Heterocyclic compounds as KIT kinase inhibitors

Abstract

Described herein are compounds of Formula I that are wild-type and oncogenic mutant c-KIT kinase inhibitors and their use in the treatment of conditions such as cancer. # imgabs0 #

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application No. 63 / 287,857 filed on December 9, 2021 and U.S. Provisional Application No. 63 / 329,674 filed on April 11, 2022, the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0003] Gain-of-function mutations in the type III receptor tyrosine kinases KIT and PDGFRA are present in many cancers and myeloproliferative diseases. For example, gastrointestinal stromal tumors (GIST) are driven by activating mutations in KIT (~80%) and PDGFRA (~5-10%). Mutations in KIT drive >90% of cases of systemic mastocytosis (SM) and mast cell leukemia (MCL), as well as a small but significant percentage of acute myeloid leukemia (AML), germ cell tumors, and melanoma. PDGFRA mutations or gene rearrangements have also been observed in cancers such as eosinophilic leukemia and glioblastoma. KIT and / or PDGFRA gene amplification may also be oncogenic in gliomas and lung cancers.

[0004] Most of the primary and secondary resistance mutations in KIT and PDGFRA are located within the switch region present in the intracellular kinase domain. KIT and PDGFRA are named "dual switch kinases" based on the observation that they each incorporate a) an autoinhibitory switch within the intracellular juxtamembrane domain (JMD) and b) a major activation loop (AL) switch within the kinase domain. Several studies have shown that this dual switch mechanism regulates KIT and PDGFRA cellular kinase activity by controlling the kinase conformation. In fact, phosphorylation of one or more amino acids triggers a conformational change that causes the kinase to activate from an inactive (or "off") state to an active (or "on") state. Disruption of one or more of these switch control mechanisms can cause the kinase to abnormally adopt an active type I conformation. In approximately 70% of GIST patients, primary activating mutations are found in KIT exon 11, encoding the JMD inhibitory switch, resulting in loss of function of the inhibitory switch, shifting the conformational equilibrium toward the active type I form. A small fraction of primary activating mutations and almost all secondary resistance mutations in GISTs are mutations located in the master AL switch found on exons 17 and 18 of KIT and exon 18 of PDGFRA, respectively, or in the switch pocket region adjacent to the ATP binding pocket on exons 13 and 14 of KIT and exons 14 and 15 of PDGFRA. These gain-of-function mutations also stabilize the active type I conformation. Specifically, the D816 switch residue of KIT (exon 17) and the analogous D842 residue of PDGFRA (exon 18) are critical for the AL switch to reside in the type II closed state. Mutations of these aspartate residues to valine (KIT D816V and PDGFRA D842V mutants) cause a conformational change in the protein, resulting in the kinase switching from an inactive state (type II conformation) to an active state (type I conformation). Diseases caused by mast cell proliferation, such as systemic mastocytosis (SM) and mantle cell lymphoma (MCL), and a small subset of acute myeloid leukemia (AML) are driven by primary mutations in the master AL switch of KIT (e.g., D816V or N822K). Similarly, the D842V mutation within the PDGFRA master AL switch is the most common primary mutation observed in a small subset of PDGFRA-mutant GISTs.

[0005] The treatment of metastatic GIST was revolutionized with the advent of tyrosine kinase inhibitors (TKIs), led by imatinib, a potent inhibitor of primary exon 11 JMD KIT mutations, which was approved as first-line therapy for advanced GIST in 2002. Although most GIST patients respond well to imatinib treatment, approximately 10-14% of treated patients are found to be insensitive to imatinib therapy. In addition, more than half of early imatinib responders develop resistance within two years of imatinib therapy. This resistance is mainly attributed to the formation of secondary mutations within KIT (e.g., exon 13V654A within the switch pocket or various exon 17 mutations within the AL switch). Subsequently, sunitinib and regorafenib were approved as second- and third-line therapies for imatinib-resistant GIST. Sunitinib preferentially inhibits secondary KIT mutations in exons 13 and 14 but not in the exon 17 / 18 AL switch. In contrast, regorafenib predominantly inhibits a subset of secondary mutations in exon 17 and only weakly inhibits secondary mutations in KIT exons 13 and 14.

[0006] Examination of individual GIST patient biopsies obtained from different progressive metastases suggests that a complex heterogeneous array of primary and multiple secondary KIT mutations may exist within the same patient and in different metastatic lesions. This observation further complicates the selection of appropriate TKI-based therapy. In addition, the off-target kinase activity of sunitinib and regorafenib can lead to tolerability issues that require significant clinical treatment management (e.g., drug holidays, dose reductions). The necessary adjustments in the duration of therapy treatment may also exacerbate the development of additional secondary resistance mutations. From a safety perspective, the use of avapritinib is also limited due to black-box label restrictions due to central nervous system (CNS) adverse events.

[0007] There is a clear unmet need for tyrosine kinase inhibitors with potent inhibitory activity against a broad range of clinically relevant KIT and PDGFRA mutants and an improved safety and tolerability profile compared to currently available GIST treatments. Summary of the invention

[0008] Described herein, in part, are compounds that are inhibitors of wild-type and oncogenic mutant c-KIT kinase and methods of their use, such as for treating cancers driven by c-KIT kinase mutations, e.g., primary (KIT exon 9 or 11) and secondary (exons 13, 14, 17, and 18) c-KIT mutations.

[0009] In one embodiment, described herein is a compound represented by Formula I:

[0010]

[0011] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0012] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0013] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0014] Q is selected from the group consisting of:

[0015] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0016] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0017] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0018] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0019] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0020] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0021] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0022] QLE combined with free choice The group composed of;

[0023] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0024] R 1 Selected from the group consisting of: H, haloalkyl,

[0025] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0026] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0027] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0028] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0029] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0030] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0031] R 2is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0032] R 3 is selected from the group consisting of F and alkoxy;

[0033] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0034] R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0035] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0036] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0037] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0038] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0039] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0040] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0041] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0042] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0043] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0044] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0045] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0046] n is 0, 1, 2, 3 or 4; and

[0047] p is 1, 2, or 3,

[0048] The restriction is that the compound is not:

[0049] DETAILED DESCRIPTION

[0050] The features and other details of the present disclosure will now be described more clearly. Specific terms used in this specification, embodiments and appended claims are collected here. These definitions should be read in light of the remainder of the present disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art are generally understood.

[0051] definition

[0052] The definitions set forth in this application are intended to clarify terminology used throughout this application.

[0053] 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 herein belongs. Unless otherwise indicated to the contrary, as used in the specification and the appended claims, the following terms have the meanings assigned to facilitate understanding of the present disclosure.

[0054] As used herein, the singular forms "a," "an," and "the" include plural referents 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.

[0055] As used herein, unless otherwise indicated, the following definitions shall apply. For purposes of the present disclosure, chemical elements are determined according to the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th Edition. 1994. In addition, 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 Edition, Smith, MB and March, J., eds., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0056] As used herein, the term "herein" means the entire application.

[0057] 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 instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted as well as instances where the alkyl group is unsubstituted.

[0058] It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the disclosed compounds to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art as well as those described below. If a substituent is substituted with more than one group, it will be appreciated that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.

[0059] As used herein, the term "optionally substituted" means that one to six hydrogen atoms in a given structure are replaced by a group of a specified substituent, including but not limited to hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, alkoxy, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy and -OC(=O)-CH2-Oalkyl. Preferably, "optionally substituted" means that one to four hydrogen radicals in a given structure are replaced by the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by substituents as mentioned above. It should be understood that the substituents may be further substituted.

[0060] As used herein, the term "substituted" refers to a portion of a substituent having a replacement hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "substituted" includes implicit restrictions, i.e., such substitutions are based on the permitted valences of the substituted atoms and substituents, and the substitution produces a stable compound, such as it does not spontaneously undergo conversion (such as by reorganization, cyclization, elimination, etc.). As used herein, the term "substituted" is encompassed to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, permissible substituents may be one or more and the same or different. For the purposes of the present application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the heteroatom valence.

[0061] Substituents may include any of the substituents described herein, for example, such substituents, if not otherwise specified, may include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, 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. It will be understood by those skilled in the art that the substituents themselves may be substituted where appropriate. For example, substituents for substituted alkyl groups may include substituted and unsubstituted forms of amino, azido, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates), and silane groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF3, -CN, and the like. Unless specifically stated as "unsubstituted," references to chemical moieties herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted variants as well as unsubstituted variants.

[0062] As used herein, the term "alkyl" refers to a fully saturated straight or branched non-aromatic hydrocarbon. Typically, unless otherwise defined, a straight or branched alkyl has 1 to about 20 carbon atoms, preferably 1 to about 10, such as C1-C6 alkyl or such as C1-C6 alkyl. Examples of straight and branched alkyls 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 and the like. In addition, the term "alkyl" as used throughout the specification, examples and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to an alkyl moiety having a substituent replacing hydrogen on one or more carbons of the hydrocarbon backbone. "Alkyl" groups may be optionally substituted.

[0063] The term "C x -C y " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, or alkoxy is intended to include groups containing from x to y carbons in the chain. For example, the term "C x -C y ” refers to a substituted or unsubstituted saturated hydrocarbon group containing x to y carbons in the chain, including straight chain alkyl groups and branched chain alkyl groups, including halogenated alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates hydrogen when the group is in the terminal position and a bond when it is in the interior.

[0064] As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and salts thereof, such as the moiety that can be represented by the formula:

[0065]

[0066] Where R z Each independently represents hydrogen or a hydrocarbon group, or R z The group together with the N atom to which it is attached completes a heterocyclyl having 4 to 8 atoms in the ring structure.

[0067] As used herein, the terms "amide" and "amido" refer to a group represented by:

[0068]

[0069] Where R x , R y and R z Each independently represents hydrogen or a hydrocarbon group, or R y and R z The heterocyclyl radical, together with the nitrogen atom to which it is attached, has from 4 to 8 atoms in the ring structure.

[0070] As used herein, the term "alkoxy" refers to a straight or branched, saturated aliphatic (alkyl) hydrocarbon group bound to an oxygen atom attached to a core structure. Preferably, the alkoxy has one to six carbon atoms, i.e., a C1-C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, 3-methylbutoxy, and the like. As used herein, the term "alkoxy" may be optionally substituted, as defined above.

[0071] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogens. For example, a monohaloalkyl group may have chlorine, bromine, iodine or fluorine atoms. Dihalo and polyhaloalkyl groups may have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like.

[0072] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3) or trifluoroethoxy (-OCH2CF3).

[0073] As used herein, the term "hydrocarbyl" refers to an aliphatic hydrocarbon group. The hydrocarbyl portion may be a "saturated alkyl," meaning that it does not contain any olefin or alkyne moieties. The hydrocarbyl portion may also be an "unsaturated alkyl" portion, meaning that it contains at least one olefin or alkyne moiety. The "olefin" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, which is connected to the rest of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. The "alkyne" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon triple bond, which is connected to the rest of the molecule by a single bond. The hydrocarbyl portion, whether saturated or unsaturated, may be branched or straight chain.

[0074] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0075] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0076] As used herein, the term "cycloalkyl" alone or in combination with other terms refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic and tricyclic rings. Typically, unless otherwise defined, monocyclic cycloalkyls have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., C3-C4). 10 Cycloalkyl or for example C 3- C6 cycloalkyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and similar groups. The second ring of the bicyclic cycloalkyl or the second or third ring of the tricyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic and tricyclic molecules, wherein one, two or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl, wherein each of the rings shares two adjacent atoms with another ring. The second ring of the fused bicyclic cycloalkyl or the second or third ring of the fused tricyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. "Cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyl can be further substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, alkyl substituted by carbonyl, -CF3, -CN and similar groups. Cycloalkyl can alternatively be a polycyclic ring with more than two rings. Examples of polycyclic cycloalkyl include bridging, fusion and spirocyclic carbocyclic groups. As used herein, the term "cycloalkyl" may be optionally substituted as defined above.

[0077] As used herein, the term "cycloalkyloxy" refers to a cycloalkyl group bound to an oxygen atom connected to a core structure. Exemplary cycloalkyloxy groups include, but are not limited to, cycloalkyloxy groups of 3-6 carbon atoms, referred to herein as C3-C6 cycloalkyloxy groups. Exemplary cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclohexyloxy, and the like.

[0078] As used herein, the term "cyano" refers to a -CN group.

[0079] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0080]

[0046] The terms "halo" or "halogen," as used herein, alone or in combination with other terms, refer to chlorine, fluorine, bromine and iodine.

[0081] 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).

[0082] As used herein, the terms "heterocyclyl", "heterocycloalkyl", "heterocyclyl" and "heterocycle" refer to substituted or unsubstituted non-aromatic ring structures, including monocyclic, polycyclic (e.g., bicyclic, tricyclic) bridged or fused ring structures, preferably 3-10 membered rings, more preferably 3-7 membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Attachment of the heterocyclyl substituent may occur via a carbon atom or via a heteroatom. Examples of "heterocyclic radicals" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxothiomorpholinyl, oxypiperazinyl, oxypiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolyl, indolylmethyl, 2-azabicyclo[2.2.2]octyl, azoctyl, chromanyl, xanthenyl, lactone, lactam and the like and N-oxides thereof. Heterocyclic radicals may be optionally substituted with one or more suitable groups. Examples of "heterocyclic radicals" include, but are not limited to, morpholine mimetics. Examples of morpholine mimetics include, but are not limited to

[0083]

[0084] As used herein, the term "heterocyclyloxy" refers to a heterocyclyl group bound to an oxygen atom attached to a core structure. Exemplary heterocyclyloxy groups include, but are not limited to, heterocyclyloxy 3- to 10-membered rings, referred to herein as C3-C10 heterocyclyloxy groups. Exemplary heterocyclyloxy groups include, but are not limited to, oxetanyloxy, azetidinyloxy, tetrahydrofuranyloxy, piperidinyloxy, piperazinyloxy, and the like.

[0085] "Combination therapy" is a treatment that involves administering two or more therapeutic agents, eg, a compound of the disclosure and a MAPK pathway inhibitor, to a patient in need thereof.

[0086] "Disease," "disorder," and "condition" are used interchangeably herein.

[0087] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. The compounds described herein can be administered not only to mammals such as humans, but also to other mammals, such as animals in need of veterinary treatment, such as domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like), and laboratory animals (e.g., rats, mice, guinea pigs and the like).

[0088] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when properly administered to animals or humans. For human administration, preparations should meet sterility, pyrogenicity and general safety and purity standards as required by the FDA Office of Biologics standards.

[0089] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of these media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional or enhanced therapeutic functions.

[0090] As used herein, the term "one or more pharmaceutically acceptable salts" refers to salts having acidic or basic groups that may be present in the compounds used in the composition. Compounds included in the compositions of the present disclosure that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, 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 disclosure that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts and iron salts. The compounds included in the disclosed compositions that include basic or acidic moieties may also form pharmaceutically acceptable salts with various amino acids. The disclosed compounds may contain acidic groups and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compounds may exist in the form of acid addition salts, zwitterions or base salts.

