ULK inhibitors and methods of use thereof

Abstract

Described herein are compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 403,417, filed September 2, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Autophagy (literally meaning "self-eating") is a process that allows cells to recycle organelles, proteins, stored lipids, glucagon, and other materials for the purpose of generating nutrients under stress. These cellular contents are recycled by engulfment in small vesicles called autophagosomes. The autophagosomes then bind to lysosomes, which degrade the contents for recycling nutrients to the cell. Tumor cells tend to activate autophagy because they have high metabolic demands, experience cellular stress, and often live in a hypoxic environment with limited blood flow and nutrient supply. Furthermore, chemotherapy and targeted anticancer therapies have been shown to induce autophagy as a therapeutic resistance mechanism, and the combination of autophagy inhibition (by genetic loss-of-function mutations in autophagy genes or by pharmacological means) with chemotherapy regimens has been shown to suppress tumor proliferation and cause tumor cell apoptosis to a greater extent than single-agent chemotherapy.

[0003] Mutant RTK, RAS, and RAF proteins cause approximately 70% of all human cancers (including 95% of pancreatic cancers and 45% of colorectal cancers), and treatment of these mutant RTK / RAS / RAF cancers is currently an area of ​​high unmet medical need. These cancers are highly proliferative and depend on basal levels of autophagy for survival, suggesting that inhibiting autophagy in these "autophagy-dependent" cancers is a viable therapeutic approach.

[0004] ULK1 kinase is an autophagy initiation protein and a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stresses, including nutrient deprivation and energy depletion. Nutrient deprivation activates ULK kinase activity through inhibition of mTORC1, and energy depletion activates ULK kinase activity through activation by the AMP-activated protein kinase AMPK. Importantly, kinase-dead mutants of ULK kinases block the initiation of canonical autophagy, suggesting that small-molecule inhibitors of ULK kinase activity can block autophagy.

[0005] Further mechanistic studies showed that genetic deletion of ULK1 inhibits autophagy in cancer cells, attenuating FOX3A turnover and upregulating the pro-apoptotic protein PUMA. In addition to the classical activation of canonical autophagy, ULK1 kinase activity has been shown to be required for Bcl-2-L-13-mediated mitophagy (autophagy of damaged mitochondria).

[0006] ULK1 and ULK2 kinases have also been demonstrated to rewire glucose metabolism in cancer cells.

[0007] Autophagy is also upregulated in cancer host cells and tissues. Autophagy in pancreatic stellate cells has been demonstrated to support tumor growth. Pancreatic stellate cells have been shown to support tumor metabolism in pancreatic cancer through autophagic alanine secretion. Inhibition of autophagy in host tissues has been demonstrated to result in depletion of circulating arginine (an amino acid required for tumor metabolism and growth) through increased liver-mediated arginase secretion. ULK1 kinase activation has also been shown to inactivate the STING pathway in immune cells through inhibitory phosphorylation of STING, mediating a negative feedback mechanism to limit interferon-mediated innate immune cell responses. Therefore, autophagy is activated not only in tumor cells (cancer cell-autonomous) but also in other cells in the tumor microenvironment or host tissues (cancer cell-nonautonomous), supporting tumor survival and growth.

[0008] It has been demonstrated that inhibition of receptor tyrosine kinases (RTKs), such as EGFR, can promote autophagy in some cancers, including glioblastoma, human vulvar squamous cell carcinoma, colorectal adenocarcinoma, and non-small cell lung cancer, via signaling through the EGFR→Ras→RAF→MEK→ERK pathway. EGFR can also suppress autophagy via the EGFR→PI3K→AKT1→mTORC1 pathway by activating the mTORC1 complex and inactivating the downstream ULK1. Pharmacological inhibition of either PI3K with LY294002 or mTOR with rapamycin has been demonstrated to promote the expression of autophagy-related proteins LC3-II / I, p62, and beclin-1, providing additional rationale for combining such targeted therapeutics or chemotherapeutic agents with inhibitors of autophagy.

[0009] Mutant Ras cancers are dependent on autophagy. In pancreatic cancer, mutant Ras signals primarily through the MAPKAP pathway. Mutant Ras activates RAF kinase, which then activates MEK kinase and ultimately ERK kinase: mutant Ras → RAF → MEK → ERK. Despite the fact that mutant Ras signaling is via the MAPKAP pathway, inhibitors of this pathway have provided little or no clinical benefit in clinical trials when used as single agents. Recently, it has been reported that inhibition of the MAPKAP pathway induces autophagy as a compensatory survival mechanism. Combining an MEK inhibitor with the autophagy inhibitor hydroxychloroquine synergistically resulted in the regression of several mutant Ras or BRAF cancers. Similarly, combining an ERK inhibitor with the autophagy inhibitors hydroxychloroquine or chloroquine synergistically resulted in the inhibition of mutant Ras pancreatic cancers. It has been demonstrated that genetic depletion of RAF kinases (CRAF and BRAF) results in synergistic antitumor activity in mutant Ras cancer cell lines when autophagy is also genetically depleted.

[0010] ULK1 / 2 inhibitors, when used in combination with RTK inhibitors, MAPKAP pathway inhibitors, PI3K / AKT pathway inhibitors, chemotherapeutic agents, and / or other targeted therapies, may represent a promising treatment regimen for patients with mutant Ras cancers.

[0011] Mutations in the gene encoding the LRRK2 kinase cause Parkinson's disease. LRRK2 point mutations are found in both familial (hereditary) and sporadic Parkinson's disease patients. The most common LRRK2 mutation in Parkinson's disease is the LRRK2 G2019S mutation. These LRRK2 mutations are gain-of-function mutations that cause overactivation of LRRK2 signaling. Continuous autophagy is a process used by brain neurons to maintain health and homeostasis. Autophagy is the process by which cells identify, localize, and destroy obsolete organelles and structural elements within the cell. In particular, for proteins known to aggregate in neurons, autophagy eliminates such toxic protein aggregates to maintain neuronal health. LRRK2 activity inhibits autophagy, and the LRRK2 G2019S gain-of-function mutation further inhibits autophagy and is associated with an aggressive form of Parkinson's disease.

[0012] Increased LRRK2 kinase activity has also been associated with immune-mediated inflammatory diseases, such as colitis and Crohn's disease, as well as inflammatory bowel disease. In the gastrointestinal tract, LRRK2 is present on antigen-presenting cells, including dendritic cells. LRRK2 activity has been shown to be important in Dectin-1-mediated innate immune responses, including activation of the NFkB pathway and increased TNF-α production in dendritic cells from Crohn's disease patients.

[0013] Inhibitors of LRRK2 are sought after for the treatment of neurodegenerative diseases, including Parkinson's disease, as well as gastrointestinal diseases, including Crohn's disease, ulcerative colitis, and inflammatory bowel disease. Summary of the Invention

[0014] Described herein are compounds that are inhibitors of autophagy, pharmaceutical compositions, and their use as medicaments in the treatment of disorders such as cancer, as well as processes for their preparation and pharmaceutical compositions containing them as active ingredients. Such pharmaceutical compositions may contain the compounds described herein as the sole active agent or in combination with other active agents in the presence of a pharmaceutically acceptable excipient. In one embodiment, the compounds described are inhibitors of ULK kinase activity, including ULK1 and ULK2 activity.

[0015] For example, compounds described herein have Formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; 2 is selected from the group consisting of N, CH, CF, and C—Cl; 1 , X 2 , and X 3are N; A is selected from the group consisting of optionally substituted heteroaryl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano), and optionally substituted phenyl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano); E is H, haloalkyl, optionally substituted alkyl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano), optionally substituted cycloalkyl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano), Y is independently selected from the group consisting of haloalkyl, haloalkoxy, hydroxy, and cyano, where any alkyl is further optionally substituted with alkoxy or cycloalkyl), optionally substituted heteroaryl (where the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, where any alkyl is further optionally substituted with alkoxy or cycloalkyl), and optionally substituted heterocyclyl (where the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, where any alkyl is further optionally substituted with alkoxy or cycloalkyl); [ka] wherein s1 is a moiety covalently attached to the ring; and R 1 is alkyl or haloalkyl, and R 2 and R 3are each independently selected from the group consisting of H, alkoxy, haloalkyl, optionally substituted alkyl (wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl), optionally substituted cycloalkyl (wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of optionally substituted c-linked heterocyclyl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano); optionally substituted heteroaryl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano); However, R 2 and R 3 If one of the is H, the other R 2 and R 3 is not H, but Y [ka] If R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and R 4is an optionally substituted alkyl (wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl), optionally substituted cycloalkyl (wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl), and optionally substituted C-linked heterocyclyl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano), optionally substituted heteroaryl (the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano), with the proviso that X 1 , X 2 and X 3 is CH and Y is [ka] and R 4 C optionally substituted with one or more fluorine atoms 1~5 provided that if A is optionally substituted phenyl, then E is not alkyl substituted with an amine.

[0016] In another embodiment, described herein is a pharmaceutical composition comprising a compound described herein (e.g., Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII described herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof) and a pharmaceutically acceptable carrier or excipient.

[0017] In another embodiment, provided herein is a method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein.

[0018] In another embodiment, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein.

[0019] In another embodiment, provided herein is a method of treating a disorder selected from the group consisting of gastrointestinal stromal tumor, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, leukemia, cervical cancer, cancer that metastasizes to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein.

[0020] In some embodiments, the method further comprises administering to the patient one or more additional therapeutic agents. DETAILED DESCRIPTION OF THE INVENTION

[0021] The features and other details disclosed herein will now be more particularly described. Certain terms used in the specification, examples, and claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0022] definition The definitions set forth in this application are intended to clarify terms used throughout this application.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used in this specification and the appended claims, unless intended to the contrary, the following terms have the meanings set forth to facilitate understanding of this disclosure.

[0024] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0025] As used herein, the following definitions shall apply unless otherwise specified. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Smith, M.B. and March, J., eds. John Wiley & Sons, New York: 2001, the entire contents of both of which are incorporated herein by reference.

[0026] As used herein, the term "herein" means the entire application.

[0027] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where alkyl can be substituted and cases where alkyl is not substituted.

[0028] It is understood that the substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skill in the art to provide chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and by the methods described below. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0029] As used herein, the term "optionally substituted" refers to the replacement of 1 to 6 hydrogen atoms in a given structure with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, aminoalkyl, cyano, haloalkyl, and haloalkoxy. Preferably, "optionally substituted" refers to the replacement of 1 to 4 hydrogen radicals in a given structure with a substituent. More preferably, 1 to 3 hydrogen radicals are replaced by a substituent. It is understood that the substituent may be further substituted.

[0030] As used herein, the term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution results in a stable compound, e.g., one that does not spontaneously undergo transformations, such as by rearrangement, cyclization, elimination, and the like, subject to the permissible valences of the substituted atom and substituent. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this application, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom.

[0031] Substituents can include any of the substituents described herein. Unless otherwise specified, such substituents can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, alkoxy, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that, where appropriate, the substituents themselves can be substituted. For example, substituents of substituted alkyls can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0032] As used herein, the term "acyl" refers to the group -C(=O)-R w (In the formula, R w is an optionally substituted alkyl). An example of "acyl" is R w C1~C 10 Alkyl (C1-C 10 acyl) or C1-C 6-Examples include, but are not limited to, alkyl(C1-C6 acyl). In some embodiments, each occurrence of an optionally substituted substituent is independently selected from the group consisting of H, OH, alkoxy, cyano, F, and amino. Additional examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3).

[0033] As used herein, the term "alkyl" refers to a fully saturated, straight-chain or branched, non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group, unless otherwise defined, can have 1 to about 20 carbon atoms, preferably 1 to about 10, e.g., C1-C6 alkyl, or e.g., C1-C6. Examples of straight-chain and branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. "Alkyl" groups can be optionally substituted.

[0034] "C x ~C y The term " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, "C x ~C yThe term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents a hydrogen when the group is in a terminal position and a bond when it is internal.

[0035] As used herein, the term "alkoxy" refers to a straight or branched chain saturated aliphatic (alkyl) hydrocarbon group attached to an oxygen atom that is bonded to a core structure. Preferably, the alkoxy group has 1 to 6 carbon atoms, i.e., can be a C1-C6 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and the like.

[0036] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogens. Monohaloalkyl radicals can have, for example, a chlorine, bromine, iodine, or fluorine atom. Dihalo and polyhaloalkyl radicals can have two or more of the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and the like.

