Protein tyrosine phosphatase inhibitor combinations

Abstract

Provided herein are methods using a combination comprising a protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1), and an additional therapeutic agent for treating diseases favorably responsive to PTPN1 or PTPN2 inhibitor treatment, e.g., a cancer or a metabolic disease.

Description

PROTEIN TYROSINE PHOSPHATASE INHIBITOR COMBINATIONSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 517,196 filed August 2, 2023; which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies) have been shown to be effective in treating in a variety of cancers, dramatically improving outcomes in some populations refractory to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance continue to limit the patient populations who could benefit from checkpoint blockade.

[0003] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phospho-tyrosine specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is controlled post-transcriptionally by the existence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form which has a C-terminal ER retention motif. The 45 kDa isoform can passively transfuse into the cytosol under certain cellular stress conditions. Both isoforms share anN-terminal phospho-tyrosine phosphatase catalytic domain. PTPN2 negatively regulates signaling of non- receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lek). As a critical negative regulator of the JAK- STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also called PTP1B), and shares similar enzymatic kinetics. Data from a loss of function in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model show that deletion of Ptpn2 gene in tumor cells improved response to the immunotherapy regimen of a GM-CSF secreting vaccine (GV AX) plus PD-1 checkpoint blockade. Loss of PTPN2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth suppression. The same screen also revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under immunotherapy selective pressure, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[0004] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase- IB (PTP1B), has been shown to play a key role in insulin and leptin signaling and is a primarySUBSTITUTE SHEET (RULE 26)mechanism for down-regulating both the insulin and leptin receptor signaling pathways. Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet. Thus, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.SUMMARY OF THE INVENTION

[0005] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of:(a) a compound of Formula (I):Formula (I), as disclosed herein; and (b) an additional therapeutic agent.

[0006] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (III):Formula (III) as disclosed herein; and(b) an additional therapeutic agent.

[0007] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.

[0008] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.

[0009] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.

[0010] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.SUBSTITUTE SHEET (RULE 26)

[0011] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.

[0012] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.

[0013] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.

[0014] In some embodiments, the additional therapeutic agent is an anticancer agent.

[0015] In some embodiments, the additional therapeutic agent is an immunotherapeutic agent.

[0016] In some embodiments, the immune checkpoint inhibitor is atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab.

[0017] In some embodiments, the additional therapeutic agent is chemotherapeutic agent.

[0018] In some embodiments, the chemotherapeutic agent is cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or a combination thereof.

[0019] In some embodiments, the additional therapeutic agent is radiation therapy (RT).

[0020] In some embodiments, the additional therapeutic agent is a VEGF inhibitor.

[0021] In some embodiments, the VEGF inhibitor is aflibercept, axitinib, bevacizumab, cabozatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ramucirumab, regorafenib, sorafenib, sunitunib, tivozanib, or vandetanib.

[0022] In some embodiments, the additional therapeutic agent is a bi-specific antibody or T cell engager.

[0023] In some embodiments, the T cell engager is bintrafusp alfa, blinatumomab, elranatamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR-1701, tebentafusp, or teclistamab.

[0024] In some embodiments, the additional therapeutic agent is CAR-T cell therapy.

[0025] In some embodiments, the CAR-T cell therapy is axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel.

[0026] In some embodiments, the additional therapeutic agent is a KRAS G12C inhibitor.

[0027] In some embodiments, the KRAS G12C inhibitor is adagrasib or sotorasib.

[0028] In some embodiments, the additional therapeutic agent is a cancer vaccine.

[0029] In some embodiments, the cancer vaccine is BCG, sipuleucel-T, or talimogene laherparepvec (T- VEC).

[0030] In some embodiments, the additional therapeutic agent is a HER2-targeted therapy.

[0031] In some embodiments, the HER2-targeted therapy is lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab emtansine (T-DM1), trastuzumab, tucatinib, or zongertinib.

[0032] In some embodiments, the additional therapeutic agent is a CXCR4 antagonist.SUBSTITUTE SHEET (RULE 26)

[0033] In some embodiments, the CXCR4 antagonist is plerixafor.INCORPORATION BY REFERENCE

[0034] 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

[0035] 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.

[0036] 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 manna- 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.

[0037] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0038] “oxo” refers to =O.

[0039] “Amine” refers to -NH2;

[0040] “Hydroxy” refers to -OH;

[0041] “Carboxyl” refers to -COOH.

[0042] “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-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n- butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl andSUBSTITUTE SHEET (RULE 26)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 aCi-Cio alkyl. In some embodiments, the alkyl is a C1-C6alkyl. In some embodiments, the alkyl is a Ci- Cs alkyl. In some embodiments, the alkyl is aCi-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is 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.

[0043] “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-C6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is 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.

[0044] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is 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-5-SUBSTITUTE SHEET (RULE 26)or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0045] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is 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.

[0046] “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.

[0047] “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, fluor anthenyl, 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.

[0048] “Arylene” refers to a divalent aryl as defined above. Unless stated otherwise specifically in the specification, an arylene 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 arylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the arylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the arylene is optionally substituted with halogen.SUBSTITUTE SHEET (RULE 26)

[0049] “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. l]hexyl, bicyclo[2.2.1]heptyl, bi cyclo[2.2.2] octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimeihyl-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, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. 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.

[0050] “Cycloalkylene” refers to a divalent cycloalkyl as defined above. Unless stated otherwise specifically in the specification, a cycloalkylene 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 cycloalkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkylene is optionally substituted with one or more halogen, -CN, -OH, or - OMe. In some embodiments, the cycloalkylene is optionally substituted with halogen.

[0051] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.SUBSTITUTE SHEET (RULE 26)

[0052] “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.

[0053] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0054] “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.

[0055] “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.

[0056] “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, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0057] “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 combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a 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.

[0058] “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 ofSUBSTITUTE SHEET (RULE 26)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 quaternized. 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-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2- oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the di saccharides, 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, theSUBSTITUTE SHEET (RULE 26)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, withone 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, -COOH, - 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.

[0059] “Heterocycloalkylene” refers to a divalent heterocycloalkyl as defined above. Unless stated otherwise specifically in the specification, an heterocycloalkylene 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 heterocycloalkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the heterocycloalkylene is optionally substituted with halogen.

[0060] “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 sulfur atoms 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. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5- membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or 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,SUBSTITUTE SHEET (RULE 26)benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, , isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl-1H- 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, - CF3, -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.

[0061] “Heteroarylene” refers to a divalent heteroaryl as defined above. Unless stated otherwise specifically in the specification, an heteroarylene 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 heteroarylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroarylene is optionally substituted with one or more halogen, -CN, -OH, or - OMe. In some embodiments, the heteroarylene is optionally substituted with halogen.

[0062] 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.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0063] 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, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subjectSUBSTITUTE SHEET (RULE 26)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.

[0064] 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.

[0065] “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.

[0066] “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.

[0067] As used herein, the term “PTPN2-mediated” disorder or disease or alternatively “disease or disorder associated with PTPN2” means any disease or other deleterious condition in which PTPN2 or a mutant thereof is known to play a role. Accordingly, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN2, or a mutant thereof, is known to play a role.

