 3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-2H-l,2,3-triazol-2-yl)azetidine-l-carboxylate (72.9 mg, 152 pmol, 44% yield, 97.7% purity). ’HNMR. DMSO-t / 6400 MHz: 5 = ppm 8.50 (s, 1H), 7.73 (s, 1H), 7.41 (dd, J= 11.4, 2.4 Hz, 1H), 7.17 (br s, 2H), 7.10 - 7.08 (m, 1H), 6.24 (s, 2H), 5.71 - 5.65 (m, 1H), 4.79 (t, J= 5.6 Hz, 1H), 4.53 (br s, 2H), 4.34 (br s, 2H), 4.03 (t, J= 5.0 Hz, 2H), 3.56 (q, J= 5.4 Hz, 2H). LCMS. (ESI+): m / z 468.1 (M+H)+.

[0257] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.19.General Scheme 1.19.Example 72: 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(l-(l-(3-hydroxypropanoyl)azetidin-3- yl)-lH-pyrazol-4-yl)nicotinonitrile

[0258] To a solution of 3-(3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)pyridin-4-yl)- lH-pyrazol-l-yl)azetidin-l-yl)-3-oxopropyl acetate (310 mg, 629 pmol, 1.00 eq) in H2O (1 mL), THF (4 mL) and MeOH (2 mL) was added K2CO3 (174 mg, 1.26 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 15 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (5 mL) and extracted with EtOAc / THF (1 / 1, 10 mL * 2). TheWSGR Docket No. 59792-717.601 combined organic layers were washed with brine (10 mL), dried over anhydrous ISfeSC , filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 20% - 50% B over 8.0 min) to give 2-amino-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)-4-(l-(l-(3-hydroxypropanoyl)azetidin-3- yl)-lH-pyrazol-4-yl)nicotinonitrile (85.0 mg, 189 pmol, 30% yield, 100% purity). 'H NMR. DMSO-t / e 400 MHz: 5 = ppm 8.53 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 7.38 (dd, J= 11.4, 2.6 Hz, 1H), 7.07 (dd, J = 8.0, 2.6 Hz, 1H), 7.00 (s, 2H), 6.22 (s, 2H), 5.45 - 5.41 (m, 1H), 4.66 - 4.62 (m, 2H), 4.47 (dd, J= 9.0, 5.4 Hz, 1H), 4.34 (t, J= 9.0 Hz, 1H), 4.18 (dd, J= 5.4, 10.0 Hz, 1H), 3.65 (br t, J= 5.8 Hz, 2H), 2.28 (t, J= 6.4 Hz, 2H). LCMS. (ESI+): m / z 451.1 (M+H)+.

[0259] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.21.General Scheme 1.21.Example 75: 2-amino-4-(2,3-dihydropyrazolo[5,l-b]oxazol-6-yl)-6-(6-fluorobenzo[d] [l,3]dioxol-4- yl)nicotinonitrile

[0260] Step 1 : To a solution of ethyl 2,3-dihydropyrazolo[5,l-b]oxazole-6-carboxylate (1.00 g, 5.49 mmol, 1.00 eq) in THF (100 mL) was added LiAlH4 (2.50 M, 3.29 mL, 1.50 eq) at 0 °C under N2. The mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched with 10% NaOH (30 mL) at 0 °C under N2 and extracted with EtOAc (15 mL x 4). The combined organic layers were washed with brine (20 mL), dried over anhydrous ISfeSCL, filtered, and concentrated under reduced pressure to give (2,3-dihydropyrazolo[5,l-b]oxazol-6-yl)methanol (700 mg, crude) as a white solid. ’H NMR. CDCfi 400 MHz: 5 = ppm 5.37 (s, 1H), 5.00 (t, J= 8.0 Hz, 2H), 4.52 (d, J= 5.2 Hz, 2H), 4.23 (t, J= 8.0 Hz, 2H). Step 2: To a mixture of (2,3-dihydropyrazolo[5,l-b]oxazol-6-yl)methanol (700 mg, 5.00 mmol, 1.00 eq) in CHCh (16 mL) was added MnCE (3.47 g, 40.0 mmol, 8.00 eq) at 15 °C under N2. The mixture was stirred at 62 °C for 1.5 h under N2. The reaction mixture was filtered and the filtrate was concentrated to give 2,3-dihydropyrazolo[5,l-b]oxazole-6-carbaldehyde (600 mg, crude) as a white solid. ’H NMR. CDCh 400 MHz: 5 = ppm 9.76 (s, 1H), 5.87 (s, 1H), 5.13 (br t, J= 8.0 Hz, 2H), 4.41 (br t, J= 8.0 Hz, 2H).

[0261] Step 3: To a solution of l-(6-fluoro-l,3-benzodioxol-4-yl)ethanone (300 mg, 1.65 mmol, 1.00 eq) in TFE (6 mL) were added NFLOAc (152 mg, 1.98 mmol, 1.20 eq), propanedinitrile (131 mg, 1.98 mmol, 124 pL, 1.20 eq) and 2,3-dihydropyrazolo[5,l-b]oxazole-6-carbaldehyde (227mg, 1.65 mmol,WSGR Docket No. 59792-717.6011.00 eq) at 15 °C. The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by re -crystallization from MeCN (25 mL) at 15 °C to give 2-amino-4-(2,3-dihydropyrazolo[5,l-b]oxazol-6-yl)-6-(6- fhrorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (86.8 mg, 238 pmol, 14% yield, 100% purity). 'H NMR. DMSO-6400 MHZ: 5 = ppm 7.73 (s, 1H), 7.41 (dd, J= 11.6, 2.8 Hz, 1H), 7.06 (dd, J= 8.0, 2.8 Hz, 1H), 6.96 (s, 2H), 6.23 (s, 2H), 6.10 (s, 1H), 5.14 (t, J= 8.0 Hz, 2H), 4.42 (t, J= 8.0 Hz, 2H). LCMS. (ESI+): m / z 366.2 (M+H)+.

[0262] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.22.General Scheme 1.22.Example 79: 2-amino-4-(2-cyclobutyl-2H-l,2,3-triazol-4-yl)-6-(6-fluorobenzo[d] [l,3]dioxol-4- yl)nicotinonitrile

[0263] Step 1: To a solution of methyl 2H-l,2,3-triazole-4-carboxylate (2.00 g, 15.7 mmol, 1.00 eq) and bromocyclobutane (2.55 g, 18.9 mmol, 1.78 mL, 1.20 eq) in DMF (30 mL) was added CS2CO3 (10.3 g,31.5 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by slow addition of H2O (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (commercial hexanes / ethyl acetate, from 1 / 0 to 20 / 1) to give methyl 2-cyclobutyl-2H- l,2,3-triazole-4-carboxylate (1.50 g, 8.28 mmol, 53% yield). 'H NMR. CDCh 400 MHz: 5 = ppm 8.06 (s, 1H), 5.18 (quin, J= 8.4 Hz, 1H), 3.96 (s, 3H), 2.81 - 2.74 (m, 2H), 2.56 - 2.54 (m, 2H), 1.97 - 1.90 (m, 2H).

