CCR4 inhibitors and methods of use thereof

Abstract

Described herein are CCR4 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of CCR4-mediated disorders or diseases.

Description

CCR4 INHIBITORS AND METHODS OF USE THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 589,480 filed October 11, 2023, U.S. Provisional Application Serial No. 63 / 623,743 filed January 22, 2024, and U.S. Provisional Application Serial No. 63 / 642,294 filed May 3, 2024; which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] Chemokines are chemotactic cytokines that are released by a wide variety' of cells to attract macrophages, T cells, eosinophils, basophils, and neutrophils to sites of inflammation.

[0003] There are two classes of chemokines, CXC (a) and CC (P). depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C). The a-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory' activity protein (MGSA) are chemotactic primarily for neutrophils, whereas P-chemokines, such as RANTES, MIP-1 α, MIP-lp, monocyte chemotactic protein- 1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils, and basophils.

[0004] The chemokines bind specific cell-surface receptors belonging to the family of G-protein- coupled seven-transmembrane-domain proteins which are tenned “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR-1 (or “CKR-1” or “CC-CKR-1”) MIP-1 α, MIP-lp, MCP-3, RANTES; CCR-2A and CCR- 2B (or ‘ CKR-2A’7 ‘CKR-2A” or “CC-CKR-2A” / “CC-CKR2A”) MCP-1, MCP-3, MCP-4; CCR-3 (or “CKR-3” or “CC-CKR.-3”) eotaxin, RANTES, MCP-3; CCR-4 (or “CKR-4” or “CC-CKR-4”) MIP-1 α, RANTES, MCP-1; CCR-5 (or “CKR-5” or “CC-CKR-5”) MIP-1 α, RANTES, MIP-1β; and the Duffy blood-group antigen RANTES, MCP-1. The P-chemokines include eotaxin, MIP (“macrophage inflammatory protein”), MCP (“monocyte chemoattractant protein”) and RANTES (“regulation-upon- activation, normal T expressed and secreted”).

[0005] Chemokine receptors, such as CCR1 , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CXCR3, CXCR4, have been implicated as being important mediators of inflammatory' and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

[0006] CC Chemokine Receptor 4, CCR4, is a G protein-coupled receptor that binds to chemokines including Macrophage-Derived Chemokine (MDC; a CC chemokine reported to be a chemoattractant for the Th2 subset of peripheral blood T cells, dendritic cells, and natural killer [NK] cells), and TARC (thymus and activation-regulated chemokine), which is also produced by monocytes and dendritic cells.

[0007] While the global distribution of CCR4 is unknown, the receptor is expressed on approximately 20% of adult peripheral blood effecior / memory CD4 t T cells. CCR4 is purportedly present on almost all T cells that have a skin homing phenotype, the CTLA+ T cells. Thus CCR4 may be an important player in skin pathologies in winch leukocytes participate.

[0008] Identification of compounds that modulate CCR4 function represent an attractive avenue into the development of new therapeutic agents.SUMMARY OF THE INVENTION

[0009] Disclosed herein is a compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (XI) as defined herein.

[0010] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0011] Also disclosed herein is a method of treating a CCR4-mediated disease in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof to the subject. In some embodiments, the disease is inflammatory bowel disease, Crohn’s disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer’s disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, or granuloma development.INCORPORATION BY REFERENCE

[0012] 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 DESCRIPTION OF THE INVENTIONDefinitions

[0013] 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” and 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.

[0014] 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.

[0015] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0016] “Oxo” refers to =0.

[0017] “Amino” refers to -NH2.

[0018] “Hydroxy” refers to -OH.

[0019] “Carboxyl” refers to -COOH.

[0020] “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 “C1-C6alkyl”, 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 C1-C6alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkylgroup 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 optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0021] “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 the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl”, 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 optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0022] “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-C6alkynyl”, 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 optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0023] “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, thealkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, - NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, - CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0024] “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 optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0025] “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 optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0026] “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 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully 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 fully 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, bicyclo [1.1. 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, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is 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 optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0027] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0028] “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.

[0029] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0030] “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.

[0031] “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.

[0032] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CDs, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0033] “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 C1-C6heteroalkyl 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 combinationsthereof 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 C1-C6heteroalkyl 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 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 optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0034] “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 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 fully 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 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully 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 fully 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, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3- oxo-1, 3-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 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 optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0035] “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 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 sulfuratoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be 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[I,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-lH-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 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 optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0036] 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 un-substituted (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 ).

[0037] 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.

[0038] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, thesubject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.

[0039] 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.

[0040] “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.

[0041] “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.

[0042] As used herein, a “disease or disorder associated with CCR4” or, alternatively, “a CCR4- mediated disease or disorder” means any disease or other deleterious condition in which CCR4, or a mutant thereof, is known or suspected to play a role.Compounds

[0043] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a CCR4-mediated disease or disorder.

[0044] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y1is N, NR7, O, S, or CR8;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y2is N, NR9, O, S, or CR10;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y3is N, NR11, O, S, or CR12;R11is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R12is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo;

[0045] In some embodiments of a compound of Formula (I), Y1is N. In some embodiments of a compound of Formula (I), Y1is NR7. In some embodiments of a compound of Formula (I), Y1is O. In some embodiments of a compound of Formula (I), Y1is S. In some embodiments of a compound of Formula (I), Y1is CR8.

[0046] In some embodiments of a compound of Formula (I), Y2is N. In some embodiments of a compound of Formula (I), Y2is NR9. In some embodiments of a compound of Formula (I), Y2is O. Insome embodiments of a compound of Formula (I), Y2is S. In some embodiments of a compound of Formula (I), Y2is CR10.

[0047] In some embodiments of a compound of Formula (I), Y3is N. In some embodiments of a compound of Formula (I), Y3is NR11. In some embodiments of a compound of Formula (I), Y3is O. In some embodiments of a compound of Formula (I), Y3is S. In some embodiments of a compound of Formula (I), Y3is CR12.

[0048] In some embodiments of a compound of Formula (some embodiments of a compound of Formulaprovided that R10is not hydrogen. In some embodiments of a compound ofFormulasome embodiments of a compound of,some embodiments of a compound of Formula (I),n. In some embodiments of a compound of Formula,

[0049] In some embodiments of a compound of Formula (I), X1is N. In some embodiments of a compound of Formula (I), X1is CR5.

[0050] In some embodiments of a compound of Formula (I), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R5is hydrogen.

[0051] In some embodiments of a compound of Formula (I), X2is N. In some embodiments of a compound of Formula (I), X2is CR6.

[0052] In some embodiments of a compound of Formula (I), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R6is hydrogen.

[0053] In some embodiments of a compound of Formula (I), R7is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R7is hydrogen. In some embodiments of a compound of Formula (I), R7is C1-C6alkyl.

[0054] In some embodiments of a compound of Formula (I), R8is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R8is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (I), R8is hydrogen.

[0055] In some embodiments of a compound of Formula (I), R9is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R9is hydrogen. In some embodiments of a compound of Formula (I), R9is C1-C6alkyl.

[0056] In some embodiments of a compound of Formula (I), R10is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), R10is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), R10is hydrogen, halogen, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R10is halogen, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R10is hydrogen, -NRcRd, C1-C6alkyl, or Ci- C6haloalkyl. In some embodiments of a compound of Formula (I), R10is -NRcRd, C1-C6alkyl, or Ci- C6haloalkyl. In some embodiments of a compound of Formula (I), R10is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R10is halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R10is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (I), R10is hydrogen. In some embodiments of a compound of Formula (I), R10is not hydrogen.

[0057] In some embodiments of a compound of Formula (I), R11is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R11is hydrogen. In some embodiments of a compound of Formula (I), R11is C1-C6alkyl. In some embodiments of a compound of Formula (I), R11is not methyl.

[0058] In some embodiments of a compound of Formula (I), R12is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R12is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (I), R12is hydrogen.

[0059] Disclosed herein is a compound of Formula (Ila), (lib), or (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci -C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci -C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0060] In some embodiments of a compound of Formula (Ila) or (lib), Z1is C and Z2is N. In some embodiments of a compound of Formula (Ila) or (lib), Z1is N and Z2is C.

[0061] In some embodiments of a compound of Formula (Ila) or (lib), Y3is N. In some embodiments of a compound of Formula (Ila) or (lib), Y3is CR12.

[0063] In some embodiments of a compound of Formula (lib),some embodiments of a compound of Formula (lib),some embodiments of a compound of Formula (lib),some embodiments of a compound of Formula (lib),

[0064] In some embodiments of a compound of Formula (Ila), (lib), or (lie), X1is N. In some embodiments of a compound of Formula (Ila), (lib), or (lie), X1is CR5.

[0065] In some embodiments of a compound of Formula (Ila), (lib), or (lie), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Ila), (lib), or (lie), R5is hydrogen.

[0066] In some embodiments of a compound of Formula (Ila), (lib), or (lie), X2is N. In some embodiments of a compound of Formula (Ila), (lib), or (lie), X2is CR6.

[0067] In some embodiments of a compound of Formula (Ila), (lib), or (lie), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Ila), (lib), or (lie), R6is hydrogen.

[0068] In some embodiments of a compound of Formula (lib), R8is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (lib), R8is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (lib), R8is hydrogen.

[0069] In some embodiments of a compound of Formula (lib) or (lie), R10is hydrogen, halogen, Ci- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (lib) or (lie), R10is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (lib) or (lie), R10is hydrogen.

[0070] In some embodiments of a compound of Formula (Ila), (lib), or (lie), R12is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Ila), (lib), or (lie), R12is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (Ila), (lib), or (lie), R12is hydrogen.

[0071] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III); wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X3is N or CR7;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X4is N or CR8;R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y1is N or CR9;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Z1is C and Z2is N or Z1is N and Z2is C; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0072] In some embodiments of a compound of Formula (III), Z1is C and Z2is N. In some embodiments of a compound of Formula (III), Z1is N and Z2is C.

[0073] In some embodiments of a compound of Formula (III), X1is N. In some embodiments of a compound of Formula (III), X1is CR5.

[0074] In some embodiments of a compound of Formula (III), X2is N. In some embodiments of a compound of Formula (III), X2is CR6.

[0075] In some embodiments of a compound of Formula (III), X3is N. In some embodiments of a compound of Formula (III), X3is CR7.

[0076] In some embodiments of a compound of Formula (III), X4is N. In some embodiments of a compound of Formula (III), X4is CR8.

[0077] In some embodiments of a compound of Formula (some embodiments of a compound of Formulasome embodiments of a compound of Formulame embodiments of a compound of Formula

[0078] In some embodiments of a compound of Formula (III), Y1is N. In some embodiments of a compound of Formula (III), Y1is CR9.

[0079] In some embodiments of a compound of Formula (III), R9is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), R9is hydrogen.

[0080] In some embodiments of a compound of Formula (III), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), R5is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (III), R5is hydrogen.

[0081] In some embodiments of a compound of Formula (III), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), R6is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (III), R6is hydrogen.

[0082] In some embodiments of a compound of Formula (III), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), R7is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (III), R7is hydrogen.

[0083] In some embodiments of a compound of Formula (III), R8is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), R8is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (III), R8is hydrogen.

[0084] Disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl,C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y1is N or CR7;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y2is N or CR8;R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y3is N or CR9;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y4is N or CR10;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Cdictcroalkyl. C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo; provided that at least one of Y1, Y2, Y3, and Y4is N.

[0085] In some embodiments of a compound of Formula (IV), Y1is N. In some embodiments of a compound of Formula (IV), Y1is CR7.

[0086] In some embodiments of a compound of Formula (IV), Y2is N. In some embodiments of a compound of Formula (IV), Y2is CR8.

[0087] In some embodiments of a compound of Formula (IV), Y3is N. In some embodiments of a compound of Formula (IV), Y3is CR9.

[0088] In some embodiments of a compound of Formula (IV), Y4is N. In some embodiments of a compound of Formula (IV), Y4is CR10.

[0089] In some embodiments of a compound of Formula (some embodiments of a compound of Formulasome embodiments of a compound of Formulasome embodiments of a compound of Formulasome embodiments of a compound of Formula

[0090] In some embodiments of a compound of Formula (IV), X1is N. In some embodiments of a compound of Formula (IV), X1is CR5.

[0091] In some embodiments of a compound of Formula (IV), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), R5is hydrogen.

[0092] In some embodiments of a compound of Formula (IV), X2is N. In some embodiments of a compound of Formula (IV), X2is CR6.

[0093] In some embodiments of a compound of Formula (IV), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), R6is hydrogen.

[0094] In some embodiments of a compound of Formula (IV), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), R7is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (IV), R7is hydrogen.

[0095] In some embodiments of a compound of Formula (IV), R8is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), R8is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (IV), R8is hydrogen.

[0096] In some embodiments of a compound of Formula (IV), R9is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), R9is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (IV), R9is hydrogen.

[0097] In some embodiments of a compound of Formula (IV), R10is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), R10is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV), R10is hydrogen.

[0098] Disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo;each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Z1is C or N;Z2is C or N; provided that Z1and Z2are not both N;Ring B is a cycloalkyl or heterocycloalkyl; each R7is independently halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; or two R7on the same atom are taken together to form an oxo; s is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo; provided that

[0099] In some embodiments of a compound of Formula (V), Z1is C and Z2is N. In some embodiments of a compound of Formula (V), Z1is N and Z2is C. In some embodiments of a compound of Formula (V), Z1is C and Z2is C.

[0100] In some embodiments of a compound of Formula (V), X1is N. In some embodiments of a compound of Formula (V), X1is CR5.

[0101] In some embodiments of a compound of Formula (V), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V), R5is hydrogen.

[0102] In some embodiments of a compound of Formula (V), X2is N. In some embodiments of a compound of Formula (V), X2is CR6.

[0103] In some embodiments of a compound of Formula (V), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V), R6is hydrogen.

[0104] In some embodiments of a compound of Formula (V), Ring B is a cycloalkyl. In some embodiments of a compound of Formula (V), Ring B is a heterocycloalkyl. In some embodiments of a compound of Formula (V), Ring B is a 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (V), Ring B is a 5 - to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0105] In some embodiments of a compound of Formula (V), Ring B is a 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0106] In some embodiments of a compound of Formula (V), Ring B is pyrrolidinyl.

[0107] In some embodiments of a compound of Formula (V), Ring B is a 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0108] In some embodiments of a compound of Formula (V), Ring B is a 6-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0109] In some embodiments of a compound of Formula (V), Ring B is a 6-membered heterocycloalkyl comprising one that is N.

[0110] In some embodiments of a compound of Formula (V), Ring B is a 6-membered heterocycloalkyl comprising one that is O.

[0111] In some embodiments of a compound of Formula (V), each R7is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), each R7is independently halogen, C1-C6alkyl, Ci- C6haloalkyl, or cycloalkyl; or two R7on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), each R7is independently cycloalkyl; or two R7on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), two R7on the same atom are taken together to form an oxo.

[0112] In some embodiments of a compound of Formula (V), s is 0, 1, 2, or 3. In some embodiments of a compound of Formula (V), s is 2 or 3. In some embodiments of a compound of Formula (V), s is 1. In some embodiments of a compound of Formula (V), s is 2. In some embodiments of a compound of Formula (V), s is 3.

[0113] In some embodiments of a compound of Formula (. In some embodiments of a compound of Formula (

[0114] In some embodiments of a compound of Formula

[0115] In some embodiments of a compound of Formula

[0116] Disclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (VI); wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X3is N or CR7;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Z1is C or N;Z2is C or N; provided that Z1and Z2are not both N;Y is C orN;Y1is N, CR8, or C(=O);R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y2is N, NR9, or CR10;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo; provided that Y and Y1are not both N and Y and Y2are not both N.

[0117] In some embodiments of a compound of Formula (VI), Z1is C and Z2is N. In some embodiments of a compound of Formula (VI), Z1is N and Z2is C. In some embodiments of a compound of Formula (VI), Z1is C and Z2is C.

[0118] In some embodiments of a compound of Formula (VI), Y is C. In some embodiments of a compound of Formula (VI), Y is N.

[0119] In some embodiments of a compound of Formula (VI), Y1is N. In some embodiments of a compound of Formula (VI), Y1is CR8. In some embodiments of a compound of Formula (VI), Y1is C(=O).

[0120] In some embodiments of a compound of Formula (VI), Y2is N. In some embodiments of a compound of Formula (VI), Y2is NR9. In some embodiments of a compound of Formula (VI), Y2is CR10.

[0121] In some embodiments of a compound of Formula (some embodiments of a compound of Formula (some embodiments of a compound of Formula (some embodiments of a compound of Formula ( some embodiments of a compound of Formula ( some embodiments of a compound of Formula ( some embodiments of a compound of Formula ( some embodiments of a compound of Formula ( ome embodiments of a compound of Formula (V some embodiments of a compound of Formula ( some embodiments of a compound of Formula (

[0122] In some embodiments of a compound of Formula (VI), X1is N. In some embodiments of a compound of Formula (VI), X1is CR5.

[0123] In some embodiments of a compound of Formula (VI), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R5is hydrogen.

[0124] In some embodiments of a compound of Formula (VI), X2is N. In some embodiments of a compound of Formula (VI), X2is CR6.

[0125] In some embodiments of a compound of Formula (VI), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R6is hydrogen.

[0126] In some embodiments of a compound of Formula (VI), X3is N. In some embodiments of a compound of Formula (VI), X3is CR7.

[0127] In some embodiments of a compound of Formula (VI), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R7is hydrogen.

[0128] In some embodiments of a compound of Formula (VI), R8is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R8is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (VI), R8is hydrogen.

[0129] In some embodiments of a compound of Formula (VI), R9is hydrogen, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (VI), R9is hydrogen, -S(=O)2Ra, -C(=O)Ra, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R9is hydrogen, -S(=O)2Raor -C(=O)Ra. In some embodiments of a compound of Formula (VI), R9is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R9is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (VI), R9is hydrogen or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R9is C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R9is hydrogen. In some embodiments of a compound of Formula (VI), R9is C1-C6alkyl.