[0037] As used herein, the term "haloalkoxy" refers to a radical in which one or more of the hydrogen atoms of an alkoxy group has been replaced with one or more halogens. Representative examples of "haloalkoxy" groups include, but are not limited to, difluoromethoxy (-OCHF), trifluoromethoxy (-OCF), or trifluoroethoxy (-OCHCF).

[0038] As used herein, the terms "amine" and "amino" refer to both unsubstituted and substituted amines, as well as salts thereof, e.g., [ka] wherein R z each independently represents hydrogen or a hydrocarbyl group, or R z The groups, together with the N atom to which they are attached, complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0039] As used herein, the terms "amide" and "amido" mean [ka] wherein R x , R y , and R z each independently represents hydrogen or a hydrocarbyl group, or R y and R z together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0040] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0041] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0042] As used herein, the term "cycloalkyl," alone or in combination with other term(s), refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic rings. Typically, monocyclic cycloalkyl groups, unless otherwise defined, have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., C3 to C6). 10Cycloalkyl, or, for example, C3-C6 cycloalkyl). Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The second ring of a bicyclic cycloalkyl, or the second or third ring of a tricyclic cycloalkyl, can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic and tricyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl, or the second or third ring of a fused tricyclic cycloalkyl, can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkyl" group is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like. Cycloalkyls can alternatively be polycyclic, having more than two rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls. As used herein, the term "cycloalkyl" can be optionally substituted, as defined above.

[0043] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (fused rings), where at least one of the rings is aromatic, and the other cyclic rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The term "fused" means that a second ring is attached to or formed by having two adjacent atoms in common with the first ring. The term "fused" is equivalent to the term "condensed." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, phenol, aniline, indanyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indazoyl, imidazoyl, indolinyl, isoindolinyl, and the like. As used herein, the term "aryl" may be optionally substituted as defined above.

[0044] As used herein, the terms "heterocyclyl," "heterocycloalkyl," "heterocycle," and "heterocyclic" refer to non-aromatic, saturated, or partially saturated ring systems containing 3-15 members, monocyclic, polycyclic (including, e.g., bicyclic, tricyclic), bridged, or fused ring systems having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O), NH, or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazodinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxapiperazivir, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups can be optionally substituted with one or more suitable groups by one or more of the aforementioned groups. Preferably, "heterocycloalkyl" refers to a 5- to 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and N-oxides thereof. As used herein, the term "heterocyclyl" may be optionally substituted as defined above.

[0045] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic ring structure, preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, which ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic) containing 8 to 20 ring atoms, preferably 5 to 10 rings, which may be covalently linked or may be fused atoms in which two or more atoms are common to two adjacent rings, and at least one of the rings is heteroaromatic; for example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The ring may contain N or S atoms, where the N or S atoms are optionally oxidized or the N atoms are optionally quaternized. All heteroaryls are optionally substituted. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryls include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, and dibenzothienyl. , benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, alpha-carboline, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, fluoropyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothienyl, acridinyl, and the like.As used herein, the term "heteroaryl" may be optionally substituted as defined above.

[0046] As used herein, the term "cyano" refers to the group --CN.

[0047] As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0048] As used herein, the terms "halo" or "halogen," alone or in combination with other term(s), mean chloro, fluoro, bromo, and iodo.

[0049] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0050] As used herein, the term "hydrocarbyl" refers to a group that has at least one carbon-hydrogen bond and a primarily carbon backbone, but which may optionally contain heteroatoms, that does not have =0 or =S substituents and is bonded through carbon atoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (with =0 substituent on the bonded carbon) and ethoxy (bonded through an oxygen rather than a carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0051] As used herein, the terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which one or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0052] The compounds of the present disclosure may contain one or more chiral centers and therefore exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the arrangement of substituents around the stereogenic carbon atom, although those of skill in the art will recognize that the structure may implicitly indicate a chiral center. The compounds described herein encompass all stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers are sometimes referred to as "(±)" in nomenclature, although those of skill in the art will recognize that the structure may implicitly indicate a chiral center.

[0053] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures according to resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the mixture of enantiomers to a chiral auxiliary, recrystallizing or chromatographically separating the resulting mixture of diastereomers, and liberating the optically pure product from the auxiliary; (2) salt formation using an optically active resolving agent; (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective synthesis, i.e., chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the creation of new stereocenters or the transformation of existing ones, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0054] The present disclosure also encompasses isotopically labeled compounds that are identical to the compounds recited herein except for the replacement of one or more atoms with an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18F, and 36 For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium to form deuterated compounds.

[0055] As used herein, "deuterated" means that at least one hydrogen atom has been replaced by deuterium. In any sample of a deuterated compound, it is likely that some individual molecules of the compound will have hydrogen rather than deuterium at a particular position. However, the proportion of molecules of the deuterated compound that have deuterium at a particular position will be much greater than that which occurs naturally. Deuterium at the deuterated positions is enriched.

[0056] "Pharmaceutically or pharmacologically acceptable" includes molecular substances and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.

[0057] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the present compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts with pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1-1′-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds included in the compositions of the present invention that are acidic in nature can form pharmacologically acceptable base salts with various cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the compositions of the present invention that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0058] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one of the compounds disclosed herein prepared together with one or more pharmaceutically acceptable carriers.

[0059] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0060] "Disease," "disorder," and "condition" are used interchangeably herein.

[0061] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0062] "Combination therapy" is a treatment that includes administering two or more therapeutic agents, e.g., a compound of the present disclosure and an RTK pathway inhibitor, a MAPKAP pathway inhibitor, a PI3K inhibitor, an mTOR inhibitor, an immunomodulatory agent, or a chemotherapeutic agent, or a combination thereof, to a patient in need thereof.

[0063] An "RTK pathway inhibitor" is an inhibitor of the RTK signaling pathway. Inhibitors of this pathway include KIT inhibitors (e.g., ripretinib, avaprinib, sunitinib, AZD3229, THE-630, and imatinib, and pharmaceutically acceptable salts thereof), EGFR inhibitors (e.g., cetuximab, osimertinib, and afatinib, and pharmaceutically acceptable salts thereof), PDGFRα inhibitors (e.g., ripretinib, JNJ10198409, and pharmaceutically acceptable salts thereof), and the like. pharmaceutically acceptable salts thereof), VEGFR inhibitors (e.g., regorafenib, axitinib, and pazopanib, and pharmaceutically acceptable salts thereof), anti-VEGF therapeutic agents (e.g., bevacizumab), BCR-Ab inhibitors (e.g., imatinib, nilotinib, dasatinib, or pharmaceutically acceptable salts thereof), and ALK inhibitors (e.g., lorlatinib and alectinib, and pharmaceutically acceptable salts thereof).

[0064] "MAPKAP pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Inhibitors of this pathway include Ras inhibitors (e.g., AMG-510, MRTX849, GDC-6036, MRTX-1133, RMC-9805, RMC-6291, and RMC-6236, and pharmaceutically acceptable salts thereof), RAF inhibitors (e.g., LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, velbarafenib, KIN-2787, and VS-6766, and pharmaceutically acceptable salts thereof), and the like. and pharmaceutically acceptable salts thereof), MEK inhibitors (e.g., trametinib, selumetinib, cobimetinib, binimetinib, mirdametinib, and VS-6766, and pharmaceutically acceptable salts thereof), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ERAS-007, and ASTX-029, and pharmaceutically acceptable salts thereof). The terms "MAPKAP pathway inhibitor" and "MAPKAP kinase inhibitor" are used interchangeably herein.

[0065] As used herein, a "therapeutically effective amount" refers to an amount of a subject compound that elicits a biological or medicinal response in a tissue, system, or animal (e.g., a mammal or human) being examined by a researcher, veterinarian, physician, or other clinician. The compounds described herein are administered in therapeutically effective amounts to treat disorders.

[0066] The term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as diminishment, reduction, modulation, or elimination.

[0067] As used herein, "compounds of the disclosure" include compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0068] compound In one embodiment, described herein is a compound of formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X 2 , and X 3 provided that no more than two of A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; Y is [ka] wherein s1 is a moiety covalently attached to the ring; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other one is not H, Or, if Y is [ka] If R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 4 teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; however, X 1 , X 2 , and X 3 is CH and Y is [ka] and R 4 C optionally substituted with one or more fluorine atoms 1~5 provided that if A is optionally substituted phenyl, then E is not alkyl substituted with an amine.

[0069] In some embodiments, X 1 is CH. In other embodiments, X 1is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2 is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0070] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0071] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0072] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0073] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0074] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0075] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0076] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0077] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0078] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0079] In some embodiments, R 4 is selected from the group consisting of optionally substituted alkyl and cycloalkyl. In some embodiments, R 4 is methyl, [ka] is selected from the group consisting of:

[0080] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0081] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0082] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0083] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0084] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0085] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6are independently H, alkyl, cycloalkyl, or haloalkyl.

[0086] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0087] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0088] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0089] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0090] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0091] In another embodiment, described herein is a compound of formula II: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X 2 , and X 3 provided that no more than two of A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0092] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2 is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0093] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0094] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0095] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0096] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0097] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0098] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0099] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl [ka] is selected from the group consisting of:

[0100] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0101] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0102] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0103] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0104] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0105] In some embodiments, A is pyrazole and E is [ka] wherein: R 5is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0106] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0107] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0108] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0109] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0110] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0111] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0112] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0113] In one embodiment, described herein is a compound of formula III: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 is selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0114] In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2 is CH. In other embodiments, X 2 is CF, C-Cl, or N.

[0115] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0116] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0117] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0118] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0119] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0120] In some embodiments, R 2is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0121] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl [ka] is selected from the group consisting of:

[0122] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0123] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0124] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0125] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0126] In some embodiments, A is pyrazole and E is [ka] wherein: R 5is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0127] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0128] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0129] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0130] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0131] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0132] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0133] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0134] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0135] In one embodiment, described herein is a compound of formula IV: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 is selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0136] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 2 is CH. In other embodiments, X 2 is CF, C-Cl, or N.

[0137] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0138] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0139] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0140] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0141] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0142] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0143] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0144] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0145] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0146] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0147] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0148] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0149] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0150] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0151] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6are independently H, alkyl, cycloalkyl, or haloalkyl.

[0152] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0153] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0154] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0155] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0156] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0157] In one embodiment, described herein is a compound of formula V: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 is selected from the group consisting of N, CH, CF, and C—Cl; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0158] In some embodiments, X 2 is CH. In other embodiments, X 2 is CF, C-Cl, or N.

[0159] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0160] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0161] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0162] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0163] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0164] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0165] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0166] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0167] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0168] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0169] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0170] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0171] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0172] In some embodiments, E is [ka] wherein: R 5are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0173] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0174] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0175] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0176] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0177] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0178] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0179] In another embodiment, described herein are compounds of formula VI: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 is selected from the group consisting of N, CH, and CF; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0180] In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N.

[0181] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0182] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0183] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0184] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0185] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0186] In some embodiments, R 2is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0187] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0188] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0189] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0190] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0191] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0192] In some embodiments, A is pyrazole and E is [ka] wherein: R 5is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0193] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0194] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0195] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0196] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0197] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0198] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0199] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0200] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0201] In one embodiment, described herein is a compound of formula VII: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0202] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0203] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0204] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0205] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0206] In some embodiments, R は、 H. In some embodiments, R2 は、 H, R3は、 In another embodiment, R 2 is H and R 3is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0207] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0208] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0209] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0210] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0211] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0212] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0213] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0214] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0215] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0216] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0217] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0218] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0219] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0220] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0221] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0222] In another embodiment, described herein are compounds of formula VIII: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X 2 , and X 3 provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0223] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2 is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0224] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0225] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0226] In some embodiments, R 2is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0227] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0228] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0229] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0230] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0231] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0232] In some embodiments, E is [ka] wherein: R 5are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0233] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0234] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0235] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0236] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0237] In one embodiment, described herein is a compound of formula IX: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 is selected from the group consisting of N, CH, CF, and C—Cl; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0238] In some embodiments, X 2 is CH. In other embodiments, X 2is CF, C-Cl, or N.

[0239] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0240] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0241] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0242] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0243] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0244] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0245] In some embodiments, E is [ka] wherein: R 5is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0246] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0247] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0248] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0249] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0250] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0251] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0252] In another embodiment, described herein are compounds of formula X: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 is selected from the group consisting of N, CH, and CF; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0253] In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N.