[0264] Step 2: To a solution of methyl 2-cyclobutyl-2H-l,2,3-triazole-4-carboxylate (1.40 g, 7.73 mmol, 1.00 eq) in MeOH (20 mL) was added NaBH4 (731 mg, 19.3 mmol, 2.50 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 h under N2. Then the mixture was heated to 40 °C and stirred for15.5 h under N2. The reaction was quenched by saturated NH4CI (60 mL) at 0 °C under N2 and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (commercial hexanes / ethyl acetate, from 9 / 1 to 4 / 1) to give (2-cyclobutyl-2H-l,2,3- triazol-4-yl)methanol (1.00 g, 6.53 mmol, 85% yield). 'H NMR. CDCI3 400 MHz: 5 = ppm 7.57 (s, 1H), 5.08 (quin, J= 8.4 Hz, 1H), 4.78 (s, 2H), 2.70 - 2.67 (m, 2H), 2.54 - 2.51 (m, 2H), 1.94 - 1.89 (m, 2H).WSGR Docket No. 59792-717.601

[0265] Step 3: To a solution of (2-cyclobutyl-2H-l,2,3-triazol-4-yl)methanol (1.00 g, 6.53 mmol, 1.00 eq) in THF (10 mL) was added MnCL (11.4 g, 131 mmol, 20.0 eq) at 15 °C. The mixture was stirred at 100 °C for 2 h. The reaction mixture was fdtered and the fdter cake was rinsed with THF (80 mL). Then the combined fdtrates were concentrated under reduced pressure to give 2-cyclobutyl-2H-l,2,3-triazole- 4-carbaldehyde (1.00 g, crude). ’H NMR CDCh 400 MHz: 5 = ppm 10.08 (s, 1H), 8.05 (s, 1H), 5.21 - 5.12 (m, 1H), 2.75 - 2.70 (m, 2H), 2.57 - 2.54 (m, 2H), 1.97 - 1.93 (m, 2H).

[0266] Step 4: To a solution of 2-cyclobutyl-2H-l,2,3-triazole-4-carbaldehyde (200 mg, 1.32 mmol, 1.00 eq), l-(6-fluoro-l,3-benzodioxol-4-yl)ethanone (241 mg, 1.32 mmol, 1.00 eq) and propanedinitrile (87.4 mg, 1.32 mmol, 83.3 pL, 1.00 eq) in TFE (8 mL) was added NFLOAc (153 mg, 1.98 mmol, 1.50 eq) at 15 °C. The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by trituration with in MeOH (12 mL) at 15 °C for 0.2 h. After filtration and drying under vacuum to give 2-amino-4-(2 -cyclobutyl -2H- 1,2,3 -triazol-4-yl)-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (184 mg, 479 pmol, 36% yield, 98.3% purity). 'HNMR. DMSO-6400 MHZ: 5 = ppm 8.39 (s, 1H), 7.72 (s, 1H), 7.41 (dd, J =11.4, 2.8 Hz, 1H), 7.15 (s, 2H), 7.08 (dd, J= 8.0, 2.8 Hz, 1H), 6.24 (s, 2H), 5.28 (quin, J= 8.2 Hz, 1H), 2.67 - 2.52 (m, 4H), 1.92 - 1.88 (m, 2H). LCMS. (ESI+): m / z 379.0 (M+H)+.

[0267] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.23.General Scheme 1.23.Example 81: 2-amino-6-(6-cyclopropylbenzo[d][l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4- yl)nicotinonitrile

[0268] Step 1 : To a solution of methyl 6-bromobenzo[d][l,3]dioxole-4-carboxylate (5.00 g, 19.3 mmol, 1.00 eq) and cyclopropylboronic acid (2.16 g, 25.1 mmol, 1.30 eq) in toluene (40 mL) and H2O (4 mL) were added K3PO4 (14.3 g, 67.4 mmol, 3.49 eq), Pd(OAc)2 (433 mg, 1.93 mmol, 9.99e-2 eq) and tricyclohexylphosphane (541 mg, 1.93 mmol, 625 pL, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. The mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by MPLC (SiCL, Commercial hexanes / Ethyl acetate = 1 / 0 to 0 / 1) to give methyl 6-cyclopropylbenzo[d][l,3]dioxole-4-carboxylate (3.70 g, 16.8 mmol, 87% yield) as a pale yellow solid. ’HNMR. DMSO-t / 6400 MHz: 5 = ppm 7.05 (d, J= 1.8 Hz, 1H), 6.85 (d, J= 1.8 Hz, 1H), 6.09 (s, 2H), 3.80 (s, 3H), 1.95 - 1.88 (m, 1H), 0.91 - 0.87 (m, 2H), 0.62 - 0.60 (m, 2H).WSGR Docket No. 59792-717.601

[0269] Step 2: To a solution of methyl 6-cyclopropylbenzo[d][l,3]dioxole-4-carboxylate (3.70 g, 16.8 mmol, 1.00 eq) in MeOH (15 mb), THF (15 mb) and H2O (15 mb) was added NaOH (2.02 g, 50.4 mmol, 3.00 eq) at 15 °C. The mixture was stirred at 15 °C for 12 h. The mixture was diluted with H2O (50 mb) and extracted with EtOAc (20 mb x 3). The aqueous phase was adjusted to pH = 2 with 1 M of HC1. The mixture was fdtered, the fdter cake was washed with water (10 mb x 3) and the fdter cake was dried to give 6-cyclopropylbenzo[d][l,3]dioxole-4-carboxylic acid (2.90 g, crude) as a white solid. ’H NMR. DMSO-t / 6400 MHz: 5 = ppm 7.02 (d, J= 1.6 Hz, 1H), 6.81 (d, J= 1.8 Hz, 1H), 6.05 (s, 2H), 1.93 - 1.86 (m, 1H), 0.90 - 0.86 (m, 2H), 0.60 - 0.59 (m, 2H).Step 3: To a solution of 6-cyclopropylbenzo[d][l,3]dioxole-4-carboxylic acid (2.80 g, 13.6 mmol, 1.00 eq) and N-methoxymethanamine;hydrochloride (1.59 g, 16.3 mmol, 1.20 eq) in DMF (20 mb) were added HOBt (2.75 g, 20.4 mmol, 1.50 eq) and EDCI (3.90 g, 20.4 mmol, 1.50 eq) at 15 °C. The mixture was stirred at 15 °C for 12 h. The mixture was diluted with H2O (50 mb) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / Ethyl acetate = 1 / 0 to 0 / 1) to give 6-cyclopropyl-N-methoxy-N- methylbenzo[d][l,3]dioxole-4-carboxamide (1.20 g, 4.81 mmol, 35% yield).