[0068] As used herein, the term “PTPN1 -mediated” disorder or disease or alternatively “disease or disorder associated with PTPN1” means any disease or other deleterious condition in which PTPN1 or a mutant thereof is known to play a role. Accordingly, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN 1 , or a mutant thereof, is known to play a role.Compounds

[0069] Described herein are compounds of Formula (I) and (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, that are dual PTPN1 / PTPN2 inhibitors.

[0070] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a heterocycloalkyl or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -SUBSTITUTE SHEET (RULE 26)NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two Rlaon the same atom are taken together to form an oxo; n is 0-11;L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR2-, -[C(R3)2]m-, -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or - [C(R3)2]mNR2-;R2is hydrogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1-4; each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0-2;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;SUBSTITUTE SHEET (RULE 26)each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene( cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene( cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each Ris independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl. -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, - C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, Ci- C3aminoalkyl, C1-C3heteroalkyl, or Cs-Cecycloalkyl; or two R on the same atom form an oxo.

[0071] In some embodiments of a compound of Formula (I), the compound is of Formula (la):wherein R4’ is hydrogen or R4.

[0072] In some embodiments of a compound of Formula (I), the compound is of Formula (lb):SUBSTITUTE SHEET (RULE 26)Formula (lb); wherein R4’ is hydrogen or R4.

[0073] In some embodiments of a compound of Formula (I), the compound is of Formula (Ic):wherein R4’ is hydrogen or R4.

[0074] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is N-linked heterocycloallyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is C-linked heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl comprising 1 heteroatom that is N.

[0075] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is pyrrolidinyl or piperidinyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyrrolidinyl. In some embodiments of a compound of Formula (I) or (la)- (Ic), Ring A is piperidinyl.

[0076] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is bicyclic heterocycloalkyl.SUBSTITUTE SHEET (RULE 26)

[0077] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2- azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, or 2-azaspiro[3.3]heptanyl.

[0078] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 6-membered heteroaryl.

[0079] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heteroaryl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (la)- (Ic), Ring A is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 heteroatom that is N.

[0080] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is

[0081] In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -O-, -S-, -S(=O)-, -S(=O)2-, - NR2-, -[C(R3)2]m-, -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or -[C(R3)2]mNR2-.

[0082] In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -[C(R3)2]m-.

[0083] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R3are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl; or two R3are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independentlySUBSTITUTE SHEET (RULE 26)hydrogen, halogen, -OH, or C1-C6alkyl; or two R3are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (la)-(Ic), two R3are taken together to form a cycloalkyl optionally substituted with one or more R.

[0084] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R3is hydrogen.

[0085] In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 1-3. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 1 or 2. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 2.

[0086] In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH2-, -CH2CH2-, or - CH2CH2CH2-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH2-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH2CH2-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH2CH2CH2-.

[0087] In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -O-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -NR2-.

[0088] In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -NR2C(=O)- or -C(=O)NR2-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -NR2S(=O)2- or -S(=O)2NR2-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or -[C(R3)2]mNR2-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -O[C(R3)2]m- or - NR2[C(R3)2]m-. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -[C(R3)2]mO- or - [C(R3)2]mNR2-.

[0089] In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R2is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is hydrogen or C1-C6alkyl.

[0090] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R4is independently deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R4is independently deuterium or halogen. In some embodiments of a compound of FormulaSUBSTITUTE SHEET (RULE 26)(I) or (la)-(Ic), each R4is independently halogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R4is independently -ORaor C1-C6alkyl.

[0091] In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 0 or 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 0. In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 1.

[0092] In some embodiments of a compound of F ormula (I) or (la)-(Ic), W is N. In some embodiments of a compound of Formula (I) or (la)-(Ic), W is CRW

[0093] In some embodiments of a compound of Formula (I) or (la)-(Ic), Rwis hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Rwis hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Rwis hydrogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), Rwis C1-C6alkyl.

[0094] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloallyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently deuterium, halogen, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently halogen, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxy alkyl, C1-C6heteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)- (Ic), each R1is independently C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently C1-C6alkyl optionally substituted with one or more Rla.

[0095] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla.

[0096] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein eachSUBSTITUTE SHEET (RULE 26)alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C1-C6haloalkyl, Ci -Cedeuteroalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently deuterium, halogen, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (la)- (Ic), each R1is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R1is independently C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (la)-(Ic), two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (la)-(Ic), two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0097] In some embodiments of a compound of Formula (I) or (la)-(Ic), each Rlais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, Ci -Cedeuteroalkyl, Ci -Cehydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (la)-(Ic), each Rlais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloallyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each Rlais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl. C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each Rlais independently halogen, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each Rlais independently -NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each Rlais independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0098] In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-8. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-7. In some embodiments of a compound of Formula (I) or (la)- (Ic), n is 0-6. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-5. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0. In some embodiments of a compound of Formula (I) or (la)- (Ic), n is 1-8. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1-7. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1-6. In some embodiments of a compound ofSUBSTITUTE SHEET (RULE 26)Formula (I) or (Ia)-(Ic), n is 1-5. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-4. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1-3. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1 or 2. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 2. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 3. In some embodiments of a compound of Formula (I) or (la)- (Ic), n is 4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 5. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 6.

[0099] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring B is a cycloalkyl, heterocycloalkyl, or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla; or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two Rlaon the same atom are taken together to form an oxo; n is 1-11;L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR2-, -[C(R3)2]m-, -NR2S(=O)2-, -S(=O)2NR2-, -NR2C(=O)-, -C(=O)NR2-, - O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or -[C(R3)2]mNR2-;SUBSTITUTE SHEET (RULE 26)R2is hydrogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1-4; each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0-2;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)zRa, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene( cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene( cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and-21-SUBSTITUTE SHEET (RULE 26)each Ris independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl. -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(Ci- C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, - C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, Ci- C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo.

[0100] In some embodiments of a compound of Formula (II), the compound is of Formula (Ila):wherein R4’ is hydrogen or R4.

[0101] In some embodiments of a compound of Formula (II), the compound is of Formula (lib) :wherein R4’ is hydrogen or R4.

[0102] In some embodiments of a compound of Formula (II), the compound is of Formula (lie):wherein R4’ is hydrogen or R4.

[0103] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 5- to 8- membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring BSUBSTITUTE SHEET (RULE 26)is heterocycloalkyl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl comprising 1 heteroatom that is N.

[0104] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is cycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 4- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 5- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 5- to 6-membered cycloalkyl.

[0105] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 6-membered heteroaryl.

[0106] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 heteroatom that is N.

[0107] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -O-, -S-, -S(=O)-, - S(=O)2-, -NR2-, -[C(R3)2]m-, -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or -[C(R3)2]mNR2-.

[0108] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -[C(R3)2]m-.

[0109] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH2-, -CH2CH2-, or - CH2CH2CH2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH2CH2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH2CH2CH2-.

[0110] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -O-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -NR2-.SUBSTITUTE SHEET (RULE 26)

[0111] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -NR2C(=O)- or - C(=O)NR2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -NR2S(=O)2- or - S(=O)2NR2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -O[C(R3)2]m-, - NR2[C(R3)2]m-, -[C(R3)2]mO-, or -[C(R3)2]mNR2-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Lis -O[C(R3)2]m- or -NR2[C(R3)2]m-. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -[C(R3)2]mO- or -[C(R3)2]mNR2-.