[0254] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0255] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0256] In some embodiments, R 2is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0257] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0258] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0259] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0260] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0261] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0262] In some embodiments, E is [ka] wherein: R 5are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0263] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0264] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0265] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0266] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0267] In another embodiment, described herein are compounds of formula XI: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0268] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R1 is methyl. In certain embodiments, R 1 is ethyl.

[0269] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0270] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0271] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0272] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0273] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0274] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0275] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0276] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0277] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0278] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0279] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0280] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0281] In another embodiment, described herein are compounds of formula XII: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X2, and X 3 provided that no more than two of X 4 , X 5 , and X 6 are each independently selected from the group consisting of N, CH, and CF; However, X 4 , X 5 , and X 6 provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0282] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2 is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0283] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0284] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0285] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0286] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0287] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0288] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0289] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0290] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0291] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0292] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0293] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0294] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0295] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0296] In one embodiment, described herein is a compound of formula XIII: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 is selected from the group consisting of N, CH, CF, and C—Cl; X 4 , X 5 , and X 6 are each independently selected from the group consisting of N, CH, and CF; However, X 4 , X 5 , and X 6 provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3 The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0297] In some embodiments, X 2 is CH. In other embodiments, X 2 is CF, C-Cl, or N.

[0298] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0299] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0300] In some embodiments, R 2is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0301] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0302] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0303] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0304] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0305] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0306] In some embodiments, E is [ka] wherein: R 5are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0307] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0308] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0309] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0310] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0311] In one embodiment, described herein is a compound of formula XIV: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 4 , X 5 , and X 6 are each independently selected from the group consisting of N, CH, and CF; However, X 4 , X 5 , and X 6 provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 2 and R 3 are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R 2 and R 3 If one of the is H, R 2 and R 3The other of is not H, or R 2 and R 3 together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0312] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0313] In some embodiments, R 2 is H. In some embodiments, R 2 is H and R 3 is alkoxy. In other embodiments, R 2 is H and R 3 is haloalkyl. In some embodiments, R 2 is H and R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 2 is H and R 3 is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. 2 is H and R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 2 is H and R 3is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 2 is H and R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 2 is H and R 3 is heterocyclyl. In some embodiments, R 2 is H and R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0314] In some embodiments, R 2 is alkyl, e.g., methyl. In some embodiments, R 2 is cycloalkyl, for example cyclopropyl.

[0315] In some embodiments, R 3 is alkoxy. In other embodiments, R 3 is haloalkyl. In some embodiments, R 3 is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, where the cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl. In some embodiments, R 3is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is cycloalkyl optionally substituted with one or more halogens. In some embodiments, R 3 is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heteroaryl optionally substituted with haloalkyl. In some embodiments, R 3 is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano. In some embodiments, R 3 is heterocyclyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, [ka] is selected from the group consisting of:

[0316] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0317] In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: [ka]

[0318] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0319] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0320] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0321] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0322] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0323] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0324] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0325] In another embodiment, described herein is a compound of formula XV: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X 2 , and X 3provided that no more than two of A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 4 teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; however, X 1 , X 2 , and X 3 is CH and R 4 C optionally substituted with one or more fluorine atoms 1~5 provided that if A is optionally substituted phenyl, then E is not alkyl substituted with an amine.

[0326] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0327] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0328] In some embodiments, A is [ka] is selected from the group consisting of Each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, where s2 is the site covalently bonded to -NH- and s3 is the site covalently bonded to E.

[0329] In some embodiments, A is phenyl optionally substituted with halogen or alkyl.

[0330] In another embodiment, A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl. In some embodiments, A is pyrazole optionally substituted with halogen or alkyl.

[0331] In some embodiments, R 4 is selected from the group consisting of optionally substituted alkyl and cycloalkyl. In some embodiments, R 4 is methyl, [ka] is selected from the group consisting of:

[0332] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0333] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0334] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0335] In some embodiments, A is pyrazole and E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0336] In some embodiments, E is [ka] wherein: R 5are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0337] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0338] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0339] In some embodiments, A is phenyl or 6-membered heteroaryl and E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0340] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0341] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0342] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0343] In one embodiment, described herein is a compound of formula XVI: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X 2 , and X 3provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 4 teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

[0344] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X 2 is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0345] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0346] In some embodiments, R 4 is selected from the group consisting of optionally substituted alkyl and cycloalkyl. In some embodiments, R 4 is methyl, [ka] is selected from the group consisting of:

[0347] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0348] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0349] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0350] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0351] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0352] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0353] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0354] In another embodiment, described herein is a compound of formula XVII: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 1 and X 3 are each independently selected from the group consisting of N, CH, and CF; X 2 is selected from the group consisting of N, CH, CF, and C—Cl; However, X 1 , X 2 , and X3 provided that no more than two of X 4 , X 5 , and X 6 are each independently selected from the group consisting of N, CH, and CF; However, X 4 , X 5 , and X 6 provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R 1 is alkyl or haloalkyl, R 4 teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is CH and R 4 C optionally substituted with one or more fluorine atoms 1~5 With the proviso that, if alkyl, E is not an alkyl substituted with an amine.

[0355] In some embodiments, X 1 is CH. In other embodiments, X 1 is CF or N. In some embodiments, X 3 is CH. In other embodiments, X 3 is CF or N. In some embodiments, X2 is CH. In another embodiment, X 2 is CF, C—Cl, or N. In some embodiments, X 1 , X 2 , and X 3 is CH.

[0356] In some embodiments, R 1 is alkyl, e.g., methyl or ethyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0357] In some embodiments, R 4 is selected from the group consisting of optionally substituted alkyl and cycloalkyl. In some embodiments, R 4 is methyl, [ka] is selected from the group consisting of:

[0358] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0359] In some embodiments, E is [ka] wherein: R 5 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

[0360] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0361] In some embodiments, E is [ka] wherein: R 5 are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R 6 are independently H, alkyl, cycloalkyl, or haloalkyl.

[0362] In some embodiments, E is H. In other embodiments, E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy. In some embodiments, E is alkyl. In some embodiments, E is haloalkyl. In some embodiments, E is cycloalkyl optionally substituted with one or more halogens. In some embodiments, E is 4-6 membered heterocyclyl. In some embodiments, E is selected from the group consisting of H, alkyl optionally substituted with cycloalkyl, amine, or alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

[0363] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0364] In some embodiments, E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, [ka] is selected from the group consisting of:

[0365] In one embodiment, described herein is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof.

[0366] Treatment methods The compounds described herein (e.g., Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, and Formula XVII, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof) can act as inhibitors of autophagy useful in treating a disorder in a patient in need thereof. The disorder can be, for example, a tumor, e.g., a solid tumor. The disorder can also be cancer.

[0367] Exemplary disorders also include gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, leukemia, cervical cancer, cancer that metastasizes to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer. The cancer treated by the methods described herein can be a metastatic cancer.

[0368] In some embodiments, the compounds described herein are useful for treating cancer caused by a RAS mutation. In some embodiments, the cancer is caused by a KRAS mutation. In some embodiments, the cancer has additional mutations in tumor suppressor proteins, including mutations in TP53, PTEN, CDN2A / INK4A, p16, or STAG2. In some embodiments, these additional mutations occur in one or more of TP53, PTEN, CDN2A / INK4A, p16, or STAG2. In some embodiments, the cancer is pancreatic ductal adenocarcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer.

[0369] In some embodiments, confirmation of cellular inhibition of autophagy by a compound described herein is determined by monitoring autophagic flux, for example, by monitoring inhibition of autophagy-mediated clearance of an mCherry / GFP-LC3 fusion protein. In some embodiments, confirmation of cellular inhibition of autophagy by a compound described herein is determined by monitoring the accumulation of an autophagy protein, such as p62 or LC-3. In some embodiments, confirmation of cellular inhibition of autophagy by a compound described herein is determined by a decrease in clearance of luciferase-tagged LC3 protein. In some embodiments, confirmation of cellular inhibition of autophagy by a compound described herein is determined by monitoring a decrease in cellular autophagosomes, for example, by measuring fluorescent puncta using the autophagosome marker Cyto-ID.

[0370] In some embodiments, cellular inhibition of ULK kinase by the compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, cellular inhibition of ULK kinase by the compounds described herein is determined in host tissues, including immune cells.

[0371] In some embodiments, in vivo inhibition of autophagy by compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in host tissues, including immune cells. In some embodiments, in vivo inhibition of autophagic flux by compounds described herein can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in animals bearing pancreatic cancer. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in animals bearing lung cancer. In some embodiments, in vivo inhibition of ULK kinase is determined in animals bearing colorectal cancer. In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibition of autophagic flux in tumor cells or in non-tumor host tissues by monitoring inhibition of autophagosome formation or by accumulation of autophagy proteins such as p62 or LC-LIII. In some embodiments, in vivo inhibition of autophagy is determined in host tissues containing immune cells. In some embodiments, in vivo inhibition of autophagic flux can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition.

[0372] In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in xenograft studies utilizing human RAS mutant cell lines in immunodeficient mice, e.g., SCID or nude mice. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in xenograft studies utilizing human RAS mutant patient-derived tumor xenografts (PDX) in immunodeficient mice, e.g., SCID or nude mice. In some embodiments, xenograft studies include evaluation of compounds described herein in pancreatic cancer models. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in a syngeneic mouse genetically engineered model (GEM) of mutant RAS cancer. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in a mouse GEM syngeneic orthotopic pancreatic cancer model (LSL-Kras), known as the KPC model. G12D / + ;LSL-Trp53 R172H / + ;Pdx-1-Cre) or a variant of the KPC model.

[0373] In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with MEK inhibitors.In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with RAF inhibitors.In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with ERK inhibitors.In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with RAS G12C direct inhibitors.

[0374] In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein are evaluated in immunocompetent mouse cancer models to assess the immunomodulatory component to the mechanism of action of ULK inhibitors. In some embodiments, the immunocompetent mouse model is the KPC model, LSL-Kras G12D / + ;LSL-Trp53R172H / + ;Pdx-1-Cre) or a variant of the KPC model. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with a MEK inhibitor. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with a RAF inhibitor. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with an ERK inhibitor. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with a RAS G12C direct inhibitor.

[0375] In some embodiments, the immunomodulatory component of ULK inhibition is an enhancement of the innate immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhancement of the adaptive immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhancement of the activity of antigen-presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is an enhancement of the anti-tumor activity of myeloid cells, including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is an enhancement of the anti-tumor activity of natural killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is an enhancement of the activity of effector T cells, including cytotoxic T cells.

[0376] In one embodiment, provided herein is a method of treating a disorder described herein, the method comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with a ULK kinase during or after the administration course (e.g., at discrete time points such as one week, two weeks, or one month after the initial administration of a contemplated compound), wherein detecting comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay to detect inhibition of ULK kinase activity based on the level of phospho-ATG13 in the sample. In some embodiments, contemplated methods comprise optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay prior to administration of the compound and comparing the level of phospho-ATG13 in the sample obtained before administration with the level of phospho-ATG13 in a sample obtained during or after the administration course. In some embodiments, the phospho-ATG13 is p-S318ATG13.

[0377] In one embodiment, provided herein is a method of treating a disorder described herein, the method comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with a ULK kinase during or after the administration course (e.g., at discrete time points such as one week, two weeks, or one month after the initial administration of a contemplated compound), wherein detecting comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG14 antibody ELISA assay to detect inhibition of ULK kinase activity based on the level of phospho-ATG14 in the sample. In some embodiments, contemplated methods comprise optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay prior to administration of the compound and comparing the level of phospho-ATG14 in the sample obtained before administration with the level of phospho-ATG14 in a sample obtained during or after the administration course. In some embodiments, the phospho-ATG14 is p-ATG14 Ser29.

[0378] In one embodiment, provided herein is a method of treating a disorder described herein, the method comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with a ULK kinase during or after the administration course (e.g., at discrete time points, such as one week, two weeks, or one month after the initial administration of a contemplated compound), wherein detecting comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay to detect inhibition of ULK kinase activity based on the level of p62 in the sample. In some embodiments, contemplated methods comprise optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay prior to administration of the compound and comparing the level of p62 in the sample obtained before administration with the level of p62 in a sample obtained during or after the administration course.