[0270] Step 4: To a solution of 6-cyclopropyl-N-methoxy-N-methylbenzo[d][l,3]dioxole-4- carboxamide (1.20 g, 4.81 mmol, 1.00 eq) in THF (10 mL) was added MeMgBr (3.00 M, 3.21 mL, 2.00 eq) at 0 °C. The mixture was stirred at 15 °C for 2 h under N2. The mixture was diluted with saturated aqueous NH4CI solution (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (3 mL x 2), filtered, and the filter cake was dried to give l-(6- cyclopropylbenzo[d][l,3]dioxol-4-yl)ethanone (280 mg, 1.37 mmol, 29% yield) as a yellow solid.Step 5: A solution of l-(6-cyclopropylbenzo[d][l,3]dioxol-4-yl)ethanone (100 mg, 490 pmol, 1.00 eq), 1- (oxetan-3-yl)pyrazole-4-carbaldehyde (74.5 mg, 490 pmol, 1.00 eq), propanedinitrile (32.4 mg, 490 pmol, 30.8 pL, 1.00 eq) and NFLOAc (56.6 mg, 735 pmol, 1.50 eq) in TFE (4 mL) was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 7um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 45% - 70% B over 8.0 min) to give 2-amino-6-(6-cyclopropylbenzo[d][l,3]dioxol-4-yl)-4-(l-(oxetan-3- yl)-lH-pyrazol-4-yl)nicotinonitrile (31.5 mg, 76.7 pmol, 16% yield, 97.8% purity). 'H NMR. DMSO-t / e 400 MHz: 5 = ppm 8.49 (s, 1H), 8.17 (s, 1H), 7.43 (s, 2H), 6.97 (s, 2H), 6.73 (d, J= 1.2 Hz, 1H), 6.10 (s, 2H), 5.73 (t, J= 6.8 Hz, 1H), 4.94 (d, J= 7.2 Hz, 4H), 1.95 - 1.88 (m, 1H), 0.92 - 0.88 (m, 2H), 0.66 - 0.63 (m, 2H). LCMS. (ESI+): m / z 402.1 (M+H)+.WSGR Docket No. 59792-717.601

[0271] Alternatively, compounds described herein can be synthesized as described in General Scheme1.24.General Scheme 1.24.Example 86: 4-(2-(l-acetylazetidin-3-yl)-l-methyl-lH-imidazol-5-yl)-2-amino-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile

[0272] Step 1 : A solution of tert-butyl 3 -cyanoazetidine- 1 -carboxylate (13.8 g, 75.7 mmol, 1.00 eq) and hydroxylamine (5.00 g, 75.7 mmol, 13.8 m , 1.00 eq) in EtOH (350 m ) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give tert-butyl 3-(N- hydroxycarbamimidoyl)azetidine-l -carboxylate (16.3 g, crude) as a yellow solid.

[0273] Step 2: To a mixture of Raney-Ni (1.62 g) in MeOH (150 m ) was added tert-butyl 3-(N- hydroxycarbamimidoyl)azetidine-l -carboxylate (8.15 g, 37.9 mmol, 1.00 eq) at 15 °C. The suspension was degassed and purged with H2 three times. The mixture was stirred at 15 °C for 12 h under H2 (30 psi). The reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure to give tert-butyl 3 -carbamimidoylazetidine-1 -carboxylate (7.50 g, crude) as a brown solid.

[0274] Step 3: The reaction was set up in 30 parallel batches. To a solution of tert-butyl 3- carbamimidoylazetidine-1 -carboxylate (500 mg, 2.51 mmol, 1.00 eq), l,3-dihydroxypropan-2-one (452 mg, 5.02 mmol, 2.00 eq) and NH4CI (470 mg, 8.78 mmol, 3.50 eq) in NH3.H2O (10 mb) was stirred at 80 °C for 2 h. The reaction mixture was lyophilized to remove solvent. The residue was dissolved in EtOAc / THb (150 mb / 150 mb), fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250 x 70 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 0% - 30% B over 18.0 min) to give tert-butyl 3-(4- (hydroxymethyl)-lH-imidazol-2-yl)azetidine-l -carboxylate (10.0 g, crude) as a white solid.

[0275] Step 4: To a solution of tert-butyl 3-(4-(hydroxymethyl)-lH-imidazol-2-yl)azetidine-l- carboxylate (8.00 g, 31.6 mmol, 1.00 eq) in DMA (60 mb) were added KOH (3.54 g, 63.2 mmol, 2.00WSGR Docket No. 59792-717.601 eq) and Mel (1.12 g, 7.90 mmol, 492 pL, 0.250 eq) at 0 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250 x 70 mm x 10 um; mobile phase: [H2O (lOmM NH4HCO3) - MeCN]; gradient: 5% - 40% B over 18.0 min) to give tert-butyl 3 -(5 -(hydroxymethyl)- 1- methyl-lH-imidazol-2-yl)azetidine-l -carboxylate (1.64 g, crude) as a yellow solid.

[0276] Step 5: To a solution of tert-butyl 3-(5-(hydroxymethyl)-l-methyl-lH-imidazol-2-yl)azetidine-l- carboxylate (1.64 g, 6.13 mmol, 1.00 eq) in THF (150 mb) was added MnCE (8.00 g, 92.0 mmol, 15.0 eq) at 15 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 40 x 5 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 10% - 40% B over 8.0 min) to give tert-butyl 3-(5-formyl-l-methyl-lH-imidazol-2-yl)azetidine-l-carboxylate (410 mg, crude).

[0277] Step 6: A solution of tert-butyl 3-(5-formyl-l-methyl-lH-imidazol-2-yl)azetidine-l-carboxylate (200 mg, 754 pmol, 1.00 eq), l-(6-fhiorobenzo[d][l,3]dioxol-4-yl)ethanone (137 mg, 754 pmol, 1.00 eq), propanedinitrile (49.8 mg, 754 pmol, 47.5 pL, 1.00 eq) and acetic acid;ammonia (58.1 mg, 754 pmol, 1.00 eq) in TFE (4 mb) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give tert-butyl 3-(5-(2-amino-3-cyano-6-(6- fluorobcnzol d | [ 1 ,3]dioxol-4-yl)pyridin-4-yl)- 1 -methyl- lH-imidazol-2-yl)azetidine- 1 -carboxylate (370 mg, crude).

[0278] Step 7: To a solution of tert-butyl 3-(5-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-l -methyl- lH-imidazol-2-yl)azetidine-l -carboxylate (370 mg, 751 pmol, 1.00 eq) in DCM (4 mb) was added TFA (2.00 g, 17.5 mmol, 1.30 mb, 23.3 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give 2- amino-4-(2-(azetidin-3-yl)-l-methyl-lH-imidazol-5-yl)-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)nicotinonitrile (380 mg, crude, TFA salt).