[0091] The compounds of the present disclosure may contain one or more chiral centers and therefore exist as stereoisomers. The term "stereoisomer" when used herein consists of all enantiomers or diastereomers. Depending on the configuration of substituents around the stereogenic carbon atom, these compounds may be designated by the symbols "(+)", "(-)", "R" or "S", but those skilled in the art will recognize that the structure may implicitly refer to the chiral center. The compounds described in the present disclosure encompass all stereoisomers of these compounds and mixtures thereof. In nomenclature, a mixture of enantiomers or diastereomers may be designated as "(±)", but those skilled in the art will recognize that the structure may implicitly refer to the chiral center.

[0092] In this specification, the term "therapeutically effective amount" means the amount of the disclosed compound that will elicit a biological or medical response in a tissue, system or animal (e.g., mammal or human) that a researcher, veterinarian, medical doctor or other clinician is seeking. The compounds described herein are administered in a therapeutically effective amount to treat a condition.

[0093] "Treatment" includes any action that results in an improvement in, such as alleviation, reduction, regulation, or elimination of, a condition, disease, disorder, and the like.

[0094] The present disclosure also encompasses isotopically-labeled compounds identical to the compounds described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds 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. 18 F and 36 Cl. For example, the disclosed compounds may have one or more H atoms replaced with deuterium.

[0095] Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by analytical methods well known to those of ordinary skill in the art. These analytical methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary, (2) forming salts using an optically active analytical agent, (3) directly separating 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 crystallization of compounds in chiral solvents. Stereoselective syntheses as chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the generation of a new stereocenter or during the conversion of a pre-existing stereocenter are well known in the art. Stereoselective synthesis encompasses enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0096] As used herein, “compounds of the present disclosure” include compounds of Formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL, IM, IN, IO, IP, IQ, IR, IS, IT, IU, IV, IW, IX, IY, IZ, I-AA, I-AB, and I-AC, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof.

[0097] Compound

[0098] Compounds of Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF

[0099] In one embodiment, described herein is a compound represented by Formula I:

[0100]

[0101] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0102] X 1 and X 2Each independently selected from the group consisting of N, CH and CF;

[0103] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0104] Q is selected from the group consisting of:

[0105] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0106] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy and oxo;

[0107] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0108] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0109] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0110] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0111] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0112] QLE combined with free choice The group composed of;

[0113] E11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0114] R 1 Selected from the group consisting of: H, haloalkyl,

[0115] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0116] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0117] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0118] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0119] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0120] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0121] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0122] R 3 is selected from the group consisting of F and alkoxy;

[0123] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0124] R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0125] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0126] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0127] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0128] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0129] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0130] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0131] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0132] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0133] R 10 is selected from the group consisting of H and alkyl, or R 8 and R8 With R 10 The atoms connected together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0134] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0135] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0136] n is 0, 1, 2, 3 or 4; and

[0137] p is 1, 2, or 3,

[0138] The restriction is that the compound is not:

[0139]

[0140] In one embodiment, described herein is a compound represented by Formula IA:

[0141]

[0142] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0143] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0144] Q is selected from the group consisting of:

[0145] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0146] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0147] E is selected from the group consisting of: H, alkenyl, cyano, alkoxy, haloalkoxy, haloalkyl, halogen,

[0148] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0149] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0150] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0151] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0152] QLE combined with free choice The group composed of;

[0153] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0154] R 1 Selected from the group consisting of: H,

[0155] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0156] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0157] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0158] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0159] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0160] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0161] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0162] R 3 is selected from the group consisting of F and alkoxy;

[0163] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0164] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0165] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0166] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0167] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0168] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0169] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0170] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0171] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0172] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 The atoms connected together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0173] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0174] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0175] n is 0, 1, 2, 3 or 4; and

[0176] p is 1, 2, or 3,

[0177] The restriction is that the compound is not:

[0178]

[0179] In one embodiment, described herein is a compound represented by Formula IB:

[0180]

[0181] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0182] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0183] Q is selected from the group consisting of:

[0184] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0185] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0186] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0187] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0188] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0189] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0190] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0191] QLE combined with free choice The group composed of;

[0192] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0193] R 1 Selected from the group consisting of: H, haloalkyl,

[0194] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0195] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0196] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0197] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0198] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0199] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0200] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0201] R 3 is selected from the group consisting of F and alkoxy;

[0202] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0203] R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0204] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0205] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0206] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0207] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0208] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0209] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0210] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0211] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0212] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0213] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0214] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0215] n is 0, 1, 2, 3 or 4; and

[0216] p is 1, 2 or 3.

[0217] In one embodiment, described herein is a compound represented by Formula IC:

[0218]

[0219] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0220] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0221] Q is selected from the group consisting of:

[0222] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0223] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0224] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0225] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0226] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0227] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0228] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0229] QLE combined with free choice The group composed of;

[0230] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0231] R 1Selected from the group consisting of: H, haloalkyl,

[0232] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0233] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0234] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0235] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0236] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0237] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0238] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0239] R 3 is selected from the group consisting of F and alkoxy;

[0240] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0241] R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0242] R8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0243] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0244] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0245] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0246] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0247] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0248] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0249] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0250] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0251] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0252] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0253] n is 0, 1, 2, 3 or 4; and

[0254] p is 1, 2 or 3.

[0255] In one embodiment, described herein is a compound represented by Formula ID:

[0256]

[0257] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0258] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0259] Q is selected from the group consisting of:

[0260] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0261] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0262] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0263] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0264] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0265] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0266] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0267] QLE combined with free choice The group composed of;

[0268] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0269] R 1 Selected from the group consisting of: H, haloalkyl,

[0270] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0271] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0272] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0273] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0274] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0275] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0276] R 3 is selected from the group consisting of F and alkoxy;

[0277] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0278] R 6 is an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxyl, cyano and cycloalkyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0279] R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0280] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0281] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0282] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0283] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0284] R 9is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0285] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0286] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0287] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0288] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0289] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0290] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0291] n is 0, 1, 2, 3 or 4; and

[0292] p is 1, 2 or 3.

[0293] In one embodiment, described herein is a compound represented by Formula IE:

[0294]

[0295] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0296] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0297] Q is selected from the group consisting of:

[0298] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0299] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy and oxo;

[0300] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0301] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0302] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0303] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0304] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0305] QLE combined with free choice The group composed of;

[0306] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0307] R 3 is selected from the group consisting of F and alkoxy;

[0308] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0309] R 5 Selected from the group consisting of:

[0310] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0311] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0312] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0313] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0314] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0315] R 6 is an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxyl, cyano and cycloalkyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl and halogen; R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0316] R 8is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0317] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0318] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0319] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0320] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0321] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0322] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0323] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0324] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0325] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0326] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0327] n is 0, 1, 2, 3 or 4; and

[0328] p is 1, 2 or 3.

[0329] In one embodiment, described herein is a compound represented by Formula IF:

[0330]

[0331] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0332] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0333] Q is selected from the group consisting of:

[0334] wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L;

[0335] L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0336] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0337] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0338] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0339] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0340] optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or

[0341] QLE combined with free choice The group composed of;

[0342] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0343] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0344] R 3 is selected from the group consisting of F and alkoxy;

[0345] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0346] R 5 Selected from the group consisting of:

[0347] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0348] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0349] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0350] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0351] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0352] R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl;

[0353] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0354] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0355] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0356] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0357] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0358] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0359] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0360] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0361] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0362] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy;

[0363] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0364] n is 0, 1, 2, 3 or 4; and

[0365] p is 1, 2, or 3,

[0366] The restriction is that the compound is not:

[0367]

[0368] In some embodiments, R 1The optionally substituted substituents are selected from the group consisting of: H, haloalkyl, optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl at each occurrence, amine, cyano, halogen, , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

[0369] In some embodiments, R 1 Selected from the group consisting of: H,

[0370]

[0371] In some embodiments, R 1 Selected from the group consisting of: H,

[0372] In some embodiments, R 5 Selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen; optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen.

[0373] In some embodiments, R5 Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3, CF2CF3,

[0374] In some embodiments, R 5 Selected from the group consisting of: methyl,

[0375]

[0376] In some embodiments, R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

[0377] In some embodiments, R 2 Choose from H, The group composed of.

[0378] In some embodiments, R 2 For H.

[0379] In some embodiments, R 1 and R 2 together form a ring structure selected from the group consisting of:

[0380]

[0381] In some embodiments, R 2 and R 5 together form a ring structure selected from the group consisting of: Wherein s3 is the site of covalent bonding to the bicyclic structure and s4 is the site of covalent bonding to the oxygen atom.

[0382] In some embodiments, R 6 is optionally substituted C1-C6 alkyl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano and cycloalkyl.

[0383] In some embodiments, R 6 Selected from methyl and The group composed of.

[0384] In some embodiments, R 1 and R 6 together form a ring structure selected from the group consisting of: Wherein s3 is the site of covalent bonding to the bicyclic structure and s4 is the site of covalent bonding to the oxygen atom.

[0385] In some embodiments, R 5 and R 6 together form a ring structure selected from the group consisting of:

[0386]

[0387] In some embodiments, R 3 is F or alkoxy.

[0388] In some embodiments, R 3 For F.

[0389] In some embodiments, R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

[0390] In some embodiments, R 4 For H.

[0391] In some embodiments, X 1 , X 2 , X 3 and X 4 are independently CH or N, subject to the condition that X 3 and X 4 No more than one of them is N.

[0392] In some embodiments, X 1 is CH and X 2 For CH.

[0393] In some embodiments, X 1 is CH and X 2 is N.

[0394] In some embodiments, X 3 is CH and X 4 is N.

[0395] In some embodiments, X 1 N, X 2 CH, X 3 is CH and X 4 is CH; X 1 CH, X 2 N, X 3 is CH and X4 is CH; X 1 CH, X 2 CH, X 3 N and X 4 is CH; X 1 CH, X 2 CH, X 3 is CH and X 4 N; X 1 N, X 2 N, X 3 is CH and X 4 is CH; X 1 N, X 2 N, X 3 N and X 4 is CH; or X 1 N, X 2 N, X 3 is CH and X 4 is N.

[0396] In some embodiments, L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl.

[0397] In some embodiments, It is freedom to choose

[0398] Composed of groups.

[0399] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[0400] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[0401] In some embodiments, Freedom to choose

[0402] Composed of groups.

[0403] In some embodiments, E is selected from the group consisting of: H; C1-C6 alkenyl; cyano; haloalkoxy; haloalkyl; halogen; optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl, and cyano; optionally substituted C3-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of cycloalkyl and heterocyclyl.

[0404] In some embodiments, E is selected from the group consisting of: H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0405]

[0406] In some embodiments, Freedom to choose

[0407]

[0408] The group composed of.

[0409] In some embodiments, Freedom to choose

[0410] The group composed of.

[0411] In some embodiments, L is not a direct bond, and E is selected from the group consisting of H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0412]

[0413] In some embodiments, L is not a direct bond, and E is selected from the group consisting of H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0414]

[0415] In some embodiments, Selected from the group consisting of:

[0416]

[0417] In some embodiments, when L is a direct bond, Freedom to choose The group composed of.

[0418] In some embodiments, R 7 is H, alkyl or halogenated alkyl.

[0419] In some embodiments, R 7 For H.

[0420] In some embodiments, for

[0421] In some embodiments, for

[0422] In some embodiments, E is selected from the group consisting of H, fluoro, methoxy, and cyano.

[0423] In some embodiments, Freedom to choose The group composed of.

[0424] In some embodiments, Freedom to choose

[0425] The group composed of.

[0426] In some embodiments, Freedom to choose

[0427] The group composed of.

[0428] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[0429] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[0430] In some embodiments, E is selected from the group consisting of: H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0431]

[0432] In some embodiments, E is selected from the group consisting of: H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0433]

[0434] In some embodiments, Selected from the group consisting of:

[0435]

[0436] In some embodiments, R 8 is selected from the group consisting of an alkyl group, a cycloalkyl group and a heterocyclic group, and R 10 Selected from the group consisting of H and alkyl.

[0437] In some embodiments, R 8 Freedom to choose

[0438]

[0439] The group composed of 10 Selected from the group consisting of H, methyl, ethyl and isopropyl.

[0440] In some embodiments, R 8 With R 10 and R 8 and R 10 The attached N atoms together form a ring structure selected from the group consisting of:

[0441]

[0442] In some embodiments, L is a direct bond, R 8 Freedom to choose The group composed of 10 For H.

[0443] In some embodiments, R 9 Freedom to choose Composed of groups.

[0444] In some embodiments, R 11 Selected from the group consisting of H and C1-C6 alkyl.

[0445] In some embodiments, R 11 Selected from the group consisting of H and methyl.

[0446] In some embodiments, R 11 With R 9and the atoms to which they are respectively attached, together form an optionally substituted ring, wherein the substituents at each occurrence are independently selected from the group consisting of alkyl, haloalkyl, and cycloalkyl.

[0447] In some embodiments, R 11 With R 9 and the atoms to which they are respectively attached form an optionally substituted ring, wherein two occurrences of substituents together with the atoms to which they are attached form a 4- to 6-membered ring.

[0448] In some embodiments, R 11 With R 9 and the atoms to which they are respectively attached together form an optionally substituted ring selected from the group consisting of:

[0449]

[0450] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[0451] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[0452] Compounds of Formula IG, Formula IH, Formula II, Formula IJ, Formula IK, Formula IL and Formula IM

[0453] In one embodiment, described herein is a compound represented by formula IG:

[0454]

[0455] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0456] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0457] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0458] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0459] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0460] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0461] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0462] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0463] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0464] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0465] R 1 Selected from the group consisting of: H, haloalkyl,

[0466] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0467] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0468] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0469] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0470] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0471] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0472] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0473] R 3 is selected from the group consisting of F and alkoxy;

[0474] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0475] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0476] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0477] In one embodiment, described herein is a compound represented by Formula IH:

[0478]

[0479] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0480] X 1 and X 2Each independently selected from the group consisting of N, CH and CF;

[0481] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0482] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0483] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0484] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0485] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0486] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0487] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0488] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0489] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0490] R 3 is selected from the group consisting of F and alkoxy;

[0491] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0492] R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0493] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0494] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0495] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0496] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0497] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0498] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0499] In one embodiment, described herein is a compound represented by Formula II:

[0500]

[0501] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0502] X1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0503] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0504] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0505] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0506] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0507] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0508] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0509] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0510] R 1 Selected from the group consisting of: H, haloalkyl,

[0511] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0512] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0513] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0514] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0515] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0516] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0517] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0518] R 3 is selected from the group consisting of F and alkoxy;

[0519] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0520] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0521] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0522] In one embodiment, described herein is a compound represented by Formula IJ:

[0523]

[0524] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0525] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0526] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0527] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0528] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0529] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0530] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0531] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0532] R 1 Selected from the group consisting of: H, haloalkyl,

[0533] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0534] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0535] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0536] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0537] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0538] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0539] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0540] R 3 is selected from the group consisting of F and alkoxy;

[0541] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0542] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0543] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0544] In one embodiment, described herein is a compound represented by Formula IK:

[0545]

[0546] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0547] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0548] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0549] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0550] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0551] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0552] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0553] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0554] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0555] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0556] R 3 is selected from the group consisting of F and alkoxy;

[0557] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0558] R 5 Selected from the group consisting of:

[0559] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0560] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0561] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0562] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0563] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0564] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0565] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0566] In one embodiment, described herein is a compound represented by Formula IL:

[0567]

[0568] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0569] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0570] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0571] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0572] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0573] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0574] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0575] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0576] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0577] R 3 is selected from the group consisting of F and alkoxy;

[0578] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0579] R 5 Selected from the group consisting of:

[0580] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0581] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0582] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0583] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0584] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0585] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0586] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0587] In one embodiment, described herein is a compound represented by Formula IM:

[0588]

[0589] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0590] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0591] L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo;

[0592] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0593] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0594] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0595] R 1 Selected from the group consisting of: H, haloalkyl,

[0596] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0597] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0598] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0599] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0600] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0601] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0602] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0603] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0604] R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and

[0605] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0606] The restriction is that the compound is not:

[0607]

[0608] In some embodiments, R 1The optionally substituted substituents are selected from the group consisting of: H, haloalkyl, optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl at each occurrence, amine, cyano, halogen, , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

[0609] In some embodiments, R 1 Selected from the group consisting of: H,

[0610] In some embodiments, R 1 Selected from the group consisting of: H,

[0611] In some embodiments, R 5 Selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen; optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen.

