RAF kinase inhibitors and methods of use thereof

Abstract

Compounds of formula I as RAF inhibitors and their use in treatment of conditions such as cancer # imgabs0 #

Description

Cross-references

[0001] This application claims priority to U.S. Provisional Application No. 63 / 287,873, filed on December 9, 2021, and U.S. Provisional Application No. 63 / 393,445, filed on July 29, 2022, both of which are incorporated herein by reference in their entirety. Background Art

[0002] The BRAF V600X (also known as V600E) mutant form of BRAF is known to be oncogenic, and several BRAF inhibitors are currently commercially available to inhibit oncogenic BRAF V600E signaling in melanoma and other cancers. BRAF V600E signals as a monomer and has constitutive activity that is independent of upstream control by RAS. Marketed BRAF V600E inhibitors include vemurafenib, dabrafenib, and encorafenib.

[0003] With the exception of the BRAF V600X mutant, almost all other oncogenic forms of BRAF signal through the formation of homodimers (BRAF-BRAF dimers) or heterodimers (e.g., BRAF-CRAF dimers), which are difficult to treat with BRAF inhibitors such as vemurafenib, dabrafenib, and contrafenib. These dimers form in cancers driven by BRAF fusions, atypical BRAF mutations, or RAS-mutant cancers.

[0004] Oncogenic BRAF fusions are derived from genomic rearrangements, which place the 3' portion of the BRAF gene encoding the kinase domain after the 5' position of another gene. The result of the rearrangement is the expression of an oncogenic protein, which exhibits constitutive kinase activity due to the deletion of the N-terminal autoinhibitory domain of BRAF caused by genomic rearrangement. These BRAF fusions exhibit constitutive kinase activity due to spontaneous dimerization and are therefore able to perform abnormal signal transduction in cancer cells, regardless of upstream effectors or regulatory mechanisms. In addition, some 5' translocation rearrangement genes cause the N-terminal domain to further induce dimerization, thereby enhancing the activated dimerization of the BRAF fusion protein kinase domain. Since the expression of these genomic rearrangements is controlled by the promoter of the 5'-partner, overexpression of BRAF fusion transcripts is usually caused by efficient or excessive promoter activity. BRAF fusions are one of the most common kinase translocations in solid tumors. Since it was first described as an oncogene for papillary thyroid cancer in 2005, hundreds of tumors have been identified in at least 15 different tumor types in which the BRAF kinase domain is fused to one of more than 110 different 5'-partner genes. BRAF fusions have been found in papillary thyroid cancer, astrocytoma, melanoma, and have also been identified in drug-resistant EGFR mutant lung cancer. BRAF fusion proteins signal through dimerization in a RAS-independent manner and are resistant to many BRAF inhibitors (such as vemurafenib and dabrafenib), which cannot inhibit the two protomers of the signaling homodimeric BRAF fusion. Rare CRAF fusion proteins have also been shown to be tumor drivers. This type of CRAF fusion protein signals as a CRAF-CRAF homodimer.

[0005] Other so-called atypical BRAF mutations also lead to spontaneous dimerization and signaling independent of RAS control. Like BRAF fusions, these atypical BRAF mutants signal as abnormal homodimers.

[0006] RAS mutant cancers account for approximately 26-30% of all human cancers. RAS mutant cancers transmit signals through the RAS→RAF→MEK→ERKMAPK signaling pathway. In this signaling cascade, kinase-inactive RAF monomers (including ARAF, BRAF, and CRAF isoforms) are recruited to oncogenic RAS, where RAS induces kinase-active signaling to form RAF dimers. The main RAF heterodimer recruited to mutant RAS is the BRAF / CRAF heterodimer.

[0007] A combinatorial siRNA screening approach identified RAF as a dominant node in RAS-mutant cancers, and co-depletion of BRAF and CRAF, along with depletion of the autophagy gene ATG7, provided optimal synthetic lethality inhibition of RAS-mutant signaling and, in addition, an optimal therapeutic window for inhibiting signaling in RAS-mutant cells versus normal RAS wild-type cells. Furthermore, inhibition of the RAF→MEK→ERK pathway in combination with autophagy inhibitors has been reported to effectively block the growth of RAS-mutant cancers both in vitro and in vivo.

[0008] Perpendicular inhibition of the RAF→MEK→ERK pathway by pan-inhibiting RAF (specifically BRAF+CRAF) and ERK kinase activity has demonstrated an unexpectedly high degree of synergy in blocking MAPK pathway signaling in KRAS-mutant pancreatic cancer cells, organoid studies, and mouse models of KRAS-mutant pancreatic cancer. Perpendicular inhibition of RAF (BRAF+CRAF) and MEK kinase activity has also been shown to have a synergistic effect in KRAS-mutant tumors.

[0009] The importance of inhibiting BRAF and CRAF isoforms, and the requirement for inhibitors to successfully bind to and inhibit both protomers of the signaling RAF dimer, has been well documented. RAF inhibitors, particularly BRAF inhibitors, fail to successfully bind to and inhibit both protomers of the signaling RAF dimer in RAS-mutant cancers, resulting in paradoxical pathway stimulation rather than the desired pathway inhibition. Such BRAF inhibitors are contraindicated for the treatment of RAS-mutant cancers.