[0130] In some embodiments of a compound of Formula (VI), R10is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R10is C1-C6alkyl or Ci- C6haloalkyl. In some embodiments of a compound of Formula (VI), R10is hydrogen, halogen, or Ci- C6alkyl. In some embodiments of a compound of Formula (VI), R10is hydrogen, C1-C6alkyl, or Ci- C6haloalkyl. In some embodiments of a compound of Formula (VI), R10is hydrogen or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R10is C1-C6haloalkyl. In some embodiments of a compound of Formula (VI), R10is hydrogen.

[0131] Disclosed herein is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (VII); wherein:Ring A is heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X3is N or CR7;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y is C orN;Y1is N, CR8, or C(=O);R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y2is N or CR9;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;Y3is N, CR10, or C(=O);R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0132] In some embodiments of a compound of Formula (VII), Y is C. In some embodiments of a compound of Formula (VII), Y is N.

[0133] In some embodiments of a compound of Formula (VII), Y1is N. In some embodiments of a compound of Formula (VII), Y1is CR8. In some embodiments of a compound of Formula (VII), Y1is C(=O).

[0134] In some embodiments of a compound of Formula (VII), Y2is N. In some embodiments of a compound of Formula (VII), Y2is CR9.

[0135] In some embodiments of a compound of Formula (VII), Y3is N. In some embodiments of a compound of Formula (VII), Y3is CR10. In some embodiments of a compound of Formula (VII), Y3is C(=O).

[0136] In some embodiments of a compound of Formula (

[0137] In some embodiments of a compound of Formula (VII), X1is N. In some embodiments of a compound of Formula (VII), X1is CR5.

[0138] In some embodiments of a compound of Formula (VII), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R5is hydrogen.

[0139] In some embodiments of a compound of Formula (VII), X2is N. In some embodiments of a compound of Formula (VII), X2is CR6.

[0140] In some embodiments of a compound of Formula (VII), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R6is hydrogen.

[0141] In some embodiments of a compound of Formula (VII), X3is N. In some embodiments of a compound of Formula (VII), X3is CR7.

[0142] In some embodiments of a compound of Formula (VII), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R7is hydrogen.

[0143] In some embodiments of a compound of Formula (VII), R8is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R8is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (VII), R8is hydrogen.

[0144] In some embodiments of a compound of Formula (VII), R9is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (VII), R9is hydrogen, halogen, -CN, -OH, -S(=O)2Ra, Ci- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R9is hydrogen, -CN, -S(=O)2Ra, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R9is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R9is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (VII), R9is hydrogen.

[0145] In some embodiments of a compound of Formula (VII), R10is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VII), R10is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (VII), R10is hydrogen.

[0146] Disclosed herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a heterocycloalkyl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo;each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo; provided thatnot

[0147] Disclosed herein is a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a heterocycloalkyl or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb;or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R6is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci -Chalky lenc optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0148] In some embodiments of a compound of Formula (IX), X1is N. In some embodiments of a compound of Formula (IX), X1is CR5.

[0149] In some embodiments of a compound of Formula (IX), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R5is hydrogen.

[0150] In some embodiments of a compound of Formula (IX), R6is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R6is hydrogen. In some embodiments of a compound of Formula (IX), R6is C1-C6alkyl.

[0151] In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R7is halogen.

[0152] Disclosed herein is a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a bicyclic heterocycloalkyl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; each Rlais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 Rlb; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two Rlbon the same atom are taken together to form an oxo; n is 1, 2, 3, 4, 5, 6, 7, or 8;R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;X1is N or CR5;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;X2is N or CR6;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R;R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Cdictcroalkyl. C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl;or two R on the same atom are taken together to form an oxo.

[0153] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is heterocycloalkyl.

[0154] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is 3- to 12-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0155] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is 3- to 12-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0156] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is3- to 12-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0157] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is4- to 10-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0158] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is 4- to 10-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0159] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is 4- to 10-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0160] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is a monocyclic heterocycloalkyl.

[0161] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is a 3- to 6-membered monocyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0162] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is a 3- to 6-membered monocyclic heterocycloalkyl comprising one heteroatom that is N.

[0163] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0164] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is azetidinyl.

[0165] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is piperidinyl.

[0166] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is tetrahydropyridinyl .

[0167] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(IX), Ring A is piperazinyl.

[0168] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a bicyclic heterocycloalkyl.

[0169] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a 6- to 12-membered bicyclic heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0170] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a 6- to 12-membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0171] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a 6- to 12-membered bicyclic heterocycloalkyl comprising one or two heteroatoms that are N.

[0172] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a 8- to 10-membered bicyclic heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0173] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a 8- to 10-membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0174] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), Ring A is a 8- to 10-membered bicyclic heterocycloalkyl comprising one or two heteroatoms that are N.

[0175] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0176] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently -NRbC(=O)Ra, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0177] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently -NRbC(=O)Ra, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or heterocycloalkyl; wherein each alkyl, and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0178] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0179] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently C1-C6hydroxyalkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more Rla.

[0180] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently C1-C6hydroxyalkyl.

[0181] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently heterocycloalkyl independently optionally substituted with one or more Rla.

[0182] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently 3- to 10-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N; and independently optionally substituted with one or more Rla.

[0183] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently 5- to 7-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N; and independently optionally substituted with one or more Rla.

[0184] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently 5- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N; and independently optionally substituted with one or more Rla.

[0185] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl; each independently optionally substituted with one or more Rla.

[0186] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently piperidinyl independently optionally substituted with one or more Rla.

[0187] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently -C(=O)Ra.

[0188] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently -C(=O)Raand Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0189] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently -C(=O)Raand Rais independently C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0190] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each R1is independently

[0191] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rlb. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently C1-C6alkyl, C1-C6hydroxyalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rlb. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently -L-cycloalkyl; wherein cycloalkyl is independently optionally substituted with one or more Rlb. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently cycloalkyl independently optionally substituted with one or more Rlb. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently 3- to 6-membered cycloalkyl independently optionally substituted with one or more Rlb. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlais independently cyclobutyl independently optionally substituted with one or more Rlb.

[0192] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlbis independently halogen, -CN, -OH, -ORa, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), each Rlbis independently halogen, -OH, -ORa, -C(=O)ORb, C1-C6alkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)- (X), each Rlbis independently -OH, -C(=O)ORb, or C1-C6alkyl.

[0193] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), n is 1, 2, 3, or 4. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), n is 1, 2, or 3. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), n is 1 or 2. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), n is 1. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X), n is 2.

[0194] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),whereinR20is hydrogen, halogen, -CN, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 R20a; each R20ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R20aon the same atom are taken together to form an oxo; each R21is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R21on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; each R22is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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;or two R22on the same atom are taken together to form an oxo; q is 0, 1, 2, 3, or 4.

[0195] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),whereinR20is hydrogen, halogen, -CN, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 R20a; each R20ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R20aon the same atom are taken together to form an oxo; each R21is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R21on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4;each R22is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R22on the same atom are taken together to form an oxo; q is 0, 1, 2, 3, or 4.

[0196] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),whereinR20is hydrogen, halogen, -CN, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 R20a; each R20ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R20aon the same atom are taken together to form an oxo; each R21is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R21on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; each R22is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R22on the same atom are taken together to form an oxo; q is 0, 1, 2, 3, or 4.

[0197] In some embodiments, R20is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R20a. In some embodiments, R20is C1-C6alkyl or C1-C6hydroxyalkyl; wherein each alkyl is independently optionally substituted with one or more R20a. In some embodiments, R20is C1-C6hydroxyalkyl. In some embodiments, R20is -CH2CH2OH or -CH2CH2COOH. In some embodiments, R20is -CH2CH2OH.

[0198] In some embodiments, each R20ais independently halogen, -CN, -OH, -ORa, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each R20ais independently halogen, -OH, -ORa, -NRcRd, or -C(=O)ORb. In some embodiments, each R20ais independently -OH or -C(=O)ORb. In some embodiments, two R20aon the same atom are taken together to form an oxo.

[0199] In some embodiments, each R21is independently halogen, -CN, -OH, C1-C6alkyl, or Ci- C6haloalkyl. In some embodiments, each R21is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each R21is independently halogen. In some embodiments, two R21on the same atom are taken together to form an oxo.

[0200] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 0 or 1.

[0201] In some embodiments, each R22is independently halogen, -CN, -OH, C1-C6alkyl, or Ci- C6haloalkyl. In some embodiments, each R22is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each R22is independently halogen. In some embodiments, two R22on the same atom are taken together to form an oxo.

[0202] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 0 or 1.

[0203] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),

[0204] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),

[0205] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),

[0206] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),

[0207] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(X),

[0208] Also disclosed herein is a compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;Z is O, S, or CH2;Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R13is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R13on the same atom are taken together to form an oxo; r is 1, 2, 3, 4, 5, 6, 7, or 8;Ring D is 4- to 7-membered heterocycloalkyl; each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R14on the same atom are taken together to form an oxo; t is 0, 1, 2, 3, or 4;L1is absent or -C(=O)-;Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R15is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl,-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 R15a; or two R15on the same atom are taken together to form an oxo; each R15ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R15aon the same atom are taken together to form an oxo; u is 1, 2, 3, 4, 5, 6, 7, or 8; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0209] In some embodiments of a compound of Formula (XI), Z is O. In some embodiments of a compound of Formula (XI), Z is S. In some embodiments of a compound of Formula (XI), Z is CH2.

[0210] In some embodiments of a compound of Formula (XI), Ring C is aryl or heteroaryl.

[0211] In some embodiments of a compound of Formula (XI), Ring C is phenyl or a 5- or 6- membered heteroaryl. In some embodiments of a compound of Formula (XI), Ring C is phenyl or a 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0212] In some embodiments of a compound of Formula (XI), Ring C is phenyl.

[0213] In some embodiments of a compound of Formula (XI), Ring C is a 6-membered heteroaryl. In some embodiments of a compound of Formula (XI), Ring C is 6-membered heteroaryl comprising one, two, or three heteroatoms that are N. In some embodiments of a compound of Formula (XI), Ring C is 6- membered heteroaryl comprising one or two heteroatoms that are N. In some embodiments of a compound of Formula (XI), Ring C is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (XI), Ring C is pyridyl.

[0214] In some embodiments of a compound of Formula (XI), Ring C is 5-membered heteroaryl. In some embodiments of a compound of Formula (XI), Ring C is 5 -membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (XI), Ring C is 5-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, S, and N.

[0215] In some embodiments of a compound of Formula (XI), Ring C is a bicyclic heteroaryl comprising one, two, three, four, or five heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (XI), Ring C is a bicyclic heteroaryl comprising one, two, three, four, or five heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (XI), Ring C is a bicyclic heteroaryl comprising one, two, three, four, or five heteroatoms that are N.

[0217] In some embodiments of a compound of Formula (XI), each R13is independently halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, or cycloalkyl. In some embodiments of a compound ofFormula (XI), each R13is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XI), each R13is independently halogen, C1-C6alkyl, or Ci- C6haloalkyl. In some embodiments of a compound of Formula (XI), each R13is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (XI), each R13is independently halogen or C1-C6haloalkyl.

[0218] In some embodiments of a compound of Formula (XI), r is 0, 1, 2, or 3. In some embodiments of a compound of Formula (XI), r is 1, 2, or 3. In some embodiments of a compound of Formula (XI), r is 1 or 2. In some embodiments of a compound of Formula (XI), r is 0, 1, or 2. In some embodiments of a compound of Formula (XI), r is 0 or 1. In some embodiments of a compound of Formula (XI), r is 0. In some embodiments of a compound of Formula (XI), r is 1. In some embodiments of a compound of Formula (XI), r is 2. In some embodiments of a compound of Formula (XI), r is 3.

[0219] In some embodiments of a compound of Formula (* is the attachment point to Z.[002211 In some embodiments of a compound of Formula (, wherein * is the attachment point to Z.

[0223] In some embodiments of a compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Xia), (Xlb), (XIc), (Xld), or (Xie):wherein:R2is halogen;R3is halogen;R13a, R13b, R13C, and R13dare independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, Ci- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; and / or R13aand R13bare taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R; and / or R13band R13care taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;Ring D is 4- to 6-membered heterocycloalkyl; each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R14on the same atom are taken together to form an oxo; t is 0, 1, or 2;Ring E is 4- to 6-membered heterocycloalkyl;each R15is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a; or two R15on the same atom are taken together to form an oxo; each R15ais independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl; u is 1, 2, or 3; each Rais independently C1-C6alkyl or C1-C6haloalkyl; each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, -NHCi-Csalkyl, -N(Ci-C3alkyl)2, Ci- Csalkyl, or Ci-Cshaloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0224] In some embodiments of a compound of Formula (Xla)-(XIe), R2is chloro. In some embodiments of a compound of Formula (Xla)-(XIe), R3is chloro.

[0225] In some embodiments of a compound of Formula (Xla)-(XIe), R13a, R13b, R13c, and R13dare independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), R13a, R13b, R13c, and R13dare independently hydrogen, halogen, -CN, or C1-C6alkyl. In some embodiments of a compound of Formula (Xla)-(XIe), R13a, R13b, R13C, and R13dare independently hydrogen or C1-C6alkyl.

[0226] In some embodiments of a compound of Formula (Xia), (Xlb), or (Xie), R13aand R13bare taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xia), (Xlb), or (Xie), R13aand R13bare taken together to form a cycloalkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xia), (Xlb), or (Xie), R13aand R13bare taken together to form a cycloalkyl.

[0227] In some embodiments of a compound of Formula (Xia), (Xld), or (Xie), R13band R13care taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xia), (Xld), or (Xie), R13band R13care taken together to form a cycloalkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xia), (Xld), or (Xie), R13band R13care taken together to form a cycloalkyl.

[0228] In some embodiments of a compound of Formula (Xlb), R13aand R13bare independently hydrogen, halogen, -CN, or C1-C6alkyl; or R13aand R13bare taken together to form a cycloalkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xlb), R13aand R13bare independently halogen or C1-C6alkyl; or R13aand R13bare taken togetherto form a cycloalkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xlb), R13aand R13bare independently hydrogen or C1-C6alkyl; or R13aand R13bare taken together to form a cycloalkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xlb), R13aand R13bare independently C1-C6alkyl; or R13aand R13bare taken together to form a cycloalkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Xlb), R13dis hydrogen, halogen, -CN, or C1-C6alkyl. In some embodiments of a compound of Formula (Xlb), R13dis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (Xlb), R13dis hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (Xlb), R13dis hydrogen.

[0229] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is a 4- to 6-membered monocyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0230] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is a 4- to 6-membered monocyclic heterocycloalkyl comprising one heteroatom that is N.

[0231] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is a 4- to 5-membered monocyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0232] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is a 4- to 5-membered monocyclic heterocycloalkyl comprising one heteroatom that is N.

[0233] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0234] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is azetidinyl.

[0235] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is piperidinyl.

[0236] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is tetrahydropyridinyl.

[0237] In some embodiments of a compound of Formula (Xla)-(XIe), Ring D is piperazinyl.

[0238] In some embodiments of a compound of Formula (Xla)-(XIe), each R14is independently halogen, -CN, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl.

[0239] In some embodiments of a compound of Formula (Xla)-(XIe), each R14is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each R14is independently C1-C6alkyl.

[0240] In some embodiments of a compound of Formula (Xla)-(XIe), t is 0 or 1. In some embodiments of a compound of Formula (Xla)-(XIe), t is 0. In some embodiments of a compound of Formula (Xla)-(XIe), t is 1.

[0241] In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0242] In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is 5- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0243] In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is 5 -membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0244] In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0245] In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl. In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is piperidinyl or morpholinyl. In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is piperidinyl. In some embodiments of a compound of Formula (Xla)-(XIe), Ring E is pyrrolidinyl.

[0246] In some embodiments of a compound of Formula (Xla)-(XIe), each R15is independently Ci- C6alkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a.

[0247] In some embodiments of a compound of Formula (Xla)-(XIe), each R15is independently Ci- C6alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (Xla)-(XIe), each R15is independently cycloalkyl independently optionally substituted with one or more R15a.

[0248] In some embodiments of a compound of Formula (Xla)-(XIe), each R15is independently 3- to 6-membered cycloalkyl independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (Xla)-(XIe), each R15is independently cyclobutyl independently optionally substituted with one or more R15a.

[0249] In some embodiments of a compound of Formula (Xla)-(XIe), each R15is independently Ci- C6hydroxyalkyl.

[0250] In some embodiments of a compound of Formula (Xla)-(XIe), each R15ais independently halogen, -CN, -C(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each R15ais independently halogen, -OH, -ORa, -C(=O)ORb, C1-C6alkyl, or Ci- C6hydroxyalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each R15ais independently -C(=O)ORb, or C1-C6alkyl.

[0251] In some embodiments of a compound of Formula (Xla)-(XIe), u is 1 or 2. In some embodiments of a compound of Formula (Xla)-(XIe), u is 1. In some embodiments of a compound of Formula (Xla)-(XIe), u is 2.

[0252] In some embodiments of a compound of Formula (some embodiments of a compound of Formula (Xla)-(XIe),

[0253] In some embodiments of a compound of Formula (Xla)-(XIe), each Rais independently Ci- C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each Rais independently C1-C6alkyl.

[0254] In some embodiments of a compound of Formula (Xla)-(XIe), each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each Rbis independently hydrogen or C1-C6alkyl.

[0255] In some embodiments of a compound of Formula (Xla)-(XIe), each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each Rcand Rdare independently hydrogen or C1-C6alkyl.

[0256] In some embodiments of a compound of Formula (Xla)-(XIe), each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, -NHCi-Csalkyl, -N(Ci-C3alkyl)2, Ci-Galkyl. or Ci-Cshaloalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (Xla)-(XIe), each R is independently halogen, Ci-Calkyl. or Ci-Cshaloalkyl. In some embodiments of a compound of Formula (Xla)-(XIe), each R is independently halogen or Ci -Chalky I.