[0612] In some embodiments, R 5 Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3, CF2CF3,

[0613] In some embodiments, R 5 Selected from the group consisting of: methyl,

[0614] In some embodiments, R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

[0615] In some embodiments, R 2 Choose from H, Composed of groups.

[0616] In some embodiments, R 2 For H.

[0617] In some embodiments, R 3 is F or alkoxy.

[0618] In some embodiments, R 3 For F.

[0619] In some embodiments, R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

[0620] In some embodiments, R 4 For H.

[0621] In some embodiments, X 1 , X 2 , X 3 and X 4 are independently CH or N, subject to the condition that X 3 and X 4 No more than one of them is N.

[0622] In some embodiments, X 1 is CH and X 2 For CH.

[0623] In some embodiments, X 1 is CH and X 2 is N.

[0624] In some embodiments, X3 is CH and X 4 is N.

[0625] In some embodiments, L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl.

[0626] In some embodiments, Selected from the group consisting of:

[0627]

[0628] In some embodiments, Selected from the group consisting of:

[0629]

[0630] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[0631] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[0632] In some embodiments, Selected from the group consisting of:

[0633]

[0634] In some embodiments, Selected from the group consisting of:

[0635]

[0636] In some embodiments, R 7 is H, alkyl or halogenated alkyl.

[0637] In some embodiments, R 7 For H.

[0638] In some embodiments, E is selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl, and cyano; optionally substituted C3-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl, and cyano; H; C1-C6 alkenyl; cyano; haloalkoxy; haloalkyl and halogen.

[0639] In some embodiments, when L is optionally substituted with (E 11 ) m When the alkyl group is substituted, E is selected from the group consisting of H, fluorine, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0640]

[0641] In some embodiments, when L is optionally substituted with (E 11 ) m When the alkyl group is substituted, E is selected from the group consisting of H, fluorine, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano,

[0642]

[0643] Alkenyl,

[0644] In some embodiments, Selected from the group consisting of:

[0645]

[0646] In some embodiments, Freedom to choose

[0647]

[0648] Composed of groups.

[0649] In some embodiments, Selected from the group consisting of:

[0650]

[0651] In some embodiments, Freedom to choose Composed of groups.

[0652] In some embodiments, Freedom to choose The group composed of.

[0653] In some embodiments, when L is a direct bond, Freedom to choose The group composed of.

[0654] In some embodiments, R 7 With L and R 7 Together with the N atom to which L is attached, form an optionally substituted ring, wherein the substituents at each occurrence are independently selected from the group consisting of alkyl, cycloalkyl and haloalkyl.

[0655] In some embodiments, R 7 With L and R 7 Together with the N atom to which L is attached, an optionally substituted ring is formed wherein two occurrences of the substituents together with the atoms to which they are attached form a 4 to 6 membered ring.

[0656] In some embodiments, R 7 With L and R 7 Together with the N atom to which L is attached, a

[0657] The ring structure of the group.

[0658] Compounds of Formula IN, Formula IO, Formula IP and Formula IQ

[0659] In one embodiment, described herein is a compound represented by Formula IN:

[0660]

[0661] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0662] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0663] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0664] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0665] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0666] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0667] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0668] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0669] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0670] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0671] R 1 Selected from the group consisting of: H, haloalkyl,

[0672] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0673] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0674] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0675] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0676] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0677] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0678] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0679] R 3 is selected from the group consisting of F and alkoxy;

[0680] R 4 is selected from the group consisting of H, F, alkyl and alkoxy; and

[0681] m is independently 0, 1, 2, 3 or 4 at each occurrence,

[0682] The restriction is that the compound is not:

[0683]

[0684] In one embodiment, described herein is a compound represented by Formula IO:

[0685]

[0686] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0687] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0688] X 3 and X 4are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0689] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0690] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0691] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0692] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0693] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0694] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0695] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0696] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0697] R3 is selected from the group consisting of F and alkoxy;

[0698] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0699] R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0700] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0701] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0702] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0703] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and

[0704] m is independently 0, 1, 2, 3 or 4 at each occurrence,

[0705] The restriction is that the compound is not:

[0706]

[0707] In one embodiment, described herein is a compound represented by Formula IP:

[0708]

[0709] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0710] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0711] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0712] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0713] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0714] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0715] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0716] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0717] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0718] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0719] R 3 is selected from the group consisting of F and alkoxy;

[0720] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0721] R 5 Selected from the group consisting of:

[0722] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0723] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0724] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0725] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0726] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and

[0727] m is independently 0, 1, 2, 3 or 4 at each occurrence,

[0728] The restriction is that the compound is not:

[0729]

[0730] In one embodiment, described herein is a compound represented by Formula IQ:

[0731]

[0732] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0733] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0734] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, and

[0735] Optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl, and cyano;

[0736] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0737] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0738] R 3 is selected from the group consisting of F and alkoxy;

[0739] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0740] R 5 Selected from the group consisting of:

[0741] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0742] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0743] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0744] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0745] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and

[0746] m is independently 0, 1, 2, 3 or 4 at each occurrence,

[0747] The restriction is that the compound is not:

[0748]

[0749] In some embodiments, R 1 The optionally substituted substituents are selected from the group consisting of: H, haloalkyl, optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl at each occurrence, amine, cyano, halogen, , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

[0750] In some embodiments, R 1 Selected from the group consisting of: H,

[0751] In some embodiments, R 1 Selected from the group consisting of: H,

[0752]

[0753] In some embodiments, R 5 Selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen; optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen.

[0754] In some embodiments, R 5 Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3,

[0755] In some embodiments, R 5 Selected from the group consisting of: methyl,

[0756] In some embodiments, R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

[0757] In some embodiments, R 2 Choose from H, The group composed of.

[0758] In some embodiments, R 2 For H.

[0759] In some embodiments, R 3 is F or alkoxy.

[0760] In some embodiments, R 3 For F.

[0761] In some embodiments, R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

[0762] In some embodiments, R 4 For H.

[0763] In some embodiments, X 1 , X 2 , X 3 and X 4 are independently CH or N, subject to the condition that X 3 and X 4 No more than one of them is N.

[0764] In some embodiments, X 1 is CH and X 2 For CH.

[0765] In some embodiments, X 1 is CH and X 2 is N.

[0766] In some embodiments, X 3 is CH and X 4 is N.

[0767] In some embodiments, X 1 N, X 2 CH, X 3 is CH and X 4 is CH; X 1 CH, X 2 N, X 3 is CH and X 4 is CH; X 1 CH, X 2 CH, X 3 N and X 4 is CH; X 1 CH, X 2 CH, X 3 is CH and X 4 N; X 1 N, X 2 N, X 3 is CH and X 4 is CH; X 1 N, X 2 N, X 3 N and X 4 is CH; or X 1 N, X 2 N, X 3 is CH and X 4 is N.

[0768] In some embodiments, L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl.

[0769] In some embodiments, Freedom to choose Composed of groups.

[0770] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[0771] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[0772] In some embodiments, Freedom to choose Composed of groups.

[0773] In some embodiments, for

[0774] In some embodiments, for

[0775] In some embodiments, E is selected from the group consisting of optionally substituted amide, wherein the substituents are independently selected at each occurrence from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl, and cyano; H; cyano; haloalkoxy; haloalkyl and halogen.

[0776] In some embodiments, E is selected from the group consisting of H, fluoro, methoxy, and cyano.

[0777] In some embodiments, Freedom to choose Composed of groups.

[0778] Compounds of Formula IR, Formula IS, Formula IT and Formula IU

[0779] In one embodiment, described herein is a compound represented by Formula IR:

[0780]

[0781] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0782] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0783] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0784] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0785] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0786] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0787] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0788] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0789] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0790] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0791] R 1 Selected from the group consisting of: H, haloalkyl,

[0792] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0793] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0794] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0795] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0796] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0797] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0798] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0799] R 3 is selected from the group consisting of F and alkoxy;

[0800] R 4 is selected from the group consisting of H, F, alkyl and alkoxy; and

[0801] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0802] In one embodiment, described herein is a compound represented by Formula IS:

[0803]

[0804] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0805] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0806] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0807] L is selected from a direct bond and optionally11 ) m The group consisting of substituted C1-C6 alkyl;

[0808] E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen,

[0809] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0810] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0811] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0812] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0813] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0814] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0815] R 3 is selected from the group consisting of F and alkoxy;

[0816] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0817] R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0818] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0819] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0820] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0821] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and

[0822] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0823] In one embodiment, described herein is a compound represented by Formula IT:

[0824]

[0825] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0826] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0827] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0828] E is selected from the group consisting of: H, cyano, alkoxy, haloalkoxy, haloalkyl, halogen,

[0829] An optionally substituted amido group, wherein the substituents are independently selected at each occurrence from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0830] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0831] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano,

[0832] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0833] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0834] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0835] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0836] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0837] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0838] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0839] R 3 is selected from the group consisting of F and alkoxy;

[0840] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0841] R 5 Selected from the group consisting of:

[0842] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0843] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence,

[0844] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0845] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0846] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and

[0847] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0848] In one embodiment, described herein is a compound represented by Formula IU:

[0849]

[0850] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0851] L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl;

[0852] E is selected from the group consisting of: H, cyano, alkoxy, haloalkoxy, haloalkyl, halogen,

[0853] An optionally substituted amido group, wherein the substituents are independently selected at each occurrence from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0854] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0855] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano,

[0856] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0857] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0858] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano,

[0859] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0860] Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl;

[0861] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0862] R 2is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0863] R 3 is selected from the group consisting of F and alkoxy;

[0864] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0865] R 5 Selected from the group consisting of:

[0866] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0867] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence,

[0868] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0869] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0870] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and

[0871] m is independently 0, 1, 2, 3 or 4 at each occurrence.

[0872] In some embodiments, R 1The optionally substituted substituents are selected from the group consisting of: H, haloalkyl, optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl at each occurrence, amine, cyano, halogen, , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

[0873] In some embodiments, R 1 Selected from the group consisting of: H,

[0874] In some embodiments, R 1 Selected from the group consisting of: H,

[0875] In some embodiments, R 5 Selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen; optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen.

[0876] In some embodiments, R 5Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3,

[0877] In some embodiments, R 5 Selected from the group consisting of: methyl,

[0878] In some embodiments, R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

[0879] In some embodiments, R 2 Choose from H, The group composed of.

[0880] In some embodiments, R 2 For H.

[0881] In some embodiments, R 3 is F or alkoxy.

[0882] In some embodiments, R 3 For F.

[0883] In some embodiments, R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

[0884] In some embodiments, R 4 For H.

[0885] In some embodiments, X 1 , X 2 , X 3 and X 4 are independently CH or N, subject to the condition that X 3 and X 4 No more than one of them is N.

[0886] In some embodiments, X 1 is CH and X 2 For CH.

[0887] In some embodiments, X 1 is CH and X 2 is N.

[0888] In some embodiments, X 3 is CH and X 4 is N.

[0889] In some embodiments, X 1 N, X 2 CH, X 3 is CH and X 4 is CH; X 1 CH, X 2 N, X 3 is CH and X 4 is CH; X 1 CH, X 2 CH, X 3 N and X 4 is CH; X 1 CH, X 2 CH, X 3 is CH and X 4 N; X 1 N, X 2 N, X 3 is CH and X 4 is CH; X 1 N, X 2 N, X 3 N and X 4 is CH; or X 1 N, X 2 N, X 3 is CH and X 4 is N.

[0890] In some embodiments, L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl.

[0891] In some embodiments, Selected from the group consisting of:

[0892]

[0893] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[0894] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[0895] In some embodiments, Selected from the group consisting of:

[0896]

[0897] In some embodiments, Selected from the group consisting of:

[0898]

[0899] In some embodiments, wherein Selected from the group consisting of:

[0900]

[0901] In some embodiments, E is selected from the group consisting of optionally substituted amido, wherein the substituents are independently selected at each occurrence from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C6 heterocyclyl, and optionally substituted C3-C6 cycloalkyl, wherein the substituents of the optionally substituted C1-C6 alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, halo The substituents of the optionally substituted C3-C6 heterocyclyl are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, and the substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; optionally substituted C3-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; optionally substituted heteroalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; optionally substituted heteroalkyl Cycyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of cycloalkyl, heterocyclyl and H; cyano; alkoxy; haloalkoxy; haloalkyl and halogen.

[0902] In some embodiments, E is selected from the group consisting of: H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0903]

[0904] In some embodiments, E is selected from the group consisting of: H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0905]

[0906] In some embodiments, Selected from the group consisting of:

[0907]

[0908] Compounds of Formula IV, Formula IW, Formula IX and Formula IY

[0909] In one embodiment, described herein is a compound represented by Formula IV:

[0910]

[0911] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0912] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0913] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0914] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0915] R 1 Selected from the group consisting of: H, haloalkyl,

[0916] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0917] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0918] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0919] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[0920] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[0921] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[0922] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0923] R 3 is selected from the group consisting of H, F and alkoxy;

[0924] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0925] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0926] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0927] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0928] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0929] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and

[0930] n is 0, 1, 2, 3 or 4.