[0010] There is a need to identify RAF inhibitors that can inhibit multiple RAF isoforms. In particular, there is a need to identify RAF inhibitors that can inhibit both BRAF and CRAF isoforms. In particular, there is a need to identify RAF inhibitors that can inhibit both the RAF protomer present in the signaling BRAF / BRAF homodimer and both protomers in the BRAF / CRAF heterodimer. Such pan-RAF inhibitors have shown utility in treating BRAFV600X-driven cancers, cancers with atypical BRAF mutations, BRAF fusion cancers, CRAF fusion cancers, and RAS mutant cancers. SUMMARY OF THE INVENTION

[0011] Described herein are compounds that are RAF inhibitors and methods of use thereof. In some embodiments, the compound is a BRAF or CRAF inhibitor. In some embodiments, the compound can be used to treat cancers driven by oncogenic forms of RAS or BRAF. In some embodiments, the compound inhibits BRAF and CRAF isoforms. In some other embodiments, the compound inhibits the RAF protomer present in the signal transduction BRAF / BRAF homodimer and the two protomers present in the signal transduction BRAF / CRAF heterodimer. In some other embodiments, the compound inhibits ARAF, BRAF, and CRAF present in the signal transduction homodimer or heterodimer.

[0012] In one embodiment, the present invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from CR 3 and N; X 2 Selected from the group consisting of N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and NL 2 -E 2 ; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 , C=O, N and NL 3 -E 3 ; Its restriction condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N; When X 2 When N, X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E3 、CN(R 4 )-L 3 -E 3 and N; When X 3 When N, X 2 Selected from the group consisting of N, CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; When X 2 When C=O, X 3 for NL 3 -E 3 ; When X 3 When C=O, X 2 for NL 2 -E 2 ; X 5 independently selected from the group consisting of CH, CF, and N; X 6 independently selected from the group consisting of CH and CF; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E2 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; U is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2) mNH-; wherein the optionally substituted heterocyclyl or heterocyclyl(CH2) m NH- is independently present at each occurrence and optionally replaced by one or more occurrences of R 9 replace; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; p is independently 0, 1, or 2 at each occurrence; and m is independently 0, 1, 2, 3, or 4 at each occurrence; The restrictions are When X 1 and X 2 N, X 5 and X 6 are independently selected from CH and CF, X 4 CR 3 , R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 1 and X 4 N, X 5 and X 6 are independently selected from CH and CF, X 2 CL 2 -E 2 , L 2 For direct keys, E 2 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; When X 6 CH, X 5 is CH or CF, X 4 CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following groups: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, X 1 CH or N, X 4 CH, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0013] In another embodiment, described herein is a pharmaceutical composition comprising a compound described herein (eg, a compound of the invention as described herein) and a pharmaceutically acceptable carrier or excipient.

[0014] In another embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (eg, a compound of the invention as described herein).

[0015] In another embodiment, described herein is a method of treating a condition selected from the group consisting of histiocytosis, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, blood-borne cancer, hairy cell leukemia, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of the invention as described herein). Detailed Description of the Invention

[0016] The features and other details of the present invention will now be described in more detail. Specific terms used in this specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the present invention and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. definition

[0017] The definitions set forth in this application are intended to clarify terminology used throughout this application.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art who are familiar with the subject matter of this application. Unless otherwise indicated, as used in the specification and appended claims, the following terms have the meanings assigned to facilitate understanding of the present invention.

[0019] When a bond to a substituent is shown to intersect a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on that ring. If a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of the specified formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, substituent positions, and / or variables are permissible only if such combinations result in stable compounds.

[0020] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0021] As used herein, the term "herein" refers to the entire application.

[0022] As used herein, "deuterated" means that at least one hydrogen atom has been replaced with deuterium. In any sample of a deuterated compound, some discrete molecules of the compound may have hydrogen instead of deuterium at a given position. However, the percentage of molecules of the deuterated compound with deuterium at a given position will be much greater than that of the naturally occurring compound. Deuterium is enriched at the deuterated position.

[0023] 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. For example, "optionally substituted alkyl" means that the alkyl group may be substituted as well as instances where the alkyl group is unsubstituted.

[0024] It will be appreciated that those skilled 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 itself substituted with more than one group, it will be understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.

[0025] As used herein, the term "optionally substituted" refers to the replacement of one to six hydrogen atoms in a given structure with a group of a specified substituent, including, but not limited to, hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OC(=O)-CH2-Oalkyl. Preferably, "optionally substituted" refers to the replacement of one to four hydrogen atoms in a given structure with the substituents mentioned above. More preferably, one to three hydrogen atoms are replaced with the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0026] As used herein, the term "substituted" refers to a portion of a substituent that replaces 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 atom and substituent, and the substitution produces a stable compound, e.g., it does not spontaneously undergo transformation (e.g., by reorganization, cyclization, elimination, etc.). As used herein, the term "substituted" is encompassed to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, permissible substituents may be one or more and the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents, and / or any permissible substituents of an organic compound described herein that satisfy the heteroatom valence.

[0027] Substituents may include any of the substituents described herein, for example, such substituents, if not otherwise specified, may include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, heteroaralkyl, 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 of substituted alkyl groups may include substituted and unsubstituted forms of amino, azido, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfonamide, and sulfonate), and silanyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted and unsubstituted variants.

[0028] As used herein, the term "alkyl" refers to a fully saturated straight or branched chain non-aromatic hydrocarbon. Typically, unless otherwise defined, a straight or branched chain alkyl group has 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms, for example, C1-C 10Alkyl, or for example, C1-C6 alkyl. Examples of straight-chain and branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl, and the like. Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. "Alkyl" groups may be optionally substituted.

[0029] The term "C x -C y ” when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing 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 carbon atoms in the chain, including straight-chain alkyl groups and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates hydrogen when the group is at the terminal position and indicates a bond when it is internal.

[0030] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom, having no =O or =S substituents, and typically having at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, for purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups, but substituents such as acetyl (which has a =O substituent on the carbon to which it is attached) and ethoxy (which is attached through an oxygen rather than a carbon bond) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof. "Hydrayl" groups may be optionally substituted.