[0379] In one embodiment, provided herein is a method of treating a disorder described herein, the method comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with ULK kinase during or after the administration course (e.g., at discrete time points, such as one week, two weeks, or one month after the initial administration of a contemplated compound), wherein detecting comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a pBeclin antibody ELISA assay to detect inhibition of ULK kinase activity based on the level of pBeclin in the sample. In some embodiments, contemplated methods comprise optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a pBeclin antibody ELISA assay prior to administration of the compound and comparing the level of p62 in the sample obtained before administration with the level of pBeclin in a sample obtained during or after the administration course.

[0380] The compounds provided herein can be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be understood that the dosage required for any particular application will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, any concomitant medications or special diets the patient may be following, and other factors that will be recognized by those skilled in the art, and that the appropriate dosage will ultimately be at the discretion of the attending physician. To treat the above-mentioned clinical conditions and diseases, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration can include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0381] Treatment can be continued for as long or as short a period as desired. The composition may be administered, for example, one to four times daily or more. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinitely. The treatment period can be terminated when the desired results are achieved.

[0382] Combination therapy The compounds described herein, such as those of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, can be administered in combination with one or more additional therapeutic agents to treat the disorders described herein, such as the cancers described herein. For example, the present disclosure provides pharmaceutical compositions comprising a compound described herein, such as those of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII described herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and one additional therapeutic agent are administered. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII described herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII described herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately.For example, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII described herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example, a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as one therapeutic agent, and one or more additional therapeutic agents, such as chemotherapeutic agents. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII defined herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. Two or more agents in combination therapy can be administered simultaneously, but this is not required. For example, administration of a first agent (or combination of agents) can occur minutes, hours, days, or weeks before administration of a second agent (or combination of agents). Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or more weeks of each other.In some cases, even longer intervals are possible.In many cases, it is desirable, but not necessary, for two or more drugs used in combination therapy to be present in the patient's body at the same time.

[0383] Combination therapy can also include two or more administrations of one or more of the agents used in the combination, with the component agents being administered in a different order. For example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination, e.g., in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0384] Combination therapy can also include two or more administrations of one or more agents used in combination using different routes of administration. Each of the one or more agents may be administered independently orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in a unit dosage formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration can include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0385] In some embodiments, the one or more additional therapeutic agents that may be administered in combination with a compound described herein (e.g., Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof) can be an RTK pathway inhibitor, a MAPKAP pathway inhibitor, a PI3K inhibitor, an mTOR inhibitor, an immunomodulatory agent, or a chemotherapeutic agent, or any combination thereof.

[0386] In some embodiments, the additional therapeutic agent is a RTK pathway inhibitor, including, for example, KIT inhibitors, EGFR inhibitors, PDGFRα inhibitors, VEGFR inhibitors, anti-VEGF therapeutics, BCR-ABL inhibitors, and ALK inhibitors.

[0387] Exemplary KIT inhibitors include, but are not limited to, ripretinib, avaprinib, sunitinib, AZD3229, THE-630, and imatinib, and pharmaceutically acceptable salts thereof. Exemplary EGFR inhibitors include, but are not limited to, cetuximab, osimertinib, and afatinib, and pharmaceutically acceptable salts thereof.

[0388] Exemplary PDGFRα inhibitors include, but are not limited to, ripretinib, JNJ10198409, or pharmaceutically acceptable salts thereof. Exemplary VEGFR inhibitors include, but are not limited to, regorafenib, axitinib, and pazopanib, and pharmaceutically acceptable salts thereof. Exemplary anti-VEGF therapeutic agents include bevacizumab. Exemplary BCR-Abl inhibitors include, but are not limited to, imatinib, nilotinib, dasatinib, or pharmaceutically acceptable salts thereof. Exemplary ALK inhibitors include, but are not limited to, lorlatinib and alectinib, and pharmaceutically acceptable salts thereof.

[0389] In some embodiments, the additional therapeutic agent is a MAPKAP pathway inhibitor, including, for example, a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.

[0390] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, mirdametinib, and VS-6766, and pharmaceutically acceptable salts thereof.

[0391] Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, lavoxertinib, VX-11e, ERAS-007, and ASTX-029, and pharmaceutically acceptable salts thereof.

[0392] Exemplary RAF inhibitors include, but are not limited to, LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, berbalafenib, KIN-2787, and VS-6766, and pharmaceutically acceptable salts thereof.

[0393] Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, GDC-6036, MRTX-1133, RMC-9805, RMC-6291, and RMC-6236, and pharmaceutically acceptable salts thereof.

[0394] In some embodiments, the additional therapeutic agent is a PI3K inhibitor or an mTOR inhibitor.

[0395] Exemplary PI3K inhibitors include, but are not limited to, alpelisib, LY294002, and omipalisib, and pharmaceutically acceptable salts thereof.

[0396] Exemplary mTOR inhibitors include, but are not limited to, rapamycin, everolimus, PF04691502, and PP242, and pharmaceutically acceptable salts thereof.

[0397] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer, including radiation therapy, antitubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, antiestrogens, antiandrogens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, antiangiogenic agents, proteasome inhibitors, PARP inhibitors, cell cycle-regulating kinase inhibitors, thalidomide, lenalidomide, antibody-drug-conjugates (ADCs), immunotherapeutics including immunomodulators, targeted therapeutic agents, cancer vaccines, and CAR-T cell therapy.

[0398] In one embodiment, the additional therapeutic agent is an antitubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatin, or maytansinoid), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA The A intercalating agent or DNA topoisomerase inhibitor may be a chemotherapeutic agent, including, but not limited to, doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin, camptothecins, such as topotecan, irinotecan, or exatecan, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate.

[0399] In some embodiments, the additional therapeutic agent is selected from the group consisting of an antitubulin agent, vinorelbine, a DNA alkylating agent, a DNA intercalating agent, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, irinotecan, and methotrexate.

[0400] In some embodiments, the additional therapeutic agent is erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, ripretinib, avapritinib, JNJ10198409, nilotinib, idelalisib, ibrutinib, BLU-28 kinase inhibitors, including but not limited to, tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; antiandrogens, including but not limited to, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate; steroids, including but not limited to, prednisone and dexamethasone; neraparib, olaparib, talazoparib, and PARP inhibitors, including but not limited to rinotecan, camptothecin, exatecan, and topotecan; topoisomerase I inhibitors, including but not limited to anthracyclines, etoposide, etoposide phosphate, and mitoxantrone; histone deacetylase (HDAC) inhibitors, including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; proteasome inhibitors, including but not limited to bortezomib and carfilzomib, biologic agents, including but not limited to thalidomide, lenalidomide, pomalidomide, trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab; anti-PD-1 agents, including pembrolizumab, nivolumab, pidilizumab, and cemiplimab; anti-PD-L1 agents, including atezolizumab, avelumab, durvalumab, and BMS-936559;These may be kinase inhibitors, including but not limited to agents including bevacizumab and aflibercept, as well as antibody-drug conjugates (ADCs) with DM1, DM4, MMAE, MMAF, or camptothecin payloads, brentuximab vedotin and trastuzumab emtansine, radiation therapy, therapeutic vaccines (including but not limited to sipuleucel-T);

[0401] In some embodiments, the additional therapeutic agent is an anti-PD-1 or anti-PDL-1 therapeutic, including but not limited to, pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, avelumab, or dostallimab; an anti-TIM3 (anti-HAVcr2) therapeutic, including but not limited to, TSR-022 or MBG453; an anti-LAG3 therapeutic, including but not limited to, leratolimab, LAG525, or TSR-033; a CD40 agonist therapeutic, including but not limited to, anti-4-1BB (anti-CD37, anti-TNFRSF9), SGN-40, CP-870,893, or RO7009789; The therapeutic agent may be an immunomodulatory agent, including but not limited to: an anti-CD47 therapeutic, an anti-CD20 therapeutic, an anti-CD38 therapeutic; a STING agonist, including but not limited to ADU-S100, MK-1454, ASA404, or an amide benzimidazole; an anthracycline, including but not limited to doxorubicin or mitoxantrone; a hypomethylating agent, including but not limited to azacitidine or decitabine; or another immunomodulatory agent, including but not limited to an epidermal growth factor inhibitor, a statin, metformin, an angiotensin receptor blocker, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone.

[0402] In some embodiments, the additional therapeutic agent is an immunomodulatory agent selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, avelumab, cetuximab, TSR-022, MBG453, leratolimab, LAG525, TSR-033, SGN-40, CP-870,893, RO7009789, Hu5F9-G4, ADU-S100, MK-1454, ASA404, doxorubicin, mitoxantrone, azacitidine, decitabine, a statin, metformin, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, and dostarlimab, and pharmaceutically acceptable salts thereof.

[0403] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone-releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0404] In some embodiments, the additional therapeutic agent is everolimus, trabectedin, abraxane, TLK286, AV-299, DN-101, pazopanib, GSK690693, RTA744, ON0910.Na, ADAD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AMAD1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, obatumunab, zanolimumab, edotecarin, tetradrine, rubiteca , tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypti, Bio1111, 131-I-TM-601, ALT-110, BIO140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO1001, IPdR1KRX-0402, lucanton, LY317615, neurodiab, vitespan, Rta744, Sdx102, talampanel, atrasentan, Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine Vin, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, ADAD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazoline ol, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-j-quinolone, vatalanib, AG-013736, AVE-0005, acetate salt of [D-Ser(But)6,Azgly10](pyro-Glu-His-Trp-Ser)-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate salt [C. 59 H 84 N18Oi4 -(C2H4O2) x(wherein x=1 to 2.4) (SEQ ID NO: 4), goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, furutanide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipipalnib; amifosti NVP-LAQ824, steroylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, alnsculin, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epinephrine Rubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Glevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesenna, methotrexate, mitotrexate, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, primamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin Syn, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenyluracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barbicine, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, maristat, COL-3, neovastatin, BMS-275291, squamine, endostatin, SU5416,SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftox, gefitinib, bortezimib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxybenzoates , pipendoxifene, ella-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, doxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM33637 2, L-779, 450, PEG-filgrastim, darbepoetin, erythroid-stimulating factor, zoledronic acid, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole le, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibrittomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, steroids, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam,Selected from the group consisting of alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, procloperazine, granisetron, ondansetron, dolasetron, tropisetron, spegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, MRTX849, MRTX1133, AMG510, GDC-6036, RMC-9805, RMC-6291, RMC-6236, belvarafenib, KIN-2787, ERAS-007, ASTX-029, and mixtures thereof.

[0405] Pharmaceutical compositions and kits Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most appropriate administration form in any particular case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated as a unit dose and / or may be formulated for oral or subcutaneous administration.

[0406] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form containing one or more of the compounds described herein as active ingredients mixed with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. The active ingredient may be formulated with a conventional non-toxic pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0407] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound provided herein, or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0408] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrants, such as agar, charcoal, etc. Examples of suitable additives include calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents such as paraffin, (6) absorption accelerators such as quaternary ammonium compounds, (7) wetting agents such as acetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0409] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0410] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0411] Suspensions may contain, in addition to the subject composition, suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0412] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but become liquid at body temperature, and thus melt in the body cavity and release the active agent(s).

[0413] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0414] Ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0415] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0416] The compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing aqueous aerosols, liposomal preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used to minimize exposure of the drug to shear, which can result in degradation of the compounds contained in the subject compositions. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject compositions with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0417] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, and may contain antioxidants, buffers, bacteriostats, solutes that render the solution isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0418] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0419] In another aspect, an enteral pharmaceutical formulation is provided, comprising the disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof. The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and predominantly soluble in intestinal fluids at a specific pH. The small intestine is the portion of the digestive tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5.

[0420] Thus, the enteric material does not dissolve until a pH of, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl meth ...cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl meth Examples of suitable enteric dispersions include copolymers of acrylate and methacrylic acid, methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copalcollophorium, and several commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is known or can be readily determined in vitro. While the foregoing is a list of potential materials, one skilled in the art with the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that will meet the objectives described herein.

[0421] Advantageously, kits are provided herein for use by a purchaser in need of, for example, cancer treatment. Such kits include an appropriate dosage form, such as those described above, and instructions describing how to use such dosage form to mediate, reduce, or prevent inflammation. The instructions instruct the purchaser or a medical professional to administer the dosage form according to an administration mode known to those skilled in the art. Such kits can be advantageously packaged and sold in single or multiple kit units. One example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed to the plastic foil with the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through the openings.