[0931] In one embodiment, described herein is a compound represented by Formula IW:

[0932]

[0933] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0934] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0935] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[0936] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0937] R 2is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0938] R 3 is selected from the group consisting of H, F and alkoxy;

[0939] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0940] R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0941] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[0942] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[0943] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0944] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0945] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0946] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0947] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0948] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0949] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and

[0950] n is 0, 1, 2, 3 or 4.

[0951] In one embodiment, described herein is a compound represented by Formula IX:

[0952]

[0953] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0954] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[0955] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0956] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0957] R 3 is selected from the group consisting of H, F and alkoxy;

[0958] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0959] R 5 Selected from the group consisting of:

[0960] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0961] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0962] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen;

[0963] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0964] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0965] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0966] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0967] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0968] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0969] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and

[0970] n is 0, 1, 2, 3 or 4.

[0971] In one embodiment, described herein is a compound represented by Formula IY:

[0972]

[0973] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0974] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[0975] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[0976] R 3 is selected from the group consisting of H, F and alkoxy;

[0977] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[0978] R 5 Selected from the group consisting of:

[0979] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[0980] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[0981] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen;

[0982] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[0983] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[0984] R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[0985] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[0986] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[0987] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[0988] R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and

[0989] n is 0, 1, 2, 3 or 4.

[0990] In some embodiments, R 1The optionally substituted substituents are selected from the group consisting of: H, haloalkyl, optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl at each occurrence, amine, cyano, halogen, , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

[0991] In some embodiments, R 1 Selected from the group consisting of: H,

[0992] In some embodiments, R 1 Selected from the group consisting of: H,

[0993]

[0994] In some embodiments, R 5 Selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido being independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl being independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, and halogen; optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, and halogen; optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, and halogen.

[0995] In some embodiments, R5 Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3,

[0996]

[0997] In some embodiments, R 5 Selected from the group consisting of: methyl,

[0998] In some embodiments, R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

[0999] In some embodiments, R 2 Choose from H, Composed of groups.

[1000] In some embodiments, R 2 For H.

[1001] In some embodiments, R 3 is F, H or alkoxy.

[1002] In some embodiments, R 3 For F.

[1003] In some embodiments, R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

[1004] In some embodiments, R 4 For H.

[1005] In some embodiments, X 1 and X 2 are independently CH or N.

[1006] In some embodiments, X 1 is CH and X 2 For CH.

[1007] In some embodiments, X 1 is CH and X 2 is N.

[1008] In some embodiments, L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl.

[1009] In some embodiments, Selected from the group consisting of:

[1010]

[1011] In some embodiments, Selected from the group consisting of:

[1012]

[1013] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[1014] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[1015] In some embodiments, Selected from the group consisting of:

[1016]

[1017] In some embodiments, Selected from the group consisting of:

[1018]

[1019] In some embodiments, R 8 Selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups.

[1020] In some embodiments, R 8 Selected from the group consisting of C1-C6 alkyl, cycloalkyl and heterocyclic groups.

[1021] In some embodiments, R 10 Selected from the group consisting of H and alkyl.

[1022] In some embodiments, R 10 Selected from the group consisting of H and C1-C6 alkyl.

[1023] In some embodiments, R 8 is selected from the group consisting of an alkyl group, a cycloalkyl group and a heterocyclic group, and R 10 Selected from the group consisting of H and alkyl.

[1024] In some embodiments, R 8 Selected from the group consisting of:

[1025] And R 10 Selected from the group consisting of H, methyl, ethyl and isopropyl.

[1026] In some embodiments, R 8 With R 10 and R 8 and R 10 The connected N atoms together form a ring structure selected from the group consisting of

[1027]

[1028] In some embodiments, L is a direct bond, R 8 Freedom to choose The group composed of 10 For H.

[1029] Compounds of Formula IZ, Formula I-AA, Formula I-AB and Formula I-AC

[1030] In one embodiment, described herein is a compound represented by Formula IZ:

[1031]

[1032] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1033] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[1034] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[1035] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[1036] R 1 Selected from the group consisting of: H, haloalkyl,

[1037] optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[1038] The substituents of the optionally substituted amido group are independently C1-C6 alkyl at each occurrence, and

[1039] The substituents of the optionally substituted heterocyclyl are independently, at each occurrence, C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[1040] optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo,

[1041] optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and

[1042] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy;

[1043] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[1044] R 3 is selected from the group consisting of H, F and alkoxy;

[1045] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[1046] R 9is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[1047] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[1048] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[1049] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[1050] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The atoms respectively attached are taken together to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and

[1051] p is 1, 2, or 3,

[1052] The restriction is that the compound is not:

[1053]

[1054] In one embodiment, described herein is a compound represented by Formula I-AA:

[1055]

[1056] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1057] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[1058] X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N;

[1059] E11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[1060] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[1061] R 3 is selected from the group consisting of H, F and alkoxy;

[1062] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[1063] R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[1064] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[1065] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[1066] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[1067] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[1068] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[1069] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[1070] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[1071] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[1072] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The atoms respectively attached are taken together to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and

[1073] p is 1, 2, or 3,

[1074] The restriction is that the compound is not:

[1075]

[1076] In one embodiment, described herein is a compound represented by Formula I-AB:

[1077]

[1078] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1079] X 1 and X 2 Each independently selected from the group consisting of N, CH and CF;

[1080] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[1081] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[1082] R 3 is selected from the group consisting of H, F and alkoxy;

[1083] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[1084] R 5 Selected from the group consisting of:

[1085] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[1086] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[1087] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[1088] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[1089] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[1090] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[1091] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[1092] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[1093] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[1094] R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The atoms respectively attached are taken together to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and

[1095] p is 1, 2, or 3,

[1096] The restriction is that the compound is not

[1097]

[1098] In one embodiment, described herein is a compound represented by Formula I-AC:

[1099]

[1100] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1101] E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo;

[1102] R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen;

[1103] R 3 is selected from the group consisting of H, F and alkoxy;

[1104] R 4 is selected from the group consisting of H, F, alkyl and alkoxy;

[1105] R 5 Selected from the group consisting of:

[1106] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein

[1107] The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and

[1108] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen,

[1109] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and

[1110] optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen;

[1111] R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein

[1112] The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl,

[1113] The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and

[1114] The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano;

[1115] R 11 is selected from the group consisting of H and alkyl, or R9 and R 9 With R 11 The atoms respectively attached are taken together to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and

[1116] p is 1, 2, or 3,

[1117] The restriction is that the compound is not:

[1118]

[1119] In some embodiments, R 1 The optionally substituted substituents are selected from the group consisting of: H, haloalkyl, optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl at each occurrence, amine, cyano, halogen, , C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

[1120] In some embodiments, R 1 Selected from the group consisting of: H,

[1121]

[1122] In some embodiments, R 1 Selected from the group consisting of: H,

[1123] In some embodiments, R 5Selected from the group consisting of optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, the substituents of the optionally substituted amido are independently C1-C6 alkyl at each occurrence, the substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen; optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen.

[1124] In some embodiments, R 5 Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3,

[1125]

[1126] In some embodiments, R 5 Selected from the group consisting of: methyl,

[1127] In some embodiments, R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

[1128] In some embodiments, R 2 Choose from H, Composed of groups.

[1129] In some embodiments, R 2 For H.

[1130] In some embodiments, R 1 and R 2 together form a ring structure selected from the group consisting of:

[1131]

[1132] In some embodiments, R 2 and R 5 together form a ring structure selected from the group consisting of:

[1133] Wherein s3 is the site of covalent bonding to the bicyclic structure and s4 is the site of covalent bonding to the oxygen atom.

[1134] In some embodiments, R 3 is H, F or alkoxy.

[1135] In some embodiments, R 3 For F.

[1136] In some embodiments, R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

[1137] In some embodiments, R 4 For H.

[1138] In some embodiments, X 1 and X 2 are independently CH or N.

[1139] In some embodiments, X 1 is CH and X 2 For CH.

[1140] In some embodiments, X 1 is CH and X 2 is N.

[1141] In some embodiments, L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl.

[1142] In some embodiments, Selected from the group consisting of:

[1143]

[1144] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

[1145] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

[1146] In some embodiments, Selected from the group consisting of:

[1147]

[1148] In some embodiments, R 9 It is a C1-C6 alkyl group.

[1149] In some embodiments, R 9 It is an alkyl group.

[1150] In some embodiments, R 9 Selected from the group consisting of:

[1151]

[1152] In some embodiments, R 11 Selected from the group consisting of H and alkyl.

[1153] In some embodiments, R 11 Selected from the group consisting of H and C1-C6 alkyl.

[1154] In some embodiments, R 9 is a C1-C6 alkyl group, and R 11 Selected from the group consisting of H and C1-C6 alkyl.

[1155] In some embodiments, R 9 Selected from the group consisting of: And R 11 Selected from the group consisting of H and methyl.

[1156] In some embodiments, R 11 With R 9 and R 9 and R 11 The respectively attached atoms together form an optionally substituted ring structure having 4 to 7 atoms in the ring structure, wherein the optional substituents at each occurrence are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy.

[1157] In some embodiments, R 11 With R 9 and R 9 and R 11 The respectively attached atoms together form an optionally substituted ring structure selected from the group consisting of:

[1158]

[1159] In one embodiment, described herein is a compound selected from the group consisting of:

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

[1167] Combination therapy

[1168] In one embodiment, described herein is about a combination therapy involving the disclosed compounds and one or more therapeutic agents. The combination therapy described herein can be used by itself, or further combined with one or more additional therapeutic agents (e.g., one or more additional therapeutic agents described below). For example, the disclosed compounds can be administered together with cancer targeted therapeutic agents, cancer targeted biological agents, immune checkpoint inhibitors or chemotherapeutic agents. These therapeutic agents can be administered together with another therapeutic agent described herein or sequentially in the combination therapy.

[1169] Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. Alternatively, combination therapy can be achieved by administering two or more therapeutic agents in a single formulation.

[1170] Combination therapy also encompasses other combinations. Although two or more agents in combination therapy can be administered simultaneously, it is not necessarily so. For example, the administration of the first agent (or combination of agents) can be several minutes, hours, days or weeks ahead of the administration of the second agent (or combination of agents). Therefore, the administration of two or more agents can be within a few minutes each other, or within 1, 2, 3, 6, 9, 12, 15, 18 or 24 hours each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 14 days each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or weeks each other. In some cases, even longer time intervals are also possible. Although in many cases, the two or more agents used in combination therapy need to be present in the patient's body at the same time, it is not necessarily so.

[1171] Combination therapy may also include two or more administrations of one or more of the agents used in combination using different orders of the component agents. For example, if agent X and agent Y are used in combination, they may be administered one or more times in any combination in order, e.g., in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[1172] In some embodiments, the additional therapeutic agent may include, but is not limited to, a cytotoxic agent, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, afarib), tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon α-2b, pegylated interferon α-2b, aromatase combination, gemcitabine, uracil mustard mustard), chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphatephosphate), leucovirin, oxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate,citrate, goserelinacetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimersodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, and valrubicin.

[1173] In some embodiments, the additional therapeutic agent may include, but is not limited to, AKT inhibitors, alkylating agents, all-trans retinoic acid, anti-androgens, azacitidine, BCL2 inhibitors, BCL-XL inhibitors, BCR-ABL inhibitors, BTK inhibitors, BTK / LCK / LYN inhibitors, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitors, CDK4 / 6 inhibitors, CDK9 inhibitors, CBP / p300 inhibitors, EGFR inhibitors, endothelin receptor antagonists, RAF inhibitors, MEK (mitogen-activated protein kinase) inhibitors, ERK inhibitors, farnesyl transferase inhibitors. agents, FLT3 inhibitors, glucocorticoid receptor agonists, HDM2 inhibitors, histone acetylase inhibitors, IKKβ inhibitors, immunomodulatory drugs (IMiDs), ingenol, ITK inhibitors, JAK1 / JAK2 / JAK3 / TYK2 inhibitors, MTOR inhibitors, PI3 kinase inhibitors, dual PI3 kinase / MTOR inhibitors, proteasome inhibitors, protein kinase C agonists, SUV39H1 inhibitors, TRAIL, VEGFR2 inhibitors, Wnt / β-catenin signaling inhibitors, decitabine, and anti-CD20 monoclonal antibodies.

[1174] In some embodiments, the additional therapeutic agent is an immunomodulator selected from the group consisting of: CTLA4 inhibitors, such as but not limited to ipilimumab and tremelimumab; PD1 inhibitors, such as but not limited to pembrolizumab and nivolumab; PDL1 inhibitors, such as but not limited to atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), avelumab, PDR001; 1BB or 41BB ligand inhibitors, such as but not limited to urelumab and PF-05082566; OX40 ligand agonists, such as but not limited to MEDI6469; GITR agents, such as but not limited to TRX518; CD27 inhibitors, such as but not limited to varlilumab; TNFRSF25 or TL1A inhibitors; CD40 agonists, such as but not limited to CP-870893; HVEM or LIGHT or LTA or BTLA or CD160 inhibitors; LAG3 inhibitors, such as but not limited to BMS-986016; TIM3 inhibitors; Siglecs inhibitors; ICOS or ICOS ligand agonists; B7 H3 inhibitors, such as but not limited to MGA271; B7 H4 inhibitors; VISTA inhibitors; HHLA2 or TMIGD2 inhibitors; butyrophilin inhibitors, including BTNL2 inhibitors; CD244 or CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIR inhibitors, such as but not limited to lirilumab; inhibitors of ILT and LIR; NKG2D and NKG2A inhibitors, such as but not limited to IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors, such as but not limited to emactuzumab, cabiralizumab, pexidartinib, ARRY382, BLZ945; IDO inhibitors, such as but not limited to INCB024360; thalidomide, lenalidomide, TGFβ inhibitors, such as but not limited to galunisertib; adenosine or CD39 or CD73 inhibitors;CXCR4 or CXCL12 inhibitors, such as, but not limited to, ulocuplumab and (3S, 6S, 9S, 12R, 17R, 20S, 23S, 26S, 29S, 34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propionamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4, 7,10,18,21,24,27,30-nonoxo-9,23-bis(3-ureidopropyl)trihydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclotriacontane-12-carboxamide BKT140; phosphatidylserine inhibitors such as, but not limited to, bavituximab; SIRPA or CD47 inhibitors such as, but not limited to, CC-90002; VEGF inhibitors such as, but not limited to, bevacizumab; and neuropilin inhibitors such as, but not limited to, MNRP1685A. ;

[1175] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of, but not limited to, anti-tubulin agents (paclitaxel, paclitaxel protein-bound particles for injectable suspension, such as nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxalipla The invention also includes but is not limited to tin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalators (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine and methotrexate.