[0031] As described herein, Q can be an amide bond -NH-C(O)- or a reverse amide bond -C(O)-NH-. An amide bond -NH-C(O)-, where the -NH at the amide bond is directly connected to a compound containing R as described herein. 1 and R 2When the -NH- ring of the reverse amide bond is directly attached to E as described herein, the -NH of the reverse amide bond is directly attached to E as described herein. 1 (For example, in Formula I, IA, I-AA, I-AB, I-AC, IB, IB, IC, I-CA, ID, I-DA, I-DB, IE, I-EA, I-EB, IF, I-FA, IG, I-GA, IH, I-HA, IJ, I-JA, IK, I-KA, IL, I-LA, IM, IN, I-NA, IO, IO, IP, I-PA, IQ, I-QA, IR, I-RA, IS, I-SA-i, I-SA-ii or IT compounds).

[0032] As used herein, the term "alkoxy" refers to a straight or branched, saturated aliphatic (alkyl) hydrocarbon group bonded to an oxygen atom attached to a core structure. Preferably, the alkoxy group has one to six carbon atoms, i.e., it is a C1-C6 alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and the like. "Alkoxy" groups may be optionally substituted.

[0033] As used herein, the term "alkoxyalkyl" refers to an alkyl group (as defined above) substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethylene- and ethyl-O-ethylene-. "Alkoxyalkyl" groups can be optionally substituted.

[0034] 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 halogen atoms that are the same or different. 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. A "haloalkyl" group may be optionally substituted.

[0035] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are replaced by one or more halogens. Representative examples of "haloalkoxy" include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3). A "haloalkoxy" group may be optionally substituted.

[0036] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom on the ring is carbon. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbon atoms are shared by two adjacent rings (fused rings), at least one of which is aromatic, for example, the other ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. The term "fused" refers to attaching or forming a second ring by sharing two adjacent atoms with the first ring. The term "fused" is equivalent to the term "condensed". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, phenol, aniline or dihydroindanyl and similar groups. Unless otherwise specified, all aryl groups described herein may be optionally substituted.

[0037] As used herein, the terms "polycyclic group," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which one or more atoms are shared by two adjacent rings, e.g., the rings are "fused rings." Each ring in the polycycle may be substituted or unsubstituted. In certain embodiments, each ring in the polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0038] As used herein, the term "acyl" refers to the group -C(=O)-R w , where R w is an optionally substituted alkyl group. Examples of "acyl" include, but are not limited to, w C1-C 10 Alkyl (C1-C 10 acyl), or C1-C 6- In some embodiments, the optionally substituted substituents are independently selected at each occurrence from the group consisting of H, OH, alkoxy, cyano, F, and amino. Other examples of "acyl" include: -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3)2.

[0039] As used herein, the term "carbamyl" refers to a group represented by:

[0040] where R z independently represents hydrogen or an optionally substituted hydrocarbon group, or R z The group, together with the -NC(=O)-O- moiety to which it is attached, completes a heterocyclic ring having 5 to 8 atoms in the ring structure, which may be optionally substituted.

[0041] As used herein, the term "formyl" refers to the group -C(=O)H.

[0042] 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: where R z independently represents hydrogen or an optionally substituted hydrocarbon group, or R z The group, together with the nitrogen atom to which it is attached, completes a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0043] As used herein, the terms "amide" and "amido" each refer to a group represented by: where R x 、R y and R z Each independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R z Together with the nitrogen atom to which it is attached, the heterocyclic ring has 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0044] As used herein, the term "amidine" refers to a group represented by: where R x 、R y and R z Each independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R z The group, together with the nitrogen atom to which it is attached, completes a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0045] As used herein, the term "urea" refers to a group represented by: where R x 、R y and R z Each independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R zTogether with the nitrogen atom to which it is attached, the heterocyclic ring has 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0046] As used herein, "alkylamino" and "alkylamine" refer to an amino group as defined above that is substituted with at least one alkyl group.

[0047] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0048] As used herein, the term "amidoalkyl" refers to an alkyl group substituted with an amide group.

[0049] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0050] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkyl-S-.

[0051] As used herein, the term "sulfanyl" refers to an alkyl group substituted with a thiol group.

[0052] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0053] 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. Generally, unless otherwise defined, monocyclic cycloalkyl groups have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., C3-C 10 Cycloalkyl, or for example C 3- C6 cycloalkyl). Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The second ring of a bicyclic cycloalkyl, or the second or third ring of a tricyclic cycloalkyl, can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyls include bicyclic and tricyclic molecules in which the two rings share one, two, or three or more atoms. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl, or the second or third ring of a fused tricyclic cycloalkyl, can be selected from saturated, unsaturated, and aromatic rings. "Cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyls can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like. Cycloalkyls can alternatively be polycyclic with more than two rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclics.

[0054] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

[0055] As used herein, the term "carbocycle" or "carbocyclic" includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of the fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle when the valence permits. Exemplary "carbocycles" include: cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decahydronaphthalene, 4,5-naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

[0056] As used herein, the term "cyano" refers to a -CN group.

[0057] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0058]

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

[0059] 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).

[0060] As used herein, the terms "heterocyclyl," "heterocycloalkyl," "heterocycle," and "heterocyclic" refer to non-aromatic, saturated or partially saturated, including monocyclic, polycyclic (e.g., bicyclic, tricyclic), bridged, or fused ring systems of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxathiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octyl, azocinyl, chromanyl, xanthenyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent may occur through a carbon atom or through a heteroatom. A heterocycloalkyl group may be optionally substituted through one or more of the aforementioned groups with one or more suitable groups. Preferably, "heterocyclyl" refers to a 5- to 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and N-oxides thereof. More preferably, "heterocyclyl" includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. All heterocyclyls are optionally substituted with one or more of the aforementioned groups.

[0061] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic ring structure, preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic) containing 8 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be covalently linked or fused, wherein two or more atoms are shared by two adjacent rings, wherein at least one of the rings is heteroaromatic, for example, the other cyclic ring may be: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The rings may contain N or S atoms, wherein the N or S atoms are optionally oxidized, or the N atom is optionally quaternized. All heteroaryl groups are optionally substituted. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthracene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizine 1-Hydroxy-1-dopoxy-1-pyridyl, ...