[0279] Step 8: To a solution of 2-amino-4-(2-(azetidin-3-yl)-l-methyl-lH-imidazol-5-yl)-6-(6- fhrorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (380 mg, 750 pmol, 1.00 eq, TFA salt) in THF (5 mb) and H2O (1 mb) were added Na2CC>3 (239 mg, 2.25 mmol, 3.00 eq) and acetyl chloride (58.9 mg, 750 pmol, 53.4 pL, 1.00 eq) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (10 mb) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mb), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.04% HC1) - MeCN]; gradient: 5% - 30% B over 8.0 min) to give 4-(2-(l-acetylazetidin-3-yl)-l-methyl-lH-imidazol- 5-yl)-2-amino-6-(6-fhrorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (83.9 mg, 175 pmol, 23% yield, 98.2% purity, HC1 salt).1H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.04 (br s, 1H), 7.51 - 7.31 (m, 4H), 7.15 (dd, J = 8.0, 2.6 Hz, 1H), 6.22 (s, 2H), 4.57 - 4.53 (m, 2H), 4.41 (br t, J= 6.6 Hz, 1H), 4.30 - 4.21 (m, 2H), 3.66 (s, 3H), 1.84 (s, 3H). LCMS. (ESI+): m / z 435.2 (M+H)+.WSGR Docket No. 59792-717.601

[0280] Alternatively, compounds described herein can be synthesized as described in General Scheme 1.25.General Scheme 1.25.Example 87: 4-(2-(l-acetylazetidin-3-yl)-l-methyl-lH-imidazol-4-yl)-2-amino-6-(6- fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile

[0281] Step 1: To a solution of methyl 2-bromo-l -methyl- lH-imidazole-4-carboxylate (2.50 g, 11.4 mmol, 1.00 eq) in THF (40 mL) was added DIBAL-H (1.00 M, 28.5 mL, 2.50 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. The mixture was stirred at 20 °C for 12 h under N2. The reaction mixture quenched by MeOH (100 mL) at 0 °C and concentrated under reduced pressure to give (2-bromo-l -methyl- lH-imidazol-4-yl)methanol (2.18 g, crude).

[0282] Step 2: To a solution of (2-bromo-l -methyl- lH-imidazol-4-yl)methanol (2.00 g, 10.5 mmol, 1.00 eq) in THF (100 mL) was added Mn02 (9.10 g, 105 mmol, 10.0 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture filtered and the filtrate was concentrated under reduced pressure to give 2 -bromo- 1 -methyl- lH-imidazole-4-carbaldehyde (2.20 g, crude) as a white solid.

[0283] Step 3: A solution of 2-bromo-l -methyl- lH-imidazole-4-carbaldehyde (2.20 g, 11.6 mmol, 1.00 eq), l-(6-fluoro-l,3-benzodioxol-4-yl)ethanone (2.12 g, 11.6 mmol, 1.00 eq), propanedinitrile (769 mg, 11.6 mmol, 733 pL, 1.00 eq) and acetic acid;ammonia (897 mg, 11.6 mmol, 1.00 eq) in TFE (20 mb) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was triturated with MeOH (30 mL) at 20 °C for 10 min to give 2-amino-4-(2- bromo-1 -methyl- lH-imidazol-4-yl)-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (1.68 g, 4.04 mmol, 35% yield) as a white solid.

[0284] Step 4: The reaction was set up in six parallel batches. To a solution of 2-amino-4-(2 -bromo- 1- methyl-lH-imidazol-4-yl)-6-(6-fluorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (100 mg, 240 pmol, 1.00 eq) and tert-butyl 3 -bromoazetidine -1 -carboxylate (340 mg, 1.44 mmol, 6.00 eq) in DMA (2 mL) were added [Ir(dF(CF3)ppy)2(dtbbpy)]PFe (2.70 mg, 2.40 pmol, 0.0100 eq), NiCL.dtbbpy (2.39 mg, 6.01 pmol,WSGR Docket No. 59792-717.6010.0250 eq), TTMSS (59.8 mg, 240 pmol, 74.1 pL, 1.00 eq) and Na2COs (50.9 mg, 481 pmol, 2.00 eq) at 20 °C. The mixture was stirred at 30 °C for 12 h with 34 W LED (450 nm) under N2. Six batches were combined. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 250 x 50 mm x 10 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 45% - 75% B over 10.0 min) to give tert-butyl 3-(4-(2-amino-3-cyano-6- (6-fluorobenzo[d] [ 1 ,3]dioxol-4-yl)pyridin-4-yl)- 1 -methyl- lH-imidazol-2-yl)azetidine- 1 -carboxylate (120 mg, crude) as an off-white solid.

[0285] Step 5: To a solution of tert-butyl 3-(4-(2-amino-3-cyano-6-(6-fluorobenzo[d][l,3]dioxol-4- yl)pyridin-4-yl)-l -methyl- lH-imidazol-2-yl)azetidine-l -carboxylate (90.0 mg, 183 pmol, 1.00 eq) in DCM (3 m ) was added TFA (1.54 g, 13.5 mmol, 1.00 m , 73.7 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give 2- amino-4-(2-(azetidin-3-yl)- 1 -methyl- lH-imidazol-4-yl)-6-(6-fluorobenzo[d] [ 1 ,3]dioxol-4- yl)nicotinonitrile (90.0 mg, crude, TFA salt).

[0286] Step 6: To a solution of 2-amino-4-(2-(azetidin-3-yl)-l-methyl-lH-imidazol-4-yl)-6-(6- fhrorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (90.0 mg, 178 pmol, 1.00 eq, TFA salt) in THF (3 mb) and H2O (1 mb) were added Na2COs (56.5 mg, 533 pmol, 3.00 eq) and acetyl chloride (14.0 mg, 178 pmol, 12.6 pL, 1.00 eq) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.04% HC1) - MeCN]; gradient: 20% - 40% B over 8.0 min) to give 4-(2-(l-acetylazetidin-3-yl)-l-methyl-lH-imidazol-4-yl)-2- amino-6-(6-fhiorobenzo[d][l,3]dioxol-4-yl)nicotinonitrile (50.3 mg, 106 pmol, 59% yield, 98.9% purity, HC1 salt). ’H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.07 (s, 1H), 7.83 (s, 1H), 7.42 (dd, J= 11.4, 2.0 Hz, 1H), 7.09 (dd, J= 7.8, 2.0 Hz, 1H), 6.24 (s, 2H), 4.53 - 4.43 (m, 2H), 4.24 - 4.22 (m, 1H), 4.18 - 4.16 (m, 2H), 3.70 (s, 3H), 1.81 (s, 3H). LCMS. (ESI+): m / z 435.2 (M+H)+.WSGR Docket No. 59792-717.601

[0287] Alternatively, compounds described herein can be synthesized as described in General Scheme 2.General Scheme 2.Example 7: 2-amino-6-(imidazo[l,5-a]pyridin-8-yl)-4-(l-(oxetan-3-yl)-l / f-pyrazol-4- yl)nicotinonitrile

[0288] Step 1. A mixture of methyl lH-pyrazole-4-carboxylate (105 g, 833 mmol, 1.00 eq), K2CO3 (230 g, 1.67 mol, 2.00 eq) and PMB-C1 (156 g, 999 mmol, 136 mb, 1.20 eq) in DMF (1000 mb) was stirred at 100 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (100 mb) at 0 °C for 20 min to give methyl l-(4- methoxybenzyl)- lH-pyrazole-4-carboxylate as a white solid (175 g). The resulting product was used as is.