[1176] In some embodiments, the additional therapeutic agent is selected from the group consisting of paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, docetaxel, ixabepilone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide, doxorubicin , PEGylated liposomal doxorubicin, daunorubicin, idarubicin, epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, methotrexate, erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, quizartinib, tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, abiraterone acetateacetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, prednisone, dexamethazone, irinotecan, camptothecin, topotecan, etoposide, etoposide phosphate, mitoxantrone, vorinostat, romidepsin, panobinostat, valproic acid, belinostat, DZNep 5-aza-2'-deoxycytidine, bortezomib, carfilzomib, thalidomide, lenalidomide and pomalidomide, trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, labrolizumab, nivolumab, MPDL3280A, bevacizumab, aflibercept, brentuximab vedotin, ado-trastuzumab enmetazocyl, radiation therapy, and sipuleucel T.

[1177] In some embodiments, the additional therapeutic agent is a kinase inhibitor selected from the group consisting of erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, and quizartinib.

[1178] In some embodiments, one or more additional therapeutic agents that can be administered in combination with the compounds provided herein can be MAPK pathway inhibitors. Such MAPK pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

[1179] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof. Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and pharmaceutically acceptable salts thereof. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446, and pharmaceutically acceptable salts thereof.

[1180] In some embodiments, the additional therapeutic agent is an anti-PD1 therapeutic agent. Examples of anti-PD1 therapeutic agents that can be administered in combination with the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof as described herein include, but are not limited to, nivolumab, pidilizumab, tislelizumab, AMP-224, AMP-514, and pembrolizumab.

[1181] In some embodiments, the additional therapeutic agent is selected from the group consisting of: immunomodulators, including but not limited to anti-PD-L1 therapeutics, including atezolizumab, durvalumab, BMS-936559, and avelumab; anti-TIM3 therapeutics, including TSR-022 and MBG453; anti-LAG3 therapeutics, including relatlimab, LAG525, and TSR-033; C D40 agonist therapeutics, including SGN-40, CP-870,893 and RO7009789; anti-CD47 therapeutics, including Hu5F9-G4; anti-CD20 therapeutics; anti-CD38 therapeutics; and other immunomodulatory therapeutics, including thalidomide, lenalidomide, pomalidomide, prednisone and dexamethasone. In some embodiments, the additional therapeutic agent is avelumab.

[1182] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of an anti-tubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, nab-paclitaxel (abraxane), docetaxel, ixabepilone, taxiterem, vincristine, or vinorelbine); an LHRH antagonist, including but not limited to leuprolide, goserelin, triptorelin, or histrelin; an anti-androgen, including but not limited to abiraterone, flutamide, bicalutamide, nilutamide, cyproterone acetate, tadalafil, tadalafil, styrene, phenytoin, tadalafil, styrene, phenytoin, styrene ... acetate, enzalutamide, and apalutamide; antiestrogens, including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, and temozolomide); temozolomide); DNA intercalators (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, methotrexate, bortezomib, and carfilzomib.

[1183] In some embodiments, the additional therapeutic agent is selected from the group consisting of targeted therapeutic agents, including kinase inhibitors erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, nib), regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, idelalisib, quizartinib, avapritinib, BLU-667, BLU-263, Loxo 292, larotrectinib and quizartinib; antiestrogens, 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, acetate); steroids, including but not limited to prednisone and dexamethasone; PARP inhibitors, including but not limited to neraparib, olaparib and rucaparib; topoisomerase I inhibitors, including but not limited to irinotecan, camptothecin and topotecan; topoisomerase II inhibitors, including but not limited to etoposide, etoposide phosphate and mitoxantrone;Histone deacetylase (HDAC) inhibitors, including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; DNA methylation inhibitors, including but not limited to DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including but not limited to bortezomib and carfilzomib, thalidomide, lenalidomide, idomide, pomalidomide; biologics, including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab; vaccines, including but not limited to sipuleucel-T; and radiation therapy. ;

[1184] In some embodiments, the additional therapeutic agent is selected from: a TIE2 immunokinase inhibitor, including rebastinib or ARRY-614.

[1185] In some embodiments, the additional therapeutic agent is selected from: a TIE2 immunokinase inhibitor, including rebastinib or ARRY-614, and an anti-PD1 therapeutic agent.

[1186] In some embodiments, the additional therapeutic agent is selected from: anti-angiogenic agents, including AMG386, bevacizumab and aflibercept; and antibody-drug conjugates (ADCs), including brentuximab, trastuzumab emtansine; and ADCs containing a payload, such as a derivative of camptothecin, pyrrolobenzodiazepinedimer (PBD), indolinobenzodiazepine dimer (IGN), DM1, DM4, MMAE or MMAF.

[1187] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone releasing hormone (LHRH) analogs including goserelin and leuprolide.

[1188] In some embodiments, the additional therapeutic agent is selected from: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, 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, ofatunab atumtunab), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx102. talampanel, atrasentan, Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine istine), temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-L-glutamic acid disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate citrate), anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl]-quinolinone, vatalanib, AG-013736, AVE-0005, acetate of [D-Ser(Bu t)6,Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18Oi4-(C2H4O2)x, wherein x=1 to 2.4], goserelin acetate acetate, leuprolideacetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate,acetate), CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG)Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin, daunorubicin, hexamethylenetetracycline, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole ), lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustardmustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosinearabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, malimastat rimastat), COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithelone B B), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab etuximab), granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustardmustard), methylprednisolone, ibritumomabtiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomaldaunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron n), aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[1189] In some embodiments, the additional therapeutic agent is an HSP90 inhibitor (e.g., AT13387). In some embodiments, the additional therapeutic agent is cyclophosphamide. In some embodiments, the additional therapeutic agent is an AKT inhibitor (e.g., perifosine). In some embodiments, the additional therapeutic agent is a BCR-ABL inhibitor (e.g., nilotinib). In some embodiments, the additional therapeutic agent is an mTOR inhibitor (e.g., RAD001). In some embodiments, the additional therapeutic agent is a FGFR inhibitor (e.g., erdafitinib, KO947, or BGJ398). In some embodiments, the additional therapeutic agent is an anti-PDL1 therapeutic agent. In some embodiments, the additional therapeutic agent is a Bcl2 inhibitor (e.g., venetoclax). In some embodiments, the additional therapeutic agent is an autophagy inhibitor (e.g., hydroxychloroquine). In some embodiments, the additional therapeutic agent is a MET inhibitor.

[1190] Pharmaceutical compositions and kits

[1191] In one embodiment, a pharmaceutical composition is described herein, comprising a compound of the present disclosure formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides a pharmaceutical composition comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These preparations include preparations suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, but in any given case, the most suitable form of administration will be determined according to the degree and severity of the condition being treated and according to the properties of the specific compound used. For example, the disclosed composition can be formulated in unit dosage form, and / or can be formulated for oral or subcutaneous administration.

[1192] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, which contain one or more of the compounds of the present disclosure as active ingredients in admixture with organic or inorganic carriers or excipients suitable for external, enteral or parenteral administration. The active ingredients can be compounded, for example, with conventional non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other suitable use form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[1193] For the preparation of solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier such as conventional tablet ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents such as water to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or its non-toxic, pharmaceutically acceptable salt. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[1194] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the disclosed compositions are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following substances: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) Humectants such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (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 composition may also contain a buffer. Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycols and the like.

[1195] Tablets can be made by compression or molding optionally with one or more adjunct ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be made by molding a mixture of the disclosed composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as dragees, capsules, pills, and granules can be optionally scored or prepared with coatings and shells such as enteric coatings and other coatings known in the art of pharmaceutical formulation.

[1196] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the disclosed compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, 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, tetrahydrofuran methanol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[1197] Suspensions, in addition to the compositions of the present disclosure, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[1198] Formulations for rectal or vaginal administration may be presented in the form of suppositories which may be prepared by mixing the disclosed compositions with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates and which are solid at room temperature but liquid at room temperature and therefore will melt in the body cavity and release the active agent.

[1199] Dosage forms for transdermal administration of the disclosed compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

[1200] Ointments, pastes, creams and gels may contain, in addition to the compositions of the disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[1201] In addition to the compositions of the present disclosure, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[1202] The pharmaceutical compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, liposomal formulation or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Sonic nebulizers may be used because they minimize the exposure of the agent to shear forces that may cause degradation of the compounds contained in the compositions of the present disclosure. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions of the present disclosure with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary with the requirements of the particular compositions of the present disclosure, but typically include nonionic surfactants (Tweens, Pluronics or polyethylene glycols); harmless proteins, such as serum albumin; sorbitan esters; oleic acid; lecithin; amino acids, such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[1203] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise a composition of the present disclosure and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use, which sterile powders may contain antioxidants, buffers, bacteriostats, solutes or suspending agents which render the formulation isotonic with the blood of the intended recipient, or thickening agents.

[1204] Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[1205] In one embodiment, an enteral pharmaceutical preparation is provided, which includes a compound of the present disclosure, an enteric substance, and a pharmaceutically acceptable carrier or excipient thereof. An enteric substance refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluids at a specific pH. The small intestine is a portion of the gastrointestinal tract (intestine) 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 terminal ileum is about 7.5.

[1206] Thus, enteric materials are insoluble, for example, until a pH of 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 methacrylate and methacrylic acid; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers; natural resins such as zein, shellac and copal colophorium; and several commercially available enteric dispersion systems (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 easily determined in vitro. The foregoing materials are a list of possible materials, but those skilled in the art who have the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric substances that meet the goals described herein.

[1207] Advantageously, kits are provided herein for use by consumers who, for example, need to treat cancer. These kits include suitable dosage forms such as those described above; and instructions describing methods of using the dosage forms to mediate, reduce or prevent inflammation. The instructions will guide consumers or medical personnel to apply the dosage forms according to modes of administration known to those skilled in the art. These kits can advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister package. Blister packages are well known in the packaging industry and are widely used to package drug unit dosage forms (tablets, capsules and the like). Blister packages generally consist of a relatively rigid material sheet covered with a preferably transparent plastic material foil. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the groove, and the relatively rigid material sheet is sealed against the plastic foil at the foil face opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet strength is such that the tablet or capsule can be removed from the blister packaging by manually applying pressure on the recess, thereby forming an opening in the sheet at the location of the recess. Subsequently, the tablet or capsule can be removed via the opening.

[1208] It may be desirable to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, so that the numbers correspond to the days in the regimen when the tablets or capsules so specified should be taken. Another example of such a memory aid is a calendar printed on a card, such as "First week, Monday, Tuesday, ... etc.; Second week, Monday, Tuesday, ... etc. ". Other variations of the memory aid are obvious. A "daily dose" may be a single tablet or capsule or several pills or capsules taken on a specified day. In addition, a daily dose of the first compound may consist of one tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[1209] Methods and uses

[1210] The compounds described herein can act as KIT inhibitors and are therefore useful for treating diseases and disorders, such as cancer, in patients in need thereof. Exemplary diseases include, but are not limited to, gastrointestinal stromal tumors (GIST), NF-1-deficient gastrointestinal stromal tumors, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors, KIT-driven gastrointestinal stromal tumors, PDGFRA-driven gastrointestinal stromal tumors, melanoma, acute myeloid leukemia, germ cell tumors of seminoma or malignant germ cell tumors, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic leukemia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. In some embodiments, the disease is gastrointestinal stromal tumor (GIST). In some embodiments, the disease is KIT-activated gastrointestinal stromal tumor (GIST). In some embodiments, KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the disease is melanoma. In some embodiments, the melanoma is KIT-activated melanoma. In some embodiments, KIT-activated melanoma has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma. In some embodiments, the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentigo melanoma, amelanotic melanoma, and desmoplastic melanoma. In some embodiments, the non-cutaneous melanoma is selected from the group consisting of ocular melanoma and mucosal melanoma.

[1211] In one embodiment, the use of the pharmaceutical composition can be used to prepare a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic leukemia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma and non-small cell lung cancer. In some embodiments, the disease is gastrointestinal stromal tumor (GIST). In some embodiments, the disease is KIT-activated gastrointestinal stromal tumor (GIST). In some embodiments, KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the disease is melanoma. In some embodiments, the melanoma is KIT-activated melanoma. In some embodiments, the KIT-activated melanoma has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma. In some embodiments, the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentigo melanoma, amelanotic melanoma, and desmoplastic melanoma. In some embodiments, the non-cutaneous melanoma is selected from the group consisting of ocular melanoma and mucosal melanoma.

[1212] The disclosed compounds can provide the dosage of the best drug efficacy to be administered to patients (animals and humans) who need such treatment. It should be understood that the dosage required to be used in any particular application will vary with different patients, not only with the selected specific compound or composition, but also with the route of administration, the nature of the condition treated, the age and condition of the patient, the simultaneous drug treatment or the special diet followed by the patient, and other factors recognized by those skilled in the art, wherein the appropriate dose is ultimately determined by the attending physician. For the treatment of the clinical conditions and diseases mentioned above, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectal administration in the form of dosage unit preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection or infusion technology.

[1213] Treatment can be continued for a long period of time or a short period of time as needed. The composition can be administered according to a regimen of, for example, one to four times a day 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 1 year, or an indefinite period of time. The treatment period can be terminated when the desired result is achieved.

[1214] Example

[1215] Compounds described herein can be prepared in a variety of ways based on the disclosure of teachings contained herein and synthetic methods in the art. In the description of the following synthetic methods, it should be understood that, unless otherwise stated, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration and processing procedures) can be selected as standard conditions for the reaction. It will be appreciated by those skilled in the art that the functional groups present on each part of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions are obvious to those skilled in the art, and therefore alternative methods are indicated. The starting material in the embodiment is commercially available or easily prepared from known materials by standard methods.

[1216] The structures of intermediates and exemplified compounds were named using ChemDraw version 10 or 12 (CambridgeSoft Corporation, Cambridge, MA).