[0062] Regarding E as described herein 1 , E 1 A ring not selected from the group consisting of: Where s1 is the same as L 1 The site of covalent attachment; and s2 is the site of covalent attachment to H or an optionally substituted substituent.

[0063] As used herein, the term "sulfonamide" is represented by: where R x 、R y and R z represents independently at each occurrence hydrogen, optionally substituted hydrocarbon, or R z The group, together with the nitrogen atom to which it is attached, completes a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0064] As used herein, the term "sulfone" or "sulfonyl" refers to the group -S(O)2-R 6d , where R 6d represents an optionally substituted hydrocarbon group.

[0065] "Combination therapy" is a treatment that involves administering to a patient in need thereof two or more therapeutic agents, eg, a compound of the invention and a MAPK pathway inhibitor.

[0066] "Disease," "disorder," and "condition" are used interchangeably herein.

[0067] "Individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, 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 requiring veterinary treatment, for example, livestock (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).

[0068] As used herein, the MAPK pathway is a signal transduction pathway comprising RAS→RAF→MEK→ERK.

[0069] "MAPK pathway inhibitors" are inhibitors of the MAP kinase signal transduction pathway. Inhibitors of this pathway include: RAS inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120, connefenib), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996, ERAS-007). The terms "MAPK pathway inhibitors" and "MAPK kinase inhibitors" are used interchangeably herein.

[0070] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when appropriately 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.

[0071] 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, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0072] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0073] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts having acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of the basic compounds are acids that form non-toxic acid addition salts; the non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, include but are 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, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). The compounds included in the compositions of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the compositions of the present invention that include basic or acidic moieties may also form pharmaceutically acceptable salts with various amino acids. Compounds of the present invention may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a base salt.

[0074] The compounds of the present invention may contain one or more chiral centers and therefore exist in the form of stereoisomers. The term "stereoisomer" when used herein consists of all enantiomers or diastereomers. Depending on the configuration of the substituents around the stereogenic carbon atom, these compounds can be specified by the symbols "R" or "S", but those skilled in the art will recognize that the structure can implicitly represent the chiral center. These compounds can also be specified by "(+)" and "(-)" based on their optical rotation properties. The compounds described in the present invention encompass various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers can be designated by the symbol "(±)" in nomenclature, but those skilled in the art will recognize that the structure can implicitly represent the chiral center.

[0075] In this specification, the term "therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit the biological or medical response of a tissue, system, or animal (e.g., mammal or human) that is being sought by a researcher, veterinarian, medical doctor, or other clinician. The compounds described herein are administered in a therapeutically effective amount to treat a condition.

[0076] "Treatment" includes any action that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, or elimination.

[0077] The present invention 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 compounds of the invention may have one or more H atoms substituted with deuterium.

[0078] 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 resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) attaching the 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) salt formation using an optically active resolving agent, (3) direct separation of the 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 liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective syntheses, 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.

[0079] As used herein, “compounds of the present invention” include compounds of Formula I, IA, I-AA, I-AB, I-AC, IB, I-BA, IC, I-CA, ID, I-DA, I-DB, IE, I-EA, I-EB, IF, I-FA, IG, I-GA, IH, I-HA, IJ, I-JA, IK, I-KA, IL, I-LA, IM, IN, I-NA, IO, I-OA, IP, I-PA, IQ, I-QA, IR, I-RA, IS, I-SA-i, I-SA-ii, and IT, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof. Compound

[0080] In one embodiment, provided herein is a compound represented by Formula I: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from CR 3 and N; X 2 Selected from the group consisting of N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and NL 2 -E 2 ; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 , C=O, N and NL 3 -E 3 ; The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N; When X 2 When N, X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; When X 3 When N, X 2 Selected from the group consisting of N, CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; When X 2 When C=O, X 3 for NL 3 -E 3 ; When X 3 When C=O, X 2 for NL 2 -E 2 ; X 5independently selected from the group consisting of CH, CF, and N; X 6 independently selected from the group consisting of CH and CF; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; U is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2) m NH-; wherein the optionally substituted heterocyclyl or heterocyclyl(CH2) m NH- is independently present at each occurrence and optionally replaced by one or more occurrences of R 9 replace; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; p is independently 0, 1, or 2 at each occurrence; and m is independently 0, 1, 2, 3, or 4 at each occurrence; The restrictions are When X 1 and X 2 N, X 5 and X 6 are independently selected from CH and CF, X 4 CR 3 , R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 1 and X 4 N, X 5 and X 6 are independently selected from CH and CF, X 2 CL 2 -E 2 , L 2 For direct keys, E 2 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E1 a heterocyclic group that is not N-bonded; When X 6 CH, X 5 is CH or CF, X 4 CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following groups: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, X 1 CH or N, X 4 CH, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0081] In some embodiments, U is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2). m NH-; wherein the optionally substituted heterocyclyl or heterocyclyl(CH2) m NH- is independently present at each occurrence and optionally replaced by one or more occurrences of R 9 replace.