[0422] For example, it may be desirable to provide a memory aid on the kit in the form of numbers next to the tablets or capsules, which numbers correspond to the days of the regimen on which the tablets or capsules so designated should be taken. Another example of such a memory aid is, for example, a calendar printed on a card, such as "Week 1, Monday, Tuesday, ...etc... Week 2, Monday, Tuesday, ..." etc. Other types of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule to be taken on a given day, or multiple tablets or capsules. Also, a daily dose of a first compound can consist of one tablet or capsule, and a daily dose of a second compound can consist of multiple tablets or capsules, or vice versa. The memory aid should reflect this.

[0423] Example The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods set forth below, all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and workup procedures, may be selected to be standard conditions for the reaction unless otherwise specified. Those skilled in the art of organic synthesis understand that the functionality present on various portions of the molecule must be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods are therefore indicated. The starting materials in the examples are commercially available or readily prepared by standard methods from known materials.

[0424] The following abbreviations are used in this disclosure and have the following definitions: "ADP" is adenosine diphosphate, "aq" is aqueous solution, "ATP" is adenosine triphosphate, "Ar" is argon gas, "Boc" is tert-butyl carbonate, "BSA" is bovine serum albumin, "conc" is concentrated, "DBU" is 1,8-diazabicyclo[5.4.0]undec-7-ene, "DCM" is dichloromethane, "DDQ" is 2,3-dichloro-5,6-dicyano-para-benzoquinone, and "DCE" is 1,2-dichloroethane. where "DIEA" is N,N-diisopropylethylamine, "DMF" is N,N-dimethylformamide, "DMSO-d6" is dimethylsulfoxide-deuterated, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" is electrospray ionization, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is hour(s), "HO" is water, "HFIP" is hexafluoroisopropanol, and "IC" is abbreviation for "IC" in the stanford English text. 50 " is the 50% inhibitory concentration, "HOBt" is hydroxybenzotriazole, "KF" is potassium fluoride, "LDA" is lithium diisopropylamide, "LiOH" is lithium hydroxide, "M" is molar concentration, "MeCN" is acetonitrile, "MeOH" is methanol, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is minute(s), "MS" is mass spectrometry, "MTBE" is methyl tert-butyl ether, "m / z" is mass / charge, "Na2CO3" is sodium carbonate, "NADH" is nicotinamide adenine dinucleotide, "NaHCO3" is sodium bicarbonate, and "Na 2SO4" is sodium sulfate, "NMR" is nuclear magnetic resonance, "PBS" is phosphate buffered saline, "Pd" is palladium, "Pd(OAc)2" is palladium(II) acetate, "PMB" is para-methoxybenzyl, "rt" is room temperature also known as "ambient temperature", understood to comprise the range of normal laboratory temperatures ranging from 15 to 25°C, "SM" is starting material, and "S N " is a nucleophilic substitution, and "T 3P " is 1-propanephosphonic anhydride, "TBAI" is tetrabutylammonium iodide, "TEA" is triethylamine, "TFE" is trifluoroethanol, "THF" is tetrahydrofuran, "Xantphos" is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and "Yb(OTF)3" is tris(((trifluoromethyl)sulfonyl)oxy)ytterbium.

[0425] general chemistry Exemplary compounds described herein are accessible by the general synthetic methods illustrated in the following schemes, intermediate preparations, and accompanying examples.

[0426] Synthesis scheme Scheme 1 [ka] Scheme 1 shows an exemplary preparation of intermediates 1.3a and 1.3b. Both bromide 1.1 and ester 1.2 can be converted to R 1 under Lewis acid conditions, such as tris(((trifluoromethyl)sulfonyl)oxy)ytterbium, in an aprotic solvent at elevated temperature. 1 C(OR 1 )3 to give alkoxyalkylidenes 1.3a and 1.3b, respectively.

[0427] Scheme 2 [ka] Scheme 2 shows an exemplary preparation of intermediate 2.3. The reaction of 2.1 with amine R under typical amide coupling conditions 2 R 3 Amide coupling reaction with NH affords amide 2.2. Amide 2.2 can be converted to R under Lewis acid conditions such as tris(((trifluoromethyl)sulfonyl)oxy)ytterbium at elevated temperature in an aprotic solvent. 1 C(OR 1 )3 to give the alkoxyalkylidene 2.3.

[0428] Scheme 3 [ka] Scheme 3 shows an exemplary preparation of key intermediates 3.2a and 3.2b. Both bromide 1.3a and ester 1.3b are reacted with amine EA-NH2 via a substitution reaction in a protic solvent such as MeOH and EtOH to give 3.1a and 3.1b, respectively. Aryl bromide 3.1a (R = Br) is fluorocarbonylated using N-formylsaccharin and KF under a Pd catalyst such as Pd(OAc)2 in DMF at elevated temperatures to give acyl fluoride 3.2a (Org. Lett., 2013, 15, 5360-5373). Hydrolysis of 3.1b (R = COOCH3) under basic conditions such as LiOH in a polar solvent such as MeOH, water, and 1,4-dioxane gives carboxylic acid 3.2b.

[0429] Scheme 4 [ka] Scheme 4 shows an exemplary preparation of intermediate 4.7. A common acylating agent R 4Friedel-Crafts acylation with COCl affords ketone 4.2. Ketone 4.2 is reacted with P-Cl in the presence of a base such as CsCO in DMF to afford P-protected (P can be a benzyl or PMB group) compound 4.3. Compound 4.3 is silyl enolized with trimethylchlorosilane in an aprotic solvent such as acetonitrile under sodium iodide-tertiary amine or LDA conditions, followed by DCM to afford enolate 4.4. Compound 4.6 can be prepared by (1) the R reaction of silyl enol ether 4.4 in polyfluoroalcohols (TFE and HFIP) as solvents without a catalyst. 4a Alkylation of enol ether 4.4 with Br (alpha-keto bromide) (CN104844401) and alkylating reagent alkyl chloride R 4a Cl or alkyl ether R 4a -OR 4a (Tetrahedron, 2009, 65, 5462-5471), (3) the alkylation of silyl enol ether 4.4 with alkylating reagent R 4a Compound 4.6 can be prepared by Pd-catalyzed dual ligand-compatible alkylation with Br (ACS Catalysts, 2020, 10, 1334-1343), and (4) photocatalytic decarboxyalkylation of enol ether 4.4 with reagent 4.5 using TBAI (Org. Chem. Frontiers, 2021, 8, 4166-4170). Compound 4.6 can be deprotected under strong acidic conditions (TFA with trifluoromethanesulfonic acid) or mildly oxidative conditions using DDQ to give compound 4.2 (R 4 =CH2R 4a Amide 2.2 can be converted to R under Lewis acid conditions such as tris(((trifluoromethyl)sulfonyl)oxy)ytterbium in an aprotic solvent at elevated temperature. 1 C(OR 1 )3 to give the alkoxyalkylidene 2.3.

[0430] Scheme 5 [ka] Scheme 5 shows an exemplary preparation of compounds of Formula I. The key intermediate aldehyde 5.1 can be prepared from bromide 3.1a by reaction with potassium vinyltrifluoroborate in the presence of a palladium catalyst (Suzuki reaction), followed by oxidation with OsO and sodium periodate. Aldehyde 5.1 can be prepared by the Grignard reagent R 4 Reaction with MgBr provides the secondary alcohol, which can then be oxidized using Dess-Martin periodinane in an aprotic solvent to give compounds of formula I. Alternatively, compounds of formula I can be prepared by the substitution reaction of 4.3 with the amine EA-NH2.

[0431] Scheme 6 [ka] Scheme 6 shows an exemplary preparation of compounds of Formula I. Compounds of Formula I can be prepared by the substitution reaction of 2.3 with the amine EA-NH. Pd-catalyzed aminocarbonylation of 3.1a with amines (R2R3NH) using either Mo(CO)6 or Co2(CO)8 as the CO source provides compounds of Formula I (Tetrahedron Lett., 2013, 54, 6912-6915 and J. Org. Chem., 2021, 86, 5530-5537). Alternatively, compounds of Formula I can be prepared by the substitution reaction of acyl fluorides 3.2a with amines (R2R3NH). 2 In another embodiment, acid 3.2b can be prepared by coupling an amine (R NH) to an amine (R NH) in the presence of an amide coupling reagent such as EDC, T3P, and HATU in an aprotic solvent such as DCM. 2 R 3 NH) to give the compound of formula I.

[0432] Preparation of intermediates. Using the synthetic procedures and methods described herein and methods well known to those skilled in the art, the following compounds were made.

[0433] General Method A: Amide Formation Example A1: 2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide [ka] A suspension of 2-oxoindoline-5-carboxylic acid (5.0 g, 28 mmol) in DCM (150 mL) was treated with HOBt (4.5 g, 30 mmol) and EDC (5.7 g, 30 mmol). The reaction was stirred at room temperature for 15 minutes, and then 2,2,2-trifluoroethan-1-amine (3.4 g, 34 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. DIEA (4.9 mL, 28 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with EtOAc, and the organic layer was washed with aqueous 1.0 M HCl (50 mL) and then saturated NaHCO solution (3x). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide (4.5 g, 62%). 1 H NMR(500MHz,DMSO-d6):d10.67(s,1H),8.90(t,J=6.4Hz,1H),7.86(s,1H),7.84(s, 1H), 6.88(d, J=8.0Hz, 1H), 4.01-4.10(m, 2H), 3.54(s, 2H), MS(ESI)m / z:259.0(M+H + ).

[0434] General Method B: Carbonylation Example A2: N-isobutyl-2-oxoindoline-5-carboxamide [ka] A solution of 5-bromoindolin-2-one (1.5 g, 7.1 mmol) in 1,4-dioxane (15 mL) was treated with Na2CO3 (2.2 g, 21 mmol) at room temperature, and the solution was then purged with nitrogen for 5 minutes. Mo(CO)6 (0.93 g, 3.5 mmol) and Hellmann-Beller catalyst (0.33 g, 0.35 mmol) were added, and the nitrogen purging was continued for another 5 minutes. 2-Methylpropan-1-amine (1.6 g, 21 mmol) was added, and the reaction mixture was heated at 145 °C for 16 hours. The reaction was diluted with DCM and filtered through a pad of celite. The filtrate was washed with saturated NaHCO3, and the organic phase was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (MeOH / DCM) to afford N-isobutyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (0.48 g, 29%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6):d10.52(s,1H),8.20(t,J=5.2Hz,1H),7.71(m, 2H),6.82(d,J=8.8Hz),1H),3.51(s,2H),3.05(t,J=6.8Hz,2H),1.82(m,1H),0.86(d,J=6.4Hz,6H),MS(ESI)m / z:233.2(M+H + ).

[0435] General Method C: Friedel-Crafts Acylation Example A3: 5-Acetylindolin-2-one [ka] An RBF was charged with AlCl (2.5 g, 19 mmol) and DCE (8 mL), and the solution was then cooled to 0 °C in an ice-water bath. Oxindole (1.0 g, 7.7 mmol) was added, and acetyl chloride (1.1 mL, 15 mmol) was added dropwise over 5 min. The reaction was allowed to warm gradually to room temperature and then stirred at room temperature overnight. The reaction mixture was carefully added to ice (300 mL), and the slurry was stirred until the ice melted. The solid was filtered, washed with water, and dried in a vacuum oven for 2 h to give 5-acetylindolin-2-one (1.15 g, 86%) as a tan solid. 1 H NMR(500MHz,DMSO-d6):d10.74(s,1H),7.85(dd,J=8.2,1.7Hz,1H),7.79(s,1H),6.89(d,J=8.2Hz),1H),3.54(s,2H),2.49(s,3H).

[0436] Using general methods A, B, and C above, the intermediates in Table A below were prepared. [Table A-1] [Table A-2] [Table A-3]

[0437] General Method D: Enol Ether Formation in Lewis Acids Example B1: (Z)-3-(1-ethoxypropylidene)-2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide [ka] A suspension of 2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide (A1, 4.5 g, 17 mmol) and 1,1,1-triethoxypropane (7.0 mL, 35 mmol) in DCE (80 mL) was treated with Yb(OTf) (0.54 g, 0.87 mmol). The reaction mixture was heated at 80 °C overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was suspended in MeCN, and the solid was collected by vacuum filtration to give (Z)-3-(1-ethoxypropylidene)-2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide (4.4 g, 73%) as a pale purple solid. MS (ESI) m / z: 343.2 (M+H + ).

