RAF kinase inhibitors and methods of use thereof

Abstract

# imgabs0 # Described herein are compounds (I) as RAF inhibitors and their use in the treatment of conditions such as cancer.

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application Nos. 63 / 287,866, filed December 9, 2021, and 63 / 393,440, filed July 29, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] The BRAF V600X (i.e., V600E) mutant form of BRAF is known to be oncogenic, and a variety of BRAF inhibitors are currently commercially available to inhibit the signaling of oncogenic BRAF V600E in melanoma and other cancers. BRAF V600E signals as a monomer and has constitutive activity that is independent of upstream control by RAS. Commercially available BRAF V600E inhibitors include vemurafenib, dabrafenib, and encorafenib.

[0004] 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 enrafenib. Such dimers form in cancers driven by BRAF fusions, atypical BRAF mutations, or RAS-mutated cancers.

[0005] Oncogenic BRAF fusions arise from genomic rearrangements that place the 3' portion of the BRAF gene encoding the kinase domain after another gene at the 5' position. The result of the rearrangement is the expression of oncogenic proteins that exhibit constitutive kinase activity due to the loss 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 capable of aberrant signaling in cancer cells, independent of upstream effectors or regulatory mechanisms. Furthermore, some 5' translocation rearrangement genes enable the N-terminal domain to further induce dimerization, thereby enhancing the activated dimerization of the BRAF fusion protein kinase domain. Because the expression of these genomic rearrangements is controlled by the promoter of the 5' partner, overexpression of BRAF fusion transcripts is often caused by efficient or excessive promoter activity. BRAF fusions are one of the most common kinase translocations in solid tumors. Since its first description as an oncogene in 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'-terminal partner genes. BRAF fusions have been found in papillary thyroid cancer, astrocytomas, melanomas, and have also been identified in drug-resistant EGFR-mutant lung cancers. BRAF fusion proteins signal through dimerization in a RAS-independent manner and are resistant to many BRAF inhibitors, such as vemurafenib and dabrafenib, which are unable to inhibit the two protomers of the signaling homodimeric BRAF fusion. Rare CRAF fusion proteins have also been shown to be tumor drivers. These CRAF fusion proteins signal as CRAF-CRAF homodimers.

[0006] Other so-called atypical BRAF mutations also lead to spontaneous dimerization and signaling that is independent of RAS control. Like BRAF fusions, these atypical BRAF mutants signal as abnormal homodimers.

[0007] RAS mutant cancers account for approximately 26-30% of all human cancers. RAS mutant cancers transmit signals via the RAS→RAF→MEK→ERK signaling pathway. In this signaling cascade, kinase-inactive RAF monomers (including ARAF, BRAF, and CRAF isoforms) are recruited to oncogenic RAS, where RAS induces the formation of kinase-active signaling RAF dimers. The main RAF heterodimer recruited to mutant RAS is the BRAF / CRAF heterodimer.

[0008] 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, gave the best synthetic lethal inhibition of RAS-mutant signaling and, in addition, provided the best therapeutic window for inhibiting signaling in both RAS-mutant and 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 in vitro and in vivo.

[0009] Perpendicular inhibition of the RAF→MEK→ERK pathway through pan-inhibition of RAF (particularly 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 murine models of KRAS-mutant pancreatic cancer. Perpendicular inhibition of RAF (BRAF+CRAF) and MEK kinase activity has also been shown to be synergistic in KRAS-mutant tumors.

[0010] 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.

[0011] There is a need to identify RAF inhibitors that can inhibit multiple RAF isoforms, particularly BRAF and CRAF isoforms, and in particular, both RAF protomers present in signaling BRAF / BRAF homodimers and BRAF / CRAF heterodimers. Such pan-RAF inhibitors have found utility in treating BRAF V600X-driven cancers, atypical BRAF mutation cancers, BRAF fusion cancers, CRAF fusion cancers, and RAS mutant cancers. Summary of the Invention

[0012] This document describes, in part, compounds that are RAF inhibitors, such as BRAF or CRAF inhibitors, and methods of use thereof, such as for treating cancers driven by oncogenic forms of RAS or BRAF. In one embodiment, the compounds of the present invention inhibit BRAF and CRAF isoforms. In another embodiment, the compounds of the present invention inhibit both RAF protomers present in signaling BRAF / BRAF homodimers and BRAF / CRAF heterodimers.

[0013] In one embodiment, described herein is a compound represented by Formula I:

[0014]

[0015] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0016] X 1 and X 4 Each independently CR 5 or N;

[0017] X 5 and X 6 are each independently CH, CF or N;

[0018] X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ;

[0019] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or NL 3 -E 3 ,

[0020] The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N;

[0021] The restriction condition is that when X 2 When N, X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH;

[0022] The restriction condition is that when X 3 When N, X 2 N, CH, COL2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ;

[0023] The restriction condition is that when X 2 When C=O, X 3 for NL 3 -E 3 ;

[0024] The restriction condition is that when X 3 When C=O, X 2 for NL 2 -E 2 ;

[0025] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0026] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[0027] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0028] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0029] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0030] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0031] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0032] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0033] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0034] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0035] 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;

[0036] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[0037] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0038] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0039] 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;

[0040] E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone,

[0041] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0042] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0043] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0044] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0045] 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;

[0046] Z is L 7 -E 7 ,in:

[0047] L 7 For direct keys

[0048] E 7 Selected from the group consisting of:

[0049] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0050] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0051] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0052] p is independently 0, 1, or 2 at each occurrence;

[0053] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0054] R 2 Selected from the group consisting of: H and F;

[0055] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0056] R 4 is independently at each occurrence H or alkyl; and

[0057] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0058] The restrictions are

[0059] When E 7 is morpholinyl, X 2 and X 4 Both N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0060] When E 7 is morpholinyl, X 1 and X 4 Both N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0061] When E 7 is morpholinyl, X 1 、X 4 、X 5 and X 6 CH, R 1 -CH 3 , X 2 is N, and X 3 CL 3 -E 3 When L 3 -E 3is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5-membered or 6-membered heteroaryl, or amide;

[0062] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X 2 N, X 3 CL 3 -E 3 , L 3 is a direct key, and E 3 When it is morpholinyl, then E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl;

[0063] When E 7 is morpholinyl, X 1 CH, X 2 N, X 3 COL 3 -E 3 , X 4 CH, X 6 is CH, CD or CF, and R 3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl; when E 7 is morpholinyl, X 1 CH, X 2 COL 2 -E 2 , X 3 N, X 4 CH, X 6 is CH, CD or CF, and R 3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[0064] When E 7 is morpholinyl, X 1 CH, X 2 N, X 3 COL3 -E 3 , X 4 CH, X 6 If CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0065] When E 7 is morpholinyl, X 1 CH, X 2 COL 2 -E 2 , X 3 N, X 4 is CH, and X 6 When it is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0066] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[0067] X 2 Selected from the group consisting of:

[0068] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[0069] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[0070] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and

[0071] (iv) N,

[0072] Then X 3 Do not select a group consisting of:

[0073] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0074] (ii) COL 3 -E 3 , where OL 3 -E 3 Selected from the group consisting of methoxy, 2-hydroxyethoxy and 2,3-dihydroxypropoxy;

[0075] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0076] (iv) N;

[0077] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[0078] X 2 Selected from the group consisting of:

[0079] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[0080] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[0081] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and

[0082] (iv) N,

[0083] Then E 7 Not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl;

[0084] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, X 2 C=O, and X 3 for NL 3 -E 3 When L3 -E 3 is not selected from the group consisting of H, methyl, hydroxy-ethyl, hydroxy-propyl and 2,3-dihydroxypropyl; and

[0085] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 CH, X 6 is CH, CD or CF, X 2 is N, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0086] In another embodiment, described herein is a pharmaceutical composition comprising a compound described herein (eg, a compound of the present application as described herein) and a pharmaceutically acceptable carrier or excipient.

[0087] 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 present application as described herein).

[0088] In another embodiment, described herein is a method of treating a disorder 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, blood-borne cancers, 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 present application as described herein). DETAILED DESCRIPTION

[0089] The features and other details of this application will now be described in more detail. Certain terms used in the specification, examples, and appended claims are collected here. These definitions should be read in conjunction with the remainder of this application and will be 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 of ordinary skill in the art.

[0090] definition

[0091] The definitions set forth in this application are intended to clarify the terms used in this application.

[0092] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this invention belongs. As used in the specification and appended claims, unless otherwise specified, the following terms have the indicated meanings to facilitate understanding of this application.

[0093] When a bond to a substituent crosses a bond connecting two atoms in a ring, the substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom to which it is bonded to the rest of the compound of a given general formula, the substituent may be bonded via any atom in the substituent. Combinations of substituents, positions of substituents, and / or variables are permissible only if such combinations result in stable compounds.

[0094] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0095] As used herein, the term "herein" refers to the entire application.

[0096] As used herein, "deuterated" means that at least one hydrogen atom has been replaced by deuterium. In any sample of a deuterated compound, some discrete molecules of the compound may contain hydrogen instead of deuterium at a particular position. However, the percentage of molecules of the deuterated compound with deuterium at a particular position will be much greater than occurs naturally. Deuterium at the deuterated position is enriched.

[0097] 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 as well as instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted as well as instances where the alkyl group is not substituted.

[0098] It will be understood that substituents and substitution patterns on the disclosed compounds can be selected by one of ordinary skill in the art to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and 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.

[0099] 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 specified substituents, including but not limited to hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH2-Oalkyl. Preferably, "optionally substituted" refers to the replacement of one to four hydrogen atoms in a given structure with the above-mentioned substituents. More preferably, one to three hydrogen atoms are replaced with the substituents described above. It is understood that the substituents may be further substituted.

[0100] As used herein, the term "substituted" refers to a portion of a substituent having a hydrogen on one or more carbons that replaces the skeleton. It should be understood that "replacement" or "substituted" includes implicit prerequisites, i.e., such substitutions meet the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" should include all allowed substituents of an organic compound. In a broad sense, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Allowed substituents can be one or more and can be the same or different for appropriate organic compounds. For the purposes of this application, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any allowed substituents of an organic compound that satisfies the heteroatom valence as described herein.

[0101] Substituents may include any substituent described herein, for example, if not otherwise specified, such substituents may include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxyacyl, 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 moiety. It will be understood by those skilled in the art that the substituents themselves may be substituted if appropriate. For example, the substituents of substituted alkyl groups can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates) and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF3, -CN, etc. Unless specifically stated as "unsubstituted", chemical moieties mentioned herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted and unsubstituted variants.

[0102] As used herein, the term "alkyl" refers to a fully saturated straight or branched chain non-aromatic hydrocarbon. Typically, 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 10 Alkyl or for example C1-C6 alkyl, unless otherwise defined.The example of straight chain and branched alkyl includes but not limited to methyl, ethyl, 1-propyl group (n-propyl), 2-propyl group, normal-butyl, sec-butyl, the tert-butyl, 1-amyl group, 2-amyl group, 3-amyl group, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl etc.In addition, the term " alkyl " used in whole specification, embodiment and claims is intended to include " unsubstituted alkyl " and " substituted alkyl ", the latter refers to the alkyl part of the substituent of the hydrogen on one or more carbons that replace hydrocarbon backbone." alkyl " group can be optionally substituted.

[0103] When used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "C x -C y " is meant to include groups containing from x to y carbons in the chain. For example, the term "C x -C y ” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight and branched chain alkyl groups containing from x to y carbons in the chain, including halogenated alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents hydrogen when the group is in the terminal position and represents a bond if it is internal.

[0104] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primary carbon backbone, but may optionally include heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl groups, but substituents such as acetyl (which has a =O substituent on the connecting carbon) and ethoxy (which is connected through oxygen rather than carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. An "hydrocarbyl" group may be optionally substituted.

[0105] As used herein, the term "alkoxy" refers to a straight or branched saturated aliphatic (alkyl) hydrocarbon group connected to an oxygen atom attached to a core structure. Preferably, the alkoxy group has 1 to 6 carbon atoms, i.e., it can be a C1-C6 alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyl, tert-butoxy, pentyloxy, 3-methylbutoxy, and the like. The "alkoxy" group can be optionally substituted.

[0106] 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-, ethyl-O-ethylene-. An "alkoxyalkyl" group can be optionally substituted.

[0107] 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 can have chlorine, bromine, iodine, or a fluorine atom. Dihalo and polyhaloalkyl groups can have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, bischloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, bisfluoroethyl, difluoropropyl, etc. A "haloalkyl" group can be optionally substituted.

[0108] 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" groups include, but are not limited to, difluoromethoxy (-OCF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (OCH2CF3). A "haloalkoxy" group may be optionally substituted.