[0289] Step 2. To a solution of methyl acetate (52.6 g, 711 mmol, 56.5 mb, 1.00 eq) in THF (1500 mb) at -70 °C under N2 atmosphere, KHMDS (1.00 M, 1.42 L, 2.00 eq) was added dropwise. The resulting mixture was stirred for 30 min. Following which, the product from the previous step (175 g, 711 mmol, 1.00 eq) in THF (300 mb) was added to the mixture at -70 °C. The resulting mixture was then allowed to warm to 25 °C and stirred for a further 12 h. The reaction was quenched by saturated NaHCOs (1000 mb), then extracted with ethyl acetate (300 mb x 3). The combined organic layers were washed with brine (500 mb), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to give methyl 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-3-oxopropanoate as a yellow oil (90.0 g, 312 mmol, 44% yield).

[0290] Step 3. A mixture of the ketoester product from the previous step (64.0 g, 222 mmol, 1.00 eq), propanedinitrile (17.6 g, 266 mmol, 16.8 mb, 1.20 eq) and NFEOAc (20.5 g, 266 mmol, 1.20 eq) in TFEWSGR Docket No. 59792-717.601(100 mL) was stirred at 80 °C for 12 h. Following which, H2O (1500 mL) was added to the mixture, and the aqueous mixture was extracted with EtOAc (500 mL x 6). The combined organic layers were dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (80 mL) at 0 °C for 20 min to give 2-amino-6-hydroxy-4-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)nicotinonitrile as a yellow solid (30.0 g, 93.4 mmol, 42% yield).

[0291] Step 4. 1,1,1 -trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (105 g, 294 mmol, 3.50 eq) in DMF (40 mL) at 0 °C was added to a solution of the product obtained from the previous step (27.0 g, 84.0 mmol, 1.00 eq) and K2CO3 (58.1 g, 420 mmol, 5.00 eq in DMF (300 mL). The resulting mixture was stirred at 25 °C for 12 h. H2O (1500 mL) was then added, and the aqueous mixture was extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to give 6-amino-5-cyano-4-(l-(4-methoxybenzyl)-lH- pyrazol-4-yl)pyridin-2-yl trifluoromethanesulfonate as a yellow solid (25.0 g, 55. 1 mmol, 66% yield).

[0292] Step 5. To a solution of the trifluoromethane sulfonate product from the previous step (5.00 g, 11.0 mmol, 1.00 eq), Xphos Pd G4 (949 mg, 1.10 mmol, 0.100 eq) and tributyl(tributylstannyl)stannane (28.6 g, 49.3 mmol, 24.7 mL, 4.47 eq) in dioxane (100 mL) at 25 °C, LiCl (1.40 g, 33.1 mmol, 678 pL, 3.00 eq) was added. The resulting mixture was stirred at 100 °C for 12 h under N2. At which point, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to give 2-amino-4-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-6-(tributylstannyl)nicotinonitrile as a yellow oil (1.50 g, 2.52 mmol, 23% yield).

[0293] Step 6. To a solution of the stannane product (400 mg, 673 pmol, 1.00 eq) and 8- bromoimidazo[l,5-a]pyridine (199 mg, 1.01 mmol, 1.50 eq) in DMF (4 mL) at 25 °C, [2-(2- aminophenyl)phenyl]palladium(l+); bis(l-adamantyl)-butyl-phosphane;methanesulfonate (49.0 mg, 67.3 pmol, 0. 100 eq) were added. The mixture was stirred at 100 °C for 12 h under N2. H2O (10 mL) was added, and the resulting mixture was filtered. The filter cake was washed by EtOAc (2 mL), then purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 15% - 45% B over 8.0 min) to give 2-amino-6-(imidazo[l,5-a]pyridin-8-yl)-4-(l-(4- methoxybenzyl)- lH-pyrazol-4-yl)nicotinonitrile as a brown solid (100 mg, 237 pmol, 35% yield).

[0294] Step 7. A mixture of the imidazo compound isolated in the previous step (100 mg, 237 pmol, 1.00 eq) in TFA (2 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 lOOx 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to give 2-amino-6-(imidazo[ l,5-a]pyridin-8-yl)-4-(lH-pyrazol-4-yl)nicotinonitrile as a yellow solid (40.0 mg, crude) as a yellow solid.

[0295] Step 8. A mixture of the free pyrazole (40.0 mg, 133 pmol, 1.00 eq), CS2CO3 (43.3 mg, 133 pmol, 1.00 eq) and 3-iodooxetane (24.4 mg, 133 pmol, 1.00 eq) in DMF (2 mL) was stirred at 80 °C for 0.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue wasWSGR Docket No. 59792-717.601 purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 35% B over 8.0 min) to give 2-amino-6-(imidazo[l,5-a]pyridin-8-yl)-4-(l- (oxetan-3-yl)-lH-pyrazol-4-yl)nicotinonitrile formic acid salt (10.7 mg, 26.5 pmol, 20.0% yield, 100% purity, 1.0 FA). Total yield for 8 steps, 0.2%. 'H NMR. DMSO-t / 6400 MHz: 5 = ppm 8.76 (s, 1H), 8.56 - 8.54 (m, 2H), 8.41 (s, 1H), 8.30 (s, 1H), 8.26 (br s, 1H), 7.70 (d, J= 6.8 Hz, 1H), 7.60 (s, 1H), 7.13 (s, 2H), 6.87 (t, J= 6.8 Hz, 1H), 5.78 (quin, J= 6.8 Hz, 1H), 5.03 (quin, J= 6.6 Hz, 4H). LCMS. (ESI+): m / z 358.1 (M+H)+.