[0438] Using general method D above, the intermediates in Table B below were prepared. [Table B-1] [Table B-2] [Table B-3] [Table B-4] [Table B-5]

[0439] General Method E: Substitution Reactions Example C1: Ethyl (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxylate [ka] A solution of ethyl (Z)-3-(1-ethoxypropylidene)-2-oxoindoline-5-carboxylate (B5, 5.0 g, 17 mmol) and 1-isopropyl-1H-pyrazol-4-amine (2.2 g, 17 mmol) in EtOH (50 ml) was heated to 90° C. overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was treated with MTBE and sonicated for 15 minutes. The solid was then filtered to afford Ethyl (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxylate (5.6 g, 87%) was obtained as a brown solid. 1 H NMR(500MHz,DMSO-d6):d11.69(s,1H),10.96(s,1H),8.01(s,1H),7.86(d,J=1.6Hz,1H),7.68(dd,J=8.2,1.5Hz,1H),7.56(s,1H),6.98(d , J=8.2Hz, 1H), 4.50(m, 1H), 4.28(q, J=7.1Hz, 2H), 2.77(q,J=7.6Hz,2H),1.44(d,J=6.7Hz,6H),1.23-1.34(m,6H), MS(ESI)m / z:369.2(M+H + ).

[0440] Using general procedure E above, the intermediates in Table C below were prepared. [Table C-1] [Table C-2] [Table C-3] [Table C-4] [Table C-5]

[0441] General method F: Hydrolysis Example D1: (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxylic acid [ka] A solution of ethyl (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxylate (C1, 5.6 g, 15 mmol) in a mixture of MeOH:1,4-dioxane:HO (2:1:1, 80 mL) was treated with LiOH hydrate (1.03 g, 25 mmol). The reaction mixture was heated at 70 °C overnight. The reaction was cooled to room temperature, and the volatiles were removed under reduced pressure. The crude product was purified by reverse-phase column chromatography (0–100% MeCN / HO (0.1% HCOOH)) to afford (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxylic acid (1.16 g, 23%) as a brown solid. 1 H NMR(500MHz,DMSO-d6):d12.41(s,1H),11.68(s,1H),10.91(s,1H),8.01(s,1H),7.86(s,1H),7.67(dd,J=8.1,1.5Hz,1H),7.56(s, 1H),6.96(d,J=8.1Hz,1H),4.50(m,1H),2.76(q,J=7.6Hz,2H),1.44(d,J=6.8Hz,6H),1.26(t,J=7.6Hz,3H),MS(ESI)m / z:341.2(M+H + ).

[0442] Using general procedure F above, the intermediates in Table D below were prepared. [Table D]

[0443] General Method G: Pd-Catalyzed Fluorocarbonylation Using N-Formylsaccharin Example E1: (Z)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carbonyl fluoride [ka] A solution of (Z)-5-bromo-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (C4, 0.50 g, 1.1 mmol) in DMF (7 mL) was treated with KF (0.16 g, 2.7 mmol). The reaction mixture was sparged with Ar for 5 minutes. Palladium(II) acetate (16 mg, 0.07 mmol) and Xantphos (0.06 g, 0.11 mmol) were added, and the mixture was then sparged with Ar for 5 minutes. N-formylsaccharin (0.74 g, 3.6 mmol) was added, and the vial was immediately sealed. The vial was then heated at 80° C. overnight. The reaction was cooled to room temperature, and the cooled material was transferred to a 10 mL volumetric flask and diluted to the mark with fresh DMF. For calculation purposes, conversion was assumed to be 100% and the final concentration of (Z)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carbonyl fluoride (0.46 g, 100%) was assumed to be 0.1 M. No additional data was collected on this product.

[0444] Using general method G above, the intermediates in Table E below were prepared. [Table E]

[0445] General Method H: Substitution Reactions with Acyl Fluorides Example 1: (R,Z)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxo-N-((tetrahydrofuran-2-yl)methyl)indoline-5-carboxamide [ka] (Z)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carbonyl fluoride (E1, 0.14 g, 0.32 mmol) in DMF (3 mL) was treated with triethylamine (0.2 mL, 1.43 mmol) at room temperature. (R)-(tetrahydrofuran-2-yl)methanamine (0.07 g, 0.70 mmol) was added, and the reaction was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, and the residue was diluted with aqueous Na2CO3 (50%). The combined organic extracts were dried over anhydrous Na2SO4, and the solvent was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (5–90% HO / MeCN (0.1% HCOOH)). The main fraction was collected and treated with aqueous Na2CO3 (50%). The solution was extracted with DCM (4x) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (R,Z)-3-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxo-N-((tetrahydrofuran-2-yl)methyl)indoline-5-carboxamide (0.10 g, 55%). 1 H NMR(500MHz,DMSO-d6):d11.70(s,1H),10.77(s,1H),8.36(t,J=5.8Hz,1H),8.01(s,1H),7.75(s,1H),7.55(s, 1H), 7.54(dd, J=8.1, 1.5Hz, 1H), 6.90(d, J=8.1Hz, 1H), 4.09(m, 1H), 3.97(m, 1H), 3.76(m,1H), 3.61(q, J=7.3Hz) , 1H), 3.25-3.35(m, 2H), 2.87(m, 2H), 2.79(m, 2H), 2.72(m, 1H), 2.25(t,J=11.5Hz,2H),2.01(m,2H),1.83-1.9 2(m,3H),1.75-1.82(m,2H),1.58(m,1H),1.22(t,J=(7.5Hz,3H),0.98(d,J=6.6Hz,6H),MS(ESI)m / z:507.4(M+H + ).

[0446] Method I: Aminocarbonylation with Co2(CO)8 Example 2: (Z)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-N,N-dimethyl-2-oxoindoline-5-carboxamide [ka] A solution of (Z)-5-bromo-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (C4, 200 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was treated with 2.0 M dimethylamine in THF (0.5 mL, 1.0 mmol). Palladium(II) acetate (6 mg, 0.026 mmol), xanphos (18 mg, 0.031 mmol), N,N-dimethylpyridin-4-amine (110 mg, 0.90 mmol), and Co(CO) (37 mg, 0.11 mmol) were added. The vial was sealed and heated to 90 °C in a microwave for 2.5 h. The reaction was diluted with EtOAc (10 mL), and the blue solid was filtered off and rinsed with EtOAc (5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (0–90% MeCN / HO (0.1% HCOOH)). The major peak was collected, treated with saturated NaHCO solution, and stirred at room temperature for 30 minutes. The solution was extracted with 20% MeOH / DCM (3x), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by SfaKP Amino D column chromatography (0–20% MeOH / DCM) to give (Z)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-N,N-dimethyl-2-oxoindoline-5-carboxamide (160 mg, 78%). 1H NMR(500MHz,DMSO-d6):d11.68(s,1H),10.71(s,1H),8.01(s,1H),7.54(s,1H) ,7.27(s,1H),7.06(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),4.09(m,1H),2.96( s,6H),2.82-2.92(m,2H),2.71(q,J=7.7Hz,3H),2.25(m,2H),2.01(m,2H),1.8 9(m,2H),1.21(t,J=7.6Hz,3H),0.98(d,J=6.5Hz,6H),MS(ESI)m / z:451.2(M+H + ).

[0447] Method J: Aminocarbonylation with Mo(CO)6 Example 3: (Z)—N-((5-cyclopropyltetrahydrofuran-2-yl)methyl)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxamide [ka] A solution of (Z)-5-bromo-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (C4, 0.25 g, 0.55 mmol) in 1,4-dioxane (5 mL) was treated with Na2CO3 (0.18 g, 1.7 mmol) and (5-cyclopropyltetrahydrofuran-2-yl)methanamine (0.13 g, 0.93 mmol). The mixture was sparged with Ar for 2 min, then Mo(CO)6 (0.072 g, 0.27 mmol) and Hellmann-Beller catalyst (0.051 g, 0.054 mmol) were added. The reaction mixture was sealed and heated to 50 °C for 6 h. The reaction was diluted with DCM (20 mL) and filtered through a pad of celite. The filtrate was washed with saturated NaHCO3 to remove organics. The aqueous phase was extracted with DCM (2x), and the combined organics were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% (1% NHOH / MeOH) / DCM and 0-40% DCM / MeOH). The fractions were combined and concentrated under reduced pressure, and the residue was treated with MeCN. The solution was sonicated for 10 min. The solid was filtered and washed with MeCN to give (Z)-N-((5-cyclopropyltetrahydrofuran-2-yl)methyl)-3-(1-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxamide (0.11 g, 35%) as a white solid. 1H NMR (500MHz, DMSO-d6): δ11.71(d,J=1.9Hz,1H),10.78(s,1H),8.36(m,1H),8.02(s,1H),7.76(m,1 H), 7.56(m, 2H), 6.91(d, J=8.1Hz, 1H), 3.92-4.13(m, 2H), 3.38(q, J=7.0Hz, 1H), 3.15-3.30(m, 2H), 2.68-2.94(m, 5H), 2.17-2.34(brm, 2H), 1.83-2.07(m, 6H), 1.54-1.71(m, 2H), 1.23(t, J=7.6Hz, 3H )), 0.99(d,J=6.6Hz,6H), 0.85(m,1H), 034-0.47(m,2H),0.12-0.27(m,2H), MS(ESI)m / z:547.4(M+H + ).

[0448] Method K: Substitution Reaction Example 4: (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide [ka] A solution of (Z)-3-(1-ethoxypropylidene)-2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide (B1, 0.25 g, 0.73 mmol) in EtOH (2 mL) was treated with 1-isopropyl-1H-pyrazol-4-amine (0.091 g, 0.73 mmol). The reaction was heated at 80 °C overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% MeOH / DCM) to give a pale orange solid. The orange solid was triturated from MeCN and the solid was then filtered to give (Z)-3-(1-((1-methyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxo-N-(2,2,2-trifluoroethyl)indoline-5-carboxamide (0.14 g, 46%) as a pale orange solid. 1H NMR (500MHz, DMSO-d6): δ11.75(s,1H),10.87(s,1H),8.90(t,J=6.3Hz,1H),8.02(s,1H),7.81(d,J=1.6Hz,1H),7.62(dd,J=8.2,1.6Hz,1H),7.57( s, 1H), 6.96 (d, J=8.1Hz, 1H), 4.51 (m, 1H), 4.09 (m, 2H), 2.83 (q, J=7.6Hz, 2H),1.45(d,J=6.6Hz,6H),1.26(t,J=7.5Hz,3H),MS(ESI)m / z:422.2(M+H + ).

[0449] General Method L: Amide Formation Example 5: (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-N-((3-methyloxetan-3-yl)methyl)-2-oxoindoline-5-carboxamide [ka] A solution of (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carboxylic acid (D1, 0.15 g, 0.44 mmol) in DCM (5 mL) was treated with EDC (0.10 g, 0.53 mmol) and HOBt (10 mol%). The reaction was allowed to stir for 10 min, then DIEA (0.096 mL, 0.55 mmol) and (3-methioxetan-3-yl)methanamine (0.053 g, 0.53 mmol) were added and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO (30 mL) and the solution was extracted with DCM (3x). The combined organics were dried over anhydrous MgSO, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (0-20% DCM / MeOH) to give (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-N-((3-methyloxetan-3-yl)methyl)-2-oxoindoline-5-carboxamide (0.02 g, 12%) as a white solid. 1H NMR(500MHz,DMSO-d6):d11.71(s,1H),10.79(s,1H),8.47(t,J=6.1Hz,1H) ,8.00(s,1H),7.77(s,1H),7.56(d,J=7.5Hz,2H),6.93(d,J=8.1Hz,1H),4. 47-4.53(m, 3H), 4.19(d, J=5.7Hz, 2H), 3.44(d,J=6.0Hz,2H),2.81(q,J=7. 6Hz,2H),1.44(d,J=6.7Hz,6H),1.23-1.27(m,6H),MS(ESI)m / z:424.2(M+H + ).

[0450] General Method M: Suzuki Reaction and Oxidation Example 6a: (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carbaldehyde [ka] To a stirred solution of potassium(I) trifluoro(vinyl)borate (4.3 g, 32.0 mmol) and (Z)-5-bromo-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (C7, 4.0 g, 10.6 mmol) in 1,4-dioxane:water (4:1, 45 mL), K2CO3 (4.4 g, 32.0 mmol) was added at room temperature, and the reaction mixture was degassed with a nitrogen balloon for 20 minutes. Then, PdCl2(dppf).DCM (0.87 g, 1.0 mmol) was added, and the reaction mixture was stirred at 100 °C for 20 hours. The reaction mixture was filtered through a bed of Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (40% EtOAc / hexanes) to afford (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-5-vinylindolin-2-one (5.0 g, 73%) as an off-white solid. 1H NMR(400MHz,DMSO-d6):d11.67(s,1H),10.59(s,1H),7.98(s,1H),7.53(s,1H),7.33(s,1H),7.12(d,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H),5.62(d, J=17.6Hz,1H),5.06(d,J=10.8Hz,1H),4.49(t,J=6.4Hz,1H),2.75(q,J=7.6Hz,2H),1.42(d,J=6.4Hz,6H),1.24(brs,3H),MS(ESI)m / z:323.1(M+H) + ).