[0112] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R3are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl; or two R3are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R3is independently hydrogen, halogen, -OH, or C1-C6alkyl; or two R3are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R3are taken together to form a cycloalkyl optionally substituted with one or more R.

[0113] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R3is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R3is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R3is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R3is hydrogen.

[0114] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), m is 1-3. In some embodiments of a compound of Formula (II) or (na)-(IIc), m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), mis 2.

[0115] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), R2is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), R2is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), R2is hydrogen or C1-C6alkyl.

[0116] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R4is independently deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R4is independently deuterium or halogen. In some embodiments of a compound of FormulaSUBSTITUTE SHEET (RULE 26)(II) or (IIa)-(IIc), each R4is independently halogen. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R4is independently -ORaor C1-C6alkyl.

[0117] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), p is 0 or 1. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), p is 0. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), p is 1.

[0118] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), W is N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), W is CRT

[0119] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Rwis hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Rwis hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Rwis hydrogen. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Rwis C1-C6alkyl.In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R1is independently deuterium, halogen, -CN, -OH, -ORa, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a.

[0120] In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R1is independently deuterium, halogen, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R1is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R1is independently C1-C6alkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (II) or (na)-(IIc), two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (na)-(IIc), two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1-8. In some embodiments of a compound of Formula (II) or (na)-(IIc), n is 1-7. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1-6. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1-5. In some embodiments of a compound of Formula (II) or (na)-(IIc), n is 1-4. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-3. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1SUBSTITUTE SHEET (RULE 26)or 2. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 2. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 3. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 4. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 5. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 6.

[0121] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a 7- to 15-membered cycloalkyl or a 7- to 15-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 0-6;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;SUBSTITUTE SHEET (RULE 26)RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)zRa, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo.SUBSTITUTE SHEET (RULE 26)

[0122] In some embodiments of a compound of Formula (III), Ring A is a 7- to 10-membered cycloalkyl or 7- to 10-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), Ring A is a 7- to 8-membered cycloalkyl or 7- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N.

[0123] In some embodiments of a compound of Formula (III), Ring A is a 7- to 10-membered cycloalkyl. In some embodiments of a compound of Formula (III), Ring A is a 7- to 9-membered cycloalkyl. In some embodiments of a compound of Formula (III), Ring A is a 7- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (III), Ring A is a 7-membered cycloalkyl. In some embodiments of a compound of Formula (III), Ring A is a 7- to 10-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, andN. In some embodiments of a compound of Formula (III), Ring A is a 7- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), Ring A is a 7-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 or 2 heteroatoms selected from O and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 heteroatom that is O. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 heteroatom that is N.

[0124] In some embodiments of a compound of Formula (III), X is N. In some embodiments of a compound of Formula (III), X is CRX.

[0125] In some embodiments of a compound of Formula (III), Rxis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III), Rxis hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (III), Rxis halogen. In some embodiments of a compound of Formula (III), Rxis fluoro.

[0126] In some embodiments of a compound of Formula (III), Y is N. In some embodiments of a compound of Formula (III), Y is CRY.

[0127] In some embodiments of a compound of Formula (III), RYis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III), RYis hydrogen, deuterium, halogen, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (III), RYis -OH.

[0128] In some embodiments of a compound of Formula (III), Z is N. In some embodiments of a compound of Formula (III), Z is CRZ.

[0129] In some embodiments of a compound of Formula (III), Rzis hydrogen, deuterium, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III), Rzis hydrogen.SUBSTITUTE SHEET (RULE 26)

[0130] In some embodiments of a compound of Formula (III), W is N. In some embodiments of a compound of Formula (III), W is CRT

[0131] In some embodiments of a compound of Formula (III), Rwis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III), Rwis hydrogen.

[0132] In some embodiments of a compound of Formula (III), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -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-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III), each R1is independently deuterium, halogen, -ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III), each R1is independently -ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo.

[0133] In some embodiments of a compound of Formula (III), each R1is independently -ORa, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently -NRcRd; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III), each R1is independently -NRcRd. In some embodiments of a compound of Formula (III), each R1is independently C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo.

[0134] In some embodiments of a compound of Formula (III), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl. C1-C6hydroxyalkyl. C1-C6aminoalkyl. cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently -OH, -ORa, -NRcRd,SUBSTITUTE SHEET (RULE 26)C1-C6alkyl, C1-C6haloalkyl, C1-C6aminoalkyl, or heterocycloalkyl; wherein each alkyl, and heterocycloalkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently -OH, -NRcRd, C1-C6alkyl, C1-C6aminoalkyl, or heterocycloalkyl; wherein each alkyl, and heterocycloalkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently C1-C6alkyl independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (III), each R1is independently C1-C6alkyl.

[0135] In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen or C1-C6alkyl.

[0136] In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (III), each R1ais independently -CN or -NRcRd.

[0137] In some embodiments of a compound of Formula (III), n is 1-4. In some embodiments of a compound of Formula (III), n is 1-3. In some embodiments of a compound of Formula (III), n is 1 or 2. In some embodiments of a compound of Formula (III), n is 0 or 1. In some embodiments of a compound of Formula (III), n is 0. In some embodiments of a compound of Formula (III), n is 1. In some embodiments of a compound of Formula (III), n is 2. In some embodiments of a compound of Formula (III), n is 3.SUBSTITUTE SHEET (RULE 26)

[0138] In some embodiments of a compound of Formula (III),

[0139] Described herein is a compound of F ormula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a 6- to 15-membered bicyclic cycloalkyl or a 6- to 15-membered bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo;SUBSTITUTE SHEET (RULE 26)each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 1-6;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), orSUBSTITUTE SHEET (RULE 26)C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo.In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered fused bicyclic cycloalkyl.

[0140] In some embodiments of a compound of Formula (IV), Ring A is 8- to 10-membered fused bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered bridged bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10- membered bridged bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered spirocyclic bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10-membered spirocyclic bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered fused bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10- membered fused bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered bridged bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10-membered bridged bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered spirocyclic bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10-membered spirocyclic bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O and N. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 or 2 heteroatoms selected from O andN. In some embodiments of aSUBSTITUTE SHEET (RULE 26)compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 heteroatom that is O. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 heteroatom that is N.

[0141] In some embodiments of a compound of Formula (IV),,wherein n’ is 1-5; and R2is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl.

[0142] In some embodiments, n’ is 0 or 1. In some embodiments, n’ is 1 or 2. In some embodiments, n’ is 2 or 3. In some embodiments, n’ is 0. In some embodiments, n’ is 1. In some embodiments, n’ is 2. In some embodiments, n’ is 3.

[0143] In some embodiments, R2is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, R2is C1-C6alkyl.

[0144] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula (IVa):wherein Ring B is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.

[0145] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula (IVb):5UB5TITUTE SHEET (RULE 26)Formula (IVb); wherein Ring C is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.

[0146] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula (IVc):wherein Ring D is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.