[0257] Also disclosed herein is a compound of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (XII); wherein:R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2;Ring F is 5 -membered heteroaryl; each R16is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R16on the same atom are taken together to form an oxo; v is 1, 2, 3, 4, 5, 6, 7, or 8;Ring D is 4- to 7-membered heterocycloalkyl; each R14is independently halogen, -CN, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R14on the same atom are taken together to form an oxo; t is 0, 1, 2, 3, or 4;L1is absent or -C(=O)-;Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R15is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 R15a; or two R15on the same atom are taken together to form an oxo; each R15ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R15aon the same atom are taken together to form an oxo;u is 1, 2, 3, 4, 5, 6, 7, or 8; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R; andL is absent or Ci-Csalkylene optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Csheteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0258] In some embodiments of a compound of Formula (XII), Ring F is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (XII), Ring F is 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (XII), Ring F is 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (XII), Ring F is 5- membered heteroaryl comprising one or two heteroatoms selected from the group consisting of S and N. In some embodiments of a compound of Formula (XII), Ring F is 5-membered heteroaryl comprising one or two heteroatoms that are N. In some embodiments of a compound of Formula (XII), Ring F is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, or triazolyl. In some embodiments of a compound of Formula (XII), Ring F is thiazolyl.

[0259] In some embodiments of a compound of Formula (XII), each R16is independently halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XII), each R16is independently halogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (XII), each R16is independently halogen, C1-C6alkyl.

[0260] In some embodiments of a compound of Formula (XII), v is 0, 1, or 2. In some embodiments of a compound of Formula (XII), v is 0 or 1. In some embodiments of a compound of Formula (XII), v is 1 or 2. In some embodiments of a compound of Formula (XII), v is 0. In some embodiments of a compound of Formula (XII), v is 1. In some embodiments of a compound of Formula (XII), v is 2.

[0261] Also disclosed herein is a compound of Formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (XIII); wherein:R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;W is NH, O, S, or CH2; each X is independently CH or N; each R14is independently halogen, -CN, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R14on the same atom are taken together to form an oxo; t is 0, 1, 2, 3, or 4;L1is absent or -C(=O)-;Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R15is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 R15a; or two R15on the same atom are taken together to form an oxo;each R15ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R15aon the same atom are taken together to form an oxo; u is 1, 2, 3, 4, 5, 6, 7, or 8; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R; andL is absent or Ci-Csalkylene optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Cdictcroalkyl. C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0262] In some embodiments of a compound of Formula (some embodiments of a compound of Formula (embodiments of a compound of Formula (

[0263] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 3- to 12-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0264] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 3- to 12-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0265] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 3- to 12-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0266] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 4- to 10-membered heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0267] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 4- to 10-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0268] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 4- to 10-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0269] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a monocyclic heterocycloalkyl.

[0270] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 3- to 6-membered monocyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0271] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 3- to 6-membered monocyclic heterocycloalkyl comprising one heteroatom that is N.

[0272] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 4- to 6-membered heterocycloalkyl.

[0273] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is 4- or 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0274] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0275] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is azetidinyl.

[0276] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is piperidinyl.

[0277] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is tetrahydropyridinyl.

[0278] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is piperazinyl.

[0279] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a bicyclic heterocycloalkyl.

[0280] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 6- to 12-membered bicyclic heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0281] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 6- to 12-membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0282] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 6- to 12-membered bicyclic heterocycloalkyl comprising one or two heteroatoms that are N.

[0283] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 8- to 10-membered bicyclic heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, S, and N.

[0284] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 8- to 10-membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0285] In some embodiments of a compound of Formula (XI)-(XIII), Ring D is a 8- to 10-membered bicyclic heterocycloalkyl comprising one or two heteroatoms that are N.

[0286] In some embodiments of a compound of Formula (XI)-(XIII), each R14is independently halogen, -CN, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl.

[0287] In some embodiments of a compound of Formula (XI)-(XIII), each R14is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XI)-(XIII), each R14is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (XI)-(XIII), each R14is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (XI)-(XIII), each R14is independently halogen. In some embodiments of a compound of Formula (XI)-(XIII), each R14is independently C1-C6alkyl.

[0288] In some embodiments of a compound of Formula (XI)-(XIII), t is 0, 1, or 2. In some embodiments of a compound of Formula (XI)-(XIII), t is 0 or 1. In some embodiments of a compound of Formula (XI)-(XIII), t is 0. In some embodiments of a compound of Formula (XI)-(XIII), t is 1.

[0289] In some embodiments of a compound of Formula (XI)-(XIII), L1is absent. In some embodiments of a compound of Formula (XI)-(XIII), L1is -C(=O)-.

[0290] In some embodiments of a compound of Formula (XI) or (XII), Ring E is 3- to 10-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0291] In some embodiments of a compound of Formula (XI) or (XII), Ring E is 5- to 7-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0292] In some embodiments of a compound of Formula (XI) or (XII), Ring E is 5- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0293] In some embodiments of a compound of Formula (XI)-(XIII), Ring E is 5- to 6-membered heterocycloalkyl comprising one heteroatom selected from the group consisting of O and N.

[0294] In some embodiments of a compound of Formula (XI)-(XIII), Ring E is 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0295] In some embodiments of a compound of Formula (XI)-(XIII), Ring E is piperidinyl or morpholinyl.

[0296] In some embodiments of a compound of Formula (XI) or (XII), Ring E is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0297] In some embodiments of a compound of Formula (XI)-(XIII), Ring E is piperidinyl.

[0298] In some embodiments of a compound of Formula (XI)-(XIII), Ring E is 5 -membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0299] In some embodiments of a compound of Formula (XI)-(XIII), Ring E is pyrrolidinyl.

[0300] embodiments of a compound of Formula (XI)-(XIII), each R15is independently C1-C6alkyl, Ci- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (XI)- (XIII), each R15is independently C1-C6alkyl, C1-C6hydroxyalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (XI)-(XIII), each R15is independently Ci- C6hydroxyalkyl. In some embodiments of a compound of Formula (XI)-(XIII), each R15is independently -L-cycloalkyl; wherein cycloalkyl is independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (XI)-(XIII), each R15is independently cycloalkyl independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (XI)- (XIII), each R15is independently 3- to 6-membered cycloalkyl independently optionally substituted with one or more R15a. In some embodiments of a compound of Formula (XI)-(XIII), each R15is independently cyclobutyl independently optionally substituted with one or more R15a.

[0301] In some embodiments of a compound of Formula (XI)-(XIII), each R15ais independently halogen, -OH, -ORa, -C(=O)ORb, C1-C6alkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (XI)-(XIII), each R15ais independently -OH, -C(=O)ORb, or C1-C6alkyl. In some embodiments of a compound of Formula (XI)-(XIII), each R15ais independently -C(=O)ORbor Ci- C6alkyl.

[0302] In some embodiments of a compound of Formula (XI)-(XIII), u is 1, 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (XI)-(XIII), u is 1, 2, 3, 4, or 5. In some embodiments of a compound of Formula (XI)-(XIII), u is 1, 2, 3, or 4. In some embodiments of a compound of Formula (XI)-(XIII), u is 1, 2, or 3. In some embodiments of a compound of Formula (XI)-(XIII), u is 1 or 2. In some embodiments of a compound of Formula (XI)-(XIII), u is 0, 1, or 2. In some embodiments of a compound of Formula (XI)-(XIII), u is 0. In some embodiments of a compound of Formula (XI)-(XIII), u is 1. In some embodiments of a compound of Formula (XI)-(XIII), u is 2. In some embodiments of a compound of Formula (XI)-(XIII), u is 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (XI)-(XIII), u is 2, 3, 4, or 5. In some embodiments of a compound of Formula (XI)-(XIII), u is 2, 3, or 4. In some embodiments of a compound of Formula (XI)-(XIII), u is 2 or 3.

[0303] In some embodiments of a compound of Formula (XI)-(XIII),

[0304] In some embodiments of a compound of Formula (XI)-(XIII),

[0305] In some embodiments of a compound of Formula (XI)-(XIII),

[0306] In some embodiments of a compound of Formula (XI)-(XIII),

[0307] In some embodiments of a compound of Formula (XI)-(XIII),

[0308] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), R2is halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), R2is halogen. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), R2is chloro.

[0309] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), R3is halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), R3is halogen. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), R3is chloro.

[0310] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), each R4is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0311] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), m is 0. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), m is 1. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII), m is 0 or 1. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (IIII)-(XIII), m is 0, 1, or 2.

[0312] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), or (III)-(XIII),CN

[0313] In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), (V), (VIII)-(X), (XII), or (XIII), W is NH or O. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), (V), (VIII)-(X), (XII), or (XIII), W is NH. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), (V), (VIII)-(X), (XII), or (XIII), W is O. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), (V), (VIII)-(X), (XII), or (XIII), W is S. In some embodiments of a compound of Formula (I), (Ila), (lib), (lie), (V), (VIII)-(X), (XII), or (XIII) W is CH2.

[0314] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl; 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 C1-C6alkyl, C1-C6haloalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6haloalkyl.

[0315] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl; 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- C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; whereineach alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6haloalkyl.

[0316] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl; 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, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci- C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6haloalkyl.

[0317] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R.

[0318] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is Ci-C3alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is Ci alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C2alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C3alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0319] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCi- C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci- C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, or Ci-C3heteroalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci- C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, or Ci-C3heteroalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, Ci-C3alkyl, or Ci-C3haloalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -OH, Ci-C3alkyl, or Ci-C3haloalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen or Ci-C3alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen. In some embodiments of a compound disclosed herein, each R is independently Ci-C3alkyl.

[0320] 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.

[0321] In some embodiments, the compound is selected from a compound found in table 1 :TABLE 1or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.* Stereochemistry at heterocycloalkyl group assigned arbitrarily.

[0322] In some embodiments, the compound is selected from the group consisting of:a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0323] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0324] In some embodiments, the compound is selected from the group consisting of:

[0325] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0326] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0327] In some embodiments, the compound is selected from the group consisting of:salt, solvate, or stereoisomer thereof.

[0328] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0329] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0330] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0331] In some embodiments, the compound is selected from the group consisting of:

[0332] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0333] In some embodiments, the compound is selected from the group consisting of:

[0334] In some embodiments, the compound is selected from the group consisting of:stereoisomer thereof.

[0335] In some embodiments, the compound is selected from the group consisting of:stereoisomer thereof.

[0336] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0337] 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 someembodiments, 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

[0338] 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. C6rtain 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 their 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. For example any -CH3 can be replaced with a -CDs.

[0339] 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

[0340] 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.-I l l-

[0341] 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.

[0342] 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, methane sulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalene sulfonate, 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.

[0343] 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, 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, methanesulfonic acid, ethane sulfonic 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-l- 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.

[0344] 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 alky 1)4 hydroxide, and the like.

[0345] 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 nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0346] 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.

[0347] 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.Method of Treatment

[0348] Disclosed herein are methods of treating diseases or disorders in a subject, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0349] Disclosed herein are methods of treating diseases or disorders mediated by CCR4 comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt. solvate, or stereoisomer thereof.

[0350] In some embodiments, diseases or disorders mediated by CCR4 include contact hypersensitivity, atopic dermatitis, allergic airway hypersensitivity, atherosclerosis, diseases of innate immunity (e g., septic shock), and diseases or conditions caused by platelet aggregation or thrombosis. In some embodiments, diseases or disorders mediated by CCR4 include, but are not limited to, contact hypersensitivity, atopic dermatitis, and other skin diseases (e.g., psoriasis), asthma, allergic rhinitis, atherosclerosis, septic shock, angina, myocardial infarction, restenosis, ischemia / reperfusion injury, and stroke. In some embodiments, diseases or disorders mediated by CCR4 include inflammation, infection, and cancer, in some embodiments, diseases or disorders mediated by CCR4 include (1 ) inflammatory orallergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis; vaginitis; psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis: spondyloarthropathies; scleroderma; hypersensitivity lung diseases, and the like, (2) autoimmune diseases, such as arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, diabetes, glomerulonephritis, and the like, (3) graft rejection (including allograft rejection and graft-v-host disease), and (4) other diseases in which undcsired inflammatory' responses are to be inhibited (e.g., atherosclerosis, myositis).

[0351] In some embodiments, diseases or disorders mediated by CCR4 include inflammatory bowel disease, Crohn’s disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer’s disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, and granuloma development.Dosing

[0352] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0353] When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0354] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0355] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0356] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.Routes of Administration

[0357] 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.

[0358] In 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. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate-release formulation. In some embodiments, the compound described herein is administered topically.Pharmaceutical Compositions / Formulations

[0359] The compounds described herein are administered to a subject, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0360] 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

[0361] Disclosed herein are methods of treating a CCR4-mediated disorder or disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0362] 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.Example

[0363] In some embodiments, the compounds disclosed herein are synthesized using Scheme A.

[0364] The commercially available dichloro -heterocycles will be reacted with the commercially available methyl benzyl amine or alcohol in the presence of a base (K2CO3 / CS2CO3) in suitable solvents to give the mono-heterocycles, then it will be coupled with the substituted ring A in either base / solvents / heating or Pd catalyst / base / solvents coupling conditions to deliver the desired products.Example 1 : 2- [(3R)-3- [l-(4- { [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}pteridin-2-yl)azetidin-3- yl]piperidin-l-yl]ethanol

[0365] Into a 20mL round-bottom flask were added 2,4-dichloropteridine (500 mg, 2.487 mmol, 1 equiv) and DMF (4 mL) at room temperature. To the above mixture was added (lR)-l-(2,4- dichlorophenyl)ethanamine (567.34 mg, 2.984 mmol, 1.2 equiv) and K2CO3 (1031.33 mg, 7.461 mmol, 3 equiv). The resulting mixture was stirred for additional 2h at 90°C. The resulting mixture was filtered, the filter cake was washed with CH2Q2 (2x2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 2-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]pteridin-4-amine (600 mg, 64.62%) as a yellow solid. LCMS (ESI, m / z . 354 [M+H]+.

[0366] Into a 8mL round-bottom flask were added 2-chloro-N-[(lR)-l-(2,4- dichlorophenyl)ethyl]pteridin-4-amine (90 mg, 0.254 mmol, 1 equiv) and DMF (2 mL) at room temperature. To the above mixture was added 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (46.77 mg, 0.254 mmol, 1 equiv) and K2CO3 (105.23 mg, 0.762 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for additional Ih at 100°C. The resulting mixture was filtered, the filter cake was washed with CH2CI2 (2x2 mL). The filtrate was concentrated under reduced pressure. The crude product (lOOmg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NFLHCCL), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 46% B to 66% B in 10 min; Wave Length: 254nm / 220nm nm;RTl(min): 8.02) to afford 2-[(3R)-3-[l-(4-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}pteridin-2- yl)azetidin-3-yl]piperidin-l-yl]ethanol (44.8 mg, 35.13%). LCMS (ESI, m / z): 502 [M+H]+. 'H NMR (400 MHz, DMSO-de) 8 9.06 (d, J= 7.2 Hz, IH), 8.73 (d, J= 2.1 Hz, IH), 8.36 (d, J= 2.0 Hz, IH), 7.58 (d, J = 2.2 Hz, IH), 7.37 (dd, J= 8.4, 2.2 Hz, IH), 5.62 (m, IH), 4.33 (m, IH), 4.04 (m, IH), 3.75 (m, 2H), 3.48 (m, 2H), 3.32 (m, IH), 2.74 (m, 2H), 2.36 (m, 3H), 1.91 (m, IH), 1.84 - 1.30 (m, 8H), 0.79 (brs, IH).Example 2: 2- [(3R)-3- [l-(7- { [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}-2-methylpyrazolo [4,3- d]pyrimidin-5-yl)azetidin-3-yl]piperidin-l-yl]ethanol

[0367] Example 2 was prepared using procedure as Example 1. ’H NMR (400 MHz, DMSO-de) 3 12.35 (s, 1H), 10.31 (d, J= 7.4 Hz, 1H), 9.50 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 7.59 (d, J= 8.5 Hz, 1H), 7.46 (dd, J= 8.5, 2.3 Hz, 1H), 5.75 (brs, 1H), 4.22 (d, J= 9.5 Hz, 1H), 4.12 (s, 3H), 4.03 (m, 2H), 3.77 (m, 2H), 3.52 (d, J= 11.9 Hz, 1H), 3.44 (s, 1H), 3.17 (d, J= 5.6 Hz, 2H), 2.87 (m, 1H), 2.67 - 2.56 (m, 2H), 2.08 (s, 1H), 1.81 (d, J= 52.9 Hz, 2H), 1.54 (d, J = 7.1 Hz, 3H), 1.04 (d, J= 13.5 Hz, 1H).Example 3: 2-[(3R)-3-(l-(7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3H-imidazo[4,5-b]pyridin-5- ylazetidin-3-yl)piperidin-l-yl]ethanol

[0368] To a stirred solution of 5,7-dichloro-3H-imidazo[4,5-b]pyridine (1 g, 5.319 mmol, 1 equiv) and SEMC1 (1.15 g, 6.915 mmol, 1.3 equiv) in DMF (15 mL) was added DIEA (1.37 g, 10.638 mmol, 2 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 2h at 100°C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 5,7-dichloro-3-([2- (trimethylsilyl)ethoxy]methylimidazo[4,5-b]pyridine (1.44 g, 85.06%) as a brown oil. LCMS:(ES, m / z):318 [M+H]+

[0369] A solution of (lR)-l-(2,4-dichlorophenyl)ethanol (450.21 mg, 2.357 mmol, 1.5 equiv) in DMF (5 mL) was treated with Potassium carbonate (1.2 eq) for 30 min at 0°C under nitrogen atmosphere followed by the addition of 5,7-dichloro-3-([2-(trimethylsilyl)ethoxy]methylimidazo[4,5-b]pyridine (500 mg, 1.571 mmol, 1 equiv) dropwise at 100 °C. The resulting mixture was stirred for Ih at 100 °C under air atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 5-chloro-7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3-([2-(trimcthylsilyl)cthoxy |mcthylimidazo|4.5-b|pyridinc (650 mg, 87.50%) as a light brown oil. LCMS(ES, m / z):472 [M+H]+