[0109] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes a polycyclic ring system 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 rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. The term "fused" refers to a second ring connected or formed by sharing two adjacent atoms with the first ring. The term "fused" is equivalent to the term "condensed". Examples of aryl include, but are not limited to, phenyl, naphthyl, phenanthrenyl, phenol, aniline or indenyl, etc. Unless otherwise specified, all aryl groups described herein may be optionally substituted.

[0110] 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 common to two adjacent rings, e.g., the rings are "fused rings." Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0111] 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, R w C1-C 10 Alkyl (C1-C 10 In some embodiments, each occurrence of an optionally substituted substituent is independently selected from 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.

[0112] As used herein, the term "carbamyl" refers to a

[0113]

[0114] Represents a group, wherein R z independently represents hydrogen or an optionally substituted hydrocarbon group, or R z The groups, together with the -NC(=O)-O- moiety to which they are attached, form a heterocyclic ring having from 5 to 8 atoms in the ring structure, which may be optionally substituted.

[0115] As used herein, the term "formyl" refers to the group -C(=O)H.

[0116] As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and their salts, for example,

[0117]

[0118] The part that is shown,

[0119] where R z independently represents hydrogen or an optionally substituted hydrocarbon group, or R z The groups, together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0120] As used herein, the terms "amide" and "amido" each refer to an

[0121]

[0122] The group represented by

[0123] 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 groups, together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0124] As used herein, the term "amidine" refers to a

[0125]

[0126] The group represented by

[0127] 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 groups, together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0128] As used herein, the term "urea" refers to

[0129]

[0130] The group represented by

[0131] where R x 、R y and R zEach independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R z The groups, together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0132] As used herein, the terms "alkylamino" and "alkylamine" refer to an amino group, as defined above, substituted with at least one alkyl group.

[0133] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0134] As used herein, the term "amidoalkyl" refers to an alkyl group substituted with an amide group.

[0135] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0136] 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-.

[0137] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0138] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0139] As used herein, the term "cycloalkyl" alone or in combination with other terms refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., C3-C 10 Cycloalkyl or, for example, C3-C6 cycloalkyl), unless otherwise defined. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The second ring of a bicyclic cycloalkyl or the two or three rings of a tricyclic cycloalkyl can be selected from saturated rings, unsaturated rings, and aromatic rings. Cycloalkyls include bicyclic and tricyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl or the two or three rings of a fused tricyclic cycloalkyl can be selected from saturated rings, unsaturated rings, and aromatic rings. "Cycloalkenyl" refers to a cyclic hydrocarbon containing one or more double bonds. Cycloalkyls can be further substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc. Cycloalkyls can also be polycyclic with more than two rings. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.

[0140] As used interchangeably herein, the term "cycloalkylalkyl" or "carbocycloalkyl" refers to an alkyl group substituted by a cycloalkyl group. The alkyl groups of the carbocycloalkyl and / or cycloalkylalkyl groups may be further substituted as defined above for cycloalkyl and alkyl groups, respectively.

[0141] 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 another ring. Each ring of the fused carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In an exemplary embodiment, an aromatic ring, such as a phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. 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 position or positions capable of carrying a hydrogen atom.

[0142] As used herein, the term "cyano" refers to a -CN group.

[0143] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0144] As used herein, the term "halo" or "halogen," alone or in combination with other terms, refers to chlorine, fluorine, bromine, and iodine.

[0145] 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).

[0146] As used herein, the terms "heterocyclyl," "heterocycloalkyl," "heterocycle," and "heterocycle" refer to non-aromatic, saturated or partially saturated, 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), the remaining ring atoms being independently selected from 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, dioxothiomorpholine, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyran, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octyl, oxazolinyl, tryptophan, xanthine, and N-oxides thereof. The attachment of the heterocycloalkyl substituent can occur through carbon atoms or heteroatoms. The heterocycloalkyl group can optionally be substituted with one or more suitable groups to form one or more of the above groups. Preferably, "heterocyclyl" refers to a 4- to 6-membered ring selected from the group consisting of 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 heterocyclyl groups are optionally substituted with one or more of the above groups.

[0147] As used herein, "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. If the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group is optionally attached to the alkyl group at the nitrogen atom. The heterocyclyl group and / or the alkyl group in the heterocyclylalkyl group may be further substituted as defined above for heterocyclyl and alkyl groups, respectively.

[0148] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic 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 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more rings (bicyclic, tricyclic or polycyclic), the ring containing 8 to 20 ring atoms, suitably 5 to 10 ring atoms. The ring atoms can be covalently linked, or fused, wherein two or more atoms are shared with two adjacent rings, wherein at least one ring is heteroaromatic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. The ring can contain N or S atoms, wherein the N or S groups are optionally oxidized, or the N groups are optionally quaternized. All heteroaryls are optionally substituted. Any suitable ring position of the heteroaryl moiety can be covalently linked to a defined chemical structure. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, quinolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzodithienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pterinyl, 9H-carbazolyl, α-carbolinyl, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridine 1-Hydroxy-1-dopoxy-1-pyridinyl, ...

[0149] Regarding the E 1 , E 1 Do not choose freedom

[0150]

[0151] The rings in the group 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.

[0152] As used herein, the term "sulfonamide" refers to:

[0153]

[0154] where R x 、R y and R z represents independently at each occurrence hydrogen, optionally substituted hydrocarbyl or R z The groups, together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0155] As used herein, the term "sulfone" refers to the group -S(O)2-R 6 , where R 6 represents an optionally substituted hydrocarbon group.

[0156] As used herein, ZH is an alcohol or an amine, wherein the H is directly attached to the oxygen or nitrogen within the Z moiety.

[0157] As used herein, ZB(OR)2 is a boronic acid or a boronic ester, wherein the boronic ester is directly bonded to a carbon within the Z moiety.

[0158] "Combination therapy" is a treatment method comprising administering to a patient in need thereof two or more therapeutic agents, such as a compound of the present application and a MAPK pathway inhibitor.

[0159] "Disease," "disorder," and "condition" are used interchangeably herein.

[0160] "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 preferably humans. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0161] The MAPK pathway used herein is a signal transduction pathway comprising RAS→RAF→MEK→ERK.

[0162] "MAPK pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120, anchorenib), MEK inhibitors (e.g., trametinib, dimethyltinib, selumetinib, cobimetinib) and ERK inhibitors (e.g., uritinib, SCH772984, LY3214996). The terms "MAPK pathway inhibitors" and "MAPK kinase inhibitors" are used interchangeably herein.

[0163] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by the U.S. Food and Drug Administration's Office of Biologics.

[0164] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonicity agents, absorption delaying agents, and the like that are compatible with pharmaceutical administration. The use of such media and formulations 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 function.

[0165] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0166] The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the composition. The basic compounds contained in the compositions of the present application are capable of forming a variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate. The acidic compounds contained in the present composition are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. The compounds comprising basic or acidic moieties included in the present composition can also form pharmaceutically acceptable salts with various amino acids. The compounds of the present application may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compound may exist in the form of an acid addition salt, a zwitterion or a base.

[0167] The compounds of the present application may contain one or more chiral centers and therefore exist in the form of stereoisomers. The term "stereoisomer" as used herein includes all enantiomers or diastereomers. Depending on the configuration of substituents around the stereogenic carbon atoms, these compounds can be represented by the symbols "R" or "S", but those skilled in the art will recognize that the structure can implicitly represent the chiral center. Depending on their optical rotation properties, these compounds can also be named "(+)" and "(-)". The compounds currently described include various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers can be represented by the symbol "(±)" in nomenclature, but those skilled in the art will recognize that the structure can implicitly represent the chiral center.

[0168] As used herein, the term "therapeutically effective amount" refers to the amount of a test compound that will elicit the biological or medical response of a tissue, system, or animal (e.g., a 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.

[0169] "Treat" includes any effect, eg, alleviating, reducing, modulating, or eliminating, thereby improving a condition, disease, disorder, or the like.

[0170] The present application also includes isotopically labeled compounds, which are 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 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 For example, the compounds of the present application may have one or more H atoms substituted with deuterium.

[0171] Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. Examples of such resolution methods are (1) attaching the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary, (2) forming salts using an optically active resolving agent, (3) directly separating 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 synthesis is a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers in the process of creating a new stereocenter or converting an existing stereocenter, as is well known in the art. Stereoselective synthesis involves enantioselective and diastereoselective transformations and may involve the use of chiral auxiliary agents. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley VCH: Weinheim, 2009.

[0172] As used herein, “compounds of the present application” include Formula I, Formula IA, Formula IB, Formula IC, Formula I-CA, Formula ID, Formula I-DA, Formula IE, Formula I-EA, Formula IF, Formula I-FA, Formula I-FB, Formula IG, Formula I-GA, Formula IH, Formula I-HA, Formula IJ, Formula I-JA, Formula I-JB, Formula IJC, Formula IK, Formula I-KA, Formula IL, Formula I-LA, Formula IM, Formula I-MA, Formula IN, Formula I-NA, Formula IO, Formula I-OA, Formula IP, Formula I-PA, Formula IQ, Formula I-QA, Formula IR, Formula I-RA, Formula IS, Formula I-SA, Formula IT, and Formula I-TA.

[0173] Compound

[0174] In one embodiment, a compound represented by Formula I is provided:

[0175]

[0176] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0177] X 1 and X 4 Each independently CR 5 or N;

[0178] X 5and X 6 are each independently CH, CF or N;

[0179] X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ;

[0180] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or NL 3 -E 3 ,

[0181] The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N;

[0182] The restriction condition is that when X 2 When N, X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH;

[0183] The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ;

[0184] The restriction condition is that when X 2 When C=O, X 3 for NL 3 -E 3 ;

[0185] The restriction condition is that when X 3 When C=O, X 2 for NL 2 -E 2 ;

[0186] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0187] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[0188] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0189] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0190] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0191] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0192] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0193] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0194] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0195] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0196] 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;

[0197] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[0198] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0199] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0200] 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;

[0201] E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone,

[0202] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0203] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0204] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0205] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0206] 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;

[0207] Z is L 7 -E 7 ,in:

[0208] L 7 For direct keys

[0209] E 7 Selected from the group consisting of:

[0210] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0211] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0212] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0213] p is independently 0, 1, or 2 at each occurrence;

[0214] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0215] R 2 Selected from the group consisting of: H and F;

[0216] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0217] R 4 is independently at each occurrence H or alkyl; and

[0218] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0219] The restrictions are

[0220] When E 7 is morpholinyl, X 2 and X 4 Both N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0221] When E 7 is morpholinyl, X 1 and X 4 Both N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0222] When E 7 is morpholinyl, X 1 、X 4 、X 5 and X 6 CH, R 1 -CH 3 , X 2 is N, and X 3 CL 3 -E 3 When L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5-membered or 6-membered heteroaryl, or amide;

[0223] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X2 N, X 3 CL 3 -E 3 , L 3 is a direct key, and E 3 When it is morpholinyl, then E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl;

[0224] When E 7 is morpholinyl, X 1 CH, X 2 N, X 3 COL 3 -E 3 , X 4 CH, X 6 is CH, CD or CF, and R 3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl; when E 7 is morpholinyl, X 1 CH, X 2 COL 2 -E 2 , X 3 N, X 4 CH, X 6 is CH, CD or CF, and R 3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[0225] When E 7 is morpholinyl, X 1 CH, X 2 N, X 3 COL 3 -E 3 , X 4 CH, X 6 If CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0226] When E 7is morpholinyl, X 1 CH, X 2 COL 2 -E 2 , X 3 N, X 4 is CH, and X 6 When it is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0227] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, and

[0228] X 2 Selected from the group consisting of:

[0229] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[0230] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[0231] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; and

[0232] (iv) N,

[0233] Then X 3 Do not select a group consisting of:

[0234] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0235] (ii) COL 3 -E 3 , where OL 3 -E 3 selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy;

[0236] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0237] (iv) N;

[0238] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3 For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[0239] X 2 Selected from the group consisting of:

[0240] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[0241] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[0242] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and

[0243] (iv) N,

[0244] Then E 7 Not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl;

[0245] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, X 2 C=O, and X 3 for NL 3 -E 3 When L 3 -E 3 is not selected from the group consisting of H, methyl, hydroxy-ethyl, hydroxy-propyl and 2,3-dihydroxypropyl; and

[0246] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 CH, X6 is CH, CD or CF, X 2 is N, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0247] In some embodiments, the compound can be represented by Formula IA:

[0248]

[0249] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0250] X 1 and X 4 Each independently is CH, CR 5 or N;

[0251] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH or N;

[0252] X 5 and X 6 are each independently CH, CF or N;

[0253] The constraint condition is X 1 、X 3 and X 4 No more than one of them is N;

[0254] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0255] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0256] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0257] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0258] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0259] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0260] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0261] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0262] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0263] 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;

[0264] E3 is selected from the group consisting of: H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, haloalkoxy, hydroxy, alkoxy, alkoxyalkyl, sulfonyl,