[0147] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula (IVd):wherein Ring E is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.

[0148] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula (IVe):wherein Ring F is a cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, S, and N.

[0149] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula (IVf):SUBSTITUTE SHEET (RULE 26)wherein Ring G is a cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, S, and N.

[0150] In some embodiments of a compound of Formula (IV), the compound is a compound of Formula(IVg):wherein Ring H is a cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, S, and N.

[0151] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), X is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), X is CRX.

[0152] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rxis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rxis hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rxis halogen.

[0153] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Y is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Y is CRY.

[0154] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), RYis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), RYis hydrogen, deuterium, halogen, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), RYis -OH.

[0155] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Z is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Z is CRZ.

[0156] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rzis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rzis hydrogen.

[0157] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), W is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), W is CRW.

[0158] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rwis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Rwis hydrogen.

[0159] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -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-C6deuteroalkyl,SUBSTITUTE SHEET (RULE 26)C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1is independently deuterium, halogen, - ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, Ci -C6hydroxy alkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1is independently -ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1is independently -NRcRd; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1is independently C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo.

[0160] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), each R1ais independently deuterium, halogen or C1-C6alkyl.

[0161] In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 1-4. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 1-3. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 1 or 2. In some embodiments of a compound of Formula (IV) or (IVa)- (IVg), n is 0. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 1. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 2. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 3.

[0162] Disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:SUBSTITUTE SHEET (RULE 26)Formula (V), wherein:Ring A is a 3- to 15-membered cycloalkyl or a 3- to 15-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 0-6;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), orSUBSTITUTE SHEET (RULE 26)C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each Ris independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo.

[0163] In some embodiments of a compound of Formula (V), Ring A is a 3- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 5- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 6- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 6-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 3- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (V), Ring A is a 5- to 8- membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, andN. In some embodiments of a compound of Formula (V), Ring A is a 6- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (V), Ring A is a 6- membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 or 2 heteroatoms selected from O and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 heteroatom that is O. In some embodiments of a compound of Formula (V), the heterocycloallyl in Ring A comprises 1 heteroatom that is N.SUBSTITUTE SHEET (RULE 26)

[0164] In some embodiments of a compound of Formula (V), X is N. In some embodiments of a compound of Formula (V), X is CRX.

[0165] In some embodiments of a compound of Formula (V), Rxis hydrogen, deuterium, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (V), Rxis hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (V), Rxis halogen.

[0166] In some embodiments of a compound of Formula (V), Y is N. In some embodiments of a compound of Formula (V), Y is CRY.

[0167] In some embodiments of a compound of Formula (V), RYis hydrogen, deuterium, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (V), RYis hydrogen, deuterium, halogen, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (V), RYis -OH.

[0168] In some embodiments of a compound of Formula (V), W is N. In some embodiments of a compound of Formula (V), W is CRT

[0169] In some embodiments of a compound of Formula (V), Rwis hydrogen, deuterium, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (V), Rwis hydrogen, deuterium, halogen, -OH, -ORa, or -NRcRd.

[0170] In some embodiments of a compound of Formula (V), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -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-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), each R1is independently deuterium, halogen, -ORa, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), each R1is independently -ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), eachR1is independently -ORa, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (V), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (V), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a. In some embodiments of a compound of Formula (V), each R1is independently -NRcRd; or two R1on the same atom are taken togetherSUBSTITUTE SHEET (RULE 26)to form an oxo. In some embodiments of a compound of Formula (V), each R1is independently -NRcRd. In some embodiments of a compound of Formula (V), each R1is independently C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo.

[0171] In some embodiments of a compound of Formula (V), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (V), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (V), each R1ais independently deuterium, halogen or C1-C6alkyl.

[0172] In some embodiments of a compound of Formula (V), n is 1-4. In some embodiments of a compound of Formula (V), n is 1-3. In some embodiments of a compound of Formula (V), n is 1 or 2. In some embodiments of a compound of Formula (V), n is 0. In some embodiments of a compound of Formula (V), n is 1. In some embodiments of a compound of Formula (V), n is 2. In some embodiments of a compound of Formula (V), n is 3.

[0173] Disclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:U is -C(R2)2-, -O-, or -NR3-; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl,SUBSTITUTE SHEET (RULE 26)heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 1-6; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1-3;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl,SUBSTITUTE SHEET (RULE 26)heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each Ris independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo; provided that compound is not

[0174] Disclosed herein is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:U is -C(R2)2-, -O-, or -NR3-; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo;SUBSTITUTE SHEET (RULE 26)each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 1-6; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1-3;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), orSUBSTITUTE SHEET (RULE 26)C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each Ris independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo; provided that compound is not

[0175] Also disclosed herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl,SUBSTITUTE SHEET (RULE 26)heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; m is 0-6;R3is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R3a; each R3ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R3aon the same atom are taken together to form an oxo; p is 1-3;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra. -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl,SUBSTITUTE SHEET (RULE 26)C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)zRa, -S(=0)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, - S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, - N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, - C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, Ci-C2heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0176] Also disclosed herein is a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:SUBSTITUTE SHEET (RULE 26)Formula (IX), wherein: each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; m is 0-6;R3is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R3a; each R3ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R3aon the same atom are taken together to form an oxo; p is 1-3;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYor N;SUBSTITUTE SHEET (RULE 26)RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)zRa, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, - S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, - N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, - C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, Ci-C2heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl;SUBSTITUTE SHEET (RULE 26)or two R on the same atom are taken together to form an oxo.

[0177] In some embodiments of a compound of Formula (VI) or (VII), U is -C(R2)2- or -NR3-. In some embodiments of a compound of Formula (VI) or (VII), U is -C(R2)2-. In some embodiments of a compound of Formula (VI) or (VII), U is -O-. In some embodiments of a compound of Formula (VI) or (VII), U is - NR3-. In some embodiments of a compound of Formula (VI) or (VII), U is -NH- or -NCH3-. In some embodiments of a compound of Formula (VI) or (VII), U is -NH-. In some embodiments of a compound of Formula (VI) or (VII), U is -NCH3-.

[0178] In some embodiments of a compound of Formula (VI) or (VII), each R2is independently deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (VI) or (VII), each R2is independently halogen or C1-C6alkyl.

[0179] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R3a.

[0180] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R3a.

[0181] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.

[0182] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.

[0183] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen or C1-C6alkyl.

[0184] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen.

[0185] In some embodiments of a compound of Formula (VI)-(IX), R3is C1-C6alkyl.

[0186] In some embodiments of a compound of Formula (VI)-(IX), R3is C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R3a.

[0187] In some embodiments of a compound of Formula (VI)-(IX), R3is C1-C6alkyl(aryl) or C1-C6alkyl(heteroaryl); wherein each alkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R3a.

[0188] In some embodiments of a compound of Formula (VI)-(IX), R3is C1-C6alkyl(aryl); wherein each alkyl aryl is independently and optionally substituted with one or more R3a.