[0296] Alternatively, compounds described herein can be synthesized as described in General Scheme 2.1.General Scheme 2.1.Example 47: 2-amino-6-(lH-benzo[d] [l,2,3]triazol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4- yl)nicotinonitrile

[0297] Step 1. To a solution of 4-bromo-lH-benzo[d][l,2,3]triazole (200 mg, 1.01 mmol, 1.00 eq) and TSOH.H2O (19.2 mg, 101 pmol, 0.100 eq) in DCM (2 mb) was added 3,4-dihydro-2H-pyran (102 mg, 1.21 mmol, 111 pL, 1.20 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiC>2, hexane / THF = 1 / 0 to 90 / 10) to give 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH- benzo[d][l,2,3]triazole (150 mg, 532 pmol, 53% yield).

[0298] Step 2. To a solution of 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d][l,2,3]triazole (145 mg, 514 pmol, 1.20 eq) and 2-amino-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)-6-(tributylstannyl)nicotinonitrile (227 mg, 428 pmol, 1.00 eq) in DMF (3 mb) was added palladium;tritert- butylphosphane (21.9 mg, 42.8 pmol, 0.100 eq) at 20 °C. The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 35% - 65% B over 8.0 min) to give 2-amino-4-(l-(oxetan- 3-yl)-lH-pyrazol-4-yl)-6-(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d][l,2,3]triazol-4-yl)nicotinonitrile (25.0 mg, 56.5 pmol, 13% yield) as a light yellow solid.WSGR Docket No. 59792-717.601

[0299] Step 3. To a solution of 2-amino-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)-6-(l-(tetrahydro-2H- pyran-2-yl)-lH-benzo[d][l,2,3]triazol-4-yl)nicotinonitrile (25.0 mg, 56.5 pmol, 1.00 eq) in THF (5 mL) was added TFA (3.07 g, 26.9 mmol, 2.00 mL, 477 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with MeCN (3 mL) and adjusted to pH= 8 ~ 9 with DIPEA, and purified by prep-HPLC (column: Waters Xbridge BEH C18 100 x 25 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 20% - 50% B over 8.0 min) to give 2-amino-6-(lH-benzo[d][l,2,3]triazol-4-yl)-4-(l-(oxetan-3- yl)-lH-pyrazol-4-yl)nicotinonitrile (3.40 mg, 9.08 pmol, 16% yield, 95.7% purity). 'HNMR. DMSO-t / e 400 MHz: 5 = ppm 15.62 (br s, 1H), 8.76 (s, 1H), 8.50 (br d, J= 6.8 Hz, 1H), 8.42 (s, 1H), 8.22 (br d, J = 8.0 Hz, 1H), 7.87 (br s, 1H), 7.55 (t, J= 7.8 Hz, 1H), 7.33 (br s, 2H), 5.74 (t, J= 6.8 Hz, 1H), 5.03 - 4.92 (m, 4H). LCMS. (ESI+): m / z 359.2 (M+H)+.

[0300] Alternatively, compounds described herein can be synthesized as described in General Scheme 2.2.Example 58: 2-amino-6-(6-fluoro-5-methylbenzo[d][l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol- 4-yl)nicotinonitrile

[0301] Step 1. To a solution of 4-fluoro-3-methylphenol (20.0 g, 159 mmol, 1.00 eq) in AcOH (200 mL) was added Br2 (25.3 g, 159 mmol, 8.17 mL, 1.00 eq) at 0 °C. The mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1) to give 2-bromo-4-fluoro-3-methylphenol (30.0 g, 146 mmol, 92% yield) as a yellow solid. 'H NMR. DMSO-t / e 400 MHz: 5 = ppm 7.30 (d, J= 9.0 Hz, 1H), 6.81 (d, J= 7.4 Hz, 1H), 2.12 (s, 3H).

[0302] Step 2. This reaction was set up in two parallel batches. To a solution of 2-bromo-4-fluoro-3- methylphenol (15.0 g, 73.2 mmol, 1.00 eq) in TFA (150 mL) was added HMTA (21.0 g, 150 mmol, 2.05 eq) at 15 °C. The mixture was stirred at 95 °C for 12 h. The reaction mixture was cooled to 15 °C, water (150 ml) and sulfuric acid (75 ml, 50 %) were added. The mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (200 mL),WSGR Docket No. 59792-717.601 dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / Ethyl acetate = 1 / 0 to 10 / 1) to give 3-bromo-5- fluoro-2-hydroxy-4-methylbenzaldehyde (20.0 g, 85.8 mmol, 59% yield) as a yellow solid. 'H NMR. DMSO-d6400 MHz: 5 = ppm 10.27 (s, 1H), 7.53 (d, J= 8.6 Hz, 1H), 2.51 (s, 3H).

[0303] Step 3. Solution 1: {3-bromo-5-fluoro-2-hydroxy-4-methylbenzaldehyde (18.0 g, 77.2 mmol, 1.00 eq)} in {dioxane (180 mb)}. Solution 2: {H2O2 (35.0 g, 309 mmol, 29.7 mb, 30.0% purity, 4 .00 eq)}, NaOH (6.18 g, 154 mmol, 2.00 eq). The solution 1 was pumped by Pump 1 {SI, Pl, 6.761 mL / min} to flow reactor 1 {FLR1, PFA, Dynamic mixer, 6.350 (1 / 4") mm, 1 mb, 60 °C}. {FLR1, PFA, Coils reactor, 3.175 (1 / 8") mm, 64.2 mb, 60 °C}. The solution 2 was pumped by Pump 2 {S2, P2, 6.277 mL / min} to flow reactor 1 {FLR1, PFA, Dynamic mixer, 6.350 (1 / 4") mm, 1 mb, 60 °C}. {FLR1, PFA, Coils reactor, 3.175 (1 / 8") mm, 64.2 mb, 60 °C}. The residence time of flow reactor 1 was {FLR1, 5 min. The mixture was collected with a bottle was stirred at (500 mb of 1 M ice ISfeSOs). The Pump 1 and Pump 2 were started at the same time. The reaction mixture was collected after running FLR1, 5 min. Take a sample for analysis after 5 mins. The reaction mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure to give crude 1 (10.0 g, crude) and crude 2. The crude 2 was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 25% - 50% B over 8.0 min) to give 3-bromo-5-fluoro-4-methylbenzene-l,2-diol (250 mg, 1.13 mmol, 1% yield) as a white solid and 10.0 g crude 3-bromo-5-fluoro-4-methylbenzene- 1,2-diol.

[0304] Step 4. To a solution of 3-bromo-5-fluoro-4-methylbenzene-l,2-diol (155 mg, 701 pmol, 1.00 eq) and diiodomethane (207 mg, 771 pmol, 62.2 pL, 1.10 eq) in DMF (3 mL) was added K2CO3 (194 mg, 1.40 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 110 °C for 2 h. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Commercial hexanes / Ethyl acetate = 1 / 0) to give 4-bromo-6-fluoro-5- methylbenzo[d][l,3]dioxole (75.0 mg, 322 pmol, 46% yield) as a white solid. ’H NMR. DMSO-t / e 400 MHz: 5 = ppm 6.57 (d, J= 8.8 Hz, 1H), 6.02 (s, 2H), 2.24 (d, J= 2.8 Hz, 3H).