[0370] To a stirred solution of 5-chloro-7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3-([2- (trimethylsilyl)ethoxy]methylimidazo[4,5-b]pyridine (280 mg, 0.592 mmol, 1 equiv) and 2-[(3R)-3- (azetidin-3-yl)piperidin-l-yl]ethanol dihydrochloride (182.75 mg, 0.710 mmol, 1.2 equiv) in DMF (4 mL) were added C6sium carbonate (4 equiv) , Pd2(dba)s (54.22 mg, 0.059 mmol, 0.1 equiv) and XantPhos (68.52 mg, 0.118 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-[(3R)-3-(l-(7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3-([2- (trimethylsilyl)ethoxy]methylimidazo[4,5-b]pyridin-5-ylazetidin-3-yl)piperidin-l-yl]ethanol (65 mg, 17.69%) as a brown oil. LCMS:(ES, m / z):620 [M+H]+

[0371] A solution of 2-[(3R)-3-(l-(7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3-([2- (trimethylsilyl)ethoxy]methylimidazo[4,5-b]pyridin-5-ylazetidin-3-yl)piperidin-l-yl]ethanol (60 mg, 0.097 mmol, 1 equiv) and cone. Tetrabutylammonium fluoride (0.1 mL) in THF (1 mL) was stirred for 2h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions to afford 2-[(3R)- 3 -( 1 -(7-[( 1 R)- 1 -(2,4-dichlorophenyl)ethoxy] -3H-imidazo[4,5 -b]pyridin-5 -ylazetidin-3 -yl)piperidin- 1 - yl]ethanol (7.2 mg, 15.19%). LCMS:(ES, m / z):490 [M+H], ’H NMR (400 MHz, Chloroform- ) 5 11.80 -11.51 (m, 1H),7.74 (s, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J= 8.5 Hz, 1H), 6.06 (d, J = 6.7 Hz, 1H), 5.41 (m, 2H), 4.03 (dt, J= 17.1, 7.5 Hz, 2H), 3.67 (m, 4H), 3.04 - 2.78 (m, 2H), 2.72 - 2.41 (m, 3H), 2.24 (t, J = 7.6 Hz, 1H), 2.09 (dd, J= 26.8, 15.4 Hz, 2H), 1.79 (s, 3H), 1.74 (d, J= 6.2 Hz, 1H), 1.65 (s, 1H), 0.91 (d, J = 7.6 Hz, 2H).Example 4: 2-[(3R)-3-(l-{7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-lH-[l,2,3]triazolo[4,5-b]pyridin-5- yl}azetidin-3-yl)piperidin-l-yl]ethanol

[0372] A solution of (lR)-l-(2,4-dichlorophenyl)ethanol (918.51 mg, 4.808 mmol, 1 equiv) in DMF (10 mL) was treated with C6sium carbonate (1.5 equiv) for 30 min at 0°C under nitrogen atmosphere followed by the addition of 4,6-dichloro-3-nitropyridin-2-amine (1000 mg, 4.808 mmol, 1 equiv) in portions at 0°C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 90% gradient in 40 min; detector, UV 254 nm. This resulted in 6-chloro-4-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3- nitropyridin-2-amine (1045 mg, 59.95%) as a light yellow solid. LCMS (ESI, m / z . 362 [M+H]+.

[0373] To a stirred solution of 6-chloro-4-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-3-nitropyridin-2 -amine (500 mg, 1.379 mmol, 1 equiv) and 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (279.53 mg, 1.517 mmol, 1.10 equiv) in DMF (5 mL) was added K2CO3 (3.0 equiv) dropwise at room temperature. The resulting mixture was stirred for 45min at 120°C under nitrogen atmosphere. The reaction was quenched with Water at 120 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 2-[(3R)-3-(l-{6-amino-4-[(lR)-l-(2,4- dichlorophenyl)ethoxy]-5-nitropyridin-2-yl}azetidin-3-yl)piperidin-l-yl]ethanol (300 mg, 42.62%) as abrown oil. LCMS (ESI, m / z): 510 [M+H]+.

[0374] To a stirred solution of 2-[(3R)-3-(l-{6-amino-4-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-5- nitropyridin-2-yl}azetidin-3-yl)piperidin-l-yl]ethanol (398 mg, 0.780 mmol, 1 equiv) in AcOH (10 mL) was added Zn (509.80 mg, 7.797 mmol, 10.00 equiv) dropwise at room temperature. The resulting mixture was stirred for Ih at 80°C under nitrogen atmosphere. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 20% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in 2-[(3R)-3-(l-{5,6-diamino-4-[(lR)-l-(2,4-dichlorophenyl)ethoxy]pyridin-2-yl}azetidin- 3 -yl)piperidin-l-yl] ethanol (100 mg, 26.69%) as agreenish solid. LCMS (ESI, m / z): 480 [M+H]+.

[0375] To a stirred solution / mixture of 2-[(3R)-3-(l-{5,6-diamino-4-[(lR)-l-(2,4- dichlorophenyl)ethoxy]pyridin-2-yl}azetidin-3-yl)piperidin-l-yl]ethanol (100 mg, 0.208 mmol, 1 equiv) in AcOH (1000 pL) was added NaNO2(17.23 mg, 0.250 mmol, 1.20 equiv) in H2O (300 pL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Water(10mmol / L NH4HCO3)) to afford 2-[(3R)-3-(l-{7-[(lR)-l-(2,4- dichlorophenyl)ethoxy]-lH-[l,2,3]triazolo[4,5-b]pyridin-5-yl}azetidin-3-yl)piperidin-l-yl]ethanol (9.6 mg, 9.21%). LCMS (ESI, m / z): 491 [M+H]+. 'HNMR (400 MHz, Chloroform- ) 5 7.57 (dd, J= 8.5, 4.5 Hz, IH), 7.42 (d, J= 2.1 Hz, IH), 7.24 (ddd, J= 8.6, 4.5, 2.0 Hz, IH), 6.23 (q, J= 6.4 Hz, IH), 5.45 (d, J= 7.2 Hz, 1H), 4.34 - 4.06 (m, 2H), 3.86 (s, 2H), 3.72 (d, J= 5.6 Hz, 2H), 3.26 - 2.96 (m, 2H), 2.63 (t, J = 5.1 Hz, 2H), 2.55 (d, J= 9.1 Hz, 1H), 2.17 (s, 1H), 1.98 - 1.69 (m, 9H), 1.07 - 0.70 (m, 2H).Example 5: 2-((R)-3-(l-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-[l,2,5]oxadiazolo[3,4- b]pyridin-5-yl)azetidin-3-yl)piperidin-l-yl)ethan-l-ol

[0376] Into a 250mL round-bottom flask were added (lR)-l-(2,4-dichlorophenyl)ethanamine (1.10 g, 5.770 mmol, 1.2 equiv) and ACN (100 mL) at room temperature. To the above mixture was added K2CO3 (1.33 g, 9.616 mmol, 2 equiv), DIEA (1.24 g, 9.616 mmol, 2 equiv) and 4,6-dichloro-3- nitropyridin-2-amine (1 g, 4.808 mmol, 1 equiv). The resulting mixture was stirred for additional Ih at 80°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 6-chloro-N4-[(lR)-l- (2,4-dichlorophenyl)ethyl]-3-nitropyridine-2,4-diamine (1.6 g, 92.03%) as a yellow solid. LCMS (ESI, m / z): 361 [M+H]+.

[0377] Into a 40 mL round-bottom flask were added 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol dihydrochloride (355.63 mg, 1.383 mmol, 1 equiv) and DMF (5 mL) at room temperature. To the above mixture was added K2CO3 (573.29 mg, 4.149 mmol, 3 equiv) and 6-chloro-N4-[(lR)-l-(2,4- dichlorophenyl)ethyl]-3-nitropyridine-2,4-diamine (500 mg, 1.383 mmol, 1 equiv). The resulting mixture was stirred for additional 2 h at 100°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DMF (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 60% gradient in 15 min; detector, UV 254 nm. This resulted in 2-[(3R)-3-[l-(6-amino-4-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-5-nitropyridin-2-yl)azetidin-3-yl]piperidin-l-yl]ethanol (600 mg, 85.18%) as a yellow solid. LCMS (ESI, m / zy 509 [M+H]+

[0378] Into a 8mL round-bottom flask were added 2-[(3R)-3-[l-(6-amino-4-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-5-nitropyridin-2-yl)azetidin-3-yl]piperidin-l-yl]ethanol (500 mg, 0.981 mmol, 1 equiv) and DMF (4 mL) at room temperature. To the above mixture was added (acetyloxy)(phenyl-iodanyl acetate (948.40 mg, 2.943 mmol, 3 equiv). The resulting mixture was stirred for additional 2h at room temperature. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 35% gradient in 10 min; detector, UV 254 nm. This resulted in 7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-5-{3-[(3R)-l-(2- hydroxyethyl)piperidin-3 -yl]azetidin- 1 -yl } - 1 lambda5 -[ 1 ,2,5] oxadiazolo [4,3 -b]pyridin- 1 -one (300 mg, 60.24%) as a yellow solid. LCMS (ESI, m / z . 507 [M+H]+.

[0379] Into a 20mL round-bottom flask were added 7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-5- {3-[(3R)-l-(2-hydroxyethyl)piperidin-3-yl]azetidin-l-yl}-llambda5-[l,2,5]oxadiazolo[4,3-b]pyridin-l- one (200 mg, 0.394 mmol, 1 equiv) and DMF (4 mL) at room temperature. To the above mixture was added PPh3(113.72 mg, 0.433 mmol, 1.1 equiv). The resulting mixture was stirred for additional lh at 90°C. The mixture was allowed to cool down to room temperature. The reaction was quenched with IM. aq. HC1 at room temperature. The aqueous layer was extracted with EtOAc (3 x 10 mL). The aqueous layer was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD RP18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 60% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.72) to afford 2- [(3R)-3-[l-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-[l,2,5]oxadiazolo[3,4-b]pyridin-5-yl)azetidin- 3-yl]piperidin-l-yl]ethanol (5.2 mg, 2.55%). LCMS (ESI, m / z): 491 [M+H]+. ’H NMR (400 MHz, CDCL3 ) 3 7.47 d, J= 2.0 Hz, 1H), 7.34 ( , J= 8.4 Hz, 1H), 7.26-7.10 (m, 2H), 5.64 ( , J= 5.7 Hz, 1H), 5.09 - 5.02 (m, 1H), 4.99 (s, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 3.71 (m, 2H), 2.98 (m, 2H), 2.67 (m, 2H), 2.50 (m, 1H), 2.20-1.79 (m, 6H), 1.65 ( , J= 6.7 Hz, 3H), 0.98 (s, 1H).Example 6: 2-[(3R)-3-(l-{3-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylimidazo[4,5-b]pyrazin-5- yl}azetidin-3-yl)piperidin-l-yl]ethanol

[0380] A mixture of 3,5-dibromopyrazin-2-amine (1.5 g, 5.931 mmol, 1 equiv) and DMSO (10 mL) at room temperature. To the above mixture was added (lR)-l-(2,4-dichlorophenyl)ethanamine (1.35 g, 7.117 mmol, 1.2 equiv) and TEA (1.20 g, 11.862 mmol, 2 equiv) was irradiated with microwave radiation for Ih at 180 °C. The resulting mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 68% gradient in 20 min; detector, UV 254 nm. This resulted in 6-bromo-N2-[(lR)-l-(2,4-dichlorophenyl)ethyl]pyrazine-2,3-diamine (1.1 g, 50.56%) as a yellow solid. LCMS (ESI, m / z): 363 [M+H]+.

[0381] Into a 20 mL round-bottom flask were added 6-bromo-N2-[(lR)-l-(2,4- dichlorophenyl)ethyl]pyrazine-2,3-diamine (550 mg, 1.519 mmol, 1 equiv) and HOAc (5 mL) at room temperature. To the above mixture was added AC2O (465.26 mg, 4.557 mmol, 3 equiv). The resulting mixture was stirred for additional overnight at 110°C. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford 6-bromo-l-[(lR)-l-(2,4- dichlorophenyl)ethyl]-2-methylimidazo[4,5-b]pyrazine (340 mg, 57.97%) as a light yellow solid. LCMS (ESI, m / z): 385 [M+H]+.

[0382] Into a 20 mL round-bottom flask were added 6-bromo-l-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2- methylimidazo[4,5-b]pyrazine (100 mg, 0.259 mmol, 1 equiv) and DMA (4 mL, 43.020 mmol, 166.09 equiv) at room temperature. To the above mixture was added DBU (197.17 mg, 1.295 mmol, 5 equiv) and 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (95.47 mg, 0.518 mmol, 2 equiv). The final reaction mixture was irradiated with microwave radiation for 30min at 200°C. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.56) to afford 2-[(3R)-3-(l-{3-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylimidazo[4,5-b]pyrazin-5-yl}azetidin- 3 -yl)piperidin-l-yl] ethanol; bis(trifluoroacetic acid) (37.1 mg, 19.64%) as a yellow solid. LCMS (ESI, m / z): 489 [M+H]+. 'HNMR (400 MHz, Chloroform- ) 3 7.74 (d, J= 8.9, Hz, IH), 7.63 (s, IH), 7.41 (d, J= 2.1 Hz, IH), 7.34 (dd, J= 8.4, 2.1 Hz, IH), 6.52 (brs, 2H), 5.98 (m, IH), 4.27 - 3.63 (m, 8H), 3.25 (s, 2H), 2.80 - 2.51 (m, 7H), 2.18 - 1.88 (m, 6H), 1.32 - 1.02 (m, IH).Example 7 : 2- [(3R)-3- [l-(7- { [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}- [1,3] thiazolo [5,4- d]pyrimidin-5-yl)azetidin-3-yl]piperidin-l-yl]ethanol

[0383] A mixture of 4,6-dichloropyrazolo[l,5-a]pyrazine (900 mg, 4.787 mmol, 1 equiv) and (1R)-1- (2,4-dichlorophenyl)ethanamine (1091.83 mg, 5.744 mmol, 1.2 equiv), K2CO3 (344.63 mg, 14.361 mmol, 3 equiv) in DMF (12 mL) was stirred for 1 h at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was fdtered, the filter cake was washed with MeCN (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% TFA), 60% to 90% gradient in 10 min; detector, UV 254 nm. The crude product was purified by trituration with MeCN (10 mL). After filtered, the filter cake was washed with MeCN (3x10 mL). The filtrate was concentrated under reduced pressure, to afford 6-chloro-N- [(lR)-l-(2,4-dichlorophenyl)ethyl]pyrazolo[l,5-a]pyrazin-4-amine (800 mg, 48.92%) as a yellow solid. LCMS (ESI, m / z): 341 [M+H]+.

[0384] A solution of 6-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]pyrazolo[l,5-a]pyrazin-4-amine (100 mg, 0.293 mmol, 1 equiv) and 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (80.92 mg, 0.440 mmol, 1.5 equiv), CS2CO3 (286.12 mg, 0.879 mmol, 3 equiv), XPhos (13.95 mg, 0.029 mmol, 0.1 equiv) in dioxane (2 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 xlO mL). dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (30 mg) was purified by Prep-HPLC with the following conditions to afford 2-[(3R)- 3-[l-(4-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}pyrazolo[l,5-a]pyrazin-6-yl)azetidin-3-yl]piperidin-l- yl]ethanol (10.1 mg, 7.05%). LCMS (ESI, m / z): 489 [M+H]+. ’H NMR (400 MHz, Chloroform- ) 5 7.87 - 7.79 (m, 2H), 6.55 (d, J= 2.4 Hz, 1H), 6.45 (d, J= 2.4 Hz, 1H), 6.33 (dd, J= 8.4, 2.4 Hz, 1H), 5.63 (q, J= 7.1 Hz, 1H), 5.44 (d, J= 7.6 Hz, 1H), 3.97 (q, J= 7.7 Hz, 2H), 3.74 (s, 2H), 3.64 - 3.55 (m, 2H), 3.05 (s, 2H), 2.71 (s, 2H), 2.57 (s, 1H), 2.25 (s, 1H), 2.05 (d, J= 15.2 Hz, 2H), 1.81 (s, 2H), 1.67 (d, J= 6.8 Hz, 3H), 1.60 (s, 2H), 1.01 (s, 1H).Example 8: 4-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-6-(3-((R)-l-(2-hydroxyethyl)piperidin-3- yl)azetidin-l-yl)-2-methylpyridazin-3(2H)-one

[0385] Into a 20mL sealed tube were added 4-bromo-6-chloro-2-methylpyridazin-3-one (500 mg, 2.238 mmol, 1 equiv) (lR)-l-(2,4-dichlorophenyl)ethanamine (467.84 mg, 2.462 mmol, 1.1 equiv) CsF (1019.72 mg, 6.714 mmol, 3 equiv) and DMF (5 mL) at room temperature. The resulting mixture was stirred for Ih at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water at room temperature. The aqueous layer wasextracted with EtOAc (3x10 mL).The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 90% gradient in 10 min; detector, UV 254 nm. This resulted in 6-chloro-4-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-2-methylpyridazin-3-one (500 mg, 67.18%) as an off-white solid. LCMS:(ESI, m / z):332.