[0189] In some embodiments of a compound of Formula (VI)-(IX), R3is C1-C6alkyl(aryl).SUBSTITUTE SHEET (RULE 26)

[0190] In some embodiments of a compound of Formula (VI)-(IX), R3is hydrogen, methyl, ethyl,

[0191] In some embodiments of a compound of Formula (VI)-(IX), R3is methyl, ethyl,

[0192] In some embodiments of a compound of Formula (VI)-(IX), each R3ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(IX), each R3ais independently deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI)-(IX), each R3ais independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (VI)-(IX), each R3ais independently halogen or C1-C6alkyl.

[0193] In some embodiments of a compound of Formula (VI)-(IX), p is 1 or 2. In some embodiments of a compound of Formula (VI)-(IX), p is 1.

[0194] In some embodiments of a compound of Formula (VI)-(IX), X is N. In some embodiments of a compound of Formula (VI)-(IX), X is CRX.

[0195] In some embodiments of a compound of F ormula (VI)-(IX), Rxis hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (VI) -(IX), Rxis hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (VI)-(IX), Rxis halogen.

[0196] In some embodiments of a compound of Formula (VI)-(IX), ¥ is N. In some embodiments of a compound of Formula (VI)-(IX), Y is CRY.

[0197] In some embodiments of a compound of F ormula (VI)-(IX), RYis hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (VI)-(IX), RYis hydrogen, deuterium, halogen, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (VI)-(IX), RYis -OH.

[0198] In some embodiments of a compound of Formula (VI)-(IX), Z is N. In some embodiments of a compound of Formula (VI)-(IX), Z is CRZ.-51-SUBSTITUTE SHEET (RULE 26)

[0199] In some embodiments of a compound of Formula (VI)-(IX), Rzis hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (VI)-(IX), Rzis hydrogen.

[0200] In some embodiments of a compound of Formula (VI)-(IX), W is N. In some embodiments of a compound of Formula (VI)-(IX), W is CRW.

[0201] In some embodiments of a compound of Formula (VI)-(IX), Rwis hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (VI)-(IX), Rwis hydrogen.

[0202] In some embodiments of a compound of Formula (VI)-(IX), each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently deuterium, halogen, -CN, -OH, -ORa, -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-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently deuterium, halogen, -ORa, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, Ci -C6hydroxy alkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently -ORa, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently -ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R1a. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently -NRcRdor C1-C6alkyl optionally substituted with one or more R1a. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently -NRcRd; or two R1on the same atom are taken together to form an oxo.SUBSTITUTE SHEET (RULE 26)

[0203] In some embodiments of a compound of Formula (VI)-(IX), each R1is independently -NRcRd. In some embodiments of a compound of Formula (VI)-(IX), each R1is independently C1-C6alkyl optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo.

[0204] In some embodiments of a compound of Formula (VI)-(IX), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (VI)-(IX), each R1ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (VI)-(IX), each R1ais independently deuterium, halogen or C1-C6alkyl.

[0205] In some embodiments of a compound of Formula (VI) or (VII), n is 1-4. In some embodiments of a compound of Formula (VI) or (VII), n is 1-3. In some embodiments of a compound of Formula (VI) or (VII), n is 1 or 2. In some embodiments of a compound of Formula (VI) or (VII), n is 1. In some embodiments of a compound of Formula (VI) or (VII), n is not 2.

[0206] In some embodiments of a compound of Formula (VIII) or (IX), m is 0-4. In some embodiments of a compound of Formula (VIII) or (IX), m is 0-3. In some embodiments of a compound of Formula (VIII) or (IX), m is 0-2. In some embodiments of a compound of Formula (VIII) or (IX), m is 0 or 1. In some embodiments of a compound of Formula (VIII) or (IX), m is 1 or 2. In some embodiments of a compound of Formula (VIII) or (IX), m is 0. In some embodiments of a compound of Formula (VIII) or (IX), m is 1. In some embodiments of a compound of Formula (VIII) or (IX), m is 2.

[0207] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and 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 and optionally substituted with one or more R.

[0208] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each RbisSUBSTITUTE SHEET (RULE 26)independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl independently and optionally substituted with one or more R.

[0209] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and 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-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and 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; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcis cycloalkyl and Rdhydrogen.

[0210] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl.

[0211] In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -C(=O)C1-C6alkyl, -C(=O)OH, - C(=O)OC1-C6alkyl, -C(=O)NH2. -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -NH2, - NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independentlySUBSTITUTE SHEET (RULE 26)deuterium, halogen, -CN, -OH, -OC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two Ron the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.

[0212] 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.

[0213] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.TABLE 1SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)* Stereochemistry arbitrarily assignee

[0214] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.TABLE 2SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)

[0215] In some embodiments, the compound disclosed herein is a compound selected from Table 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.TABLE 3SUBSTITUTE SHEET (RULE 26)* stereochemistry randomly assignee** stereochemistry determined by co-crystallization with PTPN2

[0216] In some embodiments, the compound disclosed herein is a compound selected from Table 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.TABLE 4SUBSTITUTE SHEET (RULE 26)Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0217] 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, orSUBSTITUTE SHEET (RULE 26)interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0218] 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.

[0219] 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

[0220] 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.SUBSTITUTE SHEET (RULE 26)

[0221] 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.

[0222] 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-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, γ-hydroxy butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0223] 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, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxy ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’ -methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid 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.

[0224] 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 acceptableSUBSTITUTE SHEET (RULE 26)metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-C4 alkyl)4 hydroxide, and the like.

[0225] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0226] 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.

[0227] 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.Tautomers

[0228] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and one or more adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.Method of Treatment

[0229] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1 / PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0230] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt,SUBSTITUTE SHEET (RULE 26)solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN1 is beneficial is cancer or a metabolic disease.

[0231] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN2 is beneficial is cancer.Cancer

[0232] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat cancer.

[0233] As used herein, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers.

[0234] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, erythroleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0235] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma,SUBSTITUTE SHEET (RULE 26)lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0236] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bile duct carcinoma, bladder carcinoma, breast carcinoma, Brenner carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, cystadenocarcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, endometrioid carcinoma, epiermoid carcinoma, epithelial carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, sebaceous gland carcinoma, seminoma, serous carcinoma, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindleSUBSTITUTE SHEET (RULE 26)cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or carcinoma villosum.

[0237] In some embodiments, the cancer is acoustic neuroma, adrenal cortical cancer, adrenal gland cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchus cancer, cancer of the hematological tissues, cancer of the hepatic stellate cells, cancer of the oral cavity or pharynx, cancer of the pancreatic stellate cells, carcinoma, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecologic cancers, head and neck cancer, hemangioblastoma, Hodgkin's Disease, immunocytic amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatocarcinoma), lobular carcinoma, lung cancer, lymphoma , malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulanoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, non-Hodgkin's Lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Pagef s Disease of the Nipple, pancreatic cancer, papillary thyroid cancer, peripheral nervous system cancer, Phyllodes Tumors, pinealoma, premalignant skin lesions, primary macroglobulinemia, primary thrombocytosis, prostate cancer, renal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small bowel or appendix cancer, stomach cancer, testicular cancer, thyroid cancer, urinary bladder cancer, uterine cancer, Waldenstrom’s macroglobulinemia.Metabolic Diseases

[0238] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat a metabolic disease.