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

[0266] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0267] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0268] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0269] 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;

[0270] Z is L 7 -E 7 ,in:

[0271] L 7 is a direct key;

[0272] E 7 Selected from the group consisting of:

[0273] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0274] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0275] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0276] p is independently 0, 1, or 2 at each occurrence;

[0277] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0278] R 2 Selected from the group consisting of: H and F;

[0279] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0280] R 4 is independently at each occurrence H or alkyl; and

[0281] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0282] The restrictions are

[0283] When E 7 is morpholinyl, X 4 N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0284] When E 7 is morpholinyl, X 1 、X 4 、X 5 and X 6 CH, R 1 is -CH3, and X 3 CL 3 -E 3 When L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5-membered or 6-membered heteroaryl, or amide;

[0285] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X3 CL 3 -E 3 , L 3 is a direct key, and E 3 When it is morpholinyl, then E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl;

[0286] When E 7 is morpholinyl, X 1 CH, X 3 COL 3 -E 3 , X 4 CH, X 6 is CH or CF, and R 3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[0287] When E 7 is morpholinyl, X 1 CH, X 3 COL 3 -E 3 , X 4 CH, X 6 When it is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0288] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0289] Then X 3 Do not select a group consisting of:

[0290] (i)CL 3 -E3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0291] (ii) COL 3 -E 3 , where OL 3 -E 3 Selected from the group consisting of methoxy, 2-hydroxyethoxy and 2,3-dihydroxypropoxy;

[0292] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0293] (iv) N;

[0294] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3 is a direct key, and E 3 When selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl,

[0295] Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; and

[0296] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 CH, X 6 is CH, CD or CF, X2 is N, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0297] In some embodiments, the compound can be represented by Formula IB:

[0298]

[0299] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0300] X 1 and X 4 Each independently is CH, CR 5 or N;

[0301] The constraint condition is X 1 and X 4 No more than one of them is N;

[0302] X 5 and X 6 are each independently CH, CF or N;

[0303] X 31 O or N(R 4 );

[0304] L 1 Selected from direct bond and optional (E 11 )m substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0305] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0306] E 1is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0307] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0308] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0309] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0310] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0311] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0312] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0313] 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;

[0314] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0315] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0316] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0317] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0318] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0319] 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;

[0320] Z is L 7 -E 7 ,in:

[0321] L 7 is a direct key;

[0322] E 7 Selected from the group consisting of:

[0323] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0324] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0325] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0326] p is independently 0, 1, or 2 at each occurrence;

[0327] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0328] R 2 Selected from the group consisting of: H and F;

[0329] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0330] R 4 is independently at each occurrence H or alkyl; and

[0331] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0332] The restrictions are

[0333] When E 7 is morpholinyl, X 1 CH, X 31 O, X 4 CH, X 6 is CH or CF, and R 3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[0334] When E 7 is morpholinyl, X 1 CH, X 31 O, X 4 is CH, and X 6 When it is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0335] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0336] Then X 31 -L 3 -E 3is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; and

[0337] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When it is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0338] In some embodiments, the compound is represented by Formula IC:

[0339]

[0340] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0341] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , or CH;

[0342] X 5 and X 6 are each independently CH, CF or N;

[0343] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0344] L 3 For direct bond or optional (E 31 )p Substituted C1-C6 alkyl;

[0345] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0346] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

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

[0348] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0349] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0350] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0351] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0352] 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;

[0353] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0354] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of: H, alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0355] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl;

[0356] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0357] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0358] or two of the E3 1 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;

[0359] Z is L 7 -E 7 ,in:

[0360] L 7 is a direct key;

[0361] E 7 Selected from the group consisting of:

[0362] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0363] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0364] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0365] p is independently 0, 1, or 2 at each occurrence;

[0366] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0367] R 2 Selected from the group consisting of: H and F;

[0368] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0369] R 4 is independently at each occurrence H or alkyl; and

[0370] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0371] The restrictions are

[0372] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 4 It is CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0373] Then X 3 Do not select a group consisting of:

[0374] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0375] (ii) COL 3 -E 3 , where OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; and

[0376] (iii)CN(R 4 )-L 3 -E 3 , where N(R4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0377] (iv) N;

[0378] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 4 CH, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3 For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0379] Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; and

[0380] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5 H or F, X 5 CH, X 6 is CH, CD or CF, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0381] In some embodiments, the compound is represented by Formula I-CA:

[0382]

[0383] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0384] X5 and X 6 are each independently CH, CF or N;

[0385] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0386] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0387] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0388] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0389] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0390] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0391] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0392] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0393] 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;

[0394] Z is L 7 -E 7 ,in:

[0395] L 7 is a direct key;

[0396] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0397] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0398] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0399] R 2 Selected from the group consisting of: H and F;

[0400] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0401] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0402] In some embodiments, the compound is represented by Formula ID

[0403]

[0404] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0405] X 31 O or N(R 4 );

[0406] X 5 and X 6 are each independently CH, CF or N;

[0407] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0408] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0409] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0410] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0411] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0412] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0413] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0414] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0415] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0416] 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;

[0417] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0418] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0419] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0420] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0421] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0422] 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;

[0423] Z is L 7 -E 7 ,in:

[0424] L 7 is a direct key;

[0425] E 7 Selected from the group consisting of:

[0426] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0427] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0428] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0429] p is independently 0, 1, or 2 at each occurrence;

[0430] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0431] R 2 Selected from the group consisting of: H and F;

[0432] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0433] R 4 is independently at each occurrence H or alkyl; and

[0434] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0435] The restrictions are

[0436] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0437] Then X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; and

[0438] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5H or F, X 5 is CH, and X 6 If CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0439] In some embodiments, the compound is represented by formula I-DA:

[0440]

[0441] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0442] X 31 O or N(R 4 );

[0443] X 5 and X 6 are each independently CH, CF or N;

[0444] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when X 5 When N, L 1 Can be used with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0445] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0446] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0447] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0448] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0449] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0450] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0451] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0452] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0453] 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;

[0454] E 3 is selected from the group consisting of: haloalkoxy, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0455] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0456] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0457] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0458] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0459] 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;

[0460] Z is L 7 -E 7 ,in:

[0461] L 7 is a direct key;

[0462] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0463] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0464] p is independently 0, 1, or 2 at each occurrence;

[0465] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0466] R 2 Selected from the group consisting of: H and F;

[0467] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0468] R 4 is independently at each occurrence H or alkyl; and

[0469] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0470] In some embodiments, the compound is represented by Formula IE:

[0471]

[0472] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0473] X 1 and X 4 Each independently is CH, CR 5 or N;

[0474] The constraint condition is X 1 and X 4 No more than one of them is N;

[0475] X 5 and X 6 are each independently CH, CF or N;

[0476] L 1 Selected from direct bond and optional (E 11 )m substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0477] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[0478] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0479] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0480] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0481] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0482] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0483] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0484] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0485] 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;

[0486] E 2 is selected from the group consisting of: H, alkyl, amine, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[0487] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0488] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0489] 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;

[0490] Z is L 7 -E 7 ,in:

[0491] L 7 For direct keys

[0492] E 7 Selected from the group consisting of:

[0493] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0494] Optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano

[0495] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0496] p is independently 0, 1, or 2 at each occurrence;

[0497] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0498] R 2 Selected from the group consisting of: H and F;

[0499] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0500] R 4 is independently at each occurrence H or alkyl; and

[0501] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0502] In some embodiments, the compound is represented by formula I-EA

[0503]

[0504] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0505] X 5 and X 6 are each independently CH, CF or N;

[0506] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0507] L 2 is a direct key;

[0508] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0509] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0510] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0511] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0512] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0513] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0514] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0515] 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;

[0516] E 2 is an alkyl group;

[0517] Z is L 7 -E 7 ,in:

[0518] L 7 is a direct key;

[0519] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0520] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0521] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0522] R 2 Selected from the group consisting of: H and F;

[0523] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0524] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0525] In some embodiments, the compound is represented by Formula IF:

[0526]

[0527] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0528] X 1 and X 4 Each independently is CH, CR 5 or N;

[0529] The constraint condition is X 1 and X 4 No more than one of them is N;

[0530] X 5 and X 6 are each independently CH, CF or N;

[0531] L 1 Selected from direct bond and optional (E 11 )m substituted C1-C6 alkyl, or when with R 3 and L1 and R 3 The attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0532] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0533] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0534] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0535] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0536] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0537] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0538] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0539] 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;

[0540] E3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0541] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0542] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0543] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0544] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0545] 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;

[0546] Z is L 7 -E 7 ,in:

[0547] L 7 is a direct key;

[0548] E 7 Selected from the group consisting of:

[0549] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0550] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0551] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0552] p is independently 0, 1, or 2 at each occurrence;

[0553] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0554] R 2 Selected from the group consisting of: H and F;

[0555] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0556] R 4 is independently at each occurrence H or alkyl; and

[0557] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0558] The restrictions are

[0559] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl, then L 3 -E 3 Not selected from the group consisting of H, methyl, hydroxy-ethyl, hydroxy-propyl and 2,3-dihydroxypropyl.

[0560] In some embodiments, the compound is represented by formula I-FA or formula I-FB

[0561]

[0562] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0563] X 5 and X 6 are each independently CH, CF or N;

[0564] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0565] L 3 is a direct key;

[0566] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0567] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0568] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0569] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0570] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0571] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0572] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0573] 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;

[0574] E 3 is an alkyl group;

[0575] Z is L 7 -E 7 ,in:

[0576] L 7 is a direct key;

[0577] E 7 is an optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[0578] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0579] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0580] R 2 Selected from the group consisting of: H and F;

[0581] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0582] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0583] The constraint condition is E 7 Not oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

[0584] In some embodiments, the compound is represented by Formula IG:

[0585]

[0586] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0587] X 2 COL 2 -E 2 , CL 2 -E 2 ,CN(R4 )-L 2 -E 2 or CH;

[0588] X 3 It's COL 3 -E 3 , CL 3 -E 3 ,CN(R 4 )-L 3 -E 3 or CH;

[0589] X 5 and X 6 are each independently CH, CF or N;

[0590] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0591] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[0592] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0593] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0594] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0595] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0596] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0597] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0598] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0599] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0600] 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;

[0601] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl and sulfone, hydroxy, alkoxy and alkoxyalkyl, cyano, sulfonyl, and

[0602] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0603] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0604] 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;

[0605] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0606] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0607] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0608] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0609] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0610] 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;

[0611] Z is L 7 -E 7 ,in:

[0612] L 7 is a direct key;

[0613] E 7 Selected from the group consisting of:

[0614] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0615] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0616] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0617] p is independently 0, 1, or 2 at each occurrence;

[0618] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0619] R 2 Selected from the group consisting of: H and F;

[0620] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0621] R 4 is independently at each occurrence H or alkyl; and

[0622] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0623] The restrictions are

[0624] When E 7 is morpholinyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0625] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[0626] X 2 Selected from the group consisting of:

[0627] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[0628] (ii) COL 2 -E 2 , where OL 2 -E 2Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; and

[0629] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino;

[0630] Then X 3 Do not select a group consisting of:

[0631] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0632] (ii) COL 3 -E 3 , where OL 3 -E 3 selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; and

[0633] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0634] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3 For direct keys, E 3is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[0635] X 2 Selected from the group consisting of:

[0636] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[0637] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; and

[0638] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino;

[0639] Then E 7 Not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl;

[0640] In some embodiments, the compound is represented by the formula I-GA:

[0641]

[0642] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0643] X 5 and X 6 are each independently CH, CF or N;

[0644] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0645] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0646] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0647] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0648] optionally substituted heteroaryl, 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, and heterocyclyl,

[0649] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0650] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0651] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0652] 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;

[0653] Z is L 7 -E 7 ,in:

[0654] L 7 is a direct key;

[0655] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0656] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0657] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0658] R 2 Selected from the group consisting of: H and F;

[0659] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0660] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0661] In some embodiments, the compound is represented by Formula IH:

[0662]

[0663] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0664] X 31 O or N(R 4 );

[0665] X 5 and X 6 are each independently CH, CF or N;

[0666] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0667] L3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0668] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0669] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0670] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0671] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0672] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0673] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0674] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0675] 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;

[0676] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0677] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0678] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0679] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0680] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0681] 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;

[0682] Z is L 7 -E 7 ,in:

[0683] L 7 is a direct key;

[0684] E 7 Selected from the group consisting of:

[0685] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[0686] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0687] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0688] p is independently 0, 1, or 2 at each occurrence;

[0689] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0690] R 2 Selected from the group consisting of: H and F;

[0691] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0692] R 4 is independently selected at each occurrence from H or alkyl; and

[0693] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0694] The restrictions are

[0695] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl, then X 31 -L 3 -E 3 Not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino.