[0386] Into a 40 mL sealed tube were added 6-chloro-4-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-2- methylpyridazin-3-one (400 mg, 1.203 mmol, 1 equiv) 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (243.78 mg, 1.323 mmol, 1.1 equiv) CS2CO3 (1175.50 mg, 3.609 mmol, 3 equiv) XantPhos (55.67 mg, 0.096 mmol, 0.08 equiv) Pd2(dba)s (44.05 mg, 0.048 mmol, 0.04 equiv)and 1,4-dioxane (4 mL) at room temperature. The resulting mixture was stirred overnight at 110°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (3x50 mL).The resulting mixture was concentrated under vacuum. The crude product (400 mg) was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18, 21.2*250mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min mL / min; Gradient: 33% B to 63% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.9, 7.2(min): ) to afford 4-([(lR)-l-(2,4- dichlorophenyl)ethyl]amino-6-(3-[(3R)-l-(2-hydroxyethyl)piperidin-3-yl]azetidin-l-yl-2- methylpyridazin-3-one (3.2 mg, 0.55%). LCMS:(ESI, m / z):480.1H NMR (400 MHz, Chloroform- ) 5 7.42 (d, J= 2.2 Hz, 1H), 7.25 (m, 3H), 6.10 (d, J= 6.0 Hz, 1H), 5.04 (d, J= 3.4 Hz, 1H), 4.85 - 4.73 (m, 1H), 3.82 (m, 4H), 3.70 - 3.38 (m, 6H), 3.20 (s, 2H), 2.87 (s, 2H), 2.42 (s, 2H), 1.85 (d, J= 12.4 Hz, 2H), 1.57 (d, J = 6.7 Hz, 3H), 1.28 (s, 1H), 1.01 (s, 1H).Example 9: (5R)-5-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3- d]pyrimidin-5-yl)piperazine-l-carbonyl]pyrrolidin-2-one

[0387] To a stirred mixture of 5,7-dichloro-2-methylpyrazolo[4,3-d]pyrimidine (500 mg, 2.463 mmol, 1 equiv) and (lR)-l-(2,4-dichlorophenyl)ethanamine (702.13 mg, 3.695 mmol, 1.5 equiv) in DMF (8 mL) was added K2CO3 (1021.07 mg, 7.389 mmol, 3 equiv) in portions at room temperature under airatmosphere. The resulting mixture was stirred for 1.5 h at 120°C under air atmosphere The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TLA), 50% to 90% gradient in 10 min; detector, UV 254 nm. This resulted in 5-chloro-N-[(lR)-l-(2,4- dichlorophenyl)ethyl]-2-methylpyrazolo[4,3-d]pyrimidin-7-amine (733 mg, 83.46%) as a white foam. LCMS (ESI, m / z): 356 [M+H]+.

[0388] To a stirred solution of 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylpyrazolo[4,3- d]pyrimidin-7-amine (400 mg, 1.122 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (417.80 mg, 2.244 mmol, 2 equiv) in DME (6 mL) was added K2CO3 (465.02 mg, 3.366 mmol, 3 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 8 h at 120°C under air atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TEA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 4-(7- { [( 1 R)- 1 -(2,4-dichlorophenyl)ethyl] amino } -2-methylpyrazolo [4,3 -d]pyrimidin-5 -yl)piperazine- 1 - carboxylate (403 mg, 70.95%) as a colorless oil. LCMS (ESI, m / zy. 506 [M+H]+.

[0389] To a stirred solution of tert-butyl 4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo[4,3-d]pyrimidin-5-yl)piperazine-l-carboxylate (300 mg, 0.591 mmol, 1 equiv) in DCM (4 mL) was added HCl(gas)in 1,4-dioxane (2 mL, 65.826 mmol, 333.36 equiv) dropwise at 0°C under air atmosphere. The resulting mixture was stirred for Ih at room temperature under air atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x10 mL). The filtrate was concentrated under reduced pressure. The crude resulting mixture was used in the next step directly without further purification, to afford N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-(piperazin-l- yl)pyrazolo[4,3-d]pyrimidin-7-amine (216 mg, 90.0%) as an off-white solid. LCMS (ESI, m / zy. 406 [M+H]+.

[0390] To a stirred solution ofN-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-(piperazin-l- yl)pyrazolo[4,3-d]pyrimidin-7-amine (100 mg, 0.246 mmol, 1 equiv) and DIEA (159.05 mg, 1.230 mmol, 5 equiv) in DMF (1 mL) was added HATU (140.37 mg, 0.369 mmol, 1.5 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (10 mL). dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions to afford (5R)-5-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)piperazine-l-carbonyl]pyrrolidin-2-one (31.5 mg, 24.74%). LCMS (ESI, m / z): 517 [M+H]+.

[0391] Preparative -HPLC condition: Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min mL / min; Gradient: 36% B to 66% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.56. 'H NMR (400 MHz, Chloroform- ) 5 8.09 (s, 1H), 7.96 (d, J= 98.4 Hz, 1H), 7.44 (d, J= 2.1 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 7.24 (d, J= 8.4 Hz, 1H), 6.68 (brs, 1H), 5.96 (s, 1H), 5.67 (t, J= 6.8 Hz, 1H), 4.68 - 4.38 (m, 1H), 4.12 (s, 3H), 3.97 - 3.65 (m, 4H), 3.51 (s, 2H), 2.60 - 2.31 (m, 3H), 2.22 - 1.94 (m, 1H), 1.65 (d, J = 7.0 Hz, 3H).Example 10: 2-[(3R)-3-[l-(8-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-[l,2,4]triazolo[4,3- b]pyridazin-6-yl)azetidin-3-yl]piperidin-l-yl]ethanol

[0392] Into a 50 m round-bottom flask were added 6-chloro-[l,2,4]triazolo[4,3-b]pyridazin-8-amine (500 mg, 2.949 mmol, 1 equiv) and ACN (20 m ) at room temperature. To the above mixture was added the mixture oftBuONO (1060.70 pL, 8.847 mmol, 3 equiv) and C11CI2 (792.89 mg, 5.898 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for additional 2 h at 60°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ACN(3x20mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Q2 / MeOH 10: 1) to afford 6,8-dichloro-[l,2,4]triazolo[4,3-b]pyridazine (370 mg, 66.39%) as an off-white solid. LCMS (ESI, m / z) 189 [M+H]+.

[0393] Into a 5 mb round-bottom flask were added 6,8-dichloro-[l,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.058 mmol, 1 equiv) and DMF (4 mb) at room temperature. To the above mixture was added (1R)- l-(2,4-dichlorophenyl)ethanamine (241.36 mg, 1.270 mmol, 1.2 equiv) and DIEA (460.81 pL, 2.645 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred for additional 1 h at 100°C. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (3x1 OmL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford 6-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-[l,2,4]triazolo[4,3- b]pyridazin-8-amine (300 mg, 82.75%) as a white solid. LCMS (ESI, m / z) 342 [M+H]+.

[0394] Into a 10 mL round-bottom flask were added 6-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-[1.2.4]triazolo[4,3-b]pyridazin-8-amine (264 mg, 0.771 mmol, 1 equiv) and DMF (5.28 mL) at room temperature. To the above mixture was added 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (170.40 mg, 0.925 mmol, 1.2 equiv), and K2CO3 (2.313 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for additional 2 h at 100°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeCN (3xl0mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (X-Select Prep OBD C18 Column, 30* 150 mm; mobile phase, MeCN in Water (0.1% FA), 30% to 50% in 7 min) to afford 2-[(3R)-3-[l-(8-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-[1.2.4]triazolo[4,3-b]pyridazin-6-yl)azetidin-3-yl]piperidin-l-yl]ethanol (21.2 mg, 5.61%) as an off-white solid. LCMS (ESI, z): 490 [M+H]+. 'HNMR (400 MHz, Chloroform- d) <59.04 (s, 1H), 8.35 (d, J= 7.5 Hz, 1H), 8.19 (s, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.60 (d, J= 8.5 Hz, 1H), 7.44 (dd, J= 8.4, 2.2 Hz, 1H), 5.01 (d, J= 18.7 Hz, 2H), 3.96 - 3.52 (m, 6H), 2.81 (t, J= 11.0 Hz, 2H), 2.44 (m, 3H), 2.02 (t, J= 11.2 Hz, 1H), 1.78 - 1.56 (m, 4H), 1.55 (s, 3H), 1.45 (d, J= 12.2 Hz, 1H), 0.82 (s, 1H).Example 11: N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{4-[(2S)-pyrrolidine-2- carbonyl]piperazin-l-yl}pyrazolo[4,3-d]pyrimidin-7-amine

[0395] ’H NMR (400 MHz, Chloroform- d) 5 8.33 (s, 1H), 7.59 (s, 1H), 7.44 (d, J= 2.1 Hz, 1H), 7.33 (s, 1H), 7.20 (dd, J = 8.4, 2.1 Hz, 1H), 6.25 (d, J= 6.1 Hz, 1H), 5.67 - 5.62 (m, 1H), 4.74 (d, J= 7.4 Hz, 1H), 4.12 (s, 3H), 3.88 - 3.33 (m, 10H), 2.50 (dq, J= 16.4, 7.1 Hz, 1H), 2.22 - 2.15 (m, 3H), 2.01 (dq, J = 13.2, 7.0 Hz, 2H), 1.90 (dt, J= 12.8, 6.4 Hz, 1H), 1.61 (d, J= 6.9 Hz, 3H).Example 12: 5-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-7-(3-[(3R)-l-(2-hydroxyethyl)piperidin-3- yl]azetidin-l-yl-l-methyl-l,8-naphthyridin-4-one

[0396] Into a 40 mL vial were added 4,6-dichloropyridin-2-amine (500 mg, 3.067 mmol, 1 equiv) and5-(methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (860 mg, 4.620 mmol, 1.51 equiv) in EtOH (20 ml) at room temperature. The precipitated solids were collected by filtration and washed with EtOH (2x10 mL). This resulted in 5-([(4,6-dichloropyridin-2-yl)amino]methylidene-2,2- dimethyl-l,3-dioxane-4, 6-dione (900 mg, 92.52%) as a white solid. LCMS: (ESI, m / z)'. 317 [M+H]+.

[0397] The final reaction mixture(5-(((4,6-dichloropyridin-2-yl)amino)methylene)-2,2-dimethyl-l,3- dioxane-4, 6-dione, 900mg) in diphenylether(lOml) was irradiated with microwave radiation for lOmin at 180 °C The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford 6,8-dichloropyrido[l,2-a]pyrimidin-4-one (200 mg, 32.84%) as a yellow solid. LCMS:( ESI, z): 215 [M+H]+.

[0398] Into a 20 mL vial were added 5,7-dichloro-lH-l,8-naphthyridin-4-one (270 mg, 1.256 mmol, 1 equiv) and Mel (107.87 pL, 1.733 mmol, 1.38 equiv), K2CO3 (539.70 mg, 3.906 mmol, 3.11 equiv) in CH3CN (5 mL) at room temperature. The resulting mixture was stirred for Ih at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (PE / EA 1: 1) to afford 5,7-dichloro-l-methyl-l,8-naphthyridin-4-one (150 mg, 52.15%) as a white solid. LCMS: (ESI, z): 229 [M+H]+.

[0399] Into a 20 mL vial were added 5,7-dichloro-l-methyl-l,8-naphthyridin-4-one (150 mg, 0.655 mmol, 1 equiv) and (lR)-l-(2,4-dichlorophenyl)ethanamine (159.32 mg, 0.838 mmol, 1.28 equiv), CsF (330.25 mg, 2.175 mmol, 3.32 equiv) in DMSO (5 mL) at room temperature. The resulting mixture was stirred for 2h at 120 °C. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 7-chloro-5-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-l-methyl-l,8- naphthyridin-4-one (50 mg, 19.95%) as a white solid. LCMS: (ESI, m / z)'. 382 [M+H]+.

[0400] The final reaction mixture(7-chloro-5-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-l-methyl-l,8- naphthyridin-4-one (50 mg, 0.131 mmol, 1 equiv) ,2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]ethanol (30 mg, 0.163 mmol, 1.25 equiv) ,DBU (100 pL, 0.669 mmol, 5.12 equiv) in DMA (2 mL) was irradiated with microwave radiation for 30min at 200°C. Desired product could be detected by LCMS. The crude product (50mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 61% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.87) to afford 5-([(lR)-l-(2,4-dichlorophenyl)ethyl]amino-7-(3-[(3R)-l-(2- hydroxyethyl)piperidin-3-yl]azetidin-l-yl-l-methyl-l,8-naphthyridin-4-one (6.2 mg, 8.93%). LCMS: (ESI, m / z): 530 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 11.05 (d, J= 6.5 Hz, IH), 7.72 (d, J= 7.7 Hz, IH), 7.65 (d, J= 2.1 Hz, IH), 7.41 (dd, J= 8.4, 2.2 Hz, IH), 7.35 (d, J= 8.4 Hz, IH), 5.86 (d, J= 7.7 Hz, IH), 4.87 (t, J= 6.6 Hz, IH), 4.78 (s, IH), 4.37 (brs, IH), 3.93 (t, J= 8.3 Hz, IH), 3.83 (brs, IH), 3.63 (t, J= 7.1 Hz, IH), 3.50 (s, 3H), 2.78 (s, 2H), 2.41 (m, 3H), 1.95 (s, IH), 1.63 (s, 4H), 1.49 (d, J= 6.7 Hz, 4H), 0.82 (s, IH).Example 13: 6-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-8-{3-[(3R)-l-(2-hydroxyethyl)piperidin- 3-yl] azetidin-l-yl}pyrido [1,2-a] pyrimidin-4-one

[0401] Example 13 was prepared using Example 12 procedure. ’H NMR (400 MHz, DMSO-de) 5 11.37 (s, 1H), 10.86 (d, J = 6.6 Hz, 1H), 8.24 (s, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.4, 2.1 Hz, 2H), 7.37 (d, J = 8.5 Hz, 1H), 5.82 (d, J = 7.4 Hz, 1H), 4.90 - 4.82 (m, 1H), 4.73 (s, 1H), 3.91 (t, J = 8.2 Hz, 1H), 3.80 (s, 1H), 3.65 - 3.57 (m, 1H), 3.49 (t, J = 6.3 Hz, 3H), 2.76 (s, 2H), 2.39 (s, 3H), 1.93 (s, 1H), 1.63 (s, 4H), 1.49 (d, J = 6.7 Hz, 4H), 0.80 (s, 1H).Example 14: (5S)-5-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3- d]pyrimidin-5-yl)piperazine-l-carbonyl]pyrrolidin-2-one

[0402] Example 14 was prepared using Example 11 procedure. 'H NMR (400 MHz, Chloroform-<7) 5 7.57 (d, J= 22.8 Hz, 1H), 7.42 (d, J= 2.1 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.20 (dd, J= 8.4, 2.1 Hz, lH), 6.14 (s, 1H), 5.82 (s, 1H), 5.71 - 5.57 (m, 1H), 4.52 (dd, J= 8.3, 5.9 Hz, 1H), 4.11 (s, 3H), 3.90 -3.52 (m, 6H), 3.38 (d, J= 40.1 Hz, 2H), 2.61 - 2.47 (m, 1H), 2.47 - 2.37 (m, 2H), 2.21 - 2.02 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H).Example 15: l-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin- 5-yl)piperazin-l-yl]-3-(dimethylamino)propan-l-one

[0403] Example 15 was prepared using Example 11 procedure. 'H NMR (400 MHz, Chloroform-7) 57.53 (s, 1H), 7.41 (d, 7= 2.1 Hz, 1H), 7.34 (d, 7= 8.4 Hz, 1H), 7.18 (dd, 7= 8.4, 2.1 Hz, 1H), 6.05 (d, 7= 6.0 Hz, 1H), 5.62 (s, 1H), 4.10 (s, 3H), 3.81 - 3.54 (m, 6H), 3.53 - 3.27 (m, 2H), 2.75 (d, 7= 7.6 Hz, 2H), 2.62 (d, 7= 7.6 Hz, 2H), 2.36 (s, 6H), 1.60 (d, 7= 7.0 Hz, 3H).Example 16: N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{4-[(2R)-l-methylpyrrolidine-2- carbonyl]piperazin-l-yl}pyrazolo[4,3-d]pyrimidin-7-amine

[0404] ’H NMR (400 MHz, Chloroform-7) 5 7.55 (s, 1H), 7.42 (d, 7= 2.1 Hz, 1H), 7.34 (d, 7= 8.4 Hz, 1H), 7.19 (dd, 7= 8.4, 2.1 Hz, 1H), 6.06 (s, 1H), 5.79 - 5.53 (m, 1H), 4.11 (s, 3H), 3.86 - 3.38 (m, 8H), 3.30 - 3.02 (m, 2H), 2.40 (s, 3H), 2.23 (d, 7= 58.4 Hz, 3H), 2.07 - 1.78 (m, 2H), 1.60 (d, 7= 6.9 Hz, 3H).Example 17: 2-amino-l-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3- d]pyrimidin-5-yl)piperazin-l-yl]-2-methylpropan-l-one

[0405] Example 17 was prepared using Example 11 procedure from 2-((tert-butoxycarbonyl)amino)- 2-methylpropanoic acid starting material and Boc-deprotection was carried out using following procedure.