[0082] In some embodiments, U is where X 7 、X 8 and X 9 Independently selected from CR 3 and N, with the constraint that X 7 、X8 and X 9 No more than one of them is N; Z is -NHC(O)R 6 、-NHC(O)OR 6 or -C(O)NHR 7 ,in R 6 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein Alkyl and cycloalkyl are each optionally substituted by one or more independent occurrences of R 8 Replacement; and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0083] In some embodiments, U is where X 7 、X 8 and X 9 Independently selected from CR 3 and N, with the constraint that X 7 、X 8 and X 9 No more than one of them is N; Z is -NHC(O)R 6 ,in R 6is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein Alkyl and cycloalkyl are each optionally substituted by one or more independent occurrences of R 8 Replacement; and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0084] In some embodiments, U is where X 7 、X 8 and X 9 Independently selected from CR 3 and N, with the constraint that X 7 、X 8 and X 9 No more than one of them is N; Z is -NHC(O)R 6 , where R 6 In some embodiments, Z is -NHC(O)R 6 , where R 6 In some embodiments, Z is -NHC(O)R 6 , where R 6 In some embodiments, Z is -NHC(O)R 6 , where R 6 In some embodiments, Z is -NHC(O)R 6 , where R 6 is H. In some embodiments, Z is -NHC(O)R 6 , where R 6 CH2N(R 4 )2. In some embodiments, Z is -NHC(O)R 6 , where R 6 In some embodiments, Z is -NHC(O)R 6, where R 6 In some embodiments, Z is -NHC(O)R 6 , where R 6 It is CH2-OMe.

[0085] In some embodiments, U is where X 7 、X 8 and X 9 Independently selected from CR 3 and N, with the constraint that X 7 、X 8 and X 9 No more than one of them is N; Z is -C(O)NHR 7 ,in R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0086] In some embodiments, Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 .

[0087] In some embodiments, Z is -C(O)NHR 7 In some embodiments, Z is -C(O)NHR 7 , where R 7 is H. In some embodiments, Z is -C(O)NHR 7 , where R 7 In some embodiments, Z is -C(O)NHR 7 , where R 7 In some embodiments, Z is -C(O)NHR 7 , where R 7 In some embodiments, Z is -C(O)NHR 7 , where R 7is isopropyl. In some embodiments, Z is -NH2. In some embodiments, Z is carbamoyl. In some embodiments, Z is formyl. In some embodiments, Z is methylamino. In some embodiments, Z is ethylamino. In some embodiments, Z is β-hydroxyethylamino. In some embodiments, Z is β-methoxyethylamino. In some embodiments, Z is heterocyclyl. In some embodiments, Z is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, Z is morpholinyl. In some embodiments, Z is heterocyclylalkylamino. In some embodiments, Z is oxetanylalkylamino. In some embodiments, Z is azetidinylalkylamino. In some embodiments, Z is tetrahydropyranylalkylamino. In some embodiments, Z is heteroaryl. In some embodiments, Z is pyrazolyl. In some embodiments, Z is oxazolyl. In some embodiments, Z is oxadiazolyl. In some embodiments, Z is thiazolyl. In some embodiments, Z is selected from the group consisting of H, alkyl, and cycloalkyl. In some embodiments, Z is H. In some embodiments, Z is methyl. In some embodiments, Z is ethyl. In some embodiments, Z is isopropyl. In some embodiments, Z is cyclopropyl.

[0088] In some embodiments, U is where X 7 、X 8 and X 9 Independently selected from CR 3 and N, with the constraint that X 7 、X 8 and X 9 No more than one of them is N; Z is -NHC(O)OR 6 ,in R 6 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein Alkyl and cycloalkyl are each optionally substituted by one or more independent occurrences of R 8 Replacement; and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0089] In some embodiments, U is where X 8 、X 10 and X 11 are each independently selected from CH and N.

[0090] In some embodiments, U is where X 8 are independently selected from CH and N; X 12 For CH2, CHF, CF2, CH(CH3), C(CH3)2, NR 6 or O.

[0091] In some embodiments, the compound is represented by Formula IA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0092] In some embodiments, the compound is represented by Formula I-AA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0093] In some embodiments, the compound is represented by Formula I-AB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4.

[0094] In some embodiments, the compound is represented by Formula I-AC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, sulfone, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0095] In some embodiments, the compound is represented by Formula IB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, R 3 H, X 5 and X 6 When CH and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0096] In some embodiments, the compound is represented by formula I-BA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0097] In some embodiments, the compound is represented by Formula IC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the group consisting of N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and NL 2 -E 2 ; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; X 5 Selected from the group consisting of N, CH and CF; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When X 6 CH, X 5 is CH or CF, X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following groups: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, R 3 H, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0098] In some embodiments, the compound is represented by Formula I-CA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0099] In some embodiments, the compound is represented by Formula ID: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0100] In some embodiments, the compound is represented by Formula I-DA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0101] In some embodiments, the compound is represented by Formula I-DB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4.

[0102] In some embodiments, the compound is represented by Formula IE: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 for NL 3 -E 3 ; X 4 Selected from CR 3 and N; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restriction condition is that when L 1 When it is a direct key, E 1 It is not an N-bonded heterocyclic group.

[0103] In some embodiments, the compound is represented by Formula I-EA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0104] In some embodiments, the compound is represented by Formula I-EB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 for NL 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4.

[0105] In some embodiments, the compound is represented by Formula IF: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 for NL 2 -E 2 ; X 5 Selected from the group consisting of N, CH and CF; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclic, wherein The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 Selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restriction condition is that when L 1 When it is a direct key, E 1 It is not an N-bonded heterocyclic group.

[0106] In some embodiments, the compound is represented by formula I-FA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0107] In some embodiments, the compound is represented by Formula IG: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; X 3 Selected from the following group: CH, CL 2 -E 2 、COL 2 -E 2 、CN(R 4 )-L 2 -E 2 and N; X 5Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are X 2 and X 3 None of them is N; When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 6 CH, X 5 is CH or CF, X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following groups: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, R 3 H, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0108] In some embodiments, the compound is represented by formula I-GA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0109] In some embodiments, the compound is represented by Formula IH: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 and CN(R 4)-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1-E 1 It is not an unsubstituted methyl group.