[0696] In some embodiments, the compound is represented by formula I-HA

[0697]

[0698] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0699] X 31 O or N(R 4 );

[0700] X 5 and X 6 are each independently CH, CF or N;

[0701] L 1 Selected from direct bond and optional (E 11 ) mSubstituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0702] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0703] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0704] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0705] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0706] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0707] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0708] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0709] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0710] or two occurrences of E 11together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure;

[0711] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0712] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0713] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0714] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0715] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0716] 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;

[0717] Z is L 7 -E 7 ,in:

[0718] L 7 is a direct key;

[0719] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0720] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0721] p is independently 0, 1, or 2 at each occurrence;

[0722] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0723] R 2 Selected from the group consisting of: H and F;

[0724] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0725] R 4 is independently at each occurrence H or alkyl; and

[0726] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0727] In some embodiments, the compound is represented by Formula IJ:

[0728]

[0729] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0730] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH or N;

[0731] X 5 and X 6 are each independently CH, CF or N;

[0732] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0733] L 3 For direct bond or optional (E 31 )p Substituted C1-C6 alkyl;

[0734] E 1 Selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen

[0735] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0736] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0737] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0738] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0739] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0740] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0741] 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;

[0742] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0743] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0744] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

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

[0746] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen

[0747] 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

[0748] Z is L 7 -E 7 ,in:

[0749] L 7 Selected from the group consisting of: direct keys;

[0750] E 7 Selected from the group consisting of:

[0751] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0752] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0753] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0754] p is independently 0, 1, or 2 at each occurrence;

[0755] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0756] R 2 Selected from the group consisting of: H and F;

[0757] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0758] R 4 is independently at each occurrence H or alkyl; and

[0759] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0760] The restrictions are

[0761] When E 7 is morpholinyl, R 5 H, X 5 and X 6 CH, R 1 is -CH3, and X 3 CL 3 -E 3 , then L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5-membered or 6-membered heteroaryl, or amide;

[0762] When R 5 H, X 5 and X 6 CH, R 1 -CH3, X 3 CL 3 -E 3 , L 3 is a direct key, and E 3 When it is morpholinyl, then E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl;

[0763] When E 7 is morpholinyl, X 3 COL 3 -E 3 , R 5 H, X 6 is CH or CF, and R3 When H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[0764] When E 7 is morpholinyl, X 3 COL 3 -E 3 , R 5 H, X 6 When it is CH, CD or CF, L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0765] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0766] Then X 3 Do not select a group consisting of:

[0767] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0768] (ii) COL 3 -E 3 , where OL 3 -E 3 Selected from the group consisting of methoxy, 2-hydroxyethoxy and 2,3-dihydroxypropoxy;

[0769] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4)-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0770] (iv) N; and

[0771] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , and E 3 When selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl,

[0772] Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; and

[0773] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5 H or F, X 5 CH, X 6 is CH, CD or CF, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0774] In some embodiments, the compound can be represented by Formula I-JA:

[0775]

[0776] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0777] X 3 CL 3 -E 3or CH;

[0778] X 5 and X 6 are each independently CH, CF or N;

[0779] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0780] L 3 is a direct key;

[0781] E 1 selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen;

[0782] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0783] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0784] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0785] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0786] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0787] E 11is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0788] 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;

[0789] E 3 Selected from the group consisting of: alkyl and

[0790] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0791] Z is L 7 -E 7 ,in:

[0792] L 7 selected from the group consisting of direct keys;

[0793] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0794] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0795] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0796] R 2 Selected from the group consisting of: H and F;

[0797] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0798] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0799] In some embodiments, the compound is represented by Formula I-JB:

[0800]

[0801] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0802] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or CH;

[0803] X 5 and X 6 are each independently CH, CF or N;

[0804] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0805] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0806] E 1 Selected from the group consisting of:

[0807] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, and

[0808] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0809] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0810] or two occurrences of E 11together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure;

[0811] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0812] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and

[0813] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0814] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0815] 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;

[0816] Z is L 7 -E 7 ,in:

[0817] L 7 selected from the group consisting of direct keys;

[0818] E 7 is an optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0819] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0820] p is independently 0, 1, or 2 at each occurrence;

[0821] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0822] R 2Selected from the group consisting of: H and F;

[0823] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0824] R 4 is independently at each occurrence H or alkyl; and

[0825] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0826] In some embodiments, the compound is represented by Formula I-JC:

[0827]

[0828] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0829] X 5 and X 6 are each independently CH, CF or N;

[0830] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0831] E 1 selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen;

[0832] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0833] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0834] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

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

[0836] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0837] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0838] 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;

[0839] Z is L 7 -E 7 ,in:

[0840] L 7 selected from the group consisting of direct keys;

[0841] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0842] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0843] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0844] R 2 Selected from the group consisting of: H and F;

[0845] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0846] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0847] In some embodiments, the compound is represented by Formula IK

[0848]

[0849] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0850] X 5 and X 6 are each independently CH, CF or N;

[0851] X 31 O or N(R 4 );

[0852] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0853] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0854] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0855] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0856] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0857] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0858] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0859] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0860] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0861] 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;

[0862] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0863] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0864] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[0865] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0866] E 31is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0867] 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;

[0868] Z is L 7 -E 7 ,in:

[0869] L 7 is a direct key;

[0870] E 7 Selected from the group consisting of:

[0871] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0872] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0873] m is independently at each occurrence 0, 1, 2, 3, or 4; and

[0874] p is independently 0, 1, or 2 at each occurrence;

[0875] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0876] R 2 Selected from the group consisting of: H and F;

[0877] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0878] R 4 is independently at each occurrence H or alkyl; and

[0879] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[0880] The restrictions are

[0881] When E 7 is morpholinyl, R 5 H, X 6 CH, CD, CF, X 31 is O, and R 3 is H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[0882] When E 7 is morpholinyl, R 5 H, X 31 is O, and X 6 For CH, CD, CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[0883] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0884] Then X 31 -L 3 -E 3 Not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino;

[0885] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5 H or F, X 5 is CH, and X 6 If CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0886] In some embodiments, the compound is represented by Formula I-KA:

[0887]

[0888] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0889] X 5 and X 6 are each independently CH, CF or N;

[0890] X 31 O or N(R 4 );

[0891] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when X 5 When N, L 1 Can be used with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0892] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0893] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0894] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0895] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0896] optionally substituted heteroaryl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, the site of covalent attachment to H or the optionally substituted substituent,

[0897] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0898] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0899] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0900] 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;

[0901] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0902] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone,

[0903] 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, or cyano, cyanoalkyl, heterocyclyl, and

[0904] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, or cyano;

[0905] E 31is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0906] 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;

[0907] Z is L 7 -E 7 ,in:

[0908] L 7 is a direct key;

[0909] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0910] m is independently at each occurrence 0, 1, 2, 3, or 4; and

[0911] p is independently 0, 1, or 2 at each occurrence;

[0912] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0913] R 2 Selected from the group consisting of: H and F;

[0914] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0915] R 4 is independently at each occurrence H or alkyl; and

[0916] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0917] In some embodiments, the compound is represented by Formula IL:

[0918]

[0919] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0920] X 3 COL 3 -E3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or CH;

[0921] X 5 and X 6 are each independently CH, CF or N;

[0922] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L3 is a direct bond or optionally substituted by (E 31 ) p Substituted C1-C6 alkyl;

[0923] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0924] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0925] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0926] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0927] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0928] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0929] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0930] 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;

[0931] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[0932] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[0933] 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, or cyano, cyanoalkyl, heterocyclyl, and

[0934] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0935] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0936] 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;

[0937] Z is L 7 -E 7 ,in:

[0938] L 7 For direct keys

[0939] E 7 Selected from the group consisting of:

[0940] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[0941] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0942] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0943] p is independently 0, 1, or 2 at each occurrence;

[0944] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0945] R 2 Selected from the group consisting of: H and F;

[0946] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[0947] R 4 is independently selected at each occurrence from H or alkyl; and

[0948] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0949] The restrictions are

[0950] When E 7 is morpholinyl, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 Not a heteroaryl group;

[0951] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R5 H, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[0952] Then X 3 Do not select a group consisting of:

[0953] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[0954] (ii) COL 3 -E 3 , where OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; and

[0955] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[0956] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , and E 3 When selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl,

[0957] Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; and

[0958] When E 7is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5 H or F, X 5 CH, X 6 is CH, CD or CF, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[0959] In some embodiments, the compound can be represented by formula I-LA

[0960]

[0961] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0962] X 3 CL 3 -E 3 or CH;

[0963] X 5 and X 6 are each independently CH, CF or N;

[0964] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0965] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0966] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0967] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0968] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0969] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0970] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0971] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0972] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0973] 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;

[0974] E 3 Selected from the group consisting of: alkyl and

[0975] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0976] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[0977] or two occurrences of E 31together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure;

[0978] Z is L 7 -E 7 ,in:

[0979] L 7 is a direct key;

[0980] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[0981] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[0982] p is independently 0, 1, or 2 at each occurrence;

[0983] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[0984] R 2 Selected from the group consisting of: H and F;

[0985] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[0986] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[0987] In some embodiments, the compound is represented by Formula IM:

[0988]

[0989] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0990] X 5 and X 6 are each independently CH, CF or N;

[0991] X 31 O or N(R 4 );

[0992] L 1 Selected from direct bond and optional (E 11 ) mSubstituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[0993] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[0994] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[0995] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[0996] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[0997] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[0998] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[0999] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1000] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1001] or two occurrences of E 11together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure;

[1002] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[1003] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1004] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[1005] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1006] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1007] 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;

[1008] Z is L 7 -E 7 ,in:

[1009] L 7 is a direct key;

[1010] E 7 Selected from the group consisting of:

[1011] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1012] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1013] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1014] p is independently 0, 1, or 2 at each occurrence;

[1015] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1016] R 2 Selected from the group consisting of: H and F;

[1017] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1018] R 4 is independently at each occurrence H or alkyl; and

[1019] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1020] The restrictions are

[1021] When L 1 -E 1 for

[1022] R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[1023] Then X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; and

[1024] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5H or F, X 5 is CH, and X 6 If CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[1025] In some embodiments, the compound is represented by formula I-MA:

[1026]

[1027] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1028] X 5 and X 6 are each independently CH, CF or N;

[1029] X 31 O or N(R 4 );

[1030] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when X 5 When N, L 1 Can be used with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1031] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1032] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1033] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1034] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1035] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1036] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1037] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1038] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1039] 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;

[1040] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[1041] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1042] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[1043] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1044] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1045] 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;

[1046] Z is L 7 -E 7 ,in:

[1047] L 7 is a direct key;

[1048] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1049] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1050] p is independently 0, 1, or 2 at each occurrence;

[1051] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1052] R 2 Selected from the group consisting of: H and F;

[1053] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1054] R 4 is independently at each occurrence H or alkyl; and

[1055] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1056] In some embodiments, the compound is represented by Formula IN:

[1057]

[1058] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1059] X 2 COL 2 -E 2 , CL 2 -E 2 ,CN(R 4 )-L 2 -E 2 or CH;

[1060] X 5 and X 6 are each independently CH, CF or N;

[1061] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1062] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1063] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1064] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1065] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1066] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1067] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1068] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1069] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1070] 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;

[1071] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1072] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1073] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1074] 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;

[1075] Z is L 7 -E 7 ,in:

[1076] L 7 For direct keys

[1077] E 7 Selected from the group consisting of:

[1078] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1079] Optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano

[1080] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1081] p is independently 0, 1, or 2 at each occurrence;

[1082] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1083] R 2 Selected from the group consisting of: H and F;

[1084] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1085] R 4 is independently at each occurrence H or alkyl; and

[1086] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1087] The restrictions are

[1088] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl, then

[1089] X 2 Do not select a group consisting of:

[1090] (i)CL 2 -E 2 , where L2 -E 2 Selected from H;

[1091] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; and

[1092] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 The group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino;

[1093] In some embodiments, the compound is represented by formula I-NA:

[1094]

[1095] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1096] X 5 and X 6 are each independently CH, CF or N;

[1097] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1098] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1099] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1100] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1101] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1102] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1103] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1104] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1105] 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;

[1106] Z is L 7 -E 7 ,in:

[1107] L 7 is a direct key;

[1108] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1109] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1110] R1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1111] R 2 Selected from the group consisting of: H and F;

[1112] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[1113] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1114] In some embodiments, the compound is represented by Formula 10:

[1115]

[1116] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1117] X 2 COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 , CH or N;

[1118] X 3 CH, COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or N;

[1119] The constraint condition is X 2 and X 3 No more than one of them is N;

[1120] X 5 and X 6 are each independently CH, CF or N;

[1121] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1122] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1123] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1124] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1125] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1126] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1127] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1128] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1129] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1130] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1131] 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;

[1132] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1133] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl,

[1134] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1135] 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;

[1136] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[1137] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1138] 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, or cyano, cyanoalkyl, heterocyclyl, and

[1139] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1140] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1141] 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;

[1142] Z is L 7 -E 7 ,in:

[1143] L 7 is a direct key;

[1144] E 1 Selected from the group consisting of:

[1145] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkanoylalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1146] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1147] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1148] p is independently 0, 1, or 2 at each occurrence;

[1149] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1150] R 2 Selected from the group consisting of: H and F;

[1151] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1152] R 4 is independently at each occurrence H or alkyl; and

[1153] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1154] The restrictions are

[1155] When E 7 is morpholinyl, X 2 It is N, X 3 It's CL3 -E 3 , and L 3 is a direct key, then E 3 Not a heteroaryl group;

[1156] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetane, tetrahydrofuranyl and tetrahydropyranyl, and

[1157] X 2 Selected from the group consisting of:

[1158] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[1159] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[1160] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and

[1161] (iv) N,

[1162] Then X 3 Do not select a group consisting of:

[1163] (i)CL 3 -E 3 , where L 3 -E 3Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[1164] (ii) COL 3 -E 3 , where OL 3 -E 3 Selected from the group consisting of methoxy, 2-hydroxyethoxy and 2,3-dihydroxypropoxy;

[1165] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[1166] (iv) N; and

[1167] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3 For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[1168] X 2 Selected from the group consisting of:

[1169] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[1170] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[1171] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; and

[1172] (iv) N,

[1173] Then E 7 Not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl.