[0406] To a stirred solution of tert-butyl N-{ l-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo[4,3-d]pyrimidin-5-yl)piperazin-l-yl]-2-methyl-l-oxopropan-2-yl}carbamate (80 mg, 0.135 mmol, 1 equiv) in DCM (5 mL) was added HCl(gas)in 1,4-dioxane (22.40 mg, 0.135 mmol, 1 equiv) dropwise at room temperature. Then the mixture was stirred at room temperature for Ih. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC to afford 2-amino-l-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3- d]pyrimidin-5-yl)piperazin-l-yl]-2-methylpropan-l-one (15.0 mg, 22.57%) as an off-white solid. LCMS(ESI, m / z): 491 [M+H]+. 'HNMR (400 MHz, Chloroform- ) 5 7.58 (s, 1H), 7.41 (s, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 8.6 Hz, 1H), 6.10 (s, 1H), 5.64 (d, J = 8.6 Hz, 1H), 4.10 (s, 3H), 3.98 - 3.50 (m, 9H), 1.61 (d, J = 6.9 Hz, 3H), 1.45 (s, 6H).Example 18: N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{l-[(2R)-pyrrolidine-2-carbonyl]-3,6- dihydro-2H-pyridin-4-yl}pyrazolo[4,3-d]pyrimidin-7-amine

[0407] A solution of 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylpyrazolo[4,3- d]pyrimidin-7-amine (200 mg, 0.561 mmol, 1 equiv) in dioxane (1.20 mL) and H2O (0.30 mL) was treated with tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l- carboxylate (208.08 mg, 0.673 mmol, 1.2 equiv), Na2COs (118.87 mg, 1.122 mmol, 2 equiv), Pd(dppf)C12 (41.03 mg, 0.056 mmol, 0.1 equiv) for 5 min at room temperature. The resulting mixture was stirred for additional 2h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 0% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 4-(7-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)-3,6-dihydro-2H-pyridine-l- carboxylate (178 mg, 61.79%) as a white solid. LCMS (ESI, m / z)'. 504 [M+H]+

[0408] A solution of tert-butyl 4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo[4,3-d]pyrimidin-5-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (165 mg, 0.328 mmol, 1 equiv) in DCM (6.88 mL) was treated with TFA (1 mL) for 5 min at room temperature. The resulting mixture was stirred for additional 30min at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-(l, 2,3,6- tetrahydropyridin-4-yl)pyrazolo[4,3-d]pyrimidin-7-amine (130 mg, 95.99%) as a white solid. LCMS (ESI, m / z): 404 [M+H]+

[0409] A solution ofN-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-(l,2,3,6-tetrahydropyridin-4- yl)pyrazolo[4,3-d]pyrimidin-7-amine (130 mg, 0.322 mmol, 1 equiv) in DMF (3 mL) was treated with(2R)-l-(tert-butoxycarbonyl)pyrrolidine-2 -carboxylic acid (138.76 mg, 0.644 mmol, 2.0 equiv), DIEA (249.96 mg, 1.932 mmol, 6 equiv), HATU (183.84 mg, 0.483 mmol, 1.5 equiv) for 5 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% tol00% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl (2R)-2- [4-(7 - { [( 1 R)- 1 -(2,4-dichlorophenyl)ethyl]amino } -2-methylpyrazolo [4,3 -d]pyrimidin-5 - yl)-3,6-dihydro-2H-pyridine-l-carbonyl]pyrrolidine-l-carboxylate (90 mg, 45.10%) as a yellow solid. LCMS (ESI, m / z): 601 [M+H]+

[0410] A solution of tert-butyl (2R)-2-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo [4,3 -d]pyrimidin-5-yl)-3,6-dihydro-2H-pyridine- 1 -carbonyl]pyrrolidine- 1 -carboxylate (50 mg, 0.083 mmol, 1 equiv) in DCM (1 mb) was treated with HCl(gas)in 1,4-dioxane (1.00 mb, 3.987 mmol, 48.04 equiv) for 2 min at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water(0.05%FA), Mobile Phase B: MEOH; Flow rate: 20 mL / min mL / min; Gradient: 54% B to 84% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.5) to afford N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{ l-[(2R)-pyrrolidine-2- carbonyl]-3,6-dihydro-2H-pyridin-4-yl}pyrazolo[4,3-d]pyrimidin-7-amine; formic acid (2.7 mg, 5.82%) as a white solid. LCMS (ESI, z): 501 [M+H]+. 'HNMR (400 MHz, Chloroform- ) 5 8.50 (s, 1H), 7.89 (d, J= 4.7 Hz, 1H), 7.45 (dd, J= 8.7, 2.1 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.01 (s, 1H), 6.14 (d, J= 6.1 Hz, 1H), 5.80 (m, 1H), 4.67 (m, 2H), 4.20 (s, 3H), 4.20-4.11 (m, 2H), 4.0-3.36 (m, 5H), 2.90 - 2.60 (m, 2H), 2.14 - 2.03 (m, 2H), 1.91 (m, 2H), 1.64 (d, J= 6.9 Hz, 3H).Example 19: afford 2-[(3R)-3-(l-(7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-2-methylpyrazolo[4,3- d]pyrimidin-5-ylazetidin-3-yl)piperidin-l-yl]ethanol

[0411] A solution of (lR)-l-(2,4-dichlorophenyl)ethanol (94.10 mg, 0.493 mmol, 1 equiv) in THF (1 mb) was treated with NaH (35.46 mg, 1.479 mmol, 3 equiv) for 30min at 0 °C under nitrogen atmosphere followed by the addition of 5,7-dichloro-2-methylpyrazolo[4,3-d]pyrimidine (100 mg, 0.493 mmol, 1 equiv) in portions at room temperature. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (3x5 mL).The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0. 1% NH3.H2O), 10% to 50% gradient in 10 min;detector, UV 254 nm. This resulted in 5-chloro-7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-2- methylpyrazolo[4,3-d]pyrimidine (120 mg, 46.41%) as a white solid. LCMS:( ESI, m / z):357[M+H]+

[0412] Into a 20mL round-bottom flask were added 5-chloro-7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]- 2-methylpyrazolo[4,3-d]pyrimidine (100 mg, 0.280 mmol, 1 equiv) 2-[(3R)-3-(azetidin-3-yl)piperidin-l- yl]ethanol (77.30 mg, 0.420 mmol, 1.5 equiv) K2CO3 (193.23 mg, 1.400 mmol, 5 equiv)and DMF (1 mL) at room temperature. The resulting mixture was stirred for 2h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x10 mL).The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD RP18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 31% B to 51% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.42) to afford 2- [(3R)-3-(l-(7-[(lR)-l-(2,4-dichlorophenyl)ethoxy]-2-methylpyrazolo[4,3-d]pyrimidin-5-ylazetidin-3- yl)piperidin-l-yl]ethanol (11.5 mg, 8.11%). LCMS:(ESI, m / z):505[M+H]+. ’HNMR (400 MHz, DMSO- d6) 5 8.00 (s, 1H), 7.66 (d, J= 2.0 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.42 (dd, J= 8.4, 2.1 Hz, 1H), 6.49 (dd, J= 7.9, 5.0 Hz, 1H), 4.33 (q, J= 5.6 Hz, 1H), 4.09 (s, 3H), 3.93 (t, J= 8.2 Hz, 1H), 3.84 (t, J= 8.3 Hz, 1H), 3.64 (s, 1H), 3.48 (p, J= 6.0 Hz, 3H), 2.78 - 2.68 (m, 2H), 2.35 (ddq, J= 10.0, 5.9, 3.4 Hz, 3H), 1.90 (t, J= 11.0 Hz, 1H), 1.65 (d, J= 6.6 Hz, 3H), 1.60 (d, J= 4.0 Hz, 1H), 1.57 (s, 3H), 1.41 (d, J= 12.6 Hz, 1H), 0.76 (d, J= 10.6 Hz, 1H).Example 20: 3-((R)-3-(l-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-5-yl)azetidin-3-yl)piperidin-l-yl)-l-methylcyclobutane-l-carboxylic acid

[0413] To a stirred mixture of 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylpyrazolo[4,3- d]pyrimidin-7-amine (200 mg, 0.561 mmol, 1 equiv) and methyl 3-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]- 1 -methylcyclobutane -1 -carboxylate (448.16 mg, 1.683 mmol, 3 equiv) in DMF (3 mL) was added K2CO3 (465.02 mg, 3.366 mmol, 6 equiv) in portions at room temperature. The resulting mixture was stirred at 120°C for 2h. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, trifluoroacetic acid solution in ACN, 20% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 3-[(3R)-3-[l-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d|pyrimidin-5-yl)azctidin-3-yl |pipcridin- 1 -yl |- 1 -mcthylcyclobutanc- 1 -carboxylate (278 mg, 84.51%) as a brown solid. LCMS (ESI, m / z): 586 [M+H]+.

[0414] To a stirred solution of methyl 3-[(3R)-3-[l-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo [4,3 -d]pyrimidin-5 -yl)azetidin-3 -yl]piperidin- 1 -yl] - 1 -methylcyclobutane- 1 -carboxylate (200 mg, 0.341 mmol, 1 equiv) in THF (3 m ) and H2O (0.682 m ) was added EiOH (32.67 mg, 1.364 mmol, 4 equiv) in H2O (0.682 mb) at 0°C. The mixture was stirred at 60°C for 3h. Desired product could be detected by ECMS. The crude product was purified by Prep-HPEC with the following conditions (Column: xBridge Prep Phenyl 5pm OBD 19*250mm; Mobile Phase A: Water(10mmol / E NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mb / min mb / min; Gradient: isocratic 35%B - 65 %B IN 20 MIN; Wave Length: 220 / 254 nm; RTl(min): 13) to afford (lr*,3s*)-3-[(3R)-3-[l-(7-{[(lR)-l-(2,4- dichlorophenyl)ethyl] amino } -2-methylpyrazolo [4,3 -d]pyrimidin-5 -yl)azetidin-3 -yl]piperidin- 1 -yl] - 1 - methylcyclobutane-1 -carboxylic acid; formic acid (13.3 mg, 6.31%). ECMS (ESI, m / z): 572 [M+H]+.

[0415] Preparative -HPLC condition: Column: xBridge Prep Phenyl 5pm OBD 19*250mm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mL / min mL / min; Gradient: isocratic 35%B - 65%B IN 20 MIN; Wave Length: 220 / 254 nm; RTl(min): 13. 'H NMR (400 MHz, DMSO-de) 5 8.54 (dd, J= 7.1, 4.3 Hz, 1H), 8.33 (s, 1H), 7.79 (s, 1H), 7.62 - 7.46 (m, 2H), 7.36 (dd, J= 8.4, 2.2 Hz, 1H), 5.57 (brs, 1H), 4.05 (s, 3H), 3.83 (m, 1H), 3.75 (m, 1H), 3.54 (m, 1H), 2.80 - 2.52 (m, 2H), 2.39 - 2.22 (m, 1H), 2.14 (m, 2H), 1.91 (m, 2H), 1.71 (m, 8H), 1.60 (s, 2H), 1.46 (d, J = lA z, 3H), 1.38 (d, J= 9.8 Hz, 1H), 1.31 (d, J= 4.2 Hz, 3H), 0.80 (s, 1H).Example 21: (4-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-5-yl)piperazin-l-yl)((R)-tetrahydrofuran-2-yl)methanone

[0416] Example 21 was prepared using example 11 procedure. LCMS (ESI, m / z) 504 [M+H]+. ’H NMR (400 MHz, Chloroform- ) 37.42 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.22 - 7.17 (m, 1H), 6.09 (s, 1H), 5.77 - 5.51 (m, 1H), 4.65 (t, J = 6.5 Hz, 1H), 4.11 (s, 3H), 4.06 - 3.90 (m, 1H), 3.87 (d, J = 7.4 Hz, 1H), 3.74 - 3.46 (m, 7H), 2.31 (dq, J = 14.2, 8.3, 7.6 Hz, 1H), 2.21 - 1.77 (m, 3H), 1.62 (d, J = 6.9 Hz, 3H).Example 22: {3-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3- d]pyrimidin-5-yl)piperazin-l-yl]piperidin-l-yl}acetic acid

[0417] A solution of benzyl piperazine- 1 -carboxylate (6 g, 27.239 mmol, 1 equiv) and tert-butyl 3- oxopiperidine-1 -carboxylate (5.43 g, 27.239 mmol, 1 equiv), AcOH (0.16 g, 2.724 mmol, 0.1 equiv) in MeOH (90 mb) was stirred for 2 h at room temperature under nitrogen atmosphere . To the above mixture was added NaBFhCN (5.14 g, 81.717 mmol, 3 equiv) in portions over 5 min at 0°C. The resulting mixture was stirred for additional overnight at room temperature. The reaction was quenched by the addition of Water at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford benzyl 4-[l-(tert-butoxycarbonyl)piperidin-3-yl]piperazine-l-carboxylate (7.5 g, 68.23%) as a colorless oil. LCMS (ESI, m / z): 404 [M+H]+.

[0418] To a solution of benzyl 4- [l-(tert-butoxycarbonyl)piperidin-3-yl]piperazine-l -carboxylate (2.5 g, 6.195 mmol, 1 equiv) in EtOAc (30 mL) was added Pd / C (0.1 equiv) under nitrogen atmosphere in a 100 mL 3-necked round-bottom flask. The mixture was hydrogenated at room temperature overnight under hydrogen atmosphere using a hydrogen balloon, filtered through a C6lite pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford tert-butyl 3 -(piperazin- l-yl)piperidine-l -carboxylate (1 g, 59.92%) as a colorless oil. LCMS (ESI, m / z) 270 [M+H]+.

[0419] A solution of tert-butyl 3 -(piperazin- l-yl)piperidine-l -carboxylate (1 g, 3.712 mmol, 1 equiv) and 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylpyrazolo[4,3-d]pyrimidin-7-amine (1.32 g, 3.712 mmol, 1 equiv), DIEA (1.92 g, 14.848 mmol, 4 equiv), K2CO3 (2.05 g, 14.848 mmol, 4 equiv) in DMF (15 mL) was stirred overnight at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (150 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / LNH4HCO3), 50% to 90% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 3-[4-(7-{[(lR)-l- (2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)piperazin-l-yl]piperidine-l- carboxylate (560 mg, 25.59%) as an orange solid. LCMS (ESI, m / z) 589 [M+H]+.

[0420] To a stirred mixture of tert-butyl 3-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo[4,3-d]pyrimidin-5-yl)piperazin-l-yl]piperidine-l-carboxylate (560 mg, 0.950 mmol, 1 equiv) in DCM (8 m ) was added HCl(gas)in 1,4-dioxane (4 m ) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TA), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford N-[(lR)-l-(2,4- dichlorophenyl)ethyl] -2-methyl-5 -[4-(piperidin-3 -yl)piperazin- 1 -yl]pyrazolo [4,3 -d]pyrimidin-7 -amine hydrochloride (460 mg, 92.09%) as a brown solid. ECMS (ESI, m / z) 489 [M+H]+.

[0421] A solution of N-[( 1 R)- 1 -(2,4-dichlorophenyl)ethyl] -2-methyl-5 - [4-(piperidin-3 -yl)piperazin- 1 - yl]pyrazolo[4,3-d]pyrimidin-7-amine hydrochloride (75 mg, 0.143 mmol, 1 equiv) and AcOH (8.59 mg, 0.143 mmol, 1 equiv), glyoxylate (31.76 mg, 0.429 mmol, 3 equiv) in MeOH (2 mb) was stirred for 2 h at room temperature. To the above mixture was added NaBH3CN (26.96 mg, 0.429 mmol, 3 equiv) in portions over 5 min at 0°C. The resulting mixture was stirred for additional 2h at room temperature. The reaction was quenched by the addition of Water (10 mb) at room temperature. The aqueous layer was extracted with EtOAc (3x10 mb). The combined organic layers were washed with brine (10 mb), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPEC with the following conditions to afford {3-[4-(7-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)piperazin-l-yl]piperidin-l- yl}acetic acid (18.8 mg, 24.01%). ECMS (ESI, m / z): 547 [M+H]+.

[0422] Preparative -HPEC condition: Column: xBridge Prep Phenyl 5pm OBD 19*250mm; Mobile Phase A: Water(10mmol / E NH4HCO3), Mobile Phase B: MEOH; Plow rate: 20 mb / min mb / min; Gradient: isocratic 35%B - 65%B IN 20 MIN; Wave Eength: 220 / 254 nm; RTl(min): 13. ’H NMR (400 MHz, DMSO-de) 8 8.55 (d, J= 7.0 Hz, 1H), 7.79 (s, 1H), 7.58 (d, J= 2.2 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.36 (dd, J= 8.5, 2.2 Hz, 1H), 5.56 (t, J= 6.9 Hz, 1H), 4.32 (m, 1H), 4.05 (s, 3H), 3.49-3.44 (m, 6H), 3.3 (s, 3H), 2.99 (m, 1H), 2.42 - 2.17 (m, 6H), 1.72 (s, 2H), 1.53 (s, 1H), 1.47 (d, J= 7.1 Hz, 3H), 1.23 (d, J= 12.9 Hz, 1H).Example 23: N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{4-[(2S)-pyrrolidine-2- carbonyl]piperazin-l-yl}pyrazolo[4,3-d]pyrimidin-7-amine

[0423] Example 23 was prepared using Example 11 procedure. 'H NMR (400 MHz, Chloroform- ) 5 8.33 (s, 1H), 7.59 (s, 1H), 7.44 (d, J= 2.1 Hz, 1H), 7.33 (s, 1H), 7.20 (dd, J= 8.4, 2.1 Hz, 1H), 6.25 (d, J = 6.1 Hz, 1H), 5.67 - 5.62 (m, 1H), 4.74 (d, J= 7.4 Hz, 1H), 4.12 (s, 3H), 3.88 - 3.81 (m, 1H), 3.72 (q, J = 7.8, 6.5 Hz, 4H), 3.61 - 3.36 (m, 4H), 3.33 (dt, J= 11.1, 6.9 Hz, 1H), 2.50 (dq, J= 16.4, 7.1 Hz, 1H), 2.22 - 2.15 (m, 3H), 2.01 (dq, J= 13.2, 7.0 Hz, 2H), 1.90 (dt, J= 12.8, 6.4 Hz, 1H), 1.61 (d, J= 6.9 Hz, 3H). LCMS (ESI, m / z) 503 [M+H]+.Example 24: 5-{4-[(2R)-azetidine-2-carbonyl]piperazin-l-yl}-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]- 2-methylpyrazolo[4,3-d]pyrimidin-7-amine

[0424] Example 24 was prepared using example 11 procedure. 'H NMR (400 MHz, Chloroform- ) 5 8.42 (s, 1H), 7.58 (s, 1H), 7.48 - 7.39 (m, 1H), 7.20 (dd, J= 8.3, 2.2 Hz, 1H), 6.20 (d, J= 6.1 Hz, 1H), 5.78 - 5.49 (m, 1H), 5.11 (t, J= 8.1 Hz, 1H), 4.12 (s, 4H), 3.86 (q, J= 9.0 Hz, 1H), 3.80 - 3.62 (m, 4H), 3.57 (d, J= 7.4 Hz, 1H), 3.20 (t, J= 5.1 Hz, 2H), 3.05 (q, J= 9.5 Hz, 1H), 2.33 (dt, J= 10.5, 5.0 Hz, 1H), 1.61 (d, J = 7.0 Hz, 3H). LCMS (ESI, z): 489 [M+H]+.Example 25: 3-[l'-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin- 5-yl)-[3,4'-bipiperidin]-l-yl]propanoic acid

[0425] Into a 250mL round-bottom flask were added 4-iodopyridine (5 g, 24.390 mmol, 1 equiv), dioxane (50 mL) and H2O (10 mL) at room temperature. To the above mixture was added Pd(dppf)C12 (3.57 g, 4.878 mmol, 0.2 equiv), Na2COs (7.76 g, 73.170 mmol, 3 equiv) and l-(tert-butoxycarbonyl)- 5,6-dihydro-4H-pyridin-3-ylboronic acid (8.31 g, 36.585 mmol, 1.5 equiv). The resulting mixture was stirred for additional 2h at 100°C. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x lOOmL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 0% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 5,6-dihydro-4H-[3,4'-bipyridine]-l- carboxylate (6 g, 94.49%) as a black semi-solid. LCMS (ESI, m / z)'. 261 [M+H]+.