[0239] As used herein, the term “metabolic disease” refers to a disease or condition affecting a metabolic process in a subject. Exemplary metabolic diseases include non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. In some embodiments, a compound disclosed herein, is used to treat a metabolic disease (e.g., a metabolic disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, the method of treatment comprises decreasing or eliminating a symptom comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.SUBSTITUTE SHEET (RULE 26)Dosing

[0240] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0241] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of 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.

[0242] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).

[0243] 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.

[0244] 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.

[0245] In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.Routes of Administration

[0246] 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,SUBSTITUTE SHEET (RULE 26)subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0247] 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.Pharmaceutical Compositions / F ormulat ions

[0248] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0249] 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 & Wilkinsl999), herein incorporated by reference for such disclosure.

[0250] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

[0251] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees,SUBSTITUTE SHEET (RULE 26)effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.Combination

[0252] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a PTPN2 / N1 inhibitor disclosed herein; and (b) an additional therapeutic agent. In some embodiments, the combination therapy improves patient outcomes.

[0253] In some embodiments, the additional therapeutic agent is an anticancer agent.

[0254] In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. Use of immunotherapeutic agents in combination with other cancer treatment regimens has emerged as a promising approach to address limitations such as suboptimal efficacy, dose- dependent toxicity and acquired resistance while generating long-lasting anti-tumor immune responses and improving patient outcomes. In some embodiments, combining a PTPN2 / N 1 inhibitor with a checkpoint inhibitor enhances therapeutic efficacy and improves tumor clearance in an in vivo tumor model. In some embodiments, there is a therapeutic benefit to combining a PTPN2 / N1 inhibitor disclosed herein with a clinically approved immune checkpoint inhibitor such as, but not limited to, atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab. Further examples of checkpoint inhibitors are AMG-404, camrelizumab, ezabenlimab, pidilizumab, or spartalizumab.

[0255] PTPN2 has emerged as a validated immunotherapy target as multiple published studies have demonstrated that PTPN2 deletion in either the tumor or in the immune compartment significantly enhanced anti-tumor immunity and sensitivity to other immunotherapies such as checkpoint inhibitors (Manguso et al. 2017; LaFleur et al. 2019; Weide et al. 2020). Emerging data have also shown that PTPN1 functions as an intracellular checkpoint and that PTPN1 deletion in T cells enhanced tumor clearance (Weide et al. 2022). Recently, it was shown that a small molecule PTPN2 / N1 inhibitor enhanced T cell activation and proliferation and inhibited tumor growth in a murine syngeneic model (Liang et al. 2023).

[0256] In some embodiments, the additional therapeutic agent is chemotherapeutic agent. Chemotherapy induces cytotoxic effects on tumor cells but is also recognized for reinstating cancer cell immune surveillance and acting as an adjuvant for anti-tumor immunity (Liu et al. 2020). In some embodiments, chemotherapeutic agent includes, but is not limited to, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or a combination thereof.

[0257] In some embodiments, the additional therapeutic agent is radiation therapy (RT). Radiation therapy (RT) can induce tumor cells to release antigens and trigger local or systemic anti-tumor immunity (Demaria et al. 2016).

[0258] In some embodiments, the additional therapeutic agent is a VEGF inhibitor. Previous clinical studies demonstrated that the combination of an immune checkpoint inhibitor with an anti-angiogenic agentSUBSTITUTE SHEET (RULE 26)had synergistic effects and several of these combinations have recently been approved for the treatment of advanced renal cell carcinoma (Motzer et al. 2021; Makker et al. 2019; Jonasch et al. 2022). In some embodiments, the VEGF inhibitor includes, but is not limited to, aflibercept, axitinib, bevacizumab, cabozatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ramucirumab, regorafenib, sorafenib, sunitunib, tivozanib, and vandetanib, to potentially improve the clinical efficacy of these agents.

[0259] In some embodiments, the additional therapeutic agent is a bi-specific antibody or T cell engager.

[0260] In some embodiments, the bi-specific antibodies or T cell engagers is, but is not limited to, bintrafusp alfa, blinatumomab, elranatamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR- 1701, tebentafusp, or teclistamab. In some embodiments, the combination disclosed herein enhances T cell mediated tumor immunity as most of these bi-specific antibodies are designed to redirect T cells.

[0261] In some embodiments, the additional therapeutic agent is CAR-T cell therapy. Wiede et al. recently demonstrated that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of CAR-T therapy by augmenting both CAR-T cell activation and homing to CXCL9 / CXCL 10- expressing tumors via STAT5 signaling (Wiede et al. 2020). In some embodiments, the CAR-T cell therapy is, but is not limited to, axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel. In some embodiments, the combination disclosed herein enhances the clinical efficacy of human CAR-T cells.

[0262] In some embodiments, the additional therapeutic agent is a KRAS G12C inhibitor. Recently, it was shown that the KRAS G12C inhibitor adagrasib sensitizes tumors to immunotherapy altering immune cell populations in the tumor microenvironment (Briere et al. 2021). In some embodiments, the KRAS G12C inhibitor is, but is not limited to, adagrasib or sotorasib. Further examples of KRAS G12C inhibitors are disclosed in WO2021 / 245051, WO2021 / 245055 and WO2023 / 099612, which are herein incorporated by reference in their entireties. In particular, further examples of KRAS G12C inhibitors that can be used according to the present invention are represented by compounds Ib-1 to Ib-16, Ic-1 to Ic-9, Id-1 to Id-9 and Ie-1 of WO2021 / 245051, compounds la- 1 to la-170 of WO2021 / 245055 and compounds la-1 to la-4andlb- 1 to Ib-9 of WO2023 / 099612. Further examples of KRAS G12C inhibitors are compounds known as: divarasib (GDC-6036), opnurasib (also known as JDQ443), garsorasib (D-1553), glecirasib (JAC-21822), GFH925 / GF105 / IBI351, RMC-6291, LY3537982, JNJ-74699157 and LY3499446. In some embodiments, the combination disclosed herein potentiates anti -tumor immunity and potentially improve patient outcomes.

[0263] In some embodiments, the additional therapeutic agent is a cancer vaccine. Cancer vaccines such as, but not limited to, BCG, sipuleucel-T, and talimogene laherparepvec (T-VEC), where T-VEC is the oncolytic virus approved by the FDA, activate the immune response both locally and systemically ensuring better induction of tumor-specific effector T cell function (Vafaei at al., 2021, Ferrucci et al., 2021). Current clinical trials utilize the combination of DC-based mRNA vaccines in combination with ipilimumab to stimulate a strong T cell response (De Keersmaecker et al., 2020). In some embodiments, a combination disclosed herein promotes an additive or synergistic effect on anti-tumor immunity, thus potentially improves clinical outcomes.SUBSTITUTE SHEET (RULE 26)

[0264] In some embodiments, the additional therapeutic agent is aHER2-targeted therapy. Recent reports have demonstrated that HER2-targeted therapies can enhance anti-tumor immunity by enhancing expression of dendritic (DC) markers, boosting MHC I expression on cancer cells for ease of recognition by the immune system and enhancing recruitment of tumor-infiltrating CD4+ and CD8+ T cells (Iwata et al., 2018 & 2019). Consistent with this idea, HER2-targeted therapies such as, but not limited to, lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab emtansine (T-DM1), trastuzumab, tucatinib, and zongertinib could also be combined with a PTPN2 / N1 inhibitor to achieve more robust anti-tumor immune responses (Vafaei et al., 2022).