[0305] Step 5. To a solution of 2-amino-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)-6- (tributylstannyl)nicotinonitrile (188 mg, 354 pmol, 1.10 eq) and 4-bromo-6-fluoro-5- methylbenzo[d][l,3]dioxole (75.0 mg, 322 pmol, 1.00 eq) in dioxane (2 mL) was added Catacxium(R) A pd G3 (23.4 mg, 32.2 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 110 °C for 2 h under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 30 x 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 35% - 65% B over 9.0 min) to give 2- amino-6-(6-fluoro-5-methylbenzo[d][l,3]dioxol-4-yl)-4-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)nicotinonitrile (13.5 mg, 33.9 pmol, 11% yield, 98.8% purity). ’H NMR. DMSO-r / 6400 MHz: 5 = ppm 8.60 (s, 1H),WSGR Docket No. 59792-717.6018.25 (s, 1H), 7.03 - 6.98 (m, 4H), 6.01 (s, 2H), 5.68 (t, J= 7.0 Hz, 1H), 4.96 - 4.90 (m, 4H), 2.06 (d, J = 2.5 Hz, 3H). LCMS. (ESI+): m / z 394.1 (M+H)+.General scheme for chiral resolution, CR.Example 8: (R)-2-amino-6-(benzo[< / | [l,3]dioxol-4-yl)-4-(l-(tetrahydrofuran-3-yl)-LH-pyrazol-4- yl)nicotinonitrile

[0306] ±-2-amino-6-(bcnzo|t / | [ 1 ,3]dioxol-4-yl)-4-( 1 -(tetrahydrofuran-3-yl)- lH-pyrazol-4- yl)nicotinonitrile was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 um); mobile phase: [CCE-MeOH (0.1% NH3H2O)]; B%: 50%, isocratic elution mode) to give (R)-2-amino-6- (benzo [d\ [ 1 ,3]dioxol-4-yl)-4-( 1 -(tetrahydrofuran-3 -yl)- 1 H-py razol -4-y 1 )n icoti non i tri le (10.5 mg, 26.6 pmol, 12.5% yield, 95.1% purity) as a pale yellow solid and (R)-2-amino-6-(benzo[t / ][l,3]dioxol-4-yl)-4- (l-(tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)nicotinonitrile (19.9 mg, 51.5 pmol, 24.2% yield, 97.1% purity). Relative stereochemistry was arbitrarily assigned. ’H NMR. DMSO-t / e 400 MHz: 5 = ppm 8.43 (s, 1H), 8.07 (s, 1H), 7.61 (dd, J= 8.0, 1.2 Hz, 1H), 7.45 (s, 1H), 7.03 (dd, J= 7.6, 1.2 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 6.91 (s, 2H), 6.15 (s, 2H), 5.19 - 5.14 (m, 1H), 4.04 - 3.99 (m, 2H), 3.96 - 3.93 (m, 1H), 3.84 (td, J= 8.4, 5.2 Hz, 1H), 2.45 - 2.40 (m, 1H), 2.33 - 2.27 (m, 1H). LCMS, (ESI+): m / z 376.1 (M+H)+.

[0307] Examples 9-36 were synthesized as described in examples 1-8.WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601Example A: BCL9 Phase SeparationAbbreviations / Definitions:

[0308] U2OS: Human osteosarcoma epithelial cells

[0309] DMEM: Dulbecco's Modified Eagle Medium

[0310] FBS: Fetal bovine serum

[0311] P / S: Penicillin-streptomycin

[0312] CO2: Carbon dioxide

[0313] BCL9: B-cell lymphoma 9 protein

[0314] Corelet: Optogenetic technology that allows for light microscopic visualization of biomolecular condensate formation in living cells

[0315] GFP: Green fluorescent protein

[0316] SspB: Stringent starvation protein B

[0317] mCherry: a red fluorescent protein

[0318] DMSO: Dimethyl sulfoxideCell Culture:

[0319] U2OS cells (ATTC, HTB-96) were maintained in DMEM (ThermoFisher Scientific, 11995065), with 10% FBS and 1% P / S at 37°C, 95% relative humidity and 5% CO2.BCL9 Corelet Assay used to determine nuclear phase separation modulators:

[0320] Small molecule activity was determined with a 6-day in-cell Corelet assay using the full-length BCL9 Corelet protein construct. The Corelet BCL9 protein construct contains two components: a nuclear targeted GFP -tagged ferritin core with light-inducible dimer (iLID) domains, and an SspB binding partner domain with mCherry-tagged full length BCL9. U2OS cells (ATTC, HTB-96) were seeded in 6- well plates (Coming, 3516) at a density of 4E5 cells per well, and incubated at 37°C for 24 hours before lentiviral transduction. On the transduction day, cells received either GFP-Core alone, or were cotransduced with GFP-Core and SspB-mCherry-BCL9 lentiviral components, using 2 pg / ml polybrene in DMEM with 10% FBS and 1% P / S. After transduction, cells were incubated at 37°C for 48 hours for protein overexpression. BCL9 Corelet cells were then transferred to 384-well clear flat-bottom plates (Revvity, 6057302) using a BioTek MultiFlo FX Multimode Dispenser (Agilent), and incubated for an additional 48 hours at 37°C. Small molecules were dispensed at a final concentration range of 30pM- 0.00 IpM using an Echo 655 Liquid Handler (Beckman Coulter). Following small molecule treatment,WSGR Docket No. 59792-717.601 assay plates were incubated for 2 hours at 37°C. Assay plates then received 19 total minutes of continuous blue-light induction (4 minutes of blue light, followed by addition of 4% final paraformaldehyde solution and 15 additional minutes of blue light). After light induction and fixation, assay plates were stained with Hoechst 33342 at 1:6000 (ThermoFisher Scientific, 62249). Each assay plate included a 0% phase separation control (core-only transduced cells with DMSO treatment) and a 50% phase separation control (co-transduced cells with DMSO treatment) from which phase separation modulators where identified. Assay plates were imaged using the Opera Phenix Plus High-Content Screening system (Revvity) and analyzed with Harmony software (Revvity).

[0321] The Data from Examples A is shown in table 2.Table 2WSGR Docket No. 59792-717.601Example B: Caspase 3 / 7 Induction.

[0322] Colorectal cancer and non-cancer derived intestinal cells of both the small intestine and colon were seeded in 384 wells plate and grown overnight. The next day, compounds were added as serial dilutions and cells were treated for 24 hours. The induction of apoptosis was quantified using the caspase 3 / 7 Gio assay (Promega). Plates were incubated from 30-60 minutes prior to luminescence measurement.