[0426] Into a lOOmL round-bottom flask were added tert-butyl 5,6-dihydro-4H-[3,4'-bipyridine]-l- carboxylate (1 g, 3.841 mmol, 1 equiv) and AcOH (30 mL) at room temperature. To the above mixture was added PtCE (0.17 g, 0.768 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for additional overnight at room temperature under hydrogen atmosphere. The reaction was quenchedwith Water at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl [3,4'- bipiperidine]-l -carboxylate (1 g, 97.00%) as a black solid. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 269 [M+H]+.

[0427] Into a 40mL round-bottom flask were added 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2- methylpyrazolo[4,3-d]pyrimidin-7-amine (200 mg, 0.561 mmol, 1.00 equiv) and ACN (7 mL) at room temperature. To the above mixture was added K2CO3 (155.01 mg, 1.122 mmol, 2 equiv), DIEA (144.96 mg, 1.122 mmol, 2 equiv) and tert-butyl [3,4'-bipiperidine]-l-carboxylate (451.55 mg, 1.683 mmol, 3 equiv). The resulting mixture was stirred for additional overnight at 80°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ACN(3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in tert-butyl I'- (7- { [( 1 R)- 1 -(2,4-dichlorophenyl)ethyl] amino } -2-methylpyrazolo [4,3 -d]pyrimidin-5 -y 1) - [3 ,4'- bipiperidine]-l -carboxylate (50 mg, 15.15%) as a yellow solid. LCMS (ESI, m / z)'. 588 [M+H]+.

[0428] Into a 8mL round-bottom flask were added tert-butyl l'-(7-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)-[3,4'-bipiperidine]-l-carboxylate (50 mg, 0.085 mmol, 1 equiv) and DCM (1 mL) at room temperature. To the above mixture was added HCl(gas)in 1,4-dioxane (1 mL) at 0°C. The resulting mixture was stirred for additional 2h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in 5-{[3,4'-bipiperidin]-l'-yl}-N-[(lR)-l- (2,4-dichlorophenyl)ethyl] -2-methylpyrazolo [4,3 -d]pyrimidin-7-amine (40 mg, 96.40%) as a brown oil. LCMS (ESI, m / z): 488 [M+H]+.

[0429] Into a 8mL round-bottom flask were added 5-{[3,4'-bipiperidin]-l'-yl}-N-[(lR)-l-(2,4- dichlorophenyl)ethyl] -2-methylpyrazolo [4,3 -d]pyrimidin-7-amine (40 mg, 0.082 mmol, 1 equiv) and 2- methylpropan-2-ol (2 mL) at room temperature. To the above mixture was added EtsN (8.29 mg, 0.082 mmol, 1 equiv) and prop-2 -enoic acid (11.80 mg, 0.164 mmol, 2 equiv). The resulting mixture was stirred for additional Ih at 80°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The crude product (50mg) was purified by Prep- HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS20*250 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mL / min mL / min; Gradient: 60% B to 90% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.5) to afford 3-[l'-(7- {[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)-[3,4'-bipiperidin]-l- yl]propanoic acid; formic acid (14.5 mg, 28.73%). LCMS (ESI, m z) 606 [M+H]+. 'HNMR (400 MHz, DMSO-de) <5 8.48 (<7, J= 6.8 Hz, IH), 7.76 (s, IH), 7.57 (d, J= 2.1 Hz, IH), 7.48 (t / , J= 8.5 Hz, IH), 7.37 - 7.31 (m, IH), 5.52 (t, J= 6.9 Hz, IH), 4.51 (m, IH), 4.04 (s, 3H), 3.51 - 3.15 (m, 6H), 2.84 (s, 2H), 2.34 ( , J = 7.3 Hz, 2H), 1.99 - 1.20 (m, 10H), 1.0 - 0.72 (m, 2H).Example 26: (4-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-5-yl)piperazin-l-yl)((S)-tetrahydrofuran-3-yl)methanone

[0430] Example 26 was prepared using example 11 procedure. ’H NMR (400 MHz, DMSO-de) 5 8.63 (d, J = 7.0 Hz, 1H), 7.83 (s, 1H), 7.62 - 7.50 (m, 2H), 7.37 (dd, J = 8.5, 2.2 Hz, 1H), 5.60 (t, J = 7.0 Hz, 1H), 4.06 (s, 3H), 3.87 (t, J = 8.2 Hz, 1H), 3.74 - 3.65 (m, 3H), 3.57 (s, 3H), 3.52 - 3.36 (m, 2H), 3.32 (s, 4H), 2.01 (qd, J = 6.8, 2.9 Hz, 2H), 1.49 (d, J = 7.0 Hz, 3H). LCMS (ESI, z): 504 [M+H]+.Example 27 : 3- {3- [4-(7-{ [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}-2-methylpyrazolo [4,3- d]pyrimidin-5-yl)piperazin-l-yl]piperidin-l-yl}propanoic acid

[0431] Example 27 was prepared using Example 22 and Example 25 procedures. ’H NMR (400 MHz, Chloroform-d) 5 9.51 (brs, 3H), 8.42 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.42 (t, J = 1.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 8.4, 2.1 Hz, 1H), 6.50 (s, 1H), 5.63 (t, J = 6.4 Hz, 1H), 4.09 (s, 3H), 3.74 (d, J = 14.6 Hz, 4H), 3.23 (s, 1H), 3.09 (d, J = 11.3 Hz, 1H), 2.90 (td, J = 6.4, 3.5 Hz, 2H), 2.71 (s, 1H), 2.66 - 2.57 (m, 4H), 2.53 (s, 2H), 2.43 - 2.25 (m, 2H), 1.93 (d, J = 13.1 Hz, 2H), 1.70 (d, J = 13.2 Hz, 1H), 1.62 (d, J = 7.0 Hz, 3H), 1.46 - 1.38 (m, 1H). LCMS (ESI, m / z): 561 [M+H]+.Example 28: N-((R)-l-(2,4-dichlorophenyl)ethyl)-2-methyl-5-(4-((S)-piperidin-3-yl)piperazin-l-yl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine

[0432] A solution ofN-((R)-l-(2,4-dichlorophenyl)ethyl)-2-methyl-5-(4-((S)-piperidin-3-yl)piperazin- l-yl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (70 mg, 0.143 mmol, 1 equiv), 2-iodoethan-l-ol (73.78 mg, 0.429 mmol, 3 equiv) and EtsN (72.36 mg, 0.715 mmol, 5 equiv) in DCM (3 mL) was stirred for 2 h at 60 °C under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep-HPLC with the following conditions to afford 2-((S)-3-(4-(7-(((R)- 1 -(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo [4,3 -d]pyrimidin-5 -yl)piperazin- 1 - yl)piperidin-l-yl)ethan-l-ol (16.5 mg, 21.63%). LCMS (ESI, m / z): 533 [M+H]+. ’H NMR (400 MHz, DMSO-de) 5 8.53 (d, J = 7.0 Hz, 1H), 7.78 (s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.39 - 7.32 (m, 1H), 5.55 (t, J = 6.9 Hz, 1H), 4.32 (s, 1H), 4.05 (s, 3H), 3.32 (s, 6H), 2.89 (s, 1H), 2.75 (d, J = 10.7 Hz, 1H), 2.38 (d, J = 6.2 Hz, 2H), 2.32 (s, 6H), 1.77 (dd, J = 32.2, 11.4 Hz, 4H), 1.62 (d, J = 12.7 Hz, 1H), 1.47 (d, J = 7.1 Hz, 4H), 1.40 (s, 1H), 1.09 (s, 1H).Example 29: (5R)-5-[4-(5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-3-methyl-4-oxopyrido[2,3- d]pyrimidin-7-yl)piperazine-l-carbonyl]pyrrolidin-2-one

[0433] A solution of methyl 2-amino-4,6-dichloropyridine-3-carboxylate (500 mg, 2.262 mmol, 1 equiv) in THF (6 mL) was treated with AlMes ( .66 mL, 11.310 mmol, 5.00 equiv) for 2 min at 0 °C. The resulting mixture was stirred for additional 20 min at 0°C under nitrogen atmosphere, then added methanamine hydrochloride (458. 18 mg, 6.786 mmol, 3 equiv) for 2 min at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional 3 h at 60 °C . The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ACN (7mL). The residue was dissolved in H2O (7mL). The resulting solution was dried Na2SC>4. The residue was purified by silica gel column chromatography, eluted with EA to afford 2-amino-4,6-dichloro-N-methylpyridine-3- carboxamide (490 mg, 98.44%) as a white solid. LCMS (ESI, m / z) 220 [M+H]+

[0434] A solution of 2-amino-4,6-dichloro-N-methylpyridine-3-carboxamide (100 mg, 0.454 mmol, 1 equiv) in (diethoxymethoxy)ethane (3 mL) was treated with AcOH (0.5 mL, 8.726 mmol, 19.20 equiv) for 1 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 5,7-dichloro-3-methylpyrido[2,3-d]pyrimidin-4-one (60 mg, 57.39%) as a yellow solid. LCMS (ESI, m / z): 231 [M+H]+

[0435] A solution of 5,7-dichloro-3-methylpyrido[2,3-d]pyrimidin-4-one (116 mg, 0.504 mmol, 1 equiv) in dioxane (2 mL) was treated with (lR)-l-(2,4-dichlorophenyl)ethanamine (95.84 mg, 0.504 mmol, 1.0 equiv), DIEA (195.51 mg, 1.512 mmol, 3 equiv) for 5 min at room temperature. The resulting mixture was stirred for additional 3 at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3),0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 7-chloro-5-{[(lR)-l- (2,4-dichlorophenyl)ethyl]amino}-3-methylpyrido[2,3-d]pyrimidin-4-one (67 mg, 34.63%) as a white solid. LCMS (ESI, m / z): 384 [M+H]+

[0436] A solution of 7-chloro-5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-3-methylpyrido[2,3- d]pyrimidin-4-one (67 mg, 0.175 mmol, 1 equiv) in DMSO (1.5 mL) was treated with (5R)-5- (piperazine-l-carbonyl)pyrrolidin-2-one (41.33 mg, 0.210 mmol, 1.2 equiv), CS2CO3 (284.50 mg, 0.875 mmol, 5 equiv) for 2 min at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 4 h at 120°C.The crude product (67mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min mL / min; Gradient: 24% B to 56% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.5) to afford (5R)-5-[4-(5-{[(lR)-l-(2,4- dichlorophenyl)ethyl] amino } -3 -methyl -4-oxopyrido [2,3 -d]pyrimidin-7 -yl)piperazine- 1 - carbonyl]pyrrolidin-2-one (8.3 mg, 8.71%). LCMS (ESI, z): 545 [M+H]+. 'H NMR (400 MHz, DMSO-de) 5 9.42 (d, J= 6.6 Hz, 1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.66 (d, J= 1.8 Hz, 1H), 7.44 (m, 2H), 5.38 (s, 1H), 5.01 (t, J= 6.7 Hz, 1H), 4.57 (dd, J= 8.9, 3.9 Hz, 1H), 3.57 (dd, J= 10.0, 5.3 Hz, 4H), 3.52 (s, 2H), 3.48 - 3.41 (m, 1H), 3.23 (s, 3H), 2.38 - 2.24 (m, 1H), 2.10 (dd, J= 9.8, 6.4 Hz, 2H), 1.96 - 1.86 (m, 1H), 1.54 (d, J = 6.6 Hz, 3H).Example 30: (R)-5-(4-(7-((R)-l-(2,4-dichlorophenyl)ethoxy)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-5-yl)piperazine-l-carbonyl)pyrrolidin-2-one

[0437] Example 30 was prepared using procedure example 19 from (R)-5-(piperazine-l- carbonyl)pyrrolidin-2-one as starting material. 'H NMR (400 MHz, DMSO-de) 5 8.06 (s, 1H), 7.81 - 7.63 (m, 2H), 7.53 - 7.40 (m, 2H), 6.58 - 6.47 (m, 1H), 4.60 - 4.52 (m, 1H), 4.10 (s, 3H), 3.56 (m, 8H), 2.30 - 2.11 (m, 3H), 1.89 (s, 1H), 1.67 (d, J= 6.6 Hz, 3H). LCMS:(ESI, m / z):518[M+H]+.Example 31: (2R)-3-[(3R)-3-[l-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3- d]pyrimidin-5-yl)azetidin-3-yl]piperidin-l-yl]propane-l,2-diol

[0438] To a stirred solution of tert-butyl 3-[(3R)-piperidin-3-yl]azetidine-l-carboxylate (1.2 g, 4.993 mmol, 1 equiv) and TEA (1.52 g, 14.979 mmol, 3 equiv) in DCM (20 mL) was added allyl chlorocarbonate (0.90 g, 7.490 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of Water (50 mL) at room temperature. The aqueous layer was extracted with CH2CI2 (3x50 mL). The combined organic layers were washed with brine (1x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford prop-2-en-l-yl (3R)-3- [l-(tert-butoxycarbonyl)azetidin-3-yl]piperidine-l-carboxylate (1.3 g, 80.26%) as a colorless oil.. LCMS (ESI, m / z): 325 [M+H]+.

[0439] To a stirred solution of prop-2-en-l-yl (3R)-3-[l-(tert-butoxycarbonyl)azetidin-3-yl]piperidine- 1-carboxylate (20 mg, 0.062 mmol, 1 equiv) in DCM (20 mL) was added HCl(gas)in 1,4-dioxane (10 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, to afford prop-2-en-l-yl (3R)-3-(azetidin-3-yl)piperidine-l-carboxylate hydrochloride (1 g, 95.70%) as a colorless oil. LCMS (ESI, m / z) 225 [M+H]+.

[0440] A mixture of prop-2-en-l-yl (3R)-3-(azetidin-3-yl)piperidine-l-carboxylate hydrochloride (650 mg, 2.493 mmol, 1 equiv) and 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylpyrazolo[4,3- d]pyrimidin-7-amine (889.00 mg, 2.493 mmol, 1 equiv), K2CO3 (7.479 mmol, 3 equiv) in DMF (10 mL) was stirred overnight at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (50mL) at room temperature. The aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford prop-2-en-l-yl (3R)-3-[l-(7-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5-yl)azetidin-3-yl]piperidine-l- carboxylate (900 mg, 66.31%) as an off-white solid. LCMS (ESI, m / z): 544 [M+H]+.

[0441] A solution of prop-2-en-l-yl (3R)-3-[l-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2- methylpyrazolo[4,3-d]pyrimidin-5-yl)azetidin-3-yl]piperidine-l-carboxylate (10 mg, 0.018 mmol, 1 equiv) and pyrrolidine (705.38 mg, 9.918 mmol, 6 equiv), Pd(PPh3)4 (382.03 mg, 0.331 mmol, 0.2 equiv) in THF (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of Water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x50 mL).The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 70% gradient in 10 min; detector, UV 254 nm.to afford N- [(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{3-[(3R)-piperidin-3-yl]azetidin-l-yl}pyrazolo[4,3- d]pyrimidin-7-amine (600 mg, 78.84%) as a yellow solid. LCMS (ESI, m / z): 460 [M+H]+.

[0442] A solution ofN-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{3-[(3R)-piperidin-3- yl]azetidin-l-yl}pyrazolo[4,3-d]pyrimidin-7-amine (60 mg, 0.130 mmol, 1 equiv) and (+)-glycidol (28.96 mg, 0.390 mmol, 3 equiv), K2CO3 (54.03 mg, 0.390 mmol, 3 equiv) in DMF (2 mL) was stirred for 2 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (2 mL) at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column,C 18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions to afford (2R)-3- [(3R)-3-[l-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin-5- yl)azetidin-3-yl]piperidin-l-yl]propane-l,2-diol (20.3 mg, 29.14%). LCMS (ESI, m / z): 504 [M+H]+. 'H NMR (400 MHz, DMSO-de) 88.53 (d, J= 7.0 Hz, 1H), 7.79 (s, 1H), 7.61 - 7.46 (m, 2H), 7.36 (dd, J = 8.4, 2.2 Hz, 1H), 5.58 (q, J= 7.3 Hz, 1H), 4.52 (s, 1H), 4.32 (dd, J= 9.7, 4.4 Hz, 1H), 4.05 (s, 3H), 3.80 (dt, J= 27.5, 8.3 Hz, 2H), 3.57 (dd, J= 15.0, 7.3 Hz, 3H), 2.81 - 2.65 (m, 2H), 2.38 - 2.15 (m, 4H), 1.91 (t, J= 10.6 Hz, 1H), 1.59 (d, J= 11.8 Hz, 4H), 1.47 (d, J= 7.1 Hz, 5H), 0.82 (d, J= 34.6 Hz, 1H).Example 32: 2-((R)-3-(l-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo[4,3- d] pyrimidin-5-yl)azetidin-3-yl)piperidin-l-yl)acetic acid

[0443] Example 32 was prepared using example 31 and Example 22 procedures. ’H NMR (400 MHz, DMSO-de) 5 8.55 (d, J = 6.6 Hz, 1H), 7.79 (s, 1H), 7.61 - 7.48 (m, 2H), 7.36 (dd, J = 8.5, 2.2 Hz, 1H), 5.77 - 5.47 (m, 1H), 4.04 (s, 3H), 3.88 - 3.81 (m, 3H), 3.75 (d, J = 7.9 Hz, 2H), 3.16 (s, 2H), 3.04 (s, 2H), 2.40 (s, 1H), 2.28 (s, 1H), 2.13 (s, 1H), 1.64 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H), 0.85 (s, 1H). LCMS (ESI, m / z): 518.44 [M+H]+.Example 33: 2-((R)-3-(l-(4-((R)-l-(2,4-dichlorophenyl)ethoxy)pteridin-2-yl)azetidin-3-yl)piperidin- l-yl)ethan-l-ol

[0444] Example 33 was prepared using Example 19 procedures from 2,4-dichloropteridine as starting material. 'HNMR (400 MHz, Chloroform-d) 5 8.77 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.65 (q, J = 6.5 Hz, 1H), 4.37 - 3.55 (m, 6H), 2.87 (d, J = 33.9 Hz, 2H), 2.53 (d, J = 54.0 Hz, 3H), 2.12 (s, 1H), 1.80 (dd, J = 6.6, 2.1 Hz, 6H), 0.95 (s, 1H). LCMS (ESI, m / z 503 [M+H]+.Example 34: 5- { [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}-l [(2R)-pyrrolidine-2-carbonyl] -3', 6'- dihydro-lH,2'H- [3,4'-bipyridin] -6-one

[0445] To a stirred mixture of 5-bromo-3-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-I- methylpyridin-2-one (400 mg, 1.064 mmol, 1 equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate (493.32 mg, 1.596 mmol, 1.5 equiv) in 1,4-dioxane (30 mL) and H2O (6 mL)were added Pd(dppf)C12.CH2C12 (173.29 mg, 0.213 mmol, 0.20 equiv) and Na2COs (338.19 mg, 3.192 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of Water (50mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-l-methyl-6-oxo-3',6'- dihydro-2'H-[3,4'-bipyridine]-T-carboxylate (330 mg, 64.85%) as a light brown solid.