[0265] In some embodiments, the additional therapeutic agent is a CXCR4 antagonist. CXCR4 antagonists have been developed to impair pathological procedures and disrupt cancer cell adhesion to the stromal cells, facilitating cancer cell release into circulation (Otsuka et al., 2008; Schrader et al., 2002). In some embodiments, the combination disclosed herein confers a strong immune response and attacks the circulating cancer cells to delay tumor development and enable tumor regression. In some embodiments, the CXCR4 antagonist is, but not limited to, plerixafor.

[0266] 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.EXAMPLESExample A: Enzymatic Assay used to determine potency of PTPN2 Inhibitors

[0267] Compound activity was determined in an in vitro enzymatic assay using untagged, full-length human PTPN2 (TC45) (1-387) protein. PTPN2 was produced in E. coli as a GST-TEV fusion and the GST was removed by TEV digestion, followed by additional purification to yield full-length PTPN2 (SEQ ID 1). PTPN2 enzyme was diluted in assay buffer (50mMHEPES pH7.5, 0.2mM EDTA, ImM DTT, 0.02% Brij- 35, 0.02% BSA) to afinal concentration of 0.5 nM and added to black 384- well non- binding plates (Greiner, 781900). Compounds were subsequently added using a Tecan D300e dispenser. Following a 10 min incubation at room temperature, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 100 μM. Plates were transferred to a SpectraMax plate reader (Molecular Devices) and fluorescence intensity was measured (ex 358, em 455) after a 30 min incubation at room temperature. Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO) from which %SUBSTITUTE SHEET (RULE 26)inhibition for test compounds was calculated. A four-parameter curve fit was used to determine ICso values from % inhibition data.Example B: B16F10 Cellular Growth Inhibition Assay

[0268] Compound activity was determined using an interferon gamma (IFNγ)-induced cellular growth inhibition assay with the murine B16F10 melanoma cell line on an Agilent xCELLigence Real-Time Cell Analysis platform (RTCA). RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibrated with 50 μL of assay media (DMEM+10% FBS, Gibco 10566-024, Gibco 10082-147) at 37°C in a humidified incubator before taking an initial measurement of impedance (sweep). B16F10 cells cultured in assay media were dissociated with TrypLE Express (Gibco 12605-010) for five minutes at 37°C, diluted in 3 volumes of assay buffer, centrifuged for 5 minutes at 500xg at room temperature before diluting cells to 7,700 cells / mL in assay media, plating 130 μL / well (1,000 cells / well) in the inner 60 wells of the assay plate, and adding 150 μL of assay media to the outer wells of the plate. Cells were incubated at room temperature for 20 min to allow cells to settle before placing them in the xCELLigence reader and incubating overnight at 37°C, sweeping wells every 15 minutes. After 24 hours, well readings were paused, plates were removed from the incubator and compounds were added using a Tecan D300e dispenser. All wells were normalized to a final concentration of 0.5% DMSO. Following a 30 min incubation at 37°C, recombinant mouse IFNγ (R&D Systems™ 485MI100) was diluted to 10 ng / mL in assay media and 20 μL was added to assay wells (1 ng / mL final concentration). Assay plates were placed in the xCELLigence reader and swept every 15 minutes. After 48 hours, well readings were normalized to the time point immediately preceding compound addition and the area under the growth curve (AUC) was calculated by the RTCA software and exported. A four-parameter curve fit was used to determine compound ICso values using % inhibition for each compound concentration calculated using the DMSO vehicle with IFNγ treatment as baseline (0% inhibition) and a positive control PTPN2 inhibitor with IFNγ treatment as 100% inhibition.

[0269] The data from Example A and Example B is shown in table 5, 6, 7, and 8.TABLE 5SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)TABLE 6SUBSTITUTE SHEET (RULE 26)TABLE 7TABLE 8Example C: In Vivo Efficacy of PTPN2 / N1 Inhibitors in Combination with an Immune Checkpoint Inhibitor in an MC38 Murine Tumor Model

[0270] C57BL / 6 female mice (5-9 weeks of age) were obtained from GemPharmatech Co. Ltd and grouped up to 5 mice per cage and provided food and water ad libitum. Animals were acclimated to the facilities for a period of at least a week prior to cancer cell inoculation. The MC-38 (murine colon carcinoma) tumor cells were maintained in vitro with DMEM medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5%CO2. The cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation into the right flank. Briefly, each mouse was inoculated subcutaneously to the right lower flank region with MC-38 tumor cells (1 x 106) in 0.1 ml of PBS for tumor development. After tumor cells inoculation, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain / loss, eye / hair matting and anySUBSTITUTE SHEET (RULE 26)other abnormalities. Tumor size was monitored in two dimensions using a caliper, and the volume will be expressed in mm3 using the formula: “TV = (L x W x W) / 2, where TV is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Once TV mean reached 80-120 mm3, animals were randomly allocated to study groups (10 animals per group). This randomization was performed based on “Matched distribution” method using StudyDirector™ software, version 3.1.399.19. The date of randomization was denoted as Day 0. Treatment was initiated the day after randomization (day 1). TVs and body weights (BWs) were recorded twice per week after randomization. Dosing was conducted either orally (p.o.) for herein disclosed PTPN2 / N1 inhibitor exemplary compound 1 or intraperitoneally (i.p.) for anti -PD1 antibody (Biocell (#BP0146)) or isotype Rat IgG2a control (Biocell (#BE0089)) or both for the combination groups. Dosing of exemplary compound 1 was conducted once per day (q.d.) during the light cycle phase at 15 mg / kg. For anti-PD-1 or isotype control, compounds were dosed bi-weekly at 10 mg / kg. Exemplary compound 1 was formulated in 10% ethanol, 30% PEG-400, 60% Phosal-50 PG and was dosed at 10 μL / g. Anti-PD-1 antibody or isotype control were formulated in PBS. The individual mouse was euthanized if its tumor volume exceeds 3,000 mm3or if they lost over 20% of their BW recorded on the day of randomization. In the event of tumor ulceration and to deter cannibalization, such animals were separated immediately and singly housed and monitored daily.

[0271] Exemplary compound 1 was well tolerated either alone or in combination with anti-PD-1 antibody or isotype control. Mean percentage (%) inhibition of TVs was calculated using (mean(C)- mean(T)) / mean(C) * 100%), where mean(C) is the vehicle TV mean and mean(T) is the treatment group TV.TABLE 9. Tumor Growth Inhibition (TGI), Mean % InhibitionDates / Study DaysGroup Treatment _ _n„ O " 13 1OG0°iUPVehicle 0% 0% 0% 0% 0%Group Anti-PD-1 _3%_4% 19o / o 34% 46%02 antibodyG™upIsotype Rat IgG2a -1% -37% -44% -31% -6%G™up ExemPlarv18% 18% 37% 63% 81%04 Compound 1Anti-PDlG™up19o / o34% 69%91o / o 99o / o05 ExemplaryCompound 1„ Isotype Rat IgG2aU™upExemplary 12% -3% 25% 60% 78%Compound 1

[0272] Exemplary compound 1 led to significant tumor growth inhibition (TGI) as a single agent or in combination with isotype control by day 9. By day 16, single agent and in combination with isotype control,SUBSTITUTE SHEET (RULE 26)exemplary compound 1 reached 80% efficacy (Table 9) compared to vehicle group and had more than 50 % of animals show tumor regressions.