[0110] In some embodiments, the compound is represented by formula I-HA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0111] In some embodiments, the compound is represented by Formula IJ: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 CL 2 -E 2 , L 2 For direct keys, E 2 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0112] In some embodiments, the compound is represented by Formula I-JA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0113] In some embodiments, the compound is represented by Formula IK: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, COL 2 -E 2, CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; X 5 Selected from the group consisting of N, CH and CF; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When X 6 CH, X 5 is CH or CF, Q is -C(O)NH-, L 1 is a direct key, and E 1 When selected from the group consisting of: C3-C8 cycloalkyl, C2-C8 heterocyclic, C6-C 14 Aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When R 3 H, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0114] In some embodiments, the compound is represented by Formula I-KA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0115] In some embodiments, the compound is represented by Formula IL: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and N; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 N, R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0116] In some embodiments, the compound is represented by Formula I-LA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0117] In some embodiments, the compound is represented by Formula IM: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and N; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; X 8 Selected from the group consisting of: N and CH; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 N, R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0118] In some embodiments, the compound is represented by Formula IN: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; X 5 Selected from the group consisting of N, CH and CF; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0119] In some embodiments, the compound is represented by formula I-NA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0120] In some embodiments, the compound is represented by Formula 10: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 Selected from the following group: CH, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and N; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 2 N, R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 It is not an unsubstituted methyl group.

[0121] In some embodiments, the compound is represented by Formula I-OA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0122] In some embodiments, the compound is represented by Formula IP: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3 or 4, The restrictions are When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When R 3 H, X 5 and X 6 When CH and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0123] In some embodiments, the compound is represented by Formula I-PA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0124] In some embodiments, the compound is represented by Formula IQ: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2)mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R at each occurrence. 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3 or 4, The restrictions are When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When R 3 H, X 5 and X 6 When CH and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0125] In some embodiments, the compound is represented by Formula I-QA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) mNH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

[0126] In some embodiments, the compound is represented by Formula IR: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from CR 3 and N; X 2 Selected from the group consisting of N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and NL 2 -E 2 ; X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 , C=O, N and NL 3 -E 3 ; The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N; When X 2 When N, X3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; When X 3 When N, X 2 Selected from the group consisting of N, CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; When X 2 When C=O, X 3 for NL 3 -E 3 ; When X 3 When C=O, X 2 for NL 2 -E 2 ; X 5 Selected from the group consisting of N, CH and CF; X 8 、X 9 and X 10 Each independently selected from CR 3 and N; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 1 and X 2 N, X 5 and X 6 are independently selected from CH and CF, X 4 CR 3 , R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or when X 1 and X 4 N, X 5 and X 6 are independently selected from CH and CF, X 2 CL 2 -E 2 , L 2 For direct keys, E 2 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, each L 3 When it is a direct key, each E 3is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When X 6 CH, X 5 is CH or CF, X 4 CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following groups: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, X 1 CH or N, X 4 CH, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0127] In some embodiments, the compound is represented by formula I-RA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from CR 3 and N; X 2 and X 3 are each independently selected from the group consisting of N and CH; The constraint condition is X 1 、X 2 、X 3 and X4 No more than two of them are N; X 8 、X 9 and X 10 Each independently selected from CR 3 and N; X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; and Each m is independently 0, 1, 2, 3 or 4.

[0128] In some embodiments, the compound is represented by Formula IS: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from CR 3 and N; X 2 Selected from the group consisting of N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and NL 2 -E 2 ; X 3Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 , C=O, N and NL 3 -E 3 ; The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N; When X 2 When N, X 3 Selected from the following group: CH, CL 3 -E 3 、COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; When X 3 When N, X 2 Selected from the group consisting of N, CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; When X 2 When C=O, X 3 for NL 3 -E 3 ; When X 3 When C=O, X 2 for NL 2 -E 2 ; X 5 Selected from the group consisting of N, CH and CF; X 8 Selected from CR 3 and N; X 11 Selected from the group consisting of: O, C(R 10 )2 and NR 11 ; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 )p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 10 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and F; R 11 is independently selected at each occurrence from the group consisting of: H, alkyl, and cycloalkyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4; The restrictions are When X 1 and X 2 N, X 5 and X 6 are independently selected from CH and CF, X 4 CR 3 , R 3 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 1 and X 4 N, X 5 and X 6 are independently selected from CH and CF, X2 CL 2 -E 2 , L 2 For direct keys, E 2 is selected from H and alkyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group that is not N-bonded; or When X 6 CH, X 5 is CH or CF, X 4 CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following groups: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl and C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, X 1 CH or N, X 4 CH, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

[0129] In some embodiments, the compound is represented by Formula I-SA-i or Formula I-SA-ii: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from CR 3 and N; X 2 and X 3 are each independently selected from the group consisting of N and CH; The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N; X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following groups: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; and Each m is independently 0, 1, 2, 3 or 4.

[0130] In some embodiments, the compound is represented by Formula IT: or a pharmaceutically acceptable salt, enantiomer, ster...

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from: CR 3 and N; X 2 Selected from the following group: N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 and NL 2 -E 2 ; X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 , C=O, N and NL 3 -E 3 ; The restriction condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N; When X 2 When N, X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; When X 3 When N, X 2 Selected from the group consisting of N, CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; When X 2 When C=O, X 3 For NL 3 -E 3 ; When X 3 When C=O, X 2 For NL 2 -E 2 ; X 5 Independently selected from the group consisting of CH, CF and N; X 6 Independently selected from the group consisting of CH and CF; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; L 2 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxyl and cyano, optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 2 Selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 21 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; U is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH2) m NH-; wherein the optionally substituted heterocyclic group or heterocyclic group (CH2) m NH- is optionally substituted independently at each occurrence by one or more occurrences of R 9 replace; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; p is independently 0, 1, or 2 at each occurrence; and m is independently 0, 1, 2, 3, or 4 at each occurrence; The restriction condition is When X 1 and X 2 N, X 5 and X 6 are independently selected from CH and CF, X 4 CR 3 , R 3 is selected from H and alkyl, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 1 and X 4 N, X 5 and X 6 are independently selected from CH and CF, X 2 For CL 2 -E 2 , L 2 For direct keys, E 2 is selected from H and alkyl, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; or When X 2 Selected from COL 2 -E 2 and CN(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 When it is a direct key, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When X 3 Selected from COL 3 -E 3 and CN(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 When it is a direct key, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S; or When L 1 When it is a direct key, E 1 a heterocyclic group which is not N-bonded; When X 6 CH, X 5 is CH or CF, X 4 CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is a direct key, and E 1 Selected from the following group: C3-C8 cycloalkyl, C2-C8 heterocyclic group, C6-C 14 When aryl or C1-C9 heteroaryl, X 2 Not CN(R 4 )-L 2 -E 2 ;or When Q is -C(O)-NH- and L 1 When it is a direct key, E 1 is not H; or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or When X 3 N, X 1 CH or N, X 4 CH, X 5 and X 6 CH, X 2 When CH or C-NH2 and Q is -C(O)-NH-, then L 1 -E 1 It is not an alkyl group substituted with an amine.