[0446] To a stirred solution of tert-butyl 5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-l-methyl-6- oxo-3', 6'-dihydro-2'H-[3,4'-bipyridine]-T-carboxylate (300 mg, 0.627 mmol, 1 equiv) in DCM (12 mL) was added HCl(gas)in 1,4-dioxane (6 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in 5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-l- methyl-r,2',3',6'-tetrahydro-[3,4'-bipyridin]-6-one (230 mg, 87.26%) as a light yellow solid. LCMS (ESI, m / z): 378.3 [M+H]+.

[0447] To a stirred mixture of 5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-l-methyl-T,2',3',6'- tetrahydro-[3,4'-bipyridin]-6-one (150 mg, 0.397 mmol, 1 equiv) and (2R)-l-(tert- butoxycarbonyl)pyrrolidine-2 -carboxylic acid (128.02 mg, 0.596 mmol, 1.5 equiv) in DCM (9 mL) were added HATU (226.15 mg, 0.596 mmol, 1.50 equiv) and DIEA (256.24 mg, 1.985 mmol, 5.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 50% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl (2R)-2-(5-{[(lR)-l-(2,4- dichlorophenyl)ethyl]amino}-l-methyl-6-oxo-3',6'-dihydro-2'H-[3,4'-bipyridine]-T-carbonyl)pyrrolidine- 1-carboxylate (190 mg, 83.26%) as a yellow solid. LCMS (ESI, m / zy 575.53 [M+H]+.

[0448] To a stirred solution of tert-butyl (2R)-2-(5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-l- methyl-6-oxo-3',6'-dihydro-2'H-[3,4'-bipyridine]-T-carbonyl)pyrrolidine- 1-carboxylate (100 mg, 0.174 mmol, 1 equiv) in DCM (6 mL) was added HCl(gas)in 1,4-dioxane (3 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD Cl 8 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(0.1%LA), Mobile Phase B: ACN; Plow rate: 60 mL / min mL / min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.56) to afford 5-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-r-[(2R)-pyrrolidine-2-carbonyl]-3',6'-dihydro- lH,2'H-[3,4'-bipyridin]-6-one (24.6 mg, 30.23%). LCMS (ESI, m / z): 461.39 [M+H]+. ’H NMR (400 MHz, DMSO-de) 5 8.29 (s, 1H), 7.61 (t, J = 1.8 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.4, 2.1Hz, 1H), 7.00 (dd, J = 6.4, 2.2 Hz, 1H), 6.10 (dd, J = 7.5, 2.6 Hz, 1H), 5.98 (d, J = 2.2 Hz, 1H), 5.69 (dt, J = 14.8, 3.5 Hz, 1H), 4.77 (p, J = 6.8 Hz, 1H), 4.27 - 3.97 (m, 3H), 3.80 - 3.50 (m, 2H), 3.46 (s, 3H), 3.09 (dt, J = 10.7, 6.3 Hz, 1H), 2.86 (ddt, J = 10.2, 7.1, 4.4 Hz, 1H), 2.42 - 2.07 (m, 3H), 1.84 - 1.56 (m, 3H), 1.48 (d, J = 6.7 Hz, 3H).Example 35: (2S)-3- [(3R)-3- [1 - (7- { [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}-2-methylpyrazolo [4,3- d]pyrimidin-5-yl)azetidin-3-yl]piperidin-l-yl]propane-l,2-diol

[0449] Example 35 was prepared using Example 31 procedures. ’H NMR (400 MHz, DMSO-de) 5 8.54 (d, J = 7.1 Hz, 1H), 7.79 (s, 1H), 7.58 - 7.52 (m, 1H), 7.36 (dd, J = 8.4, 2.2 Hz, 1H), 5.72 - 5.51 (m, 1H), 4.56 (s, 1H), 4.23 (s, 1H), 4.05 (s, 3H), 3.83 (t, J = 8.2 Hz, 1H), 3.62 - 3.46 (m, 1H), 3.32 (s, 4H), 2.75 - 2.63 (m, 2H), 2.33 - 2.17 (m, 3H), 1.96 (t, J = 12.5 Hz, 1H), 1.70 - 1.21 (m,10H), 0.80 (d, J = 15.0 Hz, 1H). LCMS (ESI, m / z): 548 [M+H]+.Example 36: l-[4-(7-{[(lR)-l-(2,4-dichlorophenyl)ethyl]amino}-2-methylpyrazolo[4,3-d]pyrimidin- 5-yl)piperazin-l-yl]-2-(dimethylamino)ethanone

[0450] Example 36 was prepared using Example 11. 'H NMR (400 MHz, DMSO-de) 8 8.63 (d, J = 7.0 Hz, 1H), 7.83 (s, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.52 (s, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 5.67 - 5.51 (m, 1H), 4.06 (s, 3H), 3.55 (s, 4H), 3.45 (d, J = 5.6 Hz, 4H), 3.07 (d, J = 3.0 Hz, 2H), 2.18 (s, 6H), 1.49 (d, J = 7.0 Hz, 3H). LCMS (ESI, m / z): 491 [M+H]+.Example 37 : (2S)-3- [(3R)-3- [l-(7-{ [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}-2-methylpyrazolo [4,3- d]pyrimidin-5-yl)azetidin-3-yl]piperidin-l-yl]propane-l,2-diol

[0451] Example 37 was prepared using Example 31 procedures. ’H NMR (400 MHz, DMSO-de) 8 8.53 (d, J = 7.0 Hz, 1H), 7.79 (s, 1H), 7.65 - 7.46 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 5.58 (s, 1H), 4.53 (s, 1H), 4.33 (d, J = 4.8 Hz, 1H), 4.05 (s, 3H), 3.80 (d, J = 27.1 Hz, 2H), 3.58 (s, 2H), 2.82 - 2.65 (m, 2H), 2.37 - 2.17 (m, 4H), 1.93 (t, J = 10.8 Hz, 1H), 1.67 - 1.22 (m, 9H), 0.77 (d, J = 14.9 Hz, 1H). LCMS (ESI, m / z): 534 [M+H]+.Example 38: N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methyl-5-{l-[(2R)-pyrrolidine-2- carbonyl]piperidin-4-yl}pyrazolo[4,3-d]pyrimidin-7-amine

[0452] To a stirred mixture of Example 18 (40 mg) in MeOH (3 mL) was added PtO2 (4 mg) under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under hydrogen atmosphere. The resulting mixture was fdtered, the fdter cake was washed with MeOH (10 mL) (1x20 mL). The fdtrate was concentrated under reduced pressure. This resulted product wash purified on Prep-HPLC. ’H NMR (400 MHz, DMSO-de) 8 8.70 (t, J= 6.7 Hz, 1H), 8.24 (d,J= 25.0 Hz, 1H), 7.59 - 7.43 (m, 2H), 7.35 (dt, J= 8.6, 2.7 Hz, 1H), 5.66 (p, J= 1 A Hz, 1H), 4.28 (t, J = 17.3 Hz, 1H), 4.15 (d, J= 2.4 Hz, 3H), 4.04 (dt, J= 22.1, 8.0 Hz, 1H), 3.90 - 3.77 (m, 1H), 3.09 (dt, J =17.6, 8.3 Hz, 2H), 2.89 - 2.65 (m, 3H), 2.11 (td, J= 14.8, 7.5 Hz, 1H), 1.76 (tq, J= 19.8, 11.7, 9.0 Hz, 3H), 1.65 - 1.53 (m, 1H), 1.49 (d, J= 7.0 Hz, 3H), 1.46 - 1.30 (m, 1H). LCMS (ESI, z): 502 [M+H]+.Example 39: (4-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-5-yl)-3,6-dihydropyridin-l(2H)-yl)((R)-4-methylmorpholin-3-yl)methanone

[0453] Example 39 was prepared using Example 18 procedures. ’H NMR (400 MHz, DMSO-de) 5 8.76 (d, J = 7.3 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 6.95 (s, 1H), 5.77 (q, J = 8.4, 7.5 Hz, 1H), 4.68 - 4.36 (m, 1H), 4.20 - 4.12 (m, 3H), 4.03 (d, J = 19.7 Hz, 1H), 3.88 (s, 1H), 3.70 (q, J = 7.9, 4.6 Hz, 2H), 3.57 (q, J = 11.1, 9.4 Hz, 2H), 3.50 - 3.40 (m, 1H), 3.23 (d, J = 9.1 Hz, 1H), 2.79 (d, J = 11.4 Hz, 1H), 2.55 (s, 1H), 2.46 (s, 1H), 2.23 (td, J = 11.2, 3.1 Hz, 1H), 2.12 (d, J = 14.8 Hz, 3H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (ESI, m / z): 530.20 [M+H],Example 40: (R)-l-(4-(7-((l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo [4,3- d]pyrimidin-5-yl)piperidin-l-yl)-3-(dimethylamino)propan-l-one

[0454] Example 40 was prepared using Example 38 procedures. LCMS (ESI, m / z): 504.20 [M+H],Example 41: (S)-4-((R)-3-(l-(7-(((R)-l-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-5-yl)azetidin-3-yl)piperidin-l-yl)butane-l,3-diol

[0455] Example 41 was prepared using Example 31 procedures. 'H NMR (400 MHz, Chloroform- ) 5 7.54 (s, 1H), 7.40 (dd, J= 3.2, 2.2 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 7.19 (dd, J= 8.4, 2.1 Hz, 1H), 6.07 (s, 1H), 5.67 (s, 1H), 4.08 (s, 4H), 3.94 (dq, J= 12.6, 7.9 Hz, 2H), 3.88 - 3.72 (m, 3H), 3.58 (d, J= 6.6 Hz, 2H), 2.90 (d, J= 8.4 Hz, 1H), 2.74 (dd, J= 212, 10.9 Hz, 1H), 2.43 - 2.20 (m, 4H), 1.97 (q, J =11.6, 10.9 Hz, 1H), 1.60 (dd, J= 7.0, 2.5 Hz, 9H), 0.89 (d, J= 11.4 Hz, 1H). LCMS:(ESI, m / z): 548[M+H]+.Example 42: 2- [(3R)-3- [l-(7- { [(lR)-l-(2,4-dichlorophenyl)ethyl] amino}-2-methylpyrazolo [4,3- d]pyrimidin-5-yl)azetidin-3-yl]piperidin-l-yl]propane-l,3-diol

[0456] To a stirred mixture of tert-butyl 3-[(3R)-piperidin-3-yl]azetidine-l-carboxylate (300 mg, 1.248 mmol, 1 equiv) and 2,2-dimethyl-l,3-dioxan-5-one (812.22 mg, 6.240 mmol, 5 equiv) in DCM (3 mL) were added sodium cyanoboranuide (392.20 mg, 6.240 mmol, 5 equiv) and AcOH (74.96 mg, 1.248 mmol, 1 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirredat room temperature for 3h under air atmosphere. The reaction was quenched by the addition of Water (30mL) at room temperature. The resulting mixture was extracted with EtOAc (9 x lOmL). The combined organic layers were washed with brine (10x3 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 40% to 90% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 3-[(3R)- l-(2,2-dimethyl-l,3-dioxan-5-yl)piperidin-3-yl]azetidine-l-carboxylate (130 mg, 29.38%) as a white solid. LCMS (ESI, z): 355[M+H]+.

[0457] To a stirred mixture of tert-butyl 3-[(3R)-l-(2,2-dimethyl-l,3-dioxan-5-yl)piperidin-3- yl]azetidine-l -carboxylate (130 mg, 0.367 mmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL, 13.463 mmol, 36.71 equiv) dropwise at 0°C under air atmosphere. The resulting mixture was stirred at room temperature for Ih under air atmosphere. The reaction was quenched by the addition of Water (20mL) at room temperature. The reaction was quenched by the addition of Water (20mL) at room temperature. The resulting mixture was extracted with EtOAc (6 x lOmL). The combined organic layers were washed with brine (10x2 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]propane-l,3-diol (70 mg, 89.07%) as a white solid. LCMS (ESI, m / z . 215+H]+.

[0458] To a stirred mixture of 2-[(3R)-3-(azetidin-3-yl)piperidin-l-yl]propane-l,3-diol (40 mg, 0.187 mmol, 1 equiv) and 5-chloro-N-[(lR)-l-(2,4-dichlorophenyl)ethyl]-2-methylpyrazolo[4,3-d]pyrimidin-7- amine (99.85 mg, 0.280 mmol, 1.5 equiv) in DMF (1 mL) was added K2CO3 (128.98 mg, 0.935 mmol, 5 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 1.5 h at 120°C under air atmosphere. The reaction was quenched by the addition of Water (lOmL) at room temperature. The resulting mixture was extracted with EtOAc ( 30 mL). The combined organic layers were washed with brine (2x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (XI); wherein:R2is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R3is halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each R4is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0, 1, 2, or 3;Z is O, S, or CH2;Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R13is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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; or two R13on the same atom are taken together to form an oxo; r is 1, 2, 3, 4, 5, 6, 7, or 8;Ring D is heterocycloalkyl; each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R14on the same atom are taken together to form an oxo; t is 0, 1, 2, 3, or 4;L1is absent or -C(=O)-;Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R15is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 R15a; or two R15on the same atom are taken together to form an oxo; each R15ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 two R15aon the same atom are taken together to form an oxo; u is 1, 2, 3, 4, 5, 6, 7, or 8; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, Ci- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -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 independently optionally substituted with one or more R;L is absent or Ci-Csalkylene optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -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, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci- Csaminoalkyl, Ci-Cdictcroalkyl. C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is O.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is phenyl or a 5- or 6-membered heteroaryl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is pyridyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R13is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein r is 1 or 2.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is absent.

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (XI) is a compound of Formula (Xia), (Xlb), (XIc), (Xld), or (Xie):Formula (Xld); Formula (Xie); wherein:R2is halogen;R3is halogen;R13a, R13b, R13C, and R13dare independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, Ci- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; and / or R13aand R13bare taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R; and / or R13band R13care taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;Ring D is 4- to 6-membered heterocycloalkyl; each R14is independently halogen, -CN, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R14on the same atom are taken together to form an oxo; t is 0, 1, or 2;Ring E is 4- to 6-membered heterocycloalkyl; each R15is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a; or two R15on the same atom are taken together to form an oxo; each R15ais independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl; u is 1, 2, or 3; each Rais independently C1-C6alkyl or C1-C6haloalkyl; each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, -NHCi-Galkyl. -N(Ci-C3alkyl)2, Ci- Csalkyl, or Ci-Cshaloalkyl; and / or two R on the same atom are taken together to form an oxo.

12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R13a, R13b, R13c, and R13dare independently hydrogen, halogen, -CN, or Ci- C6alkyl.

13. The compound of claim 11 or 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13a, R13b, R13c, and R13dare independently hydrogen or C1-C6alkyl.

14. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13aand R13bare taken together to form a cycloalkyl independently optionally substituted with one or more R.

15. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13aand R13bare independently hydrogen, halogen, -CN, or C1-C6alkyl; or R13aand R13bare taken together to form a cycloalkyl independently optionally substituted with one or more R.

16. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13dis hydrogen or C1-C6alkyl.

17. The compound of any one of claims 11-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring D is azetidinyl.

18. The compound of any one of claims 11-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring E is piperidinyl or morpholinyl.

19. The compound of any one of claims 11-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring E is piperidinyl.

20. The compound of any one of claims 11-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently C1-C6alkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R15a.

21. The compound of any one of claims 11-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently C1-C6hydroxyalkyl.

22. The compound of any one of claims 11-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently cycloalkyl independently optionally substituted with one or more R15a.

23. The compound of any one of claims 11-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently 3- to 6-membered cycloalkyl independently optionally substituted with one or more R15a.

24. The compound of any one of claims 11-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently cyclobutyl independently optionally substituted with one or more R15a.

25. The compound of any one of claims 11-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15ais independently halogen, -OH, -ORa, -C(=O)ORb, Ci- C6alkyl, or C1-C6hydroxyalkyl.

26. The compound of any one of claims 11-25, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R15ais independently -C(=O)ORbor C1-C6alkyl.

27. The compound of any one of claims 11-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein u is 1 or 2.

28. The compound of any one of claims 11-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein29. The compound of any one of claims 11-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is chloro.

30. The compound of any one of claims 11-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is chloro.

31. A compound selected from a compound found in the specification (Table 1), or a pharmaceutically acceptable salt or solvate thereof.

32. A pharmaceutical composition comprising the compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

33. A method of treating a CCR4-mediated disease in a subject, comprising administering a compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof to the subject.

34. The method of claim 33, wherein the disease is inflammatory bowel disease, Crohn’s disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer’s disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, or granuloma development.

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