[1174] In some embodiments, the compound is represented by formula I-OA

[1175]

[1176] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1177] X 2 COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 , CH or N;

[1178] X 3 CH, COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or N;

[1179] The constraint condition is X 2 and X 3 No more than one of them is N;

[1180] X 5 and X 6 are each independently CH, CF or N;

[1181] L 1 Selected from direct bond and optional (E 11 )m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1182] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1183] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1184] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1185] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1186] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1187] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1188] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1189] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1190] E 11is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1191] 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;

[1192] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1193] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl,

[1194] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1195] 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;

[1196] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[1197] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1198] 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, or cyano, cyanoalkyl, heterocyclyl, and

[1199] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1200] E31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1201] 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;

[1202] Z is L 7 -E 7 ,in:

[1203] L 7 is a direct key;

[1204] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1205] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1206] p is independently 0, 1, or 2 at each occurrence;

[1207] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1208] R 2 Selected from the group consisting of: H and F;

[1209] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1210] R 4 is independently at each occurrence H or alkyl; and

[1211] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1212] In some embodiments, the compound can be represented by Formula IP:

[1213]

[1214] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1215] X 2 COL2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 , CH or N;

[1216] X 3 CH, COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or N;

[1217] The constraint condition is X 2 and X 3 No more than one of them is N;

[1218] X 5 and X 6 are each independently CH, CF or N;

[1219] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1220] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1221] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1222] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1223] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1224] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1225] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1226] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1227] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1228] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1229] 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;

[1230] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1231] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl,

[1232] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1233] 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;

[1234] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[1235] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1236] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl or cyano, cyanoalkyl and heterocyclyl, and

[1237] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, or cyano;

[1238] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1239] 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;

[1240] Z is L 7 -E 7 ,in:

[1241] L 7 is a direct key;

[1242] E 7 Selected from the group consisting of:

[1243] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1244] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1245] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1246] p is independently 0, 1, or 2 at each occurrence;

[1247] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1248] R 2 Selected from the group consisting of: H and F;

[1249] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1250] R 4 is independently at each occurrence H or alkyl; and

[1251] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1252] The restrictions are:

[1253] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[1254] X 2 Selected from the group consisting of:

[1255] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[1256] (ii) COL 2 -E 2 , where OL 2 -E2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; and

[1257] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and

[1258] (iv) N,

[1259] Then X 3 Do not select a group consisting of:

[1260] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[1261] (ii) COL 3 -E 3 , where OL 3 -E 3 selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy;

[1262] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[1263] (iv) N, and

[1264] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 5 is N or CH, X 6 CH, X3 CL 3 -E 3 , L 3 For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[1265] X 2 Selected from the group consisting of:

[1266] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[1267] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[1268] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino;

[1269] (iv) N,

[1270] Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; and

[1271] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5 H or F, X 5 CH, X 6 is CH, CD or CF, X 2 is N, and X 3 COL 3 -E 3 or CN(R 4 )-L 3 -E 3 , then L1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[1272] In some embodiments, the compound is represented by formula I-PA:

[1273]

[1274] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1275] X 5 and X 6 are each independently CH, CF or N;

[1276] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1277] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1278] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1279] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1280] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1281] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1282] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1283] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1284] 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;

[1285] Z is L 7 -E 7 ,in:

[1286] L 7 is a direct key;

[1287] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1288] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1289] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1290] R 2 Selected from the group consisting of: H and F;

[1291] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[1292] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1293] In some embodiments, the compound is represented by Formula IQ:

[1294]

[1295] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1296] X 1 Each independently CR 5 , or N;

[1297] X 2 COL 2 -E 2 , CL 2 -E 2 ,CN(R 4 )-L 2 -E 2 , CH, or N;

[1298] The constraint condition is X 1 and X 2 No more than one of them is N;

[1299] X 5 and X 6 are each independently CH, CF or N;

[1300] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1301] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1302] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1303] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1304] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1305] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1306] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1307] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1308] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1309] 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;

[1310] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1311] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl,

[1312] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1313] 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;

[1314] Z is L 7 -E 7 ,in:

[1315] L 7 is a direct key;

[1316] E 7 Selected from the group consisting of:

[1317] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1318] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1319] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1320] p is independently 0, 1, or 2 at each occurrence;

[1321] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1322] R 2 Selected from the group consisting of: H and F;

[1323] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1324] R 4 is independently at each occurrence H or alkyl; and

[1325] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1326] The restrictions are:

[1327] When E 7 is morpholinyl, X 1 CH, X 2 COL 2 -E 2 , R 5 H, X 6 is CH, CD or CF, R 3 When H, then L1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

[1328] When E 7 is morpholinyl, X 1 CH, X 2 COL 2 -E 2 , R 5 H, X 6 When it is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure;

[1329] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, X 1 N or CH, R 5 H, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[1330] Then X 2 Do not select a group consisting of:

[1331] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[1332] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[1333] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4)-L 2 -E 2 selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; and

[1334] (iv)N.

[1335] In some embodiments, the compound is represented by formula I-QA

[1336]

[1337] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1338] X 1 Each independently CR 5 or N;

[1339] X 5 and X 6 are each independently CH, CF or N;

[1340] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1341] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1342] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1343] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1344] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1345] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1346] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1347] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1348] 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;

[1349] Z is L 7 -E 7 ,in:

[1350] L 7 Direct keys;

[1351] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1352] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1353] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1354] R 2 Selected from the group consisting of: H and F;

[1355] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[1356] R5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1357] In some embodiments, the compound is represented by Formula IR:

[1358]

[1359] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1360] X 2 CH, COL 2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ;

[1361] X 3 CH, COL 3 -E 3 , CL 3 -E 3 or CN(R 4 )-L 3 -E 3 ;

[1362] X 5 and X 6 are each independently CH, CF or N;

[1363] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1364] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1365] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1366] E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1367] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1368] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1369] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1370] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1371] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1372] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1373] 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;

[1374] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1375] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1376] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1377] 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;

[1378] E 3 is selected from the group consisting of: haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl,

[1379] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1380] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl or cyano, cyanoalkyl and heterocyclyl, and

[1381] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1382] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1383] 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;

[1384] Z is L 7 -E 7 ,in:

[1385] L 7 is a direct key;

[1386] E 7 Selected from the group consisting of:

[1387] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1388] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1389] m is independently at each occurrence 0, 1, 2, 3, or 4; and

[1390] p is independently 0, 1, or 2 at each occurrence;

[1391] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1392] R 2 Selected from the group consisting of: H and F;

[1393] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1394] R 4 is independently at each occurrence H or alkyl; and

[1395] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1396] The restrictions are:

[1397] When L 1 -E 1 for R 1 is methyl, R 2 H, R 3 H, R 5 H, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl,

[1398] X 2 Selected from the group consisting of:

[1399] (i)CL 2 -E2 , where L 2 -E 2 Selected from H;

[1400] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; and

[1401] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino;

[1402] Then X 3 Do not select a group consisting of:

[1403] (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl;

[1404] (ii) COL 3 -E 3 , where OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; and

[1405] (iii)CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and

[1406] When L 1 -E 1 for R 1 is methyl, R 2H, R 3 H, R 5 H, X 5 is N or CH, X 6 CH, X 3 CL 3 -E 3 , L 3 For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and

[1407] X 2 Selected from the group consisting of:

[1408] (i)CL 2 -E 2 , where L 2 -E 2 Selected from H;

[1409] (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy;

[1410] (iii)CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; and

[1411] Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl, and

[1412] When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, R 5 H or F, X 5 CH, X 6 is CH, CD or CF, X 2 is N, and X 3 COL 3 -E 3 or CN(R4 )-L 3 -E 3 , then L 1 Not with R 3 and L 1 and R 3 The attached N atoms are taken together to form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

[1413] In some embodiments, the compound is represented by formula I-RA:

[1414]

[1415] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1416] X 5 and X 6 are each independently CH, CF or N;

[1417] L 1 Selected from direct bond and optional (E 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms, when taken together, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1418] E 1 is selected from the group consisting of: hydroxy, alkoxy, cyano, haloalkoxy, halogen,

[1419] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1420] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1421] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl,

[1422] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1423] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1424] E 11 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1425] 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;

[1426] Z is L 7 -E 7 ,in:

[1427] L 7 Direct keys;

[1428] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1429] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1430] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1431] R 2 Selected from the group consisting of: H and F;

[1432] R 3 is selected from the group consisting of: H, C1-C5 alkyl, and C3-C5 cycloalkyl; and

[1433] R 5 is independently at each occurrence selected from the group consisting of: H, alkyl, and halogen.

[1434] In some embodiments, E 1is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy and halogen,

[1435] Optionally substituted alkyl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano

[1436] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1437] optionally substituted heteroaryl, 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, and heterocyclyl, and wherein the optionally substituted heteroaryl is not

[1438]

[1439] 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.

[1440] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1441] optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1442] In some embodiments, E 1 is selected from the group consisting of: H, hydrogen, alkoxy, cyano, haloalkoxy and halogen,

[1443] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1444] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano,

[1445] optionally substituted heteroaryl, 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, and heterocyclyl, and wherein the optionally substituted heteroaryl is not

[1446]

[1447] 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,

[1448] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1449] Optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[1450] In some embodiments, the compound is represented by Formula IS:

[1451]

[1452] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1453] X 1 and X 4 Each independently CR 5 or N;

[1454] X 5 and X 6 are each independently CH, CF or N;

[1455] X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ;

[1456] X 3 COL 3 -E3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or NL 3 -E 3 ,

[1457] The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N;

[1458] The restriction condition is that when X 2 When N, X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH;

[1459] The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ;

[1460] The restriction condition is that when X 2 When C=O, X 3 for NL 3 -E 3 ;

[1461] The restriction condition is that when X 3 When C=O, X 2 for NL 2 -E 2 ;

[1462] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1463] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1464] E 1a and E 1b Each of the groups is independently selected from the group consisting of: H, alkoxy, cyano, haloalkoxy, halogen,

[1465] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1466] 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, and

[1467] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[1468] or E 1a and E 1b together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1469] Or, when E 1a and E 1b When attached to the same carbon atom, E 1a and E 1b Together with the carbon atom to which it is attached, it forms an oxo group;

[1470] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1471] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1472] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1473] or two occurrences of E 21together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl ring having 3 to 6 atoms in the ring structure;

[1474] E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone,

[1475] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1476] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[1477] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1478] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1479] 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;

[1480] W is selected from CH2, O or NR 10 The group composed of

[1481] Z is L 7 -E 7 ,in:

[1482] L 7 is a direct key;

[1483] E 7 Selected from the group consisting of:

[1484] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1485] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1486] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1487] R 2 Selected from the group consisting of: H and F;

[1488] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1489] R 4 is independently at each occurrence H or alkyl; and

[1490] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1491] R 10 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl;

[1492] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1493] p is independently 0, 1, or 2 at each occurrence;

[1494] q is independently 1, 2, or 3 at each occurrence;

[1495] The restrictions are

[1496] E 7 Not a morpholinyl group,

[1497] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X 2 N, X 3 CL 3 -E 3 , and L 3 For direct keys, and E 3 When it is morpholinyl, then E 7 is not optionally substituted C3-C6 heterocyclyl or optionally substituted 5- or 6-membered heteroaryl; and

[1498] When X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When it is CH, CD or CF, then E 7 It is not a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl.

[1499] In some embodiments, the compound is represented by formula I-SA:

[1500]

[1501] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1502] X 1 and X 4 Each independently CR 5 or N;

[1503] X 5 and X 6 are each independently CH, CF or N;

[1504] X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ;

[1505] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or NL 3 -E 3 ,

[1506] The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N;

[1507] The restriction condition is that when X 2 When N, X3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH;

[1508] The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ;

[1509] The restriction condition is that when X 2 When C=O, X 3 for NL 3 -E 3 ;

[1510] The restriction condition is that when X 3 When C=O, X 2 for NL 2 -E 2 ;

[1511] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1512] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1513] E 1a and E 1b Each of the groups is independently selected from the group consisting of: H, alkoxy, cyano, haloalkoxy, halogen,

[1514] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1515] 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, and

[1516] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[1517] or E 1a and E 1b together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1518] Or, when E 1a and E 1b When attached to the same carbon atom, E 1a and E 1b Together with the carbon atom to which it is attached, it forms an oxo group;

[1519] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1520] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1521] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1522] 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;

[1523] E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone,

[1524] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,

[1525] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[1526] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1527] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1528] 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;

[1529] W is selected from CH2, O or NR 10 The group composed of

[1530] Z is L 7 -E 7 ,in:

[1531] L 7 is a direct key;

[1532] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1533] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1534] R 2 Selected from the group consisting of: H and F;

[1535] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1536] R 4 is independently at each occurrence H or alkyl; and

[1537] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1538] R 10 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl;

[1539] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1540] p is independently 0, 1, or 2 at each occurrence;

[1541] q is independently 1, 2, or 3 at each occurrence;

[1542] The restrictions are

[1543] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X 2 N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; and

[1544] When X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When CH, CD or CF, E 7 It is not an optionally substituted 5-membered or 6-membered heteroaryl group.

[1545] In some embodiments, the compound is represented by Formula IT:

[1546]

[1547] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1548] X 1 and X 4 Each independently CR 5 or N;

[1549] X 5 and X 6 are each independently CH, CF or N;

[1550] X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ;

[1551] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or NL 3 -E 3 ,

[1552] The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N;

[1553] The restriction condition is that when X 2 When N, X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH;

[1554] The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 2 or CN(R 4 )-L 2 -E 2 ;

[1555] The restriction condition is that when X 2 When C=O, X 3 for NL 3 -E 3 ;

[1556] The restriction condition is that when X 3 When C=O, X 2 for NL 2 -E 2 ;

[1557] L2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1558] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1559] E 1a and E 1b Each of the groups is independently selected from the group consisting of: H, alkoxy, cyano, haloalkoxy, halogen,

[1560] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1561] 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, and

[1562] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[1563] or E 1a and E 1b together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1564] Or, when E 1a and E 1b When attached to the same carbon atom, E 1a and E 1b Together with the carbon atom to which it is attached, it forms an oxo group;

[1565] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1566] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1567] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1568] 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;

[1569] E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone,

[1570] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone,

[1571] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[1572] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1573] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1574] 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;

[1575] Z is L 7 -E 7 ,in:

[1576] L 7 is a direct key;

[1577] E 7 Selected from the group consisting of:

[1578] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1579] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1580] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1581] p is independently 0, 1, or 2 at each occurrence;

[1582] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1583] R 2 Selected from the group consisting of: H and F;

[1584] R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1585] R 4 is independently at each occurrence H or alkyl; and

[1586] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1587] The restrictions are

[1588] E 7 Not a morpholinyl group,

[1589] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X 2 N, X 3 CL 3 -E 3 , and L 3 When it is a direct key, and E 3 is morpholinyl; then E7 is not optionally substituted C3-C6 heterocyclyl or optionally substituted 5- or 6-membered heteroaryl; and

[1590] When X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When it is CH, CD or CF, then E 7 It is not a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl.

[1591] In some embodiments, the compound is represented by formula I-TA:

[1592]

[1593] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[1594] X 1 and X 4 Each independently CR 5 or N;

[1595] X 5 and X 6 are each independently CH, CF or N;

[1596] X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ;

[1597] X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or NL 3 -E 3 ,

[1598] The constraint condition is X 1 、X 2 、X 3 and X 4 No more than two of them are N;

[1599] The restriction condition is that when X 2 When N, X 3 COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH;

[1600] The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 2 or CN(R 4 )-L 2 -E 2 ;

[1601] The restriction condition is that when X 2 When C=O, X 3 for NL 3 -E 3 ;

[1602] The restriction condition is that when X 3 When C=O, X 2 for NL 2 -E 2 ;

[1603] L 2 For direct bond or optional (E 21 ) p Substituted C1-C6 alkyl;

[1604] L 3 For direct bond or optional (E 31 ) p Substituted C1-C6 alkyl;

[1605] E 1a and E 1b Each of the groups is independently selected from the group consisting of: H, alkoxy, cyano, haloalkoxy, halogen,

[1606] optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano,

[1607] 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, and

[1608] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone;

[1609] or E 1a and E 1b together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1610] Or, when E 1a and E 1b When attached to the same carbon atom, E 1a and E 1b Together with the carbon atom to which it is attached, it forms an oxo group;

[1611] E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and

[1612] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

[1613] E 21 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1614] 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;

[1615] E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone,

[1616] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone,

[1617] optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and

[1618] optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1619] E 31 is independently selected at each occurrence from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen;

[1620] 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;

[1621] Z is L 7 -E 7 ,in:

[1622] L 7 is a direct key;

[1623] E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano;

[1624] m is independently 0, 1, 2, 3, or 4 at each occurrence;

[1625] p is independently 0, 1, or 2 at each occurrence;

[1626] R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen;

[1627] R 2 Selected from the group consisting of: H and F;

[1628] R 3Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl;

[1629] R 4 is independently at each occurrence H or alkyl; and

[1630] R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen;

[1631] The restrictions are

[1632] When X 1 、X 4 、X 5 and X 6 CH, R 1 -CH3, X 2 N, X 3 CL 3 -E 3 , and L 3 When it is a direct bond, E3 is not a morpholinyl group; and

[1633] When X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When it is CH, CD or CF, then E 7 It is not an optionally substituted 5-membered or 6-membered heteroaryl group.

[1634] In some embodiments, E 1a Selected from the group consisting of H and OMe.

[1635] In some embodiments, E 1a Selected from the group consisting of: H, OMe, In some embodiments, E 1b is selected from the group consisting of H and OMe. 1b Selected from the group consisting of: H, OMe, In some embodiments, W is CH2 or O. In some embodiments, W is CH2.

[1636] In some embodiments, E 1 Selected from the group consisting of: H, Me, CF3, CH2CF3, OMe, OEt, OCF3, F, CN,

[1637]

[1638] In some embodiments, E 1Selected from the group consisting of H, Me, CF3, CH2CF3, OMe, OEt, OCF3, F and CN.

[1639] In some embodiments, E 1 Selected from the group consisting of:

[1640]

[1641] In some embodiments, E 1 Selected from the group consisting of:

[1642]

[1643] In some embodiments, E 11 , at each occurrence, is independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, oxetanyl, cyano, C1-C6 haloalkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, and halogen, or two occurrences of E 11 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl ring. 11 is independently selected at each occurrence from the group consisting of H, Me, CF3, OH, OMe, OEt, oxetane, OCF3, F, and CN. 11 Together with the carbon atom to which it is attached, it forms a cyclopropyl ring.

[1644] In some embodiments, L 1 Selected from the group consisting of:

[1645]

[1646] In some embodiments, L 1 is a direct bond. In some embodiments, L 1 Is optional (E 11 ) m In some embodiments, L 1 With R 3 and L 1 and R 3 The attached N atoms together form a heterocycle having from 4 to 8 atoms in the ring structure.

[1647] In some embodiments, Selected from the group consisting of:

[1648]

[1649] In some embodiments, Selected from the group consisting of:

[1650]

[1651] In some embodiments, Selected from the group consisting of:

[1652]

[1653] In some embodiments, when L 1 When it is a direct key, Selected from the group consisting of:

[1654]

[1655] In some embodiments, when L 1 When it is a direct key, Selected from the group consisting of:

[1656]

[1657] In some embodiments, when L 1 When it is a direct key, Selected from the group consisting of:

[1658]

[1659] In some embodiments, L 1 and R 3 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring having 4 to 8 atoms in the ring structure, wherein the ring structure is selected from the group consisting of:

[1660]

[1661] In some embodiments, the ring structure is selected from the group consisting of:

[1662] The carbon substituent is attached to E 1 .

[1663] In some embodiments, the ring structure is selected from the group consisting of:

[1664]

[1665] In some embodiments, the ring structure is selected from the group consisting of:

[1666]

[1667] In some embodiments, E 2is selected from the group consisting of hydroxy, C1-C6 alkoxy, C1-C6 alkoxyalkyl, cyano, sulfonyl, H, C1-C6 alkyl, amine, C1-C6 haloalkoxy, C1-C6 haloalkyl, sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amide, amine, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, oxo, cyano and C1-C6 cyanoalkyl.

[1668] In some embodiments, E 2 Selected from the group consisting of: H, Me, N(CH3)2, OH, OCH3, CN, SO2CH3 and

[1669] In some embodiments, E 2 Selected from the group consisting of: H, Me, N(CH3)2, OH, NMe2, OMe, CN and SO2CH3.

[1670] In some embodiments, E 2 for

[1671] In some embodiments, L 2 Select from direct keys, One of the attachment sites binds to E 2 .

[1672] In some embodiments, L 2 -E 2 Choose Free The group composed of.

[1673] In some embodiments, L 2 -E 2 Selected from the group consisting of: where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[1674] In some embodiments, L 2 -E 2 Selected from the group consisting of:

[1675]

[1676] In some embodiments, L 2 -E 2 for

[1677] In some embodiments, L 2 -E 2 is H, alkyl or cycloalkyl.

[1678] In some embodiments, E 3 is selected from the group consisting of hydroxy, C1-C6 alkoxy, C1-C6 alkoxyalkyl, cyano, sulfonyl, C1-C6 haloalkoxy, H, C1-C6 alkyl, C1-C6 acyl, amine, C1-C6 aminoalkyl, amide, C1-C6 haloalkyl, wherein optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, amide, amine, C1-C6 aminoalkyl, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, oxo, cyano, C1-C6 C1-C6 cyanoalkyl and sulfone, wherein the optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amide, amine, C1-C6 acyl, C1-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, cyano, cyanoalkyl and heterocyclyl, and wherein the optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy and cyano.

[1679] In some embodiments, E 3 Selected from the group consisting of: H, Me, N(R 6 )2、C(=O)Me、SO2Me、OR 6 、CN、

[1680]

[1681] Among them, R 6 is independently selected at each occurrence from the group consisting of: H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl, and one of the attachment sites is bound to E 3 .

[1682] In some embodiments, E 3 Selected from the group consisting of: H, Me, NMe2, C(=O)Me, SO2Me, OH, CN,

[1683]

[1684] In some embodiments, E3 Selected from the group consisting of: H, Me, NMe2, C(=O)Me, SO2Me, OH, CN,

[1685]

[1686] In some embodiments, E 3 Selected from the group consisting of: H, Me, N(R 6 )2、C(=O)Me、SO2Me、OR 6 、CN.

[1687] In some embodiments, E 3 Selected from the group consisting of:

[1688]

[1689] In some embodiments, E 3 Selected from the group consisting of:

[1690]

[1691] In some embodiments, E 3 Selected from the group consisting of:

[1692]

[1693] In some embodiments, E 31 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, oxetanyl, C1-C6 alkoxyalkyl, cyano, C1-C6 cyanoalkyl, C1-C66 haloalkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl and halogen, or two occurrences of E 31 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl ring. 31 is independently selected at each occurrence from the group consisting of H, Me, CF3, OH, OMe, OEt, oxetane, OCF3, CH2OH, F, and CN, or two occurrences of E 31 Together with the carbon atom to which it is attached, it forms a cyclopropyl ring.

[1694] In some embodiments, L 3 Selected from the group consisting of: direct keys,

[1695]

[1696] In some embodiments, L 3 Selected from the group consisting of: direct keys,

[1697]

[1698] In some embodiments, L 3 (E 3 )(E 31 ) p Selected from the group consisting of:

[1699]

[1700] where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[1701] In some embodiments, L 3 (E 3 )(E 31 ) p Selected from the group consisting of:

[1702]

[1703] In some embodiments, L 3 (E 3 )(E 31 ) p Selected from the group consisting of:

[1704]

[1705] In some embodiments, L 3 (E 3 )(E 31 ) p Selected from the group consisting of:

[1706]

[1707] where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[1708] In some embodiments, L 3 (E 3 )(E 31 ) p Selected from the group consisting of:

[1709] where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[1710] In some embodiments, E 7 Selected from the group consisting of:

[1711] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1712] Optionally substituted heteroaryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, urea, amine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[1713] In some embodiments, E 7 Selected from the group consisting of: H,

[1714] optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and

[1715] Optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from alkyl, alkoxy, amide, carbamoyl, urea, amine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[1716] In some embodiments, E 7 Selected from the group consisting of:

[1717]

[1718] where R 6 is independently selected at each occurrence from the group consisting of: H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; and wherein when s1 is present, s1 indicates the site of attachment to the ring and wherein refers to the position of an optional substituent, or when s1 is absent, The site of attachment to the loop is indicated.

[1719] In some embodiments, E 7 Selected from the group consisting of:

[1720]

[1721] where R6 is independently at each occurrence selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; one of the attachment sites is bound to the ring, and if more than one attachment site is present, the other attachment site is bound to the optional substituent.

[1722] In some embodiments, E 7 Selected from the group consisting of:

[1723]

[1724] where R 6 R is independently selected at each occurrence from the group consisting of: H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; 8 is selected from H, OH, alkoxy, cyano, F and amino; and R 9 is independently at each occurrence selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[1725] In some embodiments, E 7 Selected from the group consisting of:

[1726]

[1727] , where R 6 is independently at each occurrence selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[1728] In some embodiments, E 7 Selected from the group consisting of:

[1729]

[1730] In some embodiments, E 7 Selected from the group consisting of:

[1731]

[1732] , where R 8 is selected from the group consisting of: H, OH, alkoxy, cyano, F, and amino; and R 9 is independently at each occurrence selected from the group consisting of: H, C1-C6 alkyl, C3-C5 cycloalkyl.

[1733] In some embodiments, E 7 Selected from the group consisting of:

[1734]

[1735] In some embodiments, E 7 Selected from:

[1736]

[1737] , where R 8 Selected from the group consisting of: H, OH, alkoxy, cyano, F and amino.

[1738] In some embodiments, E 7 Selected from:

[1739]

[1740] where R 8 Selected from the group consisting of: H, OH, alkoxy, cyano, F and amino.

[1741] In some embodiments, E 7 Selected from:

[1742] Among them, R 9 is independently at each occurrence selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[1743] In some embodiments, E 7 Selected from the group consisting of:

[1744]

[1745] Among them, R 8 Selected from the group consisting of: H, OH, alkoxy, cyano, F and amino.

[1746] In some embodiments, E 7 Selected from the group consisting of:

[1747]

[1748] In some embodiments, E 7 Selected from:

[1749]

[1750] Among them, R 8 Selected from the group consisting of: H, OH, alkoxy, cyano, F and amino.

[1751] In some embodiments, E 7 Selected from:

[1752]

[1753] Among them, R8 Selected from the group consisting of: H, OH, alkoxy, cyano, F and amino.

[1754] In some embodiments, E 7 Selected from:

[1755] Among them, R 9 is independently at each occurrence selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[1756] In some embodiments, E 7 Selected from the group consisting of:

[1757]

[1758] In...

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 is CR 5 or N; X 5 and X 6 are each independently CH, CF or N; X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ; X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or 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; The restriction condition is that when X 2 When N, X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH; The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ; The restriction condition is that when X 2 When C=O, X 3 For NL 3 -E 3 ; The restriction condition is that when X 3 When C=O, X 2 For NL 2 -E 2 ; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 2 is a direct key or an optional 21 ) p Substituted C1-C6 alkyl; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, and 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, cyano, 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 L 7 -E 7 ,in: L 7 For direct keys E 7 Selected from the group consisting of: optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; The restriction condition is When E 7 is morpholinyl, X 2 and X 4 Both N, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not a heteroaryl group; When E 7 is morpholinyl, X 1 and X 4 Both N, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not a heteroaryl group; When E 7 is morpholinyl, X 1 , X 4 , X 5 and X 6 For CH, R 1 -CH 3 , X 2 is N, and X 3 For CL 3 -E 3 When L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5-membered or 6-membered heteroaryl, or amide; When X 1 , X 4 , X 5 and X 6 For CH, R 1 -CH3, X 2 N, X 3 For CL 3 -E 3 , L 3 is a direct key, and E 3 When it is morpholinyl, then E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl; When E 7 is morpholinyl, X 1 For CH, X 2 N, X 3 For COL 3 -E 3 , X 4 For CH, X 6 is CH, CD or CF, and R 3 When H, L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl; when E 7 is morpholinyl, X 1 For CH, X 2 For COL 2 -E 2 , X 3 N, X 4 For CH, X 6 is CH, CD or CF, and R 3 When H, L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl; When E 7 is morpholinyl, X 1 For CH, X 2 N, X 3 For COL 3 -E 3 , X 4 For CH, X 6 is CH, CD or CF, then L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure; When E 7 is morpholinyl, X 1 For CH, X 2 For COL 2 -E 2 , X 3 N, X 4 is CH, and X 6 When it is CH, CD or CF, L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure; When L 1 -E 1 for R 1 is methyl, R 2 For H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 For CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and X 2 Selected from the group consisting of: (i)CL 2 -E 2 , where L 2 -E 2 Selected from H; (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy; (iii) CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and (iv) N, Then X 3 Do not select a group consisting of: (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl; (ii) COL 3 -E 3 , where OL 3 -E 3 Selected from the group consisting of methoxy, 2-hydroxyethoxy and 2,3-dihydroxypropoxy; (iii) CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and (iv) N; When L 1 -E 1 for R 1 is methyl, R 2 For H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 For CH, X 3 For CL 3 -E 3 , L 3 For direct keys, E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, and X 2 Selected from the group consisting of: (i)CL 2 -E 2 , where L 2 -E 2 Selected from H; (ii) COL 2 -E 2 , where OL 2 -E 2 Selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy and (1-ethylpiperidin-4-yl)oxy; (iii) CN(R 4 )-L 2 -E 2 , where N(R 4 )-L 2 -E 2 Selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino and (1-hydroxypropan-2-yl)amino; and (iv) N, Then E 7 Not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl; When L 1 -E 1 for R 1 is methyl, R 2 For H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 For CH, E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, X 2 C=O, and X 3 For NL 3 -E 3 When L 3 -E 3 is not selected from the group consisting of H, methyl, hydroxy-ethyl, hydroxy-propyl and 2,3-dihydroxypropyl; and When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 For CH, X 6 is CH, CD or CF, X 2 is N, and X 3 For COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

2. A compound represented by formula IA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently is CH, CR 5 or N; X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH or N; X 5 and X 6 are each independently CH, CF or N; The restriction condition is X 1 , X 3 and X 4 No more than one of them is N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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: H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, haloalkoxy, hydroxy, alkoxy, alkoxyalkyl, sulfonyl, 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, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 Selected from the group consisting of: optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; The restriction condition is When E 7 is morpholinyl, X 4 N, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not a heteroaryl group; When E 7 is morpholinyl, X 1 , X 4 , X 5 and X 6 For CH, R 1 is -CH3, and X 3 For CL 3 -E 3 When L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5-membered or 6-membered heteroaryl, or amide; When X 1 , X 4 , X 5 and X 6 For CH, R 1 -CH3, X 3 For CL 3 -E 3 , L 3 is a direct key, and E 3 When it is morpholinyl, then E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl; When E 7 is morpholinyl, X 1 For CH, X 3 For COL 3 -E 3 , X 4 For CH, X 6 is CH or CF, and R 3 When H, L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl; When E 7 is morpholinyl, X 1 For CH, X 3 For COL 3 -E 3 , X 4 For CH, X 6 When it is CH, CD or CF, L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure; When L 1 -E 1 for R 1 is methyl, R 2 For H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, Then X 3 Do not select a group consisting of: (i)CL 3 -E 3 , where L 3 -E 3 Selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl; (ii) COL 3 -E 3 , where OL 3 -E 3 Selected from the group consisting of methoxy, 2-hydroxyethoxy and 2,3-dihydroxypropoxy; (iii) CN(R 4 )-L 3 -E 3 , where N(R 4 )-L 3 -E 3 Selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and (iv) N; When L 1 -E 1 for R 1 is methyl, R 2 For H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 For CH, X 3 For CL 3 -E 3 , L 3 is a direct key, and E 3 When selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, Then E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl and 2-oxooxazolidin-3-yl; and When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 For CH, X 6 is CH, CD or CF, X 2 is N, and X 3 For COL 3 -E 3 or CN(R 4 )-L 3 -E 3 When L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

3. A compound represented by formula IB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently is CH, CR 5 or N; The restriction condition is X 1 and X 4 No more than one of them is N; X 5 and X 6 are each independently CH, CF or N; X 31 O or N(R 4 ); L 1 Selected from direct bonds and optional 11 )m substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of: H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 Selected from the group consisting of: optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; The restriction condition is When E 7 is morpholinyl, X 1 For CH, X 31 O, X 4 For CH, X 6 is CH or CF, and R 3 When H, L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl; When E 7 is morpholinyl, X 1 For CH, X 31 O, X 4 is CH, and X 6 When it is CH, CD or CF, L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure; When L 1 -E 1 for R 1 is methyl, R 2 For H, R 3 H, X 1 is N or CH, X 4 is N or CH, X 5 is N or CH, X 6 is CH, and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, Then X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino; and When E 7 is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-membered or 6-membered heterocyclic group, X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When it is CH, CD or CF, L 1 Not with R 3 and L 1 and R 3 The attached N atoms together form an optionally substituted heterocycle having 4 to 7 atoms in the ring structure.

4. A compound represented by formula I-CA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

5. A compound represented by formula I-DA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 31 O or N(R 4 ); X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when X 5 When N, L 1 Can be used with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

6. A compound of formula I-EA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 2 is a direct key; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of H, alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 is an alkyl group; Z is L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

7. A compound represented by formula I-FA or formula I-FB: or represented by a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 an alkyl group; Z is L 7 -E 7 ,in: L 7 is a direct key; E 7 is an optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; The restriction condition is E 7 It is not oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

8. A compound represented by the formula I-GA: or represented by a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

9. A compound represented by formula I-HA: or represented by a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 31 O or N(R 4 ); X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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 H, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

10. A compound represented by formula I-JA: or represented by a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 For CL 3 -E 3 or CH; X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key; E 1 Selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen; optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 Selected from the group consisting of: alkyl 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; Z is L 7 -E 7 ,in: L 7 selected from the group consisting of direct keys; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

11. A compound represented by formula I-JB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or CH; X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 Selected from the group consisting of: optionally substituted heteroaryl, 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, and heterocyclyl, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, cyano, 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 L 7 -E 7 ,in: L 7 selected from the group consisting of direct keys; E 7 is an optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and sulfone, m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

12. A compound represented by formula I-JC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 Selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen; optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 selected from the group consisting of direct keys; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

13. A compound represented by formula I-KA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; X 31 O or N(R 4 ); L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when X 5 When N, L 1 Can be used with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituent is independently selected at each occurrence from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, the site of covalent attachment to H or the optionally substituted substituent, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, or cyano, cyanoalkyl, 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, or cyano; E 31 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 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3 or 4 at each occurrence; and p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

14. A compound represented by formula I-LA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 3 For CL 3 -E 3 or CH; X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 Selected from the group consisting of: alkyl 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

15. A compound represented by formula I-MA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; X 31 O or N(R 4 ); L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when X 5 When N, L 1 Can be used with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocyclic ring having 4 to 8 atoms in the ring structure, 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; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

16. A compound represented by formula I-NA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

17. A compound represented by formula I-OA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 2 For COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 , CH or N; X 3 CH, COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 or N; The restriction condition is X 2 and X 3 No more than one of them is N; X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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; L 2 is a direct key or an optional 21 ) p Substituted C1-C6 alkyl; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, or cyano, cyanoalkyl, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

18. A compound represented by formula I-PA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

19. A compound represented by formula I-QA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 Each independently is CR 5 or N; X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 Direct keys; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

20. A compound represented by formula I-RA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF or N; L 1 Selected from direct bonds and optional 11 ) m Substituted C1-C6 alkyl, or when with R 3 and L 1 and R 3 the attached N atoms together form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, 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 1 is selected from the group consisting of hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, 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, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and heterocyclyl, 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, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl, wherein the optionally substituted substituents are independently at each occurrence selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 ,in: L 7 Direct keys; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; and R 5 and R at each occurrence is independently selected from the group consisting of: H, alkyl, and halogen.

21. A compound as claimed in any one of claims 1 to 20, wherein: E 1 is selected from the group consisting of hydroxy, C1-C6 alkoxy, cyano, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, optionally substituted alkyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, amine, alkylamine, 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 aryl, C1-C6 alkyl, C1-C6 alkoxy, amine, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, heterocyclyl and cyano, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amine, amide, acyl, C1-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, cyano and heterocyclyl, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amide, amine, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, oxo, cyano, C1-C6 cyanoalkyl, and sulfone; and Optionally substituted aryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amide, amine, C1-C6 acyl, C1-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl and cyano.

22. A compound represented by formula I-SA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently is CR 5 or N; X 5 and X 6 are each independently CH, CF or N; X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ; X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or 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; The restriction condition is that when X 2 When N, X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH; The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 or CN(R 4 )-L 2 -E 2 ; The restriction condition is that when X 2 When C=O, X 3 For NL 3 -E 3 ; The restriction condition is that when X 3 When C=O, X 2 For NL 2 -E 2 ; L 2 is a direct key or an optional 21 ) p Substituted C1-C6 alkyl; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1a and E 1b Each of the groups is independently 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 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, 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, cyanoalkyl, and sulfone; or E 1a and E 1b together with the carbon atom to which it is attached, form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, 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, Or, when E 1a and E 1b When attached to the same carbon atom, E 1a and E 1b Together with the carbon atom to which it is attached, it forms an oxo group; E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, and 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, cyano, 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; W is selected from CH2, O or NR 10 The group composed of Z is L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; R 10 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; q is independently 1, 2, or 3 at each occurrence; The restriction condition is When X 1 , X 4 , X 5 and X 6 For CH, R 1 -CH3, X 2 N, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 is not morpholinyl; and When X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When CH, CD or CF, E 7 It is not an optionally substituted 5-membered or 6-membered heteroaryl group.

23. A compound represented by formula I-TA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: X 1 and X 4 Each independently is CR 5 or N; X 5 and X 6 are each independently CH, CF or N; X 2 N, CH, C=O, COL 2 -E 2 , CL 2 -E 2 、CN(R 4 )-L 2 -E 2 or NL 2 -E 2 ; X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , CH, C=O, N or 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; The restriction condition is that when X 2 When N, X 3 For COL 3 -E 3 , CL 3 -E 3 、CN(R 4 )-L 3 -E 3 , N or CH; The restriction condition is that when X 3 When N, X 2 N, CH, COL 2 -E 2 , CL 2 -E 2 2 or CN(R 4 )-L 2 -E 2 ; The restriction condition is that when X 2 When C=O, X 3 For NL 3 -E 3 ; The restriction condition is that when X 3 When C=O, X 2 For NL 2 -E 2 ; L 2 is a direct key or an optional 21 ) p Substituted C1-C6 alkyl; L 3 is a direct key or an optional 31 ) p Substituted C1-C6 alkyl; E 1a and E 1b Each of the groups is independently 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 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, 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, cyanoalkyl, and sulfone; or E 1a and E 1b together with the carbon atom to which it is attached, form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, 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; Or, when E 1a and E 1b When attached to the same carbon atom, E 1a and E 1b Together with the carbon atom to which it is attached, it forms an oxo group; E 2 is selected from the group consisting of: H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, 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, 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, cyano, 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 L 7 -E 7 ,in: L 7 is a direct key; E 7 is optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, alkoxy, amide, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; m is independently 0, 1, 2, 3, or 4 at each occurrence; p is independently 0, 1, or 2 at each occurrence; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and halogen; R 2 Selected from the group consisting of: H and F; R 3 Selected from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl; R 4 is independently at each occurrence H or alkyl; and R 5 is independently selected at each occurrence from the group consisting of: H, alkyl, and halogen; The restriction condition is When X 1 , X 4 , X 5 and X 6 For CH, R 1 -CH3, X 2 N, X 3 For CL 3 -E 3 , and L 3 When it is a direct key, E 3 It is not a morpholinyl group; as well as When X 1 and X 4 are each independently N, CH or CF, X 5 is CH, and X 6 When CH, CD or CF, E 7 It is not an optionally substituted 5-membered or 6-membered heteroaryl group.

24. The compound of claim 22 or 23, wherein E 1a Selected from the group consisting of H and OMe.

25. The compound of claim 24, wherein E 1a Selected from the group consisting of: H, OMe, and 26. A compound as described in any one of claims 22 to 25, wherein E 1b Selected from the group consisting of H and OMe.

27. A compound as described in any one of claims 22 to 25, wherein E 1b Selected from the group consisting of: H, OMe, and 28. The compound of any one of claims 22 and 24 to 27, wherein W is CH2 or O.

29. The compound of claim 28, wherein W is CH2.

30. A compound as described in any one of claims 1 to 21, wherein E 1 Selected from the group consisting of: H, Me, Et, CF3, CH2CF3, OMe, OEt, OCF3, CH2OCH3, F, CN, and 31. A compound as described in any one of claims 1 to 21 and 30, wherein E 1 Selected from the group consisting of: and 32. The compound of any one of claims 1 to 21 and 30, wherein E 1 Selected from the group consisting of: and 33. A compound as claimed in any one of claims 1 to 21 and 30 to 32, wherein E 11 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, oxetanyl, cyano, C1-C6 haloalkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl and halogen, or two occurrences of E 11 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl ring.

34. A compound as claimed in any one of claims 1 to 21 and 30 to 33, wherein E 11 is independently selected at each occurrence from the group consisting of H, Me, CF3, OH, OMe, OEt, oxetane, OCF3, F and CN, or two occurrences of E 11 Together with the carbon atom to which it is attached it forms a cyclopropyl ring.

35. A compound as described in any one of claims 1 to 21 or 30 to 34, wherein Selected from the group consisting of: and 36. A compound according to any one of claims 1 to 20, wherein Selected from the group consisting of: and 37. A compound according to any one of claims 1 to 20, wherein Selected from the group consisting of: and 38. A compound as described in any one of claims 1 to 20, wherein when L 1 When it is a direct key, Selected from the group consisting of: and 39. The compound of any one of claims 1 to 20, wherein when L 1 When it is a direct key, Selected from the group consisting of: and 40. The compound of any one of claims 1 to 20, wherein when L 1 When it is a direct key, Selected from the group consisting of: and 41. A compound as described in any one of claims 1 to 20, wherein L 1 and R 3 Together with the N atom to which it is attached, it forms a heterocyclic ring having 4 to 8 atoms in the ring structure, wherein the ring structure is selected from the group consisting of: and 42. A compound as described in any one of claims 1 to 20, wherein L 1 and R 3 Together with the N atom to which it is attached, it forms a heterocyclic ring having 4 to 8 atoms in the ring structure, wherein the ring structure is selected from the group consisting of: and 43. A compound as described in any one of claims 1 to 42, wherein E 2 Selected from the group consisting of hydroxy, C1-C6 alkoxy, C1-C6 alkoxyalkyl, cyano, sulfonyl, H, C1-C6 alkyl, amine, C1-C6 haloalkoxy, C1-C6 haloalkyl, sulfone and optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amide, amine, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, oxo, cyano and C1-C6 cyanoalkyl.

44. The compound of claim 43, wherein E 2 Selected from the group consisting of: H, Me, N(CH3)2, OH, OCH3, CN, SO2CH3 and 45. A compound as described in any one of claims 1 to 44, wherein L 2 Select from direct keys, and The group composed of.

46. ​​A compound as described in any one of claims 1 to 45, wherein L 2 -E 2 Freedom to choose and The group composed of.

47. A compound as described in any one of claims 1 to 46, wherein L 2 -E 2 Selected from the group consisting of: and Where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

48. A compound as described in any one of claims 1 to 47, wherein L 2 -E 2 Selected from the group consisting of: and 49. A compound as claimed in any one of claims 1 to 48, wherein: E 3 is selected from the group consisting of hydroxy, C1-C6 alkoxy, C1-C6 alkoxyalkyl, cyano, sulfonyl, C1-C6 haloalkoxy, H, C1-C6 alkyl, C1-C6 acyl, amine, C1-C6 aminoalkyl, amide, C1-C6 haloalkyl, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, amide, amine, C1-C6 aminoalkyl, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, oxo, cyano, C1-C6 cyanoalkyl and sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amide, amine, C1-C6 acyl, C1-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 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 C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy and cyano.

50. A compound as described in any one of claims 1 to 48, wherein E 3 Selected from the group consisting of: H, Me, N(R 6 )2、C(=O)Me、SO2Me、OR 6 、CN、 and Where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

51. A compound as described in any one of claims 1 to 48, wherein E 3 Selected from the group consisting of: H, Me, NMe2, C(=O)Me, SO2Me, OH, CN, and 52. A compound as described in any one of claims 1 to 48, wherein E 31 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, oxetanyl, C1-C6 alkoxyalkyl, cyano, C1-C6 cyanoalkyl, C1-C66 haloalkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl and halogen, or two occurrences of E 31 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl ring.

53. A compound as described in any one of claims 1 to 48, wherein E 31 is independently selected at each occurrence from the group consisting of H, Me, CF3, OH, OMe, OEt, oxetane, OCF3, CH2OH, F and CN, or two occurrences of E 31 Together with the carbon atom to which it is attached it forms a cyclopropyl ring.

54. A compound as described in any one of claims 1 to 53, wherein L 3 Selected from the group consisting of: direct key, and 55. A compound as described in any one of claims 1 to 54, wherein L 3 (E 3 )(E 31 ) p Selected from the group consisting of: ； Where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

56. A compound as described in any one of claims 1 to 54, wherein L 3 (E 3 )(E 31 ) p Selected from the group consisting of: and 57. A compound as described in any one of claims 1 to 54, wherein L 3 (E 3 )(E 31 ) p Selected from the group consisting of: and ; Where R 6 is independently selected at each occurrence from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

58. A compound as described in any one of claims 1 to 57, wherein E 7 is selected from the group consisting of: H, amide, urea, amine, cyano, hydroxyl, alkoxy, optionally substituted heterocyclyl, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and Optionally substituted heteroaryl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amide, urea, amine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

59. The compound of any one of claims 1 to 57, wherein E 7 Selected from the group consisting of: and Where R 6 is independently selected at each occurrence from the group consisting of: H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; and wherein when s1 is present, s1 indicates the site of attachment to the ring and wherein refers to the position of an optional substituent, or when s1 is absent, The site of attachment to the loop is indicated.

60. A compound as described in any one of claims 1 to 57, wherein E 7 Selected from the group consisting of: and Where R 9 is independently selected at each occurrence from the group consisting of: H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; and R 8 Selected from the group consisting of: H, OH, alkoxy, cyano, F and amino.

61. The compound of claim 60, wherein E 7 In each occurrence, independently selected from the group consisting of: and 62. The compound of any one of claims 1 to 57, wherein E 7 Selected from the group consisting of: and 63. The compound of any one of claims 1 to 57, wherein E 7 Selected from the group consisting of: and 64. A compound as described in any one of claims 1 to 63, wherein X 5 N and X 6 is CH or CF.

65. A compound as described in any one of claims 1 to 63, wherein X 5 is CH or CF and X 6 is N.

66. A compound as described in any one of claims 1 to 63, wherein X 5 and X 6 is CH or CF.

67. A compound as described in any one of claims 1 to 63, wherein X 5 and X 6 For CH.

68. A compound as described in any one of claims 1 to 67, wherein R 1 Selected from the group consisting of H, C1-C6 alkyl, CN and halogen.

69. The compound of any one of claims 1 to 68, wherein R 1 Selected from the group consisting of: H, Me, Et, F, Br and Cl.

70. A compound as described in any one of claims 1 to 69, wherein R 1 Select the group consisting of Me and F.

71. The compound of any one of claims 1 to 70, wherein R 2 Selected from the group consisting of H and F.

72. The compound of any one of claims 1 to 71, wherein R 2 For H.

73. The compound of any one of claims 1 to 71, wherein R 2 For F.

74. The compound of any one of claims 1 to 73, wherein R 3 It is H or Me.

75. The compound of any one of claims 1 to 74, wherein R 3 For H.

76. A compound as described in any one of claims 1 to 75, wherein R 4 It is H or C1-C6 alkyl.

77. The compound of any one of claims 1 to 76, wherein R 4 It is H or Me.

78. A compound as described in any one of claims 1 to 77, wherein R 5 It is H, C1-C6 alkyl or halogen.

79. The compound of any one of claims 1 to 78, wherein R 5 Selected from the group consisting of: H, Me, Et, F and Cl.

80. A compound as described in any one of claims 1 to 79, wherein R 5 For H.

81. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

82. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 81 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

83. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1 to 81, or a pharmaceutical composition as described in claim 82.

84. The method of claim 83, 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.

85. The method of claim 84, wherein the cancer has a BRAF oncogenic mutation.

86. The method of claim 84 or 85, wherein the cancer has a RAS oncogenic mutation.

87. The method of claim 86, wherein the RAS oncogenic mutation is a RAS Q61R or Q61K mutation.

88. The method of claim 84, wherein the cancer has an NF1 oncogenic mutation.

89. A method for treating a disease in a patient in need thereof, the disease 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 to 81 or a pharmaceutical composition as described in claim 82.

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