[0451] A solution of (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-5-vinylindolin-2-one (3.0 g, 9.3 mmol) in THF:HO (1:1, 60 mL) was treated with OsO (1.2 mL, 0.19 mmol) at 0 °C, followed by the addition of NaIO (3.0 g, 14.0 mmol). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was treated with water (70 mL) and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (70% EtOAc / hexanes) to give (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carbaldehyde (1.0 g, 33%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):d11.70(s,1H),11.08(s,1H),9.88(s,1H),8.02(s,1H),7.78(s,1H),7.58(brm,2H),7.06(d,J =8.0Hz,1H),4.50(m,1H),2.79(q,J=7.6Hz,2H),1.43(d,J=6.8Hz,6H),1.05(t,J=6.8Hz,3H);MS(ESI)m / z:325.0(M+H) + ).

[0452] General Method N: Grignard Reaction and Reduction Example 6: (Z)-5-(cyclopropanecarbonyl)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one [ka] A solution of (Z)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)-2-oxoindoline-5-carbaldehyde (6a, 1.0 g, 3.1 mmol) in THF was cooled to 0° C. and 0.5 M cyclopropylmagnesium bromide (49 mL, 24 mmol in THF) was added. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution. The solution was extracted with EtOAc (2x). The combined organic extracts were washed with water (2x), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc / hexanes) to give (Z)-5-(cyclopropyl(hydroxy)methyl)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (0.5 g, 45%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):d11.64(s,1H),10.45(s,1H),7.97(s,1H),7.52(s ,1H),7.30(s,1H),6.98(d,J=8.0Hz,1H),6.80(d,J=7.6Hz,1H),5.00(d,J= 4.0Hz,1H),4.49(m,1H),3.94(m,1H),2.75(q,J=7.2Hz,2H),1.42(d,J=8. 0Hz,6H),1.23(t,J=7.6Hz,3H),0.27-0.45(m,4H),MS(ESI)m / z:367.2(M+H + ).

[0453] A solution of (Z)-5-(cyclopropyl(hydroxy)methyl)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (0.50 g, 1.36 mmol) in DCM was cooled to 0 °C, and Dess-Martin reagent (1.15 g, 1.36 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was filtered through a Celite pad and washed with DCM. The filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc / hexanes) to give (Z)-5-(cyclopropanecarbonyl)-3-(1-((1-isopropyl-1H-pyrazol-4-yl)amino)propylidene)indolin-2-one (0.040 g, 8%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):d11.70(s,1H),10.96(s,1H),8.00(s,1H),7.86(d,J=8.0Hz,1H),7.84(d,J=1.2Hz,1H),7.56(s,1H),6.99(d,J=8.0Hz, 1H),4.50(m,1H),2.76-2.89(m,3H),1.42(d,J=8.0Hz,1H),4.50(m,1H) ,6.8Hz,6H),1.26(t,J=7.6Hz,3H),0.98(m,4H),MS(ESI)m / z:365.2(M+H + ).

[0454] Using general methods H, I, J, K, L, M, and N above, the compounds in Table E below were prepared. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

Table 6-12

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Table 6-17

Table 6-18

Table 6-19

Table 6-20

Table 6-21

Table 6-22

Table 6-23

Table 6-24

Table 6-25

Table 6-26

Table 6-27

Table 6-28

Table 6-29

Table 6-30

Table 6-31

Table 6-32

Table 6-33

Table 6-34

Table 6-35

Table 6-36

Table 6-37

Table 6-38

Table 6-39

Table 6-40

Table 6-41

Table 6-42

Table 6-43

Table 6-44

Table 6-45

Table 6-46

Table 6-47

Table 6-48

Table 6-49

Table 6-50

Table 6-51

Table 6-52

Table 6-53

Table 6-54

Table 6-55

Table 6-56

Table 6-57

Table 6-58

Table 6-59

Table 6-60

Table 6-61

Table 6-62

Table 6-63

Table 6-64

Table 6-65

Table 6-66

Table 6-67

Table 6-68

Table 6-69

Table 6-70

Table 6-71

Table 6-72

Table 6-73

[0455] Biochemical assay of ULK1 (SEQ ID NO: 1) ULK1 kinase activity was determined spectrophotometrically using a pyruvate kinase / lactate dehydrogenase coupled assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (see, e.g., Schindle et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 mL) using an assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100) containing 0.1 nM ULK1 (beryllium-derived), 0.075 mM peptide substrate (YANWLAASIYLDGKKK (SEQ ID NO: 5)), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphenol pyruvate, 0.28 mM NADH, and 1 mM ATP. Inhibition of ULK1 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C in a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with a known inhibitor) and calculated as IC 50Values ​​were calculated using software routines in Prism (GraphPad software).

[0456] ULK1 protein sequence (residues 1-283; SEQ ID NO: 1) MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKP QNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPS

[0457] Biochemical assay of ULK2 (SEQ ID NO: 2) ULK2 kinase activity was determined spectrophotometrically using a pyruvate kinase / lactate dehydrogenase coupled assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindle et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 mL) using assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl, 0.5 mM DTT, 0.1% octylglucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100) containing 1 nM ULK2 (SignalChem U02-11G), 200 mM ULKtide, 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphenol pyruvate, 0.28 mM NADH, and 1 mM ATP. Inhibition of ULK2 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 h at 30 °C in a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with a known inhibitor) and calculated as IC 50 Values ​​were calculated by four-parameter sigmoidal curve fitting using Prism (GraphPad software).

[0458] ULK2 protein sequence (residues 1-306 with N-terminal GST and His tag; SEQ ID NO: 2) MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFED RLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFMEVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSI NKKNLSKSQILLGKEIKILKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAAAMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCG SPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLMPSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVSGSSCGSSPSCRFASHHHHHH

[0459] [Table 7-1] [Table 7-2] [Table 7-3]

[0460] In Table 1, "+" indicates IC<10 nM 50 "++" indicates IC greater than 10 nM and less than or equal to 100 nM 50 "+++" indicates an IC greater than 100 nM and less than or equal to 500 nM 50 "++++" indicates IC greater than 500nM 50 Refers to...

[0461] Cellular inhibition of ULK kinase substrate ATG13 protein pATG13 levels in mutant KRasA549 cells after treatment with a ULK inhibitor in combination with trametinib A549 (KRAS mutant) human lung cancer cells (6,000 cells / well) were added to 384-well tissue culture-treated plates containing 50 μL of prewarmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin and grown overnight at 37°C, 5% CO2, and 95% humidity. The next day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control wells. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The next day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) for 10 min at 4°C with shaking.

[0462] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (CellSignaling Cat#13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked with assay diluent (Biolegend Cat#421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin linked to horseradish peroxidase (ThermoFisher Cat. No. 21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend Cat. No. 421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. Next, the background-corrected absorbance at 450 nm from the blank wells was subtracted from the test wells. Data were compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0463] pATG13 levels in mutant KRasMiaPaCa-2 cells after treatment with a ULK inhibitor in combination with trametinib MiaPaCa-2 human pancreatic cancer cells (10,000 cells / well) were added to 384-well tissue culture-treated plates containing 50 μL of prewarmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, 100 μg / mL streptomycin, and 2.5% horse serum, and grown overnight at 37°C, 5% CO2, and 95% humidity. The next day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control wells. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The next day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) for 10 min at 4°C with shaking.

[0464] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (CellSignaling Cat#13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked with assay diluent (Biolegend Cat#421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin linked to horseradish peroxidase (ThermoFisher Cat. No. 21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend Cat. No. 421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2.0 N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. Next, the background-corrected absorbance at 450 nm from the blank wells was subtracted from the test wells. Data were compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0465] pATG13 levels in mutant KRas HCT-116 cells after treatment with a ULK inhibitor in combination with trametinib HCT-116 human colon cancer cells (10,000 cells / well) were added to 384-well tissue culture-treated plates containing 50 μL of prewarmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin and grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control wells. The wells were mixed by gently shaking the plate, and then incubated overnight at 37°C. The following day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) for 10 min at 4°C with shaking.

[0466] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (CellSignaling Cat#13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked with assay diluent (Biolegend Cat#421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockl and Immunochemicals Cat#600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin linked to horseradish peroxidase (ThermoFisher Cat. No. 21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend Cat. No. 421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2.0 N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. Next, the background-corrected absorbance at 450 nm from the blank wells was subtracted from the test wells. Data were compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0467] pATG13 levels in mutant HRas T24 cells after treatment with a ULK inhibitor in combination with trametinib T24 human bladder cancer cells (25,000 cells / well) were added to a 96-well tissue culture-treated plate containing 100 μL of prewarmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin and grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 100 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.5 μL per well) was added. DMSO (0.5 μL) was added to the control wells. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) for 10 min at 4°C with shaking.

[0468] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked with assay diluent (Biolegend Cat#421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin linked to horseradish peroxidase (ThermoFisher Cat. No. 21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend Cat. No. 421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2.0 N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. Next, the background-corrected absorbance at 450 nm from the blank wells was subtracted from the test wells. Data were compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0469] In Table 2, "+" indicates IC<100 nM 50 "++" indicates an IC greater than 100 nM and less than or equal to 300 nM 50 "+++" indicates an IC of over 300 nM and less than or equal to 600 nM 50 "++++" indicates an IC of over 600 nM 50 Refers to...

[0470] Biochemical assay of LRRK2 (SEQ ID NO: 3) LRRK2 kinase activity was determined spectrophotometrically using a pyruvate kinase / lactate dehydrogenase coupled assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (see, e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 26.4 nM LRRK2 (ThermoFisher), 0.1 mM peptide substrate (RLGRDKYKTLRQIRQ (SEQ ID NO: 6)), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100). Inhibition of LRRK2 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C using a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with a known inhibitor) and calculated as IC 50 Values ​​were calculated using software routines in Prism (GraphPad software).

[0471] LRRK2 protein sequence (residues 970-2528; SEQ ID NO: 3) [Table 9]

[0472] For Table 3, "+" indicates IC<100 nM 50 "++" indicates an IC greater than 100 nM and less than or equal to 300 nM 50 "+++" indicates an IC of over 300 nM and less than or equal to 600 nM 50 "++++" indicates an IC of over 600 nM 50 Refers to...

[0473] equivalent While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations of the present embodiments will become apparent to those skilled in the art in light of this specification. The full scope of what is disclosed should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0474] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; Y is, 【Chemistry 2】 wherein s1 is a moiety covalently attached to the ring; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other one is not H, Or, Y is 【Chemistry 3】 If R ２ and R ３ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R ４ teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; however, X １ , X ２ , and X ３ is CH and Y is 【Chemistry 4】 and R ４ C optionally substituted with one or more fluorine atoms １～５ The foregoing compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, with the proviso that when A is optionally substituted phenyl, then E is not alkyl substituted with an amine.

2. Formula II: 【Chemistry 5】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or The compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided that when R2 and R3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano.

3. Formula III: 【Chemistry 6】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ３ is selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

4. Formula IV: 【Chemistry 7】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ is selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

5. Formula V: 【Chemistry 8】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ２ is selected from the group consisting of N, CH, CF, and C—Cl; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

6. Formula VI: 【Chemistry 9】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ３ is selected from the group consisting of N, CH, and CF; A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

7. Formula VII: 【Chemistry 10】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

8. Formula VIII: 【Chemistry 11】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

9. Formula IX: 【Chemistry 12】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ２ is selected from the group consisting of N, CH, CF, and C—Cl; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

10. Formula X: 【Chemistry 13】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ３ is selected from the group consisting of N, CH, and CF; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

11. Formula XI: 【Chemistry 14】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

12. Formula XII: 【Chemistry 15】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of X ４ , X ５ , and X ６ are each independently selected from the group consisting of N, CH, and CF; However, X ４ , X ５ , and X ６ provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

13. Formula XIII: 【Chemistry 16】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ２ is selected from the group consisting of N, CH, CF, and C—Cl; X ４ , X ５ , and X ６ are each independently selected from the group consisting of N, CH, and CF; However, X ４ , X ５ , and X ６ provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

14. Formula XIV: 【Chemistry 17】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X ４ , X ５ , and X ６ are each independently selected from the group consisting of N, CH, and CF; However, X ４ , X ５ , and X ６ provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ２ and R ３ are each independently H, alkoxy, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, R ２ and R ３ is H, then R ２ and R ３ The other of is not H, or R ２ and R ３ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

15. Formula XV: 【Chemistry 18】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of A is, optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; and optionally substituted phenyl, wherein each occurrence of the optionally substituted substituent is independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ４ teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; however, X １ , X ２ , and X ３ is CH and R ４ C optionally substituted with one or more fluorine atoms １～５ The foregoing compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, with the proviso that when A is an optionally substituted phenyl, then E is not an alkyl substituted with an amine.