[1217] 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, “Boc” is tert-butyl carbonate, “BSA” is bovine serum albumin, “BTFFH” is 1-(fluoro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V), “conc.” is concentrated, “Cs2CO3” is cesium carbonate, “CuCN” is copper(I) cyanide, “CuI” is copper(I) iodide, “DBU” is 1,8-diazabicyclo[5.4.0]undec-7-ene, “DCM” is dichloromethane, “DIAD” is diisopropyl azodicarboxylate, “DIEA” is N,N-diisopropylethylamine, “DMA” is N,N-dimethylacetamide, “DMAP” is 4-(dimethylamino)pyridine, “DMF” is N,N-dimethylformamide, “DMEM” is Dulbecco's modified Eagle's medium, “DMSO” is dimethyl sulfoxide, “DPPA” is diphenylphosphoryl azide, “EDC” is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, “ESI” is electrospray ionization, “Et3N” is triethylamine, “Et2O” is diethyl ether, “EtOAc” is ethyl acetate, “EtOH” is ethanol, “GST” is glutathione S-transferase, “h” is hour, “HATU” is tetramethyluronium hexafluorophosphate azabenzotriazole, “H2” is hydrogen, “HCl” is hydrochloric acid, “Hex” is hexane, “H2SO4” is sulfuric acid, “HOBt” is hydroxybenzotriazole, “IC 50" is half maximal inhibitory concentration, "K2CO3" is potassium carbonate, "KI" is potassium iodide, "K3PO4" is potassium phosphate, "LAH" is lithium aluminum hydride, "LiOH" is lithium hydroxide, "mCPBA" is m-chloroperbenzoic acid, "CH3CN" is acetonitrile, "MeOH" is methanol, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is minute, "MS" is mass spectrometry, "MTBE" is m-ethyl tert-butyl ether, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, "NaHCO3" is sodium bicarbonate, "NaOH" is sodium hydroxide, "NaOMe" is sodium methoxide, "Na2SO4" is sodium sulfate, "NH4Cl" is ammonium chloride, "NH4OH" is ammonium hydroxide, "NMR" is nuclear magnetic resonance, "OTs" is O-toluenesulfonate, "PBS" is phosphate-buffered saline, "Pd" is palladium, "Pd-C" is palladium on carbon, "Ph3P" is triphenylphosphine, "prep-HPLC" is preparative high performance liquid chromatography, "PyAOP" is ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), "rt" is room temperature, which is also known as "ambient temperature" and is understood to consist of a range of normal laboratory temperatures in the range of 15-25°C, "SFC" is supercritical fluid chromatography, and "SM" is are starting materials, "T3P" is n-propanephosphonic anhydride, "TBAF" is tert-butylammonium fluoride, "TCFH" is chloro-N,N,N′,N′-tetramethylformamidine hexafluorophosphate, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, "Tf2O" is trifluoromethanesulfonic anhydride, "THF" is tetrahydrofuran, "TrocCl" is 2,2,2-trichloroethyl chloroformate and "XtalFluor-E" is diethylaminodifluorosulfonium tetrafluoroborate.

[1218] General chemical reactions

[1219] The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the following schemes, intermediate preparations and accompanying examples.

[1220] Synthesis process

[1221] Process 1

[1222]

[1223] Scheme 1 shows an exemplary preparation of quinazoline intermediates 1-8a and 1-8b. 1-1 (2,6-difluoro-4-hydroxybenzonitrile) is reacted with R in the presence of a base (e.g., K2CO3, Cs2CO3, or NaH) and a polar aprotic solvent (DMSO, DMF, THF, or the like) at a temperature between ambient temperature and 150°C. 5-Br and R 5 -OTs (commercially available or synthesized by those skilled in the art) are alkylated to give ether 1-2. Alternatively, compound 1-1 is reacted with an alcohol (R 5 -OH) under standard Mitsunobu conditions (e.g., in the presence of Ph3P and DIAD) to give ether 1-2. Ether 1-2 is reacted with aqueous NH3 to give aniline 1-3 via aromatic substitution. Aniline 1-3 is reacted with DMF-DMA at elevated temperature to form formamidine 1-4. Cyclization of 1-4 with aniline / aminopyridine 1-5 (commercially available or synthesized by one skilled in the art) in acetic acid at elevated temperature gives quinazoline 1-6. Intermediate 1-6 is reacted with NaOMe in a dry aprotic solvent such as THF at elevated temperature to give 1-7. Finally, 1-6 and 1-7 are deprotected under acidic conditions such as HCl and TFA in an aprotic solvent such as DCM to give 1-8a (R 3 =F) and 1-8b(R 3 =OMe).

[1224] Process 2

[1225]

[1226] Scheme 2 shows an exemplary preparation of quinazoline intermediate 2-5. Compound 1-3 (see Scheme 1) is cyclized with formic acid under acidic conditions such as H2SO4 at elevated temperature to give quinazoline alcohol 2-1. Quinazoline alcohol 2-1 is reacted with thionyl chloride in the presence of catalyst DMF to give chloride 2-2. Chloride 2-2 is reacted with nucleophile 2-3 in the presence of catalyst DMAP and in the presence of base such as NaH, Et3N, Cs2CO3 in polar solvents such as DMSO, DMF, DMA, DCM, THF at 0°C to elevated temperature to give 2-4. 2-4 is subjected to nitro reduction in the presence of a hydrogenation catalyst such as palladium or nickel or mild reducing conditions such as zinc or iron and NH4Cl to give the corresponding aniline 2-5.

[1227] Process 3

[1228]

[1229] Scheme 3 shows an exemplary preparation of quinazoline intermediate 3-6. 3-1 (2-bromo-3,4-difluoro-1-nitrobenzene) and R 6Base-promoted nucleophilic substitution of -OH (commercially available or synthesized by one skilled in the art) in a polar aprotic solvent (DCM, DMSO, DMF, THF or the like) at temperatures between ambient and 70°C affords ether 3-2, which can be purified by SFC, crystallization or chromatography. Aryl bromide 3-2 is cyanated with CuCN at elevated temperature in a polar solvent such as DMA, DMF or DMSO to afford 3-3. Nitro reduction of 3-3 in the presence of a hydrogenation catalyst such as Pd or nickel or mild reducing conditions such as SnCl2, zinc or iron and NH4Cl affords the corresponding aniline 3-4. In a similar manner to Scheme 1, aniline 3-4 is reacted with DMF-DMA at elevated temperature to form carboxamidine 3-5. Cyclization of 3-5 with aniline / aminopyridine 1-5 (commercially available or synthesized by one skilled in the art) in acetic acid at elevated temperature affords boc-quinazoline, which can be deprotected under acidic conditions such as HCl and TFA in an aprotic solvent such as DCM to afford 3-6 (R 2 =OR 6 ).

[1230] Process 4

[1231]

[1232] Scheme 4 shows an exemplary preparation of quinazoline intermediate 4-3. In a similar manner to Scheme 1, aniline 4-1 (commercially available or synthesized by one skilled in the art) is reacted with DMF-DMA at elevated temperature to form carboxamidine 4-2. Cyclization of 4-2 with aniline / aminopyridine 1-5 (commercially available or synthesized by one skilled in the art) in acetic acid at elevated temperature affords boc-quinazoline, which can be deprotected under acidic conditions such as HCl and TFA in an aprotic solvent such as DCM to afford 4-3.

[1233] Process 5

[1234]

[1235] Scheme 5 shows an exemplary preparation of intermediate 5-3. 1-8a, 1-8b and 2-5 are activated with 2,2,2-trichloroethyl chloroformate (or isopropenyl chloroformate) under Schotten-Baumann conditions (e.g., in a mixture of a saturated aqueous solution of NaHCO3 and EtOAc) to give 5-1, which is further reacted with amine NHR7-LE (commercially available or synthesized by a person skilled in the art) to give urea 5-2. Alternatively, urea 5-2 can be prepared by reacting 1-8a, 1-8b and 2-5 with carboxylic acid EL-COOH (commercially available or synthesized by a person skilled in the art) under Curtius rearrangement (generating isocyanate in situ) conditions (DPPA and base [Et3N] in a suitable solvent such as 1,4-dioxane at high temperature). Finally, Pd-C catalyzes 5-2 under hydrogen to remove the protecting group to obtain intermediate 5-3.

[1236] Process 6

[1237]

[1238] Scheme 6 shows an exemplary preparation of intermediate 6-2. Amide 6-1 can be prepared by amide coupling reaction of 1-8a, 1-8b and 2-5 with acid EL-COOH (commercially available or synthesized by those skilled in the art) in the presence of coupling reagents such as T3P, TCFH, HATU, EDC and XtalFluor-E. In a similar manner to Scheme 4, Pd-C catalyzes the removal of the protecting group of 6-1 under hydrogen to obtain intermediate 6-2.

[1239] Process 7

[1240]

[1241] Scheme 7 shows an exemplary preparation of intermediate 7-2. Intermediate 6-1a and amine NHR 8 R 10 (commercially available or synthesized by one skilled in the art) in a suitable solvent such as 1,4-dioxane or THF at elevated temperature to give 7-1. Alternatively, 6-1b is reacted with an amine NR 8 R 10 H (commercially available or synthesized by those skilled in the art) is subjected to amide coupling reaction in the presence of coupling reagents such as T3P, TCFH, HATU and EDC and XtalFluor-E to give 7-1. In a similar manner to Scheme 4, Pd-C catalyzes the removal of the protecting group of 7-1 under hydrogen to give the intermediate 7-2.

[1242] Process 8

[1243]

[1244] Scheme 8 shows an exemplary preparation of compounds of Formula I. 1-8a, 1-8b, 2-5, 3-6 and 4-3 are activated with 2,2,2-trichloroethyl chloroformate (or isopropenyl chloroformate) under Schotten-Bowman conditions (e.g., in a mixture of saturated aqueous NaHCO3 and EtOAc) to give 8-1, which reacts with the amine HNR 7 -LE or alcohol HO-LE (commercially available or synthesized by those skilled in the art) is further reacted to obtain formula I as urea. Alternatively, formula I as urea can be prepared by reacting 1-8a, 1-8b, 2-5, 3-6 and 4-3 with carboxylic acid EL-COOH (commercially available or synthesized by those skilled in the art) under Curtius rearrangement (generating isocyanate in situ) conditions (DPPA and base [Et3N] in a suitable solvent such as 1,4-dioxane at high temperature). Formula I as amide can be prepared by amide coupling reaction of 1-8a, 1-8b, 2-5, 3-6 and 4-3 with acid EL-COOH (commercially available or synthesized by those skilled in the art) in the presence of coupling reagents such as T3P, TCFH, HATU, EDC and XtalFluor-E or with acyl chloride EL-COCl (commercially available or synthesized by those skilled in the art) in the presence of bases such as Et3N and DIEA. 5-3, 6-2 and 7-2 are activated with Tf2O in the presence of a base such as Et3N, DIEA, pyridine or DBU as a base in an organic solvent such as CH3CN, DCM or EtOAc to give intermediate 8-2. Sonogashira or Heck coupling reaction of 8-2 followed by appropriate reduction gives CC-linked Formula I. Alternatively, CC-linked Formula I can be prepared from 8-2 with a boric ester or a boronic acid under Suzuki conditions, followed by appropriate reduction as needed. In another embodiment, 5-3, 6-2 and 7-2 are activated with R 5 -Br and R 5 -OTs (commercially available or synthesized by one skilled in the art) is alkylated in the presence of a base (e.g., K2CO3, Cs2CO3 or NaH) and a polar aprotic solvent (DMSO, DMF, THF or the like) at a temperature between ambient temperature and 150°C to give a compound of formula I (R 1 =OR 5 , R 2 =H). Finally, the compound of formula I containing an ester functional group can be hydrolyzed under basic conditions such as LiOH or NaOH in a mixture of water / THF or 1,4-dioxane to give the corresponding acid. In a manner similar to Scheme 6, the compound of formula I as an ester is reacted with an amine NR 8 R 10 H (commercially available or synthesized by a person skilled in the art) is reacted in a suitable solvent such as 1,4-dioxane, THF at high temperature to obtain formula I (E=C(O)NR 8 R 10 ). Alternatively, the corresponding acid and amine NR8 R 10 H (commercially available or synthesized by those skilled in the art) is subjected to an amide coupling reaction in the presence of a coupling reagent such as T3P, TCFH, HATU, EDC and XtalFluor-E to obtain a compound of formula I (E=C(O)NR 8 R 10 ).

[1245] Intermediate preparation

[1246] The following compounds were made using the synthetic procedures and methods described herein and methods known to those skilled in the art:

[1247] General Method A: Alkylation with Alkyl Halides

[1248] Intermediate A1: 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile

[1249]

[1250] A suspension of 2,6-difluoro-4-hydroxybenzonitrile (50 g, 322 mmol) and 1-bromo-2-methoxyethane (50 g, 360 mmol) in DMF (300 mL) was treated with K2CO3 (100 g, 724 mmol). The resulting reaction mixture was heated at 80 ° C for 5 hours. The reaction mixture was diluted with water (700 mL) and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from hexane and MTBE to give 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (50 g, 73%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ6.38 (s, 1H), 6.15 (m, 1H), 4.06 (m, 2H), 3.63 (m, 2H), 3.29 (s, 3H); MS (ESI) m / z: 214.0 (M+H) + ).

[1251] Using General Procedure A above, the following intermediates in Table A were prepared.

[1252] Table A

[1253]

[1254]

[1255] General method B: substitution with NH4OH

[1256] Intermediate B1: 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile

[1257]

[1258] A suspension of 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (50 g, 235 mmol) in isopropanol (25 mL) was treated with ammonium hydroxide (100 mL, 856 mmol). The resulting reaction mixture was heated at 70 ° C for 10 days. The reaction mixture was cooled to room temperature and stirred. The crystalline solid was filtered, washed with cold water, and dried under high vacuum to give 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (45 g, 91%) as a white solid. MS (ESI) m / z: 211.0 (M+H + ).

[1259] Using General Procedure B above, the following intermediates in Table B were prepared.

[1260] Table B

[1261]

[1262]

[1263] Intermediate B5: 6-amino-2-fluoro-3-(2-methoxyethoxy)benzonitrile

[1264]

[1265] A stirred solution of 2-bromo-3,4-difluoro-1-nitrobenzene (5.0 g, 22.5 mmol) in DCM (100 mL) was treated with tetrabutylammonium hydrogen sulfate (0.07 g, 0.22 mmol). 2-methoxyethane-1-ol (1.75 g, 22.5 mmol) was added at room temperature, and then 1.0 M NaOH solution (30 mL) was added dropwise at the same temperature. This reaction mixture was stirred for another 3 hours at room temperature. After the starting material was completely consumed, the reaction mass was diluted with water (100 mL) and the aqueous layer was extracted with DCM (2×). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (15 to 20% EtOAc / hexane) to give 2-bromo-3-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene (3.4 g, 55%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.01 (dd, J=9.2, 1.6Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 4.35 (m, 2H), 3.71 (m, 2H), 3.31 (s, 3H).

[1266] A stirred solution of 2-bromo-3-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene (3.4 g, 11.5 mmol) in DMF (75 mL) was treated with copper (I) cyanide (2.1 g, 23.5 mmol) at room temperature. This suspension was heated at 130 °C for another 2 hours. After complete consumption of the starting material, the reaction mass was cooled to room temperature and then slowly poured into ice water (-75 mL) (solids precipitated during this addition). The solid was filtered, washed with water, and dried under high vacuum to obtain 2-fluoro-3-(2-methoxyethoxy)-6-nitrobenzonitrile (2.2 g, 80%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.29 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 4.42 (m, 2H), 3.72 (m, 2H), 3.31 (s, 3H).

[1267] A stirred solution of 2-fluoro-3-(2-methoxyethoxy)-6-nitrobenzonitrile (2.2 g, 8.9 mmol) in water (30 mL) was treated with sodium dithionite (3.2 g, 18.5 mmol) at room temperature. This suspension was heated at 100 °C for another 16 hours. After the starting material was consumed, the reaction was diluted with water (10 mL) and the aqueous layer was extracted with 10% MeOH / DCM (2×). The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to give 6-amino-2-fluoro-3-(2-methoxyethoxy)benzonitrile (0.5 g, 25%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.25 (t, J=9.6Hz, 1H), 6.52 (dd, J=9.2, 1.6Hz, 1H), 5.98 (br s,2H),4.03(m,2H),3.58(m,2H),3.29(s,3H); MS(ESI)m / z:211.1(M+H + ).