[0273] The anti-PD-1 antibody alone only reached about 46% TGI by Day 16, whereas in combination with exemplary compound 1, significant TGI was observed as early as Day 6 (34% TGI, Table 9) and reached 99% TGI by Day 16 with over 90% of animals cured of their tumors, clearly indicating that the combination of both compounds led to greater efficacy than when each was administered as a single agent.

[0274] Dosing was conducted either orally (p.o.) for herein disclosed PTPN2 / N1 inhibitor exemplary compound 2 or intraperitoneally (i.p.) for anti-PDl antibody (Biocell (#BP0146)) or both for the combination groups. Dosing of exemplary compound 2 was conducted once per day (q.d.) during the light cycle phase at 1, 2.5, 5 or 7.5 for single agent activity and 1, 2.5 or 5 mg / kg for combo activity. For anti-PD- 1 compounds were dosed bi-weekly at 10 mg / kg. Exemplary compound 2 was formulated in 10% ethanol, 30% PEG-400, 60% Phosal-50 PG and was dosed at 10 μL / g. Anti-PD-1 antibody was formulated in PBS. The individual mouse was euthanized if its tumor volume exceeds 3,000 mm3 or if they lost over 20% of their BW recorded on the day of randomization. In the event of tumor ulceration and to deter cannibalization, such animals were separated immediately and singly housed and monitored daily.

[0275] Exemplary compound 2 was well tolerated either alone or in combination with anti-PD-1 antibody or isotype control. Mean percentage (%) inhibition of TVs was calculated using (mean(C)- mean(T)) / mean(C) * 100%), where mean(C) is the vehicle TV mean and mean(T) is the treatment group TV.TABLE 10. Tumor Growth Inhibition (TGI), Mean % InhibitionSUBSTITUTE SHEET (RULE 26)

[0276] Exemplary compound 2 led to significant tumor growth inhibition (TGI) as a single agent by day 8. By day 19, exemplary compound 2 showed 37%, 81% and 94% TGI for 1, 2.5 and 7.5 mg / kg groups respectively Table 10. Tumor regression was observed in the 5 (4 out of 10 animals) and 7.5 (8 out of 10 animals) mg / kg dosing groups.

[0277] The anti-PD-1 antibody alone only reached about 57% TGI by Day 19, whereas in combination with exemplary compound 2, significant TGI was observed as early as Day 5 for group 09 (exemplary compound 2 at 5 mg / kg + anti-PD1 antibody) (30% TGI, Table 10) and reached 99% TGI by Day 19 with over 80% of animals cured of their tumors. In the combination with exemplary compound 2 at lower doses of 1 mg / kg and 2.5 mg / kg, combination reached 68% and 75% TGI, which is greater than anti-PD-1 alone (57%) Table 10, with greater number of regressions and cured observed in the single agent groups, clearly indicating that the combination of both compounds led to greater efficacy than when each was administered as a single agent.References:

[0278] Manguso, R., Pope, H., Zimmer, M. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413-418 (2017).

[0279] LaFleur, M.W., Nguyen, T.H., Coxe, M.A. et al. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat Immunol 20, 1335-1347 (2019).

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Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating cancer in a subj ect in need thereof, the method comprising administering to the subject an effective amount of(a) a compound of Formula (III):wherein:Ring A is a 7- to 15-membered cycloalkyl or a 7- to 15-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 0-6;X is CRXor N;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; is CRYor N;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl,SUBSTITUTE SHEET (RULE 26)C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)zRa, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and(b) an additional therapeutic agent.SUBSTITUTE SHEET (RULE 26)2. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of:(a) a compound of Formula (I):wherein:Ring A is a heterocycloalkyl or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; each R1ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1aon the same atom are taken together to form an oxo; n is 0-11;L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR2-, -[C(R3)2]m-, -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or - [C(R3)2]mNR2-;R2is hydrogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl,SUBSTITUTE SHEET (RULE 26)or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1-4; each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0-2;W is CRWor N;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)zRa, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene( cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene( cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each Ris independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -S(=O)C1-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(Ci- C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, - C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, Ci- C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;SUBSTITUTE SHEET (RULE 26)or two R on the same atom form an oxo; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and(b) an additional therapeutic agent.

3. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.4 A method of treating cancer in a subj ect in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.5 A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.6 A method of treating cancer in a subj ect in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.7 A method of treating cancer in a subj ect in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.8 A method of treating cancer in a subj ect in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.9 A method of treating cancer in a subj ect in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.10 The method of any one of claims 1-9, wherein the additional therapeutic agent is an anti cancer agent.11 The method of any one of claims 1-9, wherein the additional therapeutic agent is an immunotherapeutic agent.12 The method of claim 11, wherein the immune checkpoint inhibitor is atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab.13 The method of any one of claims 1-9, wherein the additional therapeutic agent is chemotherapeutic agent.14 The method of claim 13, wherein the chemotherapeutic agent is cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or a combination thereof.SUBSTITUTE SHEET (RULE 26)15. The method of any one of claims 1-9, wherein the additional therapeutic agent is radiation therapy (RT).

16. The method of any one of claims 1-9, wherein the additional therapeutic agent is a VEGF inhibitor.

17. The method of claim 16, wherein the VEGF inhibitor is aflibercept, axitinib, bevacizumab, cabozatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ramucirumab, regorafenib, sorafenib, sunitunib, tivozanib, or vandetanib.

18. The method of any one of claims 1-9, wherein the additional therapeutic agent is a bi-specific antibody or T cell engager.

19. The method of claim 18, wherein the T cell engager is bintrafusp alfa, blinatumomab, elranatamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR-1701, tebentafusp, or teclistamab.

20. The method of any one of claims 1-9, wherein the additional therapeutic agent is CAR-T cell therapy.

21. The method of claim 20, wherein the CAR-T cell therapy is axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel.

22. The method of any one of claims 1-9, wherein the additional therapeutic agent is a KRAS G12C inhibitor.

23. The method of claim 22, wherein the KRAS G12C inhibitor is adagrasib or sotorasib.

24. The method of any one of claims 1-9, wherein the additional therapeutic agent is a cancer vaccine.

25. The method of claim 24 wherein the cancer vaccine is BCG, sipuleucel-T, or talimogene laherparepvec (T-VEC).

26. The method of any one of claims 1-9, wherein the additional therapeutic agent is a HER2-targeted therapy.

27. The method of claim 26 wherein the HER2-targeted therapy is lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab emtansine (T-DM1), trastuzumab, tucatinib, or zongertinib.

28. The method of any one of claims 1-9, wherein the additional therapeutic agent is a CXCR4 antagonist.

29. The method of claim 28 wherein the CXCR4 antagonist is plerixafor.SUBSTITUTE SHEET (RULE 26)

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