2. A compound represented by formula I-AA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

3. A compound represented by formula I-AB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4.

4. A compound represented by formula I-AC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, sulfone, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

5. A compound represented by formula I-BA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

6. A compound represented by formula I-CA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

7. A compound represented by formula I-DA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, When L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

8. A compound represented by formula I-DB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 Selected from the following group: CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 4 is independently selected at each occurrence from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4.

9. A compound represented by formula I-EA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

10. A compound represented by formula I-EB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 For NL 3 -E 3 ; X 5 Selected from the group consisting of N, CH and CF; L 3 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 31 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and Each m is independently 0, 1, 2, 3 or 4.

11. A compound represented by formula I-FA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

12. A compound represented by the formula I-GA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

13. A compound represented by formula I-HA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

14. A compound represented by formula I-JA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

15. A compound represented by formula I-KA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

16. A compound represented by formula I-LA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

17. A compound represented by formula I-NA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

18. A compound represented by formula I-OA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

19. A compound represented by formula I-PA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

20. A compound represented by formula I-QA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxyl, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH2) m NH-, wherein the optionally substituted substituents on the heterocyclyl ring are independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and Each m is independently 0, 1, 2, 3 or 4.

21. A compound represented by formula I-RA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from: CR 3 and N; X 2 and X 3 Each independently selected from the group consisting of: N and CH; The restriction condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N; X 8 , X 9 and X 10 Each independently selected from: CR 3 and N; X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen; and Each m is independently 0, 1, 2, 3 or 4.

22. A compound represented by formula I-SA-i or formula I-SA-ii: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently selected from: CR 3 and N; X 2 and X 3 Each independently selected from the group consisting of: N and CH; The restriction condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N; X 5 Selected from the group consisting of N, CH and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and an optionally substituted C1-C6 alkyl group, wherein the optionally substituted substituent is (E 11 ) m ; E 1 Select from the following group: optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein The alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy and aminoalkyl, The cycloalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and The heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, Among them, when L 1 is a direct key and E 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bonded; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or two occurrences of E 11 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 Selected from the group consisting of: H and F; R 3 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen; and Each m is independently 0, 1, 2, 3 or 4.

23. The compound of any one of claims 2 to 20, wherein Z is -NHC(O)R 6 、-NHC(O)OR 6 or -C(O)NHR 7 ,in R 6 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein Alkyl and cycloalkyl are each optionally substituted by one or more independent occurrences of R 8 Replace, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 7 is selected from the group consisting of H, alkyl, cycloalkyl and heterocyclyl, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone.

24. A compound as claimed in any one of claims 2 to 20 and 23, wherein Z is -NHC(O)R 6 ,in: R 6 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein Alkyl and cycloalkyl are each optionally substituted by one or more independent occurrences of R 8 Replace, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone.

25. The compound of any one of claims 2-20 and 23, wherein Z is -C(O)NHR 7 ,in: R 7 is selected from the group consisting of H, alkyl, cycloalkyl and heterocyclyl, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone.

26. A compound as claimed in any one of claims 2 to 20 and 23, wherein Z is -NHC(O)OR 6 ,in R 6 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein Alkyl and cycloalkyl are each optionally substituted by one or more independent occurrences of R 8 Replace, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic groups, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone.

27. The compound of any one of claims 1-26, wherein Q is -NH-C(O)-.

28. The compound of any one of claims 1-26, wherein Q is -C(O)-NH-.

29. The compound of claim 1, wherein X 1 , X 4 , X 5 and X 6 Each is CH; X 2 is N; and X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N.

30. The compound of claim 1, wherein X 1 , X 4 , X 5 and X 6 Each is CH; X 2 is CH; and X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N.

31. The compound of claim 21, wherein X 1 , X 4 and X 5 Each is CH; X 2 is CH; X 8 is N; and X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N.

32. The compound of claim 1, wherein X 1 CR 3 ;X 2 and X 4 Each is N;X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ;X 5 is CH or N; and X 6 For CH.

33. The compound of claim 21, wherein X 1 and X 4 Each is CR 3 ;X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N;X 8 is N; and X 2 , X 5 and X 6 For CH.

34. The compound of claim 1, wherein X 1 and X 4 Each is CR 3 ;X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N;X 5 is N; and X 2 and X 6 For CH.

35. The compound of claim 21, wherein X 1 and X 4 Each is CR 3 ;X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N;X 5 and X 8 is N; and X 2 and X 6 For CH.

36. The compound of claim 1, wherein X 1 CR 3 , and X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ;X 2 and X 4 is N; and X 5 and X 6 For CH.