[1268] Intermediate B6: 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine

[1269]

[1270] A solution of 7-methoxy-6-(3-morpholinylpropoxy)quinazolin-4-ol (1.0 g, 3.1 mmol) in CHCl3 (25 mL) was treated with DMF (1-2 drops). Oxaloyl chloride (excess) was added dropwise to the solution. The mixture was refluxed overnight. The mixture was concentrated to dryness under reduced pressure. The residue was treated with CHCl3 (10 mL) and evaporated to dryness. The residue was wet-triturated with DCM (25 mL) and filtered to give 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine (1.0 g, 57%) as an off-white solid. MS (ESI) m / z: 320.2 (M+H + ).

[1271] General Method C: Formamidine Formation and Cyclization

[1272] Intermediate C1: tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate

[1273]

[1274] A suspension of 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (13g, 62mmol) and 1,1-dimethoxy-N,N-dimethylmethylamine (30g, 250mmol) was heated at 70°C for 2 hours. The reaction mixture was cooled to room temperature and the solution was then concentrated to give a colorless viscous intermediate. The residue was treated with tert-butyl (4-aminophenyl)carbamate (13g, 62mmol) and acetic acid (100mL). The resulting reaction mixture was heated at 70°C for 2 hours. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was treated with water (100mL) and stirred at room temperature. The solid was filtered, washed with water, and dried under high vacuum to give tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (18.6g, 70%) as a brown solid. MS (ESI) m / z: 429.2 (M+H + ).

[1275] Using General Procedure C above, the following intermediates in Table C were prepared.

[1276] Table C

[1277]

[1278]

[1279]

[1280] General Method D: Substitution with NaOMe

[1281] Intermediate D1: tert-butyl (4-((5-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate

[1282]

[1283] A stirred solution of tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (5.0 g, 11.7 mmol) in anhydrous THF (100 mL) was treated with NaOMe (25% in MeOH, 5.0 mL, 23.4 mmol) at room temperature. The reaction mixture was heated at 50 °C for 20 hours. The reaction mixture was cooled to room temperature and then slowly poured into ice water (500 mL). The precipitated solid was filtered, washed thoroughly with water, and dried under high vacuum. The solid was further purified on silica gel column chromatography (6-8% MeOH / DCM) to give tert-butyl (4-((5-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (3.0 g, 58%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ9.67(s,1H),9.29(br s,1H),8.36(s,1H),7.64(d,J=8.8Hz,2H),7.44(d,J=8.4Hz,2H),6.76(d,J=2.0Hz,1H),6.69(d,J=2 .4Hz,1H),4.23(m,2H),4.07(s,3H),3.71(m,2H),3.30(s,3H),1.48(s,9H); MS(ESI)m / z:441.1(M+H + ).

[1284] General Procedure E: Removal of Protecting Groups

[1285] Intermediate E1: N1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine hydrochloride

[1286]

[1287] A suspension of tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (12.0 g, 28 mmol) in dioxane (24 mL), 4.0 M HCl in 1,4-dioxane (24 mL, 96 mmol) was stirred at room temperature for 6 hours. MTBE was added and the solution was stirred at room temperature. The solid was filtered, washed with MTBE and acetonitrile to give N1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine hydrochloride (9.4 g, 92%) as a grey solid. 1 H NMR (500MHz, DMSO-d6): δ10.4(br s,1H),8.75(s,1H),7.56(br d,J=8.8Hz,2H),7.46(dd,J=14.4,2.0Hz,1H),7.27(br d,J=8.4Hz,2H),7.20(d,J=1.6Hz,1H),4.34(m,2H),3.73(m,2H),3.40-4.10(br s,3H),3.33(s,3H); MS(ESI)m / z:329.2(M+H) + ).

[1288] Using General Methods D and E above, the following intermediates in Table D were prepared.

[1289] Table D

[1290]

[1291]

[1292]

[1293] General Method F: Activation of Amines with TrocCl

[1294] Example F1: 2,2,2-Trichloroethyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate

[1295]

[1296] A suspension of N1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine hydrochloride (5.0 g, 14 mmol) in DCM (10 mL) was treated with TEA (4.0 g, 40 mmol). The reaction mixture was stirred at room temperature and TrocCl (5.0 g, 24 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and water (100 mL) was added. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with MTBE (60 mL) and the solid was filtered to give 2,2,2-trichloroethyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (5.8 g, 84%) as a light green solid. MS (ESI) m / z: 503.0 (M+H + ) and 505.0.

[1297] Using General Procedure F above, the following intermediates in Table E were prepared.

[1298] Table E

[1299]

[1300]

[1301]

[1302] General Method G: Coupling Reaction

[1303] Example 1: 1-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-3-(4,4,4-trifluoro-3,3-dimethylbutyl)urea

[1304]

[1305] A suspension of 2,2,2-trichloroethyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (F1, 0.30 g, 0.60 mmol) in CH3CN (10 mL) was treated with subsequent TEA (0.150 g, 0.0015 mol). 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (0.10 g, 0.52 mmol) was added, and the reaction mixture was stirred at 60 °C for 14 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL). The solution was filtered through a pad of silica gel and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and crystallized from CH3CN to give 1-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-3-(4,4,4-trifluoro-3,3-dimethylbutyl)urea (0.14 g, 46%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ8.86 (d, J=12.6Hz, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 7.5 0(d,J=8.7Hz,2H),7.38(d,J=8.7Hz,2H),7.11(dd,J=13.8,2.4Hz,1H),7.03(d, J=2.4Hz,1H),6.13(t,J=5.8Hz,1H),4.27(t,J=4.3Hz,2H),3.70(t,J=4.3Hz,2 H),3.33(s,3H),3.19(m,2H),1.62(m,2H),1.12(s,6H); MS(ESI)m / z:510.2(M+H + ).

[1306] General Method H: Curtius Reaction

[1307] Example 2: 1-(3-fluoro-3-methylbutyl)-3-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)urea

[1308]

[1309] A suspension of 5-fluoro-5-methylhexanoic acid (0.25 g, 1.7 mmol) in 1,4-dioxane (10 mL) was treated with TEA (0.5 mL). The reaction mixture was cooled to 0 ° C in an ice bath, and diphenylphosphoryl azide (0.50 g, 1.8 mmol) was added under the same conditions. The reaction mixture was slowly warmed to room temperature and then stirred at room temperature for 30 minutes. N1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine hydrochloride (E1, 0.30 g, 0.82 mmol) was added, followed by TEA (0.5 mL) and stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and a precipitate was formed. The precipitated solid was filtered out and washed with acetonitrile. The filtrate was concentrated under reduced pressure and distributed between DCM (30 mL) and water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a dark residue. The resulting solid was dissolved in DCM (10 mL) and filtered through a pad of silica gel. The filtrate was treated with CH3CN and the solid was filtered to give 1-(3-fluoro-3-methylbutyl)-3-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)urea (0.14 g, 37%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ8.86(d,J=12.6Hz,1H),8.50(s,1H),8.40(s,1H),7.50(d ,J=8.6Hz,2H),7.38(d,J=8.6Hz,2H),7.11(dd,J=13.8,2.4Hz,1H),7.03(d,J=2.3 Hz,1H),6.07(t,J=5.7Hz,1H),4.27(t,J=4.3Hz,2H),3.70(t,J=4.2Hz,2H),3.33( s,3H),3.21(m,2H),1.78(m,2H);1.36(s,3H),1.32(s,3H);MS(ESI)m / z:460.2(M+H + ).

[1310] General Method I: Amide Formation with HATU

[1311] Example 3: N-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-4,4-dimethylpentanamide

[1312]

[1313] A suspension of N1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine hydrochloride (E1, 0.20 g, 0.55 mmol) in CH3CN (10 mL) was treated with HATU (0.25 g, 0.66 mmol), DIEA (0.25 g, 1.9 mmol) and 4,4-dimethylpentanoic acid (0.10 g, 0.77 mmol). The reaction mixture was stirred at 70 °C for 30 min. The reaction mixture was cooled to room temperature and the resulting solid was filtered, washed with CH3CN to give N-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-4,4-dimethylpentanamide (0.15 g, 62%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ9.90(s,1H),8.92(d,J=12.4Hz,1H),8.42(s,1H),7.58(s,4H),7.12(dd,J=13.8,2.4Hz,1H),7.04(s,1H),4.27 (t,J=4.2Hz,2H),3.70(t,J=4.2Hz,2H),3.32(s,3H),2.27(t,J=8.2Hz,2H),1.51(t,J=8.3Hz,2H),0.90(s,9H); MS(ESI)m / z:441.2(M+H) + ).

[1314] General Procedure J: Amide Formation with Acid Chlorides

[1315] Example G1: Methyl 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoate

[1316]

[1317] A suspension of N1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine hydrochloride (E1, 0.60 g, 1.6 mmol) in DCM (10 mL) was treated with TEA (0.17 g, 1.6 mmol) at room temperature. Methyl 3-chloro-3-oxopropanoate (0.60 g, 4.4 mmol) was slowly added to the reaction mixture, and the resulting reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and water was added. The solution was stirred and the solid was filtered out, washed with water and dried under high vacuum to give methyl 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoate (0.48 g, 68%) as an off-white solid. 1H NMR (500MHz, DMSO-d6): δ10.22(s,1H),8.97(d,J=12.3Hz,1H),8.46(s,1H),7.63(d,J=9.2Hz,2H),7.59(d,J=9.2Hz,2H ), 7.15 (dd, J = 13.9, 2.4Hz, 1H), 7.06 (d, J = 2.4Hz, 1H), 4.28 (m, 2H), 3.71 (m, 2H), 3.67 (s, 3H), 3.49 (s, 2H), 3.33 (s, 3H). MS(ESI)m / z:429.0(M+H + ).

[1318] Using General Methods G, H, I and J above, the following intermediates in Table F were prepared.

[1319] Table F

[1320]

[1321]

[1322]

[1323] General Method K: Hydrolysis

[1324] Intermediate H1: 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoic acid

[1325]

[1326] A suspension of methyl 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoate (G1, 1.0 g, 2.3 mmol), lithium hydroxide hydrate (2.5 g, 60 mmol) in water (60 mL) was stirred at 50 °C for 5 hours and then at room temperature for 2 days. The resulting solid was filtered off, washed with water and dried under high vacuum to give 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoic acid (0.62 g, 64%) as a white solid. MS (ESI) m / z: 415.2 (M+H + ).

[1327] Using General Methods E and K above, the following intermediates in Table G were prepared.

[1328] Table G

[1329]

[1330]

[1331] Preparation of 1-(3-fluoro-3-methylbutyl)-3-(4-((5-fluoro-7-hydroxyquinazolin-4-yl)amino)phenyl)urea

[1332]

[1333]

[1334] Preparation of Intermediate J1: 1-(4-((7-bromooctin-4-yl)amino)phenyl)-3-(3-fluoro-3-methylbutyl)urea

[1335]

[1336] A solution of 1-(4-aminophenyl)-3-(3-fluoro-3-methylbutyl)urea hydrochloride (G6, 0.27 g, 0.99 mmol) in toluene (8 mL) was treated with DIEA (0.32 g, 2.5 mmol). 7-bromo-4-chlorooctyl (0.20, 0.82 mmol) was added and then stirred for 15 minutes. n-BuOH (2 mL) was added and then the reaction mixture was heated at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-15% (5% NH4OH / MeOH) / DCM) to obtain 1-(4-((7-bromooctyl-4-yl)amino)phenyl)-3-(3-fluoro-3-methylbutyl)urea (0.24 g, 64%). MS (ESI) m / z: 116.0 (M+H + )448.0.

[1337] General procedure L: Coupling with HATU amide

[1338] Example 4: N1-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-N3-neopentylmalonamide

[1339]

[1340] A solution of 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoic acid (H1, 0.10 g, 0.025 mmol) in DMF (1 mL) was treated with DIEA (0.10 g, 0.076 mmol). 2,2-dimethylpropan-1-amine (0.03 g, 0.033 mmol) and HATU (0.013 g, 0.033 mmol) were added and the reaction mixture was stirred at 50 °C for 2 hours. The mixture was cooled to room temperature, diluted with water (1 mL) and stirred to precipitate. The resulting solid was filtered off, washed with water and dried under high vacuum. The solid was triturated with CH3CN (3 mL) and stirred at room temperature. The resulting solid was filtered off and dried under high vacuum oven at 80 °C to afford N1-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-N3-neopentylmalonamide (0.10 g, 80%). 1 H NMR (500MHz, DMSO-d6): δ10.14(s,1H),8.98(d,J=12.3Hz,1H),8.45(s,1H),8.00(t,J=6.3Hz,1H),7.56-7.67(m,4H),7.15(dd,J=13.8,2.4Hz,1H) ,7.06(d,J=2.5Hz,1H),4.26-4.32(m,2H),3.69-3.75(m,2H),3.33(s,3H) ,3.31(s,2H),2.94(d,J=6.3Hz,2H),0.87(s,9H);MS(ESI)m / z:484.2(M+H + ).

[1341] General Method M: Amide Coupling with Heating

[1342] Example 5: N 1 -(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-N 3 -(2-methoxy-2-methylpropyl)malonamide

[1343]

[1344] A suspension of methyl 3-((4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)amino)-3-oxopropanoate (G1, 0.40 g, 0.93 mmol), 2-methoxy-2-methylpropan-1-amine (0.25 g, 2.4 mol) in CH3CN (6 mL) was stirred at 90 °C for 13 hours. The reaction mixture was cooled to room temperature, and the solution was then concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), passed through a silica pad, and washed with EtOAc (100 mL) and acetone (100 mL). The fraction from acetone contained pure compound. The fraction was concentrated under reduced pressure. The residue was recrystallized from CH3CN to give N1-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-N3-(2-methoxy-2-methylpropyl)malonamide (0.12 g, 24%) as a light yellow solid. 1 H NMR (500MHz, DMSO-d6): δ10.12(s,1H),8.97(d,J=12.3Hz,1H),8.45(s,1H),7.96(t,J=6.0Hz,1H),7.62(m,4H),7.15(dd,J=13.8,2.4Hz,1H),7. 06(d,J=2.4Hz,1H),4.29(m,2H),3.72(m,2H),3.34(s,3H),3.30(s,2H), 3.17(d,J=5.9Hz,2H),3.13(s,3H),1.09(s,6H); MS(ESI)m / z:500.2(M+H + ).