16. Formula XVI: 【Chemistry 19】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ４ teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

17. Formula XVII: 【Chemistry 20】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X １ and X ３ are each independently selected from the group consisting of N, CH, and CF; X ２ is selected from the group consisting of N, CH, CF, and C—Cl; However, X １ , X ２ , and X ３ provided that no more than two of X ４ , X ５ , and X ６ are each independently selected from the group consisting of N, CH, and CF; However, X ４ , X ５ , and X ６ provided that no more than two of E is H, haloalkyl, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; and optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, amine, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, and wherein any alkyl is further optionally substituted with alkoxy or cycloalkyl; R １ is alkyl or haloalkyl, R ４ teeth, optionally substituted alkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with alkyl, alkoxy, amine, amido, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heterocyclyl; optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted C-linked heterocyclyl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amido, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heteroaryl, wherein each occurrence of the optionally substituted substituents is independently selected from the group consisting of alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; However, X １ , X ２ , X ３ , X ４ , X ５ , and X ６ is CH and R ４ C optionally substituted with one or more fluorine atoms １～５ The foregoing compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, with the proviso that when E is alkyl, it is not alkyl substituted with an amine.

18. X １ The compound of any one of claims 1, 2, 4, 8, 12, and 15-17, wherein is CH.

19. X １ is CF or N.

20. X ３ The compound according to any one of claims 1 to 3, 6, 8, 10, 12 and 15 to 17, wherein is CH.

21. X ３ is CF or N.

22. X ２ The compound according to any one of claims 1 to 5, 8, 9, 12, 13 and 15 to 17, wherein is CH.

23. X ２ The compound according to any one of claims 1 to 5, 8, 9, 12, 13 and 15 to 17, wherein is CF, C-Cl or N.

24. X １ , X ２ , and X ３ The compound of any one of claims 1, 2, 8, 12, and 15-17, wherein is CH.

25. R １ The compound of any one of claims 1 to 24, wherein is alkyl.

26. R １ The compound according to any one of claims 1 to 25, wherein is methyl.

27. R １ The compound according to any one of claims 1 to 25, wherein is ethyl.

28. A is, 【Chemical 21】 is selected from the group consisting of 16. The compound of any one of claims 1 to 7 and 15, wherein each of these is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano, and wherein s2 is the moiety covalently bonded to -NH- and s3 is the moiety covalently bonded to E.

29. 16. The compound of any one of claims 1 to 7 and 15, wherein A is phenyl optionally substituted with halogen or alkyl.

30. 16. The compound of any one of claims 1 to 7 and 15, wherein A is a 5-6 membered heteroaryl optionally substituted with halogen or alkyl.

31. 16. The compound of any one of claims 1 to 7 and 15, wherein A is pyrazole optionally substituted with halogen or alkyl.

32. R ２ The compound according to any one of claims 1 to 14 and 18 to 31, wherein is H.

33. R ２ is H and R ３ The compound according to any one of claims 1 to 14 and 18 to 32, wherein is alkoxy.

34. R ２ is H and R ３ The compound of any one of claims 1 to 14 and 18 to 32, wherein is haloalkyl.

35. R ２ is H and R ３ is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl.

36. R ２ is H and R ３ is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano.

37. R ２ is H and R ３ 37. The compound of any one of claims 1-14, 18-32, and 36, wherein is cycloalkyl optionally substituted with one or more halogens.

38. R ２ is H and R ３ is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano.

39. R ２ is H and R ３ 40. The compound of any one of claims 1-14, 18-32, and 38, wherein is heteroaryl optionally substituted with haloalkyl.

40. R ２ is H and R ３ is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano.

41. R ２ is H and R ３ The compound of any one of claims 1 to 14, 18 to 32, and 40, wherein is heterocyclyl.

42. R ２ is H and R ３ is methyl, ethyl, n-propyl, isopropyl, 【Chemical 22】 The compound according to any one of claims 1 to 14 and 18 to 32, selected from the group consisting of:

43. R ２ The compound according to any one of claims 1 to 14 and 18 to 31, wherein is alkyl.

44. R ２ The compound of any one of claims 1 to 14, 18 to 31, and 43, wherein is methyl.

45. R ２ The compound of any one of claims 1 to 14 and 17 to 30, wherein is cycloalkyl.

46. R ２ The compound of any one of claims 1 to 14, 18 to 31, and 45, wherein is cyclopropyl.

47. R ３ The compound of any one of claims 1 to 14, 18 to 31, and 43 to 46, wherein is alkoxy.

48. R ３ The compound of any one of claims 1 to 14, 18 to 31, and 43 to 46, wherein is haloalkyl.

49. R ３ is alkyl optionally substituted with one or more alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, heterocyclyl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more halogen, alkyl, halkoalkyl, cyano, or cycloalkyl.

50. R ３ is cycloalkyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano.

51. R ３ 51. The compound of any one of claims 1-14, 18-31, 43-46, and 50, wherein is cycloalkyl optionally substituted with one or more halogens.

52. R ３ is heteroaryl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano.

53. R ３ 53. The compound of any one of claims 1-14, 18-31, 43-46, and 52, wherein is heteroaryl optionally substituted with haloalkyl.

54. R ３ is heterocyclyl optionally substituted with one or more alkyl, alkoxy, amine, amide, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano.

55. R ３ 55. The compound of any one of claims 1-14, 18-31, 43-46, and 54, wherein is heterocyclyl.

56. R ３ is methyl, ethyl, n-propyl, isopropyl, 【Chemical 23】 The compound of any one of claims 1 to 14, 18 to 32, and 43 to 46, selected from the group consisting of:

57. R ２ and R ３ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl selected from the group consisting of: 【Chemistry 24】

58. R ４ The compound of any one of claims 1 and 15-31, wherein is selected from the group consisting of optionally substituted alkyl and cycloalkyl.

59. R ４ But methyl, 【Chemistry 25】 60. The compound of any one of claims 1, 15-31, and 58, selected from the group consisting of:

60. E, 【Chemical 26】 wherein: R ５ is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl.

61. E, 【Chemical 27】 wherein: R ５ are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl, and R ６ The compound according to any one of claims 1 to 7 and 12 to 14, wherein are independently H, alkyl, cycloalkyl, or haloalkyl.

62. 60. The compound of any one of claims 1 to 59, wherein E is H.

63. 60. The compound of any one of claims 1 to 59, wherein E is alkyl optionally substituted with cycloalkyl, amine, or alkoxy.

64. 60. The compound of any one of claims 1 to 59, wherein E is alkyl.

65. 60. The compound of any one of claims 1 to 59, wherein E is haloalkyl.

66. 60. The compound of any one of claims 1 to 59, wherein E is cycloalkyl optionally substituted with one or more halogens.

67. 60. The compound of any one of claims 1 to 59, wherein E is 4- to 6-membered heterocyclyl.

68. 60. The compound of any one of claims 1 to 59, wherein E is selected from the group consisting of H, cycloalkyl, amine, or alkyl optionally substituted with alkoxy, haloalkyl, cycloalkyl optionally substituted with one or more halogens, and heterocyclyl.

69. E is H, methyl, ethyl, trifluoromethyl, difluoromethyl, 【Chemical Formula 28】 60. The compound of any one of claims 1 to 59, selected from the group consisting of:

70. A compound comprising: 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】 【Chemistry 29-7】 【Chemistry 29-8】 【Chemistry 29-9】 【Chemistry 29-10】 【Chemistry 29-11】 and pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof.

71. 71. A pharmaceutical composition comprising a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

72. 71. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

73. 71. A method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

74. 74. The method of claim 73, wherein the cancer is selected from the group consisting of gastrointestinal stromal tumor, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, leukemia, cervical cancer, cancer that metastasizes to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer.

75. 75. The method of claim 73 or claim 74, wherein the cancer is metastatic.

76. 71. A method of treating a disorder selected from the group consisting of gastrointestinal stromal tumor, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, leukemia, cervical cancer, cancer metastasizing to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

77. 77. The method of any one of claims 72 to 76, further comprising administering to the patient one or more additional therapeutic agents.

78. 78. The method of claim 77, wherein the additional therapeutic agent is an RTK pathway inhibitor.

79. 79. The method of claim 78, wherein the RTK pathway inhibitor is selected from the group consisting of a KIT inhibitor, an EGFR inhibitor, a PDGFRα inhibitor, a VEGFR inhibitor, an anti-VEGF therapeutic agent, a BCR-Abl inhibitor, and an ALK inhibitor.

80. 80. The method of claim 79, wherein the KIT inhibitor is selected from the group consisting of ripretinib, avaprinib, sunitinib, ADAD3229, THE-630, and imatinib, and pharmaceutically acceptable salts thereof.

81. 80. The method of claim 79, wherein the EGFR inhibitor is selected from the group consisting of cetuximab, osimertinib, and afatinib, and pharmaceutically acceptable salts thereof.

82. 80. The method of claim 79, wherein the PDGFRα inhibitor is ripretinib, JNJ10198409, or a pharmaceutically acceptable salt thereof.

83. 80. The method of claim 79, wherein the VEGFR inhibitor is selected from the group consisting of regorafenib, axitinib, and pazopanib, and pharmaceutically acceptable salts thereof.

84. 80. The method of claim 79, wherein the anti-VEGF therapeutic agent is selected from the group consisting of bevacizumab.

85. 80. The method of claim 79, wherein the BCR-Abl inhibitor is imatinib, nilotinib, dasatinib, or a pharmaceutically acceptable salt thereof.

86. 80. The method of claim 79, wherein the ALK inhibitor is selected from the group consisting of lorlatinib, and alectinib, and pharmaceutically acceptable salts thereof.

87. 78. The method of claim 77, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

88. 88. The method of claim 87, wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.

89. 89. The method of claim 88, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, mirdametinib, and VS-6766, and pharmaceutically acceptable salts thereof.

90. 89. The method of claim 88, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, lavoxertinib, VX-11e, ERAS-007, and ASTX-029, and pharmaceutically acceptable salts thereof.

91. 89. The method of claim 88, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, berbalafenib, KIN-2787, and VS-6766, and pharmaceutically acceptable salts thereof.

92. 89. The method of claim 88, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, GDC-6036, MRTX-1133, RMC-9805, RMC-6291, and RMC-6236, and pharmaceutically acceptable salts thereof.

93. 78. The method of claim 77, wherein the additional therapeutic agent is a PI3K pathway inhibitor or an mTOR inhibitor.

94. 94. The method of claim 93, wherein the PI3K inhibitor is selected from the group consisting of alpelisib, LY294002, and omipalisib, and pharmaceutically acceptable salts thereof.

95. 94. The method of claim 93, wherein the mTOR inhibitor is selected from the group consisting of rapamycin, everolimus, PF04691502, and PP242, and pharmaceutically acceptable salts thereof.

96. 78. The method of claim 77, wherein the additional therapeutic agent is an immunomodulatory agent.

97. 97. The method of claim 96, wherein the immunomodulatory agent is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, avelumab, cetuximab, TSR-022, MBG453, leratolimab, LAG525, TSR-033, SGN-40, CP-870,893, RO7009789, Hu5F9-G4, ADU-S100, MK-1454, ASA404, doxorubicin, mitoxantrone, azacitidine, decitabine, statins, metformin, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, and dostarlimab, and pharmaceutically acceptable salts thereof.

98. 78. The method of claim 77, wherein the additional therapeutic agent is a chemotherapeutic agent.

99. 99. The method of claim 98, wherein the chemotherapeutic agent is selected from the group consisting of antitubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, irinotecan, and methotrexate.

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