37. The compound of claim 1, wherein X 1 CR 3 ;X 4 CR 3 or N;X 3 For NL 3 -E 3 ;X 2 C=O; and X 5 and X 6 For CH.

38. The compound of claim 1, wherein X 1 and X 4 CR 3 ;X 3 C=O;X 2 For NL 2 -E 2 ; and X 5 and X 6 For CH.

39. The compound of claim 1, wherein X 1 and X 4 CR 3 ;X 2 N; X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 、CN(R 4 )-L 3 -E 3 and N; and X 5 and X 6 For CH.

40. The compound of claim 1, wherein X 1 and X 2 N; X 4 CR 3 ;X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 ; and X 5 and X 6 For CH.

41. The compound of claim 1, wherein X 1 and X 4 N; X 5 and X 6 Each is CH; X 2 Selected from the following group: CH, CL 2 -E 2 , COL 2 -E 2 、CN(R 4 )-L 2 -E 2 ; and X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

42. The compound of claim 1, wherein X 1 and X 3 N; X 4 CR 3 , X 5 and X 6 Each is CH; and X 2 Selected from the following group: CH, CL 2 -E 2 , COL 2 -E 2 and CN(R 4 )-L 2 -E 2 .

43. The compound of claim 1, wherein X 1 N; X 4 CR 3 ;X 5 and X 6 Each is CH; X 2 Selected from the following group: CH, CL 2 -E 2 , COL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; and X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

44. The compound of claim 1, wherein X 1 CR 3 ;X 2 and X 6 is CH; and X 3 , X 4 and X 5 is N.

45. The compound of claim 1, wherein X 1 CR 3 ;X 2 , X 5 and X 6 is CH; and X 3 and X 4 is N.

46. ​​The compound of claim 21, wherein X 1 CR 3 ;X 2 , X 5 and X 6 is CH; and X 3 , X 4 and X 8 is N.

47. A compound as described in any one of claims 1, 3, 8, 29-37, 39-41 and 43, wherein E 3 is selected from the group consisting of H, alkyl and cycloalkyl, wherein cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy and cyano.

48. A compound as described in any one of claims 1, 3, 8, 29-37, 39-41 and 43, wherein E 3 Selected from the group consisting of hydroxy, alkoxy and cyano.

49. A compound as described in any one of claims 1, 3, 8, 29-37, 39-41 and 43, wherein E 3 is a heterocyclyl group, wherein the heterocyclyl group is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfonyl.

50. A compound as described in any one of claims 1, 38 and 41-43, wherein E 2 is selected from the group consisting of H, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano and cyanoalkyl, alkyl, amine, haloalkoxy, haloalkyl and sulfonyl.

51. A compound as described in any one of claims 1 to 50, wherein R 1 Selected from the group consisting of H, alkyl, haloalkyl and halogen.

52. A compound as described in any one of claims 1 to 51, wherein R 1 Selected from the group consisting of methyl and fluoro.

53. A compound as described in any one of claims 1 to 52, wherein R 2 Selected from H and F.

54. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

55. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of: and 56. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

57. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of: Where R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

58. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

59. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

60. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of: Where R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

61. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

62. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

63. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of: Where R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

64. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of:

65. A compound as described in any one of claims 2-20 and 23-53, wherein the ring substituted by Z is selected from the group consisting of: Where R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

66. A compound as described in any one of claims 1 to 65, wherein E 1 Select from the following group:

67. A compound as described in any one of claims 1 to 65, wherein E 1 Select from the following group: and 68. A compound as described in any one of claims 1 to 65, wherein E 1 Select from the following group: and 69. The compound of claim 1, wherein E 1 Select from the following group: and 70. A compound as described in any one of claims 1 to 69, wherein Select from the following group: and 71. A compound as described in any one of claims 1 to 65, wherein Select from the following group: and 72. The compound of claim 1, wherein Select from the following group: and 73. A compound as described in any one of claims 1 to 65, wherein when L 1 When it is a direct key, Select from the following group: and 74. A compound as described in any one of claims 1 to 65, wherein when L 1 When it is a direct key, Select from the following group: and 75. A compound as described in any one of claims 1-65, wherein when L 1 When it is a direct key, Select from the following group: and 76. The compound of claim 1, wherein for Where X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

77. The compound of claim 1, wherein for 78. The compound of claim 1, wherein for Where X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

79. The compound of claim 1, wherein for 80. The compound of claim 1, wherein for 81. The compound of claim 1, wherein for Where X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

82. The compound of claim 1, wherein for Where X 3 For NL 3 -E 3 .

83. The compound of claim 1, wherein for Where X 3 For NL 3 -E 3 .

84. The compound of claim 1, wherein for Where X 2 For NL 2 -E 2 .

85. The compound of claim 1, wherein for Where X 2 Selected from the group consisting of CH, COL 2 -E 2 , CL 2 -E 2 and CN(R 4 )-L 2 -E 2 ; and where X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

86. The compound of claim 1, wherein for Where X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

87. The compound of claim 1, wherein for 88. The compound of claim 1, wherein for Where X 3 Selected from the following group: CH, CL 3 -E 3 , COL 3 -E 3 and CN(R 4 )-L 3 -E 3 .

89. A compound selected from the group consisting of: and pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers thereof.

90. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 89 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

91. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-89, or a pharmaceutical composition according to claim 90.

92. The method of claim 91, wherein the cancer is selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematogenous cancer, hairy cell leukemia, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

93. The method of claim 91 or 92, wherein the cancer has a BRAF oncogenic mutation.

94. The method of any one of claims 91-93, wherein the cancer has a RAS oncogenic mutation.

95. The method of claim 94, wherein the RAS oncogenic mutation is a RAS Q61R or Q61K mutation.

96. The method of any one of claims 91 to 95, wherein the cancer has an NF1 oncogenic mutation.

97. A method for treating a condition in a patient in need thereof, the condition being selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematogenous cancer, hairy cell leukemia, acute myeloid leukemia (AML), other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1-89 or a pharmaceutical composition as described in claim 90.

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