[1345] General Method N: Alkylation with Alkyl Bromides

[1346] Example 6: 1-(3-Fluoro-3-methylbutyl)-3-(4-((5-fluoro-7-isopropoxyquinazolin-4-yl)amino)phenyl)urea

[1347]

[1348] A stirred solution of 1-(3-fluoro-3-methylbutyl)-3-(4-((5-fluoro-7-hydroxyquinazolin-4-yl)amino)phenyl)urea (II, 0.20 g, 0.50 mmol) in CHCN (4 mL) was treated with CsCO (0.49 g, 1.49 mmol), KI (0.008 g, 0.05 mmol) and 2-bromopropane (0.12 g, 0.10 mmol) at room temperature. This suspension was heated at 90 °C for another 16 h. The reaction mixture was quenched with ice water (10 mL), and the solution was then extracted with 10% MeOH / DCM (3×). The...

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N; Q is selected from the group consisting of: wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L; L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE combined with free choice The group composed of; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 1 Selected from the group consisting of: H, haloalkyl, optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 7 independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy; m is independently 0, 1, 2, 3, or 4 at each occurrence; n is 0, 1, 2, 3 or 4; and p is 1, 2, or 3; The proviso is that the compound is not:

2. A compound represented by formula IA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; Q is selected from the group consisting of: wherein s1 is the site of covalent attachment to the ring; and s2 is the site of covalent attachment to L; L is selected from a direct bond and optionally 11 ) m substituted C1-C6 alkyl group, or when Q is When L and R 7 and L and R 7 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, alkoxy, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE combined with free choice The group composed of; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 1 is selected from the group consisting of: H, optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The respectively attached atoms together form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and haloalkoxy; m is independently 0, 1, 2, 3, or 4 at each occurrence; n is 0, 1, 2, 3 or 4; and p is 1, 2, or 3; The proviso is that the compound is not:

3. A compound represented by formula IG: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N; L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 1 Selected from the group consisting of: H, haloalkyl, optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

4. A compound represented by formula IH: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N; L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

5. A compound represented by formula II: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 1 Selected from the group consisting of: H, haloalkyl, optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted cycloalkyloxy, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

6. A compound represented by formula IJ: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 1 Selected from the group consisting of: H, haloalkyl, optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

7. A compound represented by formula IK: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

8. A compound represented by formula IL: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: L is selected from a direct bond and optionally 11 ) m A group consisting of substituted C1-C6 alkyl, or when with R 7 and L and R 7 the attached N atoms when taken together form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, wherein the optional substituents are selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 are independently selected from the group consisting of H, alkyl, haloalkyl or cycloalkyl; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

9. A compound represented by formula IO: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and m is independently 0, 1, 2, 3, or 4 at each occurrence; The proviso is that the compound is not:

10. A compound represented by formula IQ: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl; E is selected from the group consisting of: H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and m is independently 0, 1, 2, 3 or 4 at each occurrence, The proviso is that the compound is not:

11. A compound represented by formula IT: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl; E is selected from the group consisting of: An optionally substituted amido group, wherein the substituents are independently selected at each occurrence from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, Optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of cycloalkyl and heterocyclyl, H, cyano, alkoxy, haloalkoxy, haloalkyl, and halogen; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, oxo and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

12. A compound represented by formula IU: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: L is selected from a direct bond and optionally 11 ) m The group consisting of substituted C1-C6 alkyl; E is selected from the group consisting of: An optionally substituted amido group, wherein the substituents are independently selected at each occurrence from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl, heterocyclyl, H, cyano, alkoxy, haloalkoxy, haloalkyl, and halogen; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; and m is independently 0, 1, 2, 3 or 4 at each occurrence.

13. A compound represented by formula IV: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 1 Selected from the group consisting of: H, haloalkyl, optionally substituted alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted cycloalkyloxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, optionally substituted heterocyclyloxy, wherein the optionally substituted substituents are independently at each occurrence C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, and oxo, and optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 1 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of H, F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and n is 0, 1, 2, 3 or 4.

14. A compound represented by formula IW: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; X 3 and X 4 are independently CH or N, subject to the restriction that X 3 and X 4 No more than one of them is N; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of H, F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 is selected from the group consisting of optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and n is 0, 1, 2, 3 or 4.

15. A compound represented by formula IX: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of H, F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, oxo and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, oxo and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and n is 0, 1, 2, 3 or 4.

16. A compound represented by formula IY: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of H, F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, oxo and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, oxo and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 and R 8 With R 10 the attached N atoms together form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, and oxo; and n is 0, 1, 2, 3 or 4.

17. A compound represented by formula I-AB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 2 Each independently selected from the group consisting of N, CH and CF; E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of H, F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, oxo and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, oxo and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The atoms respectively attached are taken together to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and p is 1, 2, or 3; The limiting condition is that the compound is not:

18. A compound represented by formula I-AC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: E 11 is independently selected at each occurrence from the group consisting of H, alkyl and halogen, or two occurrences of E 11 An optionally substituted cycloalkyl group having 3 to 4 atoms in the ring structure when taken together with the C atom to which it is attached, wherein the optional substituents are selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, wherein the optionally substituted substituent is independently at each occurrence alkoxy, amine, heterocyclyl, or when combined with R 5 together form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen; R 3 is selected from the group consisting of H, F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl and alkoxy; R 5 Selected from the group consisting of: optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, oxo and halogen, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, oxo and halogen, and optionally substituted cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl, wherein The substituents of the optionally substituted alkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl and heterocyclyl, The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo and cyano, and The substituents of the optionally substituted cycloalkyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 and R 9 With R 11 The atoms respectively attached are taken together to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and p is 1, 2, or 3, The proviso is that the compound is not:

19. The compound according to claim 1 or 2, wherein R 1 Selected from the group consisting of: H, haloalkyl, Optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, The substituents of the optionally substituted heterocyclyl are independently C1-C6 alkyl, amine, cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl and oxo at each occurrence, optionally substituted C4-C6 cycloalkyloxy, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of C1-C6 alkyl, amine, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy and oxo, and Optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkoxy and hydroxy.

20. A compound according to any one of claims 1-3, 5, 6, 13 and 19, wherein R 1 Selected from the group consisting of: H, 21. A compound according to any one of claims 1-3, 5, 6, 13, 19 and 20, wherein R 1 Selected from the group consisting of: H, 22. A compound according to any one of claims 4, 7-12 and 14-18, wherein R 5 Selected from the group consisting of: Optionally substituted C1-C6 alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl, wherein The substituents of the optionally substituted amide group are independently C1-C6 alkyl at each occurrence, and The substituents of the optionally substituted heterocyclyl are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy and halogen, Optionally substituted C1-C6 heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy and halogen; and Optionally substituted C1-C6 cycloalkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy and halogen.

23. A compound according to any one of claims 4, 7-12, 14-18 and 22, wherein R 5 Selected from the group consisting of: methyl, ethyl, CF3, CHF2, CH2CF3, 24. A compound according to any one of claims 4, 7-12, 14-18, 22 and 23, wherein R 5 Selected from the group consisting of: methyl, 25. A compound according to any one of claims 1 to 24, wherein R 2 is selected from the group consisting of H and optionally substituted C1-C6 alkoxy, wherein the optionally substituted substituent is independently alkoxy, amine, heterocyclyl, or when combined with R 1 Together they form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C1-C6 alkyl and halogen.

26. A compound according to any one of claims 1 to 25, wherein R 2 Choose from H, The group composed of.

27. A compound according to any one of claims 1 to 26, wherein R 2 For H.

28. A compound according to claims 1-3, 5, 6 and 13, wherein R 1 and R 2 together form a ring structure selected from the group consisting of:

29. A compound according to any one of claims 4, 7-12 and 14-18, wherein R 2 and R 5 together form a ring structure selected from the group consisting of: Among them, s3 is the site for covalent bonding to the bicyclic structure, and s4 is the site for covalent bonding to the oxygen atom.

30. A compound according to any one of claims 13-18, wherein R 3 is H, F or alkoxy.

31. A compound according to any one of claims 1 to 30, wherein R 3 For F.

32. A compound according to any one of claims 1 to 31, wherein R 4 Selected from the group consisting of H, F, C1-C6 alkyl and alkoxy.

33. A compound according to any one of claims 1 to 32, wherein R 4 For H.

34. A compound according to any one of claims 1 to 33, wherein X 1 , X 2 , X 3 and X 4 are independently CH or N, subject to the condition that X 3 and X 4 No more than one of them is N.

35. A compound according to any one of claims 1 to 34, wherein X 1 is CH, and X 2 For CH.

36. A compound according to any one of claims 1 to 35, wherein X 1 is CH, and X 2 is N.

37. A compound according to any one of claims 1 to 36, wherein X 3 is CH, and X 4 is N.

38. according to the compound described in any one of claim 1-8 and 13-31, wherein L is selected from by direct bond and optionally (E 11 ) m The group consisting of substituted C1-C6 alkyl.

39. A compound according to any one of claims 1-12 and 19-38, wherein Selected from the group consisting of:

40. The compound according to claim 38 or 39, wherein E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

41. according to the compound described in any one of claims 32-34, wherein E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

42. A compound according to any one of claims 1-12 and 19-41, wherein Selected from the group consisting of:

43. A compound according to any one of claims 1-12 and 19-42, wherein E is selected from the group consisting of: H, C1-C6 alkenyl, cyano, haloalkoxy, haloalkyl, halogen, optionally substituted C1-C6 alkyl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted C3-C6 cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxyl and cyano, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of cycloalkyl and heterocyclyl.

44. according to the compound described in any one of claims 1-12 and 19-43, wherein E is selected from the group consisting of: H, fluorine, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl, 45. A compound according to any one of claims 1-12 and 19-38, wherein Selected from the group consisting of:

46. ​​A compound according to any one of claims 1-12 or 19-38, wherein Selected from the group consisting of:

47. according to the compound described in any one of claims 1-12, 19-38, 45 and 46, wherein L is optionally (E 11 ) m Substituted alkyl, E is selected from the group consisting of H, fluorine, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl, 48. A compound according to any one of claims 1-12, 19-38, 45 and 46, wherein L is optionally substituted by (E 11 ) m Substituted alkyl, E is selected from the group consisting of H, fluorine, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl, 49. A compound according to any one of claims 1-12, 19-38 or 45-48, wherein Selected from the group consisting of:

50. according to the compound described in any one of claims 1-12, 19-38 or 45-49, wherein when L is a direct bond, Selected from the group consisting of:

51. A compound according to any one of claims 1-42 or 45-50, wherein R 7 is H, alkyl or halogenated alkyl.

52. A compound according to any one of claims 1-42 or 45-51, wherein R 7 For H.

53. A compound according to any one of claims 1 to 2, 9 to 10 or 19 to 38, wherein for 54. A compound according to any one of claims 1-2, 9-10, 19-38 or 53, wherein for 55. A compound according to any one of claims 1-2, 9-10, 19-38, 53 or 54, wherein E is selected from the group consisting of H, fluoro, methoxy and cyano.

56. A compound according to any one of claims 1-2, 9-10, 19-38 or 53-55, wherein Selected from the group consisting of:

57. according to the compound described in any one of claims 1-2, 9-10, 18-38 or 53-56, wherein E is selected from the group consisting of: H, fluorine, methyl, trifluoromethyl, methoxy, cyano, 58. according to the compound described in any one of claims 1-2, 9-10, 19-38 or 53-57, wherein E is selected from the group consisting of: H, fluorine, methyl, trifluoromethyl, methoxy, cyano, 59. A compound according to any one of claims 1-2, 9, 10, 19-38, 45 or 46, wherein Selected from the group consisting of:

60. A compound according to any one of claims 1-2, 13-16 or 56-59, wherein Selected from the group consisting of:

61. The compound according to claim 60, wherein E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl and halogen.

62. The compound according to claim 61, wherein E 11 is independently selected at each occurrence from the group consisting of H, methyl and fluoro.

63. A compound according to any one of claims 1, 2, 13-16, 19-38 or 60, wherein R 8 is selected from the group consisting of an alkyl group, a cycloalkyl group and a heterocyclic group, and R 10 Selected from the group consisting of H and alkyl.

64. A compound according to any one of claims 1, 2, 13-16, 19-38, 60 or 63, wherein R 8 Selected from the group consisting of: And R 10 Selected from the group consisting of H, methyl, ethyl and isopropyl.

65. A compound according to any one of claims 1, 2, 13-16, 19-38, 63 or 64, wherein R 8 With R 10 and R 8 and R 10 The attached N atoms together form a ring structure selected from the group consisting of:

66. A compound according to any one of claims 19 to 38, wherein L is a direct bond, R 8 Freedom to choose The group composed of R 10 For H.

67. A compound selected from: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient.

69. A method of treating a disease in a patient in need thereof, the disease being selected from the group consisting of: gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-activated gastrointestinal stromal tumor, PDGFRa-activated gastrointestinal stromal tumor (GIST), melanoma, acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric neurodegenerative disease, Glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma and non-small cell lung cancer, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, or a pharmaceutical composition according to claim 68.

70. The method of claim 69, wherein the disease is gastrointestinal stromal tumor (GIST).

71. The method of claim 70, wherein the disease is KIT-activated gastrointestinal stromal tumor (GIST).

72. The method of claim 71, wherein the KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation.

73. The method of claim 69, wherein the disease is PDGFRa activated gastrointestinal stromal tumor (GIST).

74. The method of claim 73, wherein the PDGFRa activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from PDGFRA D842V.

75. The method of claim 69, wherein the disease is melanoma.

76. The method of claim 75, wherein the melanoma is a KIT-activated melanoma.

77. The method of claim 75, wherein the KIT activated melanoma has a baseline mutation selected from the group consisting of: a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation.

78. The method of any one of claims 75-77, wherein the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma.

79. The method of claim 78, wherein the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentigo melanoma, amelanotic melanoma, and desmoplastic melanoma.

80. The method of claim 78, wherein the non-cutaneous melanoma is selected from the group consisting of ocular melanoma and mucosal melanoma.

81. Use of the pharmaceutical composition according to claim 68 in the preparation of a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-activated gastrointestinal stromal tumor, PDGFRa-activated gastrointestinal stromal tumor (GIST), melanoma, acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma and non-small cell lung cancer.

82. The use according to claim 81, wherein the disease is gastrointestinal stromal tumor (GIST).

83. The use according to claim 81, wherein the disease is KIT-activated gastrointestinal stromal tumor (GIST).

84. The use according to claim 83, wherein the KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation and KIT exon 18 mutation.

85. The use according to claim 81, wherein the disease is PDGFRa activated gastrointestinal stromal tumor (GIST).

86. The use according to claim 85, wherein the PDGFRa activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from PDGFRA D842V.

87. The use according to claim 81, wherein the disease is melanoma.

88. The use according to claim 87, wherein the melanoma is a KIT-activated melanoma.

89. The use of claim 88, wherein the KIT activated melanoma has a baseline mutation selected from the group consisting of: KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation.

90. The use according to any one of claims 87-89, wherein the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma.

91. The use according to claim 90, wherein the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentigo melanoma, amelanotic melanoma and desmoplastic melanoma.

92. The use according to claim 90, wherein the non-cutaneous melanoma is selected from ocular melanoma and mucosal melanoma.

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