[0323] The Data from Example B are shown in table 3.Table 3WSGR Docket No. 59792-717.601NT: not testedExample CMethods

[0324] HeLa cells expressing GFP-tagged EB3, a plus-end tracking protein that labels growing microtubule ends, were either left untreated or treated with 300 nM of Compound A for 5 minutes prior to imaging by epi-fluorescence microscopy. In a parallel experiment, cells were either left untreated orWSGR Docket No. 59792-717.601 transduced with a CKAP5 -targeting CRISPR lentivirus to knockout and deplete CKAP5. Four days posttransduction, live cells were imaged with epi-fluorescence microscopy.Results:

[0325] In untreated control cells, EB3-GFP foci were readily detected along spindle microtubules, reflecting active microtubule growth. In contrast, treatment with Compound A or depletion of CKAP5 led to a marked loss of EB3-GFP puncta and a reduction in spindle size. The fact that Compound A treatment phenocopies CKAP5 depletion supports the hypothesis that CKAP5 is the molecular target of Compound A. See FIG. 1A, FIG. IB, FIG. 2A, and FIG. 2B.

[0326] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WSGR Docket No. 59792-717.601CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; and / or two R1on the same atom form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two Rlaon the same atom form an oxo; n is 0, 1, 2, 3, or 4;Ring B is 5 -membered ring; each R2is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -WSGR Docket No. 59792-717.601L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4;= is a single or a double bond;U is C or N;T is C or N; provided that not both U and T are N;X is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Y is N or CR4;R4is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Z is N or CR5;R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;R6is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2- Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;R7is hydrogen or Ci-Cealkyl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-WSGR Docket No. 59792-717.601 heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andL is absent or Ci-Csalkylene independently optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, - S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci- C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-Cealkyl. Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-Cshaloalkoxy, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, Ci-Cehctcroalkyl. Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting ofN, O, and S.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5-membered heteroaryl comprising one or two heteroatoms that are N.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl.WSGR Docket No. 59792-717.6017. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is pyrazolyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heterocycloalkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S.

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered heterocycloalkyl comprising one or two heteroatoms that are O.

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is tetrahydrofuranyl, 1,3-dioxolanyl, or pyrrolidinyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 1,3-dioxolanyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R2is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R2is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: m is 0 or 1.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: m is 0.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:U is C and T is C.WSGR Docket No. 59792-717.60119. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:U is N and T is C.

20. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:U is C and T is N.

21. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (la):Formula (la).

22. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (lb):Formula (lb).

23. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ic):Formula (Ic).

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is CR3.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is N.WSGR Docket No. 59792-717.60126. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is CR4.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is N.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z is CR5.

29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z is N.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R6is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

31. The compound of any one of claims 1 -30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R6is hydrogen, Ci-Cealkyl, or Ci-Ceaminoalkyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R6is hydrogen.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R7is hydrogen.

34. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (la-1) :Formula (la-1).

35. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ib-1):WSGR Docket No. 59792-717.601Formula (Ib-1).

36. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ic-1) :Formula (Ic-1).

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R3is hydrogen.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl.

41. The compound of any one of claims 1 -40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is halogen.

43. The compound of any one of claims 1 -42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 59792-717.601R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl.

45. The compound of any one of claims 1 -44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R5is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R5is hydrogen.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

48. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 6-membered heteroaryl comprising one or two heteroatoms that are N.

49. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

50. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N and O.

51. The compound of any one of claims 1 -46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered heteroaryl comprising one, two, or three heteroatoms that are N.

52. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting ofN, O, and S.

53. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered heteroaryl comprising one or two heteroatoms that are N.

54. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, or triazolyl.

55. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 59792-717.601Ring A is pyrazolyl ortriazolyl.

56. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is pyrazolyl.

57. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is triazolyl.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla.

59. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rla.

60. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently Ci-Ceaminoalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rla.

61. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently Ci-Ceaminoalkyl.

62. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently -L-cycloalkyl or -L-heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rla.

63. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently -L-cycloalkyl or -L-heterocycloalkyl.

64. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently cycloalkyl or heterocycloalkyl.

65. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 59792-717.601 each R1is independently heterocycloalkyl.

66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each Rlais independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -NRbC(=O)ORb, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each Rlais independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two Rlaon the same atom form an oxo.

68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each Rlais independently halogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, or Ci- Cehaloalkyl; and / or two Rlaon the same atom form an oxo.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each Rlais independently -C(=O)Raor -C(=O)NRcRd; and / or two Rlaon the same atom form an oxo.

70. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each Rlais independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two Rlaon the same atom form an oxo.

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: n is 0, 1, or 2.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: n is 0 or 1.

73. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:wherein:W1is N or CR8;R8is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl;WSGR Docket No. 59792-717.601R9is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl;R10is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a; each R10ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R10aon the same atom form an oxo;W2is N or CR11; andR11is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl.

74. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W1is CR8.

75. The compound of claim 73 or 74, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R8is hydrogen.

76. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W1is N.

77. The compound of any one of claims 73-76, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W2is CR11.

78. The compound of any one of claims 73-77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R11is hydrogen.

79. The compound of any one of claims 73-76, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W2is N.

80. The compound of any one of claims 73-79, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen.WSGR Docket No. 59792-717.60181. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

82. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

83. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

84. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.

85. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R10a.

86. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is Ci-Ceaminoalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R10a.

87. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is Ci-Ceaminoalkyl.

88. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 59792-717.601R10is -L-cycloalkyl or -L-heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R10a.

89. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is -L-cycloalkyl or -L-heterocycloalkyl.

90. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is cycloalkyl or heterocycloalkyl.

91. The compound of any one of claims 73-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is heterocycloalkyl.

92. The compound of any one of claims 73-88, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R10ais independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -NRbC(=O)ORb, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

93. The compound of any one of claims 73-88 or 92, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R10ais independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two R10aon the same atom form an oxo.

94. The compound of any one of claims 73-88 or 92 or 93, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R10ais independently halogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, or Ci- Cehaloalkyl; and / or two R10aon the same atom form an oxo.

95. The compound of any one of claims 73-88 or 92-94, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R10ais independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; and / or two R10aon the same atom form an oxo.

96. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.601WSGR Docket No. 59792-717.60198. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

99. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

100. The compound of any one of claims 1-99, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound found in Table 1 or in the specification.

101. A pharmaceutical composition comprising a compound of any one of claims 1-100, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

102. A method of modulating CKAP5 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a compound of any one of claims 1-100, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.WSGR Docket No. 59792-717.601103. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a compound of any one of claims 1-100, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

104. The method of claim 103, wherein the disease or disorder is